Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:27][C@H:26]([CH2:28][O:29]CC3C=CC=CC=3)[C@@H:17]([O:18]CC3C=CC=CC=3)[C@@H:8]2[O:9]CC2C=CC=CC=2)[C:5]2[CH:37]=[C:38]([Cl:42])[C:39]([Cl:41])=[CH:40][C:4]=2[N:3]=1.B(Cl)(Cl)Cl.CO.[NH4+].[OH-]>C(Cl)Cl>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:17]([OH:18])[C@@H:8]2[OH:9])[C:5]2[CH:37]=[C:38]([Cl:42])[C:39]([Cl:41])=[CH:40][C:4]=2[N:3]=1
Reactant: Clc1cc2nc(Cl)n([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2cc1Cl
Agent: ClB(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@@H](O)[C@@H]1O
Reaction time: 4.5 h

Procedure:
Compound 133 (1.25 g 2 mmole) was dissolved in dry CH2Cl2 (20 ml) and this solution was cooled in an acetone-dry ice bath. A 1M solution of BCl3 in CH2Cl2 (10 ml) was added and the mixture was stirred at -70° for 4.5 hr. At this point TLC showed no starting material. CH3OH (10 ml) was added and the solution was made neutral with NH4OH. The solution was evaporated in vacuo to dryness. H2O (20 ml) was added and the solution was extracted with EtOAc. The EtOAc layer was washed with H2O, dried (Na2SO4) and evaporated in vacuo to obtain a syrup. This syrup was subjected to flash column chromatography on silica gel (Kieselgel 60, 230-400 mesh) with CH2Cl --MeOH (20:1) as eluent solvent to give 134. Yield 0.551 g, 77.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH2:13][CH3:14])[CH:8]=[C:7]2[O:15][CH:16]1[CH2:33][CH:32]2[CH:18]([C:19](=[O:39])[N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]3[C:29]([C:35]([OH:37])=O)([NH:30][C:31]2=[O:34])[CH2:28]3)[CH2:17]1.C(OC1C=C(OC2CC3C(C(=O)N(C)CCCCC=CC4C(C([NH:75][S:76]([CH:79]5[CH2:81][CH2:80]5)(=[O:78])=[O:77])=O)(NC3=O)C4)C2)C2C(=C(C)C(OC)=CC=2)N=1)C>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH2:13][CH3:14])[CH:8]=[C:7]2[O:15][CH:16]1[CH2:33][CH:32]2[CH:18]([C:19](=[O:39])[N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]3[C:29]([C:35]([NH:75][S:76]([CH:79]4[CH2:81][CH2:80]4)(=[O:78])=[O:77])=[O:37])([NH:30][C:31]2=[O:34])[CH2:28]3)[CH2:17]1
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2cccc(Cl)c2n1
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2cccc(Cl)c2n1

Procedure:
The title compound (11) was prepared from 17-[8-chloro-2-ethoxyquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (10) following the procedure reported for synthesis of N-[17-[2-ethoxy-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo-[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (3): m/z=659 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:2]([NH:1][C:13]([NH:12][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=3)[N:22]=2)=[CH:19][CH:20]=1)=[S:14])[CH2:3][OH:4]
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: NC(CO)c1ccccc1Cl
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccccc1Cl

Procedure:
The title compound was prepared with 2-amino-2-(2-chlorophenyl)ethanol (Brueggemeier, U.; et al., WO 2010105770) and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.44 g, quantitative): 1H NMR (300 MHz, CDCl3) δ 7.97 (d, J=1.1 Hz, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.47-7.41 (m, 1H), 7.23-7.13 (m, 2H), 6.87-6.55 (m, 11H), 5.39 (d, J=8.3 Hz, 1H), 3.48-3.30 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[CH3:2].[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][N:8]([C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH3:20])(=[O:29])=[O:28])[CH3:2]
Reactant: CCOC(=O)CCCNc1ccccc1C(=O)OC
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)CCCN(c1ccccc1C(=O)OC)S(=O)(=O)c1ccccc1C
Yield: 90.7 %

Procedure:
A mixture of 2.65 g of methyl 2-[(4-ethoxy-4-oxobutyl)amino]benzoate, 2.0 g of 2-methylphenylsulfonyl chloride and pyridine is heated on a steam bath for 16 hours. The mixture is concentrated under a vacuum (remove pyridine) and 1N HCl added. The mixture is extracted with dichloromethane and the extract washed with 1NHCl, H2O, 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrons magnesium silicate and the filtrate evaporated to give 3.8 g of solid which is crystallized from ethanol to give crystals, m.p. 100°-102° C.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([CH3:13])[N:9]=2)[C:5]=1[C@H:14]1[CH2:16][C@@H:15]1[CH2:17][NH2:18].C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>O1CCCC1.C(=O)([O-])O.[Na+]>[F:3][C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([CH3:13])[N:9]=2)[C:5]=1[C@H:14]1[CH2:16][C@@H:15]1[CH2:17][NH:18][C:26](=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1cc2c([C@H]3C[C@@H]3CN)c(F)ccc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1C[C@@H]1c1c(F)ccc2nn(C)cc12
Yield: 103.6 %

Procedure:
A solution of 1-[(1S,2S)-2-(5-fluoro-2-methyl-2H-indazol-4-yl)cyclopropyl]methanamine dihydrochloride (230 mg, 0.787 mmol) and triethylamine (549 μL, 3.936 mmol) in tetrahydrofuran (8 mL) was stirred at room temperature for 20 min. To the reaction solution was added acetic anhydride (112 μL, 1.181 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 15 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate=0/100→5/95) to give the title compound (213 mg, yield 99%).
Reaction SMILES: C([O:8][C:9](=[O:28])[CH2:10][S:11](=[O:27])(=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)C1C=CC=CC=1.[NH2:29][CH2:30][C@@H:31]([C:33]1[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=1)[OH:32]>>[OH:32][C@H:31]([C:33]1[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=1)[CH2:30][NH:29][CH:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]([NH:12][S:11]([CH2:10][C:9]([OH:8])=[O:28])(=[O:26])=[O:27])=[CH:18][CH:17]=2)[CH2:24][CH2:23]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)CC(=O)OCc3ccccc3)cc2)CC1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(NS(=O)(=O)CC(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from [4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-acetic acid benzyl ester (which was obtained in Example 236) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 255 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40–1.60 (m, 2 H), 1.90–2.05 (m, 2 H), 2.50–2.90 (m, 5 H), 2.94 (s, 3 H), 3.50–3.65 (m, 2 H), 4.65–4.75 (m, 1 H), 6.80–6.90 (m, 3 H), 7.00–7.10 (m, 3 H), 7.23 (d, J=2.0 Hz, 1 H); MS (ES) m/z: 543.3 (MH+); HRMS Calcd. for C29H37N4O8S2(MH+): 543.1578. Found: 543.1572.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[I-].ClC1[CH:29]=[CH:28][CH:27]=[CH:26][N+]=1C.C(O)CCC>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:11]([CH2:13][C:14]([O:16][CH2:26][CH2:27][CH2:28][CH3:29])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: C[n+]1ccccc1Cl
Reactant: O=C(O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccsc1
Agent: [I-]
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCCCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccsc1
Yield: 69.6 %

Procedure:
0.55 g of 2-[2-(4-chlorophenyl)-5-(3-thienyl)-4-oxazolyl]acetic acid, 0.44 g of 2-chloro-1-methyl-pyridinium iodide, 0.13 ml of n-butanol and 0.2 g of triethylamine are treated in the same manner as described in Example 20. 0.45 g of n-butyl 2-[2-(4-chlorophenyl)-5-(3-thienyl)-4-oxazolyl]acetate is thereby obtained.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[CH3:13][C:14](O)=[O:15]>C([O-])(=O)C.[Na+]>[C:14]([NH:2][NH:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=1)(=[O:15])[CH3:13]
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(NNC(C)=O)cc1
Temperature: 80 °C
Yield: 115.7 %

Procedure:
5.5 g of methyl 4-hydrazinobenzoate are dissolved in 38.2 ml of AcOH comprising 2.4 g of sodium acetate and the mixture is heated at 80° C. for 18 hours. The inorganic material is filtered off, the filtrate is then evaporated and the residue is taken up in the minimum amount of Et2O. The mixture is filtered to produce 7.97 g of the expected compound.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2)C.[OH-].[K+]>O.C(O)C>[C:7]12([O:6][CH2:5][C:4]([OH:17])=[O:3])[CH2:16][CH:11]3[CH2:10][CH:9]([CH2:15][CH:13]([CH2:12]3)[CH2:14]1)[CH2:8]2
Reactant: CCOC(=O)COC12CC3CC(CC(C3)C1)C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)COC12CC3CC(CC(C3)C1)C2

Procedure:
A mixture of (adamantan-1-yloxy)-acetic acid ethyl ester (A. F. Noels et al. Tetrahedron, 1982, 38, 2733) (7.29 g, 29 mmol) and potassium hydroxide (2.60 g, 46 mmol) in water-ethanol (1:2 mixture, 180 ml) was heated at reflux for 2 h. The mixture was cooled, then concentrated in vacuum and acidified with concentrated hydrochloric acid. The resultant white precipitate was dissolved in ethyl acetate (200 ml). The solution was washed with brine (2×200 ml), dried (MgSO4) and the solvent was evaporated to afford white crystalline solid (5.85 g 92%). 1H NMR (300 MHz, CDCl3) 4.08 (2H, s), 2.20-1.58 (15H, m).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[CH2:6][NH:7][CH2:8][CH2:9][O:10][CH3:11].[C:21](N1C=CN=C1)([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=[O:22]>C1(C)C=CC=CC=1.C(Cl)Cl>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:14]=1)[CH2:6][N:7]([CH2:8][CH2:9][O:10][CH3:11])[C:21]([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=[O:22]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COCCNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)n1ccnc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
In a mixed solution of 37 ml of toluene and 4 ml of methylene chloride was dissolved 2.76 g of 3,5-bistrifluoromethylbenzyl-2-methoxyethylamine, added thereto was 1.78 g of 1,1′-carbonyldiimidazole, and the mixture was stirred at 60° C. for 3 hours. To the reaction mixture was added distilled water, and extracted with chloroform. The organic layer was dried over magnesium sulfate, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:acetone=9:1→2:1), to give 3.45 g of imidazole-1-carboxylic acid 3,5-bistrifluoromethylbenzyl-2-methoxyethylamide as shown in Table 133 below.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1Br)[CH:10]([NH:15][C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:18]([F:29])[CH:17]=1)[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[C-:30]#[N:31].N>CN1C(=O)CCC1.[Cu]>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:30]#[N:31])[CH:10]([NH:15][C:16]1[CH:28]=[CH:27][C:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:18]([F:29])[CH:17]=1)[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(=O)Nc1cc2c(cc1Br)C(Nc1ccc(C(=O)OC(C)(C)C)c(F)c1)CC2
Agent: [Cu]
Agent: N
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cc2c(cc1C#N)C(Nc1ccc(C(=O)OC(C)(C)C)c(F)c1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-[N-(5-acetamido-6-bromoindan-1-yl)amino]-2-fluorobenzoate (0.420 g, 0.90 mmol) in NMP (10 ml) was added copper(l) cyanide (0.137 g, 1.53 mmol). The reaction mixture was placed in an oil-bath preheated to 145° C. and stirred at this temperature for 2 hours. The reaction mixture was allowed to cool to room temperature, then poured into a mixture of aqueous ammonia (d=0.88, 5 ml) and ice (˜15 ml) and the resulting brown mixture was stirred at room temperature for ˜5 min. The brown solid was collected by filtration washed with water, then suspended in dichloromethane (60 ml). The mixture was stirred at room temperature for 5 min, dried (Na2SO4), and concentrated in vacuo. Purification by column chromatography, on elution with 40% ethyl acetate in hexane, afforded a solid that was triturated with diethyl ether/hexane. The desired compound was obtained as a white solid: 0.202 g, (55%) m.p. 172-173° C.; 1H-NMR (250 MHz, CDCl3, TMS) 1.57 (s(obscured by water peak), 9H, C(CH3)3), 2.27 (s, 3H, COCH3), 1.96, 2.65 (2×m, 2H, indanyl 2-H), 3.00 (m, 2H, indanyl 3-H), 4.30 (d, J=8.40 Hz, 1H, N-H), 4.99 (q, J=7.80 Hz, 1H, indanyl 1-H), 6.38 (m, 2H, 3,5-H), 7.52, 8.33, 7.62 (3×s, each 1H, indanyl 4-H, 7-H, CONH), 7.74 (t, J=8.60 Hz, 1H, 6-H); MS (ESL, m/z) 432 {(M+Na)+, 100%}; Found: C, 67.44; H, 5.88; N, 10.25; P, 4.63; C23H24FN3O3 requires C, 67.47; H, 5.91; N, 10.26%; F, 4.64%.
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[O:11])=[C:8]([N:19]2[C:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:22][N:21]=[C:20]2[CH2:31]O)[CH:7]=[CH:6][CH:5]=1)=[O:2].[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]([NH:3][C:4]1[C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[O:11])=[C:8]([N:19]2[C:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:22][N:21]=[C:20]2[CH2:31][N:37]2[C:36](=[O:38])[C:35]3=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]3[C:33]2=[O:43])[CH:7]=[CH:6][CH:5]=1)=[O:2]
Reactant: O=CNc1cccc(-n2c(CO)nnc2Cc2ccccc2)c1C(=O)c1ccccc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=CNc1cccc(-n2c(Cc3ccccc3)nnc2CN2C(=O)c3ccccc3C2=O)c1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 3, a mixture of 6-formamido-2'-chloro-2-[3-(hydroxymethyl)-5-benzyl-4H-1,2,4-triazol-4-yl]benzophenone, phthalimide and triphenylphosphine in tetrahydrofuran was treated with diethyl azodicarboxylate to give 6-formamido-2'-chloro-2-[3-(phthalimidomethyl)-5-benzyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [OH:1][C@:2]([CH3:18])([CH2:16][OH:17])[CH2:3][CH2:4][C:5]1[C:6](=[O:15])[C:7]([CH3:14])=[C:8]([CH3:13])[C:9](=[O:12])[C:10]=1[CH3:11].[H][H].C>C(OCC)(=O)C.[Pd]>[OH:1][C@:2]([CH3:18])([CH2:16][OH:17])[CH2:3][CH2:4][C:5]1[C:6]([OH:15])=[C:7]([CH3:14])[C:8]([CH3:13])=[C:9]([C:10]=1[CH3:11])[OH:12]
Reactant: CC1=C(C)C(=O)C(CC[C@](C)(O)CO)=C(C)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1c(C)c(O)c(CC[C@](C)(O)CO)c(C)c1O
Yield: 100.8 %

Procedure:
A solution of 0.405g (1.6mmoles) of (S)-(+)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethyl-p-benzoquinone in 20 ml of ethyl acetate was stirred in an atmosphere of hydrogen, in the presence of 0.04g of 5% by weight palladium on 95% by weight charcoal until H2 uptake ceased (ca. 1hr; 38 ml H2 absorbed). The catalyst was filtered and the filtrate was concentrated giving 0.41 g of (S)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethylhydroquinone as a tan solid, mp 124°-131.5°.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1.CCN(CC)CC.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>ClCCl>[CH2:11]([O:10][C:8]([C:6]1[O:7][C:3]([CH2:2][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:4][CH:5]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CN2CCOCC2)o1
Temperature: 45 °C
Reaction time: 24 h
Yield: 66.9 %

Procedure:
To a solution of ethyl 5-(chloromethyl)-2-furan-carboxylate (0.5 mL, 3.25 mmol) and Et3N (0.9 mL, 6.5 mmol) in dichloromethane under nitrogen was added morpholine (284 μL, 3.25 mmol) dropwise and a catalytic amount of KI. The reaction mixture was stirred at 45° C. for 24 hours, then it was concentrated in vacuo. The residue was dissolved in EtOAc and the organic layer was washed with water (2×) then brine, dried over sodium sulfate, filtered, concentrated, and dried in vacuo to give 520 mg (67% yield) of 5-morpholin-4-ylmethyl-furan-2-carboxylic acid ethyl ester as a light brown oil. 1H-NMR (d6-DMSO) δ: 7.22 (d, 1H), 6.51 (d, 1H), 4.25 (q, 2H), 3.54 (m, 6H), 2.37 (broad s, 4H), 1.27 (t, 3H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18]([OH:20])=O)=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:40]([NH:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C>[CH2:48]([N:47]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:18](=[O:20])[C:11]1[CH:10]=[C:9]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:8]([O:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[C:13]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:12]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc(C(=O)N(Cc2ccccc2)Cc2ccccc2)cc(N2CCCC2)c1Oc1ccccc1

Procedure:
In a similar manner to Example 8, piretanide can be reacted with EDC, HOBt and dibenzylamine in DMF to yield N,N-dibenzyl 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl) benzamide.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]#[N:11])=[CH:5][CH:4]=1.O1CCCC1.[OH-].[K+].[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH:28]=[CH2:29]>C(O)C>[C:10]([C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=1)([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[CH2:29][CH2:28][C:27]([O:31][CH2:32][CH3:33])=[O:30])#[N:11]
Reactant: C=CC(=O)OCC
Reactant: N#CC(c1ccc(C(F)(F)F)cc1)N1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCC(C#N)(c1ccc(C(F)(F)F)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 52.3 g. of α-(α,α,α-trifluoro-p-tolyl)-4-morpholineacetonitrile in 500 ml. of dry tetrahydrofuran is stirred at ambient temperature while 1 ml. portions of 30% potassium hydroxide in ethanol and 25 ml. portions of ethyl acrylate is added every half hour until a total of 5 ml. of the base and 150 ml. of ethyl acrylate is added. After the addition, the mixture is stirred at ambient temperature for 48 hours. Following filtration, the filtrate is concentrated, dissolved in methylene chloride, passed through magnesol and recrystallized from methylene chloride/hexane to afford ethyl γ-cyano-γ(α,α,α-trifluoro-p-tolyl)-4-morpholinebutyrate as cream colored crystals, m.p. 96° -97° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:24]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][C:19]=4[NH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[ClH:36]>C(Cl)Cl.CO>[ClH:36].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:24]4[CH2:23][CH2:22][NH:21][CH2:20][C:19]=4[NH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)=[C:4]([C:32]([F:35])([F:33])[F:34])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4ccc(F)cc4C(F)(F)F)CC3)n[nH]c2C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2ccc(F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
To a solution of tert-butyl 3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (74 mg, 0.15 mmol) in CH2Cl2 (3 mL) and methanol (1 mL) was added 2 N HCl (2 mL, 2M in Et2O). The mixture stirred for 4 h at ambient temperature. The reaction mixture was diluted with Et20 (30 mL) and the resulting solids were collected by filtration to give (4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone hydrochloride as a white solid (64 mg, 98%): 1H NMR (300 MHz, DMSO-d6) δ 13.14 (s, 1H), 9.16 (br s, 2H), 7.73-7.68 (m, 1H), 7.59-7.50 (m, 2H), 4.84-4.69 (m, 1H), 4.32-4.25 (m, 2H), 3.26-3.03 (m, 2H), 2.89-2.81 (m, 2H), 2.68-2.48 (m, 4H), 1.73 (m, 4H); ESI MS m/z 397 [M+H]+.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2>>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Brc1cnc2ccccc2c1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1cnc3ccccc3c1)O2

Procedure:
This compound was obtained by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 2,3 g (10 mmol), with 3.12 g (15 mmol) of 3-bromoquinoline as described in Example 15. The product was crystallized from methylene chloride/ethanol and was recrystallized from ethyl acetate to yield tan crystals with m.p. 199°-203°.
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([NH2:21])[CH3:20])=[CH:15][C:14]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([NH:21][C:1](=[O:11])[CH:2]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:20])=[CH:15][C:14]=1[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: CC(N)c1ccc(F)c(N2CCOCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)C=Cc1ccccc1)c1ccc(F)c(N2CCOCC2)c1
Reaction time: 16 h

Procedure:
A mixture of cinnamic acid (23 mg), 1-(4-fluoro-3-morpholin-4-yl-phenyl)-ethylamine, Preparation 26 (34 mg), DMAP (18 mg), EDC.HCl (27 mg), and Et3N (66 mg) in CH2Cl2 (4 mL) was stirred for 16 hours. Purification by fresh chromatography over silica gel (elution with 50% ethyl acetate in hexane) gave 51 mg of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:9]2[O:10][CH2:11][C@H:12]([O:13]C(C3C=CC=CC=3)=O)[C@@H:8]2[O:7][C@@H:4]1[O:5][CH3:6].[OH-].[Na+]>CO.C(OCC)(=O)C>[CH3:1][O:2][C@H:3]1[C@@H:9]2[O:10][CH2:11][C@@H:12]([OH:13])[C@@H:8]2[O:7][C@@H:4]1[O:5][CH3:6]
Reactant: CO[C@H]1O[C@@H]2[C@@H](OC[C@@H]2OC(=O)c2ccccc2)[C@@H]1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CO[C@H]1O[C@@H]2[C@@H](OC[C@H]2O)[C@@H]1OC
Yield: 85 %

Procedure:
A solution of methyl 3,6-anhydro-2-O-methyl-5-O-(phenylcarbonyl)-β-L-glucofuranoside (820 mg, 3.1 mmol) and 50% sodium hydroxide (248 mg, 3.1 mmol) in methanol (10 mL) was stilTed at room temperature for 30 minutes. The material was adsorbed on silica gel (5 g) and passed through a short column (15% ethyl acetate in hexanes to 5% methanol in ethyl acetate) to give methyl 3,6-anhydro-2-O-methyl-α-D-idofaranoside as a colorless oil, 420 mg, 85% yield. 1H NMR (400 MHz; CDCl3): 5.04 (s, 1H), 5.84-5.81 (tr, 1H), 4.44-4.42 (tr, 1H), 4.25-4.19 (m, 1H), 3.85-3.75 (m, 1H), 3.49 (s, 3H), 3.43 (s, 3H), 2.75-2.72 (d, 1H).