Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[B-](F)(F)(F)[F:22].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C1S(=O)(=O)CCC1>O>[F:22][C:10]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:7][O:8][C:9]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)on1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CCOC(=O)c1noc(-c2ccc(C(F)(F)F)cc2)c1F
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 15.7 %

Procedure:
A mixture of ethyl-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylate (0.96 g, 3.37 mmol), Selectfluor (1.25 g, 3.53 mmol), and tetramethylene sulfone (7.5 g, 62.5 mmol) was heated to 120° C. for 8 hours. After cooling to room temperature, the reaction mixture was diluted with water, stirred for 5 minutes and the resulting white crystals were collected, washed with water and purified by silica gel chromatography eluting with dichloromethane to obtain the title compound (147 mg, 0.53 mmol).
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]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24])#[CH:20].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[C:19]([C:21]1[CH:22]=[C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[CH:26][C:27]=1[F:28])#[CH:20]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: C#Cc1cc(N)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C#Cc1cc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)ccc1F
Yield: 71.9 %

Procedure:
The product is prepared according to the procedure described in example 5, using 204 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 211 mg of 3-ethynyl-4-fluoroaniline, and 195 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.126 ml of pyridine and 3 ml of N,N-dimethylformamide. 200 mg of N-(3-ethynyl-4-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].CS(C)=O.Cl.[NH2:22][CH:23]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:24]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][C:30]([O:38][CH3:39])=[C:31]([O:36][CH3:37])[CH:32]=2)[CH2:27]1)=[O:25]>C(OCC)C>[CH3:37][O:36][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:38][CH3:39])[CH2:27][N:26]([C:24](=[O:25])[C@@H:23]([NH:22][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[C:40]([CH3:41])([CH3:43])[CH3:42])[CH2:35][CH2:34]2
Reactant: COc1cc2c(cc1OC)CN(C(=O)C(N)C(C)(C)C)CC2
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1cc2c(cc1OC)CN(C(=O)[C@@H](Nc1ccccc1[N+](=O)[O-])C(C)(C)C)CC2
Temperature: 80 °C
Yield: 27 %

Procedure:
Anhydrous potassium carbonate (640 mg, 4.63 mmol) and 2-fluoronitrobenzene (820 mg, 5.81 mmol) were added to a dimethyl sulfoxide (100 ml) solution of N-(2-amino-3,3-dimethylbutyryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.05 g, 3.42 mmol) obtained in Reference example 7, and the mixture was heated at 80° C. for 90 minutes. The reaction mixture was cooled to room temperature, diluted with a diethyl ether solution (200 ml), washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:4 to 2:1) as an eluent to obtain the captioned compound (395 mg, 27%) as an orange foamy substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3([CH3:17])[O:16][CH2:15][CH2:14][O:13]3)[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br:18]N1C(=O)CCC1=O>C(#N)C>[Br:18][C:6]1[C:7]2[O:11][C:10]([C:12]3([CH3:17])[O:16][CH2:15][CH2:14][O:13]3)=[N:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc2oc(C3(C)OCCO3)nc12
Solvent: CC#N
Product: COc1ccc(Br)c2oc(C3(C)OCCO3)nc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Methoxy-2-(2-methyl-[1,3]-dioxolan-2-yl)benzoxazole (129 m), N-bromosuccinimide (107 mg) and acetonitrile (5 ml) were combined and stirred at room temperature under nitrogen for 4 h. The mixture was partitioned between water (20 ml) and ethyl acetate (20 ml). The aqueous phase was extracted with ethyl acetate (20 ml). The combined organic phases were washed with water (2×50 ml), dried over magnesium sulphate, evaporated in vacuo and purified by flash chromatography eluting with 30% ethyl acetate in hexane to yield the title compound as a white solid (95 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](F)[CH:17]=2)[C:12](=[O:21])[N:11]([OH:22])[C:10]1=[O:23])[CH3:8].C(N(CC)CC)C>C(#N)C>[CH2:7]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:17]=2)[C:12](=[O:21])[N:11]([OH:22])[C:10]1=[O:23])[CH3:8]
Reactant: C1CCNCC1
Reactant: CCn1c(=O)n(O)c(=O)c2cc(F)c(F)cc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCCCC3)cc21
Yield: 48.8 %

Procedure:
Piperidine (0.025 mL, 0.22 mmol) was added to a solution of 1-ethyl-6,7-difluoro-3-hydroxy-1H-quinazoline-2,4-dione (Example D, 0.05 g, 0.2 mmol) and triethylamine (0.06 mL, 0.4 mmol) in 20 mL of acetonitrile. The solution was heated to reflux for 23 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with 1N HCl, water, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.03 g of the title compound as a solid, mp 173-175° C.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][CH:8]=C[C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]3[CH:23]=[C:24]([C:28]4[N:29]=[CH:30][N:31]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:32]=4)[CH:25]=[C:26]([CH3:27])[C:21]=3[N:20]=[C:19]2[CH2:39][CH2:40][CH3:41])=[CH:13][CH:12]=1)(C)(C)C.F[C:43](F)(F)[C:44]([OH:46])=[O:45]>C(Cl)Cl>[CH2:39]([C:19]1[N:18]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:6]3[C:43]([C:44]([OH:46])=[O:45])=[CH:8][CH:9]=[CH:10][CH:5]=3)=[CH:12][CH:13]=2)[C:22]2[CH:23]=[C:24]([C:28]3[N:29]=[CH:30][N:31]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:32]=3)[CH:25]=[C:26]([CH3:27])[C:21]=2[N:20]=1)[CH2:40][CH3:41]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCCCn1cnc(-c2cc(C)c3nc(CCC)n(Cc4ccc(-c5ccccc5C(C)(C)C)cc4)c3c2)c1
Solvent: ClCCl
Product: CCCCCCn1cnc(-c2cc(C)c3nc(CCC)n(Cc4ccc(-c5ccccc5C(=O)O)cc4)c3c2)c1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-n-hexyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl and trifluoroacetic acid in methylene chloride.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[O:3].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:12]=1[CH2:13][OH:14].N1C=CC=CC=1>ClCCl>[OH:14][CH2:13][C:12]1[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]=1[NH:10][C:2](=[O:3])[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: Cc1cccc(N)c1CO
Reactant: COC(=O)COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)COC(=O)Nc1cccc(C)c1CO
Yield: 35.1 %

Procedure:
Starting from methoxycarbonylmethyl chloroformate (11.7 g), 2-amino-6-methylbenzyl alcohol (10.5 g) and pyridine (6.2 ml) in dichloromethane (230 ml), 6.8 g (20%) of the title compound, m.p. 70-74° C., are obtained according to the procedure indicated in Example C1, after chromatography on silica gel (eluent: ethyl acetate/petroleum ether 50/70=1:1) and crystallization from diisopropyl ether.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]=[O:9].O.[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[N:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=[C:5]([CH2:6][N:3]2[CH:7]=[CH:6][CH:5]=[C:4]2[CH:8]=[O:9])[CH:4]=1
Reactant: Cc1ccccc1
Reactant: O=Cc1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cccn1Cc1cnc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A suspension of 60% NaH (3.28 g) in THF (400 ml) was cooled to 0° C. under nitrogen atmosphere, and thereto was added pyrrol-2-carbaldehyde (7.81 g) in portions. To the mixture was added a solution of the above crude bromo compound in toluene, and the mixture was stirred at room temperature for 0.5 hour, and stirred at 40° C. for one hour, and further stirred at 50° C. for 2 hours. The mixture was cooled to room temperature, and poured into water, and extracted with ethyl acetate. The extract was washed with a saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=3/1→2/1→1/1) to give 1-(3-quinolylmethyl)-1H-pyrrol-2-carbaldehyde (10.5 g, 54%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[C:12]([Cu])#[N:13]>CN(C=O)C>[C:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([CH:3]=1)[C:12]#[N:13])(=[O:11])[CH3:10]
Reactant: N#C[Cu]
Reactant: CC(=O)c1ccc(F)c(Br)c1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(F)c(C#N)c1
Reaction time: 10 h

Procedure:
A solution of 1-(3-bromo-4-fluorophenyl)ethanone (81.3 g, 0.344 mol) in 300 mL of DMF was added CuCN (67.4 g, 0.749 mol) and the mixture was heated to reflux, and stirred under N2 for 10 h. The reaction mixture was quenched with water and extracted with ether. The organic layer was washed with brine dried over Na2SO4 and concentrated in vacuum. The residue was purified with silica gel column chromatography to give the product 5-acetyl-2-fluorobenzonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[N:8]=[CH:7]2.[NH:23]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[C:25]([CH:32]=O)=[CH:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:20][C:19]([C:16]1[CH:15]=[CH:14][C:13]([N:9]2[N:8]=[CH:7][C:6]3[C:11](=[C:2]([NH:1][CH2:32][C:25]4[C:26]5[C:27](=[N:28][CH:29]=[CH:30][CH:31]=5)[NH:23][CH:24]=4)[CH:3]=[CH:4][CH:5]=3)[C:10]2=[O:12])=[CH:18][CH:17]=1)([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1ccc(-n2ncc3cccc(N)c3c2=O)cc1
Reactant: O=Cc1c[nH]c2ncccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-n2ncc3cccc(NCc4c[nH]c5ncccc45)c3c2=O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 8-amino-2-(4-tert-butyl-phenyl)-2H-phthalazin-1-one (Example 1, Step E, 0.36 g, 1.1 mmol, 1 eq) and CH2Cl2 (50 mL) was added 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (0.16 g, 1.1 mmol, 1 eq) and NaBH(OAc)3 (0.72 g, 3.4 mmol, 3.0 eq). The reaction was stirred at RT for 12 h then quenched with H2O and extracted with CH2Cl2. The organic layer was washed with H2O and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica flash chromatography (10-75% EtOAc:hexane) to give the desired product as a yellow solid. MS m/e 424 (M+H)+. Calc'd for C26H25N5O-423.51.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20](=[O:23])[CH2:21][CH3:22]>CC(C)=O>[CH2:21]([C:20]1[O:23][C:3](=[O:4])[C:5]2=[CH:9][CH:8]=[CH:7][N:6]2[CH:19]=1)[CH3:22]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: CCC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCc1cn2cccc2c(=O)o1
Temperature: 25 °C
Reaction time: 19 h
Yield: 102 %

Procedure:
To a slurry of 2-(trichloroacetyl)pyrrole (380 mg, 1.79 mmol) and K2CO3 (780 mg, 5.7 mmol) in 5 mL acetone was added a solution of 1-bromo-2-butanone (400 mg, 2.7 mmol) in 2 mL acetone. The mixture was stirred for 19 hours at room temperature before filtering and concentrating under reduced pressure to obtain 3-ethyl-1H-pyrrolo[2,1-c][1,4]oxazin-1-one (298 mg, quantitative), which was used in the following step without purification.
Reaction SMILES: [ClH:1].[F:2][CH:3]([CH:7]([NH2:10])[CH2:8][F:9])[C:4](O)=[O:5].B#B.CO>O1CCCC1>[ClH:1].[F:9][CH2:8][CH:7]([NH2:10])[CH:3]([F:2])[CH2:4][OH:5]
Reactant: NC(CF)C(F)C(=O)O
Agent: B#B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NC(CF)C(F)CO
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.7 %

Procedure:
To a suspension of 2,4-difluoro-3-aminobutanoic acid hydrochloride (2 g, 11.4 mmol) in anhydrous tetrahydrofuran (THF) (60 mL) at 0° C. is added a solution of 1 M diborane in THF (57 mL, 57 mmol). The reaction mixture is slowly allowed to warm up to room temperature and, after stirring for 12 hours, methanol (60 mL) is added. The solvent is evaporated in vacuo, the residue dissolved in 1 N hydrochloric acid (40 mL), and the aqueous layer extracted twice with ether. The aqueous phase is concentrated in vacuo and the residue washed several times with THF to afford 1,3-difluoro-4-hydroxy-2-aminobutane hydrochloride (1.8 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C@@:10]1([C:18](=[O:19])[NH:17][C:16](=[O:20])[N:15]1[CH3:21])[CH2:9]2)=[O:4].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH:32]=O.[BH4-].[Na+]>CO>[CH3:21][N:15]1[C@@:10]2([CH2:9][C:8]3[C:12](=[CH:13][CH:14]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:1][CH2:32][C:23]4[CH:24]=[CH:25][C:26]5[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:22]=4)[CH:7]=3)[CH2:11]2)[C:18](=[O:19])[NH:17][C:16]1=[O:20]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)CN)cc1C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1C(=O)NC(=O)[C@@]12Cc1ccc(NC(=O)CNCc3ccc4ccccc4c3)cc1C2
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A stirred solution of 2-amino-N-[(4S)-3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidine-4,2′-inden]-5′-yl]acetamide from Step B (80.0 mg, 0.277 mmol) and 2-naphthaldehyde (65.0 mg, 0.416 mmol), in MeOH (3 mL) was heated to 50° C. After 5 hours, no additional formation of the intermediate imine could be observed, so the reaction was cooled to 0° C., prior to the introduction of sodium borohydride (21.0 mg, 0.555 mmol). After 10 minutes the reaction was complete. The bulk of the solvent was remove in vacuo, and the resulting residue was applied to a silica gel column for purification, eluting with DCM:MeOH (10% conc. NH4OH)—98:2 to 92:8. Product containing fractions were pooled and concentrated in vacuo to give the title compound. MS: m/z=429 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][C:13](C=O)=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:26])=[CH:12][CH:11]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cnn(-c2ccc(C=O)cc2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1cnn(-c2ccc(O)cc2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 1-(4-formylphenyl)-1H-pyrazol-4-carboxylic acid methyl ester (5.0 g) in dichloromethane (100 ml) was treated with 3-chloroperbenzoic acid for 5 minutes at room temperature. The solution was heated at 50° C. for 4 hours, during which period additional 3-chloroperbenzoic acid (1.87 g) was added. After concentration, methanol (150 ml) and potassium carbonate (9.00 g) were added to the residue, and the mixture was stirred for 14 hours at ambient temperature. The reaction mixture was poured into water, adjusted to pH 8 with 1N HCl and the resulting precipitate was collected by filtration to give 1-(4-hydroxyphenyl)-1H-pyrazol-4-carboxylic acid methyl ester (0.51 g).
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.[CH2:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:24]([N:23]([CH2:21][CH3:22])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:27])([CH3:26])[CH3:25]
Reactant: CCNC(C)(C)C
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C

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 N-ethyl-2-methylpropan-2-amine (CAN 4432-77-3) in the presence of TBTU and DIEA to give the title compound as colorless oil; MS (EI): m/e=368.5 [MH+].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH:39]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)=[O:11])=[CH:7][CH:8]=1)(=[O:39])[NH2:2]
Reactant: OO
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To the solution of rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide (0.5 g, 0.91 mmol) prepared in Example 64 in DMSO (15 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.56 mL, 18 mmol), then aqueous solution (1N) of NaOH (4 mL, 4 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatograph (50-100% EtOAc in CH2Cl2) to give rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-phenyl)-amide as a white solid (Yield 0.3 g, 58%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Cl[CH2:11][C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:11][C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:2]([CH:7]=1)[NH2:1]
Reactant: Nc1cc(Cl)ccc1S
Reactant: ClCc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Cl)ccc1SCc1ncccn1
Yield: 50.8 %

Procedure:
Following General Procedure A, the title compound (284 mg, 39%) was prepared from 2-amino-4-chlorobenzenethiol (529 mg, 3.33 mmol), 2-(chloromethyl)pyrimidine (366 mg, 2.22 mmol) and K2CO3 (1.53 g, 11.09 mmol) in DMF (10 ml).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][S:7][C:8]1[C:16]2[C:12](=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[S:14][C:15]=2[S:17][CH3:18])[CH2:11][CH2:10][C:9]=1[CH:24]=O)=[O:5])[CH3:2]>C(OC(=O)C)(=O)C>[CH3:18][S:17][C:15]1[S:14][C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]2[CH2:11][CH2:10][C:9]3[CH:24]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:7][C:8]=3[C:16]=12
Reactant: CCOC(=O)CSC1=C(C=O)CCc2c(C(=O)OCC)sc(SC)c21
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc2c(s1)-c1c(SC)sc(C(=O)OCC)c1CC2
Yield: 52.4 %

Procedure:
Ethyl 4-ethoxycarbonylmethylthio-5-formyl-6,7-dihydro-3-methylthiobenzo[c]thiophene-1-carboxylate (0.30 g) was dissolved in acetic anhydride (10 ml) and refluxed under heating for 11 hours, after which it was concentrated under reduced pressure. The residue was poured over water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:7, v/v) to yield diethyl 4,5-dihydro-8-methylthiobenzo[2,1-c:3,4-b']dithiophene-2,6-dicarboxylate (0.15 g, 52%), which was then recrystallized from ethyl acetate-hexane. Yellow prisms. Melting point 107-108° C.
Reaction SMILES: N1C=CC=CC=1.OCC[C:10]1([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[NH:14][C:13](=[O:15])[CH:12]([CH3:16])[S:11]1.[C:23]([O:26][C:27](=O)[CH3:28])(=[O:25])[CH3:24]>>[C:23]([O:26][CH2:27][CH2:28][N:14]1[C:13](=[O:15])[CH:12]([CH3:16])[S:11][CH:10]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC1SC(CCO)(c2cccnc2)NC1=O
Solvent: c1ccncc1
Product: CC(=O)OCCN1C(=O)C(C)SC1c1cccnc1
Reaction time: 2 h
Yield: 77 %

Procedure:
Pyridine (0.5 ml) was added to a solution of -(2-hydroxyethyl)-5-methyl-2-(3-pyridyl)thiazolidin-4one (0.5 g, 2.1 mmol) in acetic anhydride (2 ml) under cooling with ice. This cooling with ice was further continued for 2 hours. The product mixture was concentrated by evaporation under reduced pressure, and subjected to medium-pressure chromatography (hexaneacetone), giving 3-(2-acetoxyethyl)-5-methyl-2-(3-pyridyl)thiazolidin-4-one (0.45 g, 77% yield).
Reaction SMILES: C(OC([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:12]=2[O:11][CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.[ClH:28]>C(OCC)(=O)C>[ClH:28].[O:11]1[C:12]2[C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:13]=2[CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2C(=O)O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc2c1OCCNC2
Yield: 83.6 %

Procedure:
4-(tert-Butoxycarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-9-carboxylic acid (110 mg, 0.375 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (2 ml) were stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (72.0 mg, 83.6%) as a solid.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[O:8])[CH2:2][CH2:3]1)=[O:26]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Reaction time: 1 h

Procedure:
3.0 Grams of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril and 4.0 ml of tiethylamine were suspended in 20 ml of dichloromethane, and to the suspension was added dropwise 3.5 g of 3,4-dimethoxybenzoylchloride in 20 ml of dichloromethane under ice-cooled condition with stirring. Then the reaction was continued for additional 1 hour at a room temperature. The reaction mixture was poured into a saturated sodium bicarbonate aqueous solution and extracted with chloroform. The chloroform layer was washed with water and a saturated sodium chloride aqueous solution in this order and was dired with anhydrous sodium sulfate, and the solvent was removed by distillation. The residue thus obtained was recrystallized from ethanol-chloroform to obtain 4.1 g of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless granular crystals. Melting point: 238°-239.5° C.