Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH:9]=[CH:10][CH3:11].[NH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][N:25]=[CH:24]3)=[O:20])[CH2:14][CH2:13]1>CN(C)C=O>[CH2:8]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][N:25]=[CH:24]3)=[O:20])[CH2:14][CH2:13]1)[CH:9]=[CH:10][CH3:11]
Reactant: CC=CCCl
Reactant: O=C(NC1CCNCC1)c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC=CCN1CCC(NC(=O)c2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.1 %

Procedure:
Potassium carbonate (55.0 mg, 0.398 mmol) and 1-chloro-2-butene (17.8 mg, 0.197 mmol) were added to a solution of the N-(4-piperidinyl)-1H-indazole-5-carboxamide (40.0 mg, 0.164 mmol) obtained in Example 58 in N,N-dimethylformamide (1.2 ml), and the resulting mixture was stirred for 20 hours while being maintained at room temperature. The reaction solution was filtered and the filtrate was concentrated to dryness. The resulting crude product residue was purified by a silica gel column chromatography (eluent: chloroform/methanol/aqueous ammonia=20/1/0.1) to obtain N-[1-(but-2-enyl)piperidin-4-yl]-1H-indazole-5-carboxamide (26 mg, 54%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[N:33]=[N:34][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH3:47])[CH:42]=[N:43][CH:44]=5)=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[N:33]=[N:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH3:47])[CH:42]=[N:43][CH:44]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CCC)nn2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)nn2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[(3-propylimidazol-4-yl)methylthio]pyridazin-3-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.25 g) was dissolved in dichloromethane (10 ml), and the mixture was cooled to −78° C. 0.3-chloroperbenzoic acid (0.38 g) in dichloromethane solution (5 ml) was added dropwise to the solution. The mixture was stirred at −78° C. for 4 hours and sodium thiosulfate solution was added to the mixture. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[(3-propylimidazol-4-yl)methylsulfinyl]pyridazin-3-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 70) (0.14 g) as yellow amorphous.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:16]([C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([N+:29]([O-])=O)=[C:24]([F:32])[CH:23]=2)([CH3:19])([CH3:18])[CH3:17]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:29][C:25]4[CH:26]=[C:27]5[C:22](=[CH:23][C:24]=4[F:32])[N:21]([CH2:6][C@@H:5]([OH:1])[CH2:4][OH:3])[C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:28]5)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)c(F)cc2n1C[C@@H](O)CO

Procedure:
(R)-1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2,3-dihydroxypropyl)-6-fluoro-1H-indol-5-yl)cyclopropanecarboxamide was prepared using an experimental procedure similar to example 72 from 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid and 2-tert-butyl-6-fluoro-5-nitro-1H-indole.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([CH:16]=1)[C:13]([NH2:15])=[O:14])=[O:7].[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].CS(C)=O>O>[C:25]1([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]3[CH:9]=[CH:10][C:11]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[C:12]([CH:16]=3)[C:13]([NH2:15])=[O:14])=[O:7])[CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NC(=O)c1cc(C(=O)CCCCCl)ccc1OCc1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cc(C(=O)CCCCN2CCN(c3ccccc3)CC2)ccc1OCc1ccccc1
Temperature: 90 °C
Yield: 84.3 %

Procedure:
A mixture of 2 g of 5-(5-chlorovaleryl)-2-benzyloxy-benzamide, 1 g of 1-phenylpiperazine, 0.6 g of sodium carbonate and 10 ml of dimethyl sulfoxide was heated at 90° C. for 6 hours while stirring. After the reaction was finished, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate and concentrated. The thus produced residue was dissolved in acetone and concentrated hydrochloric acid in an amount of 2 equivalents was added thereto to produce crystals. The crystals were filtered off to obtain 2.3 g of 5-[5-(4-phenyl-1-piperazinyl)valeryl]-2-benzyloxy-benzamide (yield: 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[CH:17][C:3]=1[C:4]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][C:7]=1[CH3:16])=[O:5].[OH-].[Na+].[BH4-].[Na+]>O>[CH3:16][C:7]1[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[CH:10]=[C:11]([CH3:12])[C:6]=1[CH:4]([C:3]1[CH:17]=[C:18]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:19]=[CH:20][C:2]=1[Cl:1])[OH:5]
Reactant: Cc1cc(C(=O)O)cc(C)c1C(=O)c1cc(-n2ccnc2)ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(=O)O)cc(C)c1C(O)c1cc(-n2ccnc2)ccc1Cl
Reaction time: 3 h
Yield: 94.8 %

Procedure:
To a solution of 6.4 g of 2-chloro-5-(1-imidazolyl)- 2',6'-dimethyl-4'-carboxybenzophenone and 0.8 g of sodium hydroxide in 35 ml of water is added 1.4 g of sodium borohydride, and the mixture is stirred at 70°-75° C. for 3 hours. After completion of the reaction, a small amount of an insoluble substance is filtered off from the warm mixture and the filtrate is adjusted to pH 4 with concentrated hydrochloric acid under stirring at 80°-90° C. The precipitated crystals are collected by filtration under reduced pressure, washed with water and acetone and dried to give 6.1 g of α-(2,6-dimethyl-4-carboxyphenyl)-2-chloro-5-(1-imidazolyl)benzenemethanol, melting at 317°-320° C. with decomposition as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][C:13]([O:15]C(C)C)=[O:14])=[C:5]2[CH3:19].[OH-].[Na+].CO>O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:5]2[CH3:19]
Reactant: Cc1c(CCC(=O)OC(C)C)[nH]c2ccc(F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(CCC(=O)O)[nH]c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 102 %

Procedure:
A mixture of isopropyl 5-fluoro-3-methyl-1H-indole-2-propanoate (0.42 g),1N sodiumhydroxide (6.3 ml) and methanol (20 ml) are stirred at room temperature for 4 hours. The reaction mixture is poured into water, washed with methylene chloride, acidified with 1N HCl and extracted with methylene chloride. The organic layer, dried and evaporated, affords 0.36 g of 5-fluoro-3-methyl-1H-indole-2-propanoic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:12]([CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=4)[N:19]([CH2:27][C:28]([OH:30])=[O:29])[C:18]=3[CH3:31])=[CH:13][S:14][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C>[Pd].C(O)C>[C:5]1([S:8]([C:11]2[C:12]([CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=4)[N:19]([CH2:27][C:28]([OH:30])=[O:29])[C:18]=3[CH3:31])=[CH:13][S:14][CH:15]=2)(=[O:10])=[O:9])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: Cc1c(Cc2cscc2S(=O)(=O)c2ccc(Cl)cc2)c2cc(F)ccc2n1CC(=O)O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1c(Cc2cscc2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 40 °C
Reaction time: 15 h
Yield: 83.4 %

Procedure:
A mixture of {3-[4-(4-chlorobenzenesulfonyl)thiophen-3-ylmethyl]-5-fluoro-2-methylindol-1-yl}acetic acid (0.031 g), triethylamine (0.300 mL), palladium on charcoal (0.012 g) and ethanol (5.0 mL) was stirred under an atmosphere of hydrogen at 40° C. for 15 hours. The mixture was filtered through Celite and the filtrate concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (1:19 to 49:1 by volume) to afford the title compound as a pale yellow solid (0.024 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[N:12]=[CH:13][N:14]=[C:7]1[CH:6]=[CH:5]2.[SH:15][C:16]1[CH:17]=[C:18]([C:22]2([C:28]#[N:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:12]1[N:8]2[C:9]3[C:4]([CH:5]=[CH:6][C:7]2=[N:14][CH:13]=1)=[CH:3][C:2]([S:15][C:16]1[CH:17]=[C:18]([C:22]2([C:28]#[N:29])[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH:19]=[CH:20][CH:21]=1)=[CH:11][CH:10]=3
Reactant: Brc1ccc2c(ccc3ncnn32)c1
Reactant: N#CC1(c2cccc(S)c2)CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#CC1(c2cccc(Sc3ccc4c(ccc5ncnn54)c3)c2)CCOCC1
Temperature: 110 °C

Procedure:
8b (66 mg, 0.25 mmol) and 4-(3-Mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (8c, 90 mg, 0.32 mmol) were dissolved in 1,4-dioxane (5 mL) and degassed for 10 minutes with N2. iPr2NEt (0.15 mL, 0.80 mmol) was added, followed by Pd2dba3 (10 mg, 0.01 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12 mg, 0.02 mmol), and the mixture was degassed with N2 for an additional 10 minutes. The reaction was sealed and heated overnight at 110° C. Additional catalyst was added after 24 hours to push the reaction to completion, and the mixture was heated at 110° C. for another 2 hours. The reaction was cooled to room temperature and purified by silica gel chromatography (25-100% EtOAc in hexanes) to give the desired product, 8d.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[C:10](=O)([O-])[O-].[K+].[K+].CI.[C:18](=O)([O:34]N1C(=O)CCC1=O)[O:19][CH2:20][CH:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2>O1CCOCC1.O>[CH:32]1[C:33]2[CH:21]([CH2:20][O:19][C:18]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([S:6][CH3:10])([CH3:5])[CH3:4])=[O:34])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]=2[CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(S)[C@H](N)C(=O)O
Reactant: O=C([O-])[O-]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CI
Product: CSC(C)(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 1 h
Yield: 137.5 %

Procedure:
To a solution of L-penicillamine (0.60 g, 4.02 mmol) in mixture of water (20 mL) and dioxane (20.0 mL) at room temperature were added potassium carbonate (11.04 g, 79.9 mmol) and methyl iodide (0.31 mL, 4.98 mmol), and the mixture was stirred for 1 hour. 9−fluorenylmethyl succinimidyl carbonate (5.39 g, 16.0 mmol) was added, and the reaction was stirred at room temperature for 12 hours. The reaction was evaporated, and the residue was partitioned between ether and water, and the mixture was adjusted to pH 3 with 2 N HCl. The organic was washed with brine and dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with 10% methanol in dichloromethane to give the product (2.13 g).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][CH2:7][CH:8]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.CS([C:24]1[N:29]=[CH:28][C:27]2=[CH:30][CH:31]=[C:32]([C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)[N:26]2[N:25]=1)=O.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[F:16][C:14]([F:17])([F:15])[C:13]([NH:12][CH:8]1[C:9](=[O:11])[NH:10][C:4]2[CH:3]=[C:2]([NH:1][C:24]3[N:29]=[CH:28][C:27]4=[CH:30][CH:31]=[C:32]([C:33]5[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:37][CH:38]=5)[N:26]4[N:25]=3)[CH:20]=[CH:19][C:5]=2[CH2:6][CH2:7]1)=[O:18]
Reactant: Nc1ccc2c(c1)NC(=O)C(NC(=O)C(F)(F)F)CC2
Reactant: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(-c2ccc3cnc(Nc4ccc5c(c4)NC(=O)C(NC(=O)C(F)(F)F)CC5)nn23)cc1
Temperature: 130 °C
Yield: 32.7 %

Procedure:
Into a 8-dram vial, N-(8-Amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-2,2,2-trifluoro-acetamide (39.4 mg, 0.137 mmol), 2-Methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (105 mg, 0.313 mmol), Cesium fluoride (41.7 mg, 0.274 mmol), tert-Butyl alcohol (0.80 mL) and N,N-Diisopropylethylamine (0.0478 mL, 0.274 mmol) were added. The reaction mixture was heated at 130° C. overnight. HPLC suggested no starting material. The solvent was evaporated. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give 2,2,2-Trifluoro-N-{8-[7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl}-acetamide as a yellow solid (25 mg, 32%). LCMS (E/I+) 559.07 (M+H). NMR 1H (DMSO-d6)-9.96 (s, 1H0, 9.74 (s, 1H), 9.65 (bs, 1H), 9.08 (s, 1H), 8.46 (d, 2H, J=7.72 Hz), 8.04 (d, 2H, J=7.72 Hz), 7.59 (s, 1H), 7.54 (d, 1H, J=8.49 Hz), 7.35 (bs, 1H), 7.28 (d, 1H, J=7.72 Hz), 7.03 (d, 1H, J=4.62 Hz), 4.29 (bs, 1H), 3.22 (s, 3H), 2.63-2.72 (m, 2H), 2.24-2.35 (m, 2H).
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].[C:17]1([CH2:27]Cl)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.OS([O-])(=O)=O.[K+]>C(O)C.CCCCCC>[C:17]1([CH2:27][C:6]([NH:5][C:2](=[O:4])[CH3:3])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: ClCc1cccc2ccccc12
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na]
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)C(Cc1cccc2ccccc12)(NC(C)=O)C(=O)OCC
Temperature: 25 °C

Procedure:
Sodium (28 mmol; 0.64 g) is introduced into 50 cm3 of absolute ethanol, under inert atmosphere. At 0° C., diethyl 2-acetamidomalonate (28 mmol; 6.08 g) dissolved in 35 cm3 of absolute ethanol is added, followed by dropwise addition, with a syringe, of (1-naphthyl)methyl chloride (28 mmol; 4.1 cm3). The mixture is maintained at reflux until the starting material has disappeared (6 h, then overnight at room temperature and then 2 h at reflux). The reaction medium is poured onto a KHSO4 (0.05M; 240 cm3)/hexane (120 cm3) mixture and stirred vigorously. A white precipitate, which is the expected malonic derivative, is recovered.
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1)(=O)=O)([O-])=O.C([O-])([O-])=O.[K+].[K+].[CH2:46](Br)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CC#N>[N:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:23]2[C:32]3[N:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH2:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(Cc1ccc(CNC2CCCc3cccnc32)cc1)Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(CN(Cc2ccc(CNCc3ccccn3)cc2)C2CCCc3cccnc32)cc1
Reaction time: 18 h
Yield: 60.6 %

Procedure:
To a stirred solution of N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (0.220 g, 0.390 mmol) in CH3CN (8 mL), at room temperature, was added powdered K2CO3 (0.153 g, 1.11 mmol) followed by excess benzyl bromide (0.20 mL, 1.68 mmol). After 18 hours, the reaction mixture was concentrated and the residue was partitioned between CH2Cl2 (10 mL) and water (5 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by radial chromatography (2 mm plate, 20:1 CH2Cl2—CH3OH) provided the desired product (0.106 g, 44%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[NH:25][C:24]4=[O:32])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:6][C:3]=1[C:4]#[N:5].[CH3:39][NH2:40]>CC(O)C>[CH3:39][NH:40][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[NH:25][C:24]4=[O:32])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)nc1Cl
Reactant: CN
Solvent: CC(C)O
Product: CNc1nc(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)c(-c2ccccc2)cc1C#N
Temperature: 150 °C

Procedure:
A mixture of 2-Chloro-6-(4-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl]-5-phenylnicotinonitrile (2-6, 0.040 g, 0.077 mmol) and methylamine (2M in THF, 0.192 mL, 0.385 mmol) in i-PrOH (1 mL) were heated@150° C. for 15 min. in the microwave. The mixture was concentrated, taken up in DMF and purified by reverse phase HPLC (6-1; 5% CH3CN: 95% H2O+0.01% TFA to 95% CH3CN: 5% H2O+0.01% TFA). 1H-NMR (500 MHz, d6 DMSO) δ 10.93 (s, 1H), 9.59 (bs, 1H), 8.00 (s, 1H), 7.37-7.47 (m, 4H), 7.18-7.37 (m, 5H), 7.12 (dd, J=1.96, 8.06, 2H), 6.95-7.05 (m, 3H), 4.43-4.53 (m, 1H), 4.32 (d, J=5.00, 2H), 3.47 (d, J=10.99, 2H), 3.10-3.25 (m, 2H), 2.94 (d, J=4.39, 3H), 255-2.69 (m, 2H), 1.92 (d, J=11.48, 2H). HRMS m/z (M+H) Calcd: 515.2554, found: 515.2552.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([N:44]3[CH2:50][CH2:49][CH2:48][N:47]([CH2:51][CH2:52][O:53][C:54](=[O:56])[NH2:55])[CH2:46][CH2:45]3)=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[C:54]([O:53][CH2:52][CH2:51][N:47]1[CH2:48][CH2:49][CH2:50][N:44]([C:42]([C@@H:26]2[CH2:25][C@H:24]([SH:23])[CH2:28][N:27]2[C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])=[O:43])[CH2:45][CH2:46]1)(=[O:56])[NH2:55]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCN(CCOC(N)=O)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)OCCN1CCCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h

Procedure:
2.7 ml of trifluoroacetic acid and 88 μl of trifluoromethanesulfonic acid were added, whilst ice-cooling, to a solution of 308 mg of (2S,4S)-4-(4-methoxybenzylthio)-2-[4-(2-carbamoyloxyethyl) -1-homopiperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine dissolved in 543 μl of anisole, and the resulting mixture was stirred a the same temperature for 1 hour. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 32(1), to afford 315 mg of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([OH:18])C#C.C(N(CC)CC)C.[C:26]1([CH3:32])C=CC=C[CH:27]=1>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:13][CH2:32][C:26]#[CH:27])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCO
Reactant: O=C(Cl)CCCCCc1ccccc1
Reactant: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C#CCOC(=O)CCCCCc1ccccc1
Temperature: 0 °C

Procedure:
65.7 Grams of 6-phenylhexanoyl chloride was added by drops to a mixture of 19.2 g of propargyl alcohol, 34.7 g of triethylamine and 500 ml of dry toluene with stirring and ice-cooling. After dropwise addition, the resultant solution was stirred for additional 12 hours at room temperature. The thus stirred solution was poured into ice water. The toluene layer was separated from the resulting mixture. The aqueous layer was extracted once with toluene. These toluene layers were combined, washed with water and then with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off from the dried layer under reduced pressure. The resulting residue was distilled under reduced pressure to obtain 157.9 g of propargyl 6-phenylhexanoate.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C@H:3]([N:7]1[CH:11]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:9]=[N:8]1)[CH2:4][C:5]#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:42].Cl>C(Cl)Cl.O>[F:1][C:2]([F:29])([F:30])[C@H:3]([N:7]1[CH:11]=[C:10]([C:12]2[C:13]3[CH:20]=[CH:19][N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:9]=[N:8]1)[CH2:4][CH:5]=[O:42]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H](CC#N)C(F)(F)F)c3)ncnc21
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H](CC=O)C(F)(F)F)c3)ncnc21
Temperature: -47.5 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To a −70° C. solution of (3R)-4,4,4-trifluoro-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (1.06 g, 0.00243 mol) (see, Example 93, Step 1) in DCM (10 mL, 0.2 mol) was added 1.0 M diisobutylaluminum hydride in DCM (4.8 mL). The resulting mixture was stirred for 3 h and allowed to warm during this time interval from −70 to −25° C., after which the reaction was cooled back at −70° C. Methanol (1.5 mL, 0.037 mol) was added, followed by 2.0 M HCl in water (15 mL). Insoluble material was then filtered from the reaction mixture. The organic filtrate was washed sequentially with: 2.0 M HCl in water, water and saturated aqueous NaCl. The washed organic phase was dried over sodium sulfate and was concentrated using a rotory evaporator to give 0.58 g of the crude product as a pale yellow foam/solid. The crude product was chromatographed with 0-80% ethyl acetate/hexanes to give the purified product (0.9 g) as a pale orange oil (47% yield).