Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2].[CH3:11][S:12]([NH:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([N:22]2[CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1)(=[O:14])=[O:13].[OH-].[NH4+].[P:29](=[O:33])([OH:32])([OH:31])[OH:30]>C(#N)C.CO>[P:29](=[O:30])([OH:33])([OH:32])[OH:31].[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:24][CH2:23][NH:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([NH:15][S:12]([CH3:11])(=[O:13])=[O:14])=[CH:26][CH:25]=1)[CH3:2]
Reactant: CCCCCCCNCC
Reactant: CS(=O)(=O)Nc1ccc(C(=O)N2CC2)cc1
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: CCCCCCCN(CC)CCNC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
0.60 g (4.16 mmol) of N-ethylheptanamine and 0.50 g (2.08 mmol) of 1-[4-[(methylsulfonyl)amino]benzoyl]aziridine are dissolved in 10 mL of acetonitrile and the solution is warmed to 50° C. for 48 hours. The reaction is monitored by thin-layer chromatography (silica gel (EM); acetonitrile:conc. ammonium hydroxide (90:10)). After 48 hours, the reaction mixture is evaporated and the resultant solid is dissolved in 20 mL of methylene chloride. This solution is extracted with 2×10 mL of 1N aq. sodium hydroxide. The aqueous extract is acidified to pH=1 with 6N aq. hydrochloric acid and extracted with 2×15 mL of methylene chloride. The combined organic extracts are neutralized with saturated aqueous sodium bicarbonate and washed with 10 mL of water. The organic layer is dried over sodium sulfate, filtered and evaporated on a rotary evaporator to provide an oil. This oil is dissolved in 20 mL of 50% aqueous methanol and titrated to pH=4.5 with 0.1N aq. phosphoric acid. This solution is evaporated on the rotary evaporator and residual water is removed by azeotroping with 20 mL of alcohol. This residue is crystallized from 8 mL of reagent alcohol to provide the title compound.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C@@H:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:5]1[NH:13]C(=O)OC(C)(C)C>O1CCOCC1.CO>[CH3:2][O:3][C@@H:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:5]1[NH2:13].[ClH:1]
Reactant: CO[C@@H]1Cc2ccccc2[C@@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CO[C@@H]1Cc2ccccc2[C@@H]1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (0.048 g, 1.2 mmol, 60% dispersion in mineral oil) was added to a mixture of the above intermediate in N,N-dimethylformate (2.3 mL) under N2. The mixture was stirred at r.t. for 10 min., and methyl iodide (0.075 mL, 1.2 mmol) was added. The reaction mixture was stirred at r.t. overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-30%) to afford tert-butyl (1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-ylcarbamate [LCMS (M+Na)+: 286.1]. 2 mL of 4 N HCl in 1,4-dioxane was added to a solution of tert-butyl (1S,2R)-2-methoxy-2,3-dihydro-1H-inden-1-ylcarbamate in methanol (1 mL). The reaction mixture was stirred at r.t. overnight. The volatiles were removed under reduced pressure to afford the desired product as HCl salt.
Reaction SMILES: Cl.[CH3:2][NH2:3].[C:4]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1)(=[O:6])[CH3:5]>N1C=CC=CC=1.C(Cl)Cl>[CH3:2][NH:3][S:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:4](=[O:6])[CH3:5])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: CN
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(NC(C)=O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of methylamine hydrochloride (1.4 g) in pyridine (5 ml) was added 4-acetamidobenzenesulfonyl chloride (2.3 g), and the mixture was stirred at 50° C. for 2 hours. The residue obtained by an evaporation of pyridine under a reduced pressure was dissolved in methylene chloride (50 ml), washed with water, 1 N hydrochloric acid, and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Evaporation of the solvent under a reduced pressure gave N-methyl-4-(acetamido)benzenesulfonamide (1.6 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:12][NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][C@H:25]([CH3:27])[O:24][C@H:23]([CH3:28])[CH2:22]3)=[CH:17][CH:16]=2)=O)=[CH:6][CH:5]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:32].O.[OH-].[Na+]>C(COC)OC>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:32][C:14]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][C@H:25]([CH3:27])[O:24][C@H:23]([CH3:28])[CH2:22]4)=[CH:17][CH:16]=3)=[N:13][N:12]=2)=[CH:6][CH:5]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)c1ccc(C(=O)NNC(=O)c2ccc(N3C[C@@H](C)O[C@@H](C)C3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(-c2nnc(-c3ccc(N4C[C@@H](C)O[C@@H](C)C4)cc3)s2)cc1
Temperature: 25 °C
Yield: 128.9 %

Procedure:
To a solution of 4-[N′-[4-(cis-2,6-dimethylmorpholin-4-yl)benzoyl]hydrazinocarbonyl]benzoic acid methyl ester (100 mg) in dimethoxyethane (3 ml) was added phosphorus pentasulfide (82 mg). The mixture was refluxed for 5 hours. After cooling to ambient temperature, the reaction mixture was poured into cold water and the mixture was adjusted to pH 11 with 1N-sodium hydroxide aqueous solution. The resulting precipitates were filtered, washed with water and dried to give 4-[5-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl][1,3,4]thiadiazol-2-yl]benzoic acid methyl ester (97.4 mg).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B1OC(C)(C)C(C)(C)O1)[CH3:2].Cl[C:20]1[C:29]([CH3:30])=[N:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[N:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(OCC)(=O)C>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:20]1[C:29]([CH3:30])=[N:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:31]([F:32])([F:33])[F:34])[CH:26]=2)[N:21]=1)[CH3:2]
Reactant: Cc1nc2cc(C(F)(F)F)ccc2nc1Cl
Reactant: CCSc1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCSc1ccccc1-c1nc2ccc(C(F)(F)F)cc2nc1C
Temperature: 70 °C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
A mixture of 0.52 g of 2-ethylsulfanylphenylboronic acid pinacol ester, 0.40 g of 2-chloro-3-methyl-6-trifluoromethylquinoxaline, 0.02 g of tris(dibenzylideneacetone)dipalladium(0), 0.05 g of 2-dicyclohexylphosphino-2′,6′-dimethoxyphenyl, 0.84 g of tripotassium phosphate and 6 ml of 1,4-dioxane was stirred at 70° C. for 2 hours. 0.30 g of tripotassium phosphate was added to the cooled reaction mixture, and the mixture was stirred under heat-reflux for 3 hours. Ethyl acetate and water were added to the cooled reaction mixture, and the mixture was filtered. The filtrate was extracted with ethyl acetate and then dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.21 g of 2-(2-ethylsulfanylphenyl)-3-methyl-6-trifluoromethylquinoxaline (Compound of Present Invention 2).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[C:4](Cl)[N:3]=1.[NH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>C(O)CCC>[NH2:1][C:2]1[N:3]=[C:4]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]2)[C:5]([NH2:9])=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: Nc1nc(Cl)c(N)c(N[C@H]2CC[C@H](O)CC2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2,5-diamino-4,6-dichloropyrimidine (10.5 g, 58.6 mmol), trans-4-aminocyclohexanol (6.75 g, 58.6 mmol, 1 equiv.), sodium bicarbonate (17.2 g, 205 mmol, 3.5 equiv.) and 1-butanol (210 mL) were heated together at 150° C. in a sealed tube. After 3 days, when the reaction appeared to be complete (by LCMS), the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. Water (150 mL) was added to the residue with stirring at room temperature for 30 min, and the dark red solid filtered under vacuo to give, after drying, 10 g (66% yield) of the desired product. 1H NMR (300 MHz, d6-DMSO) δ, ppm: 6.14 (d, 1H), 5.57 (s, 2H), 4.54 (d, 1H), 3.90 (s, 2H), 3.81-3.76 (m, 1H), 3.40-3.32 (m, 1H), 1.86-1.82 (m, 4H), 1.28-1.20 (m, 4H); MS (EI) m/z 258.1 (MH)+.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[F:7][C:8]1[C:30]([CH:31]=C)=[CH:29][C:11]2[C:12]3[N:16]([CH2:17][CH2:18][O:19][C:10]=2[CH:9]=1)[CH:15]=[C:14]([C:20]1[N:21]([CH:26]([CH3:28])[CH3:27])[N:22]=[C:23]([CH3:25])[N:24]=1)[N:13]=3.CC(C)=[O:35].O>CC(O)(C)C.CCOC(C)=O.[Os](=O)(=O)(=O)=O>[F:7][C:8]1[C:30]([CH:31]=[O:35])=[CH:29][C:11]2[C:12]3[N:16]([CH2:17][CH2:18][O:19][C:10]=2[CH:9]=1)[CH:15]=[C:14]([C:20]1[N:21]([CH:26]([CH3:28])[CH3:27])[N:22]=[C:23]([CH3:25])[N:24]=1)[N:13]=3
Reactant: C=Cc1cc2c(cc1F)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2cc(C=O)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
Osmium tetraoxide (1.8 mL of a 2.5% solution in tBuOH) and sodium periodate (1.51 g, 7.08 mmol) were added to a solution of 8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-9-vinyl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (1.0 g, 2.83 mmol) in an acetone-water mixture (5:1, 60 mL). The reaction mixture was stirred vigorously for 24 h at RT. The mixture was diluted with EtOAc (100 mL), washed with water and brine, dried (Na2SO4) and concentrated in vacuo to give the title compound (968 mg, 2.72 mmol, 96%) as a pale yellow oil. The product was taken on without further purification. LCMS (Method J): RT=2.78 min, [M+H]+ =356
Reaction SMILES: [SiH3:1][SiH2:2][SiH2:3][SiH2:4][SiH2:5][SiH2:6][SiH2:7][SiH2:8][SiH2:9][SiH2:10][SiH3:11].[F:12][C:13]([F:19])([F:18])[S:14]([OH:17])(=[O:16])=[O:15]>ClCCl>[F:12][C:13]([F:19])([F:18])[S:14]([O:17][SiH2:11][SiH2:10][SiH2:9][SiH2:8][SiH2:7][SiH2:6][SiH2:5][SiH2:4][SiH2:3][SiH2:2][SiH3:1])(=[O:16])=[O:15]
Reactant: [SiH3][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH3]
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(O[SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH2][SiH3])C(F)(F)F

Procedure:
In an argon atmosphere, to a tetrahydrofuran solution (1 ml) of 52 mg (0.15 mmol) of octaethylcyclotetrasilane was added 0.58 ml (0.15 mmol) of a tetrahydrofuran solution (0.27M) of phenyldimethylsilyllithium, and stirred at 0° C. for 15 minutes. Then, tetrahydrofuran was distilled out under vacuum, and hexane (1 ml) was added to give a hexane solution (Solution 1). A dichloromethane solution (1 ml) of 49 mg (0.05 mmol) of undecasilane (8) obtained in Example 8 was treated with 7.5 mg (0.05 mmol) of trifluoromethanesulfonic acid at room temperature for 30 minutes to afford 1-(trifluoromethanesulfonyloxy)undecasilane. Then, dichloromethane was distilled out under vacuum, and hexane (1 ml) was added to give a hexane solution (Solution 2). The Solution 1 was added to the Solution 2 at -78° C. and stirred for 15 minutes. Methanol (0.1 ml) and triethylamine (0.1 ml) were added, then saturated aqueous sodium bicarbonate solution (2 ml) was added, stirred, the hexane layer was separated, and dried with magnesium sulfate. The resulting crude product was purified by a silica gel column chromatography (hexane) to give 36 mg (41% yield) of hexadecasilane (9) as a colorless crystal.
Reaction SMILES: CO.[Li+].[BH4-].[Br:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](OCC)=[O:11].[NH4+].[Cl-]>C(Cl)Cl>[Br:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][OH:11]
Reactant: CCOC(=O)C(C)(CCCBr)c1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: ClCCl
Product: CC(CO)(CCCBr)c1ccccc1
Temperature: 0 °C
Yield: 73.4 %

Procedure:
Methanol (5.24 g, 164 mmol) was added drop-wise to a stirred suspension of LiBH4 (3.45 g, 150 mmol) in anhydrous CH2Cl2 (150 mL) under N2 atmosphere. After the addition of ethyl 5-bromo-2-methyl-2-phenyl-pentanoate (23.70 g, 106 mmol), the reaction mixture was heated to reflux overnight. The reaction mixture was cooled to 5° C. and hydrolyzed with ice (ca. 30 g) and NH4Cl solution (150 mL) for 1 h. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×150 mL). The combined organic layers were washed with NH4Cl solution (3×100 mL), dried over MgSO4 and concentrated in vacuo to furnish 5-bromo-2-methyl-2-phenyl-pentan-1-ol (20 g, 96.8%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm) 7.34-7.14 (m, 5H), 3.60 (m, 1H), 3.48 (m, 1H), 3.29 (t, J=6.0 Hz, 2H), 1.96-1.44 (m, 5H), 1.32 (s, 3H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm) 144.25, 128.59, 126.71, 126.41, 72.44, 43.15, 37.06, 34.64, 27.58, 21.61. HRMS (LSIMS, nba): Calcd. for C2H16Br (MH+—H2O): 239.0435, found: 239.0444.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([C:10]2[S:11][C:12]3[C:17]([N:18]=2)=[CH:16][CH:15]=[C:14]([C:19]2([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:21][CH2:20]2)[N:13]=3)[CH:7]=[C:6]([CH3:28])[C:3]=1[CH:4]=O.[NH:29]1[CH2:32][CH2:31][CH2:30]1>>[N:29]1([CH2:4][C:3]2[C:6]([CH3:28])=[CH:7][C:8]([C:10]3[S:11][C:12]4[C:17]([N:18]=3)=[CH:16][CH:15]=[C:14]([C:19]3([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:20][CH2:21]3)[N:13]=4)=[CH:9][C:2]=2[CH3:1])[CH2:32][CH2:31][CH2:30]1
Reactant: C1CNC1
Reactant: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1C=O
Product: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1CN1CCC1

Procedure:
Reaction of 2,6-dimethyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (29.3 mg, 76 μmol) and azetidine (18 μL, 267 μmol) according to Reference R and the general procedure for reductive amination gave 2-(4-(azetidin-1-ylmethyl)-3,5-dimethylphenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine as a light yellow solid. MS (ESI) m/z: Calculated: 425.2; Observed: 426.1 (M++1). 3-(Azetidin-1-yl)-N-(2,6-dimethyl-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)propan-1-amine was also obtained from this reaction as a light yellow solid. MS (ESI) m/z: Calculated: 482.3; Observed: 483.2 (M++1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1.[CH2:24]1[O:32][C:31]2[CH:30]=[CH:29][C:28]([N:33]=[C:34]=[O:35])=[CH:27][C:26]=2[O:25]1>>[CH2:24]1[O:32][C:31]2[CH:30]=[CH:29][C:28]([NH:33][C:34]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]3[CH2:9][CH2:10][CH:11]([C:14]4[C:18]5[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=5[O:16][N:15]=4)[CH2:12][CH2:13]3)=[O:35])=[CH:27][C:26]=2[O:25]1
Reactant: OCCCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Product: O=C(Nc1ccc2c(c1)OCO2)OCCCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 51.7 %

Procedure:
Starting from 3-[1-(1-hydroxyhex-6-yl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazole (270 mg, 0.84 mmol) and 3,4-methylenedioxyphenylisocyanate (297 mg, 1.69 mmol) using the procedure described in example 12B was prepared 210 mg (51.8%) of the title compound as an amorphous solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]1([CH3:29])[CH2:27][CH:26]([OH:28])[CH2:25][CH2:24][NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:23]3[CH2:24][CH2:25][CH:26]([OH:28])[CH2:27][C:22]3([CH3:29])[CH3:21])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC1(C)CC(O)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC(O)CCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 2,2-dimethylpiperidin-4-ol (937681-12-4) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=396.6 [MH+].
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[CH:9]([N:19]3C(=O)C4=CC=CC=C4C3=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>O1CCCC1>[NH2:19][CH:9]1[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:18]
Reactant: O=C1Nc2ccccc2C(c2ccccc2)=NC1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
A mixture of (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-2H-1,4-benzodiazepine-2-one (8.2 g), hydrazine hydrate (1.08 g) and tetrahydrofuran (160 ml) was stirred for 1.0 hour at room temperature and heated under reflux for 1.5 hours. After the precipitates were filtered off, the filtrate was evaporated to small volume and the equivalent volume of diisopropyl ether was added 15 thereto The precipitates were collected by filtration to give (3RS)-1,3-dihydro-3-amino-5-phenyl-2H-1,4-benzodiazepine-2-one (3.64 g).
Reaction SMILES: C(OC([N:8]1[CH:17]([C:18](=[O:47])[NH:19][CH:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[C:21]([N:23]2[CH2:27][CH:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:25][CH:24]2[CH2:36][CH:37]=[CH2:38])=[O:22])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:36]([CH:24]1[CH2:25][CH:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:27][N:23]1[C:21](=[O:22])[CH:20]([NH:19][C:18]([CH:17]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8]1)=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=1)[CH:37]=[CH2:38]
Reactant: C=CCC1CC(OCc2ccccc2)CN1C(=O)C(Cc1ccc(F)cc1)NC(=O)C1Cc2ccccc2CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCC1CC(OCc2ccccc2)CN1C(=O)C(Cc1ccc(F)cc1)NC(=O)C1Cc2ccccc2CN1
Reaction time: 5 h

Procedure:
3-[2-(2-Allyl-4-benzyloxy-pyrrolidin-1-yl)-1-(4-fluorobenzyl)-2-oxo-ethylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, 55, (200 mg) is dissolved into CH2Cl2 (3 mL) and trifluoroacetic acid (1 mL) is added. The reaction mixture is stirred for 5 hours and concentrated. The residue is purified by reverse phase HPLC to afford 50 mg of the desired product. 1H NMR (CDCl3, 300 MHz) δ 6.80˜7.50 (m, 13H), 5.75 (m, 1H), 5.06 (m, 2H), 4.30˜4.70 (m, 6H), 4.06 (m, 2H), 3.75 (m, 1H), 2.90˜3.30 (m, 6H), 2.69 (m, 1H), 2.23 (m, 1H), 1.80˜2.00 (m, 2H); MS (ES-MS) m/z 542 (M+1).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]([Sn](CCCC)(CCCC)CCCC)=[CH:13][N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[C:29]1[S:30][C:31]2[C:37]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)=[C:36]([C@H:45]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:46]([O:48][CH3:49])=[O:47])[C:35]([CH3:55])=[CH:34][C:32]=2[N:33]=1.O1CCOCC1>C(OCC)(=O)C.[F-].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:51]([O:50][C@@H:45]([C:36]1[C:35]([CH3:55])=[CH:34][C:32]2[N:33]=[C:29]([C:12]3[S:11][C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]4)=[N:14][CH:13]=3)[S:30][C:31]=2[C:37]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:46]([O:48][CH3:49])=[O:47])([CH3:54])([CH3:52])[CH3:53]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(N2CCN(C(C)C)CC2)s1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cnc(N4CCN(C(C)C)CC4)s3)sc2c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A 5 mL microwave reaction tube was charged with 2-(4-isopropylpiperazin-1-yl)-5-(tributylstannyl)thiazole (39 mg, 0.078 mmol), (S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (40 mg, 1.1 eq.), Pd(PPh3)4 (15 mg, 15 mol %), CuI (5 mg, 30 mol %) and dioxane (1 mL). The reaction was heated to 110° C. in oil bath for 1 hour. Reaction mixture was diluted with ethyl acetate and saturated NaF aqueous solution was added and stirred for 30 minutes. Extracted with ethyl acetate and the organic layer was concentrated and purified via Combiflash (0-100% Ethyl acetate in hexane) to give desired compound. LCMS-ESI+: calc'd for C31H38ClN4O3S2: 613.2 (M+H+); Found: 613.2 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[N:4]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:21]([S:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[S:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].CCOCC>C(C(C)=O)C>[Cl:13][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[CH:12][C:3]([CH2:2][O:14][C:15]3[CH:16]=[C:17]([CH:21]([S:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[S:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:18]=[CH:19][CH:20]=3)=[N:4]2)=[CH:9][CH:8]=1
Reactant: COC(=O)CCSC(SCCC(=O)OC)c1cccc(O)c1
Reactant: Clc1ccc2ccc(CBr)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCC(C)=O
Product: COC(=O)CCSC(SCCC(=O)OC)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1

Procedure:
A mixture of 2-bromomethyl-7-chloroquinoline (2.5 g) (Step 2), phenol (Step 1) (3.4 g) and K2CO3 (3 g) was heated at reflux for 4 hours in methyl ethyl ketone (100 ml). The reaction mixture was cooled and ether (100 ml) was added. The suspension was filtered and evaporated. Flash chromatography of the residue using 30% ethyl acetate in hexane afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2=[N:15][N:16]([CH3:18])[CH2:17][N:13]2[C:12]2[S:19](=[O:22])[CH2:20][CH2:21][C:11]=2[CH2:10][N:9]=1.[H-].[Na+].[CH3:25]I>CN(C)C=O.CCOCC>[CH3:25][CH:20]1[S:19](=[O:22])[C:12]2[N:13]3[CH2:17][N:16]([CH3:18])[N:15]=[C:14]3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][CH2:10][C:11]=2[CH2:21]1
Reactant: CI
Reactant: CN1CN2C(=N1)C(c1ccccc1Cl)=NCC1=C2S(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1CC2=C(N3CN(C)N=C3C(c3ccccc3Cl)=NC2)S1=O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
1 g of 6-o-chlorophenyl-8-methyl-1,2-dihydro-4H-s-triazolo[3,4-c]-thieno[2,3-e][1,4]diazepin-1-one is dissolved in 25 ml of dimethylformamide, and 0.09 g of sodium hydride (50% in mineral oil) is added, and the resulting mixture is heated at 60° C on a water bath with stirring for 30 minutes. After cooling to room temperature, a solution of 0.6 g of methyl iodide in 5 ml of ether is added dropwise, and the whole mixture is stirred at room temperature for 7 hours. Then the reaction mixture is poured into ice water, the precipitated crystals are filtered off, and the filtrate is extracted with chloroform. The extract is washed with water, dried over anhydrous magnesium sulfate, and the chloroform is removed under reduced pressure. The residue is recrystallized from a mixture of ligroin and ethanol to give the title compound as white crystals, melting at 199°-200° C.