Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[C:13]([O:14]C)=[C:12]([F:16])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9]>C(Cl)Cl.C1COCC1.O>[F:5][C:6]1[C:13]([OH:14])=[C:12]([F:16])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: COc1c(F)ccc(C=O)c1F
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1ccc(F)c(O)c1F
Temperature: -10 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
1M BBr3 in DCM (2.179 ml) was added dropwise in about 30 min. to a stirred solution of 2,4-difluoro-3-methoxybenzaldehyde (0.25 g, 1.452 mmol) in DCM, cooled at −10° C. and under nitrogen atmosphere The solution was stirred for 4 hrs at RT and then diluted with a mixture of THF/H2O (9/1) and heated for 30 min. at 80° C. The solvent was removed and the residue was partitioned between 10N NaOH and Et2O. The aqueous layer was acidified with 10 N HCl and extracted with Et2O/EtOAc (2/1). Organic layers were dried over sodium sulphate and evaporated to give 2,4-difluoro-3-hydroxybenzaldehyde (225 mg) as pale brown powder.
Reaction SMILES: C(OCC)(=O)C.[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[O:20])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C-:21]#[N:22].[K+]>O>[OH:20][CH:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:21]#[N:22]
Reactant: O=CCCCCCCc1ccccc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC(O)CCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A two-phase mixture of ethyl acetate (30 mL) and water (35 mL) containing 7-phenylheptanal (5.2 g) and KCN (7.1 g) was stirred vigorously at room temperature for 24 h. The layers were separated and the aqueous phase was washed with water, dried (Na2SO4) and concentrated to yield 2-hydroxy-8-phenyloctanenitrile as an oil.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([OH:13])[CH2:8]1>CN(C)C=O>[ClH:1].[Cl:1][CH2:2][C:3]([O:13][CH:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH3:6])[CH2:8]1)=[O:4]
Reactant: CN1CCCC(O)C1
Reactant: O=C(Cl)CCl
Solvent: CN(C)C=O
Product: CN1CCCC(OC(=O)CCl)C1
Product: Cl
Reaction time: 24 h
Yield: 108.7 %

Procedure:
11.3 g of Chloroacetylchloride were added to a solution of 11.4 g of N-methyl-3-piperidinol in 20 ml of dimethylformamide, at 20° to 25° C. The reaction product, which formed immediately, was allowed to stand at this temperature for 24 hours. It was then collected by filtration and recrystallized from isopropanol to provide 12.4 g of N-methyl-3-piperidyl chloroacetate hydrochloride. (II, R=CH3, R1 =R2 =R3 =H, X=Cl), m.p. 168° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[NH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18](Cl)[N:17]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[NH2:15][C:16]1[N:17]=[C:18]([NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC(Nc2ccc([N+](=O)[O-])c(N)n2)C1
Temperature: 120 °C

Procedure:
500 mg (2.11 mmol) of tert-butyl 3-aminopiperidine-1-carboxylate, 772 mg (4.22 mmol) of 2-amino-6-chloro-3-nitropyridine and 1.05 ml (6.34 mmol) of diisopropylethylamine were suspended in 18 ml of DMSO and heated in a microwave reactor at 120° C. for 45 min. The reaction mixture was purified by preparative reverse-phase HPLC. This gave 600 mg (81% of theory) of the product as a solid.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH2:19]([C:21]1[N:31]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH:40][C:41](=O)[O:42]C3C=CC=CC=3)=[CH:34][CH:33]=2)[C:24]2=[N:25][C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:23]2[N:22]=1)[CH3:20].O>CN(C=O)C>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:41]([NH:40][CH2:39][CH2:38][C:35]2[CH:36]=[CH:37][C:32]([N:31]3[C:24]4=[N:25][C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:23]4[N:22]=[C:21]3[CH2:19][CH3:20])=[CH:33][CH:34]=2)=[O:42])(=[O:8])=[O:9])=[CH:3][CH:2]=1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Reaction time: 0.08 h
Yield: 49.7 %

Procedure:
To a stirred solution of 4-biphenylsulfonamide (Greenlee, W. J.; Walsh, T. F.; et al. Eur. Pat. Appl., EP 617001 (1994)., 56 mg, 0.24 mmol) in DMF (3 mL) was added NaH (60% oil dispersion, 20 mg, 0.5 mmol) at room temperature. After 5 min, phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1, 100 mg, 0.24 mmol) was added, and the mixture was stirred for an additional 1 h. The mixture was poured into water (50 mL) and extracted with diethyl ether (2×50 mL). The combined extracts were washed with water (50 mL), brine (50 mL) and dried (MgSO4). Removal of solvent gave white oily solids. Purification by preparative TLC (ethyl acetate) gave 66 mg (50%) of the title compound as a colorless oil: MS (ESI) m/z 554 (M+H)+; 1H-NMR (CDCl3) δ 8.06 (2H, d, J=8.6 Hz), 7.13 (2H, d, J=8.6 Hz), 7.60–7.53 (2H, m), 7.48–7.36 (3H, m), 7.21 (2H, d, J=8.4 Hz), 7.12 (2H, d, J=8.3 Hz), 6.92 (1H, s), 6.11 (1H, br.t, J=5.5 Hz), 3.54 (2H, dt, J=5.9, 6.0 Hz), 2.89 (2H, J=6.0 Hz), 2.64 (2H, q, J=7.5 Hz), 2.66 (3H, s), 2.40 (3H, s), 1.18 (3H, t, J=7.5 Hz).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[CH2:19]([N:26]1[CH2:31][C:30](=O)[CH2:29][C:28](=[O:33])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:19]([N:26]1[CH2:31][C:30]2[NH:1][C:2]([CH3:8])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[CH:13]([C:12]3[CH:15]=[CH:16][C:17]([F:18])=[C:10]([Br:9])[CH:11]=3)[C:29]=2[C:28](=[O:33])[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CC(=O)CN(Cc2ccccc2)C1
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1ccc(F)c(Br)c1
Solvent: CCO
Product: COC(=O)C1=C(C)NC2=C(C(=O)CN(Cc3ccccc3)C2)C1c1ccc(F)c(Br)c1
Yield: 53.6 %

Procedure:
A solution of methyl 3-aminocrotonate (0.58 g, 5 mmol), 3-bromo-4-fluorobenzaldehyde (1.0 g, 5 mmol) and N-benzylpiperidine-3,5-dione (Ziegler, J. Amer. Chem. Soc. (1973), 95, 7458-7464) (1.1 g, 5 mmol) in ethanol (5 mL) was heated at reflux in a sealed tube for 24 hours and concentrated. Purification of the residue on silica gel eluting with 5% ethanol/methylene chloride provided the title compound (1.3 g) as a yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]=[CH:10][CH:9]=[CH:8]2.N1C=CC=CC=1.[Br:23]Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]=[CH:10][C:9]([Br:23])=[CH:8]2
Reactant: COC(=O)Cc1cc2cccnc2cc1F
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1cc2cc(Br)cnc2cc1F
Temperature: 25 °C
Yield: 73 %

Procedure:
To a mixture of (7-fluoro-quinolin-6-yl)-acetic acid methyl ester (14.0 g, 63.9 mmol) and pyridine (10.4 mL, 127.8 mmol) in 200 mL of carbon tetrachloride was added bromine (6.6 mL, 127.8 mmol) in a dropwise fashion. The mixture was heated to reflux for 2 hrs before being cooled to ambient temperature. The liquid in the flask was decanted and washed with NaHCO3 and water. The dark solid on the bottom of the flask was treated with NaHCO3 and dichloromethane. The combined organic layers were washed with water, dried (Na2SO4) and evaporated to dryness. The crude product was purified via flash column chromatography eluting with petroleum ether/ethyl acetate (40/1˜3/1) to return 13.9 g (75% yield) of the title compound as white crystalline solid. 1H NMR (DMSO-d6): δ 8.89 (s, 1H), 8.27 (m, 1H), 7.66˜7.74 (m, 2H), 3.87 (s, 2H), 3.74 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10]([O:12][C:13]3[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[CH:11][C:6]=2[C:5](=[O:20])[N:4]([CH2:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:3]1=[O:31].[Li+].CC([N-]C(C)C)C.[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]=[O:46])=[CH:43][CH:42]=1>C1COCC1.CC(=O)OCC.O>[Cl:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]([OH:46])[C:11]2[C:6]3[C:5](=[O:20])[N:4]([CH2:21][CH2:22][CH2:23][O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:3](=[O:31])[N:2]([CH3:1])[C:7]=3[N:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:43][CH:42]=1
Reactant: Cc1ccc(Oc2cnc3c(c2)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)cn1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Oc2cnc3c(c2C(O)c2ccc(Cl)cc2)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 6.7 %

Procedure:
To a solution of 1-methyl-6-((6-methylpyridin-3-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (450 mg, 1.06 mmol) in THF (8 mL) at −78° C. was added LDA (2M in THF, 2.11 mL, 4.24 mmol) dropwise. The reaction was stirred at −78° C. for 1 h. then a solution of 4-chlorobenzaldehyde (296.6 mg, 2.11 mmol) in THF (2 mL) was added dropwise. The reaction was stirred for 30 min at −78° C. then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 1:1) to give 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-6-((6-methylpyridin-3-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (40 mg, 6.7% yield) as an oil. LCMS: MH+ 567 and TR=1.400 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>ClCCl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:9][C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[NH2:1])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(N)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2cc(C)ccc2N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
400 mg of 2-amino-5-methylphenol was dissolved in 6.5 ml of dichloromethane, and 476 μl of triethylamine and 619 mg of p-toluene sulfonylchloride were added and stirred at room temperature for 1 hour. To the reaction mixture, 60 ml of water was added, and extracted with 60 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified using silica gel column chromatography (hexane:ethyl acetate=3:1) to yield 730.1 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]O)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][Cl:19])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(OCc2ccccc2)n1
Solvent: c1ccccc1
Product: ClCc1cccc(OCc2ccccc2)n1
Reaction time: 8 h

Procedure:
A mixture of 2-benzyloxy-6-hydroxymethylpyridine (1.5 g, 7.0 mmol) and thionyl chloride (10 mL, 137 mmol) in benzene (25 mL) was stirred at room temp. overnight. The product mixture was concentrated under vacuum. The residue was partitioned between chloroform and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 5% methanol in chloroform. Collection and concentration of appropriate fractions provided 2-benzyloxy-6-chloromethylpyridine as clear, colorless oil. This alkylating reagent was passed through a small plug of activated basic alumina immediately before use.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][N:18]=1>>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:19][N:18]=1
Reactant: BrCc1ccc(Br)nc1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(Cc2ccc(Br)nc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-Cyanophenyl) amino]pyrimidine and 2-bromo-5-(bromomethyl)pyridine
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:12]=[C:11]([NH:13]C(=O)OC(C)(C)C)[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([CH2:6][C:7]2[N:12]=[C:11]([NH2:13])[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CN2CCCC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(CN2CCCC2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.6 %

Procedure:
To a solution of tert-butyl 6-(pyrrolidin-1-ylmethyl)pyridin-2-ylcarbamate 82 (750 mg, 2.71 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (4.0 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 6 h and then concentrated under reduced pressure. Saturated aqueous Na2CO3 was added to the resulting residue until the solution pH reached 9. The mixture was then extracted with ethyl acetate (3×25 mL). The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure to afford 49 (440 mg, 92% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:7]([CH2:13][CH2:14][CH2:15][CH3:16])[C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[O:5][CH:6]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[OH:25][C:6]1[O:5][C:4]([N:7]([CH2:13][CH2:14][CH2:15][CH3:16])[C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[N:3][C:2]=1[CH3:1]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCN(C(=O)C(C)C)c1nc(C)co1
Solvent: ClCCl
Product: CCCCN(C(=O)C(C)C)c1nc(C)c(O)o1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
4-methyl-2-(N-butyl isobutyramido)oxazole (15 g., 0.067 m.) in dry methylene chloride (100 c.c.) was cooled to 0° C during the addition of m-chloroperbenzoic acid (16 g., 0.023 m.) over 1 hour. The mixture was then stirred at room temperature for 40 hours. The precipitated m-chlorobenzoic acid was then filtered off and the filtrate evaporated to dryness. The residue was taken in ether (100 c.c.) and stirred with 5% aqueous sodium sulphite solution for 1 hour. The organic phase was then separated and washed successively with aqueous sodium carbonate (× 2) and water, and then dried and evaporated to give a brown oil, 13.9 g.
Reaction SMILES: [CH2:1]1[O:38][C:37]2[CH:36]=[CH:35][C:5]([CH2:6][N:7]([S:22]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([O:32][CH3:33])=[CH:27][C:26]=3[CH3:34])(=[O:24])=[O:23])[C@H:8]([CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][C:3]=2[O:2]1.FC(F)(F)C(O)=O>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:1]1[O:38][C:37]2[CH:36]=[CH:35][C:5]([CH2:6][N:7]([S:22]([C:25]3[C:26]([CH3:34])=[CH:27][C:28]([O:32][CH3:33])=[CH:29][C:30]=3[CH3:31])(=[O:23])=[O:24])[C@H:8]([CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=2[O:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNS(C)(=O)=O)C(=O)OC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNS(C)(=O)=O)C(=O)O)c(C)c1
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A solution of tert-butyl 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionate (1.37 g, 2 mmol) in 20% trifluoracetic acid-methylene chloride (15 ml) was stirred for 1 hour. Extra trifluoroacetic acid (0.5 ml) was added and stirring continued for two hours. The material was then condensed on the rotary evaporator and the residue was taken up in toluene (40 ml) and again condensed. This procedure was repeated twice (2×40 ml toluene, to remove traces of trifluoracetic acid) to provide 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionic acid as a tan green foamy solid (1.02 g).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[C:5]=1[NH2:6])([O-:3])=[O:2].N1C=CC=CC=1.[F:24][C:25]([F:30])([F:29])[C:26](Cl)=[O:27].FC(F)(F)C(O)=O>C(O)C>[N+:1]([C:4]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[C:5]=1[NH:6][C:26](=[O:27])[C:25]([F:30])([F:29])[F:24])([O-:3])=[O:2]
Reactant: Nc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=C(Cl)C(F)(F)F
Solvent: CCO
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-])C(F)(F)F

Procedure:
A solution of 25.1 g. of 2,6-dinitro-4-trifluoromethylaniline in 100 ml. of pyridine was treated with trifluoroacetyl chloride, which has been prepared from 10 ml. of trifluoroacetic acid. Ethanol was added to the resulting mixture until it was homogeneous, and the reaction mixture was then evaporated under vacuum. The residue after evaporation was washed with water, dried, dissolved in acetone, and filtered. Chloroform was added to the filtrate until the product precipitated. The precipitate was separated by filtration and dried to obtain the purified intermediate, 2',6'-dinitro-4'-trifluoromethyl-2,2,2-trifluoroacetanilide.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[SH:34]>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)[O:4][C:3](=[O:25])[C:2]([S:34][C:28]3[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:27]=3[Cl:26])=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: Sc1cccc(Cl)c1Cl
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3cccc(Cl)c3Cl)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 2,3-dichlorothiophenol was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: [C-:1]#[C-:2].[Li+].[Li+].[Cl:5][CH2:6][CH2:7][CH2:8][CH2:9]C(=O)C.O.[O:14]1[CH2:19][CH2:18]OCC1>>[Cl:5][CH2:6][CH2:7][CH2:8][CH2:9][C:19]([OH:14])([CH3:18])[C:1]#[CH:2]
Reactant: CC(=O)CCCCCl
Reactant: [C-]#[C-]
Reactant: C1COCCO1
Agent: [Li+]
Solvent: O
Product: C#CC(C)(O)CCCCCl

Procedure:
200 g (2.17 mol) of lithium acetylide in the form of the ethylenediamine complex were suspended in 800 ml of dry dioxane and, while stirring vigorously and cooling in ice, 269.2 g (2.0 mol) of 1-chloro-5-hexanone were rapidly added dropwise, during which the temperature rose to 48° C. The exothermic reaction was allowed to subside while stirring for 3 hours without further external cooling, 500 ml of water were cautiously added, the mixture was filtered, most of the dioxane was distilled off under reduced pressure, the aqueous phase was extracted exhaustively with chloroform, the extract was dried over sodium sulfate, the solvent was evaporated off under reduced pressure, and the residue was subjected to fractional distillation.
Reaction SMILES: [BH4-].[Na+].CO.[Cl:5][C:6]1[CH:29]=[C:28]([F:30])[C:27]([NH:31]C(=O)C(F)(F)F)=[CH:26][C:7]=1[O:8][C:9]1[CH:23]=[CH:22][C:12]2[N:13]=[C:14]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[S:15][C:11]=2[C:10]=1[C:24]#[N:25]>C(O)C>[NH2:31][C:27]1[C:28]([F:30])=[CH:29][C:6]([Cl:5])=[C:7]([CH:26]=1)[O:8][C:9]1[CH:23]=[CH:22][C:12]2[N:13]=[C:14]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])[S:15][C:11]=2[C:10]=1[C:24]#[N:25]
Reactant: N#Cc1c(Oc2cc(NC(=O)C(F)(F)F)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: N#Cc1c(Oc2cc(N)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a solution of sodium borohydride (266 mg, 7.02 mmol) in ethanol (10 mL) was added dropwise methanol (1 mL), and N-(6-{2-chloro-4-fluoro-5-[(trifluoroacetyl)amino]phenoxy}-7-cyano-1,3-benzothiazol-2-yl)cyclopropanecarboxamide (350 mg, 0.70 mmol) was added to the suspension. The reaction mixture was stirred at 60° C. for 1 hr, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (100 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (50 ml) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (ethyl acetate/n-hexane=50/50), and the band containing the object product was scraped off, and eluted with 10% tetrahydrofuran/ethyl acetate. The obtained solution was purified by basic silica gel column chromatography (eluate: ethyl acetate). The obtained solution was concentrated under reduced pressure to give the title compound (180 mg, 64%) as a white powder.
Reaction SMILES: [OH:1][CH:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[S:5](=[O:12])(=[O:11])[N:4]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:3]1.C([Li])CCC.[S:26](=[O:28])=[O:27].[NH2:29]OS(O)(=O)=O.[ClH:35]>>[ClH:35].[OH:1][CH:2]1[C:7]2[CH:8]=[C:9]([S:26]([NH2:29])(=[O:28])=[O:27])[S:10][C:6]=2[S:5](=[O:12])(=[O:11])[N:4]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:3]1
Reactant: O=S=O
Reactant: NOS(=O)(=O)O
Reactant: O=S1(=O)c2sccc2C(O)CN1CCN1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Product: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)N(CCN1CCOCC1)CC2O

Procedure:
The product from Step A (1.84 g, 5.79 mmol) was treated sequentially with n-butyllithium (2.2 equivalents), sulfur dioxide, hydroxylamine-O-sulfonic acid and methanolic HCl in much the same was as described in Example 4 to furnish the desired product as a white solid: mp 118°-125° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][O:9][CH:8]=1.[C:12]1(=[O:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.[Cl-].[NH4+]>CCCCCC.CCOCC.C1COCC1>[O:9]1[CH:10]=[CH:11][C:7]([C:12]2([OH:21])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[CH:8]1
Reactant: O=C1CCc2ccccc21
Reactant: Brc1ccoc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: OC1(c2ccoc2)CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104 %

Procedure:
To a solution of 2.7 ml (0.027 mol) of 10M n-butyllithium in hexane in 70 ml of ether cooled to -78° C. was added 4 g (0.027 mol) of 3-bromofuran and the mixture was stirred for 15 min. To the above cooled mixture was added 3.17 g (0.024 mol) of indanone in 10 ml of THF and the mixture was allowed to warm to room temperature, and then stirred for 20 min. To the mixture was added saturated ammonium chloride solution and the resulting mixture was extracted with ethyl acetate (3×100 ml), and the organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 5 g of crude 1-(3-furyl)-indan-1ol, as an orange oil, which was used directly in the next step.