Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([S:16](Cl)(=[O:18])=[O:17])[CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13].C([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=O.C(N(CC)CC)C>O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([S:16]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)(=[O:18])=[O:17])[CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13]
Reactant: COc1cc(S(=O)(=O)Cl)cc(OC)c1OC
Reactant: O=CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cc(S(=O)(=O)N2CCNCC2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 80 %

Procedure:
75 ml of a methylene chloride solution containing 7.40 g of 3,4,5-trimethoxybenzenesulfonyl chloride were dropped into 150 ml of a methylene chloride solution containing 3.80 g of N-formylpiperazine and 7.73 ml of triethylamine in an ice bath. The mixture was then stirred for 30 minutes at 0° to 5° C., after which it was poured into water and extracted twice with methylene chloride. The combined methylene chloride extracts were washed with 10% w/v aqueous hydrochloric acid and with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and condensed by evaporation under reduced pressure. The residue (9.86 g) was dissolved in a mixture of 150 ml of tetrahydrofuran, 75 ml of methanol and 50 ml of a 10% w/v aqueous solution of sodium hydroxide, and then stirred for 14 hours at room temperature. At the end of this time, the reaction solution was poured into water and extracted 4 times with methylene chloride. The combined methylene chloride extracts were washed with water, dried over anhydrous sodium sulfate and condensed by evaporation under reduced pressure. The residue was crystallized from a mixture of hexane and ethyl acetate, to give 7.02 g of the title compound as crystals, melting at 131° to 133° C.
Reaction SMILES: CON(C)[C:4](=[O:13])[C:5]1[C:6](=[CH:8][C:9](Cl)=[CH:10][CH:11]=1)[NH2:7].Br[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1N)[O:19][CH3:20].[Li]CCCC.Cl>C1COCC1>[NH2:7][C:6]1[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=1[C:4]([C:16]1[CH:23]=[CH:22][CH:21]=[C:18]([O:19][CH3:20])[CH:17]=1)=[O:13]
Reactant: CON(C)C(=O)c1ccc(Cl)cc1N
Reactant: COc1ccc(N)c(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2ccccc2N)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 82.9 %

Procedure:
In a flame-dried round bottom flask 4-chloroanthranilic acid N-methoxy-N-methylamide (4.58 g, 21.3 mmol) and m-bromoanisidine (4.02 g, 21.5 g) were dissolved in THF (185 mL) and the resulting solution was cooled to -78° C. With vigorous stirring, 2 equiv of nBuLi in hexanes (26.9 mL, 1.6 M, 43.0 mmol) was added dropwise by a syringe pump at 0.6 mL/min. After 20 min, 40 mL of 1 N hydrochloric acid was carefully added, the mixture was extracted with ethyl acetate (300 mL), and the ethyl acetate was washed with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated in vacuo. Flash chromatography with hexanes/ethyl acetate (95:5, then 75:25) afforded 3.75 g (67% yield) of 2-amino-3'-methoxybenzophenone as a yellow oil. 1H NMR (50 MHz, CDCL3): δ 3.83 (s, 3), 6.17 (b, 2), 6.55 (dd, 1, J=2.0, 8.5), 6.72 (d, 1, J=2.0), 7.06 (dd, 1, J=2.6, 8.5), 7.13 (m, 2), 7.35 (t, 1, J=7.8), 7.39 (d, 1, J=8.5). 2-Amino-4-chloro-3'-methoxybenzophenone was converted to 2-amino-4-chloro-3'-hydroxybenzophenone (below) prior to full characterization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([S:15][CH2:16][CH3:17])([F:14])[F:13])[CH2:11][O:10]1.[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:11][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[C:12]([S:15][CH2:16][CH3:17])([F:14])[F:13]
Reactant: c1nc[nH]n1
Reactant: CCSC(F)(F)C1(c2ccc(F)cc2F)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-2-[(ethylthio)(difluoro)methyl]oxirane (4.3 g, 0.016 mol) in DMSO (50 ml), 1,2,4-triazole (2.98 g, 0.043 mol) and potassium carbonate (5.96 g, 0.043 mol) were added, followed by stirring at 60° C. for 2 hours. After the completion of the reaction, water was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue so obtained was crystallized from isopropyl ether--ethyl acetate, whereby 2-(2,4-difluorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol (1.5 g, yield: 25%) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=1.S(Cl)(Cl)=O.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CO>C1COCC1.[NH4+].[Cl-]>[NH4+:3].[OH-:16].[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C@@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([N:35]3[CH2:34][CH2:33][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:37][CH2:36]3)=[O:17])[CH2:13][CH2:14]2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)[C@H]2CC[C@@H](Nc3cc(Cl)ncc3[N+](=O)[O-])CC2)CC1
Product: [OH-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
cis-4-(2-Chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylic acid (1.000 g, 3.34 mmol) was suspended in thionyl chloride (12.18 mL, 167 mmol), and the mixture was stirred at RT for 30 minutes. The reaction mixture was concentrated in vacuo, dissolved in THF (33.4 mL), and then cooled to 0° C. under a nitrogen atmosphere. To the cooled reaction was added tert-butyl-piperazine-1-carboxylate (0.684 g, 3.67 mmol) as a solution in THF (1 mL). The reaction mixture was stirred at 0° C. for 15 minutes and allowed to warm to RT and stirred overnight. To the reaction mixture was added additional tert-butyl-piperazine-1-carboxylate (0.684 g, 3.67 mmol) in THF (1 mL) (×2, stirring for about 1 h after each addition). Upon completion, the reaction mixture was diluted with aqueous NH4Cl and extracted with DCM (×2). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residual material was purified via silica gel chromatography, eluting with isocratic 90:10:1 DCM:MeOH:NH4OH, to provide tert-butyl 4-(cis-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarbonyl)piperazine-1-carboxylate (1.51 g, 70% yield) as a yellow solid. MS m/z=468.0 [M+H], calc 467.95 for C21H30ClN5O5.
Reaction SMILES: CSC.[CH2:4]([O:6][C:7](=[O:28])[CH2:8][N:9]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH:15]([CH3:19])[CH2:14][C:13]2=[O:20])[CH3:5].[O:29]1CCCC1>C(OCC)(=O)C>[CH3:19][CH:15]1[C:16]2[C:12](=[CH:11][C:10]([NH:9][C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[C:13](=[O:20])[CH2:14]1.[CH2:4]([O:6][C:7](=[O:28])[CH2:8][N:9]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH:15]([CH3:19])[CH2:14][CH:13]2[OH:20])[CH3:5]
Reactant: C1CCOC1
Reactant: CCOC(=O)CN(Cc1ccccc1)c1ccc2c(c1)C(=O)CC2C
Solvent: CCOC(C)=O
Solvent: CSC
Product: CC1CC(=O)c2cc(NC(=O)c3ccccc3)ccc21
Product: CCOC(=O)CN(Cc1ccccc1)c1ccc2c(c1)C(O)CC2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
As presented in the following reaction formula, a mixture of boran (BH3) in methyl sulfide (Me2S; 1.4 mL, 0.014 mol) was added to a solution of [benzyl-(1-methyl-3-oxo-indan-5-yl)-amino]-acetic acid ethyl ester (4 g, 0.011 mol) and tetrahydrofuran (THF; 50 mL), and the reaction mixture was refluxed for 2 hours. The mixture of BH3 in Me2S (1.4 mL, 0.014 mol) was added several times in a divided manner until there was no reactant left. The reaction was terminated with methanol (10 mL) at 0° C. The resulting mixture was heated to room temperature and stirred for 0.5 hours. The mixture was concentrated to give a crude product. The crude product was purified by silica gel (30 g) column chromatography (product of Merck Co., Ltd.) using an eluent of pentane (PE):ethyl acetate (5:1 (by volume)) to give the desired product [benzyl-(3-hydroxy-1-methyl-indan-5-yl)-amino]-acetic acid ethyl ester (1.4 g, yield: 32%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:18]3C=C[N:20]=[CH:19]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:27](=NO)(N)[CH2:28][CH2:29]C.C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][N:20]=[C:19]([CH2:27][CH2:28][CH3:29])[N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Reactant: CCCC(N)=NO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCc1noc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)n1

Procedure:
41.20 g (112.1 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole and 12.6 g (123.4 mmol) of butyramidoxime are stirred at 60° for 2.5 hours in 200 ml of N,N-dimethylformamide. The cooled suspension is then filtered; the filter residue is rinsed with ether and dried. The product obtained is stirred at 1120° for 3 hours with 350 ml of glacial acetic acid. The reaction mixture is evaporated and the residue is dissolved in methylene chloride. The solution is washed with a saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. By recrystallization of the residue from methylene chloride and ethyl acetate there is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-1-(3-propyl-1,2,4-oxadiazol-5-yl)-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepin-9-one of melting point 176°-178°.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16]I.[Na+].[Cl-]>CN(C=O)C.O>[Cl:13][CH2:14][CH2:15][CH2:16][O:9][C:5]1[CH:4]=[C:3]([N:2]([CH3:10])[CH3:1])[CH:8]=[CH:7][CH:6]=1
Reactant: CN(C)c1cccc(O)c1
Reactant: ClCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1cccc(OCCCCl)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 103.6 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-(dimethylamino)phenol (3.50 g, 25.51 mmol) in DMF (30 mL) was slowly added over 10 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.80 g of an 80% dispersion in mineral oil, 26.79 mmol) in DMF (40 mL). The mixture was allowed to warm to ambient temperature and further stirred for 1.25 h. The resulting brown mixture was cooled to 0-5C. To this slurry was added drop-wise over 5 min, 1-chloro-3-iodopropane (6.26 g, 30.62 mmol). The resulting reddish brown mixture was stirred at ambient temperature for 4.25 h. Cold water (35 mL) was carefully added, followed by saturated NaCl solution (35 mL). The resulting mixture was extracted with ether (4×50 mL). The combined dull-yellow ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation producing a light-brown oil (5.65 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]2[CH:18]([C:19]3[O:20][C:21]([S:24][C:25]4[NH:29][C:28]5[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=5[N:26]=4)=[CH:22][CH:23]=3)[C:17]3[C:16](=[O:34])[CH2:15][C:14]([CH3:36])([CH3:35])[CH2:13][C:12]=3[NH:11][C:10]=12)=[O:5])C.[OH-].[Na+]>C(O)C.O>[NH:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[S:24][C:21]1[O:20][C:19]([CH:18]2[C:17]3[C:16](=[O:34])[CH2:15][C:14]([CH3:36])([CH3:35])[CH2:13][C:12]=3[NH:11][C:10]3=[C:6]([C:4]([OH:5])=[O:3])[NH:7][CH:8]=[C:9]23)=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(Sc2nc3ccccc3[nH]2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(=O)C2=C(C1)Nc1c(c[nH]c1C(=O)O)C2c1ccc(Sc2nc3ccccc3[nH]2)o1
Temperature: 40 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of 330 mg (0.657 mmol) of 9-[5-(1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-6,6-dimethyl-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester in 10 ml ethanol and 1 ml water was added 263 mg of sodium hydroxide in a round bottom flask. The reaction mixture was heated at 40° C. with stirring for 8 hours, and at 30° C. overnight. Water was added to the reaction mixture and it was extracted twice with ethyl acetate. The organic layers were washed with water and brine and dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting oily residue was dissolved in 1 ml methanol and 14 ml of dichloromethane and purified by chromatography on a prepacked 75 g 15-40 μm silica gel cartridge (eluting solvent: dichloromethane/methanol from 98/2 to 92/8 v/v in 50 min; rate: 40 mL/min). The fractions containing the desired product were combined and concentrated to dryness under reduced pressure giving 106 mg of 9-[5-(1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-6,6-dimethyl-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid (34% yield). Analytical LC/MS method B: [M+H]+=475.5; retention time: 3.01 min; 95% UV purity. 300 MHz 1H NMR (DMSO-d6) δ (ppm): 0.91 (s, 3H); 0.98 (s, 3H); 2.05 (d, J=17.0 Hz, 1H); 2.16 (d, J=17.0 Hz, 1H); 2.50 (d partially masked, J=17.0 Hz, 1H); 2.61 (d, J=17.0 Hz, 1H); 5.14 (s, 1H); 5.97 (d, J=3.5 Hz, 1H); 6.73 (d, J=3.0 Hz, 1H); 6.83 (d, J=3.5 Hz, 1H); de 7.10 à 7.20 (m, 2H); 7.40 (d large, J=8.0 Hz, 1H); 7.52 (d large, J=8.0 Hz, 1H); 8.32 (s large, 1H); 11.3 (s large, 1H); 12.25 (m wide, 1H); 12.3 (s large, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].Cl[CH2:14][CH:15]1[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][CH2:14][CH:15]1[CH2:17][CH2:16]1
Reactant: CS(=O)(=O)c1ccc(O)c(Br)c1
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CS(=O)(=O)c1ccc(OCC2CC2)c(Br)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 28.2 %

Procedure:
A mixture of 2-bromo-4-methanesulfonylphenol (7.2 g, 29 mmol), (chloromethyl)cyclopropane (4.3 g, 32 mmol) and K2CO3 (8 g, 58 mmol) in acetone (80 mL) was stirred at 80° C. for 5 h. The mixture was quenched with water (40 mL). Extractive work up with ethyl acetate and purification by preparative HPLC gave the title compound (2.5 g, 28.6%). 1H NMR (CDCl3, 400 MHz) δ 8.12 (d, J=2.3 Hz, 1H), 7.84 (dd, J1=2.3 Hz, J2=8.7 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H), 3.99 (d, J=6.7 Hz, 2H), 3.05 (s, 3H), 1.23-1.43 (m, 1H), 0.70 (d, J=7.9 Hz, 2H), 0.44 (d, J=5.4 Hz, 2H).
Reaction SMILES: C([O:5]C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:23][CH2:22][C:21]3[N:20]=[C:19]([CH2:24][CH2:25][CH3:26])[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17][C:16]=3[C:15]2=[O:32])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:33].C(OC(C)C)(C)C>>[OH2:5].[ClH:33].[ClH:33].[O:32]=[C:15]1[N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:23][CH2:22][C:21]2[N:20]=[C:19]([CH2:24][CH2:25][CH3:26])[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17][C:16]1=2
Reactant: CCCc1nc2c(cc1C(=O)OCC)C(=O)N(C1CCN(C(=O)OC(C)(C)C)CC1)CC2
Agent: Cl
Solvent: CC(C)OC(C)C
Product: CCCc1nc2c(cc1C(=O)OCC)C(=O)N(C1CCNCC1)CC2
Product: O
Reaction time: 4 h

Procedure:
Ethyl 6-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (14.9 g) was added to 2M hydrogen chloride (ethanol solution, 167 mL) at room temperature. The mixture was stirred for 4 hours. Diisopropyl ether (1.00 L) was added to the reaction mixture. The mixture was stirred for 30 minutes. The precipitate was collected by filtration, washed with diisopropyl ether, dried under reduced pressure to give the title compound (13.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:26])[N:20]([CH2:22][C:23](O)=[O:24])[N:21]=[C:8]2[N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[C:6]=1[CH3:37])=[O:4].[CH:38]([N:41]([CH:44]([CH3:46])C)[CH2:42]C)(C)C.CN(C(ON1N=NC2C=[CH:59][CH:60]=[N:61][C:56]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:26])[N:20]([CH2:22][C:23](=[O:24])[N:61]([CH2:60][CH2:59][CH2:46][CH2:44][N:41]([CH3:38])[CH3:42])[CH3:56])[N:21]=[C:8]2[N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=2)[C:6]=1[CH3:37])=[O:4]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CC(=O)O)c(=O)n2C1c1ccc(C#N)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CC(=O)N(C)CCCCN(C)C)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
Intermediate 17 (50 mg, 0.10 mmol) was dissolved in DMF (1 mL). and diisopropylethylamine (50 μL, 0.29 mmol) and HATU (41 mg, 0.11 mmol) were added. The reaction mixture was stirred at RT for 30 minutes, then N,N,N-trimethylbutanediamine (38 mg, 0.29 mmol) was added, and stirring was continued for a further 18 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-10% (2M NH3 in MeOH) in DCM to yield the title compound as a white solid (34 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][NH:10][C:9](=O)[CH2:8][CH2:7][C:6]=2[CH:13]=1.CSC.B>COCCOC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1
Reactant: O=C1CCc2cc(Br)ccc2CN1
Agent: B
Solvent: COCCOC
Solvent: CSC
Product: Brc1ccc2c(c1)CCCNC2
Yield: 13.9 %

Procedure:
To a solution of 7-bromo-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one (35 g, 146 mmol) in 1,2-dimethoxyethane (400 mL) was added a solution of borane dimethyl sulfide complex (1.0 M in tetrahydrofuran, 40 mL) under nitrogen and the resulting mixture was stirred under reflux overnight. The reaction was quenched with methanol, acidified with 2 M hydrochloric acid and then stirred for further 2 hours. The resulting mixture was concentrated in vacuo and the residue was purified by preparative HPLC to give 4.6 g of product. MS obsd. (ESI+) [(M+H)+] 226. 1H NMR (400 MHz, CDCl3) δ ppm 7.21 (d, J=5 Hz, 1 H), 7.15-7.13 (dd, J=2.0, 8.0 Hz, 1 H), 6.89 (d, J=8 Hz, 1 H), 3.79 (s, 2 H), 3.11-3.08 (m, 2 H), 2.82-2.79 (m, 2 H), 2.38 (brs, 1 H), 1.63-1.61 (m, 2 H).
Reaction SMILES: [C:1](Cl)([Cl:3])=[S:2].[C:5]1([N:11]2[C:15]([SH:16])=[N:14][N:13]=[N:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCN(CC)CC>C1COCC1>[Cl:3][C:1]([S:16][C:15]1[N:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:12]=[N:13][N:14]=1)=[S:2]
Reactant: S=C(Cl)Cl
Reactant: Sc1nnnn1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: S=C(Cl)Sc1nnnn1-c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
To a solution of thiophosgene (1.29 g, 0.0112 mol) in THF (40 ml) at 5° C. was added a solution of 1-phenyl-1H-tetrazole-5-thiol (2.0 g, 0.0112 mol) and Et3N (1.94 ml, 0.0134 mol) in THF (30 ml). The mixture was stirred at 5° C. for 30 min and then at r.t. for 1 hr. 20 min. The precipitate was filtered and washed with THF. The filtrate was evaporated in vacuo. To the obtained residue was added ether and the insoluble material was filtered off. The filtrate was evaporated in vacuo to give a solid which was recrystallized from CHCl3 --hexane. 0.91 g of the compound was obtained. 27.6% yield. IR (Nujol): 1725, 1585 cm-1.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.C(N(CC)CC)C.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([F:23])=[CH:18][N:17]=1>CCO>[Cl:15][C:16]1[N:21]=[C:20]([NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=2)[C:19]([F:23])=[CH:18][N:17]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Cl)ncc2F)n[nH]1
Reaction time: 12 h
Yield: 49.7 %

Procedure:
To a solution of 5-methyl-1H-pyrazol-3-amine (612 mg, 6.0 mmol) in absolute EtOH (10 ml) was added triethylamine (1.1 ml) and 2,4-dichloro-5-fluoropyrimidine (1.0 g, 6.0 mmol) and the resulting solution was aged at room temperature for 12 hours. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried. The solvents were removed under reduced pressure to give the title compound as a solid (679 mg). m/z: 228.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@:18]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]#[N:28])[CH2:23][CH2:22]4)([CH3:20])[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:29][NH:30][C:31](=N)[CH:32]([CH3:34])[CH3:33]>>[CH:32]([C:31]1[N:28]=[C:27]([N:24]2[CH2:23][CH2:22][CH:21]([C@@:18]3([CH3:20])[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:26][CH2:25]2)[O:29][N:30]=1)([CH3:34])[CH3:33]
Reactant: C[C@@]1(C2CCN(C#N)CC2)Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ncc2O1
Reactant: CC(C)C(=N)NO
Product: CC(C)c1noc(N2CCC([C@]3(C)Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from (S)-4-[5-(4-methanesulfonyl-phenyl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile (Intermediate 33; the configuration of the stereocenter is arbitrarily assigned) and N-hydroxy-isobutyramidine following a procedure analogous to that described in Example 2. LC (method 4): tR=1.13 min; Mass spectrum (ESI+): m/z=483 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH3:13])[NH:5][C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12].C([O-])([O-])=O.[K+].[K+].O.[C:22](Cl)(=[O:26])[CH:23]=[CH:24][CH3:25]>ClCCl>[CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH3:13])[N:5]([C:22](=[O:26])[CH:23]=[CH:24][CH3:25])[C:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12]
Reactant: COC(=O)[C@H](C)Nc1c(C)csc1C
Reactant: CC=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC=CC(=O)N(c1c(C)csc1C)[C@@H](C)C(=O)OC

Procedure:
To 6.39 g (0.03 mol) of N-(2,4-dimethylthien-3-yl-alanine-methylester, 4.15 g (0.03 mol) of K2CO3, 10 ml of water and 100 ml of dichloromethane are added without cooling 3.14 g (0.03 mol) 2-butenoyl chloride.
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:39])[C@@H:28]([N:30]([CH3:38])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH3:29])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[CH3:40][NH2:41]>O1CCCC1>[CH3:38][N:30]([C@@H:28]([CH3:29])[C:27]([NH:26][CH2:25][CH2:24][CH2:23][C:22]#[C:21][C:14]1[C:15]([NH:17][CH2:18][CH2:19][CH3:20])=[N:16][C:11]([NH:41][CH3:40])=[N:12][CH:13]=1)=[O:39])[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35]
Reactant: CN
Reactant: CCCNc1nc(On2nnc3ccccc32)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CCCNc1nc(NC)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To (S)-tert-butyl (1-((5-(2-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (K3, 50 mg), a 2.0 mol/L solution of methylamine in tetrahydrofuran (1 mL) was added at room temperature, the reaction vessel was sealed, and then the mixture was stirred at 50° C. for 5 hours by using a microwave reaction system. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 40 to 0% hexane in ethyl acetate) to obtain oily (S)-tert-butyl methyl(1-((5-(2-(methylamino)-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)carbamate (K4, 35 mg).