Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.CCN([CH:36]([CH3:38])[CH3:37])C(C)C.C1(C(Cl)=O)CC1>C(Cl)Cl>[CH:36]1([C:6]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([CH:20]([OH:22])[CH3:21])=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[O:7])[CH2:38][CH2:37]1
Reactant: CC(=O)c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(O)c1ccc(C2=CCN(C(=O)C3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of the title compound from Example 9 Step A (301 mg, 1.00 mmol) in DCM (6 mL) was added TFA (3 mL). After 15 min, the reaction mixture was concentrated in vacuo, and the crude TFA salt was used without further purification. To a solution of the crude TFA salt in DCM (5 mL) were added DIEA (263 μL, 15.1 mmol) and cyclopropanecarbonyl chloride (274 μL, 3.01 mmol), and the resulting mixture was allowed to stir at room temperature. After 45 min, the reaction mixture was quenched by addition of sat aq NaHCO3 and the aqueous phase was extracted with DCM. The organic phase was separated and concentrated in vacuo to provide the crude amide, which was used without further purification: LCMS m/z 270.5 [M+H]+. To a solution of the crude amide in MeOH (10 mL) was added NaBH4 (171 mg, 4.52 mmol), and the mixture was stirred at room temperature. After 20 min, the reaction mixture was concentrated in vacuo and was redissolved in EtOAc. The mixture was washed with sat aq NH4Cl, and the organic phase was separated, dried over sodium sulfate, and concentrated in vacuo. The crude alcohol was used without further purification: LCMS m/z 272.5 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][N:8]=[C:7]3[NH:12][CH:13]=[C:5]([C:6]=23)[CH2:4][N:3]1[CH2:14][CH:15]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]1.Cl>O1CCOCC1>[NH:17]1[CH2:18][CH2:19][CH:15]([CH2:14][N:3]2[CH2:4][C:5]3=[CH:13][NH:12][C:7]4[C:6]3=[C:11]([CH:10]=[CH:9][N:8]=4)[C:2]2=[O:1])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2Cc3c[nH]c4nccc(c34)C2=O)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1c2ccnc3[nH]cc(c23)CN1CC1CCNC1
Reaction time: 1 h
Yield: 104 %

Procedure:
To a solution of tert-butyl 3-((5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)methyl)pyrrolidine-1-carboxylate (10 mg, 0.03 mmol) in dioxane at 0° C. was added 4N HCl in dioxane (0.019 mL, 0.075 mmol) and the reaction mixture was stirred for 1 h to give a solid. The solid was filtered and dried to afford the title compound (8.0 mg) as its HCl salt. 1H NMR (400 MHz, CD3OD) δ 1.90 (br. s., 1 H) 2.24 (br. s., 1 H) 2.96 (br. s.,1 H) 3.17 (br. s., 2 H) 3.59 (d, J=5.05 Hz, 1 H) 3.71-3.83 (m, 2 H) 3.87 (br. s., 1 H) 5.18 (br. s., 2 H) 7.64 (br. s., 1 H) 7.80 (br. s., 1 H) 8.55 (br. s., 1 H). [M+H] found 257.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[F:30][C:31]([F:40])([F:39])[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[C:4]3[CH:3]=[C:2]([NH:38][C:35]4[CH:36]=[CH:37][C:32]([C:31]([F:30])([F:39])[F:40])=[CH:33][CH:34]=4)[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Product: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Nc4ccc(C(F)(F)F)cc4)cc3n2C(=O)OC(C)(C)C)cn1
Yield: 63 %

Procedure:
The title compound was prepared in 63% yield from compound (10) and 4-trifluoromethyl phenylamine using the method described for Preparation 35. 1H-NMR (CDCl3, 500 MHz): δ 1.53 (m, 9H), 1.70 (m, 9H), 6.61 (d, J=0.95 Hz, 1H), 6.81 (br s, 1H), 7.47 (d, J=8.51 Hz, 2H), 7.57 (d, J=8.20 Hz, 2H), 7.73 (m, 1H), 7.83 (d, J=0.63 Hz, 1H), 8.23 (d, J=0.63 Hz, 1H), 8.52 (d, J=0.95 Hz, 1H). 19F-NMR (CDCl3): δ −61.73.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:38]([OH:40])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[CH3:37][O:36][C:35]1[C:23]2[N:22]=[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]3[CH2:11][C@@H:10]([C:38]([N:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[O:40])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13]3)=[O:20])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]=2[CH:32]=[CH:33][CH:34]=1
Reactant: C1CCNCC1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2c(OC)cccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCCCC3)CN(C(=O)OC(C)(C)C)C2)nc2c(OC)cccc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-{{{4-methoxy-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-3-carboxylic acid (205 mg), piperidine (69 μl), HOBt (40 mg) and triethylamine (140 μl) were dissolved in DMF (10 ml), WSC.HCl (134 mg) was added, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9)-ethyl acetate was concentrated under reduced pressure to give the object product (65 mg).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[NH2:23][CH2:24][C@@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[OH:26]>>[Cl:33][C:29]1[CH:28]=[C:27]([C@@H:25]([OH:26])[CH2:24][NH:23][CH:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:21]=[CH:20][C:11]([CH2:12][CH:13]4[S:17][C:16](=[O:18])[NH:15][C:14]4=[O:19])=[CH:10][CH:9]=3)[CH2:4][CH2:3]2)[CH:32]=[CH:31][CH:30]=1
Reactant: NC[C@H](O)c1cccc(Cl)c1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Agent: Cl
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)c4cccc(Cl)c4)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and (1R)-2-amino-1-(3-chloro-phenyl)-ethanol (which was obtained in Example 1) according to the procedure of Example 73 as a pale yellowish solid; mp>195–198° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.40–1.60 (m, 2 H), 1.85–2.10 (m, 2 H), 2.60–3.50 (m, 7 H), 3.65 (brd, J=12.5 Hz, 2 H), 4.63 (dd, J=9.5, 4.1 Hz, 1 H), 4.74 (dd, J=8.8, 3.1 Hz, 1 H), 6.86 (d, J=8.7 Hz, 2 H), 7.05 (d, J=8.7 Hz, 2 H), 7.20–7.50 (m, 4 H); MS (ES) m/z: 460.0 (MH+); HRMS Calcd. for C23H26ClN3O3S (M+): 459.1383. Found: 459.1376.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:24]=[CH:25][C:26]([Br:29])=[CH:27][CH:28]=1
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccc(Br)cc3)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1ccc(Br)cc1

Procedure:
The 2-trifluoroacetamido-3-(4-bromophenyl)-6-benzoyl-imidazo[1,2-a]pyridine (3.00 g, 6.15 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 1.80 g. (75%). EA, MS(FD).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2].Cl.[CH3:15][O:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([C:7]1([NH:13][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([CH:22]3[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][O:16][CH3:15])[CH2:24][CH2:23]3)=[CH:33][CH:32]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2]
Reactant: N#CCNC(=O)C1(N)CCCCC1
Reactant: COCCN1CCC(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCN1CCC(c2ccc(C(=O)NC3(C(=O)NCC#N)CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (107 mmol), 4-[1-(2-methoxy-ethyl)-piperidin-4-yl]-benzoic acid hydrochloride (107 mmol), HOBT (107 mmol), WSCD (107 mmol) and triethylamine (107 mmol) are dissolved in DMF (250 ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure slightly basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with CH2Cl2/MeOH (with 2N NH3)=9:1 as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether/ethyl acetate and the solid filtered of and dried (vacuum). A pale powder with mp. 160-162° C., Rf=0.42 (CH2Cl2/MeOH (with 3N NH3)=9:1) is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:47]1[O:48][CH:49]=[CH:50][CH:51]=1)CCC>COCCOC.C(Cl)(Cl)Cl.CO>[O:48]1[CH:49]=[CH:50][CH:51]=[C:47]1[C:2]1[CH:3]=[C:4]2[CH2:10][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Brc1cnc2c(c1)CC1(CN3CCC1CC3)O2
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: c1coc(-c2cnc3c(c2)CC2(CN4CCC2CC4)O3)c1
Yield: 89.2 %

Procedure:
A solution containing 5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (103.5 mg, 0.351 mmol), tris(dibenzylidineacetone)dipalladium (0) (14 mg, 0.015 mmol), tri(o-tolyl)phosphine (44.4 mg, 0.146 mmol), lithium chloride (62 mg, 1.46 mmol), and 2-(tri-n-butylstannyl)furan (0.17 g, 0.476 mmol) in 1,2-dimethoxyethane (1 ml) was heated under reflux for 2 h. The solution was evaporated, and the residue was taken up in chloroform and filtered. The filtrate was evaporated then purified by HPLC using a gradient of 0-25% 1:1:2 7M methanolic ammonia:methanol:chloroform and chloroform to obtain the title compound (89 mg, 0.313 mmol, 89%) as a pale solid: electrospray MS (m/z, relative intensity) 283 ([MH]+, 100).
Reaction SMILES: Br[CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C[N+]1([O-])CC[O:18]CC1>C(#N)C>[Cl:8][C:6]1[S:7][C:3]([CH:2]=[O:18])=[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CCOC(=O)c1nc(Cl)sc1CBr
Solvent: CC#N
Product: CCOC(=O)c1nc(Cl)sc1C=O

Procedure:
Ethyl 5-(bromomethyl)-2-chloro-1,3-thiazole-4-carboxylate (Intermediate 180, 920 mg; 3.2 mmol) was dissolved in acetonitrile dried over molecular sieves. The solution was cooled to 0 C and NMO (570 mg; 1.5 equiv.) was added in a single portion. The reaction was monitored by LC/MS. An additional 1.5 equivalents of NMO was added in two portions over two hours. The reaction was concentrated to a solid residue, redissolved in EtOAc and washed with H2O. Dried the organic over Na2SO4, filtered and concentrated. No further purification. MS (ES) MH+: 220, 222 for C7H6ClNO3S.
Reaction SMILES: [OH:1][CH:2]([CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[N+:21]([O-:23])=[O:22])[CH2:3][N:4]1C(=O)C2C(=CC=CC=2)C1=O.NN>C(O)C.O>[NH2:4][CH2:3][CH:2]([OH:1])[CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[N+:21]([O-:23])=[O:22]
Reactant: O=C1c2ccccc2C(=O)N1CC(O)Cn1ccnc1[N+](=O)[O-]
Agent: NN
Solvent: CCO
Solvent: O
Product: NCC(O)Cn1ccnc1[N+](=O)[O-]
Yield: 83.3 %

Procedure:
Compound 8 (5 g, 15.8 mmol) was added to a solution of pure hydrazine (608 mg, 18.97 mmol, 1.2 equivalent) in 50 ml of ethyl alcohol and 4 ml of water. The mixture was refluxed for 2 h and then held at room temperature. The white solid (phthalhydrazide) was filtered. The filtrate was concentrated and the residue was redistributed in ethyl acetate and water. The water phase was extracted two times with ethyl acetate and the combined ethyl acetate phase was dried to give a yellowish solid as the HCl salt (9, 2.45 g, 70% yield). 1H NMR (D2O, δppm) (HCl salt): 2.91 (dd, 1H, NH2—CHa, J=13.2 Hz, 9.9 Hz), 3.21 (dd, 1H, NH2—CHb, J=13.2 Hz, 2.7 Hz), 4.19 (tt, 1H, HO—CH—, J=9.0 Hz, 3.0 Hz), 4.28 (dd, 1H, imidazole-CHa—, J=13.8 Hz, 8.7 Hz), 4.57 (dd, 1H, imidazole-CHb—, J=13.8 Hz, 2.7 Hz), 7.09 (d, 1H, J=0.9 Hz, —CH═), 7.35 (d, 1H, J=0.9 Hz, —CH═). 13C NMR (D2O, δppm). 42.06, 53.00, 66.86, 128.06, 128.92, 144.73.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[CH2:12])[C:6]2=[O:11].[CH2:13]=[C:14]([O:17][Si](C)(C)C)[CH:15]=[CH2:16].B(F)(F)F.CCOCC>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5]1([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)[C:6]2=[O:11]
Reactant: C=C1Cc2c(F)cccc2C1=O
Reactant: C=CC(=C)O[Si](C)(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CCC2(CC1)Cc1c(F)cccc1C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of 4-fluoro-2-methylene-2,3-dihydro-1H-inden-1-one (249b) (3.71 g, 22.9 mmol) and (buta-1,3-dien-2-yloxy)trimethylsilane (5.2 mL, 29.8 mmol) in DCM (200 mL) at 0° C., there was added BF3.Et2O (0.5 mL dropwise. The resulting solution was stirred at 0° C. for another 30 min, quenched with MeOH (0.3 mL), warmed to room temperature, acidified with 2N HCl aqueous solution (15 mL) and extracted with DCM (10 mL×4). The combined organic layers were dried over Na2SO4, filtered and evaporated, and the residue was purified by flash chromatography (0 to 50% EtOAc/Hexane) to give 4′-fluorospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (249c) (2.77 g, 49%). LC-MS tR=1.41 min in 3 min chromatography, MS (ESI) m/z 233 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1I.C(N(CC)CC)C.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:27]#[C:26][C:23]1[CH:24]=[CH:25][C:20]([Br:19])=[CH:21][CH:22]=1
Reactant: C#Cc1ccc(Br)cc1
Reactant: COC(=O)c1ccccc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1C#Cc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 2-iodo-benzoic acid methyl ester (1.31 g, 5.00 mmol) in DMF (10 ml) are added bis(triphenylphosphine)-palladium(II)-chloride (351 mg, 0.50 mmol), copper(I) iodide (28.5 mg, 0.15 mmol), triethylamine (2.08 ml, 15.0 mmol) and 1-bromo-4-ethynyl-benzene (905 mg, 5.00 mmol). The resulting dark brown solution is flushed with nitrogen, heated to 80° C. and stirred in a closed reaction vial at this temperature for 16 hours. The reaction mixture is allowed to cool to room temperature and partitioned between water and dichloromethane. The organic phase is washed with 1 N HCl, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 2-(4-bromo-phenylethynyl)-benzoic acid methyl ester as brown oil; HPLC/MS 3.46 min (B), [M+H] 315/317.
Reaction SMILES: [C:1](OCC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:21]([OH:25])[CH:22]([CH3:24])[CH3:23]>>[C:1]([O:25][CH2:21][CH:22]([CH3:24])[CH3:23])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)CC(=O)OCC(C)C

Procedure:
30 ml of ethyl acetoacetate were dissolved in 350 ml of i-butyl alcohol and a catalytic amount of p-toluensulphonic acid (PTSA) was added. The solution was refluxed for 18 h. The reaction mixture was evaporated in vacuo and the residue was dissolved in ether. The resulted solution was treated with s.s. NaHCO3. The organic layer was separated, dried over Na2SO4 and evaporated in vacuo. The crude oil was distilled at 66°-68° C./4 mmHg, to give 18.8 g of the title compound.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:10][C:9]=1[O:23][CH3:24].C(N(CC)CC)C>C(Cl)Cl>[CH3:24][O:23][C:9]1[CH:10]=[C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:12]=[CH:13][C:8]=1[CH2:7][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(-c2nc3ccccc3o2)ccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyrrolidine (226 μL, 2.83 mmol) was added to a stirring solution of 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (300 mg, 0.94 mmol) and triethylamine (390 μL, 2.8 mmol) in CH2Cl2 (5 mL). The mixture was stirred at rt overnight. Crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford the desired 2-[3-methoxy-4-(pyrrolidin-1-ylmethyl)phenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 7.82–7.80 (m, 1H), 7.77–7.74 (m, 1H), 7.71 (s, 1H), 7.56–7.50 (m, 2H), 7.35–7.30 (m, 2H), 3.94 (s, 3H), 3.71 (s, 2H), 2.59 (s, 4H), 1.81–1.78 (m, 4H). MS (ESI) 309 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.BrCCBr.CON(C)[C:17]([C:19]1[N:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:22]2[N:23]=[C:24]([S:27][CH3:28])[N:25]=[CH:26][C:21]=2[CH:20]=1)=[O:18].[Mg]>C1COCC1.C(OCC)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:17]([C:19]1[N:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:22]2[N:23]=[C:24]([S:27][CH3:28])[N:25]=[CH:26][C:21]=2[CH:20]=1)=[O:18]
Reactant: Clc1ccccc1CBr
Reactant: CON(C)C(=O)c1cc2cnc(SC)nc2n1-c1ccc(F)cc1
Agent: [Mg]
Solvent: BrCCBr
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSc1ncc2cc(C(=O)Cc3ccccc3Cl)n(-c3ccc(F)cc3)c2n1

Procedure:
To a round bottom flask equipped with a condenser is added Mg powder (0.35 g, 0.02 mmol) and diethyl ether (10 mL). 2-Chlorobenzyl bromide (0.10 mL, 0.76 mmol) and a catalytic amount of 1,2-dibromoethane (5 μL) is added to the reaction mixture. After an initial exotherm, the reaction solution develops a yellow color. 7-(4-Fluoro-phenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methoxy-methyl-amide, 29, (0.22 g, 0.63 mmol) is dissolved in THF (10 mL) and the Grignard reagent is then carefully transferred dropwise using a cannula using nitrogen to initiate and continue the transfer. The mixture is allowed to stir at room temperature for 2 hours after which the magnesium is removed by filtration and the filtrate concentrated in vacuo. The residue is purified by preparative HPLC to afford 64 mg of the desired product as a pale colored solid: 1H NMR (300 MHz, CDCl3) δ 9.02 (s, 1H), 7.60 (s, 1H), 7.42-7.38 (m, 1H), 7.37-7.22 (m, 5H), 7.18 (t, J=8.7 Hz, 2H), 4.40 (s, 2H), 2.44 (s, 3H); ESI+ MS: m/z (rel intensity) 411.9 (100, M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.[CH:14]1(N)[CH2:18][CH2:17][CH2:16][CH2:15]1>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:3]=1
Reactant: NC1CCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)cc1NC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A mixture of 20 g of 4-chloro-1,2-dinitrobenzene and 20 g of cyclopentylamine in 50 ml of 95° EtOH is stirred overnight at RT. The precipitate formed is filtered off and washed with 95° EtOH to give 14 g of the expected product. M.p.=75° C.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([C:5]1[C:9]([N+:10]([O-])=O)=[CH:8][N:7]([CH3:13])[N:6]=1)=[O:4]>CO.[Pd]>[NH2:10][C:9]1[C:5]([C:3]([N:2]([CH3:14])[CH3:1])=[O:4])=[N:6][N:7]([CH3:13])[CH:8]=1
Reactant: CN(C)C(=O)c1nn(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)c1nn(C)cc1N
Reaction time: 8 h

Procedure:
N,N,1-Trimethyl-4-nitropyrazole-3-carboxamide (1.22 g) was dissolved in MeOH (35 ml) and 10% Pd/C (0.3 g, 50% wet) was added. The mixture was stirred under a hydrogen atmosphere overnight and the catalyst filtered off. The solvent was removed in vacuo to yield 4-amino-N,N,1-trimethylpyrazole-3-carboxamide, 810 mg. NMR Spectrum: (CDCl3) 3.06 (m, 3H), 3.44 (m, 3H), 3.78 (s, 3H), 4.51 (m, 2H), 6.90 (s, 1H); Mass spectrum: MH+ 169
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22](=[O:31])/[CH:23]=[CH:24]/[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([CH:23]1[C:22](=[O:31])[O:13][C:12]2[NH:11][C:10]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])=[N:9][C:8]=2[CH:1]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Reactant: O=C/C=C/c1ccccc1
Product: O=C1Oc2[nH]c(-c3cc(F)ccc3F)nc2C(c2ccccc2)C1Cc1ccccc1
Yield: 73 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and trans-cinnamaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 5j as a white solid (91 mg, 73%). Analytical data for 5j: 1H NMR (500 MHz, CDCl3) δ 9.41 (br s, 1H), 7.91 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.40-7.32 (m, 5H), 7.31-7.27 (m, 1H), 7.14-7.10 (m, 2H), 7.10-7.05 (m, 1H), 7.04-6.96 (m, 3H), 4.11 (d, J=6.8 Hz, 1H), 3.64 (ddd, J=10.2, 6.8, 4.6 Hz, 1H), 3.39 (dd, J=14.9, 4.5 Hz, 1H), 2.46 (dd, J=14.9, 10.2 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 168.9, 159.1 (d, JCF=243.1 Hz), 155.4 (d, JCF=241.8 Hz), 148.9, 137.9, 137.0, 136.3, 129.2, 129.0, 128.6, 128.3, 128.0, 126.8, 118.4 (dd, JCF=12.5, 9.1 Hz), 117.1 (dd, JCF=25.7, 8.7 Hz), 116.6 (dd, JCF=24.8, 9.4 Hz), 114.5 (dd, JCF=27.0, 3.9 Hz), 111.0 (d, JCF=3.8 Hz), 47.3, 38.4, 32.7; IR (film) cm−1 1773, 1636, 1618, 1529, 1481, 1463, 1453, 1240, 1172, 1117, 1070, 766, 731; LRMS (ESI): Mass calcd for [M+H]+ C25H19F2N2O2: 417.1. found 417.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 20% IPA/hexanes; 1.0 mL/min, 280 nm), Rt1 (minor)=11.3, Rt2 (major)=17.8 min; er=98:2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>CN(C)C1C=CN=CC=1.C(#N)C>[N+:8]([C:5]1[CH:4]=[N:3][C:2]([NH:1][C:17](=[O:19])[CH3:18])=[N:7][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1ncc([N+](=O)[O-])cn1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(=O)Nc1ncc([N+](=O)[O-])cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
To a solution of 2-amino-5-nitropyrimidine (3.00 g, 21.4 mmol), 4-dimethylaminopyridine (2.61 g, 21.4 mmol) and pyridine (10.4 ml, 128 mmol) in acetonitrile (100 ml) was added acetyl chloride (3.04 ml, 42.8 mmol), the mixture was stirred at 100° C. for 1 hour. To the mixture was added acetyl chloride (2.00 ml, 28.1 mmol) and the mixture was stirred at 100° C. for 12 hours. The reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to obtain the desired product (1.22 g, 31.3%) as a solid.