Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][O:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10].CCN(C(C)C)C(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CC(=O)OCC>CC#N>[CH2:16]([CH:3]1[NH:2][C:9](=[O:10])[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[CH2:6][O:5][CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(COCc1ccccc1C(=O)O)Cc1ccccc1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C1NC(Cc2ccccc2)COCc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
To a solution of compound 1c (28 g, 87 mmol) obtained above in CH3CN (1.5 L) was added DIPEA (68 g, 520 mmol) at 0° C., followed by BOP-Cl (70 g, 275 mmol). The resulting mixture was stirred at 0° C. for 30 min and then warmed to rt overnight. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in EA, washed with 2N HCl and dried over anhydrous Na2SO4. Concentration in vacuo and purification by CC eluting with PE:EA=1:2 gave compound 1d as a yellow oil (7.0 g, 30% yield). 1H NMR (400 MHz, CDCl3): δ 7.50 (dd, J=7.6, 1.6 Hz, 1H), 7.41-7.34 (m, 2H), 7.28-7.19 (m, 4H), 7.05 (d, J=7.2 Hz, 2H), 5.83 (m, 1H), 4.82 (d, J=14.0 Hz, 1H), 4.61 (d, J=13.6 Hz, 1H), 3.82-3.78 (m, 1H), 3.78-3.67 (m, 1H), 3.58-3.55 (m, 1H), 2.75-2.71 (m, 2H). MS (ESI+): 268 [M+1]+.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=1[F:31]>>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([C:23]([O:22][CH3:21])=[O:32])=[C:25]([F:31])[CH:26]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(N)cc1F
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Product: COC(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1F

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexyl-cyclopropylmethyl-amino)-pyrimidine-4-carboxylic acid (Intermediate 13) and 4-amino-2-fluoro-benzoic acid methyl ester (Bepharm), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:22])[CH2:10][CH2:11][C:12]1[C:17](Br)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][C:13]=1[Br:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]I>[Br:21][C:13]1[CH:14]=[C:15]([O:19][CH3:20])[CH:16]=[C:17]2[C:12]=1[CH2:11][CH2:10][C:9](=[O:22])[N:8]2[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COc1cc(Br)c(CCC(=O)Nc2ccccc2Cl)c(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Br)c2c(c1)N(c1ccccc1Cl)C(=O)CC2
Yield: 62.3 %

Procedure:
N-(2-chlorophenyl)-3-(2,6-dibromo-4-methoxyphenyl)propanamide (1.40 g, 3.128 mmol), copper(I) iodide (0.895 g, 4.694 mmol), and potassium carbonate (0.865 g, 6.259 mmol) in DMF (15 ml), were heated under reflux for 30 min., cooled and evaporated in vacuo. The residue was treated with 2M hydrochloric acid (80 ml) and extracted with dichloromethane (2×50 ml). The extracts were passed through a hydrophobic frit, evaporated in vacuo and the residue purified by flash chromatography over silica (50 g) eluting with cyclohexane-ethyl acetate gradient (100:0-50:50) to give the product as a white solid (0.714 g, 62%)
Reaction SMILES: [CH3:1][C:2]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=2[CH3:31])=[C:5]2[N:6]=[C:7]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:8]=[C:9]([C:10]([NH2:12])=O)[N:4]2[N:3]=1.S(Cl)(Cl)=O.O>CN(C)C=O>[CH3:1][C:2]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[C:22]=2[CH3:31])=[C:5]2[N:6]=[C:7]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:8]=[C:9]([C:10]#[N:12])[N:4]2[N:3]=1
Reactant: Cc1nn2c(C(N)=O)cc(N3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1nn2c(C#N)cc(N3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To the solution of 2-methyl-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(4-morpholinyl)pyrazolo[1,5-a]pyrimidine-7-carboxamide (200 mg, 0.461 mmol) in N,N-Dimethylformamide (DMF) (6 mL) was added thionyl chloride (0.067 mL, 0.923 mmol). The reaction mixture was stirred at rt for 2 h. Water was added in. The solid precipitated. Filtration gave the crude product. The crude was purified on silica column (20˜50% EtOAc/Hexane) to give the titled product (0.14 g, 77%). MS (ES+) m/e 416.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH2:6][CH2:7][C@:8]([CH2:14][CH2:15][CH2:16][C@@H:17]([CH2:19][CH2:20][CH2:21][C@@H:22]([CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:23])[CH3:18])([CH3:13])[O:9]2)=[CH:4][C:3]=1[OH:30].C([O-])([O-])=O.[K+].[K+].Cl[CH2:38][C:39]([CH3:41])=[CH2:40].[Na+].[I-]>O.C(Cl)Cl.CCOC(C)=O.CC(C)=O>[CH3:13][C@@:8]1([CH2:14][CH2:15][CH2:16][C@H:17]([CH3:18])[CH2:19][CH2:20][CH2:21][C@H:22]([CH3:23])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:7][CH2:6][C:5]2[C:10](=[C:11]([CH3:12])[C:2]([CH3:1])=[C:3]([O:30][CH2:40][C:39]([CH3:41])=[CH2:38])[CH:4]=2)[O:9]1
Reactant: Cc1c(O)cc2c(c1C)O[C@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)CC2
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C=C(C)COc1cc2c(c(C)c1C)O[C@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)CC2

Procedure:
(+)-γ-tocopherol (Ex-1F-1) (300 mg, 0.72 mmol), K2CO3 (199 mg, 1.44 mmol), 3-chloro-2-methyl propene (450 μL, 5.17 mmol), NaI (˜10 mg) and acetone (8 mL) were charged to a 50 mL RBF. The reaction was heated to reflux for 20 h after which time it was deemed complete by TLC (1:9 EtOAc:Hept). The reaction was diluted with water (15 mL) and DCM (10 mL). The aqueous layer was separated and washed with DCM (3×10 mL). The combined DCM layers were dried over Na2SO4, filtered and concentrated by rotary evaporation to yield (R,R,R)-2,7,8-trimethyl-6-(2-methyl-allyloxy)-2-(4,8,12-trimethyl-tridecyl)-chroman as a pale yellow liquid (Ex-1F-2) (324 mg, 95%). The isolated product was used without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:21][C:20](=[O:22])[NH:19][N:18]=2)[CH2:13][CH2:12]1.[C:23]1([CH2:29]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:29]([N:19]1[N:18]=[C:17]([CH:14]2[CH2:15][CH2:16][N:11]([C:3]3[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[F:1])[CH2:12][CH2:13]2)[O:21][C:20]1=[O:22])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=c1[nH]nc(C2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)o1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1oc(C2CCN(c3ccc([N+](=O)[O-])cc3F)CC2)nn1Cc1ccccc1
Temperature: 0 °C
Yield: 381.5 %

Procedure:
5-[1-(2-Fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (5b, 1.23 g, 4 mmol) on reacting with C6H5CH2Br (0.82 g, 1 mmol) in DMF in the presence of base K2CO3 (1.38 g, 10 mmol) at room temperature (27° C.) for 10 h, after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography to afford pure compound 3-benzyl-5-[1-(2-fluoro-4-nitrophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (6f, 1.52 g, 96%). Nitro compound (6f, 1.59 g, 4 mmol) on reduction with SnCl2.2H2O (2.71 g, 12 mmol) in methanol and refluxed at 65° C. for 4 h, after completion of reaction methanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered through celite bed and purified in silica column (60-120) to afforded pure compound 5-[1-(4-amino-2-fluorophenyl)-4-piperidyl]-3-benzyl-2,3-dihydro-1,3,4-oxadiazol-2-one (7 h, 1.26 g, 86%). To a stirred solution of 5-nitro2-furanoic acid in DMF add. HOBT (Hydroxybenzotriazole) (0.14 g, 1 mmol), EDCI (1-Ethyl-3-(3-dimethyl aminopropyl)carbodi imide)) (0.19 g, 1 mmol) and amine compound (7 h, 0.36 g, 1 mmol) and stirred for 2 h at room temperature (27° C.), after completion of the reaction, reaction mixture is poured into ice water and extracted into chloroform finally purification by column chromatography using ethyl acetate-hexane (7:3) as eluant to afford pure compound N2-4-[4-(4-benzyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperi dino]-3-fluorophenyl-5-nitro-2-furamide (8 h, 430 mg, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[Na].[CH3:10][SH:11].C(=O)([O-])O.[Na+]>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([S:11][CH3:10])=[CH:4][N:3]=1
Reactant: Nc1cnc(Br)cn1
Reactant: CS
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: CSc1cnc(N)cn1
Temperature: 60 °C
Reaction time: 15 h
Yield: 83.6 %

Procedure:
A suspension of 2-amino-5-bromopyrazine (100 mg), 95% methanethiol sodium salt (84.8 mg) and tetrakistriphenylphosphine palladium (66.4 mg) in N,N-dimethylformamide (2.9 ml) was stirred at 60° C. for 15 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution, extracted with toluene, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was separated using silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain 67.8 mg (84%) of the desired product as a white powder.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([NH:15][C:16]2[N:21]=[C:20]([CH3:22])[CH:19]=[CH:18][CH:17]=2)=[C:7]([N+:23]([O-:25])=[O:24])[CH:6]=1)C.O.Cl>[OH-].[Na+]>[CH3:22][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:15][C:8]2[C:9]([S:11](=[O:13])(=[O:14])[NH2:12])=[CH:10][C:5]([C:4]([OH:26])=[O:3])=[CH:6][C:7]=2[N+:23]([O-:25])=[O:24])[N:21]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Nc2cccc(C)n2)c(S(N)(=O)=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(Nc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)n1

Procedure:
Ethyl-4-(2-methyl-6-pyridylamino)-3-nitro-5-sulphamyl-benzoate (2 g) was dissolved in 1N sodium hydroxide (30 ml) and heated on a steam bath for 1 hour. After cooling, water (50 ml) was added, and the pH of the reaction mixture was adjusted to 4.5 by addition of 1N hydrochloric acid. The precipitated 4-(2-methyl-6-pyridylamino)-3-nitro-5-sulphamyl-benzoic acid was collected by suction, washed with water, and dried. The compound had a melting point of 305° C (decomp.).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl[C:14]([O:16][CH3:17])=[O:15].C(OCC)(=O)C>C1COCC1.O>[CH3:17][O:16][C:14]([NH:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:15]
Reactant: COC(=O)Cl
Reactant: NCCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)NCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A stirred solution of 3-phenyl-1-propylamine (19.6 g, mmol) in THF (50 mL) and water (50 mL) was adjusted to pH 9.0 with 2N NaOH. To the reaction was added methyl chloroformate (12.3 mL, 159 mmol) dropwise while the pH was maintained at 9.0 with 2N NaOH. After the reaction was stirred for an additional 30 minutes at room temperature, ethyl acetate (250 mL) was added. The organic layer was separated, dried (MgSO4), filtered, and the filtrate was concentrated in vacuo to give a clear oil of pure title compound (28 g, 100 percent yield):
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:15][C:16]#[CH:17]>CC(C)=O.C(OCC)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:17][C:16]#[CH:15])[CH2:4][CH2:3]1
Reactant: C#CCBr
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: C#CCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.5 %

Procedure:
To a stirred, chilled suspension of 1-methylpiperazine (10.0 g, 100.0 mmol) and cesium carbonate (32.6 g, 100.0 mmol) in acetone (200 mL) was added 3-bromoprop-1-yne (11.0 mL, 100 mmol) (80% in toluene). The reaction was stirred for 18 hours at room temperature under N2. The suspension was diluted with diethyl ether (200 mL) and filtered, and the filtrate was concentrated in vacuo. The resulting residue was resuspended in diethyl ether (100 mL) and refiltered. The filtrate was concentrated to an orange oil (8.2 g). The product was distilled under high vacuum. The product distilled between 95-120° C. head temperature. The product was obtained as a colorless oil (5.46 g, 32%). 1H NMR (400 MHz, CDCl3) δ 3.31 (m, 2H), 2.89 (m, 1H), 2.3-2.6 (m, 8H), 2.30 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][C:12]([OH:27])=[C:13]([C:23]([O:25]C)=[O:24])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][C:12]([OH:27])=[C:13]([C:23]([OH:25])=[O:24])[CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2nc(N(C)C(C)C)c(-c3ccc(F)cc3)nc2cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)c(O)cc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-7-hydroxy-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (45 mg, 0.12 mmol) in methanol (30 mL) and water (1.0 mL) was added sodium hydroxide (19.5 mg, 0.49 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL), adjusted to pH 5 with hydrochloric acid (3N) to give the precipitate, which was collected by filtration to afford 2-(4-fluorophenyl)-7-hydroxy-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (38.2 mg, 88%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=2)[C:12]=1[CH3:13])=[O:7])C.Cl>C(O)C>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[N:10]2)=[CH:19][CH:18]=1)[CH3:22]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC)cc2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccc(-n2ncc(C(=O)O)c2C)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
1N Aqueous solution of sodium hydroxide (4.8 ml) was added to a solution of 1-(4-ethoxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.3 g) in ethanol (24 ml) at room temperature and stirred at 70° C. for three hours. After completion of the reaction, the reaction solution was cooled to room temperature, 1N hydrochloric acid aqueous solution was added and the precipitated solid was collected by filtration to give the titled compound (1.12 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:20]O>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:20])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)CCCOCc1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-benzyloxybutyric acid (54.8 g, 0.282 mol) in methanol (1.4 L), was added sulfuric acid (concentrated, 1.4 mL) dropwise and it was stirred at room temperature under nitrogen overnight. The reaction mixture was concentrated on a rota-vapor, the residue was then partitioned between ethyl acetate (700 mL) and saturated sodium bicarbonate aqueous solution (200 mL). The organic phase was separated, washed with brine (2×100 mL), then dried over Na2SO4 and filtered. Evaporation of solvent gave the titled compound as an oil that was used in step B without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C:5]([CH3:23])([CH3:22])[N:6]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7]2.CC([O-])(C)C.[Na+].[N:30]1([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:39]([O:38][C:36]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][C:5]([CH3:23])([CH3:22])[N:6]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:7]3)[CH2:32][CH2:31]1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC1(C)Cc2c(Br)cccc2CN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CC(C)(C)N(C(=O)OCc2ccccc2)C3)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
To 78A (600 mg, 1.60 mmol) in toluene (5 mL) was added NaOtBu (215 mg, 2.24 mmol), tert-butyl piperazine-1-carboxylate (358 mg, 1.92 mmol), Pd2(dba)3 (3.6 mg, 0.004 mmol) and BINAP (7.4 mg, 0.012 mmol). The reaction mixture was heated at 100° C. in a sealed tube. After 18 h, the reaction was cooled to rt, quenched with H2O, extracted with EtOAc twice, the combined organics were washed with H2O, brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification by silica gel column chromatography afforded 78B (500 mg, 67%) as a green liquid. MS (ESI) m/z: 480.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[C:15]([F:23])[CH:14]=1.Cl([O-])=[O:25].[Na+].CC(=CC)C.P([O-])(O)(O)=O.[Na+]>O.C(O)(C)(C)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:25])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[C:15]([F:23])[CH:14]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(OCCO)c(F)c3)cc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCO)c(F)c3)cc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 47.7 %

Procedure:
To a solution of 6-chloro-5-[3-fluoro-4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carbaldehyde (40 mg, 0.12 mmol) in water (1 mL) and t-butanol (1 mL) was added sodium chlorite (210 mg, 2.30 mmol), 2-methyl-2-butene (0.5 mL) and sodium dihydrogen phosphate (350 mg, 2.90 mmol). The reaction solution was stirred at room temperature for 10 hrs. The reaction was diluted with water (5 mL) and extracted with dichloromethane (20 mL×3). The combined organic phase was washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated to give a crude product. The crude was purified by preparative HPLC to give the title compound (20 mg, 49% yield) as off-white solid. MS (AP−) 348.0 (M−H)−. 1H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 8.01 (s, 1H), 7.60 (s, 1H), 7.20 (m, 3H), 4.21 (t, 2H), 3.95 (t, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[N-:35]=[N+:36]=[N-:37].[Na+]>CC(C)=O.O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][C:18]([N:35]=[N+:36]=[N-:37])=[O:19])=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1CCCC(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1[nH]c2ccc(Br)cc2c1CCCC(=O)N=[N+]=[N-]
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
5-Bromo-3-(3-carboxy-propyl)-1H-indole-2-carboxylic acid ethyl ester (1.2 g, 3.40 mmol, 1.0 equiv) (see Example 2) was dissolved in 30 mL of acetone, cooled to −5° C. and triethylamine (0.76 ml, 5.44 mmol, 1.6 equiv) was added. To this cold solution, ethyl chloroformate (0.6 mL, 5.44 mmol, 1.6 equiv) was added dropwise and the mixture was stirred for 30 min at 0° C. A solution of sodium azide (440 mg, 6.8 mmol, 2.0 equiv) in 2 mL of water was added slowly and the mixture was stirred for a further 1 h at 0° C. The reaction mixture was then poured into ice-water (50 mL) and extracted 3×50 mL of diethyl ether. The pooled organic fractions were washed with 1×50 mL of water, 1×50 mL of saturated sodium bicarbonate, 1×50 mL of water, dried (Na2SO4), filtered and evaporated on the rotovap to provide 3-(3-azidocarbonyl-propyl)-5-bromo-1H-indole-2-carboxylic acid ethyl ester (1.28 g, 100%) which was used without further purification.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([C:13]2[NH:17][C:16]([C:18]3([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:15][N:14]=2)[CH:7]=1.[CH2:28]([N:30]=[C:31]=[O:32])[CH3:29]>C(N(CC)CC)C>[CH2:28]([NH:30][C:31](=[O:32])[O:12][C:9]1[CH:10]=[CH:11][C:6]([CH3:5])=[CH:7][C:8]=1[C:13]1[NH:17][C:16]([C:18]2([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[CH2:19][CH2:20][CH2:21][CH2:22]2)=[N:15][N:14]=1)[CH3:29]
Reactant: CCN=C=O
Reactant: Cc1ccc(O)c(-c2nnc(C3(c4cccs4)CCCC3)[nH]2)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCNC(=O)Oc1ccc(C)cc1-c1nnc(C2(c3cccs3)CCCC2)[nH]1

Procedure:
A chloroform solution (2.7 ml) of 4-{4-methyl-[5-(1-(2-thienyl)cyclopentyl]-4H-1,2,4-triazol-3-yl}phenol (40 mg), triethylamine (103 μl), and ethyl isocyanate (57 μl) was heated at 60° C. for 5 hours. The solvent was removed by evaporation and a small amount of ethyl acetate was added to the residue. The resulting white solid was collected by filtration and washed with diethyl ether to obtain 4-{4-methyl-[5-(1-(2-thienyl)cyclopentyl]-4H-1,2,4-triazol-3-yl}phenyl ethylcarbamate (30 mg).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14](Br)[CH:15]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>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]>[CH2:1]([NH:8][C:14]1[CH:13]=[N:12][CH:11]=[C:10]([Br:9])[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cncc(Br)c1
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Brc1cncc(NCc2ccccc2)c1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-3 [B], benzylamine was reacted with 3,5-dibromopyridine in the presence of Pd2(dba)3, rac-BINAP and sodium tert-butoxide to give the title compound as a yellow solid. MS: 262.9, 264.9 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([NH:13][C:14]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:15]=3[C:16]([OH:18])=[O:17])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[CH2:26]Cl>>[CH3:26][O:17][C:16](=[O:18])[C:15]1[C:19]([F:24])=[CH:20][C:21]([F:23])=[CH:22][C:14]=1[NH:13][C:11](=[O:12])[CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1
Reactant: ClCCl
Reactant: O=C(Cc1ccc2c(c1)OCO2)Nc1cc(F)cc(F)c1C(=O)O
Product: COC(=O)c1c(F)cc(F)cc1NC(=O)Cc1ccc2c(c1)OCO2
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a 0-5° C. cooled suspension of 2-(2-benzo[1,3]dioxol-5-yl-acetylamino)-4,6-difluoro-benzoic acid (0.50 g, 1.49 mmol) in dichloromethane (20 mL) was added 2 M (trimethylsilyl)diazomethane diethyl ether solution (0.82 mL, 1.64 mmol). The mixture was stirred at room temperature for 1 h, then the solvent was evaporated, to provide the title compound (0.52 g, 98% yield).