Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:20](=[O:21])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[N:37]1([C:43]2[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=3[S:45][N:44]=2)[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>[I-].[K+].CN(C=O)C>[S:45]1[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:43]([N:37]2[CH2:38][CH2:39][N:40]([CH2:2][CH2:3][CH2:4][CH:5]3[C:20](=[O:21])[C:9]4[C:10]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[F:19])=[N:11][O:12][C:8]=4[CH2:7][CH2:6]3)[CH2:41][CH2:42]2)=[N:44]1
Reactant: O=C1c2c(-c3ccccc3F)noc2CCC1CCCCl
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2c(-c3ccccc3F)noc2CCC1CCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 80 °C
Yield: 46.1 %

Procedure:
To a solution consisting of 5-(3-chloropropyl)-3-(2-fluorophenyl)-6,7-dihydro -1,2-benzisoxazol-4(5H)-one (1.36 g) and DMF (40 ml) was added anhydrous potassium carbonate (0.3 g), diisopropylethyl amine (0.8 ml), 3-piperazinyl-1,2-benzisothiazol (1.26 g) and potassium iodide (27 mg) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80° C. for 12 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, 20% triethylamine/ether) afforded 1.0 g of 5-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]propyl]-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one as a foam. The product was flushed through alumina with dichloromethane. The hydrochloride was prepared by dissolving the free amine with menthanol and adding ethereal HCl. The salt was filtered and washed with pentane, m.p. 215° C. (dec.).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([C:21]([OH:23])=O)[CH:15]=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.C(N1C=CN=C1)(N1C=CN=C1)=O.CO[CH:39]1[CH2:44][CH2:43][NH:42][CH2:41]C1>CN(C=O)C.CO>[N:42]1([C:21]([C:16]2[CH:15]=[CH:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][CH:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)[CH:12]=3)[N:17]=2)=[O:23])[CH2:41][CH:39]=[CH:44][CH2:43]1
Reactant: COC1CCNCC1
Reactant: CC(C)N1CCC(Oc2ccc3nc(C(=O)O)ccc3c2)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)N1CCC(Oc2ccc3nc(C(=O)N4CC=CC4)ccc3c2)CC1
Yield: 14 %

Procedure:
6-(1-Isopropyl-piperidin-4-yloxy)-quinoline-2-carboxylic acid 1:1 hydrochloride (30 mg, 0.086 mmol, see intermediate 2) was dissolved in DMF (0.300 ml). 1,1′-Carbonyl-diimidazole (17 mg, 0.10 mmol) was added and the mixture was stirred for half an hour. 4-Methoxy-piperidine was added (6 mg, 0.014 mmol) and the mixture was stirred overnight. The mixture was diluted with 0.4 ml methanol and subjected to preparative HPLC purification on reversed phase material eluting with a gradient of acetonitrile/water/triethylamine. The product fractions were evaporated to dryness to yield 4.7 mg (14%) of the title compound as light brown solid. MS (m/e): 412.4 (MH+, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]3[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][CH3:19])[C:13](=[O:20])[C:9]3=[C:10]([O:11][CH3:12])[C:6]=2[C:5](=[O:21])[NH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][C:39]=1[Cl:46]>CN(C=O)C>[NH2:1][C:2]1[C:7]2[N:8]3[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][CH3:19])[C:13](=[O:20])[C:9]3=[C:10]([O:11][CH3:12])[C:6]=2[C:5](=[O:21])[N:4]([CH2:42][C:41]2[CH:44]=[CH:45][C:38]([F:37])=[C:39]([Cl:46])[CH:40]=2)[N:3]=1
Reactant: CCN1C[C@H](C)n2c(c(OC)c3c(=O)[nH]nc(N)c32)C1=O
Reactant: Fc1ccc(CBr)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCN1C[C@H](C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(N)c32)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (6S)-4-amino-8-ethyl-10-methoxy-6-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.94 g, 3.23 mmol) in anhydrous DMF (32 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (3.87 mL, 1 M, 3.87 mmol) was added. The mixture was stirred at room temperature for 15 minutes and treated with 4-fluoro-3-chlorobenzyl bromide (0.72 g, 3.23 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated under vacuum. The residue was partitioned between chloroform and dilute hydrochloric acid. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 0-20% methanol in ethyl acetate gradient. Collection and concentration of appropriate fractions provided the title material.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]([N:8]1[C@H:11]([S:12]SC2SC3C=CC=CC=3N=2)[C@@H:10]([O:23][C:24](=[O:33])[CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]1=[O:34])=[C:5]([CH3:7])[CH3:6].[BH4-].[Na+].[C:38](Br)(=[O:40])[CH3:39].C1C=CC=CC=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:35])[C:4]([N:8]1[C@H:11]([S:12][C:38](=[O:40])[CH3:39])[C@@H:10]([O:23][C:24](=[O:33])[CH2:25][O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:9]1=[O:34])=[C:5]([CH3:6])[CH3:7]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](OC(=O)COc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Reactant: CC(=O)Br
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](OC(=O)COc2ccccc2)[C@H]1SC(C)=O
Reaction time: 0.17 h

Procedure:
A solution of 687 mg (1.29 mmole) of 2-[(3S,4R)-4-(benzthiazol-2-yldithio)-3-phenoxyacetoxy-2oxoazetidin-1-yl]-3-methylcrotonic acid methyl ester in 14 ml of dimethylformamide is added to a solution, cooled to -20°, of 76 mg (2 mmole) of sodium borohydride in 10 ml of dimethylformamide and the mixture is stirred at the same temperature for 10 minutes. 7 ml of freshly distilled acetyl bromide are added to the reaction mixture, which is further stirred at 0° for 40 minutes. After adding 400 ml of benzene, the reaction mixture is washed in succession with aqueous sodium bicarbonate solution, water and sodium chloride solution, dried over sodium sulphate and concentrated by evaporation in vacuo. After chromatography over silica gel with toluene/ethyl acetate (19:1) the residue yields the title compound in the form of an oil, which is further purified on silica gel plates with toluene/ethyl acetate (4:1). The title compound is obtained in oily form.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[C:5]#N.Cl.[C:21](=O)(O)[O-:22].[Na+].C[OH:27]>>[CH3:21][O:22][C:5](=[O:27])/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:3]/[O:2][CH3:1]
Reactant: CO/N=C(/C#N)c1ccccc1Oc1ccccc1
Reactant: CO
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: CO/N=C(/C(=O)OC)c1ccccc1Oc1ccccc1
Yield: 46.7 %

Procedure:
To E-α-methoxyimino-2-phenoxyphenylacetonitrile (a mixture of E- and Z-isomers) (0.76 g, 0.003 mole) was added 30% hydrochloric acid in methanol (4.5 ml) and the mixture was stirred under reflux for 22 hours. After completion of the reaction, 8% aqueous solution of sodium bicarbonate (100 ml) was added to the reaction mixture and extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain E-α-methoxyimino-2-phenoxyphenylacetic acid methyl ester (0.40 g, 46.7%) as colorless crystals (melting point: 109°-110° C.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]2[CH:13]=[N:14][CH:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[C-:16]#[N:17].[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>C(#N)C>[ClH:1].[ClH:1].[C:16]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]2[CH:13]=[N:14][CH:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1)#[N:17]
Reactant: [C-]#N
Reactant: ClCCCCCc1cccc2cncn12
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CC#N
Product: Cl
Product: N#CCCCCCc1cccc2cncn12

Procedure:
A solution of 37 g of 5-(5-chloropentyl)-imidazo[1,5-a]pyridine, 21.7 g of potassium cyanide and 3 g of dibenzo-18-crown-6 in acetonitrile is heated under reflux for 20 hours. The acetonitrile is evaporated under reduced pressure, the residue is partitioned between water and methylene chloride, and the methylene chloride extract is evaporated to dryness. Treatment of a solution of the residue in ether with ethanolic hydrochloric acid yields 5-(5-cyanopentyl)-imidazo[1,5-a]pyridine hydrochloride melting at 178°-80°.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([O:9][C:10]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([C:22]2[O:23]C=CC=2)[CH:13]=1)=[O:11])[CH3:8]>ClC(Cl)(Cl)Cl.C(#N)C.O.[Ru](Cl)(Cl)Cl>[CH2:7]([O:9][C:10]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([C:22]([OH:23])=[O:2])[CH:13]=1)=[O:11])[CH3:8]
Reactant: CCOC(=O)c1cc(-c2ccco2)nc2ccccc12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(C(=O)O)nc2ccccc12

Procedure:
To a vigorously stirred of 8 g of sodium periodate and 20 mg of ruthenium trichloride in 37 ml of tetrachloro-methane, 37 ml of acteonitrile and 54 ml of water 2.5 g of 2-Furan-2-yl-quinoline-4-carboxylic acid ethyl ester was added at RT. Then, after 4 h additional 8 g of sodium periodate and 10 mg of ruthenium trichloride was added and the reaction mixture was stirred for an additional hour. Then, the reaction mixture was diluted with water and extracted with DCM (3×150 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was used in the next reaction step without further purification. Yield: 2.0 g.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:38]1[CH:39]=[N:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C@H:10]([NH:25]C(OCC1C=CC(OC)=CC=1)=O)[CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C>ClCCl>[NH2:25][C@@H:10]([C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:38]1[CH:39]=[N:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C#CCC[C@@H](NC(=O)OCc2ccc(OC)cc2)[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(Cl)nc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C#CCC[C@@H](N)[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(Cl)nc2)cc1
Reaction time: 3 h
Yield: 76.4 %

Procedure:
To a stirred solution of the title compound from Step A (83.0 g, 0.13 mol) in dichloromethane (400 mL) was added triethylamine (20 mL) and the resulting mixture was stirred for 3 h. The reaction mixture turned to dark red color. All volatiles were evaporated and the residue was diluted with water and based by NaHCO3. It was then extracted with dichloromethane (3×250 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography with dichloromethane/methanol=20:1 to afford 47.0 g (77%) of the title compound as yellow gum. 1H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 7.95 (d, J=8.6 Hz, 2H), 7.63 (d, J=7.8 Hz, 1H), 7.41 (d, J=8.6 Hz, 2H), 7.31 (d, J=8.6 Hz, 1H), 4.55 (d, J=4.7 Hz, 1H), 3.93 (s, 3H), 2.96-2.93 (m, 1H), 2.64-2.53 (m, 2H), 1.71-1.68 (m, 1H), 1.52-1.41 (m, 3H), 0.90 (s, 9H), 0.20 (s, 3H), 0.00 (s, 3H). MS: m/z. (EST) 473 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:14])[C:5]=1[OH:15])[CH:2]=[CH2:3].CC([O-])(C)C.[K+].C1COCC1.Cl>CS(C)=O>[OH:15][C:5]1[C:6]([CH3:14])=[C:7]([CH:12]=[CH:13][C:4]=1[CH:1]=[CH:2][CH3:3])[C:8]([O:10][CH3:11])=[O:9]
Reactant: C=CCc1ccc(C(=O)OC)c(C)c1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC=Cc1ccc(C(=O)OC)c(C)c1O
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
In a round bottom flask fitted with a dropping funnel was added methyl 4-allyl-3-hydroxy-2-methylbenzoate (4.12 g, 20 mmol) in anhydrous DMSO (20 ml) at room temperature under argon. t-BuOK in 1.0 M THF (5.61 g, 50 mmol) was added drop wise to the stirred solution. After the addition, the reaction mixture was heated at 55° C. overnight. The reaction was monitored using LCMS. After the reaction was complete, it is cooled, acidified with 1N HCl and stirred for 30 min. Aqueous work up and extraction with ethyl acetate gave the crude mixture which was purified using an ISCO system (40 g silica gel column, hexane/EtOAc solvent gradient) to give 4.12 g (77%) of the product. 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=8.2 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 6.61 (dd, J=15.9, 1.7 Hz, 1H), 6.37-6.13 (m, 1H), 3.90 (s, 3H), 2.50 (s, 3H), 1.96 (dd, J=6.6, 1.7 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:16][CH3:17])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][N:16]([S:31]([CH3:30])(=[O:33])=[O:32])[CH3:17])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CNC)c2cc(F)ccc2n1Cc1cccc2ccccc12
Reactant: CS(=O)(=O)Cl
Product: CCOC(=O)c1c(CN(C)S(C)(=O)=O)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
5-Fluoro-3-methylaminomethyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (from Example 86.1.) was reacted with methanesulfonyl chloride as described in Example 77.1. to give 5-fluoro-3-[(methanesulfonyl-methyl-amino)-methyl]-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a colorless solid. MS: 439.4 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][N:15]3[Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:8]=[C:7]([C:30]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34](Cl)[CH:33]=2)=[O:31])[CH:6]=1.[C:41](=O)([O-])[O-].[K+].[K+].CB(O)O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:40])[NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][N:15]3[Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:8]=[C:7]([C:30]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:41])[CH:33]=2)=[O:31])[CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Nc1cc(C(=O)c2cc(C)nc(Cl)c2)cc(-c2cccc3c2ccn3[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB(O)O
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)Nc1cc(C(=O)c2cc(C)nc(C)c2)cc(-c2cccc3c2ccn3[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 110 °C
Yield: 62 %

Procedure:
To 0.100 g (0.174 mmol) [3-(2-chloro-6-methyl-pyridine-4-carbonyl)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-carbamic acid methyl ester in 2.0 mL of anhydrous dioxane in a pressure tube was added 0.034 g (0.24 mmol) potassium carbonate and 0.015 g (0.24 mmol) methylboronic acid. The reaction mixture was degassed with argon and then 0.006 g (0.005 mmol) Pd(PPh3)4 was added. The reaction mixture was capped and heated at 110° C. for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate phase was washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and concentrated. The crude product was chromatographed on silica gel using 10:1 methylene chloride:methanol to give 0.060 g of [3-(2,6-dimethyl-pyridine-4-carbonyl)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-carbamic acid methyl ester. The protecting group was removed as described in Example 75 to give [3-(2,6-dimethyl-pyridine-4-carbonyl)-5-(1H-indol-4-yl)-phenyl]-carbamic acid methyl ester. 1H NMR (400 MHz, CDCl3): δ 8.50 (s, 1H), 8.12 (s, 1H), 7.79-7.75 (m, 2H), 7.40 (d, J=8.2 Hz, 1H), 7.29 (s, 2H), 7.27-7.22 (m, 2H), 7.17 (dd, J=7.3, 0.9 Hz, 1H), 7.05 (s, 1H), 6.72 (s, 1H), 3.79 (s, 3H), 2.60 (s, 6H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]1[CH:34]=[C:33](I)[CH:32]=[C:31]([F:36])[N:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C.O.O>[F:28][C:29]1[CH:34]=[C:33]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[CH:11]=2)[CH:32]=[C:31]([F:36])[N:30]=1
Reactant: Fc1cc(I)cc(F)n1
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: O=S(=O)(c1ccccc1)n1cc(-c2cc(F)nc(F)c2)c2cccnc21
Temperature: 80 °C

Procedure:
A suspension of 1-(phenylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (7.26 g, 18.9 mmol), 2,6-difluoro-4-iodopyridine (4.14 g, 17.2 mmol, Eur. J. Org. Chem., 2004, 1018 and Org. Lett. 2007, 5175), dichlorobis(triphenylphosphine) palladium(II) (0.482 g, 0.687 mmol) and 1M aqueous sodium carbonate (13.7 mL, 13.7 mmol) in dimethoxyethane/ethanol/water (7:2:3) (80 mL) was degassed and heated at 80° C. for 1.5 hours. After cooling, the suspension was filtered, washed with water and ether, and concentrated to give the crude title compound. The filtrate was diluted with water and extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, concentrated, and purified using an ISCO Companion flash system eluting with dichloromethane/hexane (7:3 to 9:1) to give the title compound. The combined products were used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:15][NH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6]([N:16]([CH3:15])[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:7])=[CH:4][CH:3]=1
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(F)c(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
4-Fluoro-5-trifluoromethylbenzoyl chloride (80 mg, 0.35 mmol, CAS RN 67515-56-4) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (35 mg, 0.18 mmol, example 1, intermediate a) and DIPEA (92 μL, 0.53 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the desired product as a waxy solid (33 mg, 48%) MS (ESI): m/z=388.9 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[NH2-].[Na+].Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH:26]2[CH2:28][CH2:29][CH:23]1[CH2:24][CH2:25]2>CCOCC.O.C1(C)C=CC=CC=1>[C:2]1([C:1]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)([CH2:20][CH2:21][N:22]2[CH2:27][CH:26]3[CH2:28][CH2:29][CH:23]2[CH2:24][CH2:25]3)[C:8]#[N:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1ccccc1
Reactant: ClCCN1CC2CCC1CC2
Reactant: Brc1cccnc1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: N#CC(CCN1CC2CCC1CC2)(c1ccccc1)c1cccnc1
Temperature: 80 °C

Procedure:
A mixture of 25 parts of benzyl cyanide, 35 parts of 3-bromopyridine and 220 parts of dry toluene is heated to 80° C. with stirring. Then, 19 parts of sodamide is added portionwise over a period of 1 hour while the temperature is maintained at 80°-85° C. with some cooling. The resultant mixture is heated to 105° C. and a solution of 56 parts of 2-(2-chloroethyl)-2-azabicyclo[2.2.2]octane in 220 parts of dry toluene is added portionwise. The mixture is then heated at 105°-110° C. for an additional 3 hours before it is cooled and 250 parts of water is added. The organic layer is separated and dried and the solvent is evaporated to leave a residue which is dissolved in ether and filtered. The ether solvent is evaporated from the filtrate and the residual oil is distilled under reduced pressure to provide 2-phenyl-2-(3-pyridyl)-4-(2-azabicyclo[2.2.2]oct-2-yl)butyronitrile. Alternately α-phenyl-3-pyridylacetonitrile (U.S. Pat. No. 3,225,054) is reacted with 2-(2-chloroethyl)-2-azabicyclo[2.2.2]octane directly.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([F:9])=[C:4]([NH:10][NH2:11])[N:3]=1.[CH:12]1([CH2:17][C@H:18]([CH2:22][N:23]([CH:32]=[O:33])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:19](O)=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13]1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[CH:12]1([CH2:17][C@@H:18]([C:19]([NH:11][NH:10][C:4]2[C:5]([F:9])=[C:6]([Cl:8])[N:7]=[C:2]([Cl:1])[N:3]=2)=[O:20])[CH2:22][N:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[O:33])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NNc1nc(Cl)nc(Cl)c1F
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(Cl)c1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
2,4-Dichloro-5-fluoro-6-hydrazinopyrimidine (358 mg 1.817 mmol), (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (746 mg, 1.508 mmol), and HOAt (247 mg, 1.817 mmol) were dissolved in 15 mL of DMF. NMM (0.798 mL, 7.27 mmol) was added, followed by EDC (348 mg, 1.817 mmol). After stirring overnight at room temperature, the reaction mixture was purified by RP-HPLC to provide {(2R)-2-(cyclopentylmethyl)-3-[2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)hydrazino]-3-oxopropyl}[(phenylmethyl)oxy]formamide (442 mg, 50%). LCMS: (M+H)+: 483.6.