Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[K+].C1OCCOCCOCCOCCOCCOC1.C1(C=CC(O)=CC=1)O.Cl[CH2:35][Ge:36]([CH3:39])([CH3:38])[CH3:37].CCCCCC.C(OC)(=O)C>C(#N)C>[C:1]([O:6][CH2:35][Ge:36]([CH3:39])([CH3:38])[CH3:37])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C[Ge](C)(C)CCl
Reactant: C=C(C)C(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Oc1ccc(O)cc1
Agent: [K+]
Solvent: CCCCCC
Solvent: COC(C)=O
Solvent: CC#N
Product: C=C(C)C(=O)OC[Ge](C)(C)C
Temperature: 80 °C

Procedure:
Approximately 225 ml of acetonitrile, 48 grams of potassium methacrylate, 2 grams of 18-crown-6 ether and 1 gram of hydroquinone was placed in a round bottom flask fitted with a condenser, stirrer, and septum inlet. The reaction mixture was heated to 80° C., using a heating mantle, and through the septum inlet approximately 45 grams of chloromethyltrimethyl germanium was added by syringe, in one aliquot. The reaction mixture was maintained for 65 hours at 80° C. with stirring. The reaction mixture was then cooled and filtered by vacuum suction through a fritted glass filter. The filtered solids were then washed with approximately 125 ml of acetonitrile and the wash filtrate combined with the first filtrate. The acetonitrile in the combined filtrate was removed by heating to 35° C. under vacuum. A 10:1 by volume mixture of n-hexane and methyl acetate was prepared. Approximately 50 ml of this mixture was added to the remaining reaction product. This combined mixture was then passed through a glass column containing 45 grams of silica adsorbent immersed in the n-hexane/methyl acetate mixture. The column was then washed with the n-hexane/methyl acetate mixture until IR analysis of the eluent showed no further trimethylgermylmethyl methacrylate. The n-hexane and methyl acetate present in the eluent were then removed under vacuum at 35° C. The remaining liquid was vacuum distilled at 4 mm Hg to yield pure trimethylgermylmethyl methacrylate (boiling point 58° C. at 4 mm Hg pressure).
Reaction SMILES: CC([O-])(C)C.[K+].[Br:7][C:8]1[CH:9]=[N:10][C:11](Cl)=[N:12][CH:13]=1.[CH3:15][S:16][C:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26]([O:28][CH3:29])=[O:27])=[CH:23][CH:24]=2)[NH:19][CH:18]=1>CN(C=O)C>[Br:7][C:8]1[CH:9]=[N:10][C:11]([N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:21]=3)[C:17]([S:16][CH3:15])=[CH:18]2)=[N:12][CH:13]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COC(=O)c1ccc2c(SC)c[nH]c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(SC)cn(-c3ncc(Br)cn3)c2c1
Temperature: 120 °C

Procedure:
Potassium tert-butylate (4.41 g, 39.36 mmol) and 5-bromo-2-chloro-pyrimidine (5.0 g, 26.2 mmol) were added to a solution of methyl 3-(methylthio)-1H-indole-6-carboxylate (5.8 g, 26.2 mmol) in DMF (60 mL). The resulting mixture was heated at 120° C. for 16 h, then cooled and poured onto ice-cold water (100 mL). The mixture was extracted with MTBE (3×50 mL) and the combined organic layers were dried over sodium sulfate and evaporated. The crude material was purified by column chromatography [100-200 mesh silica; ethyl acetate/hexane=1:9]. White solid. Yield: 6.0 g (61% of theory). HPLC-MS (method 5): Rt=4.15 min; m/z [M+H]+=379
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:16][CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14]C)=[O:13])[S:10][CH:11]=1.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:16][CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[S:10][CH:11]=1
Reactant: CCn1ncc(Cl)c1-c1csc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1ncc(Cl)c1-c1csc(C(=O)O)c1
Temperature: 50 °C
Yield: 92.1 %

Procedure:
To a solution of methyl 4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (0.3 g, 1.1 mmol) in THF/H2O (5 mL/0.5 mL) was added KOH (0.2 g, 3.4 mmol). The reaction mixture was heated to 50° C. for 4 h and then concentrated and diluted with H2O (2 mL). The pH was adjusted to 3 with aqueous HCl. The mixture was extracted with DCM (3×5 mL) and the collected organic fractions were concentrated under vacuum to give crude 4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (260 mg) which was used directly without further purification. LC-MS (ES) m/z=256 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19]([OH:21])=O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:22]1([CH2:25][NH2:26])[CH2:24][CH2:23]1>>[CH:22]1([CH2:25][NH:26][C:19]([C:12]2[C:13]([C:15]([F:18])([F:16])[F:17])=[N:14][C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)=[N:10][CH:11]=2)=[O:21])[CH2:24][CH2:23]1
Reactant: O=C(O)c1cnc(Nc2cccc(Br)c2)nc1C(F)(F)F
Reactant: NCC1CC1
Product: O=C(NCC1CC1)c1cnc(Nc2cccc(Br)c2)nc1C(F)(F)F
Yield: 26.2 %

Procedure:
In a manner similar to Reference Example 1 (c) 2-(3-bromophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (80 mg) and cyclopropylmethylamine (19 mg, ex Lancaster) afforded the title compound (24 mg). Sample purified by mass directed auto-prep.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[CH2:11][Br:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccccc2)noc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(-c2ccccc2)noc1CBr
Temperature: 25 °C
Yield: 102372 %

Procedure:
A mixture of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid ethyl ester (5.02 g, 0.02 mol), N-bromosuccinimide (4.06 g, 0.02 mmol) and benzoyl peroxide (263 mg, 1.09 mmol) in carbon tetrachloride (80 ml) was refluxed for 20 h before it was cooled to room temperature and partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, and brine before it was dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound as a yellow oil (6.35 g) that was used in the following step without further purification: 1H NMR (CDCl3, 200 MHz): δ=7.61 (m, 2H), 7.43 (m, 3H), 4.80 (s, 2H), 4.25 (q, J=7.0 Hz, 2H), 1.26 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]2)=[CH:4][CH:3]=1.C(Cl)Cl.C(N(C(C)C)CC)(C)C.[N:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C(OCC)(=O)C>[F:18][C:17]([F:20])([F:19])[C:10]1[CH:11]=[C:12]([C:13]([F:14])([F:15])[F:16])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:39]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:40])=[CH:7][CH:6]=2)[N:9]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 144 h
Yield: 19.6 %

Procedure:
To a solution of 1-(4′-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.300 g, 1.02 mmol) in of methylene chloride (5 mL) was added diisopropylethyl amine (0.18 mL, 1.0 mmol) followed by 4-morpholine carbonylchloride (0.11 mL, 1.0 mmol). The mixture was stirred at rt for 6 days, and diluted with ethyl acetate. It was then washed twice with water, dried over sodium sulfate and evaporated. Chromatography of the residue over silica gel (50% EtOAc/hexanes) gave the above-named compound (0.080 g, 19.6%) as a white solid: mp 185-186° C. NMR (CDCl3) δ 7.56 (2H, d), 7.44 (2H, d), 7.07 (1H, s), 6.51 (1H, s), 3.79 (4H, m), 3.54 (4H, m).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[CH2:21]=O>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[C:8]([OH:11])=[C:9]([CH2:21][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1COCCN1
Reactant: C=O
Reactant: CC(C)(C)c1ccc(O)c([N+](=O)[O-])c1
Solvent: CCO
Product: CC(C)(C)c1cc(CN2CCOCC2)c(O)c([N+](=O)[O-])c1

Procedure:
A solution of 4-t-butyl-2-nitro-phenol (980 mg, 5 mmol), morpholine (50 mmol) and paraformaldehyde (1.5 g, 50 mmol) in 20 mL ethanol was heated in a sealed vial at 95° C. for 6 hr. After removal of the solvent and morpholine, the residue was purified via silica gel column chromatography to afford 1.75 g target compound as a yellow solid.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[C:26]([CH3:28])=[CH2:27])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:14][C@H:13]1[CH:26]([CH3:28])[CH3:27]
Reactant: C=C(C)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Reaction time: 12 h
Yield: 107.4 %

Procedure:
A solution of tert-butyl (1R,3S,4S)-4-benzyloxycarbonylamino-3-(prop-1-en-2-yl)cyclohexylcarbamate (1.1 g) in MeOH (10 mL) was charged with 10% Pd/C, Degussa (300 mg). The reaction flask was evacuated and then back-filled with hydrogen; this was repeated three more times. The reaction was stirred under 1 atm of H2 for 12 h and then filtered and concentrated to provide tert-butyl (1R,3S,4S)-4-amino-3-isopropylcyclohexylcarbamate (780 mg). MS (ES+)=257.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:7])[CH:5]=[O:6].C(O[C:11](=[O:18])[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)C.C1(C)[C:20](C)=[CH:21][CH:22]=[CH:23][CH:24]=1>>[OH:18][C:11]1[C:17]2[C:3](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:4]([C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:5](=[O:6])[C:12]=1[N:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CN(C)C=O
Reactant: CCOC(=O)CN1CCCC1
Reactant: Cc1ccccc1C
Agent: [H-]
Agent: [Na+]
Product: O=c1c(N2CCCC2)c(O)c2cccnc2n1-c1ccccc1
Temperature: 0 °C
Yield: 60 %

Procedure:
To a solution of 1.5 g (6.5 mM) 2-anilinonicotinic acid, methylester, in dry xylenes at room temperature is added 0.69 g (14.54 M) of sodium hydride (NaH) (50 percent (%) oil emulsion) followed by addition of a small amount of N,N-dimethylformamide (DMF). The reaction mixture is heated to a temperature ranging between 85-95 degrees Centigrade (° C.) and 1.05 milliliters (mL) (6.5 mM) of ethyl-1-pyrrolidineacetate in xylene is slowly added over a period of 10 minutes. The reaction mixture is heated for 1 to 3 hours prior to the addition of aliquots of 0.32 g NaH followed by 1.05 mL of ethyl-1-pyrrolidineacetate as described above (total 3 aliquots). Following addition of the aliquots, the reaction mixture is cooled to 0° C., quenched with a slow addition of glacial acetic acid, and then water is added. The product is filtered and washed with water, acetone, methylene chloride, and acetone. The solid then obtained is dried in vacuo to give 1.20 g (60% yield) of title compound, a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[C:22]([OH:24])=[O:23])(=[O:10])=[O:9].ClC(Cl)(O[C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH2:37]([N:39]([CH2:43][CH3:44])[CH2:40][CH2:41][NH2:42])[CH3:38]>N1C=CC=CC=1>[CH2:37]([N:39]([CH2:43][CH3:44])[CH2:40][CH2:41][NH:42][C:29]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[C:22]([OH:24])=[O:23])(=[O:10])=[O:9])=[O:35])[CH3:38]
Reactant: CCN(CC)CCN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCCC2
Solvent: c1ccncc1
Product: CCN(CC)CCNC(=O)Nc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCCC2
Temperature: 70 °C
Reaction time: 18 h
Yield: 13.6 %

Procedure:
A mixture of Example 294 (30.2 mg, 0.09 mmol), triphosgene (8.5 mg, 0.03 mmol), and pyridine (1 mL) was stirred for 3 hours at 70° C., treated with N,N-diethylethylenediamine (61 μL, 0.44 mmol), stirred for 18 hours at 70° C., concentrated, and purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product (2.0 mg, 5%). MS (ESI(+)) m/e 489 (M+H)+; MS (ESI(−)) m/e 487 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.18 (d, 1H), 7.69 (dd, 1H), 7.53 (td, 1H), 7.47 (m, 1H), 7.10 (t, 1H), 6.95 (d, 1H), 6.65 (s, 1H), 3.19 (m, 6H), 2.66 (m, 4H), 1.66 (m, 4H), 1.20 (t, 6H).
Reaction SMILES: [CH:1]1([OH:4])[CH2:3][CH2:2]1.[CH3:5][C:6]1([CH3:33])[C@@H:8](/[CH:9]=[CH:10]\[C:11](O)=[O:12])[C@H:7]1[C:14]([O:16][C@H:17]([C:31]#[N:32])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:15].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:5][C:6]1([CH3:33])[C@@H:8](/[CH:9]=[CH:10]\[C:11]([O:4][CH:1]2[CH2:3][CH2:2]2)=[O:12])[C@H:7]1[C:14]([O:16][C@H:17]([C:31]#[N:32])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:15]
Reactant: OC1CC1
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OC1CC1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
0.9 ml of cyclopropanol were added to a mixture of 5.5 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[Z-2-carboxy-ethenyl]-cyclopropane-carboxylate in 26 ml of methylene chloride and 1 g of 4-dimethylamino-pyridine and 3 g of dicyclohexylcarbodiimide were added thereto at 0° C. The mixture was stirred at 20° C. for 90 minutes and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with an 85-15 cyclohexane-ethyl acetate mixture yielded 3.6 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[Z-2-(cyclopropyloxycarbonyl)-ethenyl]-cyclopropane-carboxylate melting at 62° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([C:16]#[N:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:46][CH3:47])=[O:5])[CH3:2]>C(O)C.[Ni]>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([CH2:16][NH2:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[C:28]([C:36]([F:39])([F:37])[F:38])[CH:27]=3)[C:22]([N:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:46][CH3:47])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(C#N)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)N1c2ccc(CN)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.8 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-6-cyano-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (458 mg) is dissolved in ethanol (5 ml), then thereto is added a catalytic amount of Raney nickel, and the mixture is stirred at room temperature under hydrogen for 5 hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by column chromatography (NH-silica gel; hexane: ethyl acetate=1:2→0:1) to give (2R,4S)-6-aminomethyl-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (211 mg). MS (m/z): 668 [M+H]+
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>>[ClH:26].[CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CCCCCC(=O)OC)n1Cc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Product: CCCCc1ncc(CCCCCC(=O)O)n1Cc1ccccc1Cl
Product: Cl

Procedure:
6-[2-n-Butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-4-hexenoic acid was converted to the methyl ester with methanol and ethereal hydrochloric acid. This methyl ester (302 mg) in methanol was hydrogenated with platinum oxide (25 mg) at one atmosphere of hydrogen for 2 hours. The isolated crude reduced ester was chromatographed over silica gel with 3:1 ethyl acetate/hexane to provide 0.125 g of methyl 6-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]hexanoate. Basic hydrolysis of this ester with potassium hydroxide as described in Example 11(ii) provided 6-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-hexanoic acid hydrochloride; mp 144°-145° C. (from acetone).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:31]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38](O)=[O:39].C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN1CCCC1=O>[C:28]([C:25]1([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[C:18]([NH:17][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[O:10][C:7]2[CH:8]=[CH:9][C:4]3[N:5]([CH:31]=[C:2]([NH:1][C:38]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=4)=[O:39])[N:3]=3)[N:6]=2)=[O:30])[CH2:27][CH2:26]1)#[N:29]
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Reactant: O=C(O)c1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)c6ccccn6)cn5n4)c3)c2)CC1
Yield: 66.4 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (150 mg, 0.365 mmol), pyridine-2-carboxylic acid (54 mg, 0.438 mmol), oxalyl chloride (63 μL), N,N-dimethylformamide (1 drop), tetrahydrofuran (3 mL) and N-methylpyrrolidone (5 mL) as starting materials and in the same manner as in Example 412, the title compound (125 mg, 67%) was obtained as a white powder.
Reaction SMILES: [C:1]([S:4][CH2:5]/[CH:6]=[C:7]1\[CH2:8][C:9]([CH3:24])([CH3:23])[CH2:10][C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=3)=[CH:14][C:15]\1=2)(=[NH:3])[NH2:2].C(O)(C)C.[OH-].[Na+]>Cl>[Br:22][C:18]1[CH:17]=[C:16]([C:13]2[S:12][C:11]3[CH2:10][C:9]([CH3:24])([CH3:23])[CH2:8][C:7]4([CH2:6][CH2:5][S:4][C:1]([NH2:2])=[N:3]4)[C:15]=3[CH:14]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)C/C(=C\CSC(=N)N)c2cc(-c3cccc(Br)c3)sc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC1(C)Cc2sc(-c3cccc(Br)c3)cc2C2(CCSC(N)=N2)C1
Yield: 47.8 %

Procedure:
(E)-2-(2-(3-Bromophenyl)-6,6-dimethyl-6,7-dihydrobenzo[b]thiophen-4(5H)-ylidene)ethyl carbamimidothioate (0.31 g, 0.65 mmol) was suspended in conc. HCl (aq.) (10 mL) and iso-propanol (10 mL) and refluxed for 2 h. Further portions of iso-propanol (5 mL) and conc. HCl (aq.) (15 mL) were added and the mixture was refluxed a further 18 hr. The mixture was cooled in an ice bath and then neutralised with aqueous 2 M NaOH solution. The aqueous layer was then extracted with dichloromethane (×3). The organic phases were combined, dried (MgSO4) and concentrated in vacuo to afford the title compound (0.131 g, 48%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[OH:27])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:28][C:29]1[C:34]([C:35]#[N:36])=[C:33](Cl)[N:32]=[CH:31][N:30]=1.C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[NH2:28][C:29]1[C:34]([C:35]#[N:36])=[C:33]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([S:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[OH:27])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:32]=[CH:31][N:30]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nn2ccc(Sc3ccccc3O)c2c(=O)n1-c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nn2ccc(Sc3ccccc3O)c2c(=O)n1-c1ccccc1
Yield: 38.6 %

Procedure:
(S)-2-(1-Aminoethyl)-5-((2-hydroxyphenyl)thio)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (183 mg, 0.36 mmol) was treated with 4-amino-6-chloropyrimidine-5-carbonitrile (84 mg, 0.54 mmol), and N,N-diisopropylethylamine (380 μl, 2.18 mmol) in tert-butanol according to the method described in Example 17. The crude was purified by reverse phase using SP1® Purification System to give 69 mg (38% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH3:46])[CH2:18][C:17]2[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:15]=[C:14]([C:27]3[N:28]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[C:31]([NH:36][CH3:37])[CH:30]=4)[C:13]=2[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:47]=[C:48]1[CH2:53][CH2:52][CH2:51][CH2:50][N:49]1[CH2:54][C:55]([OH:57])=O.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C:10]1([CH3:46])[CH2:18][C:17]2[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:15]=[C:14]([C:27]3[N:28]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:45])[CH3:44])[C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[C:31]([N:36]([CH3:37])[C:55](=[O:57])[CH2:54][N:49]3[CH2:50][CH2:51][CH2:52][CH2:53][C:48]3=[O:47])[CH:30]=4)[C:13]=2[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(COCc3ccccc3)C4)n(COCC[Si](C)(C)C)c2c1
Reactant: O=C(O)CN1CCCCC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C(=O)CN1CCCCC1=O)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(COCc3ccccc3)C4)n(COCC[Si](C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-{6-benzyloxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylamine (150 mg, 0.23 mmol) in N,N-dimethylformamide (3 ml) were added (2-oxopiperidin-1-yl)acetic acid obtained in Reference Example 6 (43 mg, 0.27 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (52 mg, 0.27% mmol) and 1-hydroxybenzotriazole monohydrate (37 mg, 0.27 mmol), and the mixture was stirred at room temperature overnight. To the reaction mixture were added ethyl acetate and water, and the organic layer was separated, washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give N-(2-{6-benzyloxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methyl-2-(2-oxopiperidin-1-yl)acetamide (158 mg). Under a nitrogen atmosphere, to a solution of the obtained N-(2-{6-benzyloxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methyl-2-(2-oxopiperidin-1-yl)acetamide (158 mg) in a mixed solvent of methanol (0.8 ml) and tetrahydrofuran (0.8 ml) was added 20% palladium hydroxide-carbon (150 mg) at room temperature, and the mixture was stirred under a hydrogen atmosphere at normal pressure for 4 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (120 mg, yield 75%).