Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=3[O-:28])[C:6]=2[CH:19]=1
Reactant: CC1(C)CC(c2ccccn2)c2cc(Br)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(Br)ccc2O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.1 %

Procedure:
330 mg of 6-bromo-3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 10 ml of dichloromethane at room temperature and 280 mg of m-chloroperbenzoic acid were added. After stirring at room temperature for 3 days the mixture was washed with sodium bisulphite solution, then with sodium bicarbonate solution and finally with water. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 4% (v/v) methanol/ethyl acetate for the elution to give 250 mg of 2-(6-bromo-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide as a foam. NMR (300 MHz, CDCl3): 8.35-8.30 (1H, m), 7.26-7.15 (3H, m), 7.13-7.05 (1H, dd, 6.95 (1H, broad s), 6.75 (1H, d, 9Hz), 5.28 (1H, broad s), 2.42 (1H, dd, 13Hz, 6Hz), 1.7 (1H, broad s), 1.42 (3H, s), 1.37 (3H, s). MS (EI); 335 (M+ ]Br81 ], 333 (H+ ]Br79 ]), 318 (M+ [Br81 ]-OH), 316 (M+ [Br79 ]-OH).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:6]=[CH:5]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]=[C:7]([CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:6]=[CH:5]4)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: Ic1ccc2nc(CN3CCCC3)ccc2c1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc4nc(CN5CCCC5)ccc4c3)nc2)cc1

Procedure:
Prepared according to general working method I from 6-iodo-2-pyrrolidin-1-ylmethyl-quinoline (151 mg, 0.45 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (80 mg, 0.37 mmol).
Reaction SMILES: CON(C)[C:4](=O)[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[C:12]([F:15])([F:14])[F:13].[CH:18]1[CH:19]=[CH:20][C:21]2[S:26][CH:25]=[CH:24][C:22]=2[CH:23]=1>>[S:26]1[C:25]([CH2:4][C:5]2[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=2[C:12]([F:15])([F:14])[F:13])=[CH:24][C:22]2[CH:23]=[CH:18][CH:19]=[CH:20][C:21]1=2
Reactant: c1ccc2sccc2c1
Reactant: CON(C)C(=O)c1cc(Br)ccc1C(F)(F)F
Product: FC(F)(F)c1ccc(Br)cc1Cc1cc2ccccc2s1

Procedure:
To a solution of the above N-methoxy-N-methyl-5-bromo-2-iodobenzamide (2.67 g) in N-methyl-2-pyrrolidinone (12 ml) were added copper (I) bromide (124 mg) and methyl fluorosulfonyl(difluoro)acetate (1.34 ml), and the mixture was stirred under heating for 1.5 hours. The reaction mixture was cooled to room temperature, and then, a diluted aqueous ammonia was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-85:15) to give N-methoxy-N-methyl-5-bromo-2-trifluoromethylbenzamide (1.59 g) as colorless oil. APCI-Mass m/Z 312/314 (M+H). (3) The above N-methoxy-N-methyl-5-bromo-2-trifluoromethylbenzamide and thianaphthene were treated in a manner similar to Reference Example 45 to give 1-(Benzo[b]thiophen-2-ylmethyl)-5-bromo-2-trifluoromethylbenzene as a colorless solid. ESI-Mass m/Z 369/371 (M−H).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1>ClCCl.C(#N)C>[Br:1][C:12]1[CH:11]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[CH:5]=2)[CH:15]=[CH:14][C:13]=1[OH:16]
Reactant: BrBr
Reactant: Oc1ccc(-c2cccc(F)c2)cc1
Solvent: CC#N
Solvent: ClCCl
Product: Oc1ccc(-c2cccc(F)c2)cc1Br
Reaction time: 17 h
Yield: 105.2 %

Procedure:
A solution of bromine (887 mg, 5.55 mmol) in dichloromethane (10 mL) was added dropwise to a solution of 4-(3-fluorophenyl)phenol [purchased from Combi-Blocks] (1.044 g, 5.55 mmol) in dichloromethane (10 mL) and acetonitrile (5 mL) at 0° C. under nitrogen. The reaction mixture was then stirred at 0° C. to room temperature for 17 hours. The reaction mixture was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL) containing 10% aqueous sodium thiosulfate solution (10 mL). The organic phase was separated, washed with water (100 mL) and saturated brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give an orange oil. The crude product was purified by chromatography on silica eluting with a solvent gradient of 0 to 15% ethyl acetate (containing 2% methanol) in hexanes to give 3-bromo-3′-fluoro-[1,1′-biphenyl]-4-ol (1.56 g, quant.) as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][N:11]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[C:12]([CH:14]2[CH2:19][CH2:18][N:17]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[O:13])[CH2:4][CH2:3]1.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>>[Cl:31][C:26]1[CH:25]=[C:24]([N:11]([CH2:10][CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([F:32])=[CH:34][CH:35]=3)[CH2:3][CH2:4]2)[C:12]([CH:14]2[CH2:19][CH2:18][N:17]([S:20]([CH3:23])(=[O:21])=[O:22])[CH2:16][CH2:15]2)=[O:13])[CH:29]=[CH:28][C:27]=1[Cl:30]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CS(=O)(=O)N1CCC(C(=O)N(CCCN2CCC(N)CC2)c2ccc(Cl)c(Cl)c2)CC1
Product: CS(=O)(=O)N1CCC(C(=O)N(CCCN2CCC(NC(=O)c3ccc(F)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Yield: 34 %

Procedure:
The title compound was prepared using a similar procedure to that described in example 195 from the title compound of example 199 and 4-fluorobenzoyl chloride. Yield 34%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)=O)[CH3:2].[CH3:15][NH:16][CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)[N:16]([CH3:17])[CH3:15])[CH3:2]
Reactant: CCOC(=O)C(=O)c1cccc(Br)c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)C(c1cccc(Br)c1)N(C)C
Temperature: 25 °C
Reaction time: 36 h
Yield: 15.7 %

Procedure:
A suspension of (3-bromo-phenyl)-oxo-acetic acid ethyl ester (2.0 g, 7.8 mmol), dimethylamine (19.5 mL, 2 N in THF, 39 mmol), and sodium triacetoxyborohydride (4.95 g, 23.4 mmol) in 1,2-dichloroethane (40 mL) was stirred at room temperature for 36 hours. Satuated sodium bicarbonate (50 mL) was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane to afford (3-bromo-phenyl)-dimethylamino-acetic acid ethyl ester (350 mg, 16%) as an oil. MS: m/z 286 (M+H+).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([OH:11])C>>[C:1]([O:11][CH3:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=Cc1ccccc1
Product: COC(=O)c1ccccc1

Procedure:
Substantially the same procedure as in Example 7 was repeated, except that the activated catalyst prepared in Example 4 was used, that benzaldehyde was used instead of the methacrolein, and that ethanol was used instead of the methanol, to thereby effect a reaction for producing methyl benzoate. Analysis was made with respect to the reaction mixture which was withdrawn from the outlet of the reactor 10 hours after the start of the reaction. As a result, it was found that the conversion of benzaldehyde was 76.2%, and the selectivity for methyl benzoate was 93.2%.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12](=[O:19])[C:11]=3[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][C:3]=2[O:2]1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([Mg]Br)[CH:30]=[CH:31][CH:32]=1>C1COCC1>[OH:19][C:12]1([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:32]=2)[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)=[C:11]1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Reactant: COc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1cccc(OC)c1
Reaction time: 0.25 h
Yield: 112.4 %

Procedure:
To a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (100 mg, 0.31 mmol) in THF (2 ml) under an argon atmosphere at 0° C. was added a solution of freshly prepared 3-methoxyphenyl magnesium bromide (0.31 mmol). After stirring for 15 min, additional 3-methoxyphenyl magnesium bromide (0.06 mmol) was added. Stirring was continued for 45 min, at which time thin layer chromatographic analysis indicated that the reaction was incomplete. Additional 3-methoxyphenyl magnesium bromide (0.12 mmol) was added. After stirring for 2 h more, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 15% EtOAc/hexanes to afford the title compound (150 mg, 100%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][C:10]=1[F:39].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:64][C:65]1[CH:72]=[CH:71][C:68]([C:69]#[N:70])=[CH:67][C:66]=1[O:73][CH3:74]>>[C:69]([C:68]1[CH:71]=[CH:72][C:65]([NH:64][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]3([C:12]4[C:11](=[C:10]([F:39])[C:9]([Cl:8])=[CH:14][CH:13]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:66]([O:73][CH3:74])[CH:67]=1)#[N:70]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)c(F)cc12
Reactant: COc1cc(C#N)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3c2ccc(Cl)c3F)C1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 174 (0.3 g, 0.5 mmol), was reacted with diisopropylethylamine (0.33 g, 2.5 mmol), diphenylphosphinic chloride (0.24 g, 1 mmol), then reacted with 4-amino-3-methoxy benzonitrile prepared in Example 57 (0.11 g, 0.8 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-7-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide as a off white solid (Yield 0.13 g, 33%).
Reaction SMILES: [CH:1](NC1CCCCC1)(C)C.C([Li])CCC.[CH2:16]([CH:19]1[N:22]([C:23]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])=[P:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21](=[O:53])[CH2:20]1)[CH:17]=[CH2:18]>O1CCCC1.CCCCCC>[CH2:16]([CH:19]1[N:22]([C:23]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])=[P:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:21](=[O:53])[CH:20]1[CH3:1])[CH:17]=[CH2:18]
Reactant: C=CCC1CC(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCC1C(C)C(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of N-isopropylcyclohexylamine (0.30 g) in dry tetrahydrofuran (5 ml) was stirred under argon and cooled to -78°. This was treated with a 2.5 M solution of n-butyl lithium in hexane (0.85 ml) and stirred for 10 minutes. A solution of 4-allyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidine-2-one (9) (0.50 g) in tetrahydrofuran (5 ml) was added and after 5 minutes the anion was quenched by addition of methyl iodide (0.12 ml). After a period of 10 minutes the reaction vessel was transferred to an ice bath and a further 10 minutes later the reaction was neutralized by addition of acetic acid (0.16 ml). The solvent was then stripped off and the residue partitioned between ethyl acetate and brine. The ethyl acetate solution was separated, washed with brine and dried over sodium sulphate. The product was subjected to careful column chromatography on silica gel 60 eluting with cyclohexane/ethyl acetate mixtures grading from 1:1 to 3:7. This gave 4-allyl-3-methyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidine-2-one (38) (0.10 g, 19%); νmax (CHCl3) 3000, 1735 and 1610 cm-1. Running closely behind this was recovered starting phosphorane (9) (0.17 g. 33%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([O:14]CC1C=CC=CC=1)[CH2:9]2)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([OH:14])[CH2:9]2
Reactant: O=C1c2c(cccc2[N+](=O)[O-])CN1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c1C(=O)N(O)C2
Yield: 609.2 %

Procedure:
To a solution of 7-nitro-2-benzyloxy-2,3-dihydro-1H-isoindol-1-one (Compound 186B, 2.3 g, 1.2 mmol) in methanol (30 mL) in a Parr hydrogenation flask was added 200 mg of 5% Pd/C. The mixture was hydrogenated under 40 psi hydrogen pressure at room temperature overnight. The reaction mixture was filtered through a glass filter paper and the filtrate was concentrated to afford 1.2 g of the pure product (90%). 1H NMR (CDCl3, 600 MHz): δ=4.57 (s, 2 H), 5.04 (br, 2 H), 6.57 (d, J=7.8 Hz, 1 H) 6.65 (d, J=7.5 Hz, 1 H), 7.25 (dd, J=7.5, 7.8 Hz, 1 H), 10.2 (s, br, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:18]=2)=O)[CH:5]=[C:6]([Br:10])[C:7]=1[O:8][CH3:9]>C(#N)C.P(Cl)(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Br:10])[C:7]=1[O:8][CH3:9])[CH2:11][CH:12]1[C:22]2[C:17](=[CH:18][C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1
Reactant: COc1c(Br)cc(CC(=O)NCCc2cccc(NS(C)(=O)=O)c2)cc1Br
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1c(Br)cc(CC2NCCc3cc(NS(C)(=O)=O)ccc32)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of 2-(3,5-dibromo-4-methoxy-phenyl)-N-[2-(3-methanesulfonylamino-phenyl)-ethyl]-acetamide in 15 mL of acetonitrile, phosphorus oxychloride is added. The reaction mixture is refluxed for 5 h. The residue after concentration is evaporated 3 times with MeOH, dissolved in 20 mL of MeOH, cooled with an ice bath, and NaBH4 is added by small portions. The reaction mixture is stirred overnight at room temperature, concentrated, dissolved in chloroform, washed with 1N NaOH, dried over Na2SO4, filtered, and concentrated. The residue is dissolved in methanol, and a solution of (COOH)2.2H2O in methanol is added.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([NH2:18])[CH2:13][CH2:12]2.N12CCCN=C1CCCCC2>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([NH:18][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])[CH2:13][CH2:12]2
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NC1CCc2cc(Br)ccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C. and under protective atmosphere, a solution of 2-Propanesulfonyl chloride (11.87 mL, 121 mmol) in DCM (121 mL) was added gradually to a solution of 5-bromo-2,3-dihydro-1H-inden-1-amine (12.8 g, 60.4 mmol) and 1,8-Diazabicyclo[5.4.0]undec-7-ene (4.83 mL, 32.1 mmol) in Dichloromethane (300 mL). The reaction was stirred at rt overnight. The reaction mixture was washed with 1N KHSO4 (1×) and sat NaHCO3 (2×) before being dried on Na2SO4 and solvent evaporated in vacuo to afford a green oil. Purification by column chromatography (25% EtOAc in heptane) afforded the title compound as a white solid.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[I:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:3]=1
Reactant: N#Cc1cc2c(I)n[nH]c2cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc2c(I)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cn1
Yield: 47.3 %

Procedure:
To a solution of 5.8 g of 3-iodo-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile in 70 mL of dichloromethane were added 13.1 mL of diisopropylethylamine, 2.4 g of tetra-n-butylammonium iodide and 12.0 g of trityl chloride at room temperature, and stirred at this temperature for a day. The solution was evaporated, diluted with ethyl acetate, washed successively with saturated ammonium chloride and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10), to afford 5.2 g of the title compound as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].CC(N(C)C)=O.[Br-].[CH:21]1([Zn+])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1>[CH:21]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: N#Cc1ccc(Br)c(C(F)(F)F)c1
Reactant: [Zn+]C1CCCCC1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(C2CCCCC2)c(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
A mixture of 4-bromo-3-(trifluoromethyl)benzonitrile (6 g, 24.00 mmol), DMA (30 mL), cuprous iodide (0.914 g, 4.80 mmol) and 1,1′-bis(diphenylphosphino) ferrocenedichloro palladium(II) dichloromethane complex (1.756 g, 2.400 mmol) was bubbled with nitrogen for 5 min. before 0.5 M THF solution of cyclohexylzinc bromide (100 mL, 50.0 mmol) was added over 20 min. via cannula at room temperature. The black reaction mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure. EtOAc (50 mL), water (100 mL) and saturated aqueous ammonium chloride solution (30 mL) were added. The solid was filtered off over a celite pad and washed with ethyl acetate (3×20 mL). The aqueous layer was separated and extracted with ethyl acetate (50 mL). The combined organic solutions were washed with 1 N aqueous HCl (2×40 mL) and then brine (40 mL), dried (sodium sulfate) and concentrated under reduced pressure. Flash chromatography purification (silica gel column, 20→100% ethyl acetate in hexanes) afforded 4-cyclohexyl-3-(trifluoromethyl)benzonitrile (2.77 g, 10.94 mmol, 45.6% yield) as a solid. The compound had an HPLC retention time=3.44 min. (condition C); LC/MS [M+H2O]+1=272.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)[CH3:2].[OH:13][C:14]1[CH:15]=[CH:16][C:17]2[C:18]([CH:22]=1)=[N:19][O:20][N:21]=2.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]2=[N:21][O:20][N:19]=[C:18]2[CH:22]=1)[CH3:2]
Reactant: Oc1ccc2nonc2c1
Reactant: CCOC(=O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccnc1Oc1ccc2nonc2c1
Temperature: 90 °C
Yield: 26.2 %

Procedure:
A mixture of 5.5 g (29.4 mmol.) 2-chloro nicotinic acid ethyl ester, 4.0 g (29.4 mmol.) 5-hydroxybenzofurazan and 20.1 g (61.7 mmol.) cesium carbonate in 125 ml dry dimethylforamide was heated at 90° C. for five days. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed successively with sodium bicarbonate solution, water, brine then dried (Na2SO4) and concentrated in vacuo to give a solid. Recrystallization from diethyl ether/pentane gave 2.2 g (26%) solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:25]=[N:26][N:27]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH:28]=2)[N:14]=1>CCOC(C)=O.CN(C=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:25]=[N:26][N:27]([CH:29]3[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])[CH2:33][CH2:34]3)[CH:28]=2)[N:14]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)ncc1C(F)(F)F

Procedure:
A solution of tert-butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (A134) (392 mg, 0.671 mmol) in EtOAc (40 mL) and DMF (2 mL) was stirred with 10% Pd/C (wetted with ca. 53% water, 100 mg) under a hydrogen atmosphere at room temperature overnight. The mixture was filtered through Celite and the filter cake was washed with EtOAc (50 mL). The volatiles were removed in vacuo and the resulting yellow oil was adsorbed onto silica gel and purified by silica gel column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. then 0-20% MeOH in EtOAc) to give the title compound (A135) as a yellow solid (300 mg, 76%), 1H NMR (400 MHz, Chloroform-d) δ 8.44 (s, 1H), 7.85 (s, 1H), 7.64-7.46 (m, 1H), 7.22-7.06 (m, 4H), 4.32-4.04 (m, 3H), 3.67 (s, 2H), 3.60 (s, 3H), 3.14-2.94 (m, 4H), 2.87-2.75 (m, 2H), 2.14-1.99 (m, 2H), 1.97-1.79 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: [NH:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3][C:2]1=[O:12].[C:13]([O:17][C:18]([NH:20][NH2:21])=[O:19])([CH3:16])([CH3:15])[CH3:14].C([BH3-])#N.[Na+]>CC(O)=O.O.[OH-].[Na+]>[C:13]([O:17][C:18]([NH:20][NH:21][CH:8]1[CH2:9][CH2:10][C:5]2([NH:1][C:2](=[O:12])[CH2:3][CH2:4]2)[CH2:6][CH2:7]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C1CCC2(CC1)CCC(=O)N2
Reactant: CC(C)(C)OC(=O)NN
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NNC1CCC2(CCC(=O)N2)CC1
Temperature: 25 °C
Yield: 150.8 %

Procedure:
A solution of 1-Aza-spiro[4.5]decane-2,8-dione (Chembridge corporation, 800 mg; 4.78 mmol; 1.0 eq.) and hydrazinecarboxylic acid tert-butyl ester (309 mg; 2.34 mmol; 1.1 eq.) in AcOH (5 mL) was stirred at RT for 5 min. Sodium cyanoborohydride (133 mg; 2.13 mmol; 1.0 eq.) was then added and the reaction mixture was stirred O/N at RT. It was then diluted with water and basified to pH 9 by addition of a 5N solution of NaOH. During the addition, the reaction mixture was maintained at 20° C. by addition of crushed ice. It was extracted with DCM and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound as a yellow oil (1.0 g, 98%) which was used without further purification.