Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=O)[N:18]2[CH3:28])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+]>C1COCC1.O>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][N:18]2[CH3:28])=[CH:13][CH:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CN1C(=O)c2ccccc2CC1c1ccc(C(C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1Cc2ccccc2CC1c1ccc(C(C)(C)C)cc1
Yield: 78.8 %

Procedure:
To 20 ml of THF in which 0.83 g of lithium aluminum hydride is suspended, 20 ml of a solution containing 0.32 g of 3-(4-t-butylphenyl)-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline in THF was added and the mixture was heated to reflux for 4 hours. After the reaction, 10 ml of 10% aqueous sodium hydroxide solution was gradually added to the resulting mixture cooled in iced water and the generated precipitates were removed by filtration through Celite. After concentrating the filtrate, the aqueous layer was extracted with ethyl acetate (40 ml×2). After washing the combined organic layers with brine (50 ml×1), the organic layers were dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography [hexane/ethyl acetate (6/1)] to obtain 0.24 g of 3-(4-t-butylphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1.C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:8][CH:4]2[CH2:5][CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CC1(C)CCCC(O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC2CCCC(C)(C)C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
Under a nitrogen atmosphere, add 3,3-dimethylcyclohexanol (1 g, 9.75 mmol), DMAP (238 mg, 1.95 mmol), triethylamine (2.70 mL, 19.5 mmol), and p-toluenesulfonyl chloride (2.045 g, 10.72 mmol) to DCM (25 mL) at 0° C. Stir the mixture for 1 h at 0° C. and warm to room temperature overnight. Add saturated aqueous NaHCO3 (20 mL) and separate the layers. Extract the aqueous layer with DCM (3×20 mL). Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter, and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (45 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 1:1 gradient over 60 min, 80 mL/min) to obtain the desired intermediate as a clear oil (1.93 g, 70%). MS (APCI+) m/z: 283 (M+H)+.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:7][C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=1>Cl.CC(C)=O>[CH:2]([C:6]1[S:7][C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=1)=[O:1]
Reactant: O=C(O)c1cnc(C2OCCO2)s1
Agent: Cl
Solvent: CC(C)=O
Product: O=Cc1ncc(C(=O)O)s1
Yield: 229.1 %

Procedure:
A solution of 2-(1,3-dioxolan-2-yl)thiazole-5-carboxylic acid (20 g, 0.1 mol) in hydrochloric acid (1000 mL, 3 N) and acetone (1000 mL) was heated to reflux for 6 h. The solution was then extracted with ether (5×500 mL). The combined organic phases were dried (Na2SO4) and concentrated. Flash column chromatography (petroleum ether:EtOAc, 100:1 to 5:1) afforded 2-formylthiazole-5-carboxylic acid (36 g, 76%). %). 1H NMR (DMSO-d6, 300 MHz) δ 13.90 (br, 1H), 9.92 (s, 1H), 8.63 (s, 1H).
Reaction SMILES: O[CH:2]([CH2:16][OH:17])[CH2:3][N:4]1[C:8](=[O:9])[C:7]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[NH:6][C:5]1=[O:15].O=C1NC(=O)C2(CCN([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])CC2)N1>>[O:15]=[C:5]1[N:4]([CH2:3][CH:2]2[O:17][CH2:16]2)[C:8](=[O:9])[C:7]2([CH2:10][CH2:11][N:12]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:13][CH2:14]2)[NH:6]1
Reactant: O=C1NC2(CCNCC2)C(=O)N1CC(O)CO
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)NC2=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)N(CC1CO1)C2=O

Procedure:
3-(2,3-Dihydroxypropyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione may also be prepared by reaction of tert-butyl 2,4-dioxo-1,3,8-triaza-8-spiro[4.5]decanecarboxylate with an epihalohydrin to give tert-butyl 2,4-dioxo-3-(2,3-epoxypropyl)-1,3,8-triaza-8-spiro[4.5]decanecarboxylate, followed by hydrolysis of the epoxy group and deprotection.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[O:18][CH3:19]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[C:12]([O:18][CH3:19])[CH:13]=1
Reactant: Cc1ncc[nH]1
Reactant: COc1cc(Cl)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(Cl)ccc1Cn1ccnc1C
Temperature: 25 °C
Yield: 39.7 %

Procedure:
2-Methyl imidazole (45 mg, 0.55 mmol) was dissolved in DMF. Sodium hydride (60 mg, 1.5 mmol) was added slowly. The mixture was stirred at room temperature until bubbling ceased. 1-Bromomethyl-4-chloro-2-methoxy-benzene (117 mg, 0.5 mmol) was added and the mixture was heated to 100° C. for 16 hours. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and with brine. The organic layer was dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (1:1 hexanes/ethyl acetate) to provide 47 mg (40%) of the title compound. MS (ESI) m/e 237 (M+H)+.
Reaction SMILES: [OH-].[Li+].C([O:11][CH:12]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:37][CH:36]=1)[CH:13]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:14][CH2:15][NH:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)(=O)C1C=CC=CC=1.Cl>O1CCCC1.CO.O.O>[C:38]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:39]=[CH:40][C:35]([CH2:34][CH2:33][CH:12]([OH:11])[CH:13]([CH2:14][CH2:15][NH:16][C:17](=[O:25])[C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)C(CCNC(=O)c1ccc(F)cc1)C(CCc1ccc(-c2ccccc2)cc1)OC(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CCNC(=O)c1ccc(F)cc1)C(O)CCc1ccc(-c2ccccc2)cc1
Yield: 101 %

Procedure:
Aqueous solution of lithium hydroxide (22 mg) was added to a solution of the compound (120 mg) obtained from Step 1 above, in tetrahydrofuran:methanol:water (3:1:1, 5 ml) and the reaction mixture was stirred overnight. The reaction mixture was concentrated and the residue thus obtained was taken in distilled water, acidified with dilute hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with distilled water and brine solution and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to furnish the title compound (100 mg).
Reaction SMILES: Cl.CC1(C)[O:7][CH:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([C:16]3[C:24]4[C:19](=[N:20][CH:21]=[C:22]([NH:25][C:26](=[O:42])[C:27]5[C:32]([F:33])=[CH:31][CH:30]=[C:29]([NH:34][S:35]([CH2:38][CH2:39][CH3:40])(=[O:37])=[O:36])[C:28]=5[F:41])[CH:23]=4)[NH:18][N:17]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:5][O:4]1>C1COCC1.CO>[OH:7][CH:6]([CH2:5][OH:4])[CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([NH:25][C:26](=[O:42])[C:27]4[C:32]([F:33])=[CH:31][CH:30]=[C:29]([NH:34][S:35]([CH2:38][CH2:39][CH3:40])(=[O:37])=[O:36])[C:28]=4[F:41])[CH:23]=3)[NH:18][N:17]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(-c4cccc(OCC5COC(C)(C)O5)c4)c3c2)c1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(-c4cccc(OCC(O)CO)c4)c3c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.2 %

Procedure:
1N HCl (1.0 mL) was added to a solution of N-(3-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.050 g, 0.083 mmol) in THF/MeOH (2:1, 3 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was taken up in ethyl acetate (50 mL) and saturated NaHCO3 (50 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with ethyl acetate to give N-(3-(3-(2,3-dihydroxypropoxy)phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.008 g, 17%) as a solid. 1H NMR (400 MHz, CD3OD) δ 9.0 (s, 1H), 8.7 (s, 1H), 7.7 (m, 1H), 7.6-7.4 (m, 3H), 7.1 (m, 1H), 7.0 (m, 1H), 4.2 (m, 1H), 4.1-4.0 (m, 3H), 3.7 (m, 1H), 3.1 (m, 2H), 1.9 (m, 2H), 1.1 (t, J=7.6 Hz, 3H); m/z (APCI-neg) M−1=560.1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Br:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[F:16])[NH2:12].C(N(CC)CC)C>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[C:11]([NH:12][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCl)Nc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
A solution of 4-chlorobutanoyl chloride (4.12 mL, 36.84 mmol) in DCM (50 mL) was added over 15 mins to an ice-cooled solution of 3-bromo-4-fluoro-aniline (7 g, 36.84 mmol) and triethylamine (5.12 mL, 36.84 mmol) in DCM (100 mL) under N2. After addition was complete the cooling bath was removed and the solution stirred at ambient temp for 4 h. The reaction solution was washed with water (2×150 ml) dried (MgSO4) and concentrated to a white solid, which was dried at RT under vacuum overnight to give N-(3-bromo-4-fluoro-phenyl)-4-chloro-butanamide (D57) (9.04 g);
Reaction SMILES: COC([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:11]=2)[CH2:6]1)=O.Cl>CCO>[CH:26]([C:23]1[CH:24]=[CH:25][C:20]([S:17]([NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH:7]3[CH2:8][CH2:9][NH:5][CH2:6]3)[CH:11]=2)(=[O:18])=[O:19])=[CH:21][CH:22]=1)([CH3:28])[CH3:27]
Reactant: COC(=O)N1CCC(c2cccc(NS(=O)(=O)c3ccc(C(C)C)cc3)c2)C1
Agent: Cl
Solvent: CCO
Product: CC(C)c1ccc(S(=O)(=O)Nc2cccc(C3CCNC3)c2)cc1
Yield: 25.7 %

Procedure:
3-[3-(4-Isopropyl-benzenesulfonylamino)-phenyl]-pyrrolidine-1-carboxylic acid methyl ester (900 mg, 1.13 mmol) and HCl (8M, 273.90 mmol) in EtOH (20 ml) were heated to reflux for 48 h. The mixture was extracted twice with ethyl acetate and then NaOH (2M) was added. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated sodium chloride solution, dried over MgSO4 and evaporated under reduced pressure to give the product as a brown oil (100 mg, 13%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]#[N:15])=[CH:5][CH:4]=1.[H-].[Na+].[C:18](=O)([O:21]C)[O:19][CH3:20].Cl>O1CCCC1>[C:14]([CH:13]([C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1)[C:18]([O:19][CH3:20])=[O:21])#[N:15]
Reactant: COC(=O)OC
Reactant: COc1ccc2cccc(CC#N)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C#N)c1cccc2ccc(OC)cc12

Procedure:
(7-Methoxy-naphth-1-yl)acetonitrile (20 g) is dissolved in 150 ml of anhydrous tetrahydrofuran. Sodium hydride (202.8 mmol) is added at ambient temperature, and the mixture is refluxed for 30 minutes. Dimethyl carbonate (12 ml) is added with caution, and the reaction mixture is refluxed for 30 minutes. The mixture is poured into ice-cold water, and the aqueous phase is acidified with 21 ml of 37% hydrochloric acid solution and then extracted twice with 100 ml of ether. The organic phase is washed with water, dried, decolored and evaporated. The oil obtained is precipitated from ether, and the precipitate formed is filtered off under suction and then recrystallized to yield the title product in the form of a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])COC)(=[O:13])=[O:12])=[C:7]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]=2[Cl:33])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])(=[O:13])=[O:12])=[C:7]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]=2[Cl:33])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCN(c1ccsc1C(=O)OC)S(=O)(=O)c1ccc(C(C)(C)C)cc1-c1ccncc1Cl
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1-c1ccncc1Cl
Yield: 66.7 %

Procedure:
Synthesized as described for 22 using 166 (25.0 mg, 0.049 mmol), tetrahydrofuran (1 mL) and aqueous hydrochloric acid (1 mL). Purification by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 30% v/v over 400 mL gradient elution) yielded the title product as a clear oil (15.2 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[N:15](OCCC(C)C)=[O:16].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[C:7](=[N:15][OH:16])[CH2:6]2
Reactant: CC(C)CCON=O
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)C(=O)C(=NO)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5,6-Dimethoxy-1-indanone (0.078 moles, 15 g) is dissolved in absolute ethanol (550 ml), thermostated at 50° C., and added with isoamyl nitrite (0.086 moles, 11.9 ml) and conc. HCl (11.9 ml). After a few minutes the product precipitates. The reaction is kept at 50° C. for further 3 hours, then cooled at r.t. and the solid is filtered washing with absolute ethanol (50 ml) and ethyl ether (100 ml). The product is dried in oven under vacuum at r.t. Yield: 16.3 g (94.4%)
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:23]COC)[C:13]=1[CH2:14]/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:8]([OH:10])=[O:9].OS(O)(=O)=O.[CH3:32]O>>[CH3:32][O:10][C:8](=[O:9])[C:7]1[CH:6]=[C:5]([OH:4])[C:13]([CH2:14]/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:12]([OH:23])[CH:11]=1
Reactant: CO
Reactant: COCOc1cc(C(=O)O)cc(OCOC)c1C/C=C/c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)c(C/C=C/c2ccccc2)c(O)c1
Yield: 73 %

Procedure:
To a solution of 3,5-bis-methoxymethoxy-4-((E)-3-phenyl-allyl)-benzoic acid (220 g) (18 g, 0.05 mol) in MeOH (300 mL) was added catalytic amount of conc. H2SO4 (3 mL) in one portion. The mixture was refluxed overnight. The solution was concentrated. The residue was dissolved in CH2Cl2 (75 mL) and washed with sat. NaHCO3 (25 mL). The organic layers were dried and concentrated to give a brown solid (12 g, 73% yield). 1H NMR (400 MHz, CDCl3): δ 9.63 (s, 2H), 7.11-7.34 (m, 5H), 6.93 (s, 2H), 6.32 (s, 2H), 3.77 (s, H), 3.42 (s, 2H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[S:8][CH:7]=[C:6]([C:9]2[C:13]3[C:14](=[O:20])[NH:15][CH:16]=[C:17]([C:18]#[N:19])[C:12]=3[N:11]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:10]=2)[CH:5]=1)#[N:2].C(=O)([O-])[O-:27].[K+].[K+].OO.O>CS(C)=O>[C:18]([C:17]1[C:12]2[N:11]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:10]=[C:9]([C:6]3[CH:5]=[C:4]([CH2:3][C:1]([NH2:2])=[O:27])[S:8][CH:7]=3)[C:13]=2[C:14](=[O:20])[NH:15][CH:16]=1)#[N:19]
Reactant: N#CCc1cc(-c2cn(C3CCCC3)c3c(C#N)c[nH]c(=O)c23)cs1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1c[nH]c(=O)c2c(-c3csc(CC(N)=O)c3)cn(C3CCCC3)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 3-(5-(cyanomethyl)-3-thienyl)-1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile (80 mg) obtained in Example 93 and 2M aqueous potassium carbonate solution (0.574 mL) in DMSO (3 mL) was added 30% hydrogen peroxide aqueous solution (0.235 mL) at 0° C., and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (13 mg).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([NH2:18])=O)[C:9]=3[N:8]=2)=[CH:3][CH:2]=1.N1C=CN=C1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([C:16]#[N:18])[C:9]=3[N:8]=2)=[CH:3][CH:2]=1
Reactant: NC(=O)c1cccc2[nH]c(-c3ccc(-c4ccccc4)cc3)nc12
Agent: c1c[nH]cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1cccc2[nH]c(-c3ccc(-c4ccccc4)cc3)nc12
Temperature: -30 °C
Reaction time: 4 h

Procedure:
To the solution of 2-biphenyl-4-yl-1H-benzoimidazole-4-carboxylic acid amide (0.24 g, 0.76 mmol) in pyridine (10 mL) was added imidazole (0.11 g, 1.53 mmol). The reaction mixture was cooled to −30° C. and phosphorous oxy chloride (0.3 mL, 3.1 mmol) was added drop wise. The reaction mixture was then stirred at −10° C. for 4 h. Progress of the reaction was monitored by TLC. The reaction mixture was concentrated to dryness and water was added. This mixture was extracted with ethyl acetate and the combined organic layers were concentrated. The resulting residue was purified by column chromatography using 30% ethyl acetate in hexane to get the title compound.
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][N:25]=[CH:24]3)=[O:20])[CH2:13]1)C1C=CC=CC=1>C(O)C.C(OCC)(=O)C.[Pd]>[NH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][N:25]=[CH:24]3)=[O:20])[CH2:13]1
Reactant: O=C(NC1CCCN(Cc2ccccc2)C1)c1ccc2[nH]ncc2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(NC1CCCNC1)c1ccc2[nH]ncc2c1
Reaction time: 4 h
Yield: 96.5 %

Procedure:
Ammonium formate (0.363 g) and 10% Pd—C (0.074 g) were added to a suspension of the N-(1-benzylpiperidin-3-yl)-1H-indazole-5-carboxamide (0.357 g, 1.06 mmol) obtained in Example 138 in ethanol (10 ml), and the resulting mixture was stirred for 4 hours with heating under reflux. The resulting solution was filtered by the use of Celite and then the solvent was distilled off from the filtrate to obtain a solid. The solid obtained was suspended in ethyl acetate, stirred to be washed, collected by filtration and dried under reduced pressure to obtain N-(3-piperidinyl)-1H-indazole-5-carboxamide (0.250 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[CH:4]=[N:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][CH:7]=1.C[Si]([C:25]#[N:26])(C)C>>[F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[CH:4]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:10][CH:11]=1)[C:25]#[N:26]
Reactant: NS(=O)(=O)c1ccc(N=Cc2ccc(F)cc2F)cc1
Reactant: C[Si](C)(C)C#N
Product: N#CC(Nc1ccc(S(N)(=O)=O)cc1)c1ccc(F)cc1F

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(2,4-difluorobenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a pale yellow powder (yield 88%).
Reaction SMILES: [CH3:1][C:2](=[CH2:12])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1.C.CCOCC.Cl>CO>[CH2:3]([O:4][CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)[CH:2]([CH3:12])[CH3:1]
Reactant: C=C(C)COC1CCC(=O)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)COC1CCC(=O)CC1
Yield: 61.7 %

Procedure:
16.9 g (0.1 mole) of compound (16) were dissolved in 90 ml methanol. After adding 1.8 g of palladinised charcoal (10% Pd content), the solution was hydrogenated at room temperature and normal pressure. The catalyst was then removed and the solvent was distilled off under vacuum. The 15 g of crude product which were obtained were stirred for 1 hour at room temperature with 60 ml ether and 30 ml of 4N hydrochloric acid. This was followed by neutralisation with sodium hydrogen carbonate, separation of the ether phase, and extracting twice with ether. The ethereal solution was dried over sodium sulphate and the ether was distilled off. The 10.5 g of oil obtained were purified with 1:1 diisopropyl ether/n-hexane via a silica gel column. 6.85 g of compound (21) were obtained in a yield of 40% theoretical.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31].C(N(C(C)C)CC)(C)C>>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: COC(=O)CCCCCN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCCCNC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
2-Acetylthiomethyl-3-phenylpropanoic acid is reacted with oxalyl chloride and the resulting acid chloride is then reacted with 6-aminohexanoic acid, methyl ester, hydrochloride in the presence of diisopropylethylamine as more fully described in Example 6 of European Patent Application 136,883 to give (±)-6-[[2-[(acetylthio)methyl]-1-oxo-3-phenylpropyl]amino]hexanoic acid, methyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:9][S:10]([C:13]2[CH:14]=[C:15]([CH:49]=[CH:50][CH:51]=2)[C:16]([NH:18][C:19]2[S:20][C:21]3[CH2:48][CH2:47][CH2:46][CH2:45][C:22]=3[C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)=[O:25])=[O:17])(=[O:12])=[O:11])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:52](I)[CH3:53].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([N:9]([CH2:52][CH3:53])[S:10]([C:13]2[CH:14]=[C:15]([CH:49]=[CH:50][CH:51]=2)[C:16]([NH:18][C:19]2[S:20][C:21]3[CH2:48][CH2:47][CH2:46][CH2:45][C:22]=3[C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)=[O:25])=[O:17])(=[O:12])=[O:11])[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)C1(NS(=O)(=O)c2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(N(CC)S(=O)(=O)c2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 250 mg of methyl 4-(2-{4-[({2-[(3-{[1-(ethoxycarbonyl)cyclopropyl]sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate, 0.081 mL of ethyl iodide, 142 mg of potassium carbonate, and 2.5 mL of DMF was stirred at 60° C. overnight. To the reaction mixture was added an aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-chloroform) to obtain 243 mg of methyl 4-(2-{4-[({2-[(3-{[1-(ethoxycarbonyl)cyclopropyl](ethyl)sulfamoyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate as a yellow solid.