Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:8]([O-])=O.[Na+].[Cl:12][C:13]1[S:14][C:15]([CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[CH:16][C:17]=1[C:18](=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21]>Cl.O.N1C=CC=CC=1>[Cl:12][C:13]1[S:14][C:15]([CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[CH:16][C:17]=1[C:18](=[O:24])/[C:19](=[N:8]/[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)/[C:20]([O:22][CH3:23])=[O:21]
Reactant: Nc1ccccc1
Reactant: COC(=O)CC(=O)c1cc(CN2CCOCC2)sc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)/C(=N\Nc1ccccc1)C(=O)c1cc(CN2CCOCC2)sc1Cl
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of aniline (2.52 mL) in 6M HCl (15 mL) is added dropwise a solution of NaNO2 (2.44 g) in water (8 mL) at −10° C. The solution stirs at 0° C. for 1 h and is poured into a solution of methyl 3-(2-chloro-5-(4-morpholinylmethyl)-3-thienyl)-3-oxopropanoate (Preparation 64, 3.50 g) in pyridine (15 mL) and water (8 mL) with vigorous stirring at −10° C. The solution stirs at 0° C. for 60 min and is diluted with cold water (150 mL). The aqueous layer is extracted with EtOAc (3×150 mL). The organic layers are combined, dried over MgSO4, filtered, and concentrated in vacuo. The crude red liquid (2.93 g) is utilized without any further purification. Physical characteristics: IR (liq.) 1737, 1675, 1529, 1455, 1437, 1330, 1306, 1263, 1239, 1218, 1201, 1168, 1144, 1117, 755 cm−1; MS (FAB) m/z 422 (MH+); HRMS (FAB) m/z 422.0935 (C19H20ClN3O4S+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[C:31]1[C:35]([C:36](Cl)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[C:31]1[C:35]([C:36]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCO)CC2)c1
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)OCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(3-hydroxypropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 558.2 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.O>C(OCC)(=O)C>[F:17][C:18]([F:29])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[CH:11]3)=[CH:22][CH:21]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2ccc3[nH]ccc3c2)cc1
Yield: 57.9 %

Procedure:
A stirred slurry of 6.56 g (62 mmol) Na2CO3, 3.03 g (15.5 mmol) 5-bromoindole, 3.415 g (16.5 mmol) 4-(trifluoromethoxy)phenylboronic acid, and 0.50 g (0.43 mmol) tetrakistriphenylphosphine palladium was heated to reflux for 3 hr. The reaction mixture was allowed to cool and was then poured into 300 mL water and shaken with ethyl acetate. The combined aqueous and organic phases were filtered and the organic layer was separated, dried over MgSO4, and concentrated. The residue was chromatographed on silica (eluting with 20–33% EtOAc-hexane) to afford 2.49 g (58%) 5-[4-(trifluoromethoxy)phenyl]indole as a solid.
Reaction SMILES: S([O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([O:15][CH3:16])=[CH:8][C:7]=1[CH3:17])(=O)(=O)C.[OH-].[Na+].Cl>CO.O>[CH3:17][C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=1[OH:5]
Reactant: COc1cc(C)c(OS(C)(=O)=O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C)c(O)cc1[N+](=O)[O-]
Yield: 100 %

Procedure:
In 110 ml of methanol was dissolved 15.5 g (59.4 mmol) of 2-methyl-4-methoxy-5-nitrophenyl mesylate. Then 6.5 g of sodium hydroxide dissolved in 20 ml of water was added thereto. The obtained mixture was heated under reflux for 1 hour. After cooling, concentrated hydrochloric acid was added to thereby acidify the mixture. Then 400 ml of water was added and crystals were precipitated. The crystals were collected by filtration and washed with water. Thus 10.9 g (59.4 mmol) of 2-methyl-4-methoxy-5-nitrophenol was obtained. The yield was 100%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:25]1([S:28]([NH2:31])(=[O:30])=[O:29])[CH2:27][CH2:26]1>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:31][S:28]([CH:25]1[CH2:27][CH2:26]1)(=[O:30])=[O:29])=[O:9]
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: O=C(NS(=O)(=O)C1CC1)c1cc(Cl)c(F)cc1F
Temperature: 25 °C
Yield: 50.1 %

Procedure:
A mixture of 5-chloro-2,4-difluorobenzoic acid (10.0 g, 51.93 mmol) and 1,1′-carbonyldiimidazole (10.11 g, 62.32 mmol) was stirred at reflux for 2 hours, cooled to ambient temperature, and cyclopropanesulfonamide (7.55 g, 62.32 mmol) was added. The reaction mixture was stirred at ambient temperature for 16 hours, diluted with ethyl acetate (300 mL), washed with 1M aqueous hydrochloric acid, brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was re-crystallized from ethyl acetate/hexanes mixture (1:2) to afford the title compound as a colorless solid (7.7 g, 56%): MS (ES−) m/z 294.1 (M−1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:27][N:28]([CH3:50])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:49])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([C:33](=[O:49])[NH:32][CH2:31][CH2:30][CH2:29][N:28]([CH3:50])[CH3:27])[CH:35]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CN(C)CCCNC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(C(=O)NCCCN(C)C)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv), N-(3-(dimethylamino)propyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) in water was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the desired compound (9% yield). LCMS: 544.20 (M+1)+; HPLC: 98.83% (@ 254 nm), (Rt; 5.258); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 9.00 (t, 1H), 8.70 (t, 1H), 8.64 (s, 1H), 8.39 (s, 1H), 8.38 (s, 1H), 8.19 (s, 1H), 7.92 (d, 1H, J=8 Hz), 7.64 (t, 1H, J=7.6 Hz), 5.90 (s, 1H), 5.37-5.34 (m, 1H), 4.41 (d, 2H, J=4.4 Hz), 2.28 (t, 2H, J=6.8 Hz), 2.23 (s, 3H), 2.14 (s, 6H), 2.12 (s, 3H), 1.69 (t, 2H, J=6.8 Hz), 1.55 (d, 6H, J=6.4 Hz).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CO.CCOC(C)=O>[OH2:4].[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:3][O:4][C:5]=2[CH:10]=1.[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:3][O:4][C:5]=2[CH:10]=1
Reactant: C1CNCCN1
Reactant: COc1ccc2c(Cl)noc2c1
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2c(N3CCNCC3)noc2c1
Product: O
Temperature: 140 °C

Procedure:
To a sealed tube was added 3-chloro-6-methoxy-1,2-benzisoxazole (3.0 g) and piperazine (6.0 g). The reaction was heated to 140° C. over 4 hours and then cooled to room temperature. The residue was dissolved in MeOH and further diluted with EtOAc (1 l). The precipatate was filtered and the filtrate dried over MgSO4 and concentrated in vacuo. Flash chromatography (silica gel) eluting with 30% MeOH/EtOAc provided a residue upon evaporation (3.6 g), m.p. 79-80° C.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[S:3]([C:6]1[CH:7]=[N:8][CH:9]=[C:10]([Br:12])[CH:11]=1)(=[O:5])=[O:4].[CH:14]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[CH3:1][N:2]([CH3:13])[S:3]([C:6]1[CH:7]=[N:8][CH:9]=[C:10]([Br:12])[C:11]=1[CH3:14])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1cncc(Br)c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(Br)cncc1S(=O)(=O)N(C)C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-pyridine-3-sulfonic acid dimethylamide (CAS #896160-99-9, 100 mg, 0.377 mmol) in THF (3.8 mL) at −78° C. was added lithium diisopropylamide (0.5 M solution in THF, 0.85 mL, 0.42 mmol). The reaction was stirred for 15 minutes, at which time iodomethane (0.030 mL, 0.48 mmol) was added. The reaction was stirred for an additional 15 minutes and was then quenched with saturated aqueous ammonium chloride. Next, the reaction was diluted with water, dichloromethane, and saturated aqueous sodium bicarbonate. The layers were separated and aqueous layer was extracted two additional times with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by semi-preparative reverse phase HPLC (20 to 90% acetonitrile/water w/0.1% NH4OH) to furnish 5-bromo-4-methyl-pyridine-3-sulfonic acid dimethylamide; MS: (ES+) m/z 279.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(C)(C)C.[C:20]1([CH:26]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH2:29][CH2:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(N(CC)CC)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][N:30]2[CH2:31][CH2:32][N:27]([CH:26]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:28][CH2:29]2)=[O:12])=[CH:4][CH:3]=1
Reactant: NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: Cc1ccc(C=CC(=O)O)cn1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C=CC(=O)NCCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)cn1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
To a suspension of 2.71 g of 3-(6-methyl-3-pyridyl)acrylic acid in 70 ml of dry tetrahydrofuran, a solution of 1.68 g of triethylamine in 5 ml of dry tetrahydrofuran is added at room temperature. The resulting solution is cooled to -5° C., and a solution of 2.0 g of pivaloyl chloride in 5 ml of dry tetrahydrofuran is added slowly. The mixture is stirred at the same temperature for 0.5 hour and cooled to -10° C., and a solution of 6.43 g of 4-(4-diphenylmethyl-1-piperazinyl)butylamine in 5 ml of dry tetrahydrofuran is added slowly. The mixture is stirred for 0.5 hour at between -10° C. and -5° C. and then at room temperature overnight. To the reaction mixture is added 50 ml of 10% aqueous potassium carbonate, and the resulting mixture is extracted with three 100-ml portions of ethyl acetate. The combined extracts are washed with water and dried over magnesium sulfate, and the solvent is distilled off. The residue is recrystallized from acetonitrile to give 5.63 g of the title compound, m.p. 129°-131° C.
Reaction SMILES: C1(C)C=CC=CC=1.C(N)(C)(C)C.[Br:13]Br.[CH3:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[C:19]([OH:26])[CH:20]=[CH:21][CH:22]=2)[N:17]=1>C(Cl)Cl>[Br:13][C:20]1[C:19]([OH:26])=[C:18]2[C:23]([CH:24]=[CH:25][C:16]([CH3:15])=[N:17]2)=[CH:22][CH:21]=1
Reactant: BrBr
Reactant: Cc1ccc2cccc(O)c2n1
Solvent: CC(C)(C)N
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc2ccc(Br)c(O)c2n1
Temperature: -25 °C
Yield: 60.8 %

Procedure:
To a 250 mL flask was added toluene (150 mL) and t-BuNH2 (7.26 mL, 69.1 mmol). The solution was cooled to −25° C. and bromine (1.95 mL, 38.0 mmol) was added. The solution was cooled to −78° C. and 2-methylquinolin-8-ol (5.5 g, 34.6 mmol) was added as a CH2Cl2 solution (15 mL). The reaction mixture was gradually warmed to ambient temperature over 6 hours. The mixture was washed with water (50 mL) and treated with 3.0 M aqueous NaOH (250 mL). This provided copious amounts of precipitate, which went into solution after about 600 mL water were added. The layers were mixed and separated. The alkaline extract was carefully acidified with concentrated HCl (=50 mL). The solution was extracted with CH2Cl2 (4×200 mL), the combined extracts were washed with brine and dried over Na2SO4, filtered and concentrated. The original water wash was found to contain a significant amount of product, so 10 mL 1M HCl were added and the acidic solution was extracted with CH2Cl2 (2×75 mL) and these layers were also washed with brine, dried over Na2SO4, filtered and concentrated. The organic phases were combined to provide 5.01 g (60%) of the desired product as a red/brown solid.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[O:16][C:15]([C:17](=[NH:21])OCC)=[CH:14][CH:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH2:22](N)[CH2:23][NH2:24]>C(O)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[O:16][C:15]([C:17]3[NH:21][CH2:22][CH2:23][N:24]=3)=[CH:14][CH:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCOC(=N)c1ccc(-c2ccc(OC)c(OC)c2)o1
Reactant: NCCN
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2ccc(C3=NCCN3)o2)cc1OC
Reaction time: 8 h
Yield: 66.8 %

Procedure:
A mixture of 51 g (0.16 mole) of ethyl 5-(3,4-dimethoxyphenyl)-2-furimidate hydrochloride, 11 g (0.18 mole) of ethylenediamine, and 850 ml of absolute ethanol was refluxed for 5 hrs and then kept overnight at room temperature. The solid was recrystallized from acetic acid, washed with ether, and air dried to yield 33 g (65%) of 2-[5-(3,4-dimethoxyphenyl)-2-furyl]imidazoline hydrochloride. An analytical sample was prepared by recrystallizing a sample from methanol and drying in the vacuum pistol at the temperature of refluxing CHCl3, m.p. 291°-293°.
Reaction SMILES: [ClH:1].[C:2](=[NH:12])(OCC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:13]([NH2:16])[CH:14]=[CH2:15]>CO>[ClH:1].[CH2:13]([NH:16][C:2](=[NH:12])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH:14]=[CH2:15]
Reactant: CCOC(=N)c1ccccc1
Reactant: C=CCN
Agent: Cl
Solvent: CO
Product: C=CCNC(=N)c1ccccc1
Reaction time: 48 h

Procedure:
To a solution of ethyl benzimidate hydrochloride (20 g) in methanol at 0° C. was added allyl amine. The resulting solution was allowed to stand for 2 days at 5° C. before it was evaporated to yield a solid which was collected and washed with ether to give N-allyl benzamidine hydrochloride (21.5 g) as a white solid; 300 MHz NMR: 10.1 (s,1), 9.68 (s,1), 9.29 (s,1), 7.72 (s,5), 5.92 (m,1), 5.35 (d,2), 5.26 (d,2), 4.14 (s,2).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:18]1[C@H:20]2[C:21](=[O:42])[CH:22]=[C:23]3[C@:39]([CH3:40])([C@@H:19]12)[C@@H:38]1[C@H:26]([C@H:27]2[C@:35]([CH3:41])([CH2:36][CH2:37]1)[C@@H:30]([C@H:31]([CH3:34])[CH2:32][OH:33])[CH2:29][CH2:28]2)[CH:25]=[CH:24]3.C1C=CC=CC=1>CCOCC>[O:18]1[C@H:20]2[C:21](=[O:42])[CH:22]=[C:23]3[C@:39]([CH3:40])([C@@H:19]12)[C@@H:38]1[C@H:26]([C@H:27]2[C@:35]([CH3:41])([CH2:36][CH2:37]1)[C@@H:30]([C@H:31]([CH3:34])[CH2:32][O:33][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)[CH2:29][CH2:28]2)[CH:25]=[CH:24]3
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: C[C@H](COC1CCCCO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 65 %

Procedure:
1.8 ml. of 3,4-dihydro-2H-pyran and 20 mg of anhydrous p-toluenesulphonic acid were added to a solution of 2.45 g of (20S)-1α,2α-epoxy-21-hydroxy-20-methyl-pregna-4,6-dien-3-one in 125 ml. of absolute benzene. After standing at room temperature for 1 hour, the solution was diluted with ether, washed with saturated sodium bicarbonate solution and water, dried over sodium sulphate and concentrated in a water-jet vacuum. The residue was chromatographed on 30 g of silica gel using hexane/ether (4:1) for the elution, there being obtained 2.0 g (65%) of (20S)-1α,2α-epoxy-20-methyl-21-tetrahydropyranyloxy-pregna-4,6-dien-3-one. After recrystallisation from hexane, the product melted at 101°-102° C. and was shown by thin-layer chromatography, mixed melting point and IR spectrum to be identical with the compound prepared as described in Example 7.
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14]([C:16]([C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19]2)=[O:17])[C@@H:13]([CH2:28][O:29][C:30]2[C:31]([C:36]([OH:38])=O)=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH2:45].Cl.Cl.N1CCC[C@@H]1COC1C(C(N)=O)=NC=CC=1>>[CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14]([C:16]([C@H:18]2[CH2:19][CH2:20][C@H:21]([C:24]([F:25])([F:26])[F:27])[CH2:22][CH2:23]2)=[O:17])[C@@H:13]([CH2:28][O:29][C:30]2[C:31]([C:36]([NH:45][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=3)=[O:38])=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1OC[C@H]1C[C@@H](OCOCc2ccccc2)CN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: Nc1ccccn1
Agent: Cl
Agent: NC(=O)c1ncccc1OC[C@H]1CCCN1
Product: O=C(Nc1ccccn1)c1ncccc1OC[C@H]1C[C@@H](OCOCc2ccccc2)CN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 4 of EXAMPLE 1 using 3-(((2R,4R)-4-(benzyloxymethoxy)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid (EXAMPLE 79 Step 6) and pyridin-2-amine instead of cis-4-(trifluoromethyl)cyclohexanecarboxylic acid and (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[CH:4]=[CH:3]1.[CH2:14](O)[CH3:15]>>[CH2:14]([O:12][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[S:2][CH:3]=[CH:4][C:5]=2[CH:10]=1)=[O:13])[CH3:15]
Reactant: O=C(O)c1ccc2sccc2c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc2sccc2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A saturated solution of HCl in ethanol (15 mL) is added to benzothiophene-5-carboxylic acid (1 g, 5.44 mmol) and the reaction mixture is stirred at 80° C. overnight. The solvent is removed under reduced pressure and diethyl ether and saturated sodium bicarbonate are added to the residue. The layers are separated. The organic layer is washed with saturated sodium bicarbonate and water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the title compound (1.0 g, 89%) as a pale brown oil. 1H NMR (CDCl3): δ 8.54 (s, 1H), 8.01 (d, 1H, J=8.1 Hz), 7.92 (d, 1H, J=8.1 Hz), 7.51 (d, 1H, J=5.4 Hz), 7.42 (d, 1H, J=5.4 Hz), 4.42 (c, 2H, J=6.8 Hz), 1.43 (t, 3H, J=6.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH:23][CH2:24][CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][C:28]=1[O:36][CH3:37]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([O:26][CH2:25][CH2:24][OH:23])=[C:28]([O:36][CH3:37])[CH:29]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COc1cc(C(=O)O)ccc1OCCO
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)c3ccc(OCCO)c(OC)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methyl-quinoline-3-carboxylate (Example 26b) and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (Uto, Y. et al. Bioorg. Med. Chem. Lett. 2009, 19, 4151.) as a brown solid. MS 498 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([OH:24])=[CH:11][CH:10]=3)[CH3:2].[OH-].[K+].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([O:24][CH2:27][CH:29]1[O:31][CH2:30]1)=[CH:11][CH:10]=3)[CH3:2]
Reactant: ClCC1CO1
Reactant: CCn1ncc2c(NCC3CCCCC3)c3cc(O)ccc3nc21
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(OCC4CO4)ccc3nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-ethyl-6-hydroxy-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine (2 g), DMSO (30 ml) and KOH (2 g) was stirred at room temperature for 0.5 hours, then epichlorohydrin (0.49 ml) was added and the mixture was stirred overnight. The reaction mixture was partitioned between CH2Cl2 and water, and then the CH2Cl2 layer was separated and evaporated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to afford the product which was combined with the product from a similar experimental. The combined material was purified further by column chromatography on silica gel eluting with 90% ether/t-butylmethylether, followed by crystallization from ether, to afford 1-ethyl-6-(2,3-epoxypropoxy)-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4amine, m.p. 168°-170° C.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH:13]=O)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20](=[O:29])[NH:21][CH:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)([CH3:18])([CH3:17])[CH3:16].[BH4-].[Na+]>CO>[C:15]([O:19][C:20](=[O:29])[NH:21][CH:22]1[CH2:23][CH2:24][CH:25]([NH:28][CH2:13][C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:26][CH2:27]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: O=Cc1ncccc1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCC(NCc2ncccc2-c2ccccc2)CC1

Procedure:
Using General Procedure B: Reaction of 3-phenyl-2-pyridinecarboxaldehyde and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester in MeOH with NaBH4 gave {4-[(3-phenyl-pyridin-2-ylmethyl)-amino]-cyclohexyl}-carbamic acid tert-butyl ester as a pale yellow oil. 1H NMR (CDCl3) δ 0.96-1.25 (m, 4H), 1.40 (s, 9H), 1.81 (d, 2H, J=12.3 Hz), 1.92 (d, 2H, J=11.1 Hz), 2.29-2.39 (m, 1H), 2.56 (s, 1H), 3.36 (br s, 1H), 3.83 (s, 2H), 4.08-4.41 (br m, 1H), 7.20 (dd, 1H, J=7.8, 4.8 Hz), 7.30-7.33 (m, 2H), 7.36-7.43 (m, 3H), 7.52 (dd, 1H, J=7.7, 1.5 Hz), 8.53 (dd, 1H, J=4.8, 1.8 Hz).