Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCBr.[Mg].[F:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15]1[CH:16]=[CH:17][C:18]([CH:26]=[O:27])=[N:19][C:20]=1[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23].Br[CH2:29][C:30]1[CH:31]=[C:32]([CH:41]=[CH:42][CH:43]=1)[CH2:33][O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1.[Cl-].[NH4+]>C1COCC1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[C:15]1[CH:16]=[CH:17][C:18]([CH:26]([OH:27])[CH2:29][C:30]2[CH:43]=[CH:42][CH:41]=[C:32]([CH2:33][O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)[CH:31]=2)=[N:19][C:20]=1[CH2:21][C:22]([CH3:24])([CH3:23])[CH3:25]
Reactant: COc1ccc(F)c(-c2ccc(C=O)nc2CC(C)(C)C)c1
Reactant: BrCc1cccc(COC2CCCCO2)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(C(O)Cc3cccc(COC4CCCCO4)c3)nc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
Under a nitrogen atmosphere, 1,2-dibromoethane (34 μL) was added to a mixture of magnesium (578 mg) and THF (15 mL) at room temperature, and the mixture was stirred at 50° C. for 10 min. To the reaction mixture were added 5-(2-fluoro-5-methoxyphenyl)-6-neopentylpicolinealdehyde (2.39 g) and then 2-((3-(bromomethyl)benzyl)oxy)tetrahydro-2H-pyran (4.52 g) was added, and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (980 mg) as an orange oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])[CH:8]=2)[NH:3]1.[CH:23](OCC)=[O:24].[O-]CC.[Na+].Cl>C(O)C>[OH:24][CH:23]=[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])[CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)CC(=O)N3)c1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)c1
Temperature: 78 °C
Yield: 83.8 %

Procedure:
N-[3-(2-Oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-acetamide (0.452 g, 1.54 mmol) and ethyl formate (0.370 mL, 4.60 mmol) were dissolved in anhydrous ethanol (6.50 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (2.90 mL, 7.69 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding pure N-[3-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-acetamide (0.415 g, 1.29 mmol, 84%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:5]([NH:6][CH:7]2[CH2:9][CH2:8]2)=[C:4]([O:15][CH3:16])[CH:3]=1>C(O)C.C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:11]=[C:10]([NH2:12])[C:5]([NH:6][CH:7]2[CH2:9][CH2:8]2)=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: COc1cc(Br)cc([N+](=O)[O-])c1NC1CC1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(Br)cc(N)c1NC1CC1
Temperature: 60 °C

Procedure:
4-bromo-N-cyclopropyl-2-methoxy-6-nitroaniline (1.05 g, 3.66 mmol) and iron powder (1.43 g, 25.6 mmol) were suspended in ethanol (19 mL) and acetic acid (9.5 mL). The stirred mixture was heated to 60° C. for 1 h and was diluted with EtOH (20 mL EtOH). Celite (15 g) was added and the mixture was filtered through a pad of Celite with EtOH. The filtrated was concentrated in vacuo. The crude residue was taken up in and concentrated once from 30 mL EtOH to afford crude 4-bromo-N1-cyclopropyl-6-methoxybenzene-1,2-diamine that was used immediately in the following step. LCMS-ESI+ (m/z): [M+H]+ calcd for C10H14BrN2O: 257.03; found: 257.15.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[N:28]1([C:34]2[N:35]=[CH:36][C:37]([C:40](O)=[O:41])=[N:38][CH:39]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:40]([C:37]5[CH:36]=[N:35][C:34]([N:28]6[CH2:33][CH2:32][O:31][CH2:30][CH2:29]6)=[CH:39][N:38]=5)=[O:41])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1cnc(N2CCOCC2)cn1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1cnc(N2CCOCC2)cn1

Procedure:
The title compound, white solid (107 mg, 82%), MS (ISP) m/z=522.5 [(M+H)+], mp 192.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 5-morpholin-4-yl-pyrazine-2-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH-].[K+].S(OC)(O[CH3:32])(=O)=O.O>CN(C)C=O>[CH2:24]([O:23][C:21]([C:18]1[CH:19]=[CH:20][C:15]([N:14]([CH3:32])[CH:13]=[N:12][C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)=[CH:16][CH:17]=1)=[O:22])[CH3:25]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1ccc(N=CNc2ccc(C(=O)OCC)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(N=CN(C)c2ccc(C(=O)OCC)cc2)cc1
Reaction time: 8 h

Procedure:
To a stirred solution of N,N'-bis(4-ethoxycarbonylphenyl)formamidine (6.8 g, 0.02 mol) in 50 ml of dimethylformamide was added 2.0 g of potassium hydroxide and 2 ml (0.02 mole) of dimethyl sulfate. The solution was stirred overnight and heated at 100° for 3 hrs. The reaction mixture was poured into 100 ml of water and the solid which precipated was collected by filtration and dried. The solid was triturated with 150 ml of benzene. The undissolved material was removed by filtration and the filtrate was concentrated to a solid residue. This solid residue was then triturated with 50 ml of chloroform. The remaining solids were removed by filtration. Concentration of the filtrate produced the desired product, mp 89°-91° C. ##STR10##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].IC.[C:12](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH3:12])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(O)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(C)c(Cl)c1
Reaction time: 2 h
Yield: 95.2 %

Procedure:
Heat a solution of 3-chloro-4-methylphenol (15 g, 0.11 mol), iodomethane (9.8 mL, 0.16 mol), and potassium carbonate (22 g, 0.16 mol) in DMF (200 mL) to 50° C. and stir for 2 hr. Cool the reaction to room temperature and quench with 1N aqueous HCl. Extract the aqueous with diethyl ether (Et2O). Wash the organic with brine, dry over MgSO4, and filter. Remove the solvent to afford 16.4 g (100%) of the desired product.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)N.[CH:12]([C:15]([CH3:17])=O)([CH3:14])[CH3:13]>C(O)(=O)C>[CH3:17][C:15]1[C:12]([CH3:14])([CH3:13])[C:11]2[C:3](=[CH:4][CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=2)[N:1]=1
Reactant: CC(=O)C(C)C
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: CC(=O)O
Product: CC1=Nc2ccc(C(=O)O)cc2C1(C)C
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A solution of 4-hydrazinobenzoic acid (10.0 g, 65.7 mmol), isopropylmethylketone (21.1 mL, 197 mmol) in acetic acid (35 mL) was heated under reflux in an oil bath for 20 h. After cooling to ambient temperature the solvent was evaporated off under reduced pressure and to it was added a saturated aqueous solution of NaHCO3 (50 mL) and washed with CH2Cl2 (3×40 mL). The pH of the aqueous solution was adjusted with 1 M aqueous HCl to ca. 2, and then extracted with CH2Cl2 (3×50 mL). The combined organic solution was then dried with Na2SO4, filtered and concentrated to dryness under reduced pressure to yield the desired product (10.7 g, 80%) as a brownish solid.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:8]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[C:7]([CH3:23])=[C:6]([Cl:24])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+]>CO.C(#N)C>[NH2:31][CH:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:8]([N:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[O:22])[C:7]([CH3:23])=[C:6]([Cl:24])[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(C)c(N2CCCC2=O)c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1N1CCCC1=O
Temperature: 65 °C

Procedure:
A mixture of 1-(6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl)pyrrolidin-2-one (40 mg, 0.1 mmol) and ammonium acetate (89 mg, 1.2 mmol) and sodium cyanoborohydride (15 mg, 0.23 mmol) in methanol (0.4 mL) and acetonitrile (0.4 mL) was heated at 65° C. overnight in a sealed tube. The mixture was cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (34 mg, 80%). LCMS calculated for C19H18ClFNO (M−NH2)+: m/z=330.1. found: 330.0.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1C=O>>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:22]2[CH:21]=[CH:18][C:17]([F:16])=[CH:24][C:23]=2[F:25])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1F
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(F)cc1
Product: O=S(=O)(/C=C/c1ccc(F)cc1F)Cc1ccc(F)cc1
Yield: 68 %

Procedure:
A solution of 4-fluorobenzyl sulfonylacetic acid (0.01 mol) and 2,4-difluorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 68% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:41]=[CH:40][C:39]([S:42][CH3:43])=[CH:38][CH:37]=1)=[C:34]=[O:35]>ClCCl>[CH3:43][S:42][C:39]1[CH:38]=[CH:37][C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])=[CH:41][CH:40]=1
Reactant: CSc1ccc(N=C=O)cc1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (112 mg, 0.3 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (45.5 mg, 0.45 mmol) (Aldrich), followed by the addition of 1-isocyanato-4-methylsulfanyl-benzene (59.4 mg, 0.36 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-methylsulfanyl-phenyl)-amide as a white solid (Yield 0.13 g, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.NC(N)=[O:13].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N+:6]([O-:13])[CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: NC(N)=O
Agent: OO
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(O)c1ccc(Br)c[n+]1[O-]
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a suspension of 5-bromopicolinic acid (25.0 g) and urea-hydrogen peroxide adduct (20.0 g) in acetonitrile (200 mL) was added trifluoroacetic anhydride (50 mL) at 0° C., and the mixture was stirred for 30 min. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from diethyl ether to give the title compound (19.6 g) as white crystals.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[CH:9]1([CH2:15][NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[C:1]([CH2:3][C:4]([NH:16][CH2:15][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:6])#[N:2]
Reactant: NCC1CCCCC1
Reactant: CCOC(=O)CC#N
Product: N#CCC(=O)NCC1CCCCC1
Reaction time: 2 h
Yield: 93.1 %

Procedure:
2-Cyano-N-(cyclohexylmethyl)acetamide was prepared by the method of V. Papesh, J. Org. Chem. 1951, 16, 1879-1889. Ethyl cyanoacetate (Aldrich, 18.41 mL, 173 mmol) was added to neat cyclohexanemethylamine (Aldrich, 19.585 g, 173 mmol), and the resulting solution was stirred for 2 h under nitrogen. At this time, the reaction mixture solidified. After standing for 18 h the white crystalline solid was broken up, filtered, washed with water (150 mL), and dried (0.1 Torr, 40° C.) to provide 2-cyano-N-(cyclohexylmethyl)acetamide (29.030 g, 93%), m.p. 83°-84° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[C:10]([F:18])=[C:11]([C:14]([F:17])=[CH:15][CH:16]=1)[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[C:34]3[CH:40]=[CH:39][NH:38][C:35]3=[N:36][CH:37]=2)[CH:27]=1.[OH-].[K+].O>CO>[CH2:19]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[C:10]([F:18])=[C:11]([CH:12]([C:40]2[C:34]3[C:35](=[N:36][CH:37]=[C:32]([C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)[CH:33]=3)[NH:38][CH:39]=2)[OH:13])[C:14]([F:17])=[CH:15][CH:16]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F
Reactant: c1cncc(-c2cnc3[nH]ccc3c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC(c1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F)c1c[nH]c2ncc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-dibenzylamino-2,6-difluoro-benzaldehyde (53, 0.76 g, 2.3 mmol) in methanol (50 mL) were added 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 0.40 g, 2.1 mmol, prepared as described in Example 17) and potassium hydroxide (0.50 g, 8.9 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% methanol in methylene chloride to provide the compound (54, 0.60 g, 50%). MS (ESI) [M+H+]+=533.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]([CH2:19][C:20]#[C:21][CH3:22])[C:8](=[N:16][C:17]#[N:18])OC1C=CC=CC=1)=[O:5])[CH3:2].[C:23]([O:27][C:28]([NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:23]([O:27][C:28]([NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][N:33]([C:8]([N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:19][C:20]#[C:21][CH3:22])=[N:16][C:17]#[N:18])[CH2:32]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC#CCN(CC(=O)OCC)C(=NC#N)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCN(CC(=O)OCC)C(=NC#N)N1CCCC(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10.0 g 1-ethoxycarbonylmethyl-1-(but-2-ynyl)-3-cyano-2-phenyl-isourea are added to a mixture of 10.0 g 3-tert-butoxycarbonylaminopiperidine and 4.8 g potassium carbonate in 50 ml of dimethylformamide. The reaction mixture is stirred for 1 d at ambient temperature and then a further 1.6 g potassium carbonate and 3.0 g 3-tert-butoxycarbonylaminopiperidine are added. After another 3 d at ambient temperature water is added and the mixture is extracted with ethyl acetate. The organic extracts are dried over sodium sulphate, the solvent is removed, and the residue is purified on silica gel (cyclohexane/ethyl acetate 5:1->1:2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([C@@H:18]1[CH2:22][C@H:21]([NH:23][C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:25])[C:20](=O)[CH2:19]1)=[O:17].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C(O)(=O)C.[BH3-]C#N.[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([C@@H:18]1[CH2:22][C@H:21]([NH:23][C:24]([C:26]2[S:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:25])[CH:20]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:19]1)=[O:17]
Reactant: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1=O)c1ccc(Cl)s1
Reactant: C1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)CC1N1CCCC1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-chloro-thiophene-2-carboxylic acid {(1S,4R)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-oxo-cyclopentyl}-amide (75 mg) in THF (3 ml) were added pyrrolidine (0.03 ml) and acetic acid (0.02 ml). After stirring for 1 hr at r.t., NaBH3CN (11 mg) was added and stirring of the yellow reaction mixture was continued over night, then concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2MeOH 85:15) to give 5-chloro-thiophene-2-carboxylic acid {(1S,4R)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-pyrrolidin-1-yl-cyclopentyl}-amide (40 mg) as crystalline solid. MS 529.3 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[C:29]([CH3:30])=[CH:28][C:5]2[NH:6][C:7](=S)[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1.O.[NH2:32][NH2:33].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CCC>[CH3:1][C:2]1[C:29]([CH3:30])=[CH:28][C:5]2[N:6]=[C:7]([NH:32][NH2:33])[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1C)NC(=S)CC(c1ccc(-n3c(C)nc4cnccc43)cc1)=N2
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCCO
Product: Cc1cc2c(cc1C)N=C(c1ccc(-n3c(C)nc4cnccc43)cc1)CC(NN)=N2
Temperature: 100 °C

Procedure:
A mixture of 2,3-dihydro-7,8-dimethyl-4-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-1H-[1,5]benzodiazepine-2-thione (411 mg, 1.0 mmol), hydrazine hydrate (60 mg, 1.2 mmol) and p-toluenesulphonic acid (10 mg) in n-butanol (5 ml) was heated at 100° C. for 1.5 hours. The solvent was removed under reduced pressure and the crude product was used directly for Examples 29-31.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([O:19]C)=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([OH:19])=[O:18])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1sccc1NS(=O)(=O)c1ccc(Br)cc1
Temperature: 65 °C
Yield: 9.3 %

Procedure:
To a solution of 74 (0.20 g; 5.32 mmol) in tetrahydrofuran (2.7 mL) were added aqueous sodium hydroxide (2.7 mL; 2N) and methanol (1.4 mL), sequentially. The reaction mixture was heated at 65° C. for 18 hours, allowed to cool to room temperature, and then extracted with aqueous sodium hydroxide (20 mL; 2N). The aqueous layer was washed with diethyl ether (30 mL×2), acidified with aqueous hydrochloric acid (20 mL; 6N), and extracted with dichloromethane (40 mL). The organic layer was successively washed with water (30 mL) and aqueous saturated sodium chloride (30 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield the title compound as a white solid (0.18 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-])=O)[CH:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([SH:29])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([S:29][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=2[NH2:16])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(S)cc1OC
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Product: COc1ccc(Sc2ccc(C)cc2N)cc1OC
Yield: 71.3 %

Procedure:
The product from Example 4a (11.25 g, 39.5 mmol) was reacted with 3,4-dimethoxy-benzenethiol (6.71 g, 39.5 mmol) for 18 h following the procedure from Example 4b giving the product as a solid (7.75 g, 64%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].I[CH2:22][CH2:23][CH3:24]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:22][CH2:23][CH3:24])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: CCCI
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc(-c2ccc(OC)cc2)c2cccc(F)c21
Yield: 52.1 %

Procedure:
Prepared according to Method D step B from 7-fluoro-3-(4-methoxyphenyl)-1H-indazole (0.121 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 1-iodopropane (0.096 mL, 1.0 mmol) to give the title compound (0.074 g) as a white solid.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]3[N:16]([CH2:19][CH2:20][C:21]#[N:22])[N:17]=[CH:18][C:10]=13)[CH2:2]2.[NH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:13]2[N:12]=[C:11]3[N:16]([CH2:19][CH2:20][C:21]#[N:22])[N:17]=[CH:18][C:10]3=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:14]=2)=[CH:26][CH:25]=1
Reactant: N#CCCn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
Reactant: Nc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#CCCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)nc21
Temperature: 25 °C

Procedure:
3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propanenitrile (1.75 mmol) was dissolved in toluene (32 mL) and ethanol (19 mL). 4-Aminophenylboronic acid, pinacol ester (858 mg, 3.9 mmol) was added followed by the addition of a 2M aqueous solution of Na2CO3 (7.1 mL). The mixture was degassed by bubbling a stream of nitrogen through the solution and tetrakis(triphenylphosphine)palladium (53 mg) was added. The mixture was heated under reflux for 4 h, cooled to room temperature and concentrated. The mixture was dissolved in ethyl acetate and washed with brine. The organic phase was dried over MgSO4, filtered and concentrated. The crude product was applied to a silica gel column and eluted with ethyl acetate in hexanes (30-100%) to give 547 mg of the title compound.