Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=1[C:15]([CH3:19])([CH3:18])[C:16]#[N:17].Cl[CH2:21][C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23].O>CN(C=O)C>[CH:24]1([C:22](=[O:23])[CH2:21][O:14][C:12]2[CH:11]=[CH:10][C:9]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])=[C:8]([F:7])[CH:13]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)(C#N)c1ccc(O)cc1F
Reactant: O=C(CCl)C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C#N)c1ccc(OCC(=O)C2CCCC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.1 %

Procedure:
Potassium carbonate (3.1 g, 22 mmol) was added to a solution of 2-(2-Fluoro-4-hydroxy-phenyl)-2-methyl-propionitrile (1.0 g, 6.0 mmol) and 2-Chloro-1-cyclopentyl-ethanone (3.3 g, 22 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 16 hours. The mixture was poured into water (100 mL) and extracted with EtOAc (2×50 mL). The organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (0-15% EtOAc in hexanes) to give the product (1.2 g, 75% yield) as a clear oil. 1H NMR (300 MHz, CDCl3) δ: 1.57-1.93 (m, 14H), 3.10 (m, 1H), 4.64 (s, 2H), 6.65 (d, J=9.6 Hz, 2H), 7.37 (t, J=8.9 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20]CC4C=CC=CC=4)[CH:18]=3)[C:13]([C:28]#[N:29])=[CH:12]2)=[CH:7][C:6]=1[O:30][CH2:31][O:32][CH3:33])[CH3:2].C(OCC)(=O)C>[C].[Pd].CO>[CH2:1]([O:3][C:4](=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=3)[C:13]([C:28]#[N:29])=[CH:12]2)=[CH:7][C:6]=1[O:30][CH2:31][O:32][CH3:33])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(OCc4ccccc4)cc32)cc1OCOC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(O)cc32)cc1OCOC
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(6-benzyloxy-3-cyanoindol-1-yl)-2-methoxymethoxybenzoic acid ethyl ester in a mixed solvent of ethyl acetate (60 mL) and methanol (60 mL) was added palladium-carbon powder (0.61 g) under argon atmosphere at 0° C. and this mixture was stirred at 40° C. under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (2.5 g)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.[OH-].[Na+]>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:8]2[C:9]3[CH:10]=[C:2]([F:1])[CH:3]=[C:4]([NH2:11])[C:5]=3[CH:6]=[CH:7]2)=[CH:15][CH:14]=1
Reactant: Nc1cc(F)cc2[nH]ccc12
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(F)cc2c1ccn2Cc1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
A mixture of 6-fluoro-1H-indol-4-amine (5 g, 0.033 mol), 4-chlorobenzyl chloride (5.55 g, 0.035 mol) and sodium hydroxide (1.32 g, 0.033 mol) was heated at 60° C. for 3 h. The solvent was evaporated and the residue was dissolved in EA (150 mL) and water (70 mL). The aqueous layer was extracted with EA and washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography (PE: EA=8:1) to afford the title compound. LC/MS m/z=275.1 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:24]#[N:25])[N:6]=1)=O.Cl.[NH2:27][CH2:28][CH2:29][S:30]([NH2:33])(=[O:32])=[O:31].C[O-].[Na+]>CCO>[S:30]([CH2:29][CH2:28][NH:27][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:24]#[N:25])[N:6]=1)=[O:2])(=[O:32])(=[O:31])[NH2:33]
Reactant: COC(=O)c1nc(C#N)c2ccc(=O)n(Cc3ccccc3)c2c1O
Reactant: NCCS(N)(=O)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1nc(C(=O)NCCS(N)(=O)=O)c(O)c2c1ccc(=O)n2Cc1ccccc1
Temperature: 140 °C
Yield: 22.6 %

Procedure:
A mixture of 1-benzyl-5-cyano-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (20 mg, 0.060 mmol), 2-amino-ethanesulfonic acid amide HCl salt (30 mg, 0.24 mmol), and NaOMe (13 mg, 0.23 mmol) in EtOH (2 mL) was heated at 140° C. for 6 h in a microwave reactor. The mixture was concentrated to dryness, and the residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stiffing until pH about 1, and the aqueous layer was extracted with additional EtOAc. The organic layers were combined, dried over MgSO4, and concentrated. The crude product was first purified by column chromatography (0-5% MeOH/CH2Cl2), then by preparative TLC (10% MeOH/CH2Cl2) to give 5.8 mg of the title compound. MS: (−) m/z 426.24 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([OH:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:5]2=[N:6][CH:7]=1.C(OC(=O)[C:33](Cl)([F:35])[F:34])C.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH:33]([F:35])[F:34])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][N:8]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)C(F)(F)Cl
Reactant: C[C@H](c1c(O)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H](c1c(OC(F)F)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Temperature: 70 °C

Procedure:
A mixture of tert-butyl 5-bromo-3-[(1S)-1-(2-chloro-3-fluoro-6-hydroxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (1.00 g, 2.13 mmol), chlorodifluoroacetic acid ethyl ester (2.700 mL, 21.29 mmol), K2CO3 (882.7 mg, 6.387 mmol) and DMF (40 mL, 500 mmol) was heated to 70° C. for 6 h in a sealed tube. The material was extracted with EtOAc, and washed with water (3×). The organic layer was purified via column chromatography, eluting with 3-10% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a light yellow solid. 1H NMR (400 MHz, CD3OD): δ=1.67-1.69 (m, 9H), 1.80 (d, J=7.1 Hz, 3H), 4.94-5.03 (m, 1H), 6.63 (s, 1H), 7.15 (dd, J=9.1, 4.5 Hz, 1H), 7.22-7.28 (m, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H). MS (ES+): m/z=519.03/521.03 (75/100) [MH+]. HPLC: tR=1.93 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Br[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1>[Cu]>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Brc1ccc2ccccc2c1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Cu]
Product: O=[N+]([O-])c1ccc(-c2ccc3ccccc3c2)cc1

Procedure:
202 g of 1-bromo-4-nitrobenzene and 207 g of 2-bromonaphthalene were subjected to Ullmann coupling using a copper catalyst. The product was purified by a column chromatography to obtain 2-(4-nitrophenyl)naphthalene. The product was reduced using a reduced iron to obtain 2-(4-aminophenyl)naphthalene (yield: 36%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3[S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[C:15]([C:32]3[O:33][C:34]([CH2:37]Cl)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>C(#N)C>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3[S:22]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)(=[O:23])=[O:24])=[C:15]([C:32]3[O:33][C:34]([CH2:37][N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CCl)o4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Reactant: C1COCCN1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CN5CCOCC5)o4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Temperature: 80 °C
Yield: 96.1 %

Procedure:
N-(2-Chloro-5-{4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-methylphenyl)sulfonyl]-1H-indazol-6-yl}-3-pyridinyl)methanesulfonamide (50 mg, 0.084 mmol) and morpholine (0.015 ml, 0.169 mmol) were placed in acetonitrile (5 ml) and the mixture heated at 80° C. for 4 h. Further morpholine (15 μl) was added and the reaction was continued to heat overnight. The mixture was cooled to room temperature and the mixture loaded onto an SCX (5 g) cartridge. The cartridge was washed with methanol and then eluted with 2M ammonia in methanol. The mixture was purified by chromatography on silica (20 g) cartridge eluting with 0-100% ethyl acetate in cyclohexane followed by 0-20% methanol to give the title compound (52 mg).
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3]C1.P(Cl)(Cl)(Cl)(Cl)Cl.O.[CH:15]([Cl:18])(Cl)[Cl:16]>>[Cl:16][C:15]1([Cl:18])[CH2:3][CH2:4][CH2:5][NH:6][C:1]1=[O:7]
Reactant: ClC(Cl)Cl
Reactant: O=C1CCCCN1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Product: O=C1NCCCC1(Cl)Cl
Yield: 85 %

Procedure:
Part A. δ-Valerolactam (22.22 g, 222.89 mmol) was stirred in CHCl3 (500 mL) at 0° C. PCl5 (140.0 g, 68.29 mmol) was added portionwise. The resulting slurry was stirred at reflux for 3 h until the solution became clear. The mixture was cooled in an ice bath and H2O was added carefully until the PCl5 was quenched completely. The two layers were separated. The organic layer was washed with H2O (3×) and brine (2×), dried over MgSO4, filtered, and concentrated to dryness to give 3,3-dichloro-2-piperidinone (31.63 g, yield: 85%). This solid (16.50 g, 98.80 mmol) was dissolved in DMF (20 mL), and Li2CO3 (21.93 g, 296.40 mmol, 3.0 eq) was added. The mixture was stirred at 120° C. for 1 day. The solvent was further concentrated, and 1N HCl was added to acidify the mixture. It was then extracted with CHCl3 (6×). The organic layers were washed with H2O, brine, dried over MgSO4, and concentrated to dryness to give almost pure 3-chloro-5,6-dihydro-2(1H)-pyridinone (11.13 g, 87%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.O1CCOCC1.[Pd]>[NH2:1][C:4]1[C:5]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: Nc1cccnc1Nc1ccccc1
Yield: 70.7 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 6.9 g of 3-nitro-2-phenylaminopyridine (prepared as described in Preparation 83) was hydrogenated in a mixture of 150 ml of ethanol and 50 ml of dioxane in the presence of 1.38 g of 10% w/w palladium-on-charcoal. After working up the product as described in Example 6, 4.2 g of the title compound, melting at 137-140° C., were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]2[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[CH3:18].[CH:20]1[CH:21]=[CH:22][N:23]2[CH2:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[NH:26][CH2:25][C:24]=12>>[CH:20]1[CH:21]=[CH:22][N:23]2[CH2:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]([C:13]([C:12]3[CH:16]=[CH:17][C:9]([C:6]4[CH:7]5[CH2:8][CH:3]([CH2:4][CH:5]=4)[C:2]5([CH3:1])[CH3:19])=[C:10]([CH3:18])[CH:11]=3)=[O:14])[CH2:25][C:24]=12
Reactant: Cc1cc(C(=O)O)ccc1C1=CCC2CC1C2(C)C
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C1=CCC2CC1C2(C)C
Yield: 86.2 %

Procedure:
4-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-en-2-yl)-3-methyl-benzoic acid of Step B (0.360 g, 1.40 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.284 g, 1.54 mmol) were reacted in the manner of Example 15, Step D. Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from ethyl acetate afforded the title compound (0.510 g) as white crystals, m.p. 187° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH3:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[N:6][CH:7]=1.[CH2:18]([O:20][C:21]([C:23]1([CH:27]=O)[CH2:26][CH2:25][CH2:24]1)=[O:22])[CH3:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:18]([O:20][C:21]([C:23]1([CH2:27][NH:1][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]3[N:9]([CH3:17])[C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:3]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])[CH3:19]
Reactant: CCOC(=O)C1(C=O)CCC1
Reactant: Cn1c(-c2cncc(N)c2)cc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1(CNc2cncc(-c3cc4ccccc4n3C)c2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(5-amino-pyridin-3-yl)-1-methyl-1H-indole (Example 100, 0.400 g, 1.756 mmol) and 1-formyl-cyclobutanecarboxylic acid ethyl ester (0.457 g, 2.633 mmol) in dichloromethane (13 mL) is added acetic acid (0.102 g, 1.756 mmol) and the mixture is refluxed. After 2 h, the mixture is cooled with an ice-water bath and sodium tri-acetoxyborohydride (1.175 g, 5.267 mmol) is added. After 13 h, the mixture is heated to reflux for 1.5 h, cooled to room temperature, diluted with dichloromethane, washed with 1M aqueous NaOH, water and brine. The combined aqueous phase is extracted once with dichloromethane and the combined organic phase is dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:1) to give 1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutanecarboxylic acid ethyl ester as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.28 (t, J=7.1 Hz, 3H), 1.99-2.12 (m, 4H), 2.49-2.59 (m, 2H), 3.53 (d, J=5.8 Hz, 2H), 3.78 (s, 3H), 4.12-4.18 (m, 1H), 4.20 (q, J=7.1 Hz, 2H), 6.61 (d, J=0.8 Hz, 1H), 7.04 (dd, J=2.8, 1.9 Hz, 1H), 7.15-7.19 (m, 1H), 7.26-7.30 (m, 1H), 7.39 (dd, J=8.2, 0.8 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 8.09 (d, J=2.8 Hz, 1H), 8.12 (d, J=1.9 Hz, 1H).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:14]=3[O:13][C:12]=2[C:24]=1[CH2:25][O:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32].[CH:33](N1CCCCC1)=[O:34].Cl>O1CCCC1.C(OCC)C>[CH3:23][O:22][C:20]1[CH:19]=[CH:18][C:15]2[N:16]([CH3:17])[C:11]3[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[C:24]([CH2:25][O:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[C:12]=3[O:13][C:14]=2[C:21]=1[CH2:33][OH:34]
Reactant: COCCOCOCc1c(OC)ccc2c1Oc1cc(OC)ccc1N2C
Reactant: O=CN1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCCOCOCc1c(OC)ccc2c1Oc1c(ccc(OC)c1CO)N2C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.1 %

Procedure:
8.9 ml of n-butyllithium solution were added under argon at -78° to a solution of 4.10 g (10.92 mmol) of 3,7-dimethoxy-4-[[(2-methoxyethoxy)methoxy]methyl]-10-methyl-10H-dibenzo-[b,e][1,4]oxazine in 10 ml of tetrahydrofuran and 40 ml of diethyl ether. The reaction mixture was brought slowly to 0° and stirred for 1.5 hours, whereupon the suspension was treated with 1.82 ml (1.5 eq.) of N-formylpiperidine, stirred at 0° for 30 minutes and poured into 100 g of ice, 100 ml of 0.1N hydrochloric acid solution and 150 ml of diethyl ether. The aqueous phase was extracted three times with chloroform and the combined organic phases were dried over MgSO4 and evaporated. The reddish residue was dissolved in 50 ml of tetrahydrofuran and treated at 0° under argon with 5 ml of lithium borohydride solution (2M in tetrahydrofuran). The reaction mixture was stirred at 0° for 30 minutes and then poured into 50 g of ice, 50 ml of saturated ammonium chloride solution and diethyl ether. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over MgSO4 and evaporated. The residue was chromatographed on 200 g of silica gel with ethyl acetate/hexane (2:1), whereupon, after drying in a high vacuum, 3.90 g (88.1%) of 3,7-dimethoxy-6-[[(2-methoxyethoxy)-methoxy]methyl]-10-methyl-10H-dibenzo[b,e][1,4]oxazine-4-methanol were obtained as a colourless solid of m.p. 68°-70°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)[C:6]([CH3:20])=[CH:5]2.C(Cl)(Cl)Cl.[OH:25]O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([CH3:19])=[O:25])=[CH:16][CH:17]=1)[C:6]([CH3:20])=[CH:5]2
Reactant: OO
Reactant: CSc1ccc(CC2C(C)=Cc3cc(F)ccc32)cc1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC1=Cc2cc(F)ccc2C1Cc1ccc(S(C)=O)cc1
Reaction time: 1 h

Procedure:
500 mg. (1.755 mm) of 5-fluoro-2-methyl-1-(p-methylthiobenzyl)-indene is dissolved in 5 ml. of chloroform. To this solution is added 30% hydrogen peroxide (equivalent to 2.645 mm). The reaction mixture is aged for one hour at room temperature followed by the addition of 5 ml. of glacial acetic acid and aged for an additional hour. The reaction mixture is then diluted with 25 ml. of 1:1 benzene-ether and extracted with 6 × 25 ml. of 3% aqueous sodium chloride. The solution is then dried over sodium sulfate and evaporated in vacuo to yield an oil. Recrystallization from ice-cold isopropanol gives 5-fluoro-2-methyl-1-(p-methylsulfinylbenzyl)-indene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.I[CH2:10][CH3:11]>>[CH2:10]([N:1]1[CH2:6][CH:5]=[C:4]([CH2:7][OH:8])[CH2:3][CH2:2]1)[CH3:11]
Reactant: OCc1ccncc1
Reactant: CCI
Product: CCN1CC=C(CO)CC1

Procedure:
The title compound was prepared from 4-pyridylcarbinol and iodoethane following a similar procedure to that described for the 1-methyl analogue in J. Med. Chem., 1988, 31, 545(92%).
Reaction SMILES: [H][H].[OH:3][C:4]([CH3:33])([CH3:32])[CH:5]([NH:7][C:8]1[C:20]2[C:19]3[CH:18]=[CH:17][C:16]([C:21]#[C:22][C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:15][C:14]=3[NH:13][C:12]=2[C:11]([C:29]([NH2:31])=[O:30])=[CH:10][N:9]=1)[CH3:6]>CCO.[Pd]>[OH:3][C:4]([CH3:32])([CH3:33])[CH:5]([NH:7][C:8]1[C:20]2[C:19]3[CH:18]=[CH:17][C:16]([CH2:21][CH2:22][C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[CH:15][C:14]=3[NH:13][C:12]=2[C:11]([C:29]([NH2:31])=[O:30])=[CH:10][N:9]=1)[CH3:6]
Reactant: CC(Nc1ncc(C(N)=O)c2[nH]c3cc(C#Cc4cccnc4)ccc3c12)C(C)(C)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(Nc1ncc(C(N)=O)c2[nH]c3cc(CCc4cccnc4)ccc3c12)C(C)(C)O

Procedure:
Hydrogen was bubbled through a solution of 1-[(2-hydroxy-1,2-dimethylpropyl)amino]-7-(pyridin-3-ylethynyl)-5H-pyrido[4,3-b]indole-4-carboxamide (10 mg, 0.024 mmol) and Pd/C (10%, 2.6 mg) in EtOH (1.3 mL). After complete conversion, the mixture was purged with nitrogen, filtered through a pad of Celite, and concentrate to afford the title compound. LRMS (APCI) calc'd for (C24H27N5O2) [M+H]+, 418.2. found 418.2.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[C:12]3/[C:13](=[O:21])[NH:14][C:15]4[C:20]/3=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:8][CH:9]=2)[NH:4][N:3]=1.I[C:23]1C2C(=CC(C=O)=CC=2)NN=1.CN1C2C(=CC=CC=2)CC1=O>>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[C:12]3/[C:13](=[O:21])[N:14]([CH3:23])[C:15]4[C:20]/3=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:8][CH:9]=2)[NH:4][N:3]=1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2c(I)n[nH]c2c1
Reactant: O=Cc1ccc2c(I)n[nH]c2c1
Agent: CN1C(=O)Cc2ccccc21
Product: CN1C(=O)/C(=C/c2ccc3c(I)n[nH]c3c2)c2ccccc21

Procedure:
According to the method described for (E)-3-((3-iodo-1H-indazol-6-yl)methylene)-indolin-2-one except substituting 3-iodo-1H-indazole-6-carbaldehyde (462 mg, 1.70 mmol) and 1-methylindolin-2-one (250 mg, 1.70 mmol), (E)-3-((3-iodo-1H-indazol-6-yl)methylene)-1-methylindolin-2-one was obtained (yellow-orange solid, 545 mg, 80%); MS ESI 402.2 [M+H]+, calcd for [C17H12IN3O+H]+ 402.01.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:13])([F:12])[S-:11].CN([S+](N(C)C)N(C)C)C.O>C(#N)C>[F:9][C:10]([S:11][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([F:13])[F:12]
Reactant: BrCc1ccccc1
Reactant: FC(F)(F)[S-]
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: O
Solvent: CC#N
Product: FC(F)(F)SCc1ccccc1
Yield: 82 %

Procedure:
Benzyl bromide, 16.2 g (0.095 mol), was added dropwise at 25° to 0.11 mol of tris(dimethylamino)sulfonium trifluoromethanethiolate (prepared as in Example 11) in 75 mL of acetonitrile. The reaction mixture was stirred one h and then poured into water. The aqueous mixture was extracted with ether, and the ether extracts were washed with water, dried (MgSO4), and distilled to give 15.1 g (82%) of benzyl trifluoromethyl sulfide as a colorless liquid: bp 55° (12 mm); 1H NMR (CDCl3) δ4.08 ppm (s, 2H), 7.33 ppm (s, 5H); 19F NMR (CDCl3) δ-42.5 ppm (s).
Reaction SMILES: [CH3:1][C:2]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)Cl>[O:26]1[CH2:17][CH:16]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:2]([CH3:1])([CH3:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCCCCCCOC(C)(C)C(=O)OC
Solvent: ClCCl
Product: COC(=O)C(C)(C)OCCCCCCCC1CO1
Yield: 101.3 %

Procedure:
Methyl 2-methyl-2-(8-nonenyloxy)propionate (40 g) was dissolved in 320 ml of methylene chloride, and 40.8 g of 70% 3-chloroperbenzoic acid was added with stirring under ice-cooling, and the mixture was stirred for 15 hours at room temperature. The reaction solution was filtrated to remove insolubles, and the filtrate was concentrated. The residue was dissolved in n-hexane and washed 4 times with aqueous 10% potassium carbonate solution, washed with water, dried over anhydrous magnesium sulfate and concentrated to give 43.2 g of the objective compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])=[CH2:9])=[CH:4][CH:3]=1.[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>C(O)C(F)(F)F.CC1C(C)=CC2N([C@H]3O[C@H](CO)[C@@H](OP(O[C@@H](CNC(CC[C@]4(C)[C@@H](CC(N)=O)[C@H]5[N-]C4=C(C)C4=NC(C(C)(C)[C@@H]4CCC(N)=O)=CC4=NC([C@](CC(N)=O)(C)[C@@H]4CCC(N)=O)=C(C)C4=N[C@]5(C)[C@](CC(N)=O)(C)[C@@H]4CCC(N)=O)=O)C)([O-])=O)[C@H]3O)C=NC=2C=1.O.[Co+2]>[CH2:17]([O:16][C:14]([CH:13]1[CH2:9][C:8]1([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[F:10])=[O:15])[CH3:18]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=C(F)c1ccc(Cl)cc1
Agent: [Co+2]
Agent: C/C1=C2/[N-][C@H]([C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(=O)([O-])O[C@H]2[C@@H](O)[C@@H](n3cnc4cc(C)c(C)cc43)O[C@@H]2CO)[C@]2(C)N=C(/C(C)=C3\N=C(/C=C4\N=C1[C@@H](CCC(N)=O)C4(C)C)[C@@H](CCC(N)=O)[C@]3(C)CC(N)=O)[C@@H](CCC(N)=O)[C@]2(C)CC(N)=O
Agent: CC1=C2[N-][C@H]([C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(=O)([O-])O[C@H]2[C@@H](O)[C@@H](n3cnc4cc(C)c(C)cc43)O[C@@H]2CO)[C@]2(C)N=C(C(C)=C3N=C(C=C4N=C1[C@@H](CCC(N)=O)C4(C)C)[C@@H](CCC(N)=O)[C@]3(C)CC(N)=O)[C@@H](CCC(N)=O)[C@]2(C)CC(N)=O
Solvent: OCC(F)(F)F
Solvent: O
Product: CCOC(=O)C1CC1(F)c1ccc(Cl)cc1
Yield: 68.5 %

Procedure:
Vitamin B12a (1.00 g; 0.723 mmol) was dissolved in dry trifluoroethanol (70 ml) and 1-chloro-4-(1-fluoro-vinyl)-benzene (6.50 g; 41.5 mmol) and ethyl diazoacetate (6.30 g; 50 mmol; 90% purity) was added. The solution was stirred, under reflux, under nitrogen atmosphere for 18 h. After cooling the solvent was evaporated and the residue purified by flash chromatography using 9:1 hexane/ethyl acetate. 6.9 g of 2-(4-chlorophenyl)-2-fluoro-cyclopropane carboxylic acid ethyl ester was obtained in the form of an oil (81% of theory) as a 7:3 mixture of cis/trans isomers.