Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:13].C(=O)([O-])[O-].[K+].[K+].[C:20]([O:24][C:25](=[O:49])[CH2:26][C@@:27]1([C:33]([NH:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)=[O:34])[C@H:31]([CH3:32])[CH2:30][NH:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21].C(OCC)(=O)C>CN(C)C=O>[C:20]([O:24][C:25](=[O:49])[CH2:26][C@@:27]1([C:33]([NH:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)=[O:34])[C@H:31]([CH3:32])[CH2:30][N:29]([CH2:2][C:3]2[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:13])[CH2:28]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: C[C@@H]1CNC[C@]1(CC(=O)OC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: FC(F)(F)c1cccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(Cc2c(Cl)cccc2C(F)(F)F)C[C@]1(CC(=O)OC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 40 °C
Reaction time: 48 h
Yield: 63.8 %

Procedure:
2-(Bromomethyl)-1-chloro-3-(trifluoromethyl)benzene (443 mg, 1.62 mmol) and potassium carbonate (244 mg) were added to a solution of tert-butyl 4-[(3R*,4S*)-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate obtained in Example 3b (345 mg, 0.811 mmol) in N,N-dimethylformamide (dehydrated) (10 mL), which was stirred at 45° C. for six hours and at 40° C. for two days. Ethyl acetate was added to the reaction liquid, which was washed with a 1N aqueous sodium hydroxide solution and brine. This was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to give the title compound (320 mg, yield: 63.8%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][C:22](OC)=[CH:23][C:17]=3[S:16][CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27]1>>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:26]3[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: COc1ccc2c(c1)SCCN(c1cc(Cl)c3cc(C)ccc3n1)C2
Reactant: NC1CCNC1
Product: Cc1ccc2nc(N3CCSc4ccccc4C3)cc(N3CCC(N)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 4-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine in Example 1-1) and pyrrolidin-3-amine. MS obsd. (ESI+) [(M+H)+] 391, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (s, 1 H), 7.79 (d, J=8.4 Hz, 1 H), 7.67-7.57 (m, 3 H), 7.38-7.30 (m, 2 H), 5.96 (s, 1 H), 5.17 (s, 2 H), 4.45-4.35 (m, 2 H), 4.30-4.25 (m, 1 H), 4.20-4.11 (m, 2 H), 4.05-3.91 (m, 2 H), 3.23 (t, J=4.8 Hz, 2 H), 2.51-2.50 (m, 1 H), 2.53 (s, 3 H), 2.40-2.30 (m, 1 H).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[C:18]1([CH2:24][CH2:25][NH2:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])=[N:26][CH2:25][CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)#[N:2]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: NCCc1ccccc1
Solvent: CC#N
Product: Cc1nc[nH]c1CSCCNC(=NCCc1ccccc1)NC#N
Yield: 40.9 %

Procedure:
A solution of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (2.69 g) and 2-phenylethylamine (7.2 g) in acetonitrile (50 ml) was heated under reflux for 24 hours. Following concentration and ether extraction to remove excess 2-phenylethylamine the crude product was chromatographed on a column of silica gel and eluted with ethyl acetate-isopropyl alcohol (4:1). Recrystallisation from ethanol-ether afforded the title compound (1.4 g) m.p. 135°-136°. (Found: C, 59.8; H, 6.8; N, 24.8; S, 9.4%. C17H22N6S requires: C, 59.6; H, 6.5; N, 24.5; S, 9.4%).
Reaction SMILES: Cl.[CH3:2][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[Br:23][C:24]1[CH:25]=[N:26][C:27](Cl)=[N:28][CH:29]=1>CCO>[Br:23][C:24]1[CH:25]=[N:26][C:27]([N:6]2[CH2:7][CH2:8][C:3]([CH3:2])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:5]2)=[N:28][CH:29]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCOC(=O)C1(C)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)C1(C)CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
To a solution of ii (0.9 g, 4.35 mmol) in EtOH (10 mL) was added DIPEA (2.30 mL, 13 mmol) at RT and the mixture stirred at RT for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.7 g, 3.6 mmol). The mixture was heated at 70° C. for 1 h. The solvent was evaporated and the crude residue purified by chromatography on silica eluting with 1.5% EtOAc:hexane to obtain iii (0.90 g, 75%). 1H NMR (DMSO-d6, 400 MHz): δ 1.17 (s, 3H), 1.21 (t, J=7.20 Hz, 3H) 1.40 (m, 2H), 2.00 (m, 2H), 3.24 (m, 2H), 4.11 (m, 2H), 4.15 (q, J=7.20 Hz, 2H), 8.43 (s, 2H). MS: 328.08 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH:35]([CH3:37])[CH3:36])[C:9](=[O:34])[CH2:10][N:11]1[C:20](=[O:21])[CH2:19][C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[NH:44][CH:43]=[C:42]2[CH:48]=O>>[CH2:1]([N:8]([CH:35]([CH3:37])[CH3:36])[C:9](=[O:34])[CH2:10][N:11]1[C:20](=[O:21])[C:19](=[CH:48][C:42]2[C:41]3[C:45](=[CH:46][CH:47]=[C:39]([F:38])[CH:40]=3)[NH:44][CH:43]=2)[C:18]2[N:14]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][N:17]=2)[C:13]2[CH:28]=[C:29]([F:33])[C:30]([F:32])=[CH:31][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)Cc2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Reactant: O=Cc1c[nH]c2ccc(F)cc12
Product: CC(C)N(Cc1ccccc1)C(=O)CN1C(=O)C(=Cc2c[nH]c3ccc(F)cc23)c2nnc(-c3ccccc3)n2-c2cc(F)c(F)cc21
Yield: 71.5 %

Procedure:
Following the procedure described for Example 1(A), Step A, N-benzyl-2-(8,9-difluoro-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-acetamide (Preparation 9) (100 mg, 0.198 mmol) was condensed with 5-fluoro-1H-indole-3-carbaldehyde (38.8 mg, 0.238 mmol). Purification by medium pressure chromatography eluting with 50% EtOAc in CH2Cl2 provided 91.5 mg of N-benzyl-2-[8,9-difluoro-4-(5-fluoro-1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide. 1H NMR (CDCl3) δ 7.92 (d, 1H), 7.10-7.67 (m, 13H), 6.84 (m, 1H), 6.64 (m, 1H), 4.37-4.97 (m, 5H), 4.20 (m, 1H), 1.20 (m, 6H); MS 647.4 (M+1), 645.3 (M−1).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[CH3:9][O:10][CH2:11]Cl.C(OCC)(=O)C>CN(C=O)C>[CH3:9][O:10][CH2:11][O:7][C:6]1[CH:1]=[C:2]([CH3:8])[CH:3]=[CH:4][CH:5]=1
Reactant: COCCl
Reactant: Cc1cccc(O)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOc1cccc(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Part A. Sodium hydride dispersion in mineral oil (5.05 g, 50% w/w, 105 mmol) was washed with hexane and dried under vacuum. DMF (100 mL) was added, the slurry was cooled to 0° C., and treated with a solution of m-cresol (10 mL, 95.6 mmol) in DMF (20 mL). The resulting mixture was allowed to stir for 1 h, then was treated with chloromethyl methyl ether (8.00 mL, 105 mmol) by syringe. The mixture was stirred overnight, then poured into ethyl acetate (200 mL). This was washed with water (3×200 mL) and brine (100 mL), and the aqueous phases were back-extracted in sequence with ethyl acetate. The extracts were combined, dried over magnesium sulfate, filtered and evaporated. The oily product was purified by elution through a plug of silica gel with 10:90 ethyl acetate-hexane. Evaporation then afforded the pure product, 3-(methoxymethoxy)toluene, as an oil (13.93 g, 91.5 mmol, 96%). TLC RF 0.46 (10:90 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): d 7.17 (1H, t, J=7.7 Hz), 6.86-6.81 (3H, m), 5.17 (2H, s), 3.48 (3H, s), 2.33 (3H, s). MS(H2O-GC/MS): m/e 153 (60), 121 (100).
Reaction SMILES: BrCC[C@H]1CC[C@H](CCCCC)CC1.[Mg].P(OCC)(OCC)(OCC)=O.Cl[SiH]1CCC([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[C:44]([F:46])[C:43]([O:47][C:48]([F:51])([F:50])[F:49])=[C:42]([F:52])[CH:41]=3)=[CH:36][CH:35]=2)CC1>[Cu]I.C1COCC1>[F:46][C:44]1[CH:45]=[C:40]([C:37]2[CH:36]=[CH:35][CH:34]=[CH:39][CH:38]=2)[CH:41]=[C:42]([F:52])[C:43]=1[O:47][C:48]([F:49])([F:50])[F:51]
Reactant: Fc1cc(-c2ccc(C3CC[SiH](Cl)CC3)cc2)cc(F)c1OC(F)(F)F
Agent: [Cu]I
Agent: CCCCC[C@H]1CC[C@H](CCBr)CC1
Agent: [Mg]
Solvent: CCOP(=O)(OCC)OCC
Solvent: C1CCOC1
Product: Fc1cc(-c2ccccc2)cc(F)c1OC(F)(F)F
Yield: 90.1 %

Procedure:
26.1 g (0.1 mol) of trans-1-(2-bromoethyl)-4-n-pentylcyclohexane was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 40.7 g (0.1 mol) of 4-(4-chloro-4-silacyclohexyl)3',5'-difluoro-4'-trifluoromethoxybiphenyl. After a conventional after treatment, 4-(2-(trans-4-n-pentylcyclohexyl)ethyl)-4-silacyclohexyl)-3',5'-difluoro-4'-trifluoromethoxybiphenyl was obtained. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 44.3 g (yield 90.1%) of the trans isomer.
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:9](=[O:25])[C:10]3[N:11]=[CH:12][N:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])[C:14]=3[N:15]=2)=[CH:3][CH:2]=1.[NH2:39][C:40]1[CH:44]=[CH:43][O:42][N:41]=1>O=S(Cl)Cl>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:9](=[O:25])[C:10]3[N:11]=[CH:12][N:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([NH:39][C:40]4[CH:44]=[CH:43][O:42][N:41]=4)=[O:20])[C:14]=3[N:15]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccccc5)cc4)nc32)c1
Reactant: Nc1ccon1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccon1)c1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccccc5)cc4)nc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-[2-biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzoic acid (50 mg, 0.096 mmol) in SOCl2 (1 mL) was heated at 70° C. for 1 h. The reaction mixture was concentrated, dissolved in CH2Cl2 (2 mL), and treated with 3-aminoisoxazole (2.97 mg, 0.035 mmol). The reaction mixture was stirred at room temperature for 1 h, concentrated, and purified by flash column chromatography (silica gel, 0 30% Hex/EtOAc) to give the title compound 3-[2-biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-N-isoxazol-3-yl-benzamide as a white solid. 1H NMR (CDCl3□ (ppm) 9.94 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 8.29 (s, 1H), 8.08 (d, 1H), 8.02 (d, 1H), 7.72 (t, 1H), 7.49 (d, 2H), 7.45 (d, 2H), 7.39 (t, 2H), 7.35 7.29 (m, 5H), 7.25 (br s, 1H), 7.14 (d, 2H); HPLC-MS calculated for C30H20ClN5O2 (M+H+): 585.1. Found: 585.1.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].N1C=CC=CC=1.[S:23]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24]1>ClCCl>[O:16]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:12]([F:15])([F:13])[F:14])=[N:11][N:2]1[NH:1][C:29](=[O:30])[CH2:28][C:25]1[CH:26]=[CH:27][S:23][CH:24]=1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: O=C(Cl)Cc1ccsc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cc1ccsc1)Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reaction time: 3 h
Yield: 73.6 %

Procedure:
A mixture of the product of Example 11B (30.2 mg, 0.13 mmol), pyridine (0.14 mL, 0.17 mmol), and 2-(thiophen-3-yl)acetyl chloride (24.0 mg, 0.15 mmol) in dichloromethane (0.4 mL) was stirred for 3 hours, concentrated, and chromatographed (20% acetone/hexanes) to give the title compound (33.8 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.82-11.94 (m, 1H), 8.44 (dd, J=7.9, 1.5 Hz, 1H), 8.11-8.17 (m, 1H), 8.00-8.09 (m, 2H), 7.36-7.58 (m, 2H), 7.14 (dd, J=4.9, 1.3 Hz, 1H), 3.74 (s, 2H); MS (ESI−) M/Z 352 (M−H)−.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[CH2:11][C:10](=[O:14])[N:9]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:8]2=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[N:31]([CH2:34][C:35]([O:37]CC)=[O:36])=[C:32]=[O:33]>ClCCl>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:32]([NH:31][CH2:34][C:35]([OH:37])=[O:36])=[O:33])=[C:10]([OH:14])[N:9]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:8]2=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CC(=O)N(C2CCOCC2)C(=O)N1C1CCCCC1
Reactant: CCOC(=O)CN=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCOCC2)c(=O)n(C2CCCCC2)c1=O
Reaction time: 8 h
Yield: 47.1 %

Procedure:
N-{[3-Cyclohexyl-6-hydroxy-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine. 1-Cyclohexyl-3-(tetrahydro-2H-pyran-4-yl)-2,4,6(1H,3H,5H)-pyrimidinetrione (900 mg, 3.06 mmoles) and diisopropylethylamine (1.06 mL, 6.12 mmoles) were stirred together in dry dichloromethane (50 mL) and treated with ethyl isocyanatoacetate (360 uL, 3.21 mmoles). The mixture was stirred for under argon overnight, washed twice with 1 molar hydrochloric acid, dried and evaporated. The residue was dissolved in ethanol (15 mL) and treated with 1 molar sodium hydroxide solution (2.0 mL) and 6 molar sodium hydroxide solution (2.0 mL) and stirred for 4 hours. The mixture was partitioned between ethyl acetate and 1 molar hydrochloric acid, the organic solution washed with 1 molar hydrochloric acid, dried and evaporated to a solid. The solid was triturated with diethyl ether, collected, washed with a small amount of diethyl ether and hexane to afford the title compound (570 mg, 47%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s, 1 H), 10.19 (t, J=5.56 Hz, 1 H), 4.83-4.94 (m, 1 H), 4.63 (t, J=11.49 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 3.93 (dd, J=11.12, 4.04 Hz, 2 H), 3.30-3.37 (m, 2 H), 2.56 (m, 2 H), 2.21-2.33 (m, 2 H), 1.79 (d, J=12.88 Hz, 2 H), 1.61 (s, 3 H), 1.52 (d, J=10.61 Hz, 2 H), 1.28 (q, J=12.97 Hz, 2 H), 1.11-1.18 (m, 1 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=O)[O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.COCCOC>C(#N)C>[CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[S:30])[O:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Solvent: CC#N
Solvent: COCCOC
Product: CC1(C)OC(=S)Nc2ccc(-c3ccc(C#N)[nH]3)cc21

Procedure:
5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile (14.5 kg), Lawesson's Reagent (12.1 kg, 1.16 eq.), DME (215 kg), and acetonitrile (8.96 kg) were combined and heated to reflux for at least 4 hours at less than 16 hours to form unpurified 5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile. The mixture was cooled to 18 to 28° C., quenched with water (276 kg), cooled to 10 to 20° C., stirred for at least 30 minutes, and the resulting slurry collected via filtration.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.OC1C=CC(C(OC)=O)=CC=1.[S:31]1C=CC=[C:32]1CCO>>[S:31]1[CH:32]=[CH:2][CH:3]=[C:1]1[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:18][CH:19]=1
Reactant: OCCc1cccs1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Agent: COC(=O)c1ccc(O)cc1
Product: O=C(O)CNC(=O)c1ccc(OCCc2cccs2)cc1
Yield: 65 %

Procedure:
The same reactions as in Example 9 (9a) and (9b) were conducted using methyl 4-hydroxybenzoate (1.55 g, 10.2 mmol) and 2-(2-thienyl)ethanol (1.20 mL, 10.8 mmol) to give 2.02 g of the title compound (white powder, yield: 65%).
Reaction SMILES: [F:1][C:2]1[C:10]([CH2:11][NH:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])=[CH:9][CH:8]=[C:7]([Cl:19])[C:3]=1[C:4]([OH:6])=O.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:37][CH2:38][CH:39]([F:41])[F:40])=[C:25]([CH:36]=1)[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[F:41][CH:39]([F:40])[CH2:38][O:37][C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:4](=[O:6])[C:3]2[C:7]([Cl:19])=[CH:8][CH:9]=[C:10]([CH2:11][NH:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[C:2]=2[F:1])=[CH:36][C:25]=1[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:27]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1ccc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2ccc(OCC(F)F)c(C(=O)Nc3ccc(Br)cc3)c2)c1F

Procedure:
Prepared analogously to 43b from 2-fluoro-3-(tert-butylcarbonylamino-methyl)-6-chloro benzoic acid (41 mg; 0.13 mmol), 5-amino-N-(4-bromo-phenyl)-2-(2,2-difluoro-ethoxy)benzamide (50 mg; 0.13 mmol), HATU (54 mg; 0.14 mmol), TEA (0.066 mL; 0.47 mmol) in THF (2 mL).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:22]=[CH:21][C:10]([C:11]([NH:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:23][S:24]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25].C(O)(=O)C.[CH3:37][CH:38]([CH3:41])[CH:39]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:12])=[CH:21][CH:22]=2)=[N:4][C:3]=1[CH2:23][S:24]([CH:27]1[CH2:28][CH2:29][N:30]([CH2:37][CH:38]([CH3:41])[CH3:39])[CH2:31][CH2:32]1)(=[O:25])=[O:26]
Reactant: CC(C)C=O
Reactant: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(CC(C)C)CC1
Temperature: 30 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
A solution of 4-[5-methyl-4-[(piperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-N-(pyridin-3-ylmethyl)benzamide (300 mg, 0.66 mmol, 1.00 equiv), acetic acid (59.3 mg, 0.99 mmol, 1.50 equiv) and 2-methylpropanal (57 mg, 0.79 mmol, 1.20 equiv) in 1,2-dichloroethane (3 mL) was stirred at room temperature for 4 h. Sodium triacetoxyborohydride (420 mg, 1.98 mmol, 3.00 equiv) was added in small batches and the resulting solution was stirred overnight at 30° C. The resulting mixture was concentrated under vacuum and the residue was diluted with 2 mL of methanol. The solution was loaded onto a C18 column and eluted with acetonitrile/water to give 200 mg (59%) of 4-(5-methyl-4-[[1-(2-methylpropyl) piperidine-4-sulfonyl]methyl]-1,3-oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide as a white solid. LC-MS (ES, m/z): 511 [M+H]+, 306, 256; 1HNMR (300 MHz, CD3OD, ppm) δ 8.60 (s, 1H), 8.47 (d, 1H), 8.11 (d, 2H), 7.99 (d, 2H), 7.89 (d, 1H), 7.47-7.43 (m, 1H), 4.65 (s, 2H), 4.41 (s, 2H), 3.33-3.08 (m, 3H), 2.50.
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6][C:5]=12.[Br:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:18][C:19]1[N:24]=[CH:23][C:22]([N:2]2[CH:3]=[C:4]3[C:5]([CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]3)=[N:1]2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCc2c[nH]nc2CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(Br)nc3)nc2CC1
Reaction time: 192 h

Procedure:
A mixture of 1,1-dimethylethyl 4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 9) (207 mg, 0.87 mmol), (6-bromo-3-pyridinyl)boronic acid (204 mg, 1.74 mmol), copper acetate (472 mg, 2.61 mmol), pyridine (140 μl, 1.74 mmol) and molecular sieves (4 Å, 750 mg) in dichloromethane (10 ml) was stirred open to the atmosphere for 8 days. Crude mixture was then filtered through a pad of celite and washed with dichloromethane and ammonia. After evaporation in vacuo, the residue was purified by SCX cartridge eluting with methanol first then 2M ammonia in methanol. The methanol fractions containing the product were combined and evaporated in vacuo. The residue was then purified by column chromatography on silica gel eluting with a mixture of hexane in ethyl acetate (10:1 to 1:1) to afford the title compound (D17). MS (ES+) m/e 393 and 395 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].CS([C:12]1[N:13]=[C:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]=2[N:17]=1)(=O)=O.O>CN(C=O)C>[O:22]=[C:19]1[N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]2[N:17]=[C:12]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[N:13]=[C:14]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:15]=2[CH:21]=[CH:20]1
Reactant: CS(=O)(=O)c1nc(-c2ccccc2)c2ccc(=O)n(-c3ccccc3)c2n1
Reactant: CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1nc(-c2ccccc2)c2ccc(=O)n(-c3ccccc3)c2n1
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To a solution of methylsulfonamide (200 mg, 2 mmol, 4 eq) in DMF (2 mL) was added NaH (80 mg, 2 mmol, 60% dispersion in mineral oil, 4 eq) and the reaction mixture was stirred for 30 min at 23°. To this solution was added a solution of 2-methanesulfonyl-4,8-diphenyl-8H-pyrido[2,3-d]pyrimidin-7-one (190 mg, 0.5 mmol) in DMF (1 mL) and the mixture was heated to 50°. After 1 h, H2O (10 mL) was added and then Et2O (10 mL), the layers were separated, and the organic layer was washed with satd aq NaCl, dried (MgSO4), filtered and the solvent was evaporated. The yellow residue was then purified by Flash chromatography to afford N-(7-oxo-4,8-diphenyl-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl)-methanesulfonamide (101 mg, 51% yield). 1H-NMR (CDCl3) δ 2.82 (s, 3H), 6.69 (d, 1H, J=9.8 Hz), 7.31 (m, 2H), 7.59 (m, 8H), 7.91 (d, 1H, J=9.8 Hz), LC MS (m/e)=393 (MH+).
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:10]([OH:18])(=[O:17])[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].C(OCC)(=O)C>CO>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:10]([O-:18])(=[O:17])[CH2:11][CH2:12][CH2:13][C:14]([O-:16])=[O:15]
Reactant: O=C(O)CCCC(=O)O
Agent: CN(C)C(=N)NC(=N)N
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C([O-])CCCC(=O)[O-]
Yield: 65.9 %

Procedure:
10.0 g of the metformin free-base and 3.98 g of glutaric acid were stirred in 100 ml of methyl alcohol at a temperature of 40° C., and then ethyl acetate was added thereto. The produced crystal was filtered and dried in hot air, thus obtaining 5.15 g (yield: 43.8%) of metformin glutarate.