Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.[F-:30].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>CN(C=O)C>[F:30][CH:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [F-]
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1NC(F)[C@@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
To a solution of 0.400 g of (3R,4R)-4-methylsulfonyl-3-tritylamino-2-oxoazetidine in 2 ml of DMF is added 0.590 g of tetra-n-butylammonium fluoride, and the mixture is stirred for 30 minutes at room temperature. To the reaction mixture are added ice-water and ethyl acetate. The ethyl acetate layer is separated and washed with water, followed by concentration. The residue is purified on a silica-gel column (ethyl acetate:n-hexane=1:1) to give 0.282 g of (3R)-4-fluoro-3-tritylamino-2-oxoazetidine.
Reaction SMILES: [F:1][CH:2]([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:15]([CH3:16])[C:14]([CH2:17][CH2:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24](C3CCCCO3)[N:23]=[CH:22]4)=[N:13][N:12]=2)=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:24]1[C:25]2[C:21](=[CH:20][C:19]([CH2:18][CH2:17][C:14]3[N:15]([CH3:16])[C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:34])=[CH:5][CH:6]=4)=[N:12][N:13]=3)=[CH:27][CH:26]=2)[CH:22]=[N:23]1
Reactant: Cn1c(CCc2ccc3c(cnn3C3CCCCO3)c2)nnc1Nc1ccc(OC(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(CCc2ccc3[nH]ncc3c2)nnc1Nc1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-(4-(difluoromethoxy)phenyl)-4-methyl-5-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)ethyl)-4H-1,2,4-triazol-3-amine (131 mg, 0.280 mmol) in DCM (2 mL), was added TFA (0.646 mL, 8.39 mmol) and the reaction was stirred at room temperature overnight. Solvents were concentrated and the crude product was purified by preparative HPLC on a Sunfire C18 column (150×19×5.0 m) using a gradient of ACN in 10 mM ammonium acetate (0-100%) to give 5-(2-(1H-indazol-5-yl)ethyl)-N-(4-(difluoromethoxy)phenyl)-4-methyl-4H-1,2,4-triazol-3-amine as off white solid (0.026 g, 23%). 1HNMR: 400 MHz, DMSO-d6: δ 2.96-2.98 (m, 2H), 3.08-3.10 (m, 2H), 3.34 (s, 3H), 7.07-7.09 (m, 3H), 7.27-7.28 (m, 1H), 7.47-7.49 (m, 3H), 7.63 (s, 1H), 8.00 (s, 1H), 8.57 (s, 1H), 12.98 (s, 1H). LCMS: RT 1.322 min; LCMS (ES-API), m/z 385 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (199 mg).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][C:23]=2[Cl:25])[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4Cl)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (63 mg, 66%), MS (ISP) m/z=379.4 [(M+H)+], mp 213° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 2,4-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][C:12]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:14]=2)[C:9](=[O:20])[C:8]2[CH:7]=[C:6]([S:21](Cl)(=[O:23])=[O:22])[CH:5]=[CH:4][C:3]1=2.[CH3:25][CH:26]1[CH2:31][CH:30]([CH3:32])[CH2:29][NH:28][CH2:27]1>C1COCC1>[CH3:25][CH:26]1[CH2:31][CH:30]([CH3:32])[CH2:29][N:28]([S:16]([C:12]2[CH:13]=[CH:14][C:15]3[N:2]([CH3:1])[C:3]4[C:8](=[CH:7][C:6]([S:21]([N:2]5[CH2:15][CH:10]([CH3:11])[CH2:9][CH:8]([CH3:7])[CH2:3]5)(=[O:23])=[O:22])=[CH:5][CH:4]=4)[C:9](=[O:20])[C:10]=3[CH:11]=2)(=[O:18])=[O:17])[CH2:27]1
Reactant: Cn1c2ccc(S(=O)(=O)Cl)cc2c(=O)c2cc(S(=O)(=O)Cl)ccc21
Reactant: CC1CNCC(C)C1
Solvent: C1CCOC1
Product: CC1CC(C)CN(S(=O)(=O)c2ccc3c(c2)c(=O)c2cc(S(=O)(=O)N4CC(C)CC(C)C4)ccc2n3C)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 10-methyl-9-oxo-9,10-dihydroacridine-2,7-disulfonyl dichloride from Example 7 (810 mg, 2 mmole) in THF (20 mL) was added 3,5-dimethylpiperidine (2 mL, 15 mmole) and the reaction mixture was stirred at room temperature for 6 hours. Solvent was evaporated and the residue was treated with 1 N HCl (50 mL) and stirred for 10 minutes. Yellow product was collected by filtration, washed with water and methanol and dried. Crude material was crystallized from chloroform-ethanol to provide 900 mg (80%) of yellow 11-4. MS 560 (MH+).
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][CH:8]1[C:12](=[O:13])[CH:11]=[C:10]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:9]1.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C)C=O.O>[N:22]([CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][CH:8]1[C:12](=[O:13])[CH:11]=[C:10]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:9]1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)COC1=CC(=O)C(Cc2cccc(CCI)c2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COC1=CC(=O)C(Cc2cccc(CCN=[N+]=[N-])c2)C1
Temperature: 50 °C
Yield: 76 %

Procedure:
A mixture of 30 (0.044 g, 0.11 mmol) and sodium azide (0.007 g, 0.11 mmol) in dry N,N-dimethylformamide (0.5 mL) was heated to 50° C. for 45 minutes. The reaction mixture was diluted with water and the resulting mixture extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue so obtained was dried under high vacuum to furnish the desired compound. Yield: 76%.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][C:21]2=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:26][O:27][CH2:28]Cl>C1COCC1>[CH:13]1([CH2:19][C:20]2([CH2:26][O:27][CH3:28])[CH2:25][CH2:24][O:23][C:21]2=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COCCl
Reactant: O=C1OCCC1CC1CCCCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCC1(CC2CCCCC2)CCOC1=O
Temperature: -78 °C
Reaction time: 4.5 h
Yield: 25 %

Procedure:
A solution of diisopropylamine (19.0 mL) in THF was treated dropwise with butyl lithium (82.5 mL of 1.6M solution in hexanes) at −10° C. Next the reaction mixture was cooled to −78° C. and treated dropwise with 2-(cyclohexyl-methyl)-γ-butyrolactone (18.0 mL) keeping the speed of the addition at such a rate that the temperature of the mixture remained below −60° C. After completion of the addition, the mixture was stirred for 4.5 h at −78° C., then warmed-up to −40° C. and treated dropwise at this temperature with chloromethyl methyl ether (10.8 mL). After that, the mixture was allowed to slowly warm-up to room temperature and stirred at this temperature for 60 h. The solvents were removed in vacuum and the residue was redissolved in dichloromethane, then washed with a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and finally distilled in vacuum to give 5.90 g (25%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]3)[CH:6]=[CH:7][N:8]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].Cl>ClCCl>[CH3:1][N:2]([CH2:3][C:4]1[N:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]3)[CH:6]=[CH:7][N:8]=1)[S:33]([CH3:32])(=[O:35])=[O:34]
Reactant: CNCc1nccn1-c1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1nccn1-c1ccc2c(c1)CCN2C(=O)OC(C)(C)C)S(C)(=O)=O
Reaction time: 2 h
Yield: 100.8 %

Procedure:
To tert-butyl 5-{2-[(methylamino)methyl]-1H-imidazol-1-yl}-1-indolinecarboxylate (0.20 g, 0.61 mmol; from Part H of Example 37) was added dichloromethane (6 mL) and triethylamine (0.25 mL, 0.67 mmol). Methanesulfonyl chloride (0.052, 0.67 mmol) was added in one portion, and the resulting yellow solution was stirred for 2 h. The reaction was then poured into aqueous 1N hydrogen chloride (10 mL). The layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (10 mL) and saturated aqueous sodium chloride (10 mL), dried over sodium sulfate, and concentrated to give tert-butyl 5-(2-{[methyl(methylsulfonyl)amino]methyl}-1H-imidazol-1-yl)-1-indolinecarboxylate (250 mg, 100%) as a brown oil). LC/MS (ESI+): 407.3 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:34])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:31]([CH3:33])[CH3:32])[C:28]([OH:30])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH3:35][O:36]C(=O)[C@@H](N1CC2C(=CC(C3C=CC(NC(NC4C=CC(OC)=CC=4)=O)=CC=3)=CC=2)C1=O)C(C)C>>[CH3:35][O:36][C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:34])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:31]([CH3:33])[CH3:32])[C:28]([OH:30])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:2]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(OC)cc4)cc3)cc2C1=O
Reactant: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)cc2C1=O
Product: COc1cccc(NC(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)c1
Yield: 86 %

Procedure:
The compound of example 26 was prepared analogous to compound of example 8 by hydrolysis of compound of example 27.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][NH2:25]>>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][NH:25][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: NCCc1ccccn1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: O=c1[nH]c2ncccc2c2cc(NCCc3ccccn3)ccc12
Yield: 4.5 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 456 using 6 (162 mg, 0.70 mmol) and 2-(pyridin-2-yl)ethanamine (343 mg, 2.81 mmol) to provide 477 (10 mg, 5% yield) as a white powder. LC-MS (M+H=317, obsd.=317). 1H NMR (400 MHz, DMSO-D6) δ 11.52 (s, 1H), 8.73 (dd, J=6.6, 27.5, 2H), 8.44 (d, J=4.7, 1H), 8.15 (m, 1H), 8.00 (d, J=8.8, 1H), 7.63 (m, 2H), 7.19 (m, 2H), 6.97 (t, J=43.4, 1H), 3.71 (t, J=6.9, 2H), 3.25 (t, J=6.8, 2H).
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([Mg]Br)[CH3:18]>C(OCC)C>[Si:5]([O:6][C:7]1[CH:8]=[C:9]([CH:10]([OH:11])[CH2:17][CH3:18])[CH:12]=[CH:13][CH:14]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:16])[CH3:15]
Reactant: CC[Mg]Br
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Solvent: CCOCC
Product: CCC(O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
50 g (0.21 mol) of 3-(tert-butyldimethyl-silanyloxy)benzaldehyde are dissolved in 500 ml of ethyl ether and the mixture is cooled to 0° C. 80 ml (0.24 mol) of a 3.0 M solution of ethylmagnesium bromide are added slowly, and the mixture is stirred for 5 hours. After the usual treatment, the residue obtained is purified by chromatography on a silica column (eluent ethyl acetate 20/hexane 80). A colorless oil is obtained (m=45.8 g; Y=82%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][C:15]3=[O:23])[CH:11]=[C:10]([C:24](O)=[O:25])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:27][C:28]1[N:29]=[CH:30][C:31]([CH2:34][NH2:35])=[N:32][CH:33]=1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:27][C:28]1[N:29]=[CH:30][C:31]([CH2:34][NH:35][C:24]([C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[CH:13]=[C:12]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][C:15]3=[O:23])[CH:11]=2)=[O:25])=[N:32][CH:33]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(N3C(=O)Cc4ccccc43)c2)cc1
Reactant: Cc1cnc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)cn3)cc(N3C(=O)Cc4ccccc43)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
The 4′-methyl-5-(2-oxo-2,3-dihydro-indol-1-yl)-biphenyl-3-carboxylic acid from step 3 was added to DMF (3 mL), together with C-(5-methyl-pyrazin-2-yl)-methylamine (0.1 mL), HOAt (15 mg, catalytic amount), NMM (0.4 mL) and EDCI (200 mg). The reaction mixture was stirred overnight at room temperature, then partitioned between water and ethyl acetate. The organic layer was separated and concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer chromatography (7% MeOH in dichloromethane) to give 20 mg (5% overall) of 4′-methyl-5-(2-oxo-2,3-dihydro-indol-1-yl)-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide, MS (M+H)=449.
Reaction SMILES: [Li+].[BH4-].CCOCC.C([O:10][C:11]([C:13]1[CH:20]=[C:19]2[N:15]([CH2:16][S:17][CH2:18]2)[N:14]=1)=O)C>CO>[N:14]1[N:15]2[C:19]([CH2:18][S:17][CH2:16]2)=[CH:20][C:13]=1[CH2:11][OH:10]
Reactant: CCOC(=O)c1cc2n(n1)CSC2
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: OCc1cc2n(n1)CSC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
LiBH4 (cont. 90%) (459 mg) was added to the ether (126 mL) solution of 4H-5-thia-1,6a-diazapentalen-2-carboxylic acid ethylester (2.5 g) and MeOH (0.77 mL) under a nitrogen atmosphere at room temperature, then refluxed for 1.5 h. The mixture was quenched with 1 mol/L HCl (25 mL) and stirred for 1 h at room temperature. The mixture was neutralized by saturated sodium hydrogen carbonate solution and separated. The aqueous layer was extracted with dichloromethane (10×25 mL). The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with AcOEt. The titled compound was obtained as a pale yellow solid (1.7 g, 87.9%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH:9]=[CH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)[CH2:3][CH2:2]1.[H][H]>[Pt].C(O)C>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)[CH2:3][CH2:2]1
Reactant: O=C1CCc2cc(C=CCCN3CCOCC3)ccc2N1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: O=C1CCc2cc(CCCCN3CCOCC3)ccc2N1
Yield: 81.2 %

Procedure:
2.8 Grams of 6-(4-chloro-1-butenyl)-3,4-dihydrocarbostryil and 2.1 g of sodium iodide were mixed into 40 ml of dimethylformamide and the mixture was stirred at 50° C. for 1 hour. Then into the reaction mixture was added 2.0 g of morpholine and 2.0 ml of triethylamine and was stirred at 50° C. for 1 hours. The reaction mixture was concentrated under a reduced pressure to obtain a residue and 50 ml of 5%-sodium hydrogencarbonate aqueous solution was added therein and stirred. Next, the insoluble matters formed in the mixture were collected by filtration, and were washed with water and then recrystallized from ethanol to obtain 2.2 g of 6-(4-morpholino-1-butenyl)-3,4-dihydrocarbostyril, having the melting point of 136°-139° C. in colorless needle-like crystals. Next, 2.2 g of 6-(4-morpholino-1-butenyl)-3,4-dihydrocarbostyril and 0.2 g of platinum balck were mixed into 100 ml of ethanol and was subjected to catalytic reductin under 3 kg/cm2 of hydrogen gas at a room temperature for 5 hours. The reaction mixture was filtered and the mother liquor was concentrated under a reduced pressure to obtain a residue. The residue was recrystallized from ligroinbenzene to obtain 1.8 g of 6-(4-morpholinobutyl)-3,4-dihydrocarbostyril, in colorless flake-like crystals. Melting point: 130°-132° C.
Reaction SMILES: [C:1]([C:3](=[C:9](OC)[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[NH3:17]>C1COCC1>[NH2:17]/[C:9](/[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[C:3](/[C:1]#[N:2])\[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C#N)=C(OC)C(CC)CC
Reactant: N
Solvent: C1CCOC1
Product: CCOC(=O)/C(C#N)=C(\N)C(CC)CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 10° C., 52 g (0.23 mol) of ethyl 2-cyano-3-methoxy-4-ethyl-2-hexenoate were initially charged in THF, and 20 g (0.3 mol) of 25% strength ammonia solution were added. After 2 h of stirring at 25° C., the solution was concentrated, the residue was taken up in n-hexane/diisopropyl ether (1:1) and the precipitate was filtered off with suction.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[OH-].[Li+].Cl>O1CCCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=[N:7][C:8]=2[O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:12][CH:13]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of 0.865 g 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid methyl ester in 9.0 mL tetrahydrofuran was added 3.2 mL of a 1M of lithium hydroxide in water was added and the mixture was stirred at ambient temperature for 3 h. The reaction mixture was acidified with 1M hydrochloric acid. The solid was collected by filtration washed with water and dried under high vacuum to yield 0.805 g of the title compound as white solid, 331.1 (M−H)−.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[OH-].[Na+].[C:9]1([CH3:21])[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[CH2:17][C:18](Cl)=[O:19]>O>[CH3:21][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[CH2:17][C:18]([N:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2])=[O:19]
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Reactant: CNCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)c(CC(=O)N(C)CC(=O)O)c(C)c1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
11.25 g (0.15 mol) of sarcosine and 3 g (0.075 mol) of NaOH are dissolved in 210 ml of water. While cooking the solution in a water bath 9 g (0.225 mol) of NaOH, dissolved in 45 ml of water, and 29.6 g (0.15 mol) of mesityleneacetyl chloride are added synchronously dropwise, during which addition the temperature is kept at <40 ° C. After 1 hour the mixture is acidified with concentrated HCI at 0° to 20° C., filtered off and the filtrate is dried in vacuo over P2O5 at 70° C. 37.1 g (99.3 % of theory) of N-(2,4,6-trimethyl-phenyl-acetyl)-sarcosine of a melting point of 140° C. are obtained.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)(O)[CH2:15][C:9]=2[CH:8]=[CH:7][C:6]=1[O:29][CH3:30])([CH3:3])[CH3:2]>C(O)(=O)C.O>[CH:1]([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[CH:15][C:9]=2[CH:8]=[CH:7][C:6]=1[O:29][CH3:30])([CH3:3])[CH3:2]
Reactant: COc1cc(C2(O)CCCc3c(ccc(OC)c3OC(C)C)C2)cc(OC)c1OC
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C2=Cc3ccc(OC)c(OC(C)C)c3CCC2)cc(OC)c1OC
Yield: 95.1 %

Procedure:
A mixture of the SM (40) (1.1 g, 2.64 mmol) in 30 mL of acetic acid and 100 mL of water, taken in a 250 mL round bottom flask were refluxed for 12 h. The reaction mixture was cooled and extracted with dichloromethane (3×25 mL) and the combined organic phases were dried over magnesium sulfate. The solvent evaporated and the crude product was purified by flash column chromatography (10:90 ethylacetate:hexanes), to afford 1 g (95%) of 4-Isopropoxy-3-methoxy-8-(3,4,5-trimethoxy-phenyl)-6,7-dihydro-5H-benzocycloheptene as white crystals. Rf:56 (60:40, Hex:EA)
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]2[NH:9][C:10]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][N:13]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>O1CCCC1.O>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([C:10]2[NH:9][C:8]3[CH:21]=[CH:22][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[N:11]=2)=[N:13]1
Reactant: COC(=O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Yield: 99.4 %

Procedure:
A stirred solution of 3-(5-methoxycarbonyl-1H-benzoimidazol-2-yl)-1H-indazole [84.5 mg, Example 235(ac)] and sodium hydroxide (74 mg) in tetrahydrofuran (4 mL) and water (2 mL) was heated at 75° C. overnight. The reaction mixture was evaporated and the oily residue was partitioned between ethyl acetate and water. The aqueous layer was acidified to pH 6 and extracted with ethyl acetate. The organic layers was dried over magnesium sulfate and then evaporated to give [2-(indazol-3-yl)-1H-benzoimidazol-5-yl]-carboxylic acid (80 mg) as an oil. MS: 279.14 (M+H)+. HPLC (METHOD H): RT=2.81 minutes. (b) 3-(5,6-Dimethyl-1H-benzoimidazol-5-yl)-pyrazole-4-carboxylic acid
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[N:11](C)[N:12]=[CH:13][CH:14]=2)[S:7][CH:6]=1)=[O:4].[OH-].[Na+].[CH3:18]O>>[CH3:18][N:12]1[CH:13]=[CH:14][C:10]([C:8]2[S:7][CH:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:9]=2)=[N:11]1
Reactant: COC(=O)c1csc(-c2ccnn2C)c1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: Cn1ccc(-c2cc(C(=O)O)cs2)n1
Reaction time: 1.5 h

Procedure:
5-(2-Methyl-2H-pyrazol-3-yl)-thiophene-3-carboxylic acid methyl ester (0.076 g, 0.34 mmol) was suspended in methanol (0.75 mL) then sodium hydroxide (1 M, 0.41 mL) was added and the mixture stirred for 1.5 hours. A further amount of sodium hydroxide (1 M, 0.41 mL) was added and the mixture stirred overnight. The solution was evaporated, the residue was taken up in HCl (1 N, 1.0 mL) and the resultant precipitate was collected by filtration, washed with water and dried to afford 5-(1-methyl-1H-pyrazol-3-yl)-thiophene-3-carboxylic acid as a grey solid (0.042 g).