Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH:17]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:18][C:19]([O:21]CC)=[O:20])[C:13](=[O:30])[C:12]2=[O:31])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+]>Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH:17]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:18][C:19]([OH:21])=[O:20])[C:13](=[O:30])[C:12]2=[O:31])=[CH:32][CH:33]=1)#[N:2]
Reactant: CCOC(=O)CC(c1cccnc1)N1CCN(CCCOc2ccc(C#N)cc2)C(=O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1ccc(OCCCN2CCN(C(CC(=O)O)c3cccnc3)C(=O)C2=O)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 70.1 %

Procedure:
In 70 ml of 6N hydrochloric acid was dissolved 7.0 g of ethyl 3-[4-[3-(4-cyanophenoxy)propyl]-2,3-dioxopiperazin-1-yl)-3-(pyridin-3-yl)propionate, and the solution was stirred at 50° C. for 1.5 hours and then cooled to room temperature. The reaction solution was adjusted to pH 4.0 with a 15% aqueous sodium hydroxide solution and the crystals precipitated were collected by filtration to obtain 4.6 g of 3-[4-[3-(4-cyanophenoxy)-propyl]-2,3-dioxopiperazin-1-yl]-3-(pyridin-3-yl)-propionic acid as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][NH2:5].C(N1C=CN=C1)([N:14]1C=CN=C1)=O.C(N(CC)CC)C.FC1C=C(OC)C=C(F)C=1CN1[C:40]2[N:41]=[CH:42][CH:43]=[CH:44][C:39]=2[S:38](=[O:46])(=[O:45])[N:37]([C:47]2[CH:52]=C[C:50]([O:53][CH3:54])=[C:49]([O:55][CH3:56])[CH:48]=2)[C:36]1=[O:57]>CN(C=O)C>[CH3:56][O:55][C:49]1[CH:48]=[C:47]([N:37]2[C:36](=[O:57])[N:5]([CH2:4][C:3]3[C:2]([F:1])=[CH:9][C:8]([F:10])=[CH:7][C:6]=3[F:11])[C:40]3[N:41]=[CH:42][CH:43]=[CH:44][C:39]=3[S:38]2(=[O:45])=[O:46])[CH:52]=[N:14][C:50]=1[O:53][CH3:54]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1c(F)cc(F)cc1F
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ncccc3S2(=O)=O)cnc1OC

Procedure:
The title compound (159 mg, 0.33 mmol) was prepared in two steps from (IntC4) (165 mg, 0.5 mmol), 2,4,6-trifluorobenzylamine (0.18 mL, 1.5 mmol); followed by 1,1′-carbonyldiimidazole (311 mg, 1.92 mmol), triethylamine (0.13 mL, 0.96 mmol) in DMF (1.5 mL) using the methods of (95).
Reaction SMILES: [C:1]([CH:3]=[CH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH:15][C:16](=[O:38])[CH2:17][CH:18]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)(=[O:29])=[O:28])[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:10][CH2:9][CH2:8]2)#[N:2].C(Cl)(Cl)Cl>CCO.O=[Pt]=O>[NH2:2][CH2:1][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH:15][C:16](=[O:38])[CH2:17][CH:18]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)(=[O:29])=[O:28])[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH2:10][CH2:9][CH2:8]2
Reactant: N#CC=Cc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccc(F)cc1
Agent: O=[Pt]=O
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: NCCCc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-[6-(2-Cyano-vinyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-3-(3,4-dichloro-benzenesulfonylamino)-3-(4-fluoro-phenyl)-propionamide (150 mg, 0.26 mmol) in EtOH:CHCl3 mixture (75:25, 10 mL) was added PtO2 (18 mg, 0.078 mmol). The resulting mixture was flushed under N2 gas followed by evacuating—this was done 3 times. After last evacuation, the hydrogen balloon was inserted. The reaction mixture was stirred under H2 at RT for 2 h. Solvent was separated from the PtO2 by passing through the Celite®. Solvent was evaporated in vacuo to give the final product. MS m/z: 579.11 (M+H). Calc'd. for C28H30Cl2FN3O3S-578.53.
Reaction SMILES: C([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[C:17](N1C=CN=C1)([N:19]1C=CN=C1)=O.[ClH:29].CN.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[ClH:29].[CH3:17][NH:19][C:12]([CH:11]1[CH2:15][CH2:16][NH:8][CH2:9][CH2:10]1)=[O:13]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)C1CCNCC1
Reaction time: 8 h

Procedure:
To a stirring solution of BOC-isonipecotic acid (400 mg) in N,N-dimethylformamide (4 mL) was added 1,1′-carbonyldiimidazole (560 mg). The reaction mixture was stirred overnight and then methylamine hydrochloride (280 mg) and triethylamine (0.48 mL) were added. After 5 hours the reaction mixture was diluted with ethyl acetate, washed with water, dried (MgSO4) and the solvent removed in vacuo. Treatment with HCl yielded piperidine-4-carboxylic acid methylamide, which was isolated as the hydrochloride salt.
Reaction SMILES: N1C2=CN=NC2=[CH:4]N=N1.[C:10]([NH:13][C:14]1[N:19]2[N:20]=[CH:21][C:22]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25]N=3)=[C:18]2[N:17]=[CH:16][N:15]=1)(=[O:12])[CH3:11].C(NC1N2N=CC(C3C=NC=CN=3)=C2N=CN=1)(=O)C>>[C:10]([NH:13][C:14]1[N:19]2[N:20]=[CH:21][C:22]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:4]=3)=[C:18]2[N:17]=[CH:16][N:15]=1)(=[O:12])[CH3:11]
Reactant: c1nn[nH]c2cnnc1-2
Reactant: CC(=O)Nc1ncnc2c(-c3ccncn3)cnn12
Agent: CC(=O)Nc1ncnc2c(-c3cnccn3)cnn12
Product: CC(=O)Nc1ncnc2c(-c3ccncc3)cnn12

Procedure:
By replacing the pyrazolotriazine employed in Example 4 by an equivalent quantity of the end product of Example 2 or Example 3 there is obtained, respectively, 4-acetamido-8-(4-pyrimidinyl)-pyrazolo-[1,5-a][1,3,5]triazine and 4-acetamido-8-(2-pyrazinyl)-pyrazolo[1,5-a][1,3,5]triazine.
Reaction SMILES: CO.C1(C)C=CC(S(O[CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=2)[C:14]#[N:15])(=O)=O)=CC=1.[Na].[SH:32][C:33]1[S:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>O.COCCOC>[S:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=[C:33]1[S:32][CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:17]=1)[C:14]#[N:15]
Reactant: Sc1nc2ccccc2s1
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2cccc(C(=O)c3ccccc3)c2)cc1
Agent: [Na]
Solvent: O
Solvent: COCCOC
Solvent: CO
Product: N#CC(Sc1nc2ccccc2s1)c1cccc(C(=O)c2ccccc2)c1
Yield: 83.4 %

Procedure:
Methanol (6 ml) and 3 ml of DME were added to 1.18 g of O-(p-toluenesulfonyl)-m-benzoylmandelonitrile, and the mixture was stirred in an argon atmosphere under ice cooling. Sodium salt of 2-mercaptobenzothiazole (570 mg) was added, and the mixture was stirred for 1.5 hours under ice cooling. Water (50 ml) was added, and the mixture was extracted with 30 ml of methylene chloride three times. The extract was washed with 40 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (silica gel; methylene chloride) to afford 972 mg (yield 83%) of alpha-(2-benzothiazolylthio)-(m-benzoylphenyl)acetonitrile as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[NH4+:44].[OH-]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:36](=[O:42])[NH2:44])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccccc23)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: [NH4+]
Agent: [Li]CCCC
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(n(C(N)=O)c3ccccc23)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A 10 ml portion of tetrahydrofuran (THF) solution containing 600 mg (2.20 mmol) of 2-t-butoxycarbonyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole was cooled to −78° C., mixed with 4.13 ml (6.60 mmol) of 1.6 M n-butyl lithium hexane solution and stirred for 30 minutes, while temperature of the reaction solution increased to −45° C. This was mixed with 6 ml of THF solution containing 1.31 g (4.40 mmol) of triphosgene and stirred for 3.5 hours, while temperature of the reaction solution increased to 0° C. After additional 2 hours of stirring at room temperature, the reaction solution was again cooled to −30° C. This was mixed with 20 ml of 28% ammonia aqueous solution, stirred for 30 minutes and then extracted with chloroform. The extract was washed with water, hydrochloric acid in that order and dried (Na2SO4), and then the solvent was removed by evaporation under a reduced pressure and the resulting oily material was purified by a silica gel column chromatography (140 cc; elution by ethyl acetate-hexane=2:5) to obtain 469 mg of the title compound (68% in yield).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[NH4+:5].[CH3:6][O:7][C:8]([CH2:10][O:11][N:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15])=[O:9].C(O)(C)C>CO>[C:1]([OH:4])(=[O:3])[CH3:2].[C:14]([C:13](=[N:12][O:11][CH2:10][C:8]([O:7][CH3:6])=[O:9])[C:16]([NH2:5])=[NH:17])#[N:15]
Reactant: CC(=O)[O-]
Reactant: [NH4+]
Reactant: COC(=O)CON=C(C#N)C#N
Solvent: CC(C)O
Solvent: CO
Product: CC(=O)O
Product: COC(=O)CON=C(C#N)C(=N)N
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a solution of ammonium acetate (4.62 g) in methanol (10 ml) was added 2-methoxycarbonylmethoxyiminopropanedinitrile (3.34 g) under stirring, which was continued for 2 hours at room temperature and allowed to stand overnight. To the reaction mixture was added isopropyl alcohol (15 ml) and stirred for 15 minutes. The resulting precipitate was collected by filtration, washed with isopropyl alcohol and dried to give 2-cyano-2-methoxycarbonylmethoxyiminoacetamidine acetate (3.4 g), which was recrystallized from methanol, mp. 157° to 158° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]([C:14]2[CH:18]=[C:17]([CH3:19])[O:16][C:15]=2[C:20]([F:23])([F:22])[F:21])=[O:13])=S)[CH:5]=[CH:6][CH:7]=1.[CH:24]1([NH2:31])[CH2:29][CH2:28][CH2:27][CH:26]([NH2:30])[CH2:25]1.C(N(CC)CC)C>CC#N.CO>[NH2:30][CH:26]1[CH2:27][CH2:28][CH2:29][CH:24]([NH:31][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:11][C:12]([C:14]2[CH:18]=[C:17]([CH3:19])[O:16][C:15]=2[C:20]([F:23])([F:22])[F:21])=[O:13])[CH2:25]1
Reactant: NC1CCCC(N)C1
Reactant: Cc1cc(C(=O)NC(=S)Nc2cccc(F)c2)c(C(F)(F)F)o1
Solvent: CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N=C(Nc2cccc(F)c2)NC2CCCC(N)C2)c(C(F)(F)F)o1
Temperature: 65 °C
Yield: 78.8 %

Procedure:
N-((3-Fluorophenyl)carbamothioyl)-5-methyl-2-(trifluoromethyl)furan-3-carboxamide (1.40 g, 4.05 mmol) and cyclohexane-1,3-diamine (1.38 g, 12.1 mmol) were combined in MeCN (20 mL). Triethylamine (0.818 g, 8.10 mmol), NaBiO3 (1.13 g, 4.05 mmol), and BiI3 (0.119 g, 0.203 mmol) were then added and the reaction was heated to 65° C. for 16 hours. When the reaction was complete, the solution was cooled and diluted with MeOH. Then, the resulting mixture was filtered through celite and the filtrate evaporated. The residue was re-dissolved in EtOAc and washed with water, brine, and dried over MgSO4. The organic solvent was then evaporated in vacuo to yield 1.36 g (79%) of the title compound. LCMS (ESI): calc.=426; obs. M+H=427.3 (2 overlapping peaks in ˜2:1 ratio).
Reaction SMILES: [Si]([C:5]#[N:6])(C)(C)C.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]#[N:18])=[C:10]([F:19])[CH:9]=1.[C:20]1(=O)[CH2:23]C[CH2:21]1>O1CCOCC1.[Cl-].[Cl-].[Zn+2]>[C:5]([C:20]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]#[N:18])=[C:10]([F:19])[CH:9]=1)([CH3:23])[CH3:21])#[N:6]
Reactant: O=C1CCC1
Reactant: C[Si](C)(C)C#N
Reactant: N#CCCCc1ccc(N)cc1F
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1COCCO1
Product: CC(C)(C#N)Nc1ccc(CCCC#N)c(F)c1
Yield: 95.9 %

Procedure:
TMSCN (0.14 mL, 1.01 mmol) was added to a mixture of the compound 68 (60 mg, 0.34 mmol), cyclobutanone (0.15 mL, 2.04 mmol) and ZnCl2 (4 mg, 0.04 mmol) in dioxane (1 mL) with stirring. The reaction mixture was stirred at room temperature for 1 h, and concentrated in vacuo. The residue was diluted with water, and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to give compound 70 (80 mg, 91%) as a light yellow oil. The crude product was used directly for the next step without purification.
Reaction SMILES: COC[O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.S(Cl)(Cl)=O.[CH3:21]O>>[OH:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([O:16][CH3:21])=[O:15])[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CO
Reactant: COCOc1cccc2sc(C(=O)O)cc12
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2c(O)cccc2s1

Procedure:
4-(Methoxymethyloxy)benzo(b)thiophene-2-carboxylic acid (7 g) was dissolved in methanol (140 ml) and thionyl chloride (2.0 ml) was added under ice-cooling. The mixture was refluxed under heating for 2 hr and the reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and after filtration, the solvent was evaporated under reduced pressure to give the title compound (6.0 g).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:22])[CH2:4][CH2:5][N:6]1[CH2:11][C:10]2[CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=O)[CH:14]=[N:15][C:9]=2[NH:8][C:7]1=[O:21].Cl.[CH3:24][N:25]1[CH2:31][C:30]2[CH:32]=[C:33](/[CH:36]=[CH:37]/[C:38](O)=O)C=N[C:29]=2[NH:28][C:27](=O)[CH2:26]1.CNCC1N(C)C2C(C=1)=CC=CC=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[CH3:22][N:3]([CH3:2])[CH2:4][CH2:5][N:6]1[CH2:11][C:10]2[CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18]([N:28]([CH3:29])[CH2:27][C:26]3[N:25]([CH3:24])[C:31]4[C:37]([CH:38]=3)=[CH:36][CH:33]=[CH:32][CH:30]=4)=[O:20])[CH:14]=[N:15][C:9]=2[NH:8][C:7]1=[O:21]
Reactant: CN(C)CCN1Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CNCc1cc2ccccc2n1C
Agent: Cl
Product: CN(C)CCN1Cc2cc(/C=C/C(=O)N(C)Cc3cc4ccccc4n3C)cnc2NC1=O
Yield: 22 %

Procedure:
According to the procedure of Example 1 (a), except substituting (E)-3-[3-(2-dimethylamino-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (40 mg, 22%) was prepared as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 9.98 (br s, 1H), 8.38-8.33 (m, 1H), 8.00-7.91 (m, 1H), 7.57-7.42 (m, 3H), 7.22-7.01 (m, 3H), 6.42-6.16 (m, 1H), 5.04-4.85 (m, 2H), 4.53-4.47 (m, 2H), 3.72-3.68 (m, 3H), 3.51-3.31 (m, 4H), 3.11-2.99 (m, 4H), 2.72-2.39 (m, 5H); MS (ESI) m/e 447 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([O:13][CH3:14])=[O:12].[C:15](Cl)(Cl)=[O:16].[CH:19]12[N:26]([C:27]3[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][C:28]=3[C:35]([F:38])([F:37])[F:36])[CH:23]([CH2:24][CH2:25]1)[CH2:22][CH2:21][CH2:20]2>C1(C)C=CC=CC=1.C1COCC1>[CH:23]12[N:26]([C:27]3[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:15]([NH:1][C:2]4[CH:10]=[CH:9][CH:8]=[C:7]5[C:3]=4[CH:4]=[N:5][N:6]5[C:11]([O:13][CH3:14])=[O:12])=[O:16])=[CH:29][C:28]=3[C:35]([F:38])([F:36])[F:37])[CH:19]([CH2:25][CH2:24]1)[CH2:20][CH2:21][CH2:22]2
Reactant: COC(=O)n1ncc2c(N)cccc21
Reactant: O=C(Cl)Cl
Reactant: NCc1ccc(N2C3CCCC2CC3)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)n1ncc2c(NC(=O)NCc3ccc(N4C5CCCC4CC5)c(C(F)(F)F)c3)cccc21
Temperature: 25 °C

Procedure:
Methyl 4-amino-1H-indazole-1-carboxylate (1.72 g, 9.00 mmol) in toluene (300 mL) was treated with phosgene in toluene (9.00 mL, approx. 20% w/w) via syringe. The mixture was heated at reflux for 3.5 hours, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was taken up in diethyl ether and concentrated under reduced pressure. The residue was again taken up in diethyl ether (325 mL) followed by addition of triethylamine (10 mL). The mixture was stirred briefly and then filtered. An aliquot of the filtrate (150 mL, 4.14 mmol) was treated with 4-(8-azabicyclo[3.2.1]oct-8-yl)-3-(trifluoromethyl)benzylamine (1.03 g, 3.62 mmol) in THF (10 mL). After stirring for 2 hours, the mixture was concentrated under reduced pressure to approximately 30 mL and filtered. The filter cake was washed with diethyl ether:hexane (1:1) and dried under reduced pressure to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.43 (s, 1H), 7.80 (d, 1H, J=7.8 Hz), 7.69 (d, 1H, J=8.1 Hz), 7.58 (t, 1H, J=2.0 Hz), 7.47 (m, 2H), 7.14 (d, 1H, J=8.1 Hz), 6.86 (t, 1H, J=5.8 Hz), 4.32 (d, 2H, J=5.8 Hz), 4.03 (s, 3H), 3.72 (m, 2H), 1.93 (m, 2H), 1.88-1.55 (m, 5H), 1.49 (m, 3H); MS (ESI) 502 (M+H)+.
Reaction SMILES: CO[C:3]1[C:8]([C:9]([C:11](=[C:17]([S:20][CH3:21])SC)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])=[CH:7][N:6]=[C:5]([S:22][CH3:23])[N:4]=1.[NH2:24][C:25]1C=[CH:29][CH:28]=[CH:27][C:26]=1S.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>C1(C)C=CC=CC=1.O>[CH2:15]([O:14][C:12]([C:11]1[C:9](=[O:10])[C:8]2[CH:7]=[N:6][C:5]([S:22][CH3:23])=[N:4][C:3]=2[N:24]2[C:17]=1[S:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=1)=[O:13])[CH3:16]
Reactant: Nc1ccccc1S
Reactant: CCOC(=O)C(C(=O)c1cnc(SC)nc1OC)=C(SC)SC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(=O)c2cnc(SC)nc2n2c1sc1ccccc12
Temperature: 140 °C
Yield: 55.1 %

Procedure:
A solution of ethyl 2-(4-methoxy-2-(methylthio)pyrimidine-5-carbonyl)-3,3-bis(methylthio)acrylate (475 mg, 1.27 mmol) and 2-aminobenzenethiol (200 mg, 1.60 mmol) in toluene (5 mL) was heated to dryness and continued heating neat at 140° C. for 1 h. Toluene (30 mL) and K2CO3 (350 mg, 2.53 mmol) were added to the reaction and it was heated for an additional 1 h. The reaction mixture was cooled to rt and EtOAc (100 mL) and H2O (50 mL) were added. The layers were separated and the organic layer was washed with brine (100 mL), dried over Na2SO4, and concentrated. The crude solid was triturated in Et2O to afford the desired product as a yellow solid (260 mg, 55%). MS (m/z): 372 (MH+). 1H NMR (DMSO-d6) δ: 9.37 (d, 1H), 9.30 (s, 1H), 8.06 (m, 1H), 7.65 (m, 1H), 7.54 (m, 1H), 4.35 (q, 2H), 2.78 (s, 3H), 1.34 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:17]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:29])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)N3CCCC3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(C(=O)N2CCCC2)c1
Yield: 59.7 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(pyrrolidine-1-carbonyl)-phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (120 mg, 0.31 mmol) in methanol (4.8 mL) and 1N sodium hydroxide aqueous solution (4.58 mL, 4.58 mmol) was heated to reflux for 2 h, LC-MS showed the reaction was complete. The solvent was removed in vacuo and the residual was acidified with 1N hydrochloric acid solution to pH=6. The precipitated white solid was collected by filtration and washed with dichloromethane to afford 70 mg of 3,3-dimethyl-2-(3-(pyrrolidine-1-carbonyl)-phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white powder. Yield: 60.5%. LC-MS(M+1)=379.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[C:5]([C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=1)=O.Cl.[C:19]([O:23][NH2:24])([CH3:22])([CH3:21])[CH3:20].C(O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])/[C:5](/[C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:24]\[O:23][C:19]([CH3:22])([CH3:21])[CH3:20].[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])/[C:5](/[C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:24]/[O:23][C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(c1ccc(F)c(Br)c1)c1ncccc1O
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)O/N=C(/c1ccc(F)c(Br)c1)c1ncccc1O
Product: CC(C)(C)O/N=C(\c1ccc(F)c(Br)c1)c1ncccc1O

Procedure:
A mixture of 2-(3-bromo-4-fluorobenzoyl)-3-hydroxypyridine (1.26 g), O-t-butylhydroxylamine hydrochloride (1.08 g) and ethanol (10 mL) was refluxed for 2 hours. The reaction mixture was poured into water, and subjected to extraction with ethyl acetate. The extract was washed with water and a saturated aqueous saline solution, successively, and dried (sodium sulfate), followed by evaporating the solvent under reduced pressure. The residue was subjected to purification by means of a silica gel column (ethyl acetate--hexane) to afford (E)-2-(3-bromo-α-t-butoxyimino-4-fluorobenzyl)-3-hydroxypyridine (0.89 g) and (Z)-2-(3-bromo-α-t-butoxyimino-4-fluorobenzyl)-3-hydroxypyridine (0.51 g) (compounds 17 and 16).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:13][NH2:14].[CH:15]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[N:27]=[CH:28][C:29]([C:30]4[N:14]([CH3:13])[C:4](=[O:6])[C:3]5[C:2](=[C:10]([O:11][CH3:12])[CH:9]=[CH:8][CH:7]=5)[N:1]=4)=[CH:32][CH:33]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16]1
Reactant: O=Cc1ccc(OC2CCN(C3CCC3)CC2)nc1
Reactant: CN
Reactant: COc1cccc(C(=O)O)c1N
Product: COc1cccc2c(=O)n(C)c(-c3ccc(OC4CCN(C5CCC5)CC4)nc3)nc12

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 2-amino-3-methoxybenzoic acid, methylamine and 6-[(1-cyclobutylpiperidin-4-yl)oxy]nicotinaldehyde.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([C:15]([CH3:17])=O)[CH:12]([CH3:14])[CH3:13].[CH2:18]([N:20]=[C:21]=[O:22])C>C1COCC1>[CH3:17][C:15]1([CH2:11][CH:12]([CH3:14])[CH3:13])[N:20]([CH3:18])[C:21](=[O:22])[N:6]2[C:2](=[N:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=32)[NH:1]1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CC(=O)CC(C)C
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CC(C)CC1(C)Nc2nc3ccccc3n2C(=O)N1C

Procedure:
2-Aminobenzimidazole, methyl isobutyl ketone and ethyl isocyanate were reacted as in Example 26 using an equal volume of THF as cosolvent with the excess ketone. Working up the reaction mixture gave a crude fraction of the 10-N-methylcarbamoyl derivative of the title compound which was not purified but hydrolyzed by the 10% NaOH-THF procedure of Example 1, paragraph 2. The title compound was obtained as a solid, mp 150°-157° C. The confirmatory elemental analysis is shown in Table III.