Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[O:6]=[C:7]([N:21]1[CH2:26][CH2:25][N:24]2[C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=[C:23]2[CH2:22]1)[CH:8]=[C:9]([NH2:20])[CH2:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[F:19].CC(O)C.N>C1COCC1.O>[O:6]=[C:7]([N:21]1[CH2:26][CH2:25][N:24]2[C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=[C:23]2[CH2:22]1)[CH2:8][CH:9]([NH2:20])[CH2:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[F:19]
Reactant: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: CS(=O)(=O)O
Agent: N
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: -10 °C
Reaction time: 4 h

Procedure:
In a 50 mL round bottom flask dry THF (17 mL) was taken. It was cooled to −10° C. and 2.0 M Borane methyl sulfide complex solutions in THF (7.41 mL) were added. After that methanesulfonic acid (2.4 mL) was added dropwise at −10° C. over a period of 15-30 min. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine (2.0 g) is mixed in a solvent mixture of THF (5.0 mL) and IPA (5.0 mL) and added into the reaction mixture, keeping the temperature between −10 to −5. It was stirred for 4 h at −10 to −5° C. Reaction mixture was poured into cold water. It was basified by adding aq. ammonia solution. Product was extracted in ethyl acetate. The organic layer was collected, was washed with water and dried over anhydrous sodium sulfate. Solvent was evaporated at reduced pressure to obtain the product. (Wt.-2.0 g, % Y-100%, % H2O-5.18%, % Purity by HPLC-96.6%). XRD-amorphous-FIG. 1
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl-].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][Zn+]>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([F:14])[CH:16]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: Fc1cccc(C[Zn+])c1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Agent: [Cl-]
Product: COC(=O)c1cc(Cl)cnc1Cc1cccc(F)c1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 58 from methyl 2,5-dichloronicotinate and 3-fluorobenzylzinc chloride: 1H-NMR (CDCl3) δ 8.65 (1H, d, J=2.4 Hz), 8.19 (1H, d, J=2.6 Hz), 7.26–6.84 (4H, m), 4.54 (2H, s), 3.89 (3H, s).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=1)[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].Cl.O>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[OH:3][CH:4]([C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:26][CH:27]=1)[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a solution of zinc chloride (7.39 g, 54.2 mmol) in diethyl ether (150 ml) was added sodium borohydride (4.11 g, 108.5 mmol) and the mixture was stirred at room temperature for 30 min. Insoluble material was filtered off and a solution of ethyl 3-oxo-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate (12 g, 27.1 mmol) in diethyl ether (50 ml) was added to the filtrate. The mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid was added to the reaction solution under ice-cooling to quench the reaction. Water (200 ml) was added and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give ethyl(2RS,3RS)-3-hydroxy-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionate (11.9 g, 99%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[N+:13]([C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19])([O-:15])=[O:14]>>[N+:13]([C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:19])([O-:15])=[O:14]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CN1CCc2c(N)cccc2C1
Product: CN1CCc2c(cccc2NC(=O)c2ccccc2[N+](=O)[O-])C1

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline was reacted with 2-nitrobenzoyl chloride according to the procedure of Example 19 to yield 5-(2-nitrobenzamido) -2-methyl - 1,2,3,4-tetrahydroisoquinoline; m.p. 196.5°-198° C. after purification from ethanol.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:7]1)C.[BH4-].[Li+].O>C1COCC1>[NH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[C:14]1[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][CH:6]([CH2:5][CH2:4][OH:3])[CH2:7]1)=[O:13]
Reactant: CCOC(=O)CC1CCCN(C(=O)c2cc3ccccc3[nH]2)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1cc2ccccc2[nH]1)N1CCCC(CCO)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.1 %

Procedure:
To a solution of 500 mg of indole-2-carboxylic acid and 530 mg of ethyl piperidin-3-yl acetate in 8 mL of DMF were added 610 mg of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride and 430 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 2 hours. 0.5M aqueous hydrochloric acid was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with 0.5M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 519 mg of ethyl[1-(1H-indol-2-ylcarbonyl)piperidin-3-yl]acetate. To a solution of 392 mg of the resulting ethyl[1-(1H-indol-2-ylcarbonyl)piperidin-3-yl]acetate in 7 mL of THF was added 30 mg of lithium borohydride, followed by stirring at room temperature for 1 day. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [hexane:ethyl acetate=1:0-2:1], and then crystallized from diisopropyl ether to obtain 92 mg of 2-[1-(1H-indol-2-ylcarbonyl)piperidin-3-yl]ethanol as a white solid.
Reaction SMILES: O/[C:2](/[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[C:3](/[C:10]#[N:11])\[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].O=P(Cl)(Cl)Cl.C([N:24](CC)CC)C>C(Cl)Cl>[NH2:24]/[C:2](/[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[C:3](/[C:10]#[N:11])\[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCN(CC)CC
Reactant: CCC(CC)/C(O)=C(\C#N)C(=O)OC(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC(CC)/C(N)=C(\C#N)C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
24.4 g (0.11 mol) of isopropyl (2Z)-3-hydroxy-2-cyano-4-ethyl-2-hexenoate were dissolved in CH2Cl2 and, at 25° C., 33.2 g (0.22 mol) of POCl3 were added. After cooling to 0° C., 43.8 g (0.44 mol) of triethylamine were added dropwise, and the mixture was stirred at 25° C. for 2 h. The solution was then concentrated and the residue was taken up in acetonitrile and cooled to 0° C., and 30 g (0.44 mol) of a 25 percent strength solution of ammonia were added dropwise. After 2 h of stirring, the mixture was concentrated to dryness, the residue was taken up in MTBE (methyl tert-butyl ether) and the organic phase was washed with NaOH and water, dried and concentrated. Purification by customary methods gave 10 g (40% of theory) of the title compound as a colorless solid (m.p. 140° C.).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17]Cl)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[H-].[Na+]>O1CCOCC1>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17][O:26][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Reactant: CCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCCCOCc1cc(C)cc(-n2nc3ccccc3n2)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (1.0 g, 3.2 mmol) is partly solved in dioxane (19 g) at 80° C. and 1-hexanol (6.6 g, 65 mmol) and sodium hydride (0.2 g, 4.3 mmol, 60% in mineral oil) are added subsequently. The orange reaction mixture is stirred at 80° C. for 2 hours and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with aqueous citric acid (5%) and brine. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:30) to yield 940 mg of 2-(2H-Benzotriazol-2-yl)-6-hexyloxymethyl-4-methyl-phenol.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][NH:26]1>C(#N)C>[O:13]1[C:14]2[CH:18]=[CH:17][S:16][C:15]=2[C:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[O:4][CH2:3][CH2:2][N:26]2[CH2:27][CH2:28][C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25]2)=[N:12]1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(OCCN2CCc3ccccc3C2)cc(-c2noc3ccsc23)c1
Temperature: 75 °C
Yield: 61.5 %

Procedure:
Mix 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole (0.400 g, 1.23 mmol), potassium carbonate (0.345 g, 2.50 mmol), 1,2,3,4-tetrahydroisoquinoline (0.532 g, 3.99 mmol) and acetonitrile (5.0 mL) and heat at 75° C., overnight. Cool the reaction mixture and filter through a Waters Sep-Pak 1 g silica cartridge (ethyl acetate). Combine the appropriate fractions and concentrate to give a residue. Purify the residue by column (10 g silica) chromatography using a graded solvent mixture of 10% ethyl acetate in dichloromethane to 20% ethyl acetate in dichloromethane. Dissolve the free base in ethanol and acidify with ethereal hydrochloric acid, concentrate to a sticky residue, triturate (methanol:ethyl acetate) and collect the powder. Recrystallize the powder (methanol:ethyl acetate) to obtain the title compound as white crystals (0.285 g, 56%). mp=202–204° C. Microanalysis (C, H, N) is consistent with the final, desired compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[S:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]([O:15]CC)=[O:14])=[CH:9][C:7]=2[N:8]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][CH2:3][C:4]1[S:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:7]=2[N:8]=1
Reactant: CCOC(=O)c1ccc2sc(COC)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCc1nc2cc(C(=O)O)ccc2s1

Procedure:
A mixture of 2.1 g (8.36 mmol) of ethyl 2-methoxymethylbenzothiazole-5-carboxylate and 16 mL of 2N sodium hydroxide solution was stirred into 60 mL ethanol for 1 hour at room temperature. Then the alcohol was distilled off, the crude product was taken up in 20 mL water, washed with 50 mL diethylether, and the aqueous phase was acidified with concentrated hydrochloric acid while being cooled with ice. The pinkish-beige compound thereby precipitated was suction filtered, washed with water, and dried. Yield: 1.6 g (86% of theory); Rf value: 0.12 (silica gel; dichloromethane/ethanol=29:1).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[Br:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)=[O:38])=[CH:33][C:32]=1[F:46]>C(Cl)Cl>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)([C:2]2[N:3]=[CH:4][N:5]([C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=2)[OH:38])=[CH:33][C:32]=1[F:46]
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Br)c(F)c1
Agent: CC[Mg]Br
Solvent: ClCCl
Product: OC(c1ccc(Cl)cc1)(c1ccc(Br)c(F)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 3 h

Procedure:
4-Iodo-1-trityl-1H-imidazole (1.39 g, 3.18 mmol) was dissolved in anhydrous CH2Cl2 (10 mL). To this solution was added a 3.0M solution of ethylmagnesium bromide (1.11 mL, 3.34 mmol) and stirred under Ar. After 3 hr, a solution of (4-bromo-3-fluoro-phenyl)-(4-chloro-phenyl)-methanone (1.00 g, 3.18 mmol) dissolved in CH2Cl2 (5 mL) was added dropwise and the resulting solution was stirred overnight. The reaction was quenched with satd. NH4Cl solution, diluted with satd. NaHCO3 solution to pH=8.5, and extracted with CH2C2 (3×). The combined organic layers were dried (MgSO4), concentrated and purified using SiO2 chromatography (10-20% EtOAc/Hexane) to yield the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([F:22])[CH:13]=1.[CH3:23]N(C)C=O.[H-].[Na+].CI>>[F:22][C:14]1[CH:13]=[C:12]([O:11][CH2:10][C:2]2[N:3]([CH3:23])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[C:19]([O:20][CH3:21])=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: CN(C)C=O
Reactant: COc1cc(C=O)c(F)cc1OCc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COc1cc(C=O)c(F)cc1OCc1nc2ccccc2n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.9 %

Procedure:
4-(1H-Benzimidazol-2-ylmethoxy)-2-fluoro-5-methoxy-benzaldehyde (142) (0.600 g, 2.0 mmol) was dissolved in N,N-dimethylformamide (15 mL, 190 mmol). After the addition of sodium hydride (60% dispersion in oil, 0.072 g, 3.0 mmol) the reaction was stirred for 15 minutes at room temperature. Methyl iodide (140 μL, 2.2 mmol) was added dropwise to the mixture. The reaction was stirred overnight at room temperature under an atmosphere of nitrogen. The solvent was evaporated to dryness under reduced pressure. Ethyl acetate was added and the organic portion was washed with water, dried over anhydrous sodium sulfate and concentrated. Purification with silica gel flash chromatography with a gradient of ethyl acetate in hexanes gave the desired compound as a white powder (143, 0.345 g, 55%). MS (ESI) [M+H+]+=315.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[C:34]([CH3:39])([CH3:38])[CH2:33][C:32]3([CH3:41])[CH3:40])O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:37]3[CH:36]=[C:35]4[C:31](=[CH:30][CH:29]=3)[C:32]([CH3:41])([CH3:40])[CH2:33][C:34]4([CH3:39])[CH3:38])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC1
Reactant: CC1(C)CC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3ccc4c(c3)C(C)(C)CC4(C)C)n2)CC1

Procedure:
The preparation is carried out analogously to FS 102 starting from 4-(6-bromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (US 2005/176722) and 4,4,5,5-tetramethyl-2-(1,1,3,3-tetramethylindan-5-yl)-1,3,2-dioxaborolane.
Reaction SMILES: [CH2:1]([N:8]([C:13]1[CH:22]=[CH:21][C:16]([C:17](=[O:20])[CH2:18]Br)=[CH:15][CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH2:1]([N:8]([C:13]1[CH:22]=[CH:21][C:16]([CH:17]2[CH2:18][O:20]2)=[CH:15][CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1ccc(C(=O)CBr)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)N(Cc1ccccc1)c1ccc(C2CO2)cc1

Procedure:
4-[N-Benzylmethanesulphonamido]phenacyl bromide (30 g) and sodium borohydride (4 g) in ethanol (500 ml) were stirred at room temperature for 18 hours. The solvent was then removed and the residue was taken up in ethyl acetate and washed three times with sodium bicarbonate solution and three times with brine. The organic phase was dried and evaporated to give an oil which was chromatographed on silica, "Kieselgel 60" (Merck, Trade Mark), eluting with methylene chloride. The product-containing fractions were combined and evaporated to give a solid which was triturated with hexane and filtered off to give the title compound, yield 13 g, m.p. 89°-92°.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21](=O)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[CH3:30][N:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)N>>[CH3:1][CH:2]([CH3:29])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:31]([CH3:30])[C:21]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccccc3)CC2)c1
Reactant: CN(N)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCc3c(-c4ccccc4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(4-oxo-4-phenylbutyl)-4-piperidinyl]phenyl}propanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 480.3 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Li]CCCC.C(O[B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)(C)C>C1COCC1>[CH3:24][C:19]1([CH3:25])[C:20]([CH3:23])([CH3:22])[O:21][B:17]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[CH3:7])[O:18]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccsc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccsc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a stirred solution of 2-bromo-3-methylthiophene (337 mg, 1.9 mmol) in 8 mL of THF at −40° C. was added n-BuLi (0.8 mL, 2.5 M/hexanes), and the reaction was allowed to stir for 30 min. At this time 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (775 μL, 3.8 mmol) was added, and the reaction was allowed to warm to ambient temperature, and stirring was continued for 1 h. The reaction was then cooled to 0° C. and quenched with satd aq NaHCO3 (10 mL). The mixture was poured into EtOAc (100 mL), washed with H2O (2×50 mL), dried (Na2SO4) and concentrated in vacuo. Purification of the residue by silica gel preparative thin layer chromatography (20% EtOAc-hexanes) afforded 224 mg (53%) of the title compound as an oil. 1H-NMR (CDCl3; 400 MHz): δ 1.36 (s, 12H), 2.5 (s, 3H), 6.99 (d, 1H, J=4.8 Hz), 7.50 (d, 1H, J=4.8 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:40][N:39]=[C:38]([CH3:41])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:40][N:39]=[C:38]([CH3:41])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J14) (311 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as an off-white solid (210 mg, 39%).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([CH:27]([CH2:35][CH3:36])[CH2:28][CH:29]1[CH2:32][CH:31]([CH:33]=O)[CH2:30]1)[CH3:26].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:33][CH:31]1[CH2:32][CH:29]([CH2:28][CH:27]([CH2:25][CH3:26])[CH2:35][CH3:36])[CH2:30]1
Reactant: BrC(Br)(Br)Br
Reactant: CCC(CC)CC1CC(C=O)C1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(CC)CC1CC(C=C(Br)Br)C1
Reaction time: 0.33 h

Procedure:
To a solution of carbon tetrabromide (27.0 g) in methylene chloride (27 mL) was added dropwise a solution of triphenylphosphine (42.8 g) in methylene chloride (85 mL) at ice temperature. The mixture was stirred at ice temperature for 20 min., and then to the mixture was added dropwise a solution of 3-(2-ethylbutyl)cyclobutanecarbaldehyde in methylene chloride at ice temperature. After stirring at ice temperature for 40 min., saturated aqueous sodium bicarbonate (250 mL) was added dropwise to the mixture. The aqueous layer was removed, and the organic layer was washed with water (50 mL) and brine (50 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. To the residue were added hexane/chloroform=1/1 (100 mL), silica gel (50 g) and hexane (300 mL). The mixture was filtered and the filtrate was concentrated in vacuo. To the residue was added hexane (300 mL), and the mixture was filtered. The filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: hexane) to give the title compound (9.78 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([C:12]#[N:13])[CH:3]=1.[CH3:14][CH2:15][Mg+].[Br-]>CCOCC.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:8])[NH:13][C:12]32[CH2:15][CH2:14]3)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)cc1C#N
Reactant: CC[Mg+]
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Br-]
Solvent: CCOCC
Product: O=C1NC2(CC2)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 21 %

Procedure:
To a solution of methyl 4-chloro-2-cyanobenzoate (2.0 g, 10.2 mmol) in Et2O (40 mL) was added Ti(OiPr)4 (3.43 ml, 11.7 mmol). After cooling to 0° C., a 3.0 M solution of EtMgBr in Et2O (6.8 ml, 20.4 mmol) was added slowly. The reaction was warmed to room temperature and stirred for 3 h. Upon completion, the reaction was quenched with 1.0 M HCl (20 mL) then filtered over celite. The layers were separated and the aqueous layer was washed with EtOAc (2×20 mL). The combined organics were dried over Na2SO4, then filtered and concentrated. The crude product was purified by flash chromatography over silica gel (2-5% MeOH/DCM eluent) to provide 6′-chlorospiro[cyclopropane-1,1′-isoindolin]-3′-one (400 mg, 21% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (br. s., 1H), 7.66 (d, J=8.5 Hz, 1H), 7.40-7.54 (m, 2H), 1.47 (dt, J=11.2, 2.8 Hz, 4H); MS m/z C10H8ClNO [M+1]+=194.6.