Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH2:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Si:21]([CH3:25])([CH3:24])(Cl)[Cl:22]>CCOCC>[Cl:22][Si:21]([CH3:25])([CH3:24])[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(Cl)Cl
Reactant: C1=C(c2ccccc2)Cc2ccccc21
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(Cl)C1C(c2ccccc2)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A solution of 0.96 g (5.0 mmol) of 2-phenylindene in 30 mL of Et2O was treated at −70° C. with 3.13 mL (5.0 mmol) of a 1.6 M solution of n-BuLi. After the addition, the mixture was allowed to warm to room temperature and stirred for 50 min. Then it was cooled again to −70° C. and treated with a solution of 0.65 g (5.0 mmol) of Me2SiCl2 in 10 mL of ether. When the addition was completed, the mixture was allowed to reach room temperature and stirred overnight. The resulting reaction mixture was filtered to remove LiCl and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:11]1[CH:10]=[C:9]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: Fc1ccc(Br)cc1F
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1ccc(F)c(F)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 100.6 %

Procedure:
Add copper (I) iodide (109.4 mg, 0.57 mmol), bis(triphenylphosphine)palladium (II) dichloride (365 mg, 0.52 mmol) and triethylamine (5.88 mL, 41.6 mmol), to a solution of 4-bromo-1,2-difluorobenzene (1.17 mL, 10.4 mmol) and trimethylsilylacetylene (1.89 mL, 13.5 mmol), in ethyl acetate (8 mL). Stir at 50° C. for 18h. Cool to room temperature, concentrate and purify the residue by silica gel chromatography, eluting with hexanes, to give the title compound (2.20 g, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]([OH:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[C:12]([Br:24])[N:11]([CH:25]([CH3:27])[CH3:26])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[C:13]([C:14](=[O:23])[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[C:12]([Br:24])[N:11]([CH:25]([CH3:27])[CH3:26])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(O)c2c(OCc3ccccc3)nn(C(C)C)c2Br)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2c(OCc3ccccc3)nn(C(C)C)c2Br)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
3-Benzyloxy-5-bromo-4-[hydroxyl(4-methoxyphenyl)methyl]-1-isopropyl-1H-pyrazole (0.6 g) was dissolved in dichloromethane (10 mL). To the stirred solution was added Manganese dioxide (0.5 g) at room temperature and the mixture was stirred at 50° C. for 1 hour. After the insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure to give the title compound (0.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].O[CH:15]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)S([O-])(=O)=O.[Na+].C(O)C>O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:15]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:3]=2[CH:4]=1
Reactant: Nc1ccc(Cl)cc1NCCCO
Reactant: O=S(=O)([O-])C(O)C1CCCCC1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCCCn1c(C2CCCCC2)nc2ccc(Cl)cc21

Procedure:
A mixture of 40 parts of 3-[(2-amino-5-chlorophenyl)amino]-1-propanol, 87 parts of sodium α-hydroxycyclohexanemethanesulfonate and 200 parts of ethanol is stirred and refluxed for 10 minutes. The reaction mixture is diluted with water and the solvent is evaporated. The residue is extracted a few times with trichloromethane. The combined extracts are dried, filtered and evaporated. The oily residue is triturated in 2,2'-oxybispropane: a sticky tar precipitates. The 2,2'-oxybispropane is decanted and upon stirring at room temperature, the product is allowed to precipitate. It is filtered off and dried, yielding 6-chloro-2-cyclohexyl-1H-benzimidazole-1-propanol; mp. 120.1° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)=[O:12])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:23]>[Pd].CO>[CH3:1][C:2]1([CH3:24])[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=3)=[O:12])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:23]
Reactant: CC1(C)C(=O)Nc2cc(C(=O)Nc3ccc([N+](=O)[O-])cc3)ccc21
Agent: [Pd]
Solvent: CO
Product: CC1(C)C(=O)Nc2cc(C(=O)Nc3ccc(N)cc3)ccc21
Reaction time: 2 h

Procedure:
2.6 g. (8 mmol) 2,3-Dihydro-3,3-dimethyl-N-(4-nitrophenyl)-2-oxo-(1H)-indole-6-carboxamide (from Example 6) in 50 ml. methanol were hydrogenated in the presence of 0.3 g. 10% palladium on charcoal at normal pressure and ambient temperature. After 2 hours, the reaction mixture was filtered with suction, the solvent was removed from the filtrate in a vacuum and the residue purified by column chromatography (silica gel; elution agent dichloromethane/methanol saturated with ammonia 95:5 v/v). The solvent was removed in a vacuum, the residue was digested with ethyl acetate, filtered off with suction and the residue dried in a vacuum at 100° C. There was obtained 1.4 g. (61% of theory) of the title compound; m.p. 216°-218° C. The title compound contained adhering thereto 0.5 mole of water per mole.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[C:19]1([CH:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15](=[O:17])[N:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:33][CH:25]3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: c1ccc(C2Cc3ccccc3N2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1c2ccccc2CC1c1ccccc1
Yield: 53.9 %

Procedure:
(±)-6-(Morpholin-4-yl)-2-{2-oxo-2-[2-phenyl-2,3-dihydro-1H-indol-1-yl]ethyl}pyrimidin-4(3H)-one is prepared by following the procedure described in example 1d, step 3d, using 0.50 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 0.42 g of 2-phenylindoline (which can be prepared according to Santangelo, E. M. et al. Eur. J. Org. Chem. 2008, 5915), and 0.48 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.31 ml of pyridine and 10 ml of N,N-dimethylformamide. After purification by chromatography on a 50 g column of 20-45 μm silica, elution being carried out with a 90/10 v/v dichloromethane/methanol mixture, 0.43 g of (±)-6-(morpholin-4-yl)-2-{2-oxo-2-[2-phenyl-2,3-dihydro-1H-indol-1-yl]ethyl}pyrimidin-4(3H)-one is obtained in the form of a cream-colored solid, the characteristics of which are the following:
Reaction SMILES: [OH:1]O.[F:3][C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[CH2:18][C:19](=[O:23])C(O)=O)=[CH:6][CH:5]=1.Cl>[OH-].[Na+]>[F:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[CH2:18][C:19]([OH:23])=[O:1])=[CH:24][CH:25]=1
Reactant: O=C(O)C(=O)Cc1cc([N+](=O)[O-])ccc1Oc1ccc(F)cc1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1cc([N+](=O)[O-])ccc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
560 ml. of a 10% aqueous solution of hydrogen peroxide are added dropwise at 0° over a period of 75 minutes to a solution of 142 g. of 2-(4-fluoro-phenoxy)-5-nitro-phenylpyruvic acid in 2.23 liters of 10% sodium hydroxide solution cooled to 0° C. The mixture is subsequently stirred for 3 hours at 25° C. and then acidified with 500 ml. of concentrated hydrochloric acid with cooling. This mixture is extracted twice with methylene chloride. The methylene chloride solutions are washed with water, dried over sodium sulfate and concentrated in vacuo. The residue is crystallized from benzene/hexane, and there is obtained 2-(4-fluorophenoxy)-5-nitro-phenylacetic acid having a melting point of 129°-130° C.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH2:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[C:26]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:25][CH:24]=[C:23]([CH3:35])[C:19]=1[C:20](O)=[O:21].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:20](=[O:21])[C:19]3[C:23]([CH3:35])=[CH:24][CH:25]=[C:26]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[C:18]=3[CH3:17])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1C(=O)O
Reactant: CC(C)(C)Nc1ncnc2c(N)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1C(=O)Nc1cccc2c(NC(C)(C)C)ncnc12
Yield: 5.1 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(tert-butyl)quinazoline-4,8-diamine (Intermediate-55, 275 mg, 1.27 mmol), 2,6-dimethyl-3-(pivalamidomethyl)benzoic acid (Intermediate-4, 401 mg, 1.52 mmol), oxalyl chloride (230 mg, 1.82 mmol), DMF (1 drop) and DIPEA (392 mg, 3.04 mmol) in CH2Cl2 (10 mL) to afford 30 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 9.68 (s, 1H), 8.70-8.67 (d, J=7.8 Hz, 1H), 8.44 (s, 1H), 8.13-8.10 (d, J=8.4 Hz, 1H), 7.94 (t, 1H), 7.49-7.43 (m, 2H), 7.13-7.11 (m, 2H), 4.23 (d, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 1.52 (s, 9H), 1.12 (s, 9H); MS [M+H]+: 462.44.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[F:11].Br[C:13]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[F:20][C:18]1[CH:17]=[CH:16][C:14]([NH2:15])=[C:13]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([F:11])[CH:4]=2)[CH:19]=1
Reactant: Cc1ccc(B(O)O)cc1F
Reactant: Nc1ccc(F)cc1Br
Product: Cc1ccc(-c2cc(F)ccc2N)cc1F

Procedure:
Starting from 4-methyl-3-fluorophenylboronic acid and 2-bromo-4-fluoroaniline and proceeding analogously to Example (III-1), the compound 5,3′-difluoro-4′-methylbiphenyl-2-ylamine with a logP (pH 2.3) of 2.94 is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:15][CH2:16][C:17]([OH:19])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]=1[CH3:7].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:15][CH2:16][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[C:6]=1[CH3:7]
Reactant: Cc1c(Br)cnn1CC1(OCC(=O)O)CCCCC1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(Br)cnn1CC1(OCC(=O)N2CCOCC2)CCCCC1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 174B (331 mg) in dichloromethane (10 mL) was added morpholine (174 mg), 4-dimethylaminopyridine (122 mg) and 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (287 mg). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (200 mL) and washed with water and brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the crude title compound.
Reaction SMILES: F[C:2]1[CH:22]=[CH:21][C:5]2[O:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]=[C:10]([O:11]CCN(C)C)[C:4]=2[CH:3]=1.Cl>>[O:11]=[C:10]1[C:4]2[CH:3]=[CH:2][CH:22]=[CH:21][C:5]=2[O:6][C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[CH2:9]1
Reactant: CN(C)CCOC1=Cc2ccccc2Oc2ccc(F)cc21
Agent: Cl
Product: O=C1Cc2ccccc2Oc2ccccc21

Procedure:
Reflux of 25 ml of 2-fluoro-11-[β-(dimethylamino)-ethoxy]dibenz[b,f]oxepin stock solution produced no apparent decomposition after 45 minutes. Addition of 2.5 ml of concentrated hydrochloric acid and further reflux for 10 mins gave complete decomposition to 10,11-dihydro-10-oxodibenz[b,f]oxepin.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].[H-].[Na+].[CH3:9][O:10][C:11]1([C:17]2[CH:18]=[C:19]([CH2:23]Br)[CH:20]=[CH:21][CH:22]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CN(C=O)C>[CH3:9][O:10][C:11]1([C:17]2[CH:18]=[C:19]([CH2:23][O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: COC(=O)CO
Reactant: COC1(c2cccc(CBr)c2)CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COCc1cccc(C2(OC)CCOCC2)c1
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 49.7 %

Procedure:
A solution of methyl glycolate (0.35 g, 3.9 mmol) in 5 mL of anhydrous DMF was added to a suspension of sodium hydride (0.11 g, 4.6 mmol) in 5 mL of anhydrous DMF at 5° C., and the reaction mixture was stirred for 40 minutes at 5° C. A solution of 3-[(4-methoxy)tetrahydropyran-4-yl]-α-bromotoluene (1 g, 3.9 mmol) in 10 mL of anhydrous DMF was added to the cold methyl glycolate solution while maintaining the temperature at 5° C. The mixture was stirred for 2 h at 5° C., then for 18 h at room temperature. The mixture was quenched with water (100 mL) and the aqueous solution was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with saturated brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was purified by flash column chromatography on silica gel, eluting with 25% ethyl acetate in hexane, to give 0.57 g (50%) of methyl 3-[(4-methoxy)-tetrahydropyran-4-yl]phenylmethoxyacetate as a clear oil: HRMS calcd for C16H22O5 295.1545. Found 295.1502.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:13][CH:14](O)[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:14]([CH3:15])[CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: CC(C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.4 %

Procedure:
A solution of 1.42 g (7.63 mmol) of methyl 3-chloro-4-hydroxybenzoate, 585 μL (7.63 mmol) of 2-propanol and 3.0 g (11.45 mmol) of triphenylphosphine in 20 mL of THF at 0° C. was treated with 2.25 mL (11.45 mmol) of diisopropyl azodicarboxylate. The mixture was stirred for 16 h at rt, then concentrated. Chromatography on a Biotage 40M cartridge using 19:1 v/v hexanes/EtOAc as the eluant afforded 1.77 g of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.41 (d, J=6.2, 6H), 4.63-4.70 (m, 1H), 6.93 (d, J=8.7, 1H), 7.89 (dd, J=2.2, 8.6, 1H), 8.05 (d, J=2.0, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][NH:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH3:16][C:17]([S@:20]([NH:22][CH:11]([C:8]1[CH:9]=[N:10][C:5]([NH:4][CH2:3][C:2]([F:15])([F:14])[F:1])=[CH:6][CH:7]=1)[CH3:12])=[O:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(NCC(F)(F)F)nc1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(NCC(F)(F)F)nc1
Yield: 28 %

Procedure:
The title compound is prepared in 28% yield (180 mg, colorless oil) from 1-(6-((2,2,2-trifluoroethyl)amino)pyridin-3-yl)ethanone (441 mg, 2.02 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:18])[CH2:14][S:15][CH2:16][CH3:17])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](F)[C:23]=1[C:29]([F:32])([F:31])[F:30].CCO>CN(C=O)C.Cl>[Cl:21][C:22]1[C:23]([C:29]([F:30])([F:31])[F:32])=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:18][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][S:15][CH2:16][CH3:17]
Reactant: Fc1cccc(Cl)c1C(F)(F)F
Reactant: CCSC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCSC[C@H](Oc1cccc(Cl)c1C(F)(F)F)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-2-Ethylsulfanyl-1-hydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10 mg, 40 μmol) was dissolved in DMF (174 μL). NaH (1.3 mg, 54.5 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 2-Chloro-6-fluorobenzotrifluoride (21.6 mg, 109 μmol) was added and the mixture was stirred at 100° C. for 1 hour. The mixture was cooled to room temperature, concentrated then dissolved in 1.2M HCl in EtOH (890 μL, 1.1 mmol) and stirred overnight at room temperature. The product was concentrated and the crude product was dissolved in 1:1 AcOH/H2O (1.5 mL) then purified by preparative HPLC to yield the title compound as a mono-TFA salt (3.4 mg, purity 97%). MS m/z: [M+H] calcd for C15H19ClF3NOS, 354.08. found 354.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([NH:20][NH:21][C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=O)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:49])=CC=1>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:37])=[O:38])=[CH:32][CH:31]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:49][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:21][N:20]=1)=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)NNC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OCc3ccccc3)c2[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nnc(-c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OCc4ccccc4)c3[nH]2)s1
Temperature: 50 °C
Reaction time: 5 h
Yield: 74.1 %

Procedure:
Ethyl [2-({7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}carbonyl)hydrazino](oxo)acetate (420 mg) was dissolved in tetrahydrofuran (15 mL), Lawesson's reagent (308 mg) was added, and the mixture was stirred at 50° C. for 5 hr. Lawesson's reagent (300 mg) was added again to the reaction solution, and the mixture was further stirred at 50° C. for 1 hr. The reaction solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=10:90-40:60, volume ratio), and the obtained yellow oil was crystallized from methanol to give the title compound (310 mg, yield 74%) as pale-yellow crystals. The obtained crystals was recrystallized from ethyl acetate-diethyl ether to give pale-yellow crystals. melting point 194-195° C. MS 550 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:19])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:20]N1C(=O)CCC1=O>O1CCOCC1>[NH2:1][C:2]1[C:7]2[C:8](=[O:19])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[O:11][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc(-c2cc(=O)c3c(N)cccc3o2)cc1
Solvent: C1COCCO1
Product: Nc1ccc(-c2cc(=O)c3c(N)c(Cl)ccc3o2)cc1
Yield: 18.3 %

Procedure:
2.0 g (7.93 mmol) of 5-amino-2-(4-aminophenyl)-4H-1-benzopyran-4-one (EP-A-374789) was dissolved in 50 ml of dioxane, 1.06 g (7.93 mmol) of N-chlorosuccinimide was added and the mixture was stirred under heating at reflux for 19 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:acetone=4:1) to give 710 mg (31%) of crude product. Further recrystallization from chloroform/methanol afforded 415 mg (18%) of Compound 1.
Reaction SMILES: [CH3:1][N:2](C(=O)C)[C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8](=[O:11])[CH2:9][CH3:10].[OH-].[K+]>C(O)C.O>[CH3:1][NH:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8](=[O:11])[CH2:9][CH3:10]
Reactant: CCC(=O)c1ccsc1N(C)C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(=O)c1ccsc1NC
Temperature: 95 °C

Procedure:
To a solution of 1.255 g of N-methyl-2-acetylamino-3-propionylthiophene in 25 ml of ethanol, is added 0.45 g of potassium hydroxide in 10 ml of water. The mixture is heated at 95°C for 1 hour, evaporated under reduced pressure to a residue. Water is added to the residue and extracted with dichloromethane. The dichloromethane extracts are washed with water, dried over sodium sulfate, then evaporated under reduced pressure to give an oil. The residual oil is chromatographed on silica gel, using chloroform as an eluent to give 2-methylamino-3-propionylthiophene as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.[NH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.O.ON1C2C=CC=CC=2N=N1.[ClH:42].C(N=C=NCCCN(C)C)C.CN1CCOCC1>>[ClH:42].[ClH:42].[O:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][CH2:22][NH:21][C:16](=[O:18])[C:15]2[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:20][CH:19]=2)[CH2:26][CH2:27]1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Reactant: NCCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(NCCCN1CCOCC1)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1

Procedure:
The crude product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 1.89 mmol) obtained in Step 6 of Example 1, N-(3-aminopropyl)morpholine (0.365 mL, 2.50 mmol), 1-hydroxybenzotriazole monohydrate (333 mg, 2.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510 mg, 2.67 mmol) and N-methylmorpholine (0.75 mL, 6.82 mmol) in a similar manner to Example 5, was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain a free base of Compound 97. Then the free base of Compound 97 was dissolved in ethyl acetate (5.00 mL), and the solution was added with 4 mol/L hydrogen chloride-ethyl acetate solution (1.00 mL), followed by stirring at room temperature for 30 minutes. The precipitate in the reaction mixture was filtered to obtain Compound 97 (340 mg, 78%).
Reaction SMILES: [C:1]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:14])[CH2:2]CC(OCC1C=CC=CC=1)=O.F[C:27](F)(F)[C:28]([O:30][C:31]1[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([F:40])[C:32]=1[F:41])=[O:29]>C1COCC1.[Pd]>[C:1]([O:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:14])[CH2:2][CH2:27][C:28]([O:30][C:31]1[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([F:40])[C:32]=1[F:41])=[O:29]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CCCOC(=O)CCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCOC(=O)CCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reaction time: 1 h
Yield: 90.5 %

Procedure:
Compound 3 (2.0 g, 5.7 mmol) was hydrogenated for 20 h at 40 psi in THF (100 mL) in the presence of 0.2 g of 10% Pd/C. The catalyst was removed by filtration through Celite and filtrate concentrated. The acid was dissolved in 20 mL of anhydrous CH2Cl2. Diisopropylethylamine ((0.88 g, 6.8 mmol) was added followed by pentafluorophenyl trifluoroacetate (1.9 g, 6.8 mmol). After being kept at room temperature for 1 h solvent was evaporated and residue chromatographed on silica (ethyl acetate-hexane) to afford 2.2 g (91%) of 4 as viscous liquid. 1H NMR (DMSO-d6) δ 4.05 (t, J=6 Hz, 2H), 3.04 (t, J=6 Hz, 2H), 2.72 (t, J=6 Hz, 2H), 2.26 (t, J=7 Hz, 2H), 1.78 (q, 2H), 1.38 (s, 9H).