Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[Cl-].[NH4+]>C1COCC1.C(O)C.[Fe]>[CH2:1]([O:8][C:9](=[O:27])[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([C:22](=[O:26])[N:23]([CH3:24])[CH3:25])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)c1cc(CCCC(=O)OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)C(=O)c1cc(CCCC(=O)OCc2ccccc2)ccc1N
Temperature: 100 °C
Yield: 89.2 %

Procedure:
To a mixed solution of 4-(3-dimethylcarbamoyl-4-nitrophenyl)butanoic acid benzyl ester (1.39 g) in THF (5 mL), ethanol (15 mL), and water (5 mL) was added ammonium chloride (1.0 g). After heating to 100° C., iron (838 mg) was added thereto in twice. The mixture was further heated for 1.5 hours under reflux, allowed to stand for cooling down to room temperature, and filtered through a Celite pad. The filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate, washed successively with saturated sodium bicarbonate, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound (1.14 g).
Reaction SMILES: Cl[C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1.[CH2:35]([SH:39])[CH2:36][CH2:37][CH3:38].[OH-].[K+].CN1CCCC1=O.Cl>C(OCC)(=O)C>[CH2:35]([S:39][C:2]1[CH:34]=[CH:33][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([CH3:25])[CH3:24])[C:10]=3[OH:32])[N:8]=[C:4]2[CH:3]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CCCCS
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCCSc1ccc2nn(-c3cc(C(C)(C)CC(C)(C)C)cc(C(C)(C)c4ccccc4)c3O)nc2c1
Temperature: 170 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
5-Chloro-2-(2-hydroxy-3-α-cumyl-5-tert-octylphenyl)-2H-benzotriazole (38.1 g, 0.08 mol), n-butyl mercaptan (9 g, 0.10 mol), potassium hydroxide (10.1 g, 0.18 mol) and N-methylpyrrolidone (99 g, 1.0 mol) are charged to a reactor and heated to 170° C. The reaction mass is held at 170° C. with vigorous stirring for five hours. The reaction is judged as complete using thin layer chromatogrphy. The temperature is reduced to 5° C. and 100 mL of aqueous 2N hydrochloric acid are then added to the reactor. The liquid is decantedand the solids are dissolved in ethyl acetate. The organic layer is washed with aqueous 2N hydrochloric acid followed by water. The ethyl acetate is stripped off and the product is crystallized from ethanol and toluene. The tide compound is obtained as a yellow crystalline product in 83% yield. The structure is verified by 1Hnmr.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[C:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[C:23]([F:32])[CH:22]=4)[CH:17]=3)[S:12][C:11]([CH3:34])([CH3:33])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+].Cl>C1COCC1.CCO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[C:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[C:23]([F:32])[CH:22]=4)[CH:17]=3)[S:12][C:11]([CH3:33])([CH3:34])[CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CC(C)(C)S3)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1ccc(C2=CC(C)(C)Sc3ccc(C#Cc4ccc(C(=O)O)c(F)c4)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a solution of ethyl 4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-2-fluorobenzoate (Compound 237, 125.0 mg, 0.266 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (120.0 mg, 3.0 mmol, 3.0 mL of a 1M aqueous solution). The resulting solution was stirred overnight at room temperature. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 100.0 mg (86%) of the title compound as a pale-yellow solid. 1H NMR (300 MHz, d6 -acetone) δ: 7.94 (1H, d J=7.8 Hz), 7.43-7.20 (9H, m), 5.93 (1H, s), 2.68 (2H, q, J=7.6 Hz), 1.47 (6H, s), 1.24 (3H, t, J=7.6 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[C:13]1([O:19][CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)(=O)C>ClCCl.O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([C:16]1[CH:17]=[CH:18][C:13]([O:19][CH3:20])=[CH:14][CH:15]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1

Procedure:
A mixture of 3-nitrobenzoyl chloride (3.71 g), anisole (2.0 ml) and aluminum chloride (2.67 g) in dichloromethane (50 ml) was refluxed for 1 hour. The reaction mixture was poured into a mixture of ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with ethyl acetate to give 1-(3-nitrobenzoyl)-4-methoxybenzene (955 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27](C#N)[CH:26]=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1.BrCC1C=C([N:42]2[CH:46]=[CH:45][CH:44]=[CH:43]2)C=CC=1>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:42]4[CH:46]=[CH:45][CH:44]=[CH:43]4)[CH:26]=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1
Reactant: BrCc1cccc(-n2cccc2)c1
Reactant: N#Cc1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)cc(=O)n(Cc2cccc(-n3cccc3)c2)c1=O

Procedure:
Title compound 22 was prepared by the methods used in the preparation of compound 17, except that 1-(3-bromomethyl-phenyl)-1H-pyrrole was used in the place of m-cyano-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1) δ 7.59 (d, J=7.3 Hz, 1 H), 7.48 (t, J=7.7 Hz, 1 H), 7.24-7.36 (m, 4 H), 7.21 (t, J=7.6 Hz, 2H), 7.02 (t, J=2.1 Hz, 2 H), 6.32 (t, J=2.0 Hz, 2 H), 5.42 (s, 1H), 5.11-5.20 (ABq, J=44.7, 15.9 Hz, 2 H), 5.06 (s, 2 H), 3.36 (m, 2 H), 2.98 (m, 1 H), 2.89 (m, 1 H), 2.70 (m, 1 H), 2.10 (m, 1 H), 1.88 (m, 1 H), 1.73-1.58 (m, 2 H). MS (ES) [m+H] calc'd for C28H29N6O2, 481.2. found 481.2.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2.[CH3:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1>>[CH3:24][C:25]1[CH:29]=[C:28]([CH3:30])[N:27]([C:2]2[N:11]=[C:10]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=3[N:22]=[CH:21][CH:20]=[CH:19]4)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:26]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Nc1cccc2cccnc12
Reactant: Cc1cc(C)[nH]n1
Product: Cc1cc(C)n(-c2nc(Nc3cccc4cccnc34)c3ccccc3n2)n1

Procedure:
Was prepared according to Method B from 2,4-dichloroquinazoline, 8-aminoquinoline and 3,5-dimethylpyrazole. Mp. 183.5-184.8° C.
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH:7]=[CH:8][CH3:9])[OH:3].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH3:9])[CH:10]=[C:1]([O:11][CH3:12])[C:2]=1[OH:3])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC=Cc1ccc(O)c(OC)c1
Solvent: c1ccncc1
Product: CC=Cc1cc(OC)c(O)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of isoeugenol (344 g., 2.1 moles) in 420 ml. of pyridine under nitrogen atmosphere is added 428 ml. of acetic anhydride over a period of 30 minutes. The resulting solution is stirred at room temperature overnight followed by treatment with ice-water (1400 ml.). After stirring for three hours, the resulting precipitate is filtered, washed with water (3×500 ml.) and dried in vacuo to give 381.7 g. of crude product. Acetyl isoeugenol (269 g., 62%) is obtained from washing the crude product with n-hexane.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[Cl-].[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:44]/[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=4)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: c1ccc([P+](Cc2ccccn2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2ccccn2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.6 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.80 g), [(2-pyridyl)methyl]triphenylphosphonium chloride (0.94 g), potassium carbonate (0.33 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give 2-((E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenyl)pyridine as colorless crystals (0.68 g, yield 76%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 135-136° C.
Reaction SMILES: [H-].[Na+].[H][H].[I-].[CH3:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34](=O)[CH2:33][CH2:32][CH2:31]2>CS(C)=O>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34](=[CH2:6])[CH2:33][CH2:32][CH2:31]2
Reactant: [H][H]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C=C1CCCc2cc(OC)ccc21
Temperature: 72.5 °C
Reaction time: 0.33 h
Yield: 93.8 %

Procedure:
To a dry 500 mL 3-necked round bottom flask equipped with a reflux condenser and magnetic stir bar, was charged sodium hydride (3.0 g, 172.89 mmol). The reaction flask was put under nitrogen, and 35 mL of anhydrous DMSO was added. The reaction mixture was heated to 70-75° C., and stirred at that temperature until the evolution of hydrogen ceased. The reaction mixture was cooled to room temperature and additional 25 mL of DMSO was added. Methyltriphenylphosphonium iodide (46.57 g, 115.26 mmol) was added in portions over a period of 1 h. 25 mL of additional DMSO was added to facilitate easy stirring. After the completion of addition, the reaction mixture was stirred for 20 minutes. 6-methoxytetralone (10.156 g, 57.63 mmol) dissolved in 10 mL of anhydrous DMSO was added to reaction mixture. Then, the reaction mixture was heated to 60-65° C., and stirred at that temperature for 8 h. The reaction mixture was poured into a 500 mL Erlenmeyer flask containing 150 mL of crushed ice and 150 mL of hexanes. The resulting mixture was stirred vigorously for 15 min, and then extracted with hexanes. The combined organic layers were washed DMSO:Water (1:1) and then dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. Purification by flash column chromatography (silica gel 3:97 EtOAc:Hexanes) yielded 9.42 g of 27 as white solid (94%). Rf: 0.71, (30:70, EtOAc:Hexanes).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([O:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:17]([O:19][C:20]([C:22]1([NH2:31])[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21])[CH3:18].CCN(C(C)C)C(C)C.CC(O)C.C(Cl)Cl>C(Cl)Cl>[CH2:17]([O:19][C:20]([C:22]1([NH:31][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]([CH3:16])[C:5]=2[O:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1cc(Br)cc(C(=O)O)c1OC1CCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2cc(Br)cc(C)c2OC2CCC2)Cc2ccccc2C1
Reaction time: 0.08 h

Procedure:
A 100 mL round bottom flask which contains a stirring bar is charged with 2-cyclobutoxyl-3-methyl-5-bromo-benzoic acid 317 (695 mg, 2.44 mmol) and dry DCM (8 mL). Stirring is initiated. After dissolution is complete, HTBU (924 mg, 2.44 mmol) is added. After 5 min, 2-amino-indane-2-carboxylic acid ethyl ester (500 mg, 2.44 mmol) is added followed by DIPEA (1.1 mL, 6.1 mmol). The reaction is allowed to stir for 15 days. Analysis by tlc of the reaction mixture (silica, 5% iPrOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are transferred to a separatory funnel and diluted with EtOAc (50 mL). The organic phase is washed consecutively with dilute aqueous HCl (3%, 25 mL), saturated aqueous NaHCO3 (25 mL) and brine (25 mL), and then dried over MgSO4, filtered and evaporated in vacuo to give 1.42 g of light orange solid. This solid is dissolved in 10 mL of DCM. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 10% EtOAc in heptanes over 3 column volumes followed by a linear gradient to 60% EtOAc in heptanes over 10 column volumes. 17 mL fractions of UV active eluent are collected. Fractions 4 through 9 are combined and evaporated in vacuo. This yields white solid material (0.8 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]([C:22]1[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([OH:35])=O)=[CH:28][CH:27]=1)=[O:21].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:33](=[O:35])[CH2:32][C:29]2[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:23]3[CH:36]=[CH:37][CH:38]=[CH:39][C:22]=3[C:20]([O:19][CH3:18])=[O:21])=[CH:31][CH:30]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCCNCCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccccc1OCc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCN(CCc1ccc(Cl)cc1)C(=O)Cc1ccc(COc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
N-[2-(4-Chlorophenyl)ethyl]-N-heptylamine (0.127 g, 0.500 mmol) was dissolved in DMF (10 ml), (4-{[2-(methoxycarbonyl)phenoxy]methyl}phenyl)acetic acid (0.150 g, 0.500 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.176 g, 0.549 mmol) and N-ethyl-N,N-diisopropylamine (0.136 g, 1.049 mmol) was added. The solution was stirred overnight at room temperature. EtOAc (20 ml) was added and the organic phase was washed with two portions of Na2CO3 (2×20 ml, aq). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 0.224 g of methyl 2-[(4-{2-[[2-(4-chlorophenyl)ethyl](heptyl)-amino]-2-oxoethyl}benzyl)oxy]benzoate (yield 83.7%).
Reaction SMILES: [NH2:1][C:2]1[C:21]([C:22]2[CH:27]=[C:26]([C:28](=[O:34])[NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:25]=[C:24]([NH2:35])[CH:23]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[C:30]([NH:29][C:28]([C:26]1[CH:27]=[C:22]([C:21]2[C:2]([NH:1][S:43]([CH3:42])(=[O:45])=[O:44])=[CH:3][C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=4)=[C:6]([C:16]([NH:18][CH3:19])=[O:17])[C:5]=3[CH:20]=2)[CH:23]=[C:24]([NH:35][S:43]([CH3:42])(=[O:45])=[O:44])[CH:25]=1)=[O:34])([CH3:31])([CH3:32])[CH3:33]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3cc(N)cc(C(=O)NC(C)(C)C)c3)cc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(-c3cc(NS(C)(=O)=O)cc(C(=O)NC(C)(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
To a solution of 6-amino-5-(3-amino-5-(tert-butylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (100 mg) and pyridine (0.170 mL) in CH2Cl2 (10 mL) was added methanesulfonyl chloride (72.4 mg) slowly at 0° C. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was concentrated and the residue was purified by preparative HPLC to give 5-(3-(tert-butylcarbamoyl)-5-(methylsulfonamido)phenyl)-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide 4 (92 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:31])([F:30])[C:10]([N:12]1[CH2:17][C:16]2([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[O:15][CH2:14][CH2:13]1)=[O:11].C1(C)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:31][C:9]([F:8])([F:30])[C:10]([N:12]1[CH2:17][C:16]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:15][CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C(=O)C(F)(F)F)CCO2
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(N1CCOC2(CCNCC2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Trifluoroacetic acid (66 mL) was added to a solution of tert-butyl 4-(2,2,2-trifluoroacetyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 101, step d) (4.33 g) in DCM (66 mL) and the resulting mixture was stirred at RT for 20 min. Toluene (50 mL) was added and the mixture was evaporated in vacuo (×3) to give the subtitled compound. Yield 5.52 g.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:46]=3[Cl:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Fc1cccc(CBr)c1Cl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cccc(F)c3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-chloro-3-fluorobenzene and isolated as light-yellow gums (4.9 mg, 28%). MS (m/e): 425.3 (MH+).
Reaction SMILES: C(C[CH2:5][CH2:6]/[CH:7]=[CH:8]\[C@@H:9]1[CH2:13][C@@H:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:11][N:10]1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])(O)=O.[H-].[Na+].I[CH3:38].[C:39]([O:42][CH2:43]C)(=[O:41])[CH3:40]>>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([S:25]([N:10]2[CH2:11][C@H:12]([N:14]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH3:38])[CH2:13][C@H:9]2/[CH:8]=[CH:7]\[CH2:6][CH2:5][CH2:40][C:39]([O:42][CH3:43])=[O:41])(=[O:27])=[O:26])=[CH:33][CH:32]=1
Reactant: O=C(O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1S(=O)(=O)c1ccc(Cl)cc1
Reactant: CI
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Product: COC(=O)CCC/C=C\[C@@H]1C[C@@H](N(C)S(=O)(=O)c2ccc(Cl)cc2)CN1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (2S,4R)-2-[(Z)-5-carboxy-1-pentenyl]-1-(4-chlorophenylsulfonyl)-4-(4-chlorophenylsulfonylamino)pyrrolidine (274 mg) were added sodium hydride (60 mg) and iodomethane (0.1 ml) and the mixture was stirred at room temperature for 5 hours. The solution was diluted with ethyl acetate and washed successively with water and brine. The organic solution was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel with a mixture of n-hexane and ethyl acetate (3:1) as an eluent to give (2S,4R)-1-(4-chlorophenylsulfonyl)-4-[N-(4-chlorophenylsulfonyl)-N-methylamino]-2-[(Z)-5-methoxycarbonyl-1-pentenyl]pyrrolidine (220 mg) as an oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[N:24][NH2:25])[C:19](=[O:23])[NH:20]2)=[C:16]([Br:26])[CH:15]=1)=[O:13].[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][C:37](O)=[O:38])=[CH:35][C:30]=2[CH2:29][CH2:28]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[N:24][NH:25][C:37](=[O:38])[CH2:36][C:34]3[CH:33]=[CH:32][C:31]4[O:27][CH2:28][CH2:29][C:30]=4[CH:35]=3)[C:19](=[O:23])[NH:20]2)=[C:16]([Br:26])[CH:15]=1)=[O:13]
Reactant: NN=C1C(=O)Nc2cc(C(=O)NCCCN3CCC[C@H]3CO)cc(Br)c21
Reactant: O=C(O)Cc1ccc2c(c1)CCO2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1ccc2c(c1)CCO2)NN=C1C(=O)Nc2cc(C(=O)NCCCN3CCC[C@H]3CO)cc(Br)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
(S)-4-Bromo-3-hydrazono-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid [3-(2-hydroxymethyl-pyrrolidin-1-yl)-propyl]-amide (0.22 g, 0.52 mmol) was added to a solution of (2,3-dihydro-benzofuran-5-yl)-acetic acid (0.93 g, 0.52 mmol), triethylamine (0.01 mL, 0.78 mmol) and HBTU (0.20 g, 0.52 mmol) in DMF (4 mL) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by column chromatography (20% methanol in dichloromethane) followed by HPLC (10-100% acetonitrile/water) to give 0.040 g (13%) of (S)-4-bromo-3-[(2-2,3-dihydro-benzofuran-5-yl-acetyl)-hydrazono]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid [3-(2-hydroxymethyl-pyrrolidin-1-yl)-propyl]-amide. 1H NMR (400 MHz, CD3OD) δ 7.75 (s, 1H), 7.37 (s, 1H), 7.24 (s, 1H), 7.11 (d, J=7.8 Hz, 1H), 6.65 (d, J=8.2 Hz, 1H), 4.50 (t, J=12.7 Hz, 2H), 4.10 (bs, 2H), 3.88 (dd, J=3.9 Hz, J=12.2 Hz, 1H), 3.74-3.40 (m, 6H), 3.22-3.04 (m, 4H), 2.26-1.81 (m, 6H). Mass spectrum (LCMS, ESI pos.): Calcd for C27H30BrN5O5: 584.46. Found 584.1; (M+H).