Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=[O:9])[CH2:4][CH2:5][C:6]([OH:8])=O.C[CH2:12][N:13](C(C)C)[CH:14](C)C.ClC(OCC(C)C)=O.CNC1[C:31]([CH3:41])=[N:32][N:33]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:34]=1>C(Cl)Cl>[CH3:12][N:13]([CH3:14])[C:6](=[O:8])[CH2:5][CH2:4][C:3]([N:2]([CH3:10])[C:1]1[C:31]([CH3:41])=[N:32][N:33]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:34]=1)=[O:9]
Reactant: CCN(C(C)C)C(C)C
Reactant: CNc1cn(-c2cccnc2)nc1C
Reactant: CN(C)C(=O)CCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Product: Cc1nn(-c2cccnc2)cc1N(C)C(=O)CCC(=O)N(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice cold solution of 4-(dimethylamino)-4-oxobutanoic acid (0.174 g, 1.20 mmol) in CH2Cl2 (2 mL) was added DIPEA (0.208 mL, 1.120 mmol) followed by isobutyl chloroformate (0.138 mL, 1.06 mmol). The mixture was stirred for 10 minutes, and the resulting mixed anhydride was added to a solution of N,3-dimethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.100 g, 0.531 mmol) in CH2Cl2 (0.66 mL). The reaction mixture was stirred at room temperature (about 22° C.) for one hour. The crude reaction mixture was concentrated and purified via reverse phase column chromatography (0%-100% acetonitrile (MeCN)/water) to give the desired product F62 as a white solid (0.155 g, 83%).
Reaction SMILES: F[C:2]1[C:3]([C:12]#[C:13][Si](C)(C)C)=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].C([O-])([O-])=O.[K+].[K+].[C:24]1([C@H:30]([NH2:32])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN1C(=O)CCC1>[C:24]1([C@H:30]([N:32]2[C:2]3[C:3](=[C:4]([C:10]#[N:11])[C:5]([C:6]#[N:7])=[CH:8][CH:9]=3)[CH:12]=[CH:13]2)[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C[C@H](c1ccccc1)n1ccc2c(C#N)c(C#N)ccc21
Temperature: 60 °C
Reaction time: 15 h
Yield: 51.2 %

Procedure:
An oven-dried vial was charged with 4-fluoro-3-((trimethylsilyl)ethynyl)phthalonitrile (Example 40C) (0.100 g, 0.413 mmol) and K2CO3 (0.057 g, 0.413 mmol) and sealed with a rubber septum. Anhyd NMP (2 mL) and (R)-1-phenylethanamine (0.053 mL, 0.413 mmol) were added via syringe and the mixture was stirred in a heating block at 60° C. under N2. After 15 h, the mixture was cooled, quenched by addition of satd NH4Cl, poured into water and extracted with EtOAc (×3). Combined organics were washed (water ×2, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording (R)-1-(1-phenylethyl)-1H-indole-4,5-dicarbonitrile (0.0574 g, 51% yield) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J=3.3 Hz, 1H), 7.48 (dd, J=8.6, 0.7 Hz, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.37-7.27 (m, 3H), 7.12-7.06 (m, 2H), 6.88 (dd, J=3.3, 0.7 Hz, 1H), 5.72 (q, J=7.1 Hz, 1H), 1.98 (d, J=7.0 Hz, 3H); MS (LCMS ES+) m/z 272 ([M+H]+, 5%), 289 (100%), 313 ({[M+H]+MeCN}, 23%), 335 ({[M+Na]+MeCN}, 22%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:8]([N:11]([CH2:19][C:20](O)=[O:21])[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>>[CH2:23]([N:25]([CH2:26][CH3:27])[C:20](=[O:21])[CH2:19][N:11]([S:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)(=[O:9])=[O:10])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH3:24]
Reactant: CCNCC
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)cc1
Product: CCN(CC)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(3-methyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with diethylamine
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9](Cl)=[C:8]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:25]([Li])[CH2:26][CH2:27][CH3:28]>O1CCCC1.CCCCCC>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:25][CH2:26][CH2:27][CH3:28])=[C:8]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCc1c(SCc2ccc(C(C)(C)C)cc2)cnn(C(C)(C)C)c1=O
Temperature: 0 °C

Procedure:
To a solution of 0.73 g (0.002 mol) of the 2-t-butyl-5-(p-t-butylbenzylthio)-4-chloro-3(2H)-pyridazinone thus obtained dissolved in 20 ml of tetrahydrofuran was added 3.0 ml of a solution of 10% butyl lithium dissolved in hexane at -70° C. under stirring. The reaction temperature was gradually raised from -70° C. to room temperature, and then the reaction mixture was stirred at room temperature for one hour. The reaction mixture was poured into 50 ml of ice water and extracted with 50 ml of chloroform. The resulting chloroform layer was washed with 100 ml of water, dried over anhydrous sodium sulfate and freed of solvent by distillation to give 0.65 g of a crude product. The crude product was purified by preparative thin layer chromatography on silica gel (developer:benzene) to obtain 0.38 g of 2-t-butyl-4-butyl-5-(p-t-butylbenzylthio)-3(2H)-pyridazinone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].C(N(C(C)C)CC)(C)C.[C:20]([Si:24]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)Cl)([CH3:23])([CH3:22])[CH3:21].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH2:7][O:8][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:9]=1
Reactant: OCc1cc(Br)ccc1Cl
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](OCc1cc(Br)ccc1Cl)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-Bromo-2-chlorobenzylalcohol (5.15 g) in N,N-dimethylformamide (50 ml) was added diisopropylethylamine (19.8 ml) and tert-butyldiphenylchlorosilane (11.9 ml), and the mixture was stirred at room temperature for 2 days. Under ice-cooling, to the mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with successively with 0.4 M aqueous hydrochloric acid solution (twice), water, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by an aminosilane-treated silica gel column chromatography (hexane) to give 5-bromo-2-chloro-1-(tert-butyldiphenylsiloxymethyl)benzene 77 (10.79 g) as colorless oil. APCI-Mass m/Z 476/478 (M+NH4).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5].[C:12]([NH:14][C:15]([NH2:17])=[NH:16])#[N:13].CCOCC>C1C(O)=CC=CC=1C>[ClH:2].[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH:5][C:12]([NH:14][C:15]([NH2:17])=[NH:16])=[NH:13]
Reactant: N#CNC(=N)N
Reactant: CCc1cccc(Cl)c1N
Agent: Cl
Solvent: Cc1cccc(O)c1
Solvent: CCOCC
Product: CCc1cccc(Cl)c1NC(=N)NC(=N)N

Procedure:
A mixture of 3 g. (0.0156 mole) of 2-chloro-6-ethylaniline hydrochloride and 1.35 g. (0.016 mole) of cyanoguanidine in 25 ml of m-cresol is heated on a steam bath for 1 hour. The reaction mixture is then cooled and 250 ml of ether is added. The preciptate is filtered off and dissolved in 100 ml of warm water, charcoaled and filtered and cooled in an ice bath. 10% sodium hydroxide solution is then added to make the mixture strongly basic. The mixture is then filtered and washed with water. This is then dissolved in methanol, the pH is adjusted to 7 with methanolic hydrochloric acid and the mixture evaporated to dryness, triturated with ether and filtered to obtain 1-(2-chloro-6-ethylphenyl)biguanide hydrochloride (m.p. 209°-210°C).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:3]=1.O.[NH2:20][NH2:21]>>[NH:20]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:3]=1)[NH2:21]
Reactant: NN
Reactant: Cn1cnc2c(Nc3ccncc3)nc(Cl)nc21
Solvent: O
Product: Cn1cnc2c(Nc3ccncc3)nc(NN)nc21

Procedure:
Was prepared according to Example 8 from (2-chloro-9-methyl-9H-purin-6-yl)pyridin-4-yl-amine and hydrazine monohydrate.
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([N:42]=[C:43]=[S:44])=[O:41]>C1(C)C=CC=CC=1.C(O)C>[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([N:42]=[C:43]=[S:44])=[O:41].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:43]([NH:42][C:40](=[O:41])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[F:33])=[S:44])=[CH:28][CH:27]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccccc1F
Agent: O=C(N=C=S)c1ccccc1F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4F)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
2-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (75 mg, yield 93%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].Cl[P:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(N(CC)CC)C.C1C=CC=CC=1>[C:18]1([P:17]([O:15][C:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:10][C:5]=2[C:1]([CH3:4])([CH3:3])[CH3:2])[O:15][C:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=2[C:1]([CH3:4])([CH3:3])[CH3:2])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: ClP(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(OP(Oc2ccc(C(C)(C)C)cc2C(C)(C)C)c2ccccc2)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a solution of 42.4 grams of 2,4-di-tert-butylphenol in 101 grams of triethylamine was added dropwise over a 15-minute period 17.9 grams of dichlorophenylphosphine. The reaction mixwas then heated for 6 hours at 65°-70° C. After cooling to room temperature, the reaction mixture was diluted with 50 ml of benzene and poured onto a rapidly stirred mixture of 70 grams of concentrated hydrochloric acid and 200 grams of chopped ice. The product was then isolated as in Example 17 with the product crystallized from acetonitrile as white crystals melting at 90°-93° C.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-:13].[Na+].[O:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>CO.O>[OH:15][C:19]1[C:18]([O:13][CH2:4][CH2:3][O:2][C:8]2[CH:9]=[CH:10][C:5]([C:4](=[O:11])[C:3]([OH:2])=[O:12])=[CH:6][CH:7]=2)=[CH:17][C:16]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:10][CH:9]=2
Reactant: [OH-]
Reactant: C1CCOC1
Reactant: COC(=O)C(=O)c1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCCOc2cc3ccccc3cc2O)cc1

Procedure:
A mixture of 4-[[2-(3-hydroxy)-2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.065 g) in hot methanol (2 mL) plus tetrahydrofuran (5 mL) was treated with 1N sodium hydroxide (0.5 mL) and diluted with water. The organic solvent was removed under vacuum and the residue was mixed with water, acidified with excess 2N hydrochloric acid, and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, and evaporated to give crude product. Crystallization from dichloromethane-diethyl ether provided 0.055 g of 4-[[2-(3-hydroxy-2-naphthalenyloxy) ethyl]oxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 191°-192° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[C:2]=1[OH:8].[OH-].[K+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[CH2:11]([O:7][C:3]1[C:2]([OH:8])=[N:1][CH:6]=[CH:5][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1cccnc1O
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ncccc1OCc1ccccc1
Temperature: 25 °C
Yield: 43.6 %

Procedure:
Pyridine-2,3-diol (38 g, 342.04 mmol) was added to a solution of potassium hydroxide (21 g, 374.26 mmol) in methanol (400 mL) in portions while maintaining the reaction temperature below 30° C. Benzyl bromide (64.4 g, 376.53 mmol) was then added dropwise with stirring to the reaction mixture at room temperature. The resulting solution was stirred at 40° C. for 5 hr then concentrated in vacuo. The residue was diluted with water (500 mL) and the mixture was extracted with of dichloromethane (2×500 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Recrystallization from ethanol afforded the title compound (30 g, 43%) as a white solid: 1H NMR (400 MHz, DMSO) delta 11.60 (s, 1H), 7.45-7.28 (m, 5H), 6.96-6.89 (m, 2H), 6.10-6.06 (m, 1H), 5.01 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.Cl[C:40]([O:42][CH3:43])=[O:41]>C(Cl)Cl>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([N:20]([C:40]([O:42][CH3:43])=[O:41])[CH3:21])[CH:16]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CNC1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N(C)C1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Yield: 70.2 %

Procedure:
To a solution of 25 mg of amine prepared in Example 11 and 0.05 mL of DIPEA in 0.5 mL of methylene chloride was added 12 mg of methyl chloroformate. After 1.5 h in a sealed vial, the volatiles were evaporated under a stream of nitrogen and the residue was purified on a 1 mm preparative silica gel plate eluted with ethyl acetate to afford 20 mg of title compound. Mass spec (NH3 /CI): 476 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[CH:5]2.[C:12](C1NC=CN=1)(C1NC=CN=1)=[O:13].[NH2:24][C:25]1[C:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:29][CH:28]=[CH:27][N:26]=1>>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:12]([NH:24][C:25]3[C:30]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:29][CH:28]=[CH:27][N:26]=3)=[O:13])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: Cn1ccc2cc(N)ccc21
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Product: Cn1ccc2cc(NC(=O)Nc3ncccc3OCc3ccccc3)ccc21

Procedure:
The title compound was prepared from 5-amino-1-methyl-1H-indole (D3), carbonyl diimidazole and 2-amino-3-benzyloxypyridine using a procedure similar to that described in Example 1.
Reaction SMILES: C([O:8][C:9](=O)[CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][O:13][CH3:14])C1C=CC=CC=1.[Li+].[BH4-].C1COCC1>C(OCC)C>[C:19]([O:18][C:16](=[O:17])[NH:15][C@H:11]([CH2:12][O:13][CH3:14])[CH2:10][CH2:9][OH:8])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC[C@H](CCO)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of (S)-3-tert-Butoxycarbonylamino-4-methoxy-butyric acid benzyl ester (10.4 g, 32.3 mmol) in dry diethylether (70 ml) cooled to 0° C. is treated slowly with a 2.0 M solution of LiBH4 in THF (32.2 ml, 64.4 mmol). The reaction mixture is allowed to warm to ambient temperature and then left to stir. After 6 hours the reaction mixture is quenched slowly with 0.5 M aqueous solution of citric acid and extracted with ether. The ether phase is dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography (elution with a gradient 3:7 to 6:4 ethylacetate/hexane) to afford ((S)-3-Hydroxy-1-methoxymethyl-propyl)-carbamic acid tert-butyl ester as a clear oil. [M-BOC] 120.13
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:24](F)=[C:23]3[C:18]([C:19](=[O:36])[C:20]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:21][N:22]3[C@@H:26]([CH3:30])[CH2:27][NH:28][CH3:29])=[CH:17][C:16]=2[F:37])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.Cl>CN(C)C=O.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[C:24]3[N:28]([CH3:29])[CH2:27][C@H:26]([CH3:30])[N:22]4[CH:21]=[C:20]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:19](=[O:36])[C:18]([C:23]=34)=[CH:17][C:16]=2[F:37])[CH2:13][CH2:14]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn([C@@H](C)CNC)c2c(F)c(C3(NC(=O)OCc4ccccc4)CC3)c(F)cc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn2c3c(c(C4(NC(=O)OCc5ccccc5)CC4)c(F)cc3c1=O)N(C)C[C@@H]2C
Temperature: 25 °C
Reaction time: 6 h
Yield: 52 %

Procedure:
In 5 ml of N,N-dimethylformamide was dissolved 240 mg of ethyl (S)-7-(1-benzyloxycarbonylaminocyclopropyl)-6,8-difluoro-1-[2-(N-methylamino)-1-methylethyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylate. To the resulting solution was added 80 mg of potassium carbonate. The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was added to a mixture of 20 ml of ethyl acetate and 20 ml of water. The resulting mixture was adjusted to pH 3 with 2N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. Diethyl ether was added to the residue obtained. The resulting crystals were collected by filtration to obtain 120 mg (yield: 52.2%) of ethyl (S)-10-(1-benzyloxycarbonylaminocyclopropyl)-9-fluoro-1,3-dimethyl-7-oxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]-quinoxaline-6-carboxylate.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][CH2:13][CH2:14][C:15]([OH:18])([CH3:17])[CH3:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1.O.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([O:18][C:15]([CH3:16])([CH2:14][CH2:13][O:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][CH:7]=1)(=[O:11])=[O:10])[CH3:17])(=[O:24])[CH3:23]
Reactant: CC(C)(O)CCOS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)OC(C)(C)CCOS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a mixture of the alcohol 4 (0.500 g, 1.6 mmol), ZrOCl28.H2O (0.0025 g, 0.5 mol %) in methylene chloride (5 mL), acetyl chloride (0.251 g, 3.2 mmol) is added and the reaction is stirred for overnight at 20° C. The reaction on completion, is diluted with methylene chloride (5 mL) and washed with saturated sodium bicarbonate (2×10 mL), brine (1×10 mL) and dried. The solvent is evaporated to get the crude product. 1H NMR (400 MHz, CDCl3) δ1.56 (d, J=8.0, 6H), 1.60 (d, J=8.0, 5H), 2.14 (t, J=6.8, 2H), 4.33 (t, J=6.8, 2H), 7.82 (d, J=8.1, 2H), 8.04 (d, J=8.0, 2H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9].[CH:23]1(C2N=C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)C(CC)=NC=2)CC1>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH:8]1[CH2:23][CH2:9]1
Reactant: CCc1ncc(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(Br)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting (1R,2S)-1-[(6-cyclopropyl-3-ethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.93–1.09, 1.28–1.39, 2.35–2.43, 2.60–2.67, 2.99–3.05, 3.22–3.29, 4.70, 5.04, 5.44–5.49, 7.23–7.32; MS (ESI+) for C18H20BrN3O m/z 374 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12](I)[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[I:18]C1C=C(C=CC=1)C(O)=O.FC1(F)CCNCC1>>[F:1][C:2]1([F:17])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([I:18])=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(c1cccc(I)c1)N1CCC(F)(F)CC1
Reactant: O=C(O)c1cccc(I)c1
Agent: FC1(F)CCNCC1
Product: O=C(c1ccc(I)cc1)N1CCC(F)(F)CC1

Procedure:
According to Step 77-1 in the synthetic method for compound 77-1, 4-iodobenzoic acid 1 and 4,4-difluoropiperidine 2 were used to obtain compound 83-1.
Reaction SMILES: [Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]2[NH:6][C:7]([C:9]([OH:17])([CH2:14][C:15]#[CH:16])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1COCC1.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.[Cu](I)I>[Cl:20][C:19]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:17])([CH2:14][C:15]#[C:16][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:18]=1
Reactant: C#CCC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OC(CC#Cc1ccccc1)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reaction time: 8 h

Procedure:
2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-pent-4-yn-2-ol (0.27 g; 0.83 mmol), iodobenzene (0.14 mL; 1.3 mmol), dichlorobis(triphenylphosphine)palladium (31.7 mg; 0.045 mmol), copper iodide (17.8 mg; 0.093 mmol) and triethylamine (0.25 mL; 1.8 mmol) were suspended in THF (5 mL) and the resulting mixture stirred vigorously overnight. The reaction mixture was then concentrated in vacuo and the resulting crude brown oil was purified by column chromatography (SiO2; 50% ether/CH2Cl2) to yield the title compound as an orange-yellow solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][S:12]([NH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20])(=[O:14])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].S(Cl)([Cl:32])=O>>[Cl:32][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([NH:15][S:12]([CH3:11])(=[O:14])=[O:13])[CH:17]=2)=[O:8])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: O=S(Cl)Cl
Reactant: CS(=O)(=O)Nc1cccc(CN)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CS(=O)(=O)Nc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-Bromonicotinic acid (200 mg, 0.99 mmol) was heated at reflux in thionyl chloride (2 ml) for 3 hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in DCM (2 ml), 3-methylsulphonylaminobenzylamine (200 mg, 0.10 mmol) and sodium carbonate (500 mg) were added to the solution. The reaction was stirred at room temperature for 4 hrs, filtered and the filtrate reduced to dryness under vacuum to give 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide. NMR: δH [2H6]-DMSO 9.30,(1H, t), 8.88,(1H, d), 8.28,(1H, dd), 7.67,(1H, d), 7.23,(1H, t), 7.10,(1H, s), 7.04,91H, d), 6.97,(1H, d), 4.45,(2H, d), 2.90,(3H, s).