Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[C:18]([Cl:26])[CH:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.CO.O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[C:18]([Cl:26])[CH:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cc1Cl
Temperature: 50 °C

Procedure:
Methyl 4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-chlorobiphenyl-4-carboxylate (0.30 g, 0.71 mmol) was suspended in THF (5 mL), MeOH (5 mL) and water (2.5 mL), and then NaOH (0.28 g, 7.1 mmol) was added. The reaction mixture was heated at 50° C. for 3 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure, acidified, and the resulting solid was collected by filtration. This yielded 0.34 g (quantitative) of the title compound. LC/MS m/z 399.2 (MH+), retention time 3.53 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:4]=[N:3]1.[NH2:37][CH:38]1[CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:39]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([NH:27][C:28]([NH:37][CH:38]2[CH2:39][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41]2)=[O:29])[CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(NC(=O)NC2CN(C(=O)OC(C)(C)C)C2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 59.9 %

Procedure:
To a suspension of phenyl [1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]carbamate (2.18 g) and tert-butyl 3-amino-1-azetidinecarboxylate (793 mg) in methylene chloride (20 ml) was added N-ethyldiisopropylamine (1.07 ml), and the mixture was stirred under reflux for 40 hours. To the reaction mixture was added methylene chloride, and the solution was washed successively with 10% aqueous citric acid solution, 10% aqueous sodium hydroxide solution and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 10% methanol/methylene chloride to give tert-butyl 3-[({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)amino]-1-azetidinecarboxylate (1.52 g) as a solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][C:25]([CH3:27])=O.C1COCC1.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH:25]([N:10]([C@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[CH2:15][CH2:16]1)[CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:27])[CH3:24]
Reactant: Oc1ccc([C@H]2CC[C@H](NCCCc3ccccc3)CC2)cc1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred solution of trans-4-[4-(3-phenylpropyl amino) cyclohexyl]-phenol and acetone (2 mL) in a 2:1 mixture of THF:MeOH (10 mL) was added sodium cyanoborohydride (153 mg, 2.42 mmol). The reaction mixture was heated to 60° C. and the acidity was maintained by the addition of acetic acid. The mixture was stirred overnight, quenched with 2N NaOH and concentrated under reduced pressure. Purification by flash chromatography (90:9:1 CH2Cl2:MeOH:NH4OH) gave trans-4-{4-[N-isopropyl-N-(3-phenylpropyl) amino]cyclohexyl}phenol (130 mg, 48%), as a white solid: mp 146-154° C.; IR (KBr): 3198, 2941, 1613 cm−1; 1H NMR (500 MHz, DMSO-d6) δ or s δ 7.32-7.21 (m, 5H), 6.98 (d, J=8 Hz, 2H), 6.66 (d, J=8 Hz, 2H), 3.67 (m, 1H), 3.28 (m, 2H), 3.10 (m, 2H), 2.66 (m, 2H), 2.48 (m, 1H), 2.04 (m, 1H), 2.02 (m, 2H), 1.84 (m, 2H), 1.83 (m, 2H), 1.49 (m, 2H), 1.24 (d, J=8 Hz, 3H), 1.19 (d, J=8 Hz, 3H); CI-MS (methane) (m/z): 352 [M+H]+; HRMS-API (m/z): [M+H]+ Calcd for C24H33NO, 352.2640. found: 352.2637. HPLC: method A, 6.37 minutes (95.3%); method B, 10.85 minutes (100%); Anal. Calcd for C24H33NO.HCl.0.5 NaCl: C, 69.09; H, 8.21; N, 3.36. Found: C, 69.33; H, 8.32; N, 3.22.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[C:12](O)=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])O.[Na+].P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:12]1[C:11]([N+:16]([O-:18])=[O:17])=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[CH:14][N:13]=1
Reactant: O=[N+]([O-])c1cc(-c2ccc(Cl)c(Cl)c2)cnc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=[N+]([O-])c1cc(-c2ccc(Cl)c(Cl)c2)cnc1Cl
Temperature: 120 °C

Procedure:
A mixture of 1.6 g of 5-(3,4-dichlorphenyl)-2-hydroxy-3-nitropyridine (starting material G4) and 10 ml of phosphorous oxychloride is heated under reflux to 120° C. for 3 hours. After cooling the mixture is carefully added to ice/water, then neutralized with sodium hydrogencarbonate and extracted three times with ethyl acetate. The combined organic phases are evaporated to dryness and the residue is chromatographed on a silica gel column (ethylacetate/petroleum ether 1:20). Concentration of the chromatographically pure fractions gives 0.88 g of the title compound as yellow crystals. The mass spectrum shows the molecular peak M+ at 302 Da.
Reaction SMILES: Cl[C:2]1[CH:18]=[C:17](F)[C:16]([N:20]2[C:25](=[O:26])[CH:24]=[C:23](C(F)(F)F)[NH:22][C:21]2=[O:31])=[CH:15][C:3]=1C(NS(N(C)C(C)C)(=O)=O)=O.S(OC)(OC)(=O)=O.O.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C1COCC1>[C:16]1([N:20]2[C:25](=[O:26])[CH:24]=[CH:23][NH:22][C:21]2=[O:31])[CH:15]=[CH:3][CH:2]=[CH:18][CH:17]=1
Reactant: CC(C)N(C)S(=O)(=O)NC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Solvent: O
Product: O=c1cc[nH]c(=O)n1-c1ccccc1
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
50.0 g (0.098 mol) of 2-chloro-5-[3,6-dihydro-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4-fluoro-N-{[methyl(1-methylethyl)amino]sulfonyl}benzamide, 3.2 g (0.0089 mol) of tetrabutylammonium bromide (=TBAB) and 15.1 g (0.12 mol) of dimethyl sulfate were introduced into the reaction vessel at 25° C. in a mixture of toluene, water and THF, and the mixture was heated to 40° C. Thereafter, a pH of 5.3-5.5 was established in the reaction mixture by addition of aqueous 10% strength NaOH solution. During the entire duration of the reaction, more aqueous 10% strength NaOH solution was added so that the pH during the entire course of the reaction was constantly at the pH which had been established beforehand. After the reaction had ended, stirring of the reaction mixture was continued for 3.5 h at 40° C. The phases were subsequently separated.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:24]=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[O:27][CH2:26][O:25][C:11]3=2)[N:6]=1)=[O:4].Cl>CO>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]5[O:27][CH2:26][O:25][C:11]5=4)[N:6]=[C:5]([C:3]([OH:4])=[O:2])[C:14]=3[CH3:15])=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: COC(=O)c1nc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1C)OCO3
Agent: Cl
Solvent: CO
Product: Cc1c(C(=O)O)nc2ccc3c(c2c1-c1ccc2c(c1)OCO2)OCO3

Procedure:
2.5% aqueous NaoH solution (20 ml) was added to a solution of 9-(1,3-benzodioxole-5-yl)-8-methyl-1,3-dioxolo[4,5-f]quinoline-7-carboxylic acid methyl ester in methanol (20 ml). The mixture was refluxed for one hour. 1N HCl was added to the reaction mixture to make it slightly acidic (pH 5), followed by extraction with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to yield the title compound as yellow crystals (252 mg). Some portions of the compound were recrystalized from THF to be used for elemental and instrumental analysis.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O.Cl>C1COCC1>[C:23]([O:22][C:20](=[O:19])[NH:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Nc1cccnc1Cl
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.2 %

Procedure:
To a solution of 3-amino-2-chloropyridine (5 g 38.9 mmol) in THF (35 mL) is added 2 M NaHMDS in THF (38.9 mL, 77.8 mmol). After stirring at rt for 15 min, BOC2O (7.7 g, 35.6 mmol) in THF (20 mL) is added in one portion and then stirred for 5 h at rt. 0.1% aqueous HCl is added. The mixture is extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is chromatographed through silica gel eluting with 0-50% EtOAc in heptane to afford (2-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (7.18 g, 89%). MS: 229 (M+H); 1H NMR (300 MHz, CDCl3): δ 8.52 (d, 1H), 8.05 (dd, 1H), 7.23 (dd, 1H), 7.02 (broad s, 1H), 1.55 (s, 9H)).
Reaction SMILES: [CH:1]([N:3]([C@H:5]1[C@H:10]([OH:11])[CH2:9][C@H:8]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C:20]1[CH:19]=[CH:18][C:17]([OH:24])=[CH:16][C:15]=1[CH2:14][CH2:13]3)[CH3:4])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:4][N:3]([CH3:1])[C@H:5]1[C@H:10]([OH:11])[CH2:9][C@H:8]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C:20]1[CH:19]=[CH:18][C:17]([OH:24])=[CH:16][C:15]=1[CH2:14][CH2:13]3
Reactant: CN(C=O)[C@H]1[C@H](O)C[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)[C@H]1[C@H](O)C[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C

Procedure:
A suspension of 17β-(N-formyl-N-methylamino)-oestra-1,3,5(10)-triene-3,16α-diol (5.41 g) in tetrahydrofuran (110 ml) was kept at 10° C., while lithium aluminium hydride (5.41 g) was added portionwise. The resultant mixture was refluxed for 5 h., then the excess of lithium aluminium hydride was destroyed by careful addition of water. The mixture was diluted with a 1:1 mixture of tetrahydrofuran-ethylacetate (500 ml) and refluxed for 3 h. The inorganic salts were filtered off and washed with tetrahydrofuran-ethylacetate (500 ml; 1:1) and the filtrate was evaporated to dryness. The resultant crude product was crystallised from dichloromethane-methanol to give pure 17β-dimethylamino-oestra-1,3,5(10)-triene-3,16α-diol as an amorphous solid (3.83 g; 73.9%), m.p. 240°-242° C., [α]D +43.4° (c 1.33 in pyridine).
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(NC(C)C)(C)C.[C:19]1([CH2:25][C:26]([O:28][CH3:29])=[O:27])C=CC=CC=1.CN(P(N(C)C)(N(C)C)=O)C.CI>C1COCC1.[Cl-].[NH4+].O>[C:8]1([CH:25]([CH3:19])[C:26]([O:28][CH3:29])=[O:27])[CH:7]=[CH:6][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCCC
Reactant: COC(=O)Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(C)c1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
A solution of n-butyl lithium in hexane (1.44N, 75 ml, 108 mmol) was added to a solution of diisopropylamine (11.3 g, 112 mmol) in anhydrous THF (200 ml) cooled at -20° C. under argon atmosphere, and the mixture was stirred for 30 minutes. The reaction mixture was cooled to -78° C. To this solution were added a solution of methyl phenylacetate (12.0 g, 80.0 mmol) in 15 ml of anhydrous THF and HMPA (20.6 g, 115 mmol). The mixture was stirred at -78° C. for 1 hour and then at -30° C. for 30 minutes. To this reaction solution was added a solution of methyl iodide (17.0 g, 120 mmol) in anhydrous THF (30 ml) at -78° C., and the mixture was stirred at -78° C. for 1.5 hours. The reaction mixture was allowed to warm to room temperature and diluted with an aqueous saturated solution of ammonium chloride (300 ml) and water (150 ml). The mixture was extracted with ether (400 ml). The aqueous layer was further extracted with ether (200 ml×2). The combined organic layers were washed with water (200 ml) and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was distilled (b.p. 92°-93° C./10 mmHg) to give an oil of methyl 2-phenylpropionate (11.3 g, 68.9 mmol, 86.1%). This compound was assigned to the structure by the following data:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([C:7]2[S:8][C:9](=[CH:13][C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[C:31]([F:34])([F:33])[F:32])[N:18]=[CH:17]4)[C:10](=[O:12])[N:11]=2)[C@@H:4]([CH2:35][OH:36])[CH2:3]1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:19]2[C:20]3[C:16](=[CH:15][C:14]([CH:13]=[C:9]4[S:8][C:7]([N:5]5[C@@H:4]([CH2:35][OH:36])[CH2:3][C@@H:2]([NH:1][C:37](=[O:39])[CH3:38])[CH2:6]5)=[N:11][C:10]4=[O:12])=[CH:22][CH:21]=3)[CH:17]=[N:18]2)=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:26]=1
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H]1C[C@H](CO)N(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1
Product: CC(=O)N[C@@H]1C[C@H](CO)N(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
N-{(3R,5R)-1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-5-(hydroxymethyl)pyrrolidin-3-yl}acetamide was prepared from 2-[(2R,4R)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl]-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazol-4(5H)-one (example 257) and acetic anhydride.
Reaction SMILES: [CH2:1]([C:5]1[N:6](COCC[Si](C)(C)C)[C:7]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Cl>C(O)C>[CH2:1]([C:5]1[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CCC(=O)OCC)n1COCC[Si](C)(C)C
Agent: Cl
Solvent: CCO
Product: CCCCc1nc(CCC(=O)OCC)c[nH]1
Temperature: 60 °C
Yield: 50 %

Procedure:
A solution of ethyl 3-[2-n-butyl-1-{(trimethylsilyl)ethoxymethyl}-1H-imidazol-5-yl]propanoate (0.992 g, 2.8 mmol) in ethanol (10 mL) was treated with 5N aqueous hydrochloric acid solution (20 mL), and then the reaction mixture was heated at 60° C. for 3.5 hours. The ethanol was evaporated, and the cooled aqueous solution was basified to pH 8 with 10% aqueous sodium hydroxide solution. The product was extracted into ethyl acetate, and the organic extracts were washed with brine, dried with anhydrous sodium sulfate and concentrated to give 0.314 g (50%) of ethyl 3-(2-n-butylimidazol-4-yl)-propanoate. This was dissolved in methanol (15 mL) and di-tert-butyldicarbonate (2.44 g, 11.2 mmol) and triethylamine (1.56 mL, 11.2 mmol) were added. The mixture was stirred for 18 hours at ambient temperature, the solvent was evaporated, and the residue was dissolved in hexane and applied to a flash column packed with silica gel. Elution with 8:2 hexane/ethyl acetate afforded 0.285 g (31%) of ethyl 3-[2-n-butyl-1-t-butoxycarbonyl-1H-imidazol-4-yl]propanoate as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[NH:22][C:23](=[O:26])[CH2:24]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([CH2:29][NH2:30])[OH:28].CCOC(C)=O>C(OC(C)C)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[NH:22][C:23](=[O:26])[CH2:24][NH:30][CH2:29][CH2:27][OH:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=C(CCl)Nc1cc(Cl)ccc1-c1ccccc1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)C
Product: O=C(CNCCO)Nc1cc(Cl)ccc1-c1ccccc1OCc1ccccc1
Temperature: 55 °C

Procedure:
To a solution of the product from Step C (6.9165 g, 17.25 mmol) in 25 mL of isopropyl acetate was added ethanolamine (3.84 mL, 63.7 mmol). The reaction was warmed to 55° C. for 4 hours, then cooled to room temperature. The solution was poured into EtOAc, washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The titled product was obtained as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:12])=[CH:7][CH:8]=2)[N:3]=1.C(OC(=O)C)(=O)C.[CH:20](=O)[C:21]1[CH:28]=[CH:27][CH:26]=[C:23]([CH:24]=[O:25])[CH:22]=1>C1(C)C(C)=CC=CC=1>[Cl:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2](/[CH:1]=[CH:20]/[C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[CH:24]=[O:25])=[N:3]2)=[CH:8][CH:7]=1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Reactant: O=Cc1cccc(C=O)c1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Product: O=Cc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Yield: 52 %

Procedure:
Starting with 6.56 g of 2-methyl-7-chloroquinoline, 10.4 ml of acetic anhydride and 4.95 g of isophthalaldehyde in 100 ml of xylene and using the procedure of Preparation Il, there was obtained 5.64 g of the desired product as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:11]1(=[O:18])[CH:16]=[CH:15][C:14](=[O:17])[CH:13]=[CH:12]1>O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:16]2[CH:15]=[C:14]([OH:17])[CH:13]=[CH:12][C:11]=2[OH:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1C=CC(=O)C=C1
Reactant: O=S(O)c1ccc(F)cc1
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1ccc(F)cc1)c1cc(O)ccc1O
Reaction time: 4 h

Procedure:
A solution of the title A compound, 4-fluorobenzenesulfinic acid (3 g, 18.75 mmol) in 10 mL of water is added to a solution of 1,4 benzoquinone ( 1.93 g, 17.86 mmol) in 30 mL of CH2Cl2 at RT. After 4 h, the precipitated product is collected by vacuum filtration and washed with cold CH2Cl2 and dried under vacuum to afford 2-(4-fluorobenzenesulfonyl)-benzene-1,4-diol: NMR (DMSO-d6) 6.73 (d, 1H, J=9), 6.92 (dd, 1H, J=9, 3), 7.31 (d, 1H, J=3), 7.41 (app t, 2H, J=9), 7.96 (dd, 2H, J=9, 5), 9.41 (s, 1H), 10.05 (s, 1H); ESI-MS 267 [M−1]−1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[Na+].[I-:12].C(Cl)(=O)C.[OH-].[Na+]>C(#N)C.C1COCC1>[I:12][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: Clc1ccnc2[nH]ccc12
Reactant: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Product: Ic1ccnc2[nH]ccc12
Temperature: 80 °C
Reaction time: 96 h
Yield: 47.4 %

Procedure:
To a solution of 4-Chloro-1H-pyrrolo[2,3-b]pyridine (12.9 g, 84.3 mmol) and NaI (40 g, 168 mmol) in acetonitrile (150 mL) was slowly added acetyl chloride (12.6 mL, 176 mmol). The mixture was allowed to stir at 80° C. for 4 days, and then the excess acetonitrile was removed in vacuo. 300 mL of 10% K2CO3 (aq) was added to the residue and the mixture extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with 10% sodium bisulfite (aq) and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude product (22.2 g). To a solution of this crude product in THF (150 mL) was added 1M NaOH (100 mL). The mixture was stirred at room temperature for 2 hr prior to evaporation of the solvent in vacuo, dilution with water and extraction with CH2Cl2. The extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting brown solid was purified by chromatography over silica gel and recrystallized from acetonitrile to give pure 4-Iodo-1H-pyrrolo[2,3-b]pyridine (9.75 g, 48%). MS (ES+): 245 [MH+].
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[CH2:9]([NH2:12])[CH2:10][NH2:11]>C(O)C>[CH2:6]([O:5][C:1]([NH:11][CH2:10][CH2:9][NH2:12])=[O:8])[CH3:7]
Reactant: CCOC(=O)OCC
Reactant: NCCN
Solvent: CCO
Product: CCOC(=O)NCCN

Procedure:
15 g (0.13 mol) of diethyl carbonate are heated in an oil bath at 90° C., for five hours, with 10 g (0.17 mol) of ethylenediamine under reflux. The ethyl alcohol formed during the reacton is then removed using a rotary evaporator. The product is removed from the residue by distillation in a Kugelrohr distillation apparatus.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15]>>[CH3:6][O:7][C:8](=[O:16])[C:9]1[CH:14]=[C:13]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:12]=[CH:11][C:10]=1[CH3:15]
Reactant: COC(=O)c1ccccc1C
Reactant: O=S(=O)(O)Cl
Product: COC(=O)c1cc(S(=O)(=O)Cl)ccc1C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
Chlorosulfonic acid (106.2 ml) was carefully added over 1 min with stirring under nitrogen to 2-methyl-benzoic acid methyl ester (55.9 ml, 0.4 mol). The reaction mixture was placed in an oil bath preheated to 100° C. for 15 min, then poured onto ice (1000 ml). The resulting precipitate was filtered and dissolved in ethyl acetate (400 ml). The ethyl acetate solution was washed sequentially with 10×300 ml saturated aqueous sodium bicarbonate, 300 ml water and 300 ml brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure to yield the title compound as a yellowish oil (37.3 g, 37% yield). 1H NMR (400 MHz, CDCl3) δ, 2.74 (s, 3H), 3.96 (s, 3H), 7.52 (d, 1H), 8.04 (m, 1H), 8.58 (d, 1H).
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][O:4][C@H:5]1[C@@H:10]([NH2:11])[CH2:9][CH2:8][N:7]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:6]1.[Cl:19][C:20]1[N:21]=[C:22]([C:27](O)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:19][C:20]1[N:21]=[C:22]([C:27]([NH:11][C@H:10]2[CH2:9][CH2:8][N:7]([C:12](=[O:17])[C:13]([F:16])([F:14])[F:15])[CH2:6][C@H:5]2[O:4][CH2:3][CH:2]([F:1])[F:18])=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26]
Reactant: N[C@H]1CCN(C(=O)C(F)(F)F)C[C@H]1OCC(F)F
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)C(F)(F)F)C[C@H]2OCC(F)F)nc1Cl
Yield: 66.3 %

Procedure:
The same operation as in Example (106d) was performed using cis(±)-3-(2,2-difluoroethoxy)-1-(trifluoroacetyl)piperidin-4-amine obtained in Example (121e) (0.79 g, 2.86 mmol), 4-chloro-5-ethyl-1H-imidazole 2-carboxylic acid (85% content, 0.62 g, 3 mmol), WSC hydrochloride (1.15 g, 6 mmol), HOBt (0.61 g, 4.5 mmol), DMA (15 mL) and dichloromethane (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 0.82 g of the title compound as a colorless amorphous solid (63%).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:12])([CH3:11])[CH2:7][NH:8]2)=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[CH3:42][N:43]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][C:6]1([CH3:12])[C:5]2[C:9](=[CH:10][C:2]([C:42]#[N:43])=[CH:3][CH:4]=2)[NH:8][CH2:7]1
Reactant: CC1(C)CNc2cc(Cl)ccc21
Reactant: CN1CCCC1=O
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC1(C)CNc2cc(C#N)ccc21
Temperature: 185 °C
Yield: 15 %

Procedure:
6-Chloro-3,3-dimethyl-2,3-dihydro-1H-indole (1 g, 5.5 mmol), zinc cyanide (0.74 g, 6.3 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.2 g, 0.9 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.4 g, 1.1 mmol) were combined and dissolved in N-methyl-pyrrolidinone (27.6 mL). The suspension was degassed with nitrogen for 5 minutes. The reaction was heated under microwave irradiation for 2 h at 185° C. then cooled to room temperature and the reaction was diluted with water and extracted with diethyl ether/petrol (1:1) (3×). The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. Chromatography (silica gel, gradient elution, 0-100%, EtOAc in petrol 40-60) gave the title compound (0.14 g, 15%) as pale yellow solid. MS: [M+H]+=173.