Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2([OH:20])[CH2:14]OS(C)(=O)=O)=[CH:4][CH:3]=1.[NH:23]1[CH:27]=[N:26][CH:25]=[N:24]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2([OH:20])[CH2:14][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CCC(Cc2ccc(Cl)cc2)C1(O)COS(C)(=O)=O
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC1(C)CCC(Cc2ccc(Cl)cc2)C1(O)Cn1cncn1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 0.22 g 1-(4-chlorobenzyl)-3,3-dimethyl-2-hydroxy-2-methylsulphonyloxymethylcyclopentane prepared as described in Example 1 (j), 47 mg 1,2,4-triazole and 0.1 g potassium carbonate in 3 ml N-methylpyrrolidone was warmed at 50° C. for 2 hours. A further 0.1 g potassium carbonate was then added, the temperature was raised to 120° C. and the reaction continued overnight at this temperature. The reaction mixture was then partitioned between diethyl ether and water and the organic solution flashed to give 1-(4-chlorobenzyl)-3,3-dimethyl-2-hydroxy-2-(1,2,4-triazol-1-yl)methylcyclopentane crystallised from petroleum as a single stereoisomer (Isomer A). The conversion yield of Isomer A, corrected for purity, was 72%. The structure of the product was established by n.m.r. spectroscopy. Purity of Isomer A was 90% and Isomer B was not detected.
Reaction SMILES: [I:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][NH2:14])=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].S(=O)(=O)(O)O>C1COCC1>[CH3:24][C:23]([CH3:26])([CH3:25])[C:22]([NH:14][NH:13][C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([I:1])=[CH:3][N:4]=[C:5]2[CH:10]=1)=[O:12])=[O:27]
Reactant: NNC(=O)c1ccn2c(I)cnc2c1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NNC(=O)c1ccn2c(I)cnc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
3-Iodo-imidazo[1,2-a]pyridine-7-carboxylic acid hydrazide (906 mg, 3 mmol) (prepared as described in 2 Step preparation of example 329) was suspended in THF (10 mL). Triethylamine (0.42 mL, 3 mmol) was added followed by pivaloyl chloride (0.37 mL, 3 mmol). The reaction was stirred for 2 h at room temperature. Concentrated sulphuric acid (0.5 mL) was added to the mixture and it was stirred 1 h further. The reaction was filtered, the solid washed with EtOAc and Et2O and dried to give 3-Iodo-imidazo[1,2-a]pyridine-7-carboxylic acid N′-(2,2-dimethylpropionyl) hydrazide (875 mg) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]([CH:4]([OH:23])[CH2:5][CH2:6]/[C:7](/C)=[CH:8]\[CH2:9][CH2:10]/[C:11](/C)=[CH:12]\[CH2:13][O:14]C1CCCCO1)=C.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1.CCOCC>[CH2:1]=[CH:2][CH:4]([OH:23])[CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][OH:14]
Reactant: C=C(C)C(O)CC/C(C)=C\CC/C(C)=C\COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(O)CC/C=C\CC/C=C\CO

Procedure:
A solution of 0.5 g (0.0016 mol) of (6Z,10Z)-2,6,10-trimethyl-12-[(tetrahydro-2H-pyran-2-yl)oxy]-1,6,10-dodecatrien-3-ol dissolved in 14.5 ml of tetrahydrofuran and 3.7 ml of water is treated with 167.2 mg (0.4 mol equivalents) of pyridinium p-toluenesulfonate. The solution is boiled at reflux for 17 hours. After cooling 100 ml of water and 300 ml of ether are added thereto. The organic phase is neutralized with sodium bicarbonate solution. After drying and removing the solvent the residue is chromatographed on silica gel with ether-hexane 1:1. There is obtained (6Z,10Z)-1,6,10-dodecatriene-3,12-diol which has the following bands in the IR spectrum: 3448 cm-1, 1646 cm-1, 1443 cm-1, 1375 cm-1, 998 cm-1.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][CH2:16][NH:17][C:18](=O)[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=3)=[CH:14][C:9]=2[O:8][CH2:7]1.[BH4-].[Na+].O.O.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34]>C(#N)C.CO.CCOCC>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[Br:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH:18]2[C:12]3[CH:11]=[C:10]4[O:6][CH2:7][O:8][C:9]4=[CH:14][C:13]=3[CH2:15][CH2:16][NH:17]2)=[CH:21][CH:22]=1
Reactant: O=C(Cc1ccc(Br)cc1)NCCc1ccc2c(c1)OCO2
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: Brc1ccc(CC2NCCc3cc4c(cc32)OCO4)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
Phosphorus oxychloride (119.372 g, 778.83 mmol) was added to a stirred solution of N-(2-benzo[1,3]dioxol-5-yl-ethyl)-2-(4-bromophenyl)acetamide 35 (9.400 g, 25.951 mmol) in anhydrous acetonitrile (225 mL) and refluxed for 6 h. The reaction mixture was concentrated under reduced pressure, methanol was added to it, and again concentrated the solvent under reduced pressure. The obtained residue was dissolved in methanol, to this solution was added sodium borohydride (17.700 g, 467.118 mmol) and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, the residue was dissolved in CHCl3, washed with 1N NaOH solution, water and dried over Na2SO4. The organic layer was evaporated under reduced pressure and the oily mass was dissolved in CHCl3. A solution of oxalicacid dihydrate (6.543 g, 51.902 mmol) in methanol was added to above solution with stirring at room temperature followed by addition of ether. The mixture was stirred for 2 h at the same temperature and kept in the refrigerator overnight. Filtered the solid and washed with ether, and air dried to afford 37 as white solid (9.5 g, 84%). 1H NMR (300 MHz, DMSO-d6) δ 7.55 (d, J=7.5 Hz, 2H, ArH), 7.31 (d, J=7.8 Hz, 2H, ArH), 6.79 (s, 1H, ArH), 6.73 (s, 1H, ArH), 5.99 (s, 2H, CH2), 4.63 (t, J=6.3 Hz, 1H, —CH), 3.36-3.32 (m, 2H, CH2), 3.18-3.06 (m, 2H, CH2), 2.96-2.82 (m, 2H, —CH2). MS (ES+) m/z 346 [M-(COOH)2+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].O.[NH2:10][NH2:11]>C(O)C>[NH2:6][C:5]1[NH:11][N:10]=[C:3]([CH:2]([CH3:8])[CH3:1])[CH:4]=1
Reactant: NN
Reactant: CC(C)C(=O)CC#N
Solvent: CCO
Solvent: O
Product: CC(C)c1cc(N)[nH]n1
Temperature: 25 °C
Yield: 87 %

Procedure:
4-Methyl-3-oxopentanonitrile (A) was dissolved in ethanol (140 ml) and stirred at room temperature. Hydrazine hydrate (15.7 g) was added and the resulting mixture was stirred for 1 hour at room temperature, followed by heating under refluxing for 5 hours. The solvent was distilled off under reduced pressure and the residue was subjected to distillation under reduced pressure (133°-153° C./0.06 mmHg) to obtain 33.3 g (87%) of 5-amino-3-(1-methylethyl)pyrazole (B).
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH:23]([OH:30])[CH2:24][NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:14])[NH:4][CH:3]=1.Cl.C([OH:34])C.[OH-].[Na+]>O>[CH3:27][C:26]([NH:25][CH2:24][CH:23]([OH:30])[CH2:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13](=[O:14])[CH2:12][CH2:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:2][C:3](=[O:34])[NH:4]2)([CH3:29])[CH3:28]
Reactant: CCO
Reactant: CC(C)(C)NCC(O)COc1ccccc1C(=O)CCc1cccc2[nH]cc(Cl)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)NCC(O)COc1ccccc1C(=O)CCc1cccc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 6.37 g of the product of Step A, 192 ml of N hydrochloric acid and 192 ml of ethanol was stirred for 17 hours at room temperature and was then diluted with water. The mixture was made alkaline by addition of sodium hydroxide and was extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica and eluted with a 6-3-1 chloroform-acetone-triethylamine mixture to obtain 2.32 g of 1,3-dihydro-4-[3-[2-[3-(1,1-dimethylethylamino)-2-hydroxypropoxy]-phenyl]-3-oxopropyl]-2H-indol-2-one.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].Br[CH2:15][C:16]#[N:17].C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C@@H:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([O:6][CH2:15][C:16]#[N:17])=[O:5]
Reactant: N#CCBr
Reactant: CO[C@@H](Cc1ccccc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CO[C@@H](Cc1ccccc1)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 71.2 %

Procedure:
(S)-2-Methoxy-3-phenylpropanoic acid (Compounds 7a, 0.50 g, 2.50 mmol) and 2-bromoacetonitrile (1.20 g, 10.00 mmol) were dissolved in acetonitrile (60 ml). Then triethylamine (0.50 g, 4.99 mmol) was added dropwise under ice-cooling. After stirring at room temperature for 40 minutes, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to afford the title compound (0.39 g, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:28]([C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36])#[N:29].[Cl-].[NH4+]>O1CCCC1>[C:28]([C:30]1[CH:31]=[C:32]([S:37]([N:6]([CH2:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[O:2][CH3:1])[C:7]2[S:11][N:10]=[CH:9][N:8]=2)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36])#[N:29]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
(2,4-Dimethoxy-benzyl)-(1,2,4)thiadiazol-5-yl-amine (Preparation 14, 8.010 g, 0.03200 mol) was dissolved in tetrahydrofuran (100 mL, 1.3 mol) and cooled to −78° C. 1.0 M of Lithium hexamethyldisilazide in tetrahydrofuran (35.2 mL) was added dropwise to the reaction mixture. The cooling bath was removed and the reaction was allowed to stir for 30 minutes. The reaction was cooled back to −78° C. and a solution of 3-cyano-4-fluorobenzenesulfonyl chloride (7.028 g, 0.03200 mol) in tetrahydrofuran (80 mL, 0.99 mol) was added dropwise to the reaction. The reaction was allowed to stir for 30 minutes at −78° C. The reaction was poured into saturated aqueous ammonium chloride. The aqueous phase was extracted with ethyl acetate (three times). The combined organic phase was washed twice with 10% citric acid solution, water and brine. The organic phase was dried over magnesium sulfate and evaporated to a residue. The residue was purified by column chromatography (120 g silica gel column, Hexanes to ethyl acetate gradient elution). Product fractions were combined and evaporated to a residue. The residue was triturated with 10% t-butyl methyl ether in hexanes and the resulting off-white solid collected by filtration and rinsed with hexanes. Vacuum drying gave 3.58 g of the title compound. LCMS Rt=1.66 minutes MS m/z 457 [MNa]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[CH:5][CH:4]=1)#[N:2].[Cl:18][C:19]1[C:24]([C:25]([N:27]=[C:28]=[O:29])=O)=[C:23]([F:30])[C:22]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:21][CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:23]([F:30])[C:24]=1[C:25]1[NH:27][C:28](=[O:29])[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:10]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Reactant: CC(C)(C)OC(=O)NNc1ccc(C#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C#N)cc3)c(=O)[nH]2)c1F

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(4-cyanophenyl)hydrazinecarboxylate (step-2 of Intermediate 17, 0.060 g, 0.25 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.160 g, 0.51 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.020 g of pure product. 1H NMR (400 MHz, CDCl3): δ 1.20 (s, 9H), 4.45 (d, J=5.9 Hz, 2H), 6.19 (m, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H), 8.19 (d, J=8.4 Hz, 2H), 10.72 (br s, 1H); MS (m/z): 426.27 (M−H−).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:21][CH2:22][CH3:23].[Cl:24][C:25]1[N:26]=[C:27]([C:32](O)=[O:33])[NH:28][C:29]=1[CH2:30][CH3:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:24][C:25]1[N:26]=[C:27]([C:32]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH3:20])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:21][CH2:22][CH3:23])=[O:33])[NH:28][C:29]=1[CH2:30][CH3:31]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OCC)C2)oc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)oc1C
Yield: 43.6 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-ethoxypiperidin-1-yl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (112h) (0.66 g, 2.03 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.2 g, 1 mmol), WSC hydrochloride (0.5 g, 2.5 mmol), HOBt (0.2 g, 1.5 mmol), dichloromethane (5 mL) and DMA (3 mL), to obtain 0.21 g of the title compound as a yellow amorphous solid (44%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)[N:15]=[CH:14][N:13]=3)[C:5]=2[N:6]=1.[CH2:28]([CH2:30][NH2:31])[OH:29]>O1CCOCC1>[F:25][C:24]([F:27])([F:26])[C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:15]=[CH:14][N:13]=[C:12]([O:11][C:7]3[C:5]4[N:6]=[C:2]([NH:31][CH2:30][CH2:28][OH:29])[S:3][C:4]=4[CH:10]=[CH:9][CH:8]=3)[CH:17]=2)=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Oc3cccc4sc(Br)nc34)ncn2)cc1
Reactant: NCCO
Solvent: C1COCCO1
Product: OCCNc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2s1
Temperature: 200 °C

Procedure:
To 2-bromo-4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazole, (Example 86), (90 mg, 0.2 mmol) dissolved in dioxane (1 mL) was added ethanolamine (0.06 mL, 1 mmol, Aldrich). The reaction mixture was heated in microwave synthesizer at 200° C. for 10 min, allowed to cool to room temperature and evaporated in vacuum. Purification of the residue by silica gel chromatography (1:1 of EtOAc/hexanes) provided the title compound as a white solid. MS (ESI, pos. ion) m/z: 433 (M+1).
Reaction SMILES: CN(C[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)C.C([Li])CCC.[CH3:15][C:16]([C:19]1[C:24]([OH:25])=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:22]=[C:21]([C:30](N(OC)C)=[O:31])[N:20]=1)([CH3:18])[CH3:17]>O1CCCC1>[CH3:18][C:16]([C:19]1[C:24]([OH:25])=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:22]=[C:21]([C:30]([C:6]2[NH:5][CH:9]=[CH:8][N:7]=2)=[O:31])[N:20]=1)([CH3:15])[CH3:17]
Reactant: CON(C)C(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Reactant: CN(C)Cn1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(C(=O)c2ncc[nH]2)nc(C(C)(C)C)c1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a solution of 1-[(dimethylamino)methyl]-imidazole (0.70 g, 5.6 mmol) (See Katritzky, A. R.; Rewcastle, G. W.; Fan, W-Q; J. Org. Chem. 1988, 53, 5688) in tetrahydrofuran (10 mL) at -78° C. under nitrogen atmosphere is added a 1.58M solution of n-butyllithium (3.60 mL, 5.69 mmol) in hexanes dropwise. The resulting mixture is stirred 1 hour at -78° C., warmed to ~0° C., and stirred 0.5 hours. After cooling to -78° C., 4,6-bis(1,1-dimethylethyl)-5-hydroxy-N-methoxy-N-methyl-2-pyrimidinecarboxamide (0.50 g, 1.7 mmol) in tetrahydrofuran (5 mL) is added. This mixture is warmed to room temperature, stirred for 16 hours, and quenched by addition of aqueous 2N hydrochloric acid solution. After extraction with ethyl acetate, the combined extracts are washed with water and brine solution. Concentration of the organic phase under vacuum followed by recrystallization of the organic residue from methanol and water gives 0.43 g (84%) of the title compound, mp 217°-220° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].N1C=CC=CC=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43].O>ClCCl>[CH3:41][S:42]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)n1c(-c2ccc(NS(C)(=O)=O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reaction time: 1.5 h
Yield: 44.1 %

Procedure:
4-Amino-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0820 g, 0.178 mmol) was dissolved in dichloromethane (4.0 mL), and the solution was added with pyridine (0.0430 mL, 0.534 mmol) and methanesulfonyl chloride (0.0210 mL, 0.267 mmol), followed by stirring for 1.5 hours under ice-cooling. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (chloroform/methanol=4/1) to obtain 4-methanesulfonylamino-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0423 g, yield 44%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH2:24])[CH2:19][CH2:18]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:24][CH2:23][CH:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN1CCC(CN)CC1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1NCC1CCN(C)CC1
Yield: 51.1 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with (1-methylpiperidin-4-yl)methanamine (160 mg, 1.3 mmol) to afford the desired product (170 mg, 49%) as a light yellow-brown solid: 1H NMR (500 MHz, CDCl3) δ 11.06 (br s, 1H), 8.95 (s, 1H), 8.10 (d, J=8.8 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 4.13 (t, J=6.4 Hz, 2H), 2.99-2.92 (m, 2H), 2.69 (s, 3H), 2.32 (s, 3H), 2.07-1.98 (m, 2H), 1.97-1.89 (m, 2H), 1.85-1.75 (m, 1H), 1.57-1.47 (m, 2H); ESI MS m/z 333 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[S:13][CH:14]=[CH:15][C:7]1=2)=[O:5].C(N(CC)CC)C.[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:29]([C:34](Cl)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=1>ClCCl>[S:13]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][N:6]([C:4]([C:3]3[CH:16]=[CH:17][C:18]([NH:20][C:34]([C:29]4[C:28]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:35])=[CH:19][C:2]=3[Cl:1])=[O:5])[C:7]=2[CH:15]=[CH:14]1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: Nc1ccc(C(=O)N2CCCCc3sccc32)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCCCc3sccc32)c(Cl)c1)c1ccccc1-c1ccccc1

Procedure:
As described for Example 1, a solution of 2 mmol of 4-(2-chloro-4-aminobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine and 5 mmol of triethylamine in 10 ml of dichloromethane under argon is reacted with [1,1'-biphenyl]-2-carbonyl chloride for 16 hours at room temperature to give the product as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH:21]=[CH2:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH2:21][CH3:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Solvent: CCO
Product: CCc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (11 g), bis(tricyclohexylphosphine)palladium (II) dichloride (1 g), tripotassium phosphate (13 g) and vinylboronic acid pinacol ester (10 g) were added toluene (90 mL) and water (4.5 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-methyl-5-vinylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g). 4-(3-Methyl-5-vinylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g) was dissolved in ethanol (90 mL), 5% palladium carbon-ethylenediamine complex (2 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. After celite filtration, the solvent in the filtrate was evaporated to give 4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g). 4-(5-Ethyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g) was dissolved in chloroform (20 mL), 4N hydrogen chloride/ethyl acetate (20 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added, and the precipitate was collected by filtration to give the title compound (5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=2[Cl:21])([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.[Cl-].[NH4+]>[Fe].CC1C=CC=CC=1>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]([CH3:11])([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]#[N:10])=[C:13]([Cl:21])[CH:14]=1
Reactant: CC(C#N)(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CC(C#N)(c1ccc(Cl)cc1)c1ccc(N)cc1Cl

Procedure:
A mixture of 20 parts of 4-chloro-α-(2-chloro-4-nitrophenyl)-α-methylbenzeneacetonitrile, 7 parts of iron powder, 250 parts of ammonium chloride solution 0.78N and 200 parts of methylbenzene was stirred and refluxed for 3 hours. The reaction mixture was filtered hot. The aqueous phase was separated and washed with methylbenzene. The combined organic layers were washed successively with water, sodium hydrogen carbonate solution and again with water, dried and evaporated. The residue was washed with 1,1'-oxybisethane and dried, yielding 10 parts of α-(4-amino-2-chlorophenyl)-4-chloro-α-methylbenzeneacetonitrile; mp. 135.2° C. (intermediate 24).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].[NH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][N:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:3])=[O:2]
Reactant: C1CCCNCC1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(CN2CCCCCC2)c1
Yield: 70.1 %

Procedure:
To a solution of 3-nitrobenzyl bromide (10.5 g, 48.7 mmol) in methylene chloride is added azepane (5.5 mL, 48.7 mmol) and 20.0 mL (146.1 mmol) of triethylamine, and the reaction solution is heated at 60□C under N2 for 20 minutes. After evaporating to dryness, the resulting brown residue is dissolved in methylene chloride and washed twice with saturated Na2CO3 solution, and once with brine solution. After drying over Mg2SO4, the organic solution is filtered and concentrated to give 8.0 g (70.1% yield) of brown oil.