Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.OC1C2N=NNC=2C=CC=1.[C:12]1([C:18]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[S:21](=[O:27])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:34][N:35]([CH3:50])[CH2:36][CH:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][C:47](O)=[O:48])[CH3:38].CN(C)CCCN=C=NCC>ClCCl>[CH3:50][N:35]([CH3:34])[CH2:36][CH:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][C:47]([N:24]1[CH2:25][C@H:26]2[C:18]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:19][CH2:20][S@@:21](=[O:27])[C@H:22]2[CH2:23]1)=[O:48])[CH3:38]
Reactant: O=S1CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Reactant: CC(CN(C)C)Oc1ccccc1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Product: CC(CN(C)C)Oc1ccccc1CC(=O)N1C[C@@H]2[C@H](C1)[S@](=O)CCC2(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
0.03 g of hydroxybenzotriazole hydrate is added to a solution, cooled to 0° C., of 1.06 g of (1R*, 4aR*, 7aR*) -(-) -4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide and 0.81 g of 2-[(3-dimethylamino-2-propoxy)phenyl]acetic acid in 60 cm3 of dry dichloromethane, followed by 0.77 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. After stirring for 2 hours at 0° C. and 20 hours at 20° C., the reaction mixture is washed with 20 cm3 of water and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2.4 cm, height 35 cm), eluting under a nitrogen pressure of 0.6 bar with an ethyl acetate, acetic acid and water mixture (60/10/10 by volume) and collecting fractions of 50 cm3. Fractions 8 to 19 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 60 cm3 of dichloromethane, the solution is washed with 20 cm3 of a 1N aqueous solution of sodium hydroxide, dried over magnesium sulphate and then concentrated to dryness. The solid obtained is recrystallized from an ethyl acetate and ethyl ether mixture, the crystals are washed with diisopropyl oxide, drained and dried. 0.99 g of (1R*,4aR*,7aR*)-(-)-6-{2-[(3-dimethylamino2-propoxy)phenyl]acetyl}-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide is obtained in the form of a white solid; melting point 120° C. [α]D20 =-323° ; (c=0.5; acetic acid).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C@@H:13]([C:15]1[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[O:17][N:16]=1)[CH3:14])=[O:11].[OH-].[Li+].Cl>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C@@H:13]([C:15]1[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[O:17][N:16]=1)[CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc([C@@H](C)NC(=O)c2cc3ccccc3o2)no1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](NC(=O)c1cc2ccccc2o1)c1cc(C(=O)O)on1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the crude (R)-ethyl 3-(1-(benzofuran-2-carboxamido)ethyl)isoxazole-5-carboxylate was added lithium hydroxide (0.572 mL, 1.0 M in water), and MeOH (1.0 mL). The mixture was shaken at rt for 16 h, then hydrochloric acid (0.214 mL, 4.0 M in 1,4-dioxane) was added to acidify the reaction. Most of the solvent was evaporated. To the residue was added water (1.0 mL) and DCE (3 mL). After separation, the aqueous layer was extracted with DCE (3 mL). The combined organic phases were concentrated to give crude (R)-3-(1-(benzofuran-2-carboxamido)ethyl)isoxazole-5-carboxylic acid.
Reaction SMILES: [CH2:1]([C:3]1([OH:11])[CH2:8][CH2:7][C:6]([F:10])([F:9])[CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>CN(C)C1C=CN=CC=1.CC(C)=O>[C:19]([O:11][C:3]1([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]([F:10])([F:9])[CH2:7][CH2:8]1)(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: CCC1(O)CCC(F)(F)CC1
Reactant: C=C(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1(CC)CCC(F)(F)CC1
Yield: 79.9 %

Procedure:
A four-necked flask equipped with a stirrer, a thermometer, and a dropping funnel was charged with 6.6 g (0.04 mol) of 1-ethyl-4,4-difluorocyclohexanol, 0.2 g of 4-dimethylaminopyridine, 4.9 g of triethylamine, and 20 g of acetone. The mixture was stirred to obtain a solution. A solution prepared by dissolving 4.6 g (0.044 mol) of methacrylic acid chloride in 5 g of acetone was added to the solution at 4° C. over 30 minutes. The mixture was stirred at 4° C. for 3 hours to obtain a reaction mixture. The reaction mixture was washed with water to obtain 7.42 g of 1-ethyl-4,4-difluorocyclohexyl methacrylate (hereinafter may be referred to as “compound (M-8)” ((M-8) in Table 1)). The yield of 1-ethyl-4,4-difluorocyclohexyl methacrylate with respect to 1-ethyl-4,4-difluorocyclohexanol was 78%.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][N:5]([C:8]2[N:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1)=[O:2].[BH4-].[Na+]>C(O)C>[OH:2][CH2:1][C:3]1[CH:7]=[CH:6][N:5]([C:8]2[N:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1
Reactant: CCOC(=O)c1cccnc1-n1ccc(C=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cccnc1-n1ccc(CO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 297.4 %

Procedure:
To ethyl 2-(3-formyl-1H-pyrazol-1-yl)nicotinate (6 g, 9.79 mmol) in ethanol (100 mL) at 10° C. NaBH4 (0.741 g, 19.57 mmol) was added and stirred at 25° C. for 1 hr. For work up the mixture was poured into 200 mL of ice water, extracted twice with ethyl acetate, the combined organic layers subsequently washed with water and brine, dried (MgSO4), filtered and concentrated to give 7.2 g of a yellow oil. Purification by chromatography over silica gel (eluent CH2Cl2+0-10% methanol) gave 2.36 g of the corresponding title compound as clear oil; ESI-MS [M+H]+: 248.1.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=2)[CH:6]=1
Reactant: Cc1cc(C)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.7 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(3,5-dimethylphenylamino)pyridazin-3-ylamino)cyclohexylcarbamate (30 mg, 66.0 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (151 mg, 102 μL, 1.32 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated in vacuo then diluted with dichloromethane and drops of 25% NH4OH added until the pH was measured to be ˜8. The weakly basic solution was washed with water, then the organic phase was concentrated in vacuo and purified by chromatography (silica, 30 to 100% of a 10:89.5:0.5 MeOH:dichloromethane:NH4OH solution in dichloromethane) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(3,5-dimethylphenylamino)pyridazine-3-carboxamide (17 mg, 48.0 mmol, 73%) as a light brown solid. 1H NMR (400 MHz, METHANOL-d6) δ0 ppm 6.90 (s, 2H), 6.88 (s, 1H), 6.50 (s, 1H), 4.32 (s, 1H), 1.63-1.84 (m, 6H), 1.51 (m, 2H); MS (EI/CI) m/z: 355.1 [M+H].
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:38]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:38])=[O:26])=[C:21]([O:28][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@H](C)c1ccccc1F
Reactant: N
Solvent: CO
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1F

Procedure:
In a similar manner as described for example A5, 2.50 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[(1R)-1-(2-fluorophenyl)ethoxy]thiophene-2-carboxylate and 92 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [Li]CCCC.C(S)C1C=CC=CC=1.C([C@@H]1COC(=O)N1[C:27]([C@@H:29]1[CH2:34][CH2:33][C:32]([F:36])([F:35])[CH2:31][C@H:30]1[CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:28])C1C=CC=CC=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:39]([O:38][CH2:37][C@@H:30]1[CH2:31][C:32]([F:36])([F:35])[CH2:33][CH2:34][C@H:29]1[CH2:27][OH:28])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@@H]1CCC(F)(F)C[C@H]1COCc1ccccc1
Agent: SCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OC[C@@H]1CCC(F)(F)C[C@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of n-BuLi (2.5M in hexanes, 10 mL) was added slowly to a solution of benzyl mercaptan (3.6 mL, 40 mmol) in THF (40 mL) at 0° C. The resulting pale-yellow solution was stirred at 0° C. for 10 min prior to the introduction of (4R)-4-benzyl-3-({(1R,2R)-2-[(benzyloxy)methyl]-4,4-difluorocyclohexyl}carbonyl)-1,3-oxazolidin-2-one (8.52 g, 19.2 mmol) as a solution in THF (30 mL). After 10 min, a solution of LiAlH4 (1.0 M in THF, 22 mL) was slowly added to the reaction mixture with continued stirring at 0° C. for 45 min. Ice water was then slowly added to destroy excess hydride followed by 6M HCl (20 mL) to pH 1. The mixture was extracted with two portions of ethyl acetate and the combined organics were washed with saturated aqueous NaCl and dried over Na2SO4. Concentration in vacuo and flash chromatography of the residue on silica gel eluting with 45/55 ethyl acetate/hexanes afforded {(1R,2R)-2-[(benzyloxy)methyl]-4,4-difluorocyclohexyl}methanol as a thick, colorless syrup. 1H NMR (500 MHz, d6-acetone) δ 7.36 (4H, m), 7.34-7.28 (1H, m), 4.56-4.49 (2H, m), 3.67-3.53 (5H, m), 2.20-2.12 (1H, m), 2.09-2.02 (1H, m), 1.91-1.71 (4H, m), 1.58-1.50 (2H, m).
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.C(=O)(O)[O-].[K+].[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[O:2]=[C:3]1[CH2:7][N:6]([C:25]([O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])[C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H]1CC(=O)CN1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-Methyl 4-oxopyrrolidine-2-carboxylate HCl salt (9.4 g, 52.6 mmol) was dissolved in 1,4-dioxane (210 mL) and a solution of potassiumbicarbonate (13.2 g, 131.5 mmol) in DI-water (70 mL) was added at 0° C., followed by slow addition of benzylchloroformate (15 mL, 105.2 mmol). The mixture was then let warm up to room temperature and it was stirred overnight. The resulting crude mixture was concentrated down as much as possible on the rotovap and it was diluted with EtOAc and washed twice with saturated NaHCO3 and 10% citric acid and once with saturated NaHCO3 again and then with brine. The organic layer was dried over Na2SO4 and after filtration it was concentrated down on rotovap. The crude product was then purified on normal phase column chromatography (15% EtOAc/Hexanes). (14.6 g, 100%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12]([N:15]=[C:16]=[O:17])([CH3:14])[CH3:13]>C(OCC)(=O)C>[CH:12]([NH:15][C:16]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2)=[O:17])([CH3:14])[CH3:13]
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: CC(C)N=C=O
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
To 5-aminoindolin-2-one (50 mg, 0.34 mmol) in ethyl acetate (1 mL) was added isopropylisocyanate (0.04 mL, 0.4 mmol). The solution was stirred at rt for 16 h and the product was precipitated with ether, filtered and dried to give 46 mg, 58% of a yellow solid. 1H NMR (400 MHz, CD3OD) δ 7.31 (s, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.80 (d, J=8.3 Hz, 1H), 3.90-3.83 (m, 1H), 3.51 (s, 2H), 1.77 (d, J=7.3 Hz, 6H).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[C:22]([F:25])([F:24])[F:23])=[O:5].[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Mg]Br>C1COCC1>[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[C:22]([F:25])([F:23])[F:24])=[O:5]
Reactant: Cc1ccccc1[Mg]Br
Reactant: CON(C)C(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methoxy-N-methyl-4-phenyl-8-(trifluoromethyl)quinoline-3-carboxamide (0.100 g, 0.278 mmol) was taken into THF (3 mL) and cooled to 0° C. where 2-methylphenylmagnesium bromide was added. The reaction was then allowed to stir at room temperature overnight. The reaction was quenched with MeOH and 2 M HCl and stirred for 5 minutes. The organics were removed and the resulting aqueous layer was extracted with methylene chloride, dried and concentrated. Column chromatography using 10% ethyl acetate in hexane afforded 0.057 g of the desired product as a white solid. MS (ESI) m/z 392 ([M+H]+); Anal. Calcd. for C24H16F3NO: C, 73.65; H, 4.12; N, 3.58. Found: C, 73.88; H, 3.87; N, 3.29.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH:34]([CH3:36])[CH3:35])[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:38].[Na]>O1CCOCC1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH:34]([CH3:36])[CH3:35])[C:27]([O-:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:38]
Reactant: CCOC(=O)C(=NOC(C)C)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)ON=C(C(=O)[O-])c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
A mixture of 27.7 g of the product of Step D, 150 ml of dioxane and 65 ml of 2N sodium hydroxide was refluxed for 2 hours and the mixture was cooled for crystallization of a sodium salt. The mixture was vacuum filtered and the recovered product was rinsed with a 1-1 ether-dioxane mixture and dried to obtain 16.85 g of raw sodium 2-(2-tritylamino-4-thiazolyl)-2-(1-methylethoxyimino)-acetate.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([CH2:10][C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:16][N:17]3[CH2:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:23][C:22]=3[O:34][CH3:35])=[CH:13][CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>O1CCOCC1.O>[CH:1]1([CH2:6][NH:7][C:8]([CH2:10][C:11]2[CH:19]=[C:18]3[C:14]([C:15]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:16][N:17]3[CH2:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=3[O:34][CH3:35])=[CH:13][CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCc1cn(Cc2ccc(C(=O)OC(C)(C)C)cc2OC)c2cc(CC(=O)NCC3CCCC3)ccc12
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cn(Cc2ccc(C(=O)O)cc2OC)c2cc(CC(=O)NCC3CCCC3)ccc12
Yield: 98.7 %

Procedure:
A solution of t-butyl 4-[6-(cyclopentylmethylcarbamoyl)methyl-3-(2-methoxycarbonylethyl)indol-1-ylmethyl]-3-methoxybenzoate (0.45 g) in dioxane (3 ml) was treated with triethylamine (0.27 ml) and trimethylsilyl trifluoromethanesulfonate (0.33 ml). The solution was heated at reflux for 30 min and then diluted with water to form a precipitate which was collected by filtration to give 4-[6-(cyclopentylmethycarbamoyl)methyl-3-(2-methoxycarbonylethyl)indol-1-ylmethyl]-3-methoxybenzoic acid (0.40 g, 99%) as a tan powder; partial NMR (80 MHz, CDCl3): 3.66(s, 3H, CO2CH3), 3.70(s, 2H, COCH2Ar) 3.96(s, 3H, OCH3), 5.29(s, 2H, NCH2Ar). (It will be recognized that this compound is also an example of the invention.)
Reaction SMILES: N[N:2]1[C:7](=[O:8])[C:6]2[S:9][CH:10]=[CH:11][C:5]=2[NH:4][C:3]1=[O:12].N([O-])=O.[Na+]>C(O)(=O)C.O>[NH:4]1[C:5]2[CH:11]=[CH:10][S:9][C:6]=2[C:7](=[O:8])[NH:2][C:3]1=[O:12]
Reactant: Nn1c(=O)[nH]c2ccsc2c1=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2sccc2[nH]1
Temperature: 60 °C
Yield: 49.2 %

Procedure:
To a solution of 3-amino-1H-thieno[3,2-d]pyrimidine-2,4-dione (1.70 g, 9.3 mmol) in a 1:1 mixture of acetic acid/H2O (155 mL) was added sodium nitrite (1.92 g, 27.8 mmol) portion-wise. The reaction mixture was heated to 60° C. until the evolution of brown gas ceased (2 h). Acetic acid was removed under reduced pressure and the solution was cooled to 0° C. The resulting white solid was collected by filtration to afford 0.77 g of the desired product. MS: 167.3. 1H NMR (400 MHz, d6-N,N-dimethylsulfoxide (d6-DMSO)) δ ppm 11.40 (br s, 1H), 8.04 (d, J=5.2 Hz, 1H), 6.91 (d, J=5.3 Hz, 1H), 3.34 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][NH:22][N:21]=1)=[CH:16][CH:15]=3.[F:30][C:31]([F:37])([F:36])[CH2:32][C:33](Cl)=[O:34]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([C:33](=[O:34])[CH2:32][C:31]([F:37])([F:36])[F:30])[N:21]=1)=[CH:16][CH:15]=3
Reactant: O=C(Cl)CC(F)(F)F
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4cc[nH]n4)ccc3n(C)c21
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn(C(=O)CC(F)(F)F)n4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 70 above, with the compound from Example 39 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(1H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one and 3,3,3-trifluoropropionyl chloride.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21]([OH:23])=O)[NH:3]1.[C:24]1([C@@H:30]([NH2:39])[CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([C@@H:30]([NH:39][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)=[O:23])[CH2:31][C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: Cc1ccc(C[C@H](N)c2ccccc2)cc1
Product: Cc1ccc(C[C@H](NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5NC(=O)CC[C@]5(C)[C@H]4CC[C@]23C)c2ccccc2)cc1
Yield: 81 %

Procedure:
The title compound was prepared in a yield of 81% in a similar manner to that described in Example 1 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and (S)-1-phenyl-2-(4-methylphenyl)ethylamine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=2)[CH3:9])[CH:2]=1.C(N(CC)CC)C.[NH2:26][CH2:27][C:28]1[C:29]([OH:36])=[N:30][C:31]([CH3:35])=[CH:32][C:33]=1[CH3:34]>ClCCl>[OH:36][C:29]1[C:28]([CH2:27][NH:26][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][C:10]([CH:8]([O:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH3:9])=[N:11][CH:12]=2)=[C:33]([CH3:34])[CH:32]=[C:31]([CH3:35])[N:30]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1cccnc1)c1ccc(C(=O)O)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3cccnc3)nc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.7 %

Procedure:
To a solution of 6-(1-(Pridin-3-yloxy)ethyl)nicotinic acid (150 mg, 0.61 mol) was dissolved in dichloromethane (20 mL), H-benzo[d][1,2,3]triazol-1-ol (124 mg, 0.92 mmol), 1-(3-dmethylaminopropyl)-3-ethylcarbodiimide hydrochloride (176 mg, 0.92 mmol) and triethylamine (3 mL, 1.84 mmol) were added. After stirring at room temperature for 10 minutes, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (93 mg, 0.61 mmol) was added. The mixture was stirred at room temperature for 18 hours. Once the start material was consumed, water (30 mL) was added. The mixture was extracted with dichloromethane (40 mL). The organic layer was separated and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=15/1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-(1-(pyridin-3-yloxy)ethyl)nicotinamide (50 mg, 21.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]#[N:11]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH2:11]
Reactant: N#CCc1c(F)cccc1F
Solvent: C1CCOC1
Product: NCCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 23 h
Yield: 67.4 %

Procedure:
2,6-Difluorophenylacetonitrile (15.8 g, 100 mmol) was dissolved in tetrahydrofuran (75 mL) at room temperature. The solution was cooled in an ice bath and borane THF complex (100mL, 100 mmol) was added dropwise over 15 minutes under nitrogen atmosphere. The ice bath was removed after borane addition was complete and the mixture was stirred at room temperature for 23 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride solution (20 mL) was added dropwise with stirring over 30 minutes. The reaction mixture was filtered through diatomaceous earth, concentrated to an oil, redissolved in ethyl acetate/water, and adjusted to pH 1.0 with concentrated hydrochloric acid. The mixture was filtered through diatomaceous earch and the ethyl acetate layer extracted with 1N hydrochloric acid (4×10 mL). The combined acidic aqueous extracts were washed with ethyl acetate (2×50 ml). Solid sodium chloride was added to the acidic aqueous extracts, adjusted to pH 9.0 with solid sodium bicarbonate and 5N sodium hydroxide solution, and the mixture extracted with methylene chloride (7×50 mL). The combined methylene chloride extracts were washed with brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 10.6 g (68%) of the titled product as a nearly colorless oil:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][CH2:16][O:17][C:10]=3[CH:9]=2)=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:3]=1.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[OH:34]>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[O:34][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][CH2:16][O:17][C:10]=3[CH:9]=2)=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:3]=1
Reactant: Oc1ccc(F)cc1F
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc3c(c2)OCCO3)cc1
Product: COc1ccc(-c2cc(Oc3ccc(F)cc3F)nnc2-c2ccc3c(c2)OCCO3)cc1

Procedure:
In a similar manner as in Example 2, 6-chloro-3-(3,4-ethylenedioxyphenyl)-4-(4-methoxyphenyl)pyridazine (136 mg, 0.383 mmol) and 2,4-difluorophenol were reacted as starting materials at 120° C. for 8 hours and post-treatment was then conducted, whereby the title compound was obtained as colorless prisms (113 mg, 65.7%). Melting point: 158.0-159.5° C. (ethyl acetate-hexane).