Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([OH:19])=O)[CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:20]([C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[NH2:25])[CH3:21].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>O.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][C:17](=[O:19])[NH:25][C:24]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:22]([O:20][CH3:21])[CH:23]=2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCC(=O)O)c1
Reactant: COc1ccc(N)cc1OC
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)CCc2cccc(NC(=O)OC(C)(C)C)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.2 %

Procedure:
A reaction vial was charged with 3-(3-tert-butoxycarbonylamino-phenyl)-propionic acid (90 mg, 0.34 mmol), 3,4-dimethoxylaniline (90 mg, 0.59 mmol), EDC (100 mg, 0.64 mmol) and HOBt (100 mg, 0.74 mmol). DMF (2 mL) was added, followed by Hunig's base (0.3 mL, 1.72 mmol). The mixture was stirred at room temperature overnight, and then diluted with 10 mL water. The resulting mixture was extracted with 3×10 mL ethyl acetate. The organic layers were combined and washed with water and brine, dried with Na2SO4, and evaporated to give 150 mg crude {3-[2-(3,4-dimethoxy-phenylcarbamoyl)-ethyl]-phenyl}-carbamic acid tert-butyl ester which was used without purification. The ester intermediate was dissolved in dichloromethane (4 mL), and TFA (1 mL) was added. The resulting mixture was stirred at room temperature for 2 h, then concentrated to provide the product, 3-(3-amino-phenyl)-N-(3,4-dimethoxy-phenyl)-propionamide, as a TFA salt which was used without further purification (100 mg, 71% yield, 2 steps). This intermediate (100 mg, 0.33 mmol) was then combined with 3-(2-carboxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.39 mmol), EDC (100 mg, 0.64 mmol) and HOBt (100 mg, 0.74 mmol) in a reaction vial. DMF (2 mL) was added, followed by Hunig's base (0.3 mL, 1.72 mmol). The mixture was stirred at room temperature overnight. The product was purified directly from the reaction mixture by preparative HPLC using an acetonitrile/water/formic acid gradient to afford the product, 3-(2-{3-[2-(3,4-dimethoxy-phenylcarbamoyl)-ethyl]-phenylcarbamoyl}-ethyl)-piperidine-1-carboxylic acid tert-butyl ester, as yellow oil (50 mg, 28% yield). This intermediate was then dissolved in dichloromethane (4 mL), and TFA (1 mL) was added. The resulting mixture was stirred at room temperature for 2 hours then concentrated to provide the title compound as a TFA salt (27 mg, 66% yield); MS, electrospray, 440 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.Cl.[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[CH:25][CH:26]=1>C(O)C.O1CCOCC1>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][CH3:17])=[C:8]([C:6]2[N:5]=[C:4]([NH2:18])[N:3]=[C:2]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=3)[CH:7]=2)[CH:13]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reactant: Cc1ccc(N)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(C)cc2)nc(N)n1
Reaction time: 8 h
Yield: 53.2 %

Procedure:
To a stirred suspension of 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine (0.030 g, 0.106 mmol) in ethanol (5 ml) was added a solution of hydrogen chloride in dioxane (4.0 M, 0.015 ml) followed by p-tolylamine (0.014 g, 0.127 mmol). After heating under reflux for 3.5 hours, the volatiles were evaporated under reduced pressure. The residue was treated with 1.0 M hydrochloric acid (10 ml) and stirred overnight. After filtration, the solid was dissolved in methanol (10 ml) and treated with aqueous sodium carbonate solution (1.0 M, 1 ml). After stirring for 0.5 hours, the volatiles were evaporated under reduced pressure, the solid was stirred with water (10 ml) for 15 minutes, and filtered to provide the title compound (0.020 g, 53% yield) as a white powder. 1H NMR (DMSO-d6) δ 1.37 (t, 3H, J=6.8 Hz, CH3), 2.27 (s, 3H, CH3), 4.12 (q, 2H, J=6.6 Hz, CH2), 6.25 (s, 2H, NH2), 6.75 (s, 1H, Ar), 7.10-7.14 (m, 3H, Ar), 7.40-7.42 (m, 1H, Ar), 7.55 (d, 2H, J=8.0 Hz, Ar), 7.92 (s, 1H, Ar), 9.05 (s, 1H, NH).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=3)[N:14]=[C:13]([CH3:22])[C:12]=2[CH3:23])=[C:4]([O:24][CH3:25])[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)O1>>[Cl:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:22])[C:12]([CH3:23])=[C:11]2[N:8]1[C:9]2[C:5](=[C:4]([O:24][CH3:25])[CH:3]=[C:2]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[CH:10]=2)[CH:6]=[CH:7]1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: COc1cc(Br)cc2c1ccn2-c1c(C)c(C)nc2ccc(Cl)cc12
Product: COc1cc(-c2ccncc2)cc2c1ccn2-c1c(C)c(C)nc2ccc(Cl)cc12

Procedure:
Prepared according to procedure W using 4-(6-bromo-4-methoxy-1H-indol-1-yl)-6-chloro-2,3-dimethylquinoline (0.4 g, 0.962 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.3946 g, 1.92 mmol) to give 6-chloro-4-(4-methoxy-6-(4-pyridinyl)-1H-indol-1-yl)-2,3-dimethylquinoline as a white solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 8.50 (2H, dd, J=4.6, 1.5 Hz), 8.09 (1H, d, J=8.8 Hz), 7.74 (1H, dd, J=8.9, 2.3 Hz), 7.64 (2H, dd, J=4.5, 1.6 Hz), 7.57 (1H, d, J=3.2 Hz), 7.07 (1H, s), 6.86-6.93 (3H, m), 4.07 (3H, s), 2.77 (3H, s), 2.05 (3H, s); Mass Spectrum (ESI) m/e=414.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]#[C:14][Si](C)(C)C)[CH:8]=2)[S:3]1.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:13]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[S:3][C:2]([CH3:1])([CH3:19])[CH2:11][C:10]2=[O:12])#[CH:14]
Reactant: CC1(C)CC(=O)c2cc(C#C[Si](C)(C)C)ccc2S1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1ccc2c(c1)C(=O)CC(C)(C)S2
Yield: 98.5 %

Procedure:
A solution of 2,2-dimethyl-6-trimethylsilanylethynyl-thiochroman-4-one (110.0 mg, 0.38 mmol) and K2CO3 (40.0 mg, 0.29 mmol) in 10.0 mL MeOH was stirred overnight at room temperature. The solution was diluted with H2O and extracted with Et2O. The combined organic layers were washed with H2O and saturated aqueous NaCl and dried over MgSO4. Removal of the solvent under reduced pressure afforded 81 mg (99%) of the 6-ethynyl-2,2-dimethylthiochroman-4-one as an orange oil. 1H NMR (300 MHz, CDCl3) δ:8.20 (1H, d, J=1.9 Hz), 7.46 (1H, dd, J=1.9, 8.1 Hz), 7.18 (1H, d, J=8.1 Hz), 3.08 (1H, s), 2.86 (2H, s), 1.46 (6H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[C:11]=2[F:19])O)[CH:7]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[C:11]=2[F:19])[CH:7]=1
Reactant: COc1ccc(C(O)c2cc(Br)ccc2Cl)c(F)c1F
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(Cc2cc(Br)ccc2Cl)c(F)c1F
Reaction time: 16 h
Yield: 72.4 %

Procedure:
(5-bromo-2-chloro-phenyl)-(2,3-difluoro-4-methoxy-phenyl)methanol 2d (5.1 g, 14.1 mmol) was dissolved in 40 mL methylene chloride, followed by addition of triethyl silane (6.75 mL, 42.3 mmol) and dropwise addition of boron trifluoride diethyl ether (3.57 mL, 28.2 mmol). The reaction mixture was stirred for 16 hours. Thereafter, the reaction mixture was partitioned after 20 mL saturated sodium carbonate solution were added. The aqueous phase was extracted with dichlormethane (20 mL×3) and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound 1-[(5-bromo-2-chloro-phenyl)methyl]-2,3-difluoro-4-methoxy-benzene 2e (3.55 g, white solid), yield: 72.4%. 1H NMR (400 MHz, CDCl3): δ 7.36-7.33 (m, 1H), 7.30-7.27 (m, 2H), 6.81-6.79 (m, 1H), 6.73-6.69 (m, 1H), 4.00 (s, 2H), 3.92 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][N:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[OH:20][C@H:21]1[CH2:25][CH2:24][N:23](O)[CH2:22]1>CCO>[N+:1]([C:4]1[N:5]=[CH:6][C:7]([N:23]2[CH2:24][CH2:25][CH:21]([OH:20])[CH2:22]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: O[C@H]1CCN(O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=[N+]([O-])c1ccc(N2CCC(O)C2)cn1
Temperature: 85 °C
Yield: 47.3 %

Procedure:
A solution of 2-nitro-5-bromopyridine (320 mg, 2.02 mmol) in EtOH (6 mL) was treated with diisopropylethylamine (710 μL, 520 mg, 4.04 mmol) and (S)-3-hydroxypyrrolidinol (350 mg, 4.04 mmol). The mixture was heated in a sealed tube at 85° C. for 21.5 h then cooled and partitioned between CH2Cl2 and water. The organic layer was dried over Na2SO4, filtered and concentrated and the residue was chromatographed on a silica gel column with a 40-100% EtOAc in hexanes to 0-30% THF in EtOAc gradient to afford the product, as a yellow solid (200 mg, 47% yield). HRMS m/z calcd for C9H11N3O3 [M+H]+: 210.0873; Found: 210.0873.
Reaction SMILES: [OH-].[Na+].O1CCCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[NH:22][C:23]1[C:32]([F:33])=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[C:25]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[N:37][CH:36]=2)[N:24]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CO>[C:8]([O:12][C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[NH:22][C:23]1[C:32]([F:33])=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[C:25]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[N:37][CH:36]=2)[N:24]=1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: COC(=O)c1cc(F)c(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cncc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Nc2cncc3ccccc23)c(C(=O)O)cc1F
Temperature: 65 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
A 1N sodium hydroxide aqueous solution (2 ml) was added to a solution of tetrahydrofuran (2 ml) and methanol (2 ml) containing methyl 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-5-fluoro-2-(isoquinoline 4-ylamino)nicotinate (75 mg), followed by stirring at 65° C. for 2 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled away under reduced pressure. A saturated aqueous ammonium chloride solution was added to the obtained residue, solid matter was collected by filtration and washed with water and ethyl acetate, and a yellow solid of 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-5-fluoro-2-(isoquinoline 4-ylamino)nicotinic acid (67 mg) was thus obtained.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH3:15])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[Cl:14].C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:1][O:2][NH:3][CH:4]([CH3:15])[CH2:5][C:6]1[C:7]([Cl:14])=[CH:8][C:9]([Cl:13])=[CH:10][C:11]=1[Cl:12]
Reactant: CON=C(C)Cc1c(Cl)cc(Cl)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CONC(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a stirred solution of crude 1-(2,4,6-trichloro-phenyl)-propan-2-one O-methyl-oxime prepared as described in example P4, (12.3 g, 0.046 mol) in acetic acid (120 ml), sodium cyanoborohydride (6.1 g, 0.097 mol) was added portionwise at 12 to 15° C. The reaction mass was stirred at ambient temperature for 18 hours. TLC confirmed the completion of reaction, then solvent was evaporated under reduced pressure (co-evaporation with toluene twice). The resulting residue was poured on to 1 N sodium hydroxide solution (150 ml) and extracted with dichloromethane (2×100 ml). The combined organic layer was washed with water (2×100 ml) followed by drying over anhydrous sodium sulfate before evaporating the solvent to afford crude O-Methyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (12.3 g, 100%).
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([CH3:20])=[N:11][C:12]([CH3:19])=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16])=O)(C)(C)C.[ClH:21]>CO>[ClH:21].[ClH:21].[NH2:8][C:9]1[C:10]([CH3:20])=[N:11][C:12]([CH3:19])=[CH:13][C:14]=1[C:15]([F:18])([F:16])[F:17]
Reactant: Cc1cc(C(F)(F)F)c(NC(=O)OC(C)(C)C)c(C)n1
Agent: Cl
Solvent: CO
Product: Cc1cc(C(F)(F)F)c(N)c(C)n1
Temperature: 60 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
3-tert-Butoxycarbonylamino-2,6-dimethyl-4-trifluoromethylpyridine (21.12 g, 72.8 mmol) was dissolved in methanol (70 mL), and subsequent to the addition of 10% hydrogen chloride in methanol (140 mL), the solution was stirred at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in a mixture of ethyl acetate and ether. The reaction product was collected by filtration, and washed with ether to obtain the title compound (15.64 g, 82%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:5][C:6](=[O:8])[CH:7]=1)=[O:4].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][NH2:19].O>C(O)(=O)C>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][N:19]=[C:3]([OH:4])/[C:2](/[Cl:1])=[CH:7]\[C:6]([OH:5])=[O:8]
Reactant: COc1ccccc1CCN
Reactant: O=C1C=C(Cl)C(=O)O1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1CCN=C(O)/C(Cl)=C\C(=O)O
Yield: 73.3 %

Procedure:
13.25 g (0.1 mol) of chloromaleic anhydride and 15.2 g (0.1 mol) of 2-(2-methoxyphenyl)-ethylamine are heated to the boiling point in 100 ml of glacial acetic acid for 4 hours. 100 ml of water are then added and the oil which has precipitated is extracted with methylene chloride. The methylene chloride phase is separated off, washed with water, dried and evaporated. The oil which remains crystallizes. 20.8 g (78% of theory) of chloromaleic acid N-[2-(2-methoxyphenyl)-ethyl]-imide are obtained.
Reaction SMILES: [OH-].[Li+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:13](=[O:32])[N:12]2[CH:33]([CH3:38])[C:34]([O:36]C)=[O:35])=[CH:7][CH:6]=1)#[N:4].O>ClCCl>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:20]3[C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:15]=3[N:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[C:13](=[O:32])[N:12]2[CH:33]([CH3:38])[C:34]([OH:36])=[O:35])=[CH:9][CH:10]=1)#[N:4]
Reactant: COC(=O)C(C)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C(=O)O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
Aqueous lithium hydroxide (2 M, 1.06 mL, 2.12 mmol) is added to a solution of methyl 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazolin-3(4H)-yl)propanoate (intermediate 58, 350 mg, 0.70 mmol), and the mixture is stirred at room temperature over night. Water and dichloromethane are added, and the phases are separated. The organic layer is discarded, and the aqueous layer is acidified with aqueous hydrogen chloride (1 M) and extracted with dichloromethane. The organic phase is dried over MgSO4 and concentrated under reduced pressure. Yield: 274 mg; ESI mass spectrum [M+H]+=484; Retention time HPLC: 0.90 min (Z018_S04).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12]#[N:13])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C(N)(=[S:16])C.Cl>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12](=[S:16])[NH2:13])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2C#N
Reactant: CC(N)=S
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cnc2c(c1)CCCC2C(N)=S
Yield: 63.8 %

Procedure:
3-Methyl-8-cyano-5,6,7,8-tetrahydroquinoline (1.7 g., 0.01 m.) and thioacetamide (1.5 g., 0.02 m.) were dissolved in dimethylformamide (50 ml.), the solution saturated with dry hydrogen chloride gas and then heated on a steam bath for 4 hours. The cooled reaction mixture was poured onto water (200 ml.), washed with ethyl acetate (2 × 200 ml.) and the extracts discarded. The aqueous solution was adjusted to pH 10.0 with 46% sodium hydroxide and extracted into methylene chloride (2 × 200 ml.). The combined extracts were dried (sodium sulphate), evaporated in vacuo and the residual oil triturated with isopropanol and filtered. Recrystallisation from benzene gave the title compound as pale yellow needles (1.3 g., 63%) m.p. 149°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:28](S(C2C=CC(C)=CC=2)(=O)=O)[C:16]2[N:17]=[CH:18][CH:19]=[C:20]([C:21]([O:23]C(C)(C)C)=[O:22])[C:15]=2[CH:14]=1.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:28][C:16]2[N:17]=[CH:18][CH:19]=[C:20]([C:21]([OH:23])=[O:22])[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3c(C(=O)OC(C)(C)C)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)c(-c1cc3c(C(=O)O)ccnc3[nH]1)cn2C
Yield: 51.5 %

Procedure:
A solution of 2-(5-methoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-4 carboxylic acid, tert-butyl ester [106 mg, Reference Example 2(n)] in methanol (10 mL) was treated with potassium hydroxide solution (1 mL, 5N) then heated at reflux temperature for 1 hour and then evaporated. The residue was treated with water (15 mL) and the mixture washed with ethyl acetate (10 mL). The pH of the aqueous solution was then adjusted to 4 by addition of hydrochloric acid and cooled in ice. The resulting yellow solid was filtered washed well with water and then dried at 80° C. under vacuum to give the title compound (33 mg) as a yellow solid, m.p.>300° C. MS: 322 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH3:10].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([N:19]([CH2:23][CH3:24])[C:20](Cl)=[O:21])[CH3:18].C1(C)C=CC=CC=1>C(#N)C.O>[CH2:17]([N:19]([CH2:23][CH3:24])[C:20]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH3:10])=[O:21])[CH3:18]
Reactant: COc1cccc(O)c1C
Reactant: CCN(CC)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC)C(=O)Oc1cccc(OC)c1C
Temperature: 100 °C
Reaction time: 0.98 h
Yield: 103.1 %

Procedure:
A solution of 3.15 g (22.8 mmol) of 2-hydroxy-6-methoxytoluene in 16 mL acetonitrile was added with 3.50 g (25.1 mmol) of potassium carbonate and 3.4 g (25.1 mmol) of diethylcarbamoyl chloride and heated and stirred on a 100° C. oil bath for 59 minutes. After addition of 0.6 g (4.4 mmol) of diethylcarbamoyl chloride and heated for 38 minutes, while stirring on an ice-water bath, 30 mL of toluene and 30 mL of water, were added into the reaction mixture, and the mixture was stirred for 20 minutes, transferred to a separatory funnel and settled. The aqueous layer was separated and discarded and after the organic layer was washed with 10 mL of 2 N aqueous sodium hydroxide and 10 mL of water twice, and the solvent was evaporated to obtain 5.58 g of the crude title compound. Since the mixture solidified, a part thereof was obtained as seed crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:12])([CH3:11])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]([C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([C:20]3=O)[CH2:18]1)[CH2:24]2)=[O:16].C(O)(=O)C.[BH4-].[Na+]>C(O)C.O>[CH3:13][O:14][C:15]([C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH:20]3[NH:10][CH2:9][C:8]([NH2:12])([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH3:11])[CH2:18]1)[CH2:24]2)=[O:16]
Reactant: CC(N)(CN)c1cccc(Cl)c1
Reactant: COC(=O)C12CC3CC(C1)C(=O)C(C3)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C12CC3CC(C1)C(NCC(C)(N)c1cccc(Cl)c1)C(C3)C2
Temperature: 0 °C
Reaction time: 17 h
Yield: 86.5 %

Procedure:
To a solution of 2-(3-chloro-phenyl)-propane-1,2-diamine (3.4 g) and 4-oxo-adamantane-1-carboxylic acid methyl ester (CAS 56674-88-5, 3.85 g) in ethanol (50 mL) was added acetic acid (0.7 mL) and reaction mixture was refluxed for 4 h, after which it was cooled to 0° C. and NaBH4 was added. The reaction mixture was then slowly brought to room temperature and left at stirring for 17 h. The reaction was monitored by TLC. After completion, water (30 mL) was slowly added. The reaction mixture was concentrated at reduced pressure to remove the ethanol. The aqueous layer was extracted with DCM (3×50 mL) and the organic layers were then dried over Na2SO4 and then concentrated to get crude desired 4-[2-amino-2-(3-chloro-phenyl)-propylamino]-adamantane-1-carboxylic acid methyl ester (6 g) as a mixture of E/Z isomers. The compound was used in the next step without further purification. MS (ESI): 377.4 (MH+).
Reaction SMILES: CC(C)([O:4][C:5]1[S:9][C:8]([C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][CH:6]=1)C.Cl>CO>[OH:4][C:5]1[S:9][C:8]([C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][CH:6]=1
Reactant: CCCCCC(=O)c1ccc(OC(C)(C)C)s1
Agent: Cl
Solvent: CO
Product: CCCCCC(=O)c1ccc(O)s1

Procedure:
55.0 g (0.216 mol) of 1-[5-(1,1-dimethyl-ethoxy)-2-thienyl]-1-hexanone are heated under reflux in 400 ml of methanol and 24 ml of concentrated hydrochloric acid for 2.5 hours. The mixture is then evaporated in vacuo, the residue is taken up in 500 ml of ether and the mixture is washed twice with 50 ml of water each time. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue (42.2 g of dark brown crystals, 99%) is digested with petroleum ether:diisopropyl ether =7:3.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]([C:28](=[O:40])[NH:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][C:13]2[CH:21]=[C:20](Cl)[C:19]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[C:18]3[C:14]=2[CH:15]=[N:16][NH:17]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([S:7]([NH:10][CH:11]([C:28](=[O:40])[NH:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:12][C:13]2[CH:21]=[CH:20][C:19]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[C:18]3[C:14]=2[CH:15]=[N:16][NH:17]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)COc1c(Cl)cc(CC(NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)c2cn[nH]c12
Agent: [Pd]
Solvent: CO
Product: O=C(O)COc1ccc(CC(NS(=O)(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)c2cn[nH]c12

Procedure:
{4-[2-Benzenesulfonylamino-2-(4-phenyl-butylcarbamoyl)-ethyl]-6-chloro-1H-indazol-7-yloxy}-acetic acid (8.0 mg, 0.014 mmol) is dissolved in MeOH (1.5 mL) and 10% Pd/C (5 mg) is added. The reaction is purged with N2 and then with H2. The reaction is rapidly stirred and monitored by HPLC until complete (approximately 30 h). The reaction is filtered through celite and washed with MeOH to provide {4-[2-benzenesulfonylamino-2-(4-phenyl-butylcarbamoyl)-ethyl]-1H-indazol-7-yloxy}-acetic acid. 1H NMR (500 MHz, MeOH-d4) δ 7.88 (s, 1H), 7.49–7.47 (d, 2H), 7.40 (dd, 1H), 7.25–7.21 (m, 4H), 7.15–7.13 (m, 3H), 6.70 (d, 1H), 6.49 (d, 1H), 5.37 (m, 1H), 4.45 (s, 2H), 3.97 (t, 1H), 3.6 (obs, 1H), 3.14 (dd, 1H), 3.07–3.02 (m, 2H), 2.94–2.89 (m, 2H), 2.53 (t, 2H), 1.45–1.39 (m, 2H), 1.28–1.22 (m, 2H); MS (ESI+) m/z 551 (M+H).