Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]([CH2:18][CH2:19][CH3:20])[C:4](=[O:17])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[N:8][C:9]=2[N:10]=1.CN1CCCC1=O.C(=O)([O-])[O-].[K+].[K+].[F:34][C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1>O>[F:34][C:35]1[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=1)[O:41][C:2]1[N:3]([CH2:18][CH2:19][CH3:20])[C:4](=[O:17])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[N:8][C:9]=2[N:10]=1
Reactant: Oc1cccc(F)c1
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(C)c3)[nH]c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCn1c(Oc2cccc(F)c2)nc2nc(-c3cnn(C)c3)[nH]c2c1=O
Temperature: 87.5 °C
Yield: 74.3 %

Procedure:
The first two steps were carried out as described earlier. A mixture of 2-Chloro-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one (0.1 g, 0.34 mmol), N-methyl pyrrolidone (2 ml), potassium carbonate (0.093 g, 0.68 mmol) and 3-Fluoro phenol (0.036 ml, 0.4 mmol), were heated at 85-90° C. for 20 hours. The reaction mixture was cooled to 0° C. and then added water (10 ml). The solid obtained was filtered, washed with cold water, then washed with diethyl ether, dried to obtain -(3-Fluoro-phenoxy)-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one (0.093 g, 75%) as an off white solid.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=4)[S:21][CH:22]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)C.[Li+].[OH-].Cl>>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([NH:23][C:20]2[S:21][CH:22]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([CH:9]4[CH2:8][CH2:7][CH:6]([CH2:5][C:4]([OH:32])=[O:3])[CH2:11][CH2:10]4)=[CH:13][CH:14]=3)[N:19]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)CC1CCC(c2ccc(-c3csc(Nc4cccc(OC)c4)n3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: COc1cccc(Nc2nc(-c3ccc(C4CCC(CC(=O)O)CC4)cc3)cs2)c1
Temperature: 50 °C

Procedure:
To the reaction mixture of (4-{4-[2-(3-methoxyphenylamino)-thiazol-4-yl]-phenyl}-cyclohexyl)-acetic acid ethyl ester from step B is added LiOH (10% solution, 1 mL). It is then heated at 50° C. for 18 h. The mixture is then acidified with HCl solution (1 N) to pH=5. The resulting solid is filtered and dried under high vacuum to give the title compound (26.8 mg) as a solid; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.07 (m, 2 H) 1.31-1.43 (m, 2 H) 1.50-1.52 (m, 1 H) 1.58-1.64 (m, 1 H) 1.71 (d, J=9.60 Hz, 4 H) 2.03 (d, J=6.57 Hz, 2 H) 2.27 (br. s., 1 H) 3.67 (s, 3 H) 6.43 (dd, J=7.83, 1.77 Hz, 1 H) 7.03 (dd, J=7.20, 0.88 Hz, 1 H) 7.09-7.20 (m, 4 H) 7.44 (br. s., 1 H) 7.70 (d, J=8.08 Hz, 2 H) 10.13 (br. s., 1 H); MS (M+H)+=423.2.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([O:18][CH:19]([C:26]([O:28]CC)=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:13]([Cl:31])[CH:12]=2)[C:8]2[CH:32]=[C:33]([NH:36][C:37]([NH:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[O:38])[CH:34]=[CH:35][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[C:13]([Cl:31])[C:14]([O:18][CH:19]([C:26]([OH:28])=[O:27])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:15]([Cl:17])[CH:16]=2)[C:8]2[CH:32]=[C:33]([NH:36][C:37]([NH:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[O:38])[CH:34]=[CH:35][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NC(=O)NC3CCCCC3)cc2n1Cc1cc(Cl)c(OC(C(=O)OCC)c2ccccc2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2ccc(NC(=O)NC3CCCCC3)cc2n1Cc1cc(Cl)c(OC(C(=O)O)c2ccccc2)c(Cl)c1

Procedure:
Prepared analogously to Example 1b from 2-n-butyl-1-[4-[(α-ethoxycarbonyl)benzyloxy]-3,5-dichlorobenzyl]-6-cyclohexylaminocarbonylamino-benzimidazole and 1N sodium hydroxide solution in ethanol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH3:11][C:12]1[C:16](C(B(O)O)=O)=[C:15]([CH3:22])[O:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(O)C>[S:9]1[CH:8]=[CH:7][C:6]2[CH:10]=[C:2]([C:16]3[C:12]([CH3:11])=[N:13][O:14][C:15]=3[CH3:22])[CH:3]=[CH:4][C:5]1=2
Reactant: Brc1ccc2sccc2c1
Reactant: Cc1noc(C)c1C(=O)B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1noc(C)c1-c1ccc2sccc2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 60.2 %

Procedure:
To a solution of 5-bromo-1-benzothiophene (ABCR, CAS: 133150-64-8, 1.0 6 g, 5.0 mmol) in dimethoxyethane (60 mL) and ethanol (6.0 mL) was added 3,5-dimethyl-4-isoxazoylboronic acid (1.0 g, 7.5 mmol), and 2 m sodium carbonate (2.0 mL). The reaction mixture was degassed 2-3 times, tetrakis-(triphenylphosphine)palladium (0.813 g, 0.7 mmol) was added, and the mixture was stirred for 6 h at 80° C. and concentrated. The residue was taken up in water and extracted with ethyl acetate. The organics were washed, dried and concentrated. The crude product was chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain 4-benzo[b]thiophen-5-yl-3,5-dimethyl-isoxazole (0.69 g) as a light yellow solid. MS (ISP): m/e 230.1 (M+H)+
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:16]#[N:17])[CH2:10][CH2:9][N:8]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1>N.CO.[Ni]>[CH:1]1([CH2:4][C:5]2([CH2:16][NH2:17])[CH2:6][CH2:7][N:8]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3]1
Reactant: CCS(=O)(=O)N1CCC(C#N)(CC2CC2)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCS(=O)(=O)N1CCC(CN)(CC2CC2)CC1
Reaction time: 5 h

Procedure:
A solution of 4-(cyclopropylmethyl)-1-(ethylsulfonyl)piperidine-4-carbonitrile (I-4, 3.1 mg, 11.1 mmol) in 2 M NH3/MeOH (50 mL) was treated with excess Raney Ni and agitated under an atmosphere of H2 (40 psi) in a Parr apparatus. After 5 h, the reaction was filtered through Celite (MeOH wash) and concentrated under reduced pressure to afford 1-[4-(cyclopropylmethyl)-1-(ethylsulfonyl)-piperidin-4-yl]methanamine (I-5, M+H+=261.2) as a yellow oil. This material was used in subsequent reactions without further purification.
Reaction SMILES: [S:1]1[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[NH:3][CH2:2]1.[P:10](=[O:21])([N:18]=[C:19]=[O:20])([S:14][CH2:15][CH2:16][CH3:17])[O:11][CH2:12][CH3:13]>CCOCC>[CH2:12]([O:11][P:10]([NH:18][C:19]([N:3]1[CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:5][S:1][CH2:2]1)=[O:20])([S:14][CH2:15][CH2:16][CH3:17])=[O:21])[CH3:13]
Reactant: CCCSP(=O)(N=C=O)OCC
Reactant: COC(=O)C1CSCN1
Solvent: CCOCC
Product: CCCSP(=O)(NC(=O)N1CSCC1C(=O)OC)OCC

Procedure:
To a solution of 2.2 g of methyl thiazolidine-4-carboxylate in 50 ml of ether was added dropwise with stirring at ambient temperature 3.14 g of O-ethyl S-propyl phosphoroisocyanatidothioate. The mixture was allowed to react overnight at ambient temperature and was then concentrated by evaporation under reduced pressure to obtain 5.2 (97 percent of theory) of the title compound as a colorless oil having a refractive index at 25° C. of 1.5312.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[N:18][CH:19]=1.[N+:22]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=[O:28])([O-:24])=[O:23]>O1CCCC1.CCCCCC>[N+:22]([C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]([C:15]1[C:14]([Br:13])=[CH:19][N:18]=[C:17]([O:20][CH3:21])[CH:16]=1)[OH:28])([O-:24])=[O:23]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(C(O)c2ccccc2[N+](=O)[O-])c(Br)cn1
Reaction time: 3 h
Yield: 130.8 %

Procedure:
n-Butyllithium (17.5 ml of a 1.6M hexane solution)in anhydrous tetrahydrofuran (20 ml) was added dropwise to a stirred, cooled (-72° C.) solution of diisopropylamine (3.8 ml) in anhydrous tetrahydrofuran (120 ml) under a nitrogen atmosphere. 5-Bromo-2-methoxypyridine (5.09 g, Eur. J. Med. Chem. 1977, 12, 531) in anhydrous tetrahydrofuran (15 ml) was added dropwise followed by a solution of 2-nitrobenzaldehyde (2.96 g) in anhydrous tetrahydrofuran (20 ml) keeping the temperature of the reaction mixture below -70° C. The reaction mixture was stirred for 3 hours at -60° C. to -70° C. then quenched with saturated aqueous ammonium chloride solution. The organic layer was separated, washed with water then dried (magnesium sulphate) and evaporated to dryness. The residue was combined with crude product from another reaction of identical scale then purified by column chromatography on silica using ethyl acetate/petroleum ether (60-80) (1:4) and the solid obtained recrystallised from dichloromethane/petroleum ether (60-80) to afford the title compound (8.69 g). mp 128°-131° C. Rf =0.69 in 20% diethyl ether/dichloromethane on silica plates; 1H NMR (360 MHz, CDCl3) δ 3.93 (3H, s), 6.42 (1H, s), 7.00 (1H, s), 7.31 (1H, dd, J=1 and 7 Hz), 7.49 (1H, ddd, J=1 and 7 Hz), 7.58 (1H, ddd, J=1 and 7 Hz), 8.02 (1H, dd, J=1 and 7 Hz), 8.19 (1H, s); IR (KBr) 3600-2800 cm-1.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](Cl)=[O:46])=[CH:40][CH:39]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([CH2:44][C:45]([NH:21][C:18]2[C:17](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:46])=[CH:42][CH:43]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(/C=C/c3ccccc3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2/C=C/c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 69.7 %

Procedure:
Under an argon atmosphere, to a mixture of (E)-5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-styrylpyrazin-2-amine (7b) (500 mg, 1.24 mmol) and 4-(dimethylamino)pyridine (15.3 mg, 125 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy) phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 15 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11b (563 mg, 864 μmol, 69.7%) as a yellow solid. Rf=0.29 (n-hexane/ethyl acetate=3/1); 1H NMR (400 MHz, DMSO-d6) δ 0.17 (s, 6H), 0.24 (s, 6H), 0.96 (s, 9H), 0.97 (s, 9H), 3.66 (s, 2H), 6.81-6.91 (m, 3H, includes AA′BB′), 6.99-7.04 (AA′BB′, 2H), 7.28-7.40 (m, 7H, includes AA′BB′), 7.82 (d, 1H, J=16 Hz), 8.11-8.19 (AA′BB′, 2H), 8.91 (s, 1H), 10.66 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.5 (2C), −4.6 (2C), 17.8, 17.9, 25.5 (6C), 42.0, 119.7 (2C), 120.3 (2C), 122.5, 127.1 (2C), 128.2 (2C), 128.5, 128.7 (2C), 128.9, 129.0, 130.3 (2C), 133.8, 136.0, 137.8, 142.8, 143.9, 148.0, 154.0, 156.7, 170.6; IR (KBr, cm−1) 471, 521, 638, 691, 746, 781, 806, 839, 914, 968, 1007, 1080, 1103, 1169, 1263, 1325, 1371, 1391, 1414, 1439, 1472, 1510, 1566, 1605, 1659, 2857, 2886, 2930, 2055, 3028, 3057, 3217; HRMS (ESI+) m/z 674.3203 ([M+Na]+, C38H49N3NaO3Si2+ requires 674.3205).
Reaction SMILES: [CH:1]1([N:6]([CH3:33])[C:7]2[C:8]([CH3:32])=[C:9]([CH:23]=[C:24]([C:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=3)[CH:25]=2)[C:10]([NH:12][CH2:13][C:14]2[C:15](=[O:22])[NH:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:36]([BH3-])#N.[Na+]>CO>[CH:1]1([N:6]([CH3:33])[C:7]2[C:8]([CH3:32])=[C:9]([CH:23]=[C:24]([C:26]3[CH2:27][CH2:28][N:29]([CH3:36])[CH2:30][CH:31]=3)[CH:25]=2)[C:10]([NH:12][CH2:13][C:14]2[C:15](=[O:22])[NH:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [BH3-]C#N
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C)CC3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
3-(Cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.100 g, 0.223 mmol) was dissolved in methanol (5 mL) and cooled to 0° C., formalin (0.067 g, 0.19 mL, 2.23 mmol) was added. Resulting reaction mass was stirred at same temperature for 30 minutes. Sodium cyanoborohydride (0.041 g, 0.66 mmol) was added to above reaction mass and stirred at room temperature for 4 h. After completion, solvent were removed under reduced pressure and water was added to the residue, extraction was carried out using DCM. Combined organic layers were dried, concentrated and purified by column chromatography to provide the desired compound (0.065 g, 63%): LCMS: 463.40 (M+1)+; HPLC: 98.79% (@ 254 nm) (Rt; 3.911; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.43 (s, 1H), 8.04 (t, 1H, J=4.8 Hz), 7.17 (s, 1H), 6.95 (s, 1H), 6.07 (s, 1H), 5.85 (s, 1H), 4.25 (d, 2H, J=4.8 Hz), 3.45 (m, 1H), 2.98 (bs, 2H), 2.53 (m, 2H), 2.42 (bs, 2H), 2.26 (s, 3H), 2.18 (s, 3H), 2.17 (s, 3H), 2.10 (s, 3H), 1.67 (m, 2H), 1.59 (m, 2H), 1.49 (m, 2H), 1.40 (m, 2H).
Reaction SMILES: NC1C=CC(C#N)=CN=1.[C:10]1([O:16][C:17](=[O:32])[NH:18][C:19]2[CH:24]=[C:23](OCCOC)[C:22]([C:30]#[N:31])=[CH:21][N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([O:16][C:17](=[O:32])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:30]#[N:31])=[CH:21][N:20]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COCCOc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Agent: N#Cc1ccc(N)nc1
Product: N#Cc1ccc(NC(=O)Oc2ccccc2)nc1

Procedure:
From 2-amino-5-cyanopyridine, reacted in an analogous manner to the preparation of intermediate 108. (UPLC-MS 6) tR 0.92; ESI-MS 240.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:18](/[CH3:31])=[C:19](/[F:30])\[CH:20]=[CH:21]\[C:22](\[CH3:29])=[CH:23]\[C:24]([O:26]CC)=[O:25])[C:3]=1[O:32][CH2:33][CH3:34].[OH-].[Na+]>C(O)C>[Br:1][C:2]1[C:11]2[C:10]([CH3:12])([CH3:13])[CH2:9][CH:8]=[C:7]([C:14]([CH3:17])([CH3:15])[CH3:16])[C:6]=2[CH:5]=[C:4](/[C:18](/[CH3:31])=[C:19](/[F:30])\[CH:20]=[CH:21]\[C:22](\[CH3:29])=[CH:23]\[C:24]([OH:26])=[O:25])[C:3]=1[O:32][CH2:33][CH3:34]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(c(Br)c1OCC)C(C)(C)CC=C2C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1c(/C(C)=C(F)\C=C\C(C)=C\C(=O)O)cc2c(c1Br)C(C)(C)CC=C2C(C)(C)C

Procedure:
As described in General Procedure J-1, ethyl (2E,4E,6E)-7-(4 bromo-8-tert-butyl-3-ethoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-6-fluoro-3-methyl-octa-2,4,6-trienoate (Compound A-163, 46 mg, 0.086 mmol) in ethanol was treated with a solution of 1 N NaOH to produce the title compound after purification by recrystallization from acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.C(O)CCC.[I:21][C:22]1[CH:23]=[C:24]([CH2:28][NH2:29])[CH:25]=[CH:26][CH:27]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:29][CH2:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([I:21])[CH:23]=2)[N:3]=1
Reactant: NCc1cccc(I)c1
Reactant: CCC(C)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CCCCO
Solvent: CC(C)O
Product: CCC(C)n1cnc2c(NCc3cccc(I)c3)nc(Cl)nc21
Reaction time: 22 h

Procedure:
The operation is carried out as in Stage 2 of Example 9 starting from 200 mg of the product obtained in Stage 1 of Example 9 and 4 ml of butanol and using 0.128 ml of 3-iodo-benzenemethanamine in place of the benzylamine. The reaction medium is taken to a temperature of 80 to 85° C. for approximately 22 hours, left to return to ambient temperature, diluted with 4 ml of isopropanol and placed for two days at a temperature of approximately 0° C., followed by separating, washing with 10 ml of isopropanol and drying at a temperature of approximately 50° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion of 90/10, 290 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]1([CH3:20])[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1>>[CH3:12][C:13]1([CH3:20])[CH2:18][CH2:17][CH:16]([O:19][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:15][CH2:14]1
Reactant: CC1(C)CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: CC1(C)CCC(Oc2cc(F)ccc2[N+](=O)[O-])CC1

Procedure:
Prepared analogously to III.1 from 2 ml 2,4-difluoro-nitrobenzene and 2.339 g 4,4-dimethyl-cyclohexanol.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[Cl:22][C:23]1[CH:24]=[C:25]([C:33]([OH:35])=O)[CH:26]=[N:27][C:28]=1[O:29][CH:30]([CH3:32])[CH3:31].[F:36][C:37]1[CH:45]=[CH:44][C:43](/[C:46](/[NH:49]O)=[N:47]/[H])=[C:42]2[C:38]=1[C:39]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:40][NH:41]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([C:33]2[O:35][N:47]=[C:46]([C:43]3[CH:44]=[CH:45][C:37]([F:36])=[C:38]4[C:42]=3[NH:41][CH:40]=[C:39]4[CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[N:49]=2)[CH:26]=[N:27][C:28]=1[O:29][CH:30]([CH3:31])[CH3:32]
Reactant: CC(C)Oc1ncc(C(=O)O)cc1Cl
Reactant: [H]/N=C(\NO)c1ccc(F)c2c(CCC(=O)OCC)c[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(Cl)c4)n3)ccc(F)c12
Reaction time: 2 h
Yield: 86.6 %

Procedure:
HOBT (163 mg) and EDCI (204 mg) were added to a solution of 5-chloro-6-[(1-methylethyl)oxy]-3-pyridinecarboxylic acid (118 mg) in THF (4 mL). The resulting solution was stirred for 2 hours. Ethyl 3-{4-fluoro-7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D45) (208 mg) in THF (4 mL) was added, and the reaction mixture was stirred at RT overnight. TBAF (780 mg) was then added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 2.5 hours. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography (10% EtOAc in hexane) to afford ethyl 3-[7-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoate (D48) (224 mg) as a pale yellow solid. δH (CDCl3, 400 MHz): 1.25 (3H, t), 1.46 (6H, d), 2.76 (2H, t), 3.24 (2H, t), 4.14 (2H, q), 5.51 (1H, m), 6.91 (1H, dd), 7.15 (1H, d), 8.04 (1H, dd), 8.43 (1H, d), 8.91 (1H, d), 9.67 (1H, br s). MS (ES): C23H22ClFN4O4 requires 472; found 473.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>CCO.N.O.[Ni]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH2:21])=[CH:18][CH:19]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C#N)cc2)c1
Agent: [Ni]
Agent: N
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CN)cc2)c1
Reaction time: 6 h

Procedure:
A suspension of (4′-cyano-biphenyl-3-yl)-carbamic acid tert-butyl ester (7.6 g, 26 mmol) and Raney Ni (1 g) in EtOH (500 mL) and NH3.H2O (10 mL) was hydrogenated under 50 psi of H2 at 50° C. for 6 h. The catalyst was filtered off and the filtrate was concentrated to dryness to give (4′-aminomethyl-biphenyl-3-yl)-carbamic acid tert-butyl ester, which was used directly in next step.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[O:22][C:21](=[O:23])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.Br[CH2:25][CH:26]=[CH:27][CH3:28].[NH4+].[Cl-]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:25]([C@H:20]1[CH2:19][C@H:18]([C:15]2[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=2)[O:22][C:21]1=[O:23])/[CH:26]=[CH:27]/[CH3:28]
Reactant: O=C1CC[C@H](c2ccc(F)cc2)O1
Reactant: CC=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C/C=C/C[C@H]1C[C@H](c2ccc(F)cc2)OC1=O
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
To the solution of lithium bis(trimethylsilyl)amide (2.4 mL, 2.4 mmol, 1M in THF) in anhydrous 20 mL THF at −70° C. was slowly added over 15 minutes (R)-5-(4-fluorophenyl)dihydrofuran-2(3H)-one (360 mg, 2.0 mmol) as a solution in 1.0 mL THF. The reaction mixture was stirred for 20 min at −70° C. and then for 10 min at room temperature. The mixture was cooled to −70° C. and to it was slowly added a pre-cooled solution of 1-bromo-but-2-ene (324 mg, 2.4 mmol) in 400 μl HMPA an 100 μL of THF. The resulting mixture was stirred at −70° C. for 2 h and the temperature was slowly raised over a period of 2 h. The mixture was poured into 20 mL saturated NH4Cl and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (2×20 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the product isolated by Flash column chromatography eluting with 0% to 50% ethyl acetate/hexane to the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[C:17]2[C:7]([NH:8][CH:9]=[C:10]2[CH2:11][C@@H:12]([C:14]([NH2:16])=[O:15])[NH2:13])=[CH:6][CH:5]=1)([O-])=O.[CH:19]1([N:25]2[C:29]3[CH:30]=[CH:31][C:32]([C:34](O)=[O:35])=[CH:33][C:28]=3[N:27]=[C:26]2[C:37]2[CH:41]=[CH:40][O:39][CH:38]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[NH2:1][C:4]1[CH:18]=[C:17]2[C:7](=[CH:6][CH:5]=1)[NH:8][CH:9]=[C:10]2[CH2:11][C@H:12]([NH:13][C:34]([C:32]1[CH:31]=[CH:30][C:29]2[N:25]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:26]([C:37]3[CH:41]=[CH:40][O:39][CH:38]=3)=[N:27][C:28]=2[CH:33]=1)=[O:35])[C:14](=[O:15])[NH2:16]
Reactant: NC(=O)[C@@H](N)Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Product: NC(=O)[C@H](Cc1c[nH]c2ccc(N)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
The 5-nitrotryptophan amide derivative of example 53 was coupled to the carboxylic acid of example 2 in the usual manner. The nitro group was then reduced to the corresponding amine using SnCl2 dihydrate as described in example 48, to give the title compound of example 54 after purification by preparative C18 reversed-phase HPLC.
Reaction SMILES: [C:1]([CH2:3][O:4]C(CCNC1C=CC=C(C)C=1)=O)#[N:2].CO.S(=O)(=O)(O)N.[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[N:34][C:35]2[CH:51]=[CH:50][C:38]([N:39]([CH2:48][CH3:49])[CH2:40][CH2:41][C:42](OCC#N)=[O:43])=[CH:37][C:36]=2[CH3:52])=[CH:29][CH:28]=1)([O-:26])=[O:25]>CC(C)=O.O>[N+:24]([C:27]1[CH:28]=[CH:29][C:30]([N:33]=[N:34][C:35]2[CH:51]=[CH:50][C:38]([N:39]([CH2:48][CH3:49])[CH2:40][C:41](=[C:42]=[O:43])[O:4][CH2:3][C:1]#[N:2])=[CH:37][C:36]=2[CH3:52])=[CH:31][CH:32]=1)([O-:26])=[O:25]
Reactant: CCN(CCC(=O)OCC#N)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)c(C)c1
Reactant: Cc1cccc(NCCC(=O)OCC#N)c1
Agent: NS(=O)(=O)O
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: CCN(CC(=C=O)OCC#N)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)c(C)c1

Procedure:
The diazo solution obtained was added gradually to a stirred coupling mixture of N-ethyl, N-(2-cyanomethoxycarbonylethyl)-m-toluidine (7.3 parts), methanol (50 parts), water (200 parts) and sulphamic acid (1 part). After two hours the product was isolated by filtration, washed with cold water and dried to yield, 4-(4-nitrophenylazo)-3-methyl-N-ethyl-N-(2-cyanomethoxycarbonylethyl)aniline (6.5 parts) λmax=486 nm (acetone).