Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH3:35].C(O)(C)C>>[NH2:35][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: N
Solvent: CC(C)O
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2)c(-c2ccnc(N)n2)s1
Temperature: 100 °C

Procedure:
A suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide (150 mg, 0.288 mmol) and 2M ammonia in isopropanol (8.0 mL, 16.0 mmol) was heated in a sealed tube at 100° C. overnight. The reaction mixture was evaporated onto silica gel and chromatographed (10-100% 1:9 MeOH:EtOAc in DCM). The title compound was recovered as a beige solid (38 mg, 25% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.89 (s, 1H), 7.95 (d, J=5.1 Hz, 1H), 7.41-7.68 (m, 3H), 7.31 (t, J=7.9 Hz, 1H), 7.23 (s, 1H), 7.17 (d, J=7.9 Hz, 2H), 6.74 (s, 2H), 6.01 (d, J=5.1 Hz, 1H), 1.38 (s, 9H). MS (ESI): 502.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][CH:21]([C:25](O)=[O:26])[CH2:22]3)=[CH:17][CH:16]=2)[CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:32]#[N:33].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[C:32]([C:31]1[CH:30]=[C:29]([NH:28][C:25]([CH:21]2[CH2:22][C:23]3[CH:24]=[C:15]([O:14][C:12]4[CH:11]=[CH:10][N:9]=[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:13]=4)[CH:16]=[CH:17][C:18]=3[CH2:19][CH2:20]2)=[O:26])[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=1)#[N:33]
Reactant: N#Cc1cc(N)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)O)CC3)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(C#N)cc(C(F)(F)F)c2)CC3)ccn1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A solution of 7-{[2-(tert-butoxycarbonyl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (0.653 g, 1.77 mmol), 3-amino-5-(trifluoromethyl)-benzonitrile (0.362 g, 1.94 mmol), and DMAP (0.238 g, 1.94 mmol) in DCM (10 mL) was cooled to 0° C. To this solution was added EDCI (0.339 g, 1.77 mmol). The reaction mixture was allowed to stir and warm to rt overnight. The reaction mixture was diluted with EtOAc, washed with 1N HCl and sat. aq. NaHCO3, and concentrated. The residue was purified by column chromatography to give tert-butyl 4-{[7-({[3-cyano-5-(trifluoromethyl)phenyl]-amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}pyridine-2-carboxylate (0.750 g, 79%). LCMS: (FA) ES+ 538.6.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:4]([N+:23]([O-])=O)[CH:3]=1>C(OCC)(=O)C.[Pd]>[NH2:23][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[CH:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17]
Reactant: Cc1ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(N)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.3 %

Procedure:
A solution of bis(1,1-dimethylethyl) (4-methyl-2-nitrophenyl)propanedioate (D38, 660 mg, 1.88 mmol) in ethyl acetate (25 mL) was treated with 10% Pd/C (0.5 g) and shaken under hydrogen at atmospheric pressure and room temperature for 20 hours. The mixture was filtered through Kieselguhr and the filtrate concentrated under vacuum to afford the title compound as a colourless oil (606 mg, 100%).
Reaction SMILES: C([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[OH-].[K+]>O>[OH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=Cc1ccc(O)cc1
Reaction time: 2 h
Yield: 59.1 %

Procedure:
p-Hydroxyacetophenone was converted to 1-(p-acetoxyphenyl)ethanol and then dehydrated using liquid phase dehydration in the presence of potassium acid sulfate to produce p-acetoxystyrene, according to the method of Corson et al (J. Org. Chem., 1958 23, 544). p-Acetoxystyrene (1.6 g) was added to a stirred solution of potassium hydroxide (1.4 g) in water (14 ml) at 5 degrees Centigrade. Stirring was continued at 0-5 degrees Centigrade for 2 h. The mixture was then washed with ether, and the aqueous phase neutralised with saturated sodium hydrogen carbonate solution. The product was extracted into dichloromethane, the solution was dried over anhydrous calcium chloride and the solvent removed, to yield a cloudy oil (0.7 g) which solidified on standing to a waxy solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:6]#[N:7].Cl.[NH2:13][OH:14]>CO>[OH:14][NH:13][C:6](=[NH:7])[C:5]1[CH:8]=[C:9]([CH3:11])[N:10]=[C:3]([CH2:2][OH:1])[CH:4]=1
Reactant: Cc1cc(C#N)cc(CO)n1
Reactant: NO
Agent: Cl
Solvent: CO
Product: Cc1cc(C(=N)NO)cc(CO)n1
Temperature: 25 °C
Yield: 54.5 %

Procedure:
To a solution of crude 2-hydroxymethyl-6-methyl-isonicotinonitrile (544 mg, 2.38 mmol) in methanol (50 mL), potassium tert.-butylate (933 mg, 8.31 mmol) and hydroxylamine hydrochloride (495 mg, 7.13 mmol) is added. The solution is refluxed for 2 h. The resulting suspension is cooled to rt and filtered. The solvent filtrate is evaporated and the remaining residue is suspended in water, filtered off, washed with additional water and dried under HV to give N-hydroxy-2-hydroxymethyl-6-methyl-isonicotinamidine (235 mg) as a beige powder; LC-MS: tR=0.17 min, [M+1]+=182.01; 1H NMR (D6-DMSO): δ 2.45 (s, 3H), 4.52 (d, J=5.8 Hz, 2H), 5.37 (t, J=5.8 Hz, 1H), 5.90 (s, 2H), 7.36 (s, 1H), 7.56 (s, 1H), 9.92 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.Cl>CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=C1COc2cc(O)ccc21
Reactant: COc1cccc(C=O)c1
Agent: Cl
Solvent: CO
Product: COc1cccc(C=C2Oc3cc(O)ccc3C2=O)c1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-methoxybenzaldehyde 1.125 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 1.5 hours. The solution was cooled to room temperature, and precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 1.22 g.
Reaction SMILES: [ClH:1].[C:2]([CH2:5][CH2:6][N:7]1[CH:12]=[CH:11][C:10](=[O:13])[C:9]([OH:14])=[C:8]1[CH3:15])([OH:4])=[O:3].[CH3:16]O>Cl>[ClH:1].[OH:14][C:9]1[C:10](=[O:13])[CH:11]=[CH:12][N:7]([CH2:6][CH2:5][C:2]([O:4][CH3:16])=[O:3])[C:8]=1[CH3:15]
Reactant: CO
Reactant: Cc1c(O)c(=O)ccn1CCC(=O)O
Agent: Cl
Product: COC(=O)CCn1ccc(=O)c(O)c1C
Yield: 80 %

Procedure:
1-(2'-carboxyethyl)-3-hydroxy-2-methylpyrid-4-one hydrochloride (2 g) prepared as described under (Q), is dissolved in methanol saturated with hydrogen chloride and the solution is refluxed for 3 hours. Rotary evaporation of the solution yields a white solid which on recrystallisation from methanol gives 3-hydroxy-1-(2'-methoxycarbonylethyl)-2-methylpyrid-4-one hydrochloride in 80% yield m.p. 140°-141° C., δmax 1545, 1595, 1645, 1730, 1750 cm-1, δ(d6DMSO), 2.45 (s, 3H), 2.85 (t, 2H), 3.5 (s, 3H), 4.45 (t, 2H), 7.30 (d, 1H), 8.15 (d, 1H).
Reaction SMILES: [CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:32]12[N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:36]([CH2:37][CH2:38]1)[CH2:35][NH:34][CH2:33]2>>[CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([N:34]5[CH2:33][CH:32]6[N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:36]([CH2:37][CH2:38]6)[CH2:35]5)=[O:24])=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCCCC1
Yield: 73 %

Procedure:
Following amide formation method 1, 6-(7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (75 mg, 0.178 mmol, 1.0 eq) was combined with tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (37.7 mg, 0.18 mmol, 1.0 eq) to give tert-butyl 3-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a white solid (80 mg, 0.130 mmol, 73% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 8.76 (s, 1H) 8.68 (d, J=8.59 Hz, 1H) 8.42-8.57 (m, 1H) 8.40 (d, J=2.02 Hz, 1H) 7.83 (dd, J=8.59, 2.02 Hz, 1H) 6.49 (s, 1H) 4.46-4.62 (m, 2H) 4.29 (br s, 2H) 3.19 (s, 6H) 2.56-2.73 (m, 2H) 1.84-2.12 (m, 8H) 1.65-1.84 (m, 6H) 1.54-1.65 (m, 3H) 1.52 (s, 9H);
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc(N)cc1C#N
Reaction time: 1 h
Yield: 86 %

Procedure:
A portion of 4-nitrophthalonitrile (5.15 g, 29.8 mmole) was dissolved in 125 mL methanol in a hydrogenation flask. The catalyst, 10% Pd/C (515 mg), was added to the mixture which was then flushed with H2 and stirred under 50 psi of Hz for 1 hour. The catalyst was removed by filtration and the solvent was distilled off under vacuum. The desired 4-aminophthalonitrile was obtained in 86% yield (3.66 g).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.[CH3:21][S:22][CH2:23][CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:24][CH2:23][S:22][CH3:21])=[CH:16][CH:15]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CSCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
Diethyl azodicarboxylate (13.4 g) was added over a period of 20 minutes to a stirred solution of 4-bromophenol (12 g), 2-methylthioethanol (6.4 g) and triphenylphospine (18.2 g) in tetrahydrofuran (250 ml) at -5° C. under an atmosphere of argon. The mixture was stirred at ambient temperature for 1 hour and the solvent was then removed by evaporation. The residue was partitioned between dichloromethane (150 ml) and water (150 ml). The aqueous phase was separated and extracted with dichloromethane (150 ml). The dichloromethane extracts were combined, washed with water (2×100 ml), dried (MgSO4) and evaporated. The residue was dissolved in a boiling mixture of toluene (50 ml) and n-heptane (50 ml). The solution was chilled and the precipitated triphenylphosphine oxide removed by filtration. The filtrate was evaporated and purified by medium pressure chromatography on silica gel using a 1:1 (v/v) mixture of toluene/n-heptane as eluent to give 1-(4-bromophenoxy)-2-methylthioethane as an oil (10.2 g); NMR(CDCl3): 2.2(3H,s), 2.88(2H,t), 4.12(2H,t), 6.77(2H,d) and 7.37(2H,d).
Reaction SMILES: [OH:1][C@H:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10](Cl)=[CH:11][CH:12]=1)=[O:6].[N:20]1([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[OH:1][C@H:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]([N:23]2[CH2:24][CH2:25][N:20]([C:26](=[O:27])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:35])[F:36])[CH2:21][CH2:22]2)=[CH:11][CH:12]=1)=[O:6]
Reactant: O=C(NC[C@H](O)c1ccccc1)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: O=C(NC[C@H](O)c1ccccc1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use (R)-6-chloropyridazine-3-carboxylic acid (2-hydroxy-2-phenylethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (64.5% yield). 1H NMR (500 MHz, CDCl3) δ 8.28, 8.05, 7.76, 7.64, 7.58, 7.44-7.32, 7.29, 7.00, 4.96, 4.08, 3.92-3.68, 3.61, 3.36.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:21][C:6]2=[C:7]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[S:8][C:9]([S:10]([CH3:13])(=O)=O)=[C:5]2[C:4](=[O:22])[CH2:3]1.[OH-].[Na+].[F:26][C:27]([F:31])([F:30])CS>CCO>[CH3:1][C:2]1([CH3:23])[CH2:21][C:6]2=[C:7]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[S:8][C:9]([S:10][CH2:13][C:27]([F:31])([F:30])[F:26])=[C:5]2[C:4](=[O:22])[CH2:3]1
Reactant: FC(F)(F)CS
Reactant: CC1(C)CC(=O)c2c(S(C)(=O)=O)sc(C(=O)N3CCCC3)c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(=O)c2c(SCC(F)(F)F)sc(C(=O)N3CCCC3)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 6,6-dimethyl-3-methanesulphonyl-1-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (400 mg, 1.1 mmol) in EtOH (15 mL) was added NaOH (0.7 mL of a 3 M solution, 2.3 mmol) followed by 2,2,2-trifluoroethanethiol (0.2 mL, 2.2 mmol). The mixture was stirred at room temperature for 3 h then evaporated. The residue was partitioned between EtOAc (20 mL) and NaOH (1M; 30 mL). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was triturated with ether and the colourless solid (166 mg, 35%) collected by filtration. C17H20F3NO2S2 requires: C, 52.16; H, 5.15; N, 3.58%. Found: C, 51.86; H, 4.99; N, 3.61%. 1H NMR (360 MHz, CDCl3) δ 1.05 (6H, s), 1.95-1.99 (4H, m), 2.42 (2H, s), 2.86 (2H, s), 3.57-3.63 (4H, m), 3.66 (2H, q, J=9.5 Hz). MS (ES+) 392 (M+1).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=4)[NH:23][C:19]=3[CH:20]=[N:21][CH:22]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH2:36]([C:38]1[NH:42][C:41](C=O)=[C:40]([CH3:45])[N:39]=1)[CH3:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.[Pd]>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([C:24]2[NH:25][C:18]3[C:17]([N:14]4[CH2:15][CH2:16][N:11]([CH2:9][C:41]5[NH:42][C:38]([CH2:36][CH3:37])=[N:39][C:40]=5[CH3:45])[CH2:12][CH2:13]4)=[CH:22][N:21]=[CH:20][C:19]=3[N:23]=2)=[CH:27][CH:28]=1)([CH3:34])([CH3:33])[CH3:35]
Reactant: CCc1nc(C)c(C=O)[nH]1
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCN(C(=O)OCc5ccccc5)CC4)cncc3[nH]2)cc1
Agent: [Pd]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nc(C)c(CN2CCN(c3cncc4nc(-c5ccc(C(C)(C)C)cc5)[nH]c34)CC2)[nH]1
Reaction time: 12 h
Yield: 34.6 %

Procedure:
4-[2-(4-tert-Butyl-phenyl)-3H-imidazo[4,5-c]pyridin-7-yl]-piperazine-1-carboxylic acid benzyl ester 7 (12 mg, 0.026 mmol) was dissolved in THF (2 ml) with 10% Pd/C (10 mg) and allowed to stir under a hydrogen atmosphere for 12 hours. The reaction was judged complete by MS. 2-Ethyl-5-methyl-3H-imidazole-4-carbaldehyde 8 (7 mg, 0.05 mmol) and sodium triacetoxyborohydride (15 mg. 0.072 mmol) were added, and the reaction was allowed to stir for 12 hours. It was judged complete by MS, and the crude was purified by HPLC (Method E) to yield the title product 9 (4 mg (25%), 0.009 mmol). 1H NMR (CD3OD-d4): δ 8.58 (s, 1H), 8.12 (d, J=8.6 Hz, 2H), 7.72 (s, 1H), 7.58 (d, J=8.6 Hz, 2H), 3.93 (m, 5H), 3.25 (s, 3H), 3.05 (m, 3H), 2.79 (q, J=7.4 Hz, 2H), 1.35 (s, 9H). MS (ESI-POS): [M+H]+=458; MS (ESI-NEG):[M−H]−=456.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(OCc2ccccc2)c(C=O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.6 %

Procedure:
To a solution of 2-hydroxy-5-methoxybenzaldehyde (3.0 g, 19.7 mmol) in N,N-dimethylformamide (50 mL), potassium carbonate (3.27 g, 23.6 mmol) was added and furthermore benzyl bromide (2.6 mL, 21.7 mmol) was added thereto. The reaction mixture was stirred at room temperature for 24 hours, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (4.8 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:19](=[CH:20][CH:21]=1)[C:9]1[O:10][C:11]3([CH2:17][S:18][C:8]=1[C:7](=[O:22])[C:6]2=[O:23])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([N:14]1[CH2:15][CH2:16][C:11]2([O:10][C:9]3[C:19]4[C:5]([C:6](=[O:23])[C:7](=[O:22])[C:8]=3[S:18][CH2:17]2)=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=4)[CH2:12][CH2:13]1)=[O:29]
Reactant: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCNCC2)CS1
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCN(C(=O)c3cccc(Cl)c3)CC2)CS1

Procedure:
Compound 63 was synthesized using 8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N. M.p.=130° C. (dec); 400 MHz 1H NMR (DMSO-d6) δ: 7.82 (d, J=8.6 Hz, 1H), 7.55-7.40 (m, 3H), 7.38 (d, J=7.6 Hz, 2H), 7.34 (d, J=7.4 Hz, 1H), 4.42 (bs, 1H), 3.87 (s, 3H), 3.58-3.20 (m, 4H), 3.03 (s, 2H), 2.08-2.02 (m, 2H), 1.96-1.88 (m, 2H), 1.86-1.78 (m, 2H); LCMS: 470 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31]([Si:33]([CH3:36])([CH3:35])[CH3:34])#[CH:32]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:34][Si:33]([C:31]#[C:32][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)([CH3:36])[CH3:35]
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2c(c1)CCC2=O

Procedure:
2.11 g of 5-bromoindan-1-one are suspended in 10 ml of degassed triethylamine with 67.2 mg of palladium(II) acetate and 78.6 mg of triphenylphosphine with 2.12 ml of ethynyltrimethylsilane and the mixture is stirred under reflux for 1 h. The cooled reaction mixture is concentrated, taken up with 20 ml of satd sodium hydrogencarbonate solution and 40 ml of ethyl acetate and the organic phase is washed first with water, then with satd sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo, and the residue is chromatographed on silica gel using n-heptane/ethyl acetate 3/1. 5-Trimethylsilanylethynylindan-1-one is obtained, which is dissolved in 25 ml of methanol and stirred at room temperature for 2 h with potassium carbonate. The reaction mixture is concentrated in vacuo; the residue is stirred with 25 ml of satd sodium hydrogencarbonate solution and 50 ml of ethyl acetate, and the organic phase is then separated off and filtered through a clarifying layer. The filtrate is dried over magnesium sulfate and concentrated in vacuo, and the residue is stirred with n-heptane. The precipitate is filtered off with suction and dried in vacuo. 5-Ethynylindan-1-one of melting point 157° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:17])[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:4]([CH3:18])[CH:3]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(O)(=O)C>[CH:12]1([CH2:11][C:10]([NH:9][C:5]2[C:4]([CH3:18])=[CH:3][C:2]([NH:1][CH2:25][C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=3)=[CH:7][C:6]=2[CH3:8])=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(N)cc(C)c1NC(=O)CC1CCCC1
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: Cc1cc(NCc2ccc(C(F)(F)F)cc2)cc(C)c1NC(=O)CC1CCCC1
Temperature: 150 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
N-(4-Amino-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide (207 mg) and 4-trifluoromethyl-benzaldehyde (125 uL) were dissolved in acetonitrile (2 mL) and heated to 150° C. for 5 minutes in a sealed microwave process vial. Sodium cyanoborohydride (0.7 M in methanol, 5 mL) and acetic acid (500 uL) were added and the reaction mixture was stirred at 25° C. for 16 hours. Aqueous sodium carbonate (10%, 25 mL) was added, and the product was collected by filtration to furnish 0.31 g (91% yield) of the title compound as a white solid. LC-MS (m/z) 405 (MH+); tR=3.19, (UV, ELSD) 97%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.19 (m, 2H), 1.51 (m, 2H), 1.60 (m, 2H), 1.75 (m, 2H), 1.96 (s, 6H), 2.22 (m, 3H), 4.34 (d, 2H), 6.18 (t, 1H), 6.25 (s, 2H), 7.55 (d, 2H), 7.67 (d, 2H), 8.76 (s, 1H).
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:9]([C:13]1[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:35]=[CH:36][CH:37]=2)[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31](=[O:34])(=[O:33])[NH2:32])=[O:23])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:9]([C:13]1[CH:39]=[CH:38][C:16]([CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:35]=[CH:36][CH:37]=2)[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([NH:32][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])(=[O:34])=[O:33])=[O:23])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccc(COc2cccc(C(=O)Nc3ccccc3S(N)(=O)=O)c2)cc1
Reactant: CCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
In a stream of nitrogen and at 0° C., 0.16 ml (1.10 mmol) of hexanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 438 mg (1.00 mmol) of 3-(4-t-butylbenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 2 and 249 mg (2.00 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 488 mg (yield: 91.0%) of the title compound.