Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:21][CH:22]=O)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:24]=[C:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:31]1([C:37]([N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C([BH3-])#N.[Na+].[C:48]([OH:60])(=[O:59])[CH2:49][C:50]([CH2:55][C:56]([OH:58])=[O:57])([C:52]([OH:54])=[O:53])[OH:51]>CO.C(=O)(O)[O-].[Na+].C(O)(=O)C>[C:48]([OH:60])(=[O:59])[CH2:49][C:50]([CH2:55][C:56]([OH:58])=[O:57])([C:52]([OH:54])=[O:53])[OH:51].[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:21][CH2:22][N:34]2[CH2:35][CH2:36][C:31]([N:26]3[CH2:27][CH2:28][CH2:29][CH2:30][C:25]3=[O:24])([C:37]([N:39]3[CH2:40][CH2:41][CH2:42][CH2:43]3)=[O:38])[CH2:32][CH2:33]2)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: O=C1CCCCN1C1(C(=O)N2CCCC2)CCNCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Product: CN(C[C@@H](CCN1CCC(C(=O)N2CCCC2)(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reaction time: 0.17 h

Procedure:
(S)-N-[2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methylbenzamide (350 rag) in methanol (3 mL) was added to a solution of 4-(2-oxopiperidino)-4-(pyrrolidin-1-ylcarbonyl)piperidine (330 mg) and acetic acid (0.07 mL) in methanol (5 mL). After 10 minutes, sodium cyanoborohydride (100 mg) in methanol (2 mL) was added in a single portion. After being stirred for 3 hours, the reaction mixture was diluted with aqueous sodium bicarbonate, stirred for 30 minutes, and extracted with dichloromethane. The organic extracts were dried, evaporated, and chromatographed, with dichloromethane:methanol (95:5) as eluent. The resulting material (410 mg) was dissolved in methanol containing 1 equivalent of citric acid (128 mg), evaporated, suspended and pulverized in ether, evaporated, and placed under high vacuum to give the title compound as a white solid (540 mg); MS: m/z=613(M+1), 542[(M+1)-pyrrolidine]. Analysis for C33H42Cl2N4O3 ·1.40 H2O·0.65 (C2H5)2O·1.0 C6H8O7 : Calculated: C, 56.83; H, 6.80; N, 6.37; Found: C, 56.89; H, 6.74; N, 6.27.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24](OCC)=[O:25])[CH:17]=[N:16]3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[BH4-].[Na+]>>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([CH2:24][OH:25])[CH:17]=[N:16]3)[CH2:11][CH2:10]2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cnn(C2CCN(c3ncc(CC)cn3)CC2)c1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: CCc1cnc(N2CCC(n3ncc(CO)c3C(F)(F)F)CC2)nc1

Procedure:
The title compound was synthesized using ethyl 1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate and sodium borohydride in a manner similar to that described in Example 66, Step 2.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Br:19][C:20]1[C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=[CH:23][C:21]=1N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Br:19][C:20]1[C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=[CH:23][C:21]=1[NH:13][C:12]1[C:11]2[C:10](=[CH:9][CH:8]=[C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]3=2)[N:14]=[CH:15][N:16]=1
Reactant: Nc1ccc2c(c1Br)OCO2
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc5c(c4Br)OCO5)c3c2s1
Yield: 21 %

Procedure:
Prepared from VII and 2-bromo-3,4-(methylenedioxy)aniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 21%; yellow solid, mp>260° C.; IR (KBr) νmax/cm−1 2887, 2233, 1632, 1610, 1581, 1501, 1484, 1465, 1379, 1348, 1303, 1267, 1232, 1161, 1116, 1034, 970, 929, 829; 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, 1H, J=9.0 Hz), 8.06 (s, 1H), 7.77 (d, 1H, J=9.0 Hz), 7.25 (s, 1H), 6.83 (s, 1H), 6.06 (s, 2H); HRMS calcd for C17H9N5O2SBr (M+H+): 425.9660, found 425.9646.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[O:54][N:53]=[CH:52][C:51]=2[C:55](O)=[O:56])=[CH:46][CH:45]=1>CN(C=O)C>[CH3:43][C:44]1[CH:45]=[CH:46][C:47]([C:50]2[O:54][N:53]=[CH:52][C:51]=2[C:55]([N:2]2[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([OH:11])([CH3:10])[CH3:9])[CH2:3]2)=[O:56])=[CH:48][CH:49]=1
Reactant: CC(C)(O)[C@@H]1CCCNC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC[C@@H](C(C)(C)O)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
A solution of 2-[(3R)-piperidin-3-yl]propan-2-ol hydrochloride (7 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.079 mmol, 2 equ.) in DMF (0.3 mL) was added to 5-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (9 mg). MS (ESI, pos. ion) m/z calcd for C19H24N2O3: 328.1787, found 328.1784.
Reaction SMILES: Cl.[NH2:2][OH:3].[O-]CC.[Na+].[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]=1)#[N:9]>C(O)C>[C:20]([O:19][C:17]([NH:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:8](=[N:2][OH:3])[NH2:9])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: NO
Reactant: CC(C)(C)OC(=O)Nc1cccc(C#N)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc(C(N)=NO)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (3.16 g, 0.045 mol) was added to a stirred solution of sodium ethoxide in ethanol [prepared by dissolving 1.17 g of sodium in 70 ml of ethanol]. The mixture was stirred at room temperature for 15 min then 1-cyano-3-tert-butyloxycarbonylaminobenzene (3.00 g, 0.014 mol) was added. The mixture was heated at 50° C. overnight then cooled to ambient temperature. The mixture was then filtered and the filtrate evaporated in vacuo. The residue was partitioned between ethyl acetate (50 ml) and water (50 ml). The organic phase was separated and the aqueous phase extracted with ethyl acetate (3×20 ml). The organic layers were combined, washed with brine (50 ml) then dried (Na2SO4). The solvent was evaporated to leave a pink fo.m. The foam was left at 0° C. overnight, then triturated with 1:1 petrol:ethyl acetate. The title compound was collected as a white solid (2.52 g, 73%). 1H NMR (360 MHz, D6 -DMSO)δ1.47 (9H, s), 5.69 (2H, brs), 7.24 (2H, m), 7.41 (1H, brd, J=6.5 Hz), 7.82 (1H, s), 9.35 (1H, s), 9.58 (1H, s). MS (CI, NH3) 252 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:13][CH:12]1[C:21]1[NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:24][N:25]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[CH3:57][O:58][C:59](=[O:90])[NH:60][CH:61]([C:65]([N:67]1[CH:73]([C:74]2[NH:75][C:76]([C:79]3[CH:88]=[CH:87][C:86]4[C:81](=[CH:82][CH:83]=[C:84](Br)[CH:85]=4)[CH:80]=3)=[CH:77][N:78]=2)[CH2:72][C:69]2([CH2:71][CH2:70]2)[CH2:68]1)=[O:66])[CH:62]([CH3:64])[CH3:63]>O1CCOCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:57][O:58][C:59](=[O:90])[NH:60][CH:61]([C:65]([N:67]1[CH:73]([C:74]2[NH:75][C:76]([C:79]3[CH:88]=[CH:87][C:86]4[C:81](=[CH:82][CH:83]=[C:84]([C:29]5[CH:28]=[CH:27][C:26]([C:23]6[NH:22][C:21]([CH:12]7[CH2:13][CH:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:15][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:33])[CH:6]([CH3:8])[CH3:7])=[N:25][CH:24]=6)=[CH:31][CH:30]=5)[CH:85]=4)[CH:80]=3)=[CH:77][N:78]=2)[CH2:72][C:69]2([CH2:71][CH2:70]2)[CH2:68]1)=[O:66])[CH:62]([CH3:64])[CH3:63]
Reactant: COCCOC1CC(c2ncc(-c3ccc(Br)cc3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COCCOC1CC(c2ncc(-c3ccc(-c4ccc5cc(-c6cnc(C7CC8(CC8)CN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A mixture of {1-[2[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2-methoxy-ethoxy)-pyrrolidine-1-carbonyl]-2-methyl-propyl]-carbamic acid methyl ester (169 mg), bis(pinacolato)diboron (107 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (24 mg) and potassium acetate (95 mg) in 1.6 mL of dioxane was heated to 90° C. for 1.5 hour. (1-{6-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (170 mg) in 1 mL of dioxane and 2M tripotassium phosphate (565 μl) were added and stirred at 90° C. for overnight. The mixture was purified by a preparative HPLC (10-60% MeCN—H2O; 0.1% formic acid modifier) to afford the title product (119 mg, 41%). 1H NMR (DMSO-d6, 400 MHz) δ: 8.20-8.10 (m, 2H), 7.90-7.68 (m, 6H), 7.60-7.55 (m. 2H), 7.33-7.30 (m, 2H), 5.18 (m, 1H), 5.07 (m, 1H), 4.44 (m, 1H), 4.04-3.69 (m, 6H), 3.80-3.38 (m, 5H), 3.30 (m, 9H), 2.71 (m, 1H), 2.40-1.90 (m, 5H), 0.90-0.79 (m, 12H), 0.70-0.54 (m, 4H); MS (ESI) m/z 889.5 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C1C(=O)N(Br)C(=O)C1.CSC.[Br-].N1C=NN=N1.C(N(CC)CC)C>C(Cl)Cl.CCO>[F:25][C:2]([F:1])([F:24])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: O=C1CCC(=O)N1Br
Agent: [Br-]
Agent: c1nnn[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CSC
Product: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
1-(4-Trifluoromethoxyphenyl)-3-(4-nitrophenyl)-1H-[1,2,4]triazole. A solution of NBS (0.70 g, 3.9 mmol) in 25 mL of CH2Cl2 was stirred under nitrogen at 0° C. while dimethyl sulfide (0.40 g, 6.5 mmol) was added via syringe. The solution, which forms a white solid, was then cooled to −20° C., and N-(4-nitrobenzylidene)-N-(4-trifluoromethoxyphenyl)-hydrazine (0.70 g, 2.15 mmol) in 10 mL of DCM was added. The solution was allowed to warm to ambient temperature and stirred an additional 2 h. The resulting orange solution was then diluted with 25 mL of DCM and washed with water and brine before drying and concentrating. The resulting orange solid hydrazonyl bromide (0.9 g) was then treated directly with tetrazole (154 mg, 2.2 mmol) and triethylamine (280 μL, 0.23 mmol) in 5 mL of absolute EtOH. The resulting orange-brown solution was heated at reflux for 2 h. TLC showed that the initial bromide was first converted into two yellow intermediates, which were replaced by a single, colorless, spot. The orange solution was then concentrated and purified by chromatography (2:1:2 Hexane/EtOAc/DCM), yielding 0.30 g of the title compound as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.68 (s, 1H), 8.40 (d, J=5 Hz, 2H), 8.35 (d, J=5 Hz, 2H), 7.85 (d, J=8 Hz, 2H), 7.42 (d, J=8 Hz, 2H); EIMS 350 (M+, 100), 299 (57); mp 147° C.
Reaction SMILES: O1CCO[CH:2]1[C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH:13][OH:14])=[CH:8][N:7]=1.[NH2:15][NH:16][C:17]([NH2:19])=[S:18].Cl.C(=O)(O)[O-].[Na+]>>[OH:14][NH:13][C:9]1[C:10]([CH3:12])=[CH:11][C:6]([CH:2]=[N:15][NH:16][C:17]([NH2:19])=[S:18])=[N:7][CH:8]=1
Reactant: NNC(N)=S
Reactant: Cc1cc(C2OCCO2)ncc1NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C=NNC(N)=S)ncc1NO

Procedure:
Condensation of 2-(1,3-dioxolanyl)-4-methyl-5-hydroxyaminopyridine with thiosemicarbazide in the presence of concentrated hydrochloric acid, followed by treatment with sodium bicarbonate afforded the desired 5-hydroxyamino-4-methyl-2-formylpyridine thiosemicarbazone.
Reaction SMILES: O=[C:2]([CH3:10])[CH2:3][C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C(O)(=O)C>C1C=CC=CC=1>[F:11][C:12]([F:20])([F:21])[C:13]1[CH:14]=[C:15]([NH:16][C:2]([CH3:10])=[CH:3][C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5])[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(=O)CC(=O)OC(C)C
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(=CC(=O)OC(C)C)Nc1cccc(C(F)(F)F)c1

Procedure:
To a solution of 4.33 g (30 mmol) isopropyl 3-oxobutanoate in 90 ml benzene are added 4.83 g (30 mmol) 3-(trifluoromethyl)aniline and 1.80 g (30 mmol) acetic acid. The mixture is stirred under reflux for four hours using a Dean-Stark trap to remove water. After removal of the solvent in vacuo, the residue is purified by preparative HPLC (column: YMC C18 ODS-AQ 250 mm×30 mm, 11 μm; solvent A: acetonitrile, solvent B: water; gradient: 0 min 10% A, 3 min 10% A, 11 min 90% A, 13 min 90% A, 13.2 min 10% A, 15 min 10% A; wavelength: 220 nm; injection volume: ca. 900 μl ethanol solution; number of injections: 8). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]=O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([CH3:10])[C:11](=[O:13])[O:12][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H]1C(=O)OCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 70.6 %

Procedure:
In toluene (250 mL) were suspended tert-butoxycarbonyl-L-alanine (18.9 g), paraformaldehyde (6.70 g) and p-toluenesulfonic acid monohydrate (0.19 g), and the suspension was heated at reflux while removing water produced. At the end of the reaction, the mixture was cooled to room temperature, washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline. The toluene solution was dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, and the crystals obtained were filtered to give the title compound (14.2 g) white crystals in a yield of 71%.
Reaction SMILES: [F:1][C:2]1[C:22](F)=[CH:21][C:5]2=[N:6][C:7]3[N:8]([CH3:20])[CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.C(N(CC)CC)C>CS(C)=O>[F:1][C:2]1[C:22]([N:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:27]=[CH:26][C:25]([F:24])=[CH:30][CH:29]=3)[CH2:36][CH2:35]2)=[CH:21][C:5]2=[N:6][C:7]3[N:8]([CH3:20])[CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CCN(c5ccc(F)cc5)CC4)c(F)cc3cc2c1=O
Yield: 8.3 %

Procedure:
Ethyl 7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate was prepared by analogy to the method described in Example 1, from 3.2 g of ethyl 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate, 2.16 g of 4-(4-fluorophenyl)piperazine and 3.35 cm of triethylamine in 40 cm3 of dimethyl sulphoxide. After filtering off with 2 times 15 cm3 of water and 2 times 15 cm3 of ethanol, 0.4 g of ethyl 7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate was obtained in the form of a yellow solid melting at about 310° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:19][CH:18]=1.O>C(O)(=O)C>[CH3:27][C:23]([C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])=[CH:22][CH:21]=1)([CH3:26])[C:24]#[N:25]
Reactant: Cc1ccc2ncc([N+](=O)[O-])c(Cl)c2c1
Reactant: CC(C)(C#N)c1ccc(N)cc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2ncc([N+](=O)[O-])c(Nc3ccc(C(C)(C)C#N)cc3)c2c1
Reaction time: 2 h

Procedure:
4-Chloro-6-methyl-3-nitroquinoline (Compound of Preparation H, 660 mg, 2.97 mmol) and 2-(4-aminophenyl)-2-methylpropanenitrile (570 mg, 3.56 mmol) were dissolved in acetic acid (10 ml) and stirred for 2 hours. Water was added and the yellow precipitate was filtered off, washed with water, saturated aqueous NaHCO3 and water. The yellow solid was dried to obtain the title compound. Yield: 600 mg (58%); 1H NMR (DMSO-d6, 300 MHz): δ 9.952 (s, 1H,), 9.016 (s, 1H), 8.184 (s, 1H), 7.890-7.918 (d, 1H, J=8.4 Hz), 7.699-7.727 (d, 1H, J=8.4 Hz), 7.421-7.445 (d, 2H, J=7.2 Hz), 7.082-7.108 (d, 2H, J=7.8 Hz), 2.284 (s, 3H), 1.660 (s, 6H); MS: m/z 347 (M+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[CH3:24].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:24][C:23]1[CH:22]=[CH:21][C:20]([C:2]2[N:3]=[C:4]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:19][C:18]=1[NH2:17]
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: Cc1ccc(B(O)O)cc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc(N3CCOCC3)c3sccc3n2)cc1N
Yield: 94.4 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine 4 (772 mg), 3-amino-4-methylbenzeneboronic acid (502 mg), DME (10 mL), water (5 mL), sodium carbonate (640 mg) and PdCl2(PPh3)2 (100 mg) was heated to reflux for 16 hours. The reaction mixture was then cooled, diluted with ethyl acetate, and reduced in vacuo. The residue was purified using flash chromatography to yield 2-methyl-5-(4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl)-phenylamine (930 mg).
Reaction SMILES: C1(C)C=CC(S(N[N:11]2[CH2:18][C:17](=[CH2:19])[CH2:16][CH:15](NS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][C:13](=[CH2:31])N2)(=O)=O)=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[2H-].[Al+3].[Li+].[2H-].[2H-].[2H-]>O1CCCC1>[CH3:15][C:17]1([CH:16]2[CH2:15][CH2:14][CH2:13][CH2:31][CH2:14][CH2:13][CH2:31]2)[CH2:18][NH:11][CH2:19][CH:17]([CH3:16])[CH2:18][NH:11][CH2:19]1
Reactant: C=C1CC(NS(=O)(=O)c2ccc(C)cc2)CC(=C)NN(NS(=O)(=O)c2ccc(C)cc2)C1
Agent: [2H-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC1CNCC(C)(C2CCCCCCC2)CNC1
Reaction time: 42 h
Yield: 82.4 %

Procedure:
In separate experiments a suspension of 1,5-di(4-toluenesulfonamido)-3,7-bismethylenediazacyclooctane 1a (0.223 g, 0.50 mmol) in tetrahydrofuran (50 mL) containing either lithium aluminum hydride (0.25 g, 6.6 mmol) or lithium aluminum deuteride (0.25 g, 6.0 mmol) was stirred under a nitrogen atmosphere for 42 h. The reaction mixture was quenched by the dropwise addition D2O (1 mL) followed by 40% sodium hydroxide or 40% sodium deuteroxide solution (0.5 mL) with external cooling. Stirring was continued at room temperature for 5 h and the white granular precipitate that formed was removed by filtration and washed with anhydrous ether (3×50 mL). The combined organic extracts were concentrated on a rotary evaporator to give 0.052 g 0.057 g (82%) of 5 as a colorless solid, mp XX° C. The crude product was dissolved in benzene (25 mL) to which was added H2O (3×1 mL) and the mixture was subjected to azeotropic distillation using a Dean Stark tube. Analysis of the product by Cl NH3MS showed:
Reaction SMILES: N[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([CH3:14])=[CH:6][C:3]=1[C:4]#[N:5].N(OCCC(C)C)=O>C1COCC1.CC(OC)(C)C>[CH3:14][C:7]1[CH:6]=[C:3]([CH:2]=[CH:9][C:8]=1[C:10]([F:11])([F:12])[F:13])[C:4]#[N:5]
Reactant: Cc1cc(C#N)c(N)cc1C(F)(F)F
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1cc(C#N)ccc1C(F)(F)F
Temperature: 23 °C

Procedure:
To a solution of 2-amino-5-methyl-4-trifluoromethyl-benzonitrile from step 4 (23.34 g, 117 mmol) in dry THF (350 mL) was added isoamyl nitrite (34.3 mL, 257 mmol), and the mixture was refluxed for 20 h. Additional isoamyl nitrite (16.6 mL, 129 mmol) was added and the mixture was refluxed for further 20 h. The mixture was cooled to 23° C. and diluted with TBME, the organic layer was washed with 1 N HCl, sat. NaHCO3-sol. and brine, dried over Na2SO4.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH3:13])=[O:11])(OCC)=O)C.C[O-].[Na+].[CH3:17][C:18](=O)[CH2:19][CH3:20]>O>[CH3:13][O:12][C:10](=[O:11])[CH:9]=[C:18]([CH3:17])[CH2:19][CH3:20]
Reactant: CCC(C)=O
Reactant: CCOP(=O)(CC(=O)OC)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: CCC(C)=CC(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. mixture of methyl diethylphosphonoacetate (12.7 ml, 69.3 mmol) and sodium methoxide (13.0 ml, 69.3 mmol) was added dropwise 2-butanone (5.81 ml, 69.3 mmol) over 30 min. After the addition, the mixture warmed to rt and stirred overnight. To the reaction was added 20 mL of H2O. The mixture was extracted with EtOAc (3 times). The combined organics were dried with MgSO4, filtered, and concentrated. The crude oil was distilled at 110° C. at 35 mmHg to give the desired product.
Reaction SMILES: [O-]CCCC.[Li+].[CH2:7]([O:14][C:15](=[O:30])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH:27]3[CH:25]([CH2:26]3)[CH2:24]2)=[C:19]([F:29])[CH:18]=1)[C:8]1C=CC=CC=1.CO.[C:33]([NH:36][CH2:37][C@H](OC(=O)C)CCl)(=[O:35])[CH3:34].[Cl-].[NH4+]>CN(C=O)C.[Cl-].[Na+].O.O.C1COCC1>[CH:27]12[CH2:26][CH:25]1[CH2:24][N:23]([C:20]1[CH:21]=[CH:22][C:17]([N:16]3[CH2:8][C@H:7]([CH2:37][NH:36][C:33](=[O:35])[CH3:34])[O:14][C:15]3=[O:30])=[CH:18][C:19]=1[F:29])[CH2:28]2
Reactant: O=C(Nc1ccc(N2CC3CC3C2)c(F)c1)OCc1ccccc1
Reactant: CC(=O)NC[C@@H](CCl)OC(C)=O
Agent: CCCC[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CC4CC4C3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Lithium butoxide solution (2.5 mL of a 1.0 M THF solution, 2.5 mmol) was added to a cooled (0° C.) solution of [4-(3-aza-bicyclo[3.1.0]hex-3-yl)-3-fluoro-phenyl]-carbamic acid benzyl ester (0.267 g, 0.82 mmol) in DMF (0.6 mL) and MeOH (0.060 mL, 1.64 mmol). Solid (S)-acetic acid 2-acetylamino-1-chloromethyl-ethyl ester (0.316 g, 1.64 mmol) was then added and the solution allowed to warm to room temperature and stirred for 20 h. Saturated aqueous ammonium chloride (1.0 mL) was added, along with 9 mL of H2O and 8 mL of brine. The solution was extracted with three portions of dichloromethane and the combined organic phases dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (0-3% MeOH-DCM) to provide N-({(5S)-3-[4-(3-azabicyclo[3.1.0]hex-3-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl) acetamide.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:10](#[N:14])[CH2:11][C:12]#[N:13].O>C1COCC1>[C:12]([CH:11]([C:10]#[N:14])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)#[N:13]
Reactant: COc1ccc(I)cc1
Reactant: N#CCC#N
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C#N)C#N)cc1
Yield: 63.9 %

Procedure:
To a mixture of 4-iodoanisole (2.3 g, 10 mmol), malononitrile (750 mg, 11 mmol) and KOBu-t (2.5 g, 22 mmol) in THF (40 ml) was added PdCl2 (PPh3)2 (300 mg, 0.4 mmol) at room temperature. After the mixture was refluxed for 25 hours, the mixture was poured into H2O (10 ml), and extracted with ether. The combined extracts were dried (Na2SO4), and concentrated to give a yellow oil, which was purified by a column chromatography on silica gel to give Compound 35 as a colorless solid (1.1 g, 64%).