Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][O:29][CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: COCC(=O)O
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (10.3 mg, 47%), MS (ISP) m/z=404.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (20 mg, 0.0543 mmol) and 2-methoxyacetic acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.[Li+].[Cl-].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=[O:29]>C1COCC1>[Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:28]([OH:29])[C:27]4[CH:30]=[CH:31][CH:32]=[C:25]([C:24]([F:23])([F:33])[F:34])[CH:26]=4)=[C:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1nc2n(c1C(O)c1cccc(C(F)(F)F)c1)CCOc1cc(F)c(Br)cc1-2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared similarly according to the procedure in Example 9. Methyl 10-bromo-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxylate (150 mg, 0.44 mmol) was dissolved in THF (1.3 mL, 3 mL/mmol) and the solution was cooled to 0° C. A solution of TMPMgCl/LiCl (1 M in toluene/THF, 1.6 equiv., 0.704 mL, 0.70 mmol) was added down the side of the vial slowly. The mixture was allowed to stir for 30 minutes. After 30 minutes, 3-(trifluoromethyl)benzaldehyde (1.0 equiv., 0.06 mL, 0.44 mmol) was added and the reaction continued to stir for 30 minutes. The reaction was quenched with saturated NH4Cl and extracted 3 times with methylene chloride. The organic layers were combined, dried with Na2SO4 and concentrated. The crude was purified by flash chromatography to afford 73 mg (32.2% yield) of a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:2]=1.[H-].[Na+].[C:20]([C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)#[N:21]>CN(C=O)C>[C:20]([C:22]1[CH:23]=[C:24]([S:28]([N:8]2[C:9]3[C:14](=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:15]=[C:7]2[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1)#[N:21]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: N#Cc1ccc2[nH]c(-c3cccnc3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(S(=O)(=O)n2c(-c3cccnc3)cc3cc(C#N)ccc32)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 8, 300 mg, 1.37 mmol) at 0° C. in DMF (12 mL) is added 60% sodium hydride (82 mg, 2.06 mmol) and the mixture stirred for 10 min at 0° C. The reaction mixture is then warmed to room temperature and stirred for 30 min. 3-Cyanobenzenesulfonyl chloride (552 mg, 2.74 mmol) in DMF (2 mL) is added dropwise at 0° C. and the reaction is stirred at room temperature for 1 h. The reaction is quenched by adding water (1 mL). The resulting mixture is purified by HPLC X-bridge RP18 using acetonitrile-0.1% ammonia hydroxide as an eluent to yield 1-(3-cyano-benzenesulfonyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. 1H NMR (400 MHz, CDCl3) δ ppm 7.11 (s, 1H), 7.54 (dd, J=7.8, 4.8 Hz, 1H), 7.66 (dd, J=8.1, 2.0 Hz, 1H), 7.72 (t, J=7.7 Hz, 1H), 7.86 (dd, J=8.7, 1.6 Hz, 1H), 7.94 (t, J=1.5 Hz, 1H), 7.98 (dt, J=8.2, 2.0, 1.8 Hz, 1H), 8.16 (dd, J=7.6, 1.3 Hz, 1H), 8.19 (d, J=1.0 Hz, 1H), 8.34 (d, J=8.6 Hz, 1H), 8.67 (d, J=2.8 Hz, 1H), 8.71 (dd, J=4.9, 1.6 Hz, 1H). HRMS (ESI) m/z 385.0763 [(M+H)+ Calcd for C21H13N4O2S: 385.0759].
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CO.[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:6](=[O:17])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[N:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(N)cn1
Reaction time: 4 h
Yield: 101.1 %

Procedure:
To 0.314 g (1.31 mmol) of the above nitro compound in THF-MeOH (16 mL, 1:1) was added 0.460 g of 10% Pd/C and the mixture was stirred under hydrogen (40 in/Hg) for 4 hrs. The reaction mixture was filtered through celite, washed with MeOH and concentrated to give 0.277 g (99% yield) of tert-butyl 5-aminopyridin-2-yl-carbamate as a white powder: 1H NMR (DMSO-d6) δ9.00 (br s, 1H), 7.62 (dd, J=2.7, 0.4 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 6.94 (dd, J=8.7, 2.8 Hz, 1H), 4.92 (s, 2H), 1.44 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]([CH3:25])[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=2)[N:14]=[C:13]([CH3:24])[N:12]=1.[H][H]>CC(O)=O.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]([CH3:25])[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=2)[N:14]=[C:13]([CH3:24])[N:12]=1
Reactant: COc1ccc(N(C)c2nc(C)nc3ccc([N+](=O)[O-])cc23)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(N(C)c2nc(C)nc3ccc(N)cc23)c(F)c1
Reaction time: 3 h

Procedure:
10% Pd—C (10 mg, 0.0094 mmol) was added to a soln of (2-fluoro-4-methoxy-phenyl)-methyl-(2-methyl-6-nitro-quinazolin-4-yl)-amine (127 mg, 0.371 mmol) in AcOH (3 mL) and this was reacted under 1 atm of hydrogen. After 3 h, the rxn was filtered through a 0.45 μm filter then concentrated. Satd NaHCO3 (10 mL) was added and the product extracted into CHCl3 (2×2 mL). The soln was dried (MgSO4), filtered through a plug of silica with an EtOAc wash then concd to a yellow crystalline solid (104 mg; 90%). 1H NMR (CDCl3) δ 7.61 (d, J=8.8 Hz, 1H), 7.05-6.99 (m, 2H), 6.73 (dd, J=2.8, 12 Hz, 1H), 6.66 (ddd, J=1.2, 3.2, 8.8 Hz, 1H), 6.18 (d, J=2.4 Hz, 1H), 3.82 (s, 3H), 3.51 (s(br), 2H), 3.50 (s, 3H), 2.69 (s, 3H); LC-MS (ESI+; 313 ([M+H]+)).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][C@@H:8]2[CH2:12][CH2:13][CH2:14][C@H:7]12)C.[NH3:16]>CO>[O:11]=[C:10]1[N:6]([CH2:5][C:4]([NH2:16])=[O:3])[C@H:7]2[CH2:14][CH2:13][CH2:12][C@H:8]2[CH2:9]1
Reactant: N
Reactant: CCOC(=O)CN1C(=O)C[C@@H]2CCC[C@@H]21
Solvent: CO
Product: NC(=O)CN1C(=O)C[C@@H]2CCC[C@@H]21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A example of this step is a solution of cis-hexahydro-2-oxo-cyclopenta[b]pyrrole-1(2H)-acetic acid ethyl ester (3.25 g, 0.0154 mole) in methanol (200 ml) is saturated with anhydrous ammonia and stirred at ambient temperature 24 hours. The solution is concentrated at reduced pressure to yield a solid. Recrystallization from acetonitrile yields pure cis-hexahydro-2-oxo-cyclopenta[b]pyrrole-1(2H)acetamide with a mp 142.5°-143.5° C. ##STR4##
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([N:19]=[CH:20][C:21]([S:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]3)=[N:22]2)=[CH:17][CH:16]=1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:34][CH:31]3[CH2:30][CH2:29][N:28]([CH2:27][CH2:26][S:25][C:21]4[CH:20]=[N:19][C:18]5[C:23](=[CH:24][C:15]([O:14][CH3:13])=[CH:16][CH:17]=5)[N:22]=4)[CH2:33][CH2:32]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Reactant: O=Cc1ccc2c(c1)OCCO2
Product: COc1ccc2ncc(SCCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)nc2c1

Procedure:
The title compound is prepared as a light yellow oil (2.03 g, 78% yield) following Scheme 3 and in analogy to Example 40 using 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (792 mg, 4.77 mmol 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (1.52 g, 4.77 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1I.[C:17]([C:19]1[CH:33]=[CH:32][C:22]([CH2:23][N:24]2[CH2:27][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH2:25]2)=[CH:21][C:20]=1[F:34])#[CH:18]>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]2[O:1][C:17]([C:19]3[CH:33]=[CH:32][C:22]([CH2:23][N:24]4[CH2:27][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH2:25]4)=[CH:21][C:20]=3[F:34])=[CH:18][C:3]=2[CH:4]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Reactant: O=C(c1ccccc1)c1ccc(O)c(I)c1
Product: COC(=O)C1CN(Cc2ccc(-c3cc4cc(C(=O)c5ccccc5)ccc4o3)c(F)c2)C1

Procedure:
Synthesized according to Scheme B3, Step 3 and general procedure G from (4-hydroxy-3-iodophenyl)(phenyl)methanone and methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate: yellow-orange solid. MS (ESI) m/z: Calculated: 443.2; Observed: 444 (M++1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[CH2:16][O:17][C:18]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]2[C:19]=1[C:20]([CH3:30])([CH3:29])[C:21](=O)[NH:22]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1.C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[CH2:16][O:17][C:18]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]2[C:19]=1[C:20]([CH3:30])([CH3:29])[C:21](=[S:43])[NH:22]2
Reactant: Cc1ccc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c2c1NC(=O)C2(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(OCc2cccc(OCc3ccc4ccccc4n3)c2)c2c1NC(=S)C2(C)C
Temperature: 100 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To 1.189 g (2.71 mmol) of the 4-[3-(2-quinolinylmethoxy)benzyloxy]-3,3,7-trimethyl-2,3-dihydro-1H-indol-2-one obtained in Example 13, 1.076 g (2.71 mmol) of the Lawesson's reagent and 10 ml of toluene were added, followed by stirring at a bath temperature of 100° C. for 3 hours. After CHCl3 was added to dissolve the insoluble matter, the resulting solution was subjected to chromatography on a silica gel column. Subsequent to elution with CHCl3, recrystallization was conducted from AcOEt, whereby 678 mg of the title compound were obtained as pale yellow powder (yield: 55.0%).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11].[H][H]>CC(O)C>[CH3:3][O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@@H:6]1[OH:11]
Reactant: COC1CCCCC1=O
Reactant: [H][H]
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CO[C@@H]1CCCC[C@@H]1O
Temperature: 50 °C
Reaction time: 19 h

Procedure:
In a 100 ml autoclave were charged 1.50 ml of a 0.2M solution of potassium hydroxide (0.30 mmol) in 2-propanol, 4.2 mg (0.02 mmol) of (1R,2R)-diphenylethylenediamine, 1.28 g (10.0 mmol) of 2-methoxycyclohexanone, 9.6 mg (0.01 mmol) of Rh(COD)[(R)-T-BINAP]BF4, and 8.5 ml of 2-propanol in a nitrogen atmosphere, and hydrogen was introduced therein to 50 atm. The mixture was stirred at 50° C. for 19 hours and cooled to room temperature. The disappearance of the starting material was confirmed by gas chromatography. The solvent was evaporated under reduced pressure, and the residue was distilled under reduced pressure to obtain (1S,2R)-2-methoxycyclohexanol. The optical purity of the product was found to be 34% d.e. and 14% e.e. by gas chromatography.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Se](=O)=[O:17]>O1CCOCC1>[CH3:15][O:14][C:12](=[O:13])[C:11](=[O:17])[C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: COC(=O)Cc1ccc2ncccc2c1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: COC(=O)C(=O)c1ccc2ncccc2c1
Temperature: 25 °C

Procedure:
To the solution of methyl 6-quinolineacetate (1.2 g, 6 mmmol) in dioxane (30 mL) was added Selenium dioxide (1.65 g, 15 mmol). The mixture was heated to reflux for 3 days, cooled to room temperature, filtered through Celite and concentrated. The residue was purified by chromatography (methylene chloride to 5% ethyl acetate in chloride) to a white solid (0.75 g, 58%). 1H-NMR (CDCl3): δ 9.07-9.06 (1H, q, J=1.7, 2.5 Hz), 8.62-8.61 (1H, d,J=1.7 Hz), 8.32-8.31 (2H, m), 8.22-8.20 (1H, d, J=8.8 Hz), 7.54-7.51 (1H, q, J=8.8Hz), 4.05 (3H, s).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].Cl[CH2:11][C:12]([NH:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[O:13].C(=O)([O-])O.[Cs+]>CN1C(=O)CCC1>[CH3:9][O:8][C:1](/[CH:2]=[CH:3]/[C:4]([O:6][CH2:11][C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])=[O:5])=[O:7]
Reactant: CC(C)(C)OC(=O)CNC(=O)CCl
Reactant: COC(=O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/C(=O)OCC(=O)NCC(=O)O
Yield: 12.1 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (0.68 g, 5.26 mmol) dissolved in NMP was reacted at ca. 55° C. with tert-butyl 2-(2-chloroacetylamino)acetate (0.91 g, 4.38 mmol) in the presence of CsHCO3 (1.19 g, 6.13 mmol) of the tert-butyl-protected intermediate and then purified by silica gel column chromatography (Biotage) using a mixture of ethyl acetate (EtOAc) and hexanes (1:2 to 2:3 to 1:1) as eluent. The purified product was treated with 50% trifluoroacetic acid (TFA) in dichloromethane (DCM). Removal of solvents afforded 0.13 g (12% yield) of the title compound (6). 1H NMR (CD3OD, 400 MHz): δ 6.96-6.93 (m, 2H), 4.74 (s, 2H), 3.98-3.95 (m, 2H), 3.81 (s, 3H). MS (ESI): m/z 246.00 (M+H)+, 244.02 (M−H)−.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O:22][C:23](OC(C)C)(OC(C)C)[C:24]1([O:40][CH3:41])[CH:29]=[CH:28][C:27]([CH2:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:32])=[CH:26][CH2:25]1)(C)C>C1COCC1.C(OCC)(=O)C>[OH:22][CH2:23][C:24]1([O:40][CH3:41])[CH:25]=[CH:26][C:27]([CH2:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:32])=[CH:28][CH2:29]1
Reactant: COC1(C(OC(C)C)(OC(C)C)OC(C)C)C=CC(CC(=O)Nc2ccccc2)=CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC1(CO)C=CC(CC(=O)Nc2ccccc2)=CC1
Reaction time: 2 h
Yield: 149.2 %

Procedure:
Tetra-butylammonium fluoride (4.48 mL of a 1M solution in THF) was added to a solution of 4-tri-isopropoxymethyl-2-(4′-methoxyphenyl)acetanilide (1.87 g, 4.07 mmol) in THF (12 mL) and stirred for 2 hours. The reaction was diluted with ethyl acetate and washed with saturated ammonium chloride then water and finally dried over sodium sulphate. The solvent was evaporated to afford 1.66 g of a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.C([Li])CCC.CN([CH:19]=[O:20])C>C(OCC)C>[Br:10][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1)[CH:19]=[O:20]
Reactant: COc1cc(Br)cc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(Br)cc(C=O)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 98 %

Procedure:
A solution of 1,3-dibromo-5-methoxybenzene (5.00 g, 18.8 mmol) in anhydrous diethyl ether (100 mL) was cooled to −78° C. Then a solution of n-butyllithium in hexanes (2.5 M, 8.3 mL, 20.68 mmol) was added drop-wise at −78° C. under nitrogen. After the addition was complete, the reaction was stirred at −78° C. for 45 min. After that time, anhydrous DMF (7.3 mL), 94.0 mmol) was added, the cooling bath was removed and the reaction mixture was allowed to warm to rt. The reaction was diluted with saturated aqueous NH4Cl solution (100 mL) and diethyl ether (100 mL). The organic phase was separated, washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 3-bromo-5-methoxybenzaldehyde (3.95 g, 98%) as yellow oil: 1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 7.57-7.60 (m, 1H), 7.31-7.33 (m, 2H), 3.86 (s, 3H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3][CH:2]=1.[Br:10][C:11]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>C(Cl)Cl.O>[Br:10][C:11]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[O:14]
Reactant: Cc1cccc(C(=O)Cl)c1Br
Reactant: NCCc1ccccc1
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(C(=O)NCCc2ccccc2)c1Br
Reaction time: 8 h

Procedure:
To a solution of 2-phenethylamine (0.28 mL, 2.195 mmol) in DCM (2.0 mL) was added 2-bromo-3-methylbenzoyl chloride (0.15 mL, 0.998 mmol) dropwise via syringe at ambient temperature. Mixture was allowed to stir overnight, then diluted with water (30 mL) and extracted with DCM (30 mL). The organic extract was washed with 1N HCl (2×25 mL) and 1N NaOH (2×25 mL) and dried over MgSO4. The solution was filtered and concentrated in vacuo to give 2-bromo-3-methyl-N-phenethylbenzamide as a white solid.
Reaction SMILES: [Na].Cl.[NH2:3][OH:4].[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]#[N:20])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([NH:3][OH:4])=[NH:20])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#CCC1CCN(Cc2ccccc2)CC1
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CO
Product: N=C(CC1CCN(Cc2ccccc2)CC1)NO
Temperature: 75 °C
Reaction time: 0.17 h

Procedure:
Sodium metal (0.8 g, 34.78 mmol) was dissolved in dry methanol (10 mL) at 0-10° C. and this solution was added slowly into a suspension of hydroxylamine hydrochloride (2.43 g, 34.96 mmol) in methanol (10 mL) at room temperature. The reaction mixture was stirred for 10 min until a clear solution was obtained, 2-(1-Benzylpiperidin-4-yl)acetonitrile (compound of Example 27; 3 g, 13.99 mmol) in dry methanol (20 mL) was added into the resulting reaction mixture and heated at 75° C. for 13 h. The solvent was evaporated at 50° C. to 55° C. and the crude product obtained was purified by column chromatography (silica gel, chloroform-methanol) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10](=O)[CH2:11]Cl.[CH:14]1([Mg]Br)[CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[Cl:9][C:6]1[C:7]([F:8])=[C:2]2[C:3]([CH:10]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[NH:1]2)=[CH:4][CH:5]=1
Reactant: Nc1c(C(=O)CCl)ccc(Cl)c1F
Reactant: Br[Mg]C1CC1
Solvent: Cc1ccccc1
Product: Fc1c(Cl)ccc2cc(C3CC3)[nH]c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.4 %

Procedure:
To a stirred solution of compound 2 (4.5 g, 20.3 mmol) in toluene (50 mL) was added cyclopropyl magnesium bromide (0.5 M in THF; 102.0 mL, 50.9 mmol) at 0° C. under inert atmosphere. The reaction mixture was stirred at 0° C. for 15 min and then warmed to RT and stirring was continued for additional 1 h. After completion of the reaction by TLC, the reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel chromatography; 1% EtOAc/Hexanes) to afford compound 3 (2.7 g, 63%) as an off-white solid. 1H NMR (500 MHz, DMSO-d6): δ 11.55 (s, 1H), 7.18 (d, J=8.5 Hz, 1H), 6.97 (dd, J=8.5, 6.5 Hz, 1H), 6.16 (s, 1H), 2.03-1.99 (m, 1H), 0.99-0.96 (m, 2H), 0.83-0.80 (m, 2H); LC-MS (ESI): 91.6%; m/z 208.1 (M−H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.32 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: Br[C:2]1[C:14]([O:15][CH2:16][CH3:17])=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[O:18][CH2:19][CH3:20].[Li]CCCC.[B:26](OC)([O:29]C)[O:27]C>C1COCC1>[C:9]([O:8][C:6]([C:5]1[CH:13]=[C:14]([O:15][CH2:16][CH3:17])[C:2]([B:26]([OH:29])[OH:27])=[C:3]([O:18][CH2:19][CH3:20])[CH:4]=1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: COB(OC)OC
Reactant: CCOc1cc(C(=O)OC(C)(C)C)cc(OCC)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)OC(C)(C)C)cc(OCC)c1B(O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 4-bromo-3,5-diethoxybenzoate (1 g) in THF (20 ml) was added n-BuLi (1.6M in hexane, 3.6 ml) at −78° C. under argon atmosphere and stirred at the same temperature for 1 h. To the mixture was added B(OMe)3 (777 ul) at −78° C. and the mixture was allowed to warm up to at room temperature. After stirring for further 1 h, the mixture was poured into ice-HCl aq., extracted with EtOAc, washed with brine and dried over sodium sulphate. After filtration and concentration, the residue was purified by silicagel column chromatography (hexane/EtOAc) to give the title product as a colorless solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=Cc1ccc[nH]1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: c1c[nH]c(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.7 %

Procedure:
To a solution of 1H-pyrrole-2-carbaldehyde (5.0 g, 52.5 mmol) and morpholine (5.0 mL, 57.8 mmol) in CH2Cl2 (160 mL) was added sodium triacetoxyborohydride (12.2 g, 57.8 mmol). The mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc (200 mL). The organic phase was washed with aqueous NaHCO3 and brine then dried (MgSO4), filtered and concentrated to dryness. The residue was purified by column chromatography (silica, 0-10% MeOH in CH2Cl2) to afford the sub-title compound (5.3 g, 61%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:22][C:23]#[CH:24])[CH2:9][CH2:10][N:11]([CH:19]([CH3:21])[CH3:20])[C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1.N1CCCCC1>C1(C)C=CC=CC=1.[Cu]I>[C:1]([O:5][C:6]([N:8]([CH2:22][C:23]#[C:24][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)[CH2:9][CH2:10][N:11]([CH:19]([CH3:21])[CH3:20])[C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C#CCN(CCN(C(=O)C(=O)OCC)C(C)C)C(=O)OC(C)(C)C
Reactant: Ic1cccs1
Agent: [Cu]I
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)N(CCN(CC#Cc1cccs1)C(=O)OC(C)(C)C)C(C)C

Procedure:
A solution of 340 mg of 10g, 130 μl of 2-iodothiophene, 12 mg of CuI, 21 mg of PdCl2(PPh4)2 and 200 μl of piperidine in 2 ml of degassed toluene was stirred under N2 for 3 h. The mixture was concentrated and applied to a silica column and chromatographed with a gradient of heptane/ethyl acetate, to provide 400 mg of 10h as an orange oil. Rf 0.60 (hept/ethyl acetate 1/1).