Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[CH3:12][S:13]([O-:15])=[O:14].[Na+]>C(O)C>[CH3:12][S:13]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1)(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
To a solution of 1-bromomethyl-3-nitro-benzene (5.0 g, 23 mmol) in ethanol (50 mL) was added solution of sodium methanesulfinate (3.06 g, 30 mmol) in ethanol (30 mL) and the mixture was stirred for 4 h at room temperature, then was concentrated in vacuo to volume about 20 mL and diluted with water (200 mL). Formed precipitate was filtered out, washed with water (2×100 mL) and dried to give 1-methanesulfonylmethyl-3-nitro-benzene (4.3 g; 87%) as yellowish crystalline powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)=[O:5])[CH3:2].C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][Br:20])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cccc(CBr)n1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A mixture of 6-methyl-pyridine-2-carboxylic acid ethyl ester (1.65 g, 10 mmol), NBS (1.77 g, 10 mmol), and benzoyl peroxide (100 mg) in carbon tetrachloride (20 ml) was refluxed for 14 h. After cooling to room temperature, the reaction mixture was partitioned between diethyl ether and water (120 ml, 4:1), organic layer was washed with water (2×20 ml), brine, dried (MgSO4), filtered and concentrated to give 6-bromomethyl-pyridine-2-carboxylic acid ethyl ester (2.4 g) which was used without further purification. LCMS m/z: 245 (M+1)+.
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].Cl.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[O:23]=[C:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:15]=[CH:16][C:11]([NH:10][S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:7])=[O:6])=[CH:12][CH:13]=2)[CH2:18][CH2:19]1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: CCCCS(=O)(=O)Cl
Agent: Cl
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 1-butanesulfonyl chloride and 1-(4-amino-phenyl)-piperidin-4-one hydrochloride (which was obtained in Example 224) according to the procedure B of Example 225 as a crystalline solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83 (t, J=7.3 Hz, 3 H), 1.25–1.40 (m, 2 H), 1.55–1.70 (m, 2 H), 2.40 (t, J=5.9 Hz, 4 H), 2.94 (t, J=7.6 Hz, 2 H), 3.54 (t, J=5.9 Hz, 4 H), 7.00 (d, J=9.0 Hz, 2 H), 7.09 (d, J=9.0 Hz, 2 H), 9.34 (s, 1 H); MS (ES) m/z: 311.0 (MH+); HRMS Calcd. for C15H22N2O2S(M+): 310.1351. Found: 310.1375. Anal. Calcd. for C15H22N2O2S: C, 58.04; H, 7.14; N, 9.02. Found: C, 57.78; H, 6.95; N, 8.83.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[CH:9]=[CH:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:35])[C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:26])[CH:19]=1)[CH3:4]>O1CCCC1.CO>[CH2:3]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:9]=[CH:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:35])[C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:26])[CH:19]=1)[CH3:4]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCC)c1
Yield: 78 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10.0 mmol, 4.8 eq) of sodium hydroxide and methyl 3-[2-ethoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate, obtained in the preceding step, in 10 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane/isopropyl ether, 246 mg of 3-[2-ethoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=64° C.). Yield=78% over the two steps
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH:9]([CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](Cl)[C:29]#[CH:30].[Cl-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([CH2:13][CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:30][C:29]#[CH:28])[C:15]2=[O:23])[C:10]([OH:12])=[O:11])=[O:7])=[CH:24][CH:25]=1
Reactant: C#CCCl
Reactant: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)C(CC(NC(=O)c2ccc(Cl)cc2)C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
479 Milligrams of 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionic acid 1/4-hydrate prepared in Example 3 and 70 mg of 50% sodium hydride (in oil) were admixed in 5 ml of dimethylformamide, and the mixture was stirred at a room temperature for 2 hours. Then 0.17 g of propargyl chloride was added to the reaction mixture and the whole reaction mixture was stirred at a room temperature for 7 hours. The reaction mixture was poured into 13 ml of a saturated sodium chloride aqueous solution, and the organic material was extracted with chloroform. The chloroform layer was washed with water, dried, then chloroform was removed by evaporation. The residue thus obtained was purified by means of a silica gel column chromatography to yield 80 mg of 2-(4-chlorobenzoylamino)-3-[1-(2-propynyl)oxindol-3-yl]propionic acid.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl[C:15]([O:17][CH:18]([Cl:20])[CH3:19])=[O:16]>C(Cl)Cl>[C:15](=[O:16])([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:17][CH:18]([Cl:20])[CH3:19]
Reactant: CC(Cl)OC(=O)Cl
Reactant: OC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)OC1CCCCC1
Yield: 88 %

Procedure:
A solution of 1.83 g of cyclohexanol and 1.45 g of pyridine in 30 ml of methylene chloride is cooled to -78° C. and, with stirring, 2.0 ml of 1-chloroethyl chloroformate is added dropwise to the solution over a period of 10 minutes. After completion of addition, the cold bath is removed. The mixture is stirred at room temperature for 16 hours, washed with three 30-ml portions of saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure to give 3.31 g (yield 88%) of the title compound as colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].Br[CH2:9][CH:10]=[CH:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>CO.C(N(CC)CC)C>[CH2:18]([O:17][P:13]([O:14][CH2:15][CH3:16])([CH2:12]/[CH:11]=[CH:10]/[CH2:9][NH:6][CH2:5][C:4]([O:3][CH3:2])=[O:7])=[O:20])[CH3:19]
Reactant: CCOP(=O)(CC=CCBr)OCC
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOP(=O)(C/C=C/CNCC(=O)OC)OCC
Yield: 34 %

Procedure:
A solution of glycine methyl ester hydrochloride (1.6 g, 12.7 mmol) and diethyl (4-bromo-2-butenyl)phosphonate (Example E) (3.14 g, 11.6 mmol) in methanol and triethylamine (5 ml) is heated at reflux for 16 hours. The solvent is removed in vacuo and the residue dissolved in water and extracted with chloroform (2×70 ml). The organic layer is dried over magnesium sulfate, filtered and evaporated. The residue is purified over silica gel (0-2.5% methanol in chloroform as eluant) to give 1.1 g of a clear oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH2:11][CH2:12][OH:13].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.O>C1COCC1>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][C:5]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=1[CH3:3]
Reactant: BrCCCCCCBr
Reactant: Cc1cccc(C)c1CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C)c1CCOCCCCCCBr
Yield: 52.7 %

Procedure:
NaH (46% dispersion in oil; 4.2 g) was added portionwise to a solution of 2,6-dimethylbenzenethanol (6.0 g) and 1,6-dibromohexane (19.52 g) in THF (50 ml) under nitrogen. The mixture was refluxed for 18 h and treated cautiously with H2O (20 ml). The resulting emulsion was extracted with ER (3×100 ml) and the dried extract was evaporated to leave a yellow oil. Excess 1,6-dibromohexane was removed under reduced pressure and the residue was purified on a column of silica (300 ml) [B] to give the title compound as a colourless oil (6.6 g) b.p. 110°-115°/0.4 mmHg.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]#[C:16][CH:17]2[CH2:19][CH2:18]2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:20][S:21]([CH2:24][CH2:25][N:26]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]2[CH:38]=[CH:37]C(N)=[CH:35][CH:34]=2)[CH2:28][CH2:27]1)(=[O:23])=[O:22]>>[CH:17]1([C:16]#[C:15][C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([C:14]4[CH:37]=[CH:38][C:33]([N:29]5[CH2:30][CH2:31][CH2:32][N:26]([CH2:25][CH2:24][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:27][CH2:28]5)=[CH:34][CH:35]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)[CH2:18][CH2:19]1
Reactant: COC(=O)c1sc(C#CC2CC2)cc1N=CN(C)C
Reactant: CS(=O)(=O)CCN1CCCN(c2ccc(N)cc2)CC1
Product: CS(=O)(=O)CCN1CCCN(c2ccc(-n3cnc4cc(C#CC5CC5)sc4c3=O)cc2)CC1

Procedure:
5-Cyclopropylethynyl-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester was reacted with 4-[4-(2-Methanesulfonyl-ethyl)-[1,4]diazepan-1-yl]-phenylamine by method A1. The product with the molecular weight of 496.64 (C25H28N4O3S2) was obtained in this way; MS (ESI): 497 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:19]OS(C)(=O)=O)[CH2:15]1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+].O>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:19][N:25]=[N+:26]=[N-:27])[CH2:15]1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1CCN(C(=N)NC(=O)OCc2ccccc2)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CCN(C(=N)NC(=O)OCc2ccccc2)C1
Temperature: 60 °C
Yield: 68.2 %

Procedure:
0.450 g (1.27 mmole) (3RS)-1-(N-benzyloxycarbonylamidino)-3-mesyloxymethyl pyrrolidine and 0.124 g (1.9 mmole) of sodium azide were dissolved in 10 ml dimethylformamide and heated to 60° C. for four hours followed by stirring at room temperature over night. Water was added and the mixture was extracted twice with toluene/ethyl acetate 2/1. The combined organic layer was dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography using CH2Cl2/MeOH 95/5 as eluent to yield 0.262 g (68%) of the product.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>>[C:1]([O:24][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCCCCCCCC
Temperature: 130 °C

Procedure:
A four-necked rounded bottom flask equipped with a stirrer, a thermocouple, and a nitrogen inlet tube was charged with 1 mol of behenic acid per mol of behenyl alcohol, and the contents were heated to 130° C. for 3 hours in a nitrogen atmosphere to carry out an esterification reaction. A reaction product was purified with methyl ether to provide behenyl behenate. Here, the acid value was 0.1 mgKOH/g, and the hydroxyl value was 1.2 mgKOH/g
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:21])=[C:7]2[C:15](=[C:16]([CH3:19])[C:17]=1[CH3:18])[O:14][C:10]1([CH2:13][CH2:12][CH2:11]1)[CH2:9][C:8]2=[O:20])(=O)C.C[Si]([C:26]#[N:27])(C)C.C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOC(C)=O>[NH2:27][CH2:26][C:8]1([OH:20])[C:7]2[C:15](=[C:16]([CH3:19])[C:17]([CH3:18])=[C:5]([OH:4])[C:6]=2[CH3:21])[O:14][C:10]2([CH2:11][CH2:12][CH2:13]2)[CH2:9]1
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC1(CCC1)O2
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)C(O)(CN)CC1(CCC1)O2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 5,7,8-trimethyl-4-oxo-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-yl acetate (2 g), Znl2 (100 mg) and trimethylsilyl cyanide (4 mL) was stirred at 70° C. for 2 h. A homogeneous solution was obtained. The solution was cooled down to room temperature, and THF (30 mL) was added, followed by 1 g of lithium aluminum hydride. After stirring at 60° C. for 3 h, the solution was cooled down and EtOAc was added to destroy excess lithium aluminum hydride. The mixture was poured into water and extracted with EtOAc. The EtOAc was washed with water and dried. After evaporation a white solid was obtained (1 g), which was washed with DCM to give 4-(aminomethyl)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-4,6-diol. 1H-NMR (300 MHz, CDCl3+CD3OD): δ=2.85 (AB, J=13.44 Hz, 2H), 2.36 (s, 2H), 2.35-1.60 (m, 6H), 2.11 (s, 9H) ppm. 13C-NMR (75 MHz, CDCl3+CD3OD) δ=146.82, 145.54, 124.91, 123.75, 121.01, 120.48, 76.49, 75.64, 50.07, 44.97, 34.46, 32.36, 13.75, 13.31, 12.50, 12.22 ppm. MS: (m/z)=260 (M+−OH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[C:25]([N:30]=[C:31]=[O:32])[N:24]=1>C(#N)C.O>[Cl:29][C:27]1[CH:28]=[C:23]([Cl:22])[N:24]=[C:25]([NH:30][C:31]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][C:3]([O:2][CH3:1])=[O:15])(=[O:12])=[O:13])=[O:32])[N:26]=1
Reactant: O=C=Nc1nc(Cl)cc(Cl)n1
Reactant: COC(=O)Cc1ccccc1S(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)Cc1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)cc(Cl)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.3 %

Procedure:
To 2.3 g of 2-(aminosulfonyl)benzeneacetic acid methyl ester in 30 ml of acetonitrile was added 1.5 g of anhydrous potassium carbonate and 1.6 g of 4,6-dichloropyrimidin-2-yl isocyanate. The mixture was stirred at room temperature for 6 hours, diluted with 250 g of water and acidified to a pH of about 4. The resulting solid was filtered and dried to yield 1.6 g of methyl 2-[[(4,6-dichloropyrimidin-2-yl)aminocarbonyl]aminosulfonyl]benzeneacetate, a pale yellow solid, m.p. 115°-118° C. It showed infrared absorption peaks at 1730, 1600 and 1560 cm-1 and nuclear magnetic resonance peaks at 3.7 ppm, methyl ester group; 4.2 ppm, benzeneacetic group; 6.9 ppm, pyrimidin H; 7.4-7.6 ppm, aromatic hydrogens; consistent for the product.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[C:15]1[NH:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[C:23]([O:30][CH3:31])[CH:22]=2)[N:16]=1.Cl>[Fe].CO>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([N:17]2[C:18](=[O:20])[NH:19][C:15]([C:3]3[CH:4]=[C:5]([CH:13]=[CH:14][C:2]=3[Cl:1])[CH2:6][NH:7][C:8]([CH:10]3[CH2:12][CH2:11]3)=[O:9])=[N:16]2)=[CH:22][C:23]=1[O:30][CH3:31]
Reactant: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1N
Yield: 75.5 %

Procedure:
The title compound was prepared according to the procedure as described in step-2 Intermediate-28 by using N-(4-chloro-3-(1-(3-methoxy-4-nitrophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)cyclopropanecarboxamide (0.500 g, 1.12 mmol), iron powder (catalytic amount), methanol (20 mL), conc. HCl (5.0 mL) to afford 0.350 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (s, 4H), 1.22 (br s, 2H), 1.60 (m, 1H), 3.97 (s, 3H), 4.33 (d, J=5.4 Hz, 2H), 7.45-7.58 (m, 3H), 7.70 (d, J=9.3 Hz, 1H), 7.87 (s, 1H), 8.13 (d, J=9.0 Hz, 1H), 8.71 (m, 1H), 12.30 (br s, 1H); MS (m/z): 414.09 (M+IV.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH:14]([N:16]3N=N[C:18]([CH2:21][CH3:22])=[N:17]3)[CH:13]([OH:23])[CH:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[CH2:40](C1C=NNC=1)[CH3:41]>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:22]=[C:21]([CH2:40][CH3:41])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:3]=1
Reactant: CCc1cn[nH]c1
Reactant: CCc1nnn(C2CC(n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)C(O)C2O)n1
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)c1

Procedure:
The title compound is prepared analogously to 1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Intermediate EA) by replacing 5-ethyltetrazole with 4-ethyl-1H-pyrazole. MS (ES+) m/e 544.23 (MH+)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCOCC>[Br:13][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(C)cccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(C)cccc1CBr
Reaction time: 0.33 h

Procedure:
To a solution of methyl 2,6-dimethyl-benzoate (22.0 g, 134 mmol, example 1) in CCl4 (250 mL) is added N-bromo-succinimide (19 g, 107 mmol) followed by benzoyl peroxide (1.0 g, 4.0 p mmol). The resulting solution is warmed to reflux and stirred at this temperature for 20 min. The reaction mixture is then allowed to cool before being diluted with ether (200 mL), filtered and concentrated. The residue is purified by flash chromatography (silica, 4% acetone in hexanes) to give the title compound. This product (approx. 85% purity, remainder is methyl 2,6dimethyl benzoate) is used without further purification. MS (EI) 242, 244 (M+, Br pattern).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].Cl.[NH:23]1[C:27]([C:28]2[CH:29]=[C:30]3[C:40](=[CH:41][CH:42]=2)[O:39][C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][C:31]3=[O:43])=[N:26][N:25]=[N:24]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>O.CN(C=O)C>[CH3:3][CH:2]([N:4]1[C:8]2=[N:9][C:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:11][C:12]([C:13]([N:36]3[CH2:37][CH2:38][C:33]4([CH2:32][C:31](=[O:43])[C:30]5[C:40](=[CH:41][CH:42]=[C:28]([C:27]6[NH:26][N:25]=[N:24][N:23]=6)[CH:29]=5)[O:39]4)[CH2:34][CH2:35]3)=[O:15])=[C:7]2[CH:6]=[N:5]1)[CH3:1]
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccccc3)nc21
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ncc2c(C(=O)N3CCC4(CC3)CC(=O)c3cc(-c5nnn[nH]5)ccc3O4)cc(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TEA (0.2 mL) was added to a DMF suspension (2 mL) of 1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid, 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride, EDCI and HOBT.H2O, heated at 80° C. and stirred for 2 hours. This was cooled to room temperature, iced water was added thereto, and its pH was adjusted to 2.5 with 1 N HCl solution added thereto. The resulting crystal was taken out through filtration, washed with water, washed with Et2O, and dried in vacuum at 70° C. to obtain the title compound as a pale brown powder. 1H-NMR (400 MHz, DMSO-d6) δ: 8.34 (1H, d, J=2.2 Hz), 8.26-8.21 (2H, m), 8.19 (1H, s), 8.19 (1H, dd, J=8.4, 2.6 Hz), 7.82 (1H, s), 7.58-7.47 (3H, m), 7.20 (1H, d, J=8.4 Hz), 5.33 (1H, sept, J=6.8 Hz), 4.45-4.30 (1H, m), 3.70-3.00 (3H, m), 2.95 (2H, s), 2.20-1.70 (4H, m), 1.55 (6H, d, J=6.8 Hz). MS [M+H]+=549.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[O:9]=[C:10]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=[CH:12]O1.Cl.CN(C)CCCN=C=NCC.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:10]2=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccoc1=O
Reactant: Nc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-fluoroaniline (6.5 g, 58.4 mmol) in DMF (30 mL) at ice bath temperature was added methyl 2-oxo-2H-pyran-3-carboxylate (9.0 g, 58.4 mmol). The resulting mixture was stirred for 15 min cold and was then warmed to ambient temp for 3 hours. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI—HCl) (13.5 g, 70.0 mmol) and DMAP (1.43 g, 11.7 mmol) were added and the resulting mixture was stirred at ambient temp overnight. The reaction mixture was poured into water (300 mL), extracted with ethyl acetate (3×100 mL), washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to obtain methyl 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate. This crude product was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([C:18]#[N:19])[CH:17]=2)[C:12]([OH:14])=[O:13])=[C:6]([F:20])[C:5]([CH2:21][NH:22][C:23]([C:25]2[N:29](COCC[Si](C)(C)C)[CH:28]=[N:27][C:26]=2[Cl:38])=[O:24])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([C:18]#[N:19])[CH:17]=2)[C:12]([OH:14])=[O:13])=[C:6]([F:20])[C:5]([CH2:21][NH:22][C:23]([C:25]2[NH:29][CH:28]=[N:27][C:26]=2[Cl:38])=[O:24])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(C(=O)O)c2)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)cc(C(=O)O)c1
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a solution of 3-({6-chloro-3-[({[4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazol-5-yl]carbonyl}amino)methyl]-2-fluorophenyl}oxy)-5-cyanobenzoic acid (30 mg, 0.052 mmol) in DCM (2 ml) was added TFA (2 ml). The mixture was stirred for 30 min and the solvent was removed under vacuum. The crude product was purified by Reverse Phase HPLC (MeCN/water 0.1% formic acid) to give 20 mg (86%) of the title compound as a white solid. 1H NMR (400 MHz, methanol-d4) δ ppm 8.02 (s, 1H) 7.58-7.79 (m, 2H) 7.49 (d, 1H) 7.23-7.43 (m, 2H) 4.63 (s, 2H). LC-MS (ES+) m/z 448.10, [M+H].
Reaction SMILES: O[C:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[OH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:18][C:2]([CH3:19])=[CH:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[OH:17]
Reactant: CC(C)(O)CCCCc1ccc2ccccc2c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)=CCCCc1ccc2ccccc2c1O
Reaction time: 18 h
Yield: 83.2 %

Procedure:
A solution of the compound of Example 119 (0.45 g, 0.002 mole) and p-toluenesulfonic acid (4-5 crystals) in toluene (20 mL) was heated at reflux with azeotropic removal of water. After 18 hours, the cooled solution was washed with saturated aqueous sodium bicarbonate and evaporated to provide the title compound (0.4g, 100%) as an oil; mass spectrum: m/z 240.