Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([NH:11][C:12]1[CH:28]=[CH:27][C:15]([O:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)=[C:14]([C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)[CH:13]=1)=[O:10].CN(C)C=O.[Cl:40][C:41]1[CH:49]=[CH:48][CH:47]=[C:46]2[C:42]=1[CH2:43][CH2:44][NH:45]2.Cl.CCOCC>Cl>[NH2:19][CH2:18][CH2:17][O:16][C:15]1[CH:27]=[CH:28][C:12]([NH:11][C:9]([N:45]2[C:46]3[C:42](=[C:41]([Cl:40])[CH:49]=[CH:48][CH:47]=3)[CH2:43][CH2:44]2)=[O:10])=[CH:13][C:14]=1[C:29]1[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=1
Reactant: Clc1cccc2c1CCN2
Reactant: Cn1nccc1-c1cc(NC(=O)ON2C(=O)CCC2=O)ccc1OCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(NC(=O)N2CCc3c(Cl)cccc32)ccc1OCCN
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.5 %

Procedure:
A 1 mL aliquot of tert-butyl {2-[4-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}amino)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]ethyl}carbamate in dimethylformamide (78.8 μmol) was added to 4-chloroindoline (14.52 mg, 1.2 eq) and stirred at room temperature for 18 hr. To this was added 2.0M hydrochloric acid in ether (197 μL, 5 eq) and the reaction was stirred at room temperature for 24 hr (2-3 drops of concentrated hydrochloric acid was added if the deprotection was incomplete and the resulting mixture was stirred for another 24 hr). The ether and hydrochloric acid were evaporated under a stream of nitrogen and the resulting material was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 43.5% yield. LCMS m/z (%)=412 (M+H 35Cl, 100), 414 (M+H 37Cl, 36). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.10-3.24 (m, 4 H), 3.71 (s, 3 H), 4.13-4.21 (m, 4 H), 6.34 (d, J=2.02 Hz, 1 H), 6.96 (d, J=8.08 Hz, 1 H), 7.13-7.21 (m, 2 H), 7.48-7.50 (m, 2 H), 7.64 (dd, J=8.84, 2.78 Hz, 1 H), 7.81 (d, J=7.58 Hz, 1 H), 7.92 (s, 2 H), 8.63 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.N1C=CC=CC=1>O1CCOCC1>[Br:12][C:5]1[CH:6]=[C:7]([S:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)cc1S(=O)(=O)Cl
Reactant: C1COCCN1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: Nc1ncc(Br)cc1S(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 2-amino-5-bromo-3-pyridinesulfonyl chloride (0.50 g, 1.84 mmol) in anhydrous dioxane (2 mL) cooled to 5° C. was added (0.16 mL, 1.84 mmol) of morpholine followed by (0.174 mL, 2.15 mmol) of pyridine. The reaction mixture was stirred at room temperature for 2 hrs and then heated at 50° C. for 1 hour. After cooling to room temperature, a white precipitate formed which was collected by suction filtration, washing with water and petroleum ether to give the title compound as an off-white solid. (0.539 g, 91% yield). MS (ES)+ m/e 323.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)cc1
Yield: 80 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 4-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.057 g (80%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1C(=O)N([Br:19])C(=O)C1>C1COCC1.OS(O)(=O)=O>[Br:19][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[NH2:11]
Reactant: COc1ccc(N)cc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: COc1cc(N)c(Br)cc1OC
Temperature: 25 °C

Procedure:
To a solution of 3,4-dimethoxybenzenamine (20.0 g, 0.130 mol) in dry THF (200 mL) was added concentrated H2SO4 (20 drops) under N2 at −78° C. After 10 mains, NBS (23.2 g, 0.130 mol) was added in potions at −78° C. Then the reaction mixture was allowed to gradually warm up to room temperature over 1 hour. THF was removed under reduced pressure. The residue was diluted with EtOAc (200 mL), and washed with water (80 mL×3). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuum. The residue was purified by silica gel column (15:1 hexanes/ethyl acetate) to afford 2-bromo-4,5-dimethoxyaniline as a yellow solid. MS (M+H)=232 and 234.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:8][C:6](=[O:7])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[OH:12][CH2:13][CH:14]([CH2:16]O)[OH:15].S([O-])(O)(=O)=O.[K+].O>C1(C)C=CC=CC=1>[CH3:1][C@H:2]1[CH2:8][C:6]2([O:15][CH:14]([CH2:13][OH:12])[CH2:16][O:7]2)[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1
Reactant: OCC(O)CO
Reactant: CC(C)[C@@H]1CC[C@@H](C)CC1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)[C@@H]1CC[C@@H](C)CC12OCC(CO)O2
Reaction time: 7 h

Procedure:
In a 2 l three-necked flask there are introduced 308 g of 1-menthone (2 mol), 276 g of glycerol (3 mol) and 5 g of potassium hydrogen sulphate in toluene. This mixture is refluxed in a water separator. After 7 hours, 42 g of water have separated. The mixture is neutralised and distilled.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([N:19]([CH3:21])[CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:22][NH2:23]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:23][CH3:22])[N:15]=[C:14]([N:19]([CH3:21])[CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CN
Reactant: CN(C)c1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(N(C)C)n1
Temperature: 130 °C
Reaction time: 4 h
Yield: 20.3 %

Procedure:
0.50 g (0.00153 mol) of 4-amino-N-(2-dimethylamino-6-chloro-pyrimidin-4-yl)-benzenesulfonamide were dissolved in 20 ml (0.176 mol) of 8M methylamine in ethanol and stirred in an autoclave at 130° C. for 4 hours. The reaction mixture was freed from solvent and the residue was chromatographed on silica gel with methanol/dichloromethane 1:19. There was obtained 0.10 g (21%) of 4-amino-N-(2-dimethylamino-6-methylamino-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p: 253-254° C.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH:14]=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH3:28])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]1([C:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH2:14][N:25]3[CH2:26][CH2:27][N:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[CH3:28])[CH2:23][CH2:24]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCC1CC(c2ccccc2)=NO1
Reactant: Cc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccccc1N1CCN(CCCC2CC(c3ccccc3)=NO2)CC1
Yield: 73.3 %

Procedure:
3-(3-Phenyl-4,5-dihydroisoxazol-5-yl)propanal (27.3 mg, 0.124 mmol), 1-(o-tolyl) piperazine (20.0 mg, 0.113 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (72.1 mg, 0.340 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 30.1 mg (73.1%) of the target compound was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[C:10](Cl)=[O:11].[N:13]1([CH2:19][CH2:20][NH2:21])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CCN(CC)CC>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[C:10]([NH:21][CH2:20][CH2:19][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:11]
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)Cl
Reactant: NCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc([N+](=O)[O-])cc1C(=O)NCCN1CCOCC1
Reaction time: 8 h
Yield: 87.9 %

Procedure:
1-Methyl-4-nitro-1H-pyrrole-2-carbonyl chloride (0.585 g, 4.70 mmol; see step (ii) above) in DCM (10 mL), was added dropwise to a solution of 2-(4-morpholinyl)ethanamine (0.673 g, 5.17 mmol), and NEt3 (0.735 μL, 9.42 mmol), in DCM (10 mL) over 15 min. The resulting solution was allowed to stir overnight and the reaction quenched with a 5% NaOH solution (20 mL). The layers were separated and the DCM fraction collected, dried (MgSO4), filtered and the solvent removed under reduced pressure to yield the sub-title compound as a white/pale yellow solid (1.166 g, 88%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.[Cl:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][CH:14]2[CH2:19][CH:18]([C:20](OCC)=[O:21])[C:17](=O)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH:14]2[CH2:15][CH2:16][C:17]3[N:7]=[C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:6]4=[C:20]([OH:21])[C:18]=3[CH2:19]2)=[CH:26][CH:27]=1
Reactant: Cn1cc(N)cn1
Reactant: CCOC(=O)C1CC(Cc2ccc(Cl)cc2)CCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1ncc2nc3c(c(O)c21)CC(Cc1ccc(Cl)cc1)CC3
Temperature: 25 °C
Yield: 34.2 %

Procedure:
A solution of 1-methyl-1H-pyrazol-4-amine ((J. Catalan et al., J. Heterocycl. Chem., 1985, 22, 997), 200 mg, 2.06 mmol), ethyl 5-(4-chlorobenzyl)-2-oxocyclohexanecarboxylate (EXAMPLE 69, step 3, 1.43 g, 4.85 mmol), and p-toluenesulfonic acid monohydrate (10 mg, 0.05 mmol) in toluene (15 ml) was stirred at 120° C. for 2.5 h. After cooling to room temperature, the solvent was removed in vacuo. The residue (ca. 1.5 g) was dissolved in diphenyl ether (10 ml) and heated at 240° C. for 1 h. After cooling to room temperature, the formed solid was collected by filtration, and washed with diisopropyl ether to give 231 mg (34%) of 7-(4-chlorobenzyl)-1-methyl-5,6,7,8-tetrahydro-1H-pyrazolo[4,3-b]quinolin-9-ol. 105 mg of this compound was treated with methanolic hydrochloric acid (5 ml) and the mixture was evaporated. The obtained solid was recrystallized from methanol/diisopropyl ether to give 100 mg of the title compound as a gray crystal.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]3[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]3)=[CH:10][C:9]2=[O:17])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH:24]([N:27]([CH:31]([CH3:33])[CH3:32])[CH2:28][CH2:29]Cl)([CH3:26])[CH3:25]>C(O)(C)(C)C>[CH:24]([N:27]([CH:31]([CH3:33])[CH3:32])[CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:16]3[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]3)=[CH:10][C:9]2=[O:17])=[CH:6][CH:7]=1)([CH3:26])[CH3:25]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: O=C1C=C2CCCCC2N1c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)N(CCOc1ccc(N2C(=O)C=C3CCCCC32)cc1)C(C)C
Yield: 75.7 %

Procedure:
22.9 g (0.1 mol) of 1-(4-hydroxyphenyl)-2-oxo-2,4,5,6,7,7a-hexahydro-indole were dissolved, as in Example 4, in a solution of 0.1 mol of potassium tertiary-butoxide in 100 cm3 of tertiary-butanol, and then reacted with 18 g (0.11 mol) of 2-diisopropylamino-1-chloroethane. After conventional treatment of the reaction product, and crystallization from heptane, 27 g (yield 76%) of 1-[4-(2-diisopropyaminoethoxy)-phenyl]-2-oxo-2,4,5,6,7,7a-hexahydro-indole were obtained; m.p. 86° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH3:10][O:11][CH2:12][C:13](O)=[O:14]>>[CH3:10][O:11][CH2:12][C:13]([NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])=[O:14]
Reactant: Cc1cccc(C)c1N
Reactant: COCC(=O)O
Product: COCC(=O)Nc1c(C)cccc1C

Procedure:
According to the process described in the HU-PS 202,481, after acylating 2,6-dimethylaniline with methoxyacetic acid, the N-methoxyacetyl-2,6-dimethylaniline obtained is heated together with a twofold excess of methyl DL-α-bromopropionate to 120° C., and after adding sodium methoxide in small portions to the reaction mixture obtained, the alkylation is carried out at 140° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:10]=1)[CH3:2].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C(#N)C>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:13]([C:30](=[O:31])[NH:29][C:26]2[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=2)[N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:10]=1)[CH3:2]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CCc1ccccc1-c1nc(-c2cccc(OC)c2)n[nH]1
Solvent: CC#N
Product: CCc1ccccc1-c1nc(-c2cccc(OC)c2)nn1C(=O)Nc1ccc(C)cc1
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of 5 g (0.018 mole) of 5-(2-ethylphenyl)-3-(3-methoxyphenyl)-1H-1,2,4-triazole in 50 ml of anhydrous acetonitrile, 2,25 ml (0.018 mole) of 4-methylphenyl isocyanate were added. The resulting mixture was kept in the darkness for 18 hours, then the solid which formed was recovered by filtration and the mother liquors were brought to dryness under vacuum at room temperature. The obtained residue was taken up with 20 ml of diethyl ether, the mixture was filtered and the solid on the filter was collected with the solid deriving from the first filtration. 5.9 Grams (80%) of 5-(2-ethylphenyl)-3-(3-methoxyphenyl)-1-(4-methylphenylcarbamoyl)-1H-1,2,4-triazole were obtained. M.p. 141°-42° C. (from acetonitrile). Δδ=-0.24.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(F)ccc1Br
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(F)c([N+](=O)[O-])cc1Br
Temperature: 28 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a stirred solution of 2-bromo-5-fluorotoluene (1.495 g, 7.909 mmol, Aldrich, used as received) in conc. H2SO4 (10.0 mL) at 0° C., KNO3 (0.800 g, 7.91 mmol) was added in one lot. The resulting pale yellow solution was warmed to 28° C. and stirred overnight at 28° C. It was then poured into ice (50 g) and extracted with ethyl acetate (75 mL). The ethyl acetate was dried over anhydrous Na2SO4, removed under vacuum, and the resulting oil dried further under vacuum to afford 1.832 g (98%) of the title compound as an oil; 1H NMR (CDCl3): δ 2.495 (s, 3H), 7.213 (d, 1H, J1 =11.4 Hz), 8.268 (d, 1H, J1 =7.2 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[CH3:23][O:24][CH2:25][CH2:26][O:27][P:28]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[C:38]([O:43][CH3:44])[CH:37]=1)(=[O:34])[O:29][CH2:30][CH2:31][O:32][CH3:33]>>[CH3:33][O:32][CH2:31][CH2:30][O:29][P:28]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11](=[O:12])[NH:13][CH3:14])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=2)=[C:38]([O:43][CH3:44])[CH:37]=1)(=[O:34])[O:27][CH2:26][CH2:25][O:24][CH3:23]
Reactant: COCCOP(=O)(Cc1ccc(N)c(OC)c1)OCCOC
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc(CP(=O)(OCCOC)OCCOC)cc2OC)ncc1C(F)(F)F
Yield: 61.7 %

Procedure:
The title compound was prepared according to Example 102 using 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 104A, 50.0 mg, 0.15 mmol) and bis(2-methoxyethyl)(4-amino-3-methoxybenzyl)phosphonate (Compound 217C, 55.4 mg, 0.17 mmol). 58.1 mg (61%) of the desired product obtained after purification. 1H NMR (400 MHz, MeOD) δ ppm 8.24-8.35 (m, 2H), 7.95 (d, J=8.08 Hz, 1H), 7.62 (dd, J=7.83, 1.52 Hz, 1H), 7.46 (ddd, J=8.53, 7.39, 1.52 Hz, 1H), 7.16 (td, J=7.58, 1.01 Hz, 1H), 6.96 (t, J=2.02 Hz, 1H), 6.72-6.80 (m, 1H), 4.05-4.16 (m, 4H), 3.87 (s, 3H), 3.50-3.57 (m, 4H), 3.33 (s, 6H), 3.20-3.29 (m, 2H), 2.89 (s, 3H). MS (ES+): m/z 628.16/629.20 (100/98) [MH+]. HPLC: tR=1.39 min (Micromass TOF: polar—3 min).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][C:18]([CH:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[OH:22])=[CH:17][CH2:16]2)=[CH:10][CH:9]=1.[F:33][C:34]1[CH:35]=[C:36]([N:41]=[C:42]=[O:43])[CH:37]=[C:38]([F:40])[CH:39]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:33][C:34]1[CH:35]=[C:36]([NH:41][C:42]([O:22][CH:21]([C:18]2[CH2:19][CH2:20][N:15]([CH2:14][C:11]3[CH:12]=[CH:13][C:8]([O:7][C:2]4[N:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:9][CH:10]=3)[CH2:16][CH:17]=2)[C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=2)=[O:43])[CH:37]=[C:38]([F:40])[CH:39]=1
Reactant: OC(C1=CCN(Cc2ccc(Oc3ncccn3)cc2)CC1)c1ccc(C(F)(F)F)cc1
Reactant: O=C=Nc1cc(F)cc(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(F)cc(F)c1)OC(C1=CCN(Cc2ccc(Oc3ncccn3)cc2)CC1)c1ccc(C(F)(F)F)cc1
Yield: 30.2 %

Procedure:
This compound was prepared in a manner analogous to that of Step F of Example 2, using 0.44 gram (0.0010 mole) of {1-[(4-pyrimidin-2-yloxyphenyl)methyl](4-1,2,5,6-tetrahydropyridyl)}[4-(trifluoromethyl)phenyl]methanol, 0.21 gram (0.0014 mole) of 3,5-difluorophenylisocyanate, 0.14 gram (0.0014 mole) of triethylamine, and 0.05 gram (catalyst) of 4-dimethylaminopyridine in 15 mL of methylene chloride. The reaction product was purified with column chromatography on silica gel using 10% to 25% acetone/methylene chloride mixtures as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.18 gram of Compound 786, mp 85–92° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[H-].[Na+].Cl[CH2:20][O:21][CH2:22]Cl.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:20][O:21][CH3:22])=[CH:10][CH:9]=2)[CH:15]=1
Reactant: ClCOCCl
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., to a stirred solution of 4-(5-bromo-2-chlorobenzyl)phenol (6.85 g, 23 mmol) in dimethylformamide (100 mL) was added portionswise sodium hydride (60% in mineral oil, 1.01 g, 25.3 mmol), the mixture was stirred at 0° C. for further 30 minutes. Chloromethyl ether (2.02 g, 25.3 mmol) was slowly added in drops and when the addition finished, the mixture was stirred at room temperature for further 3 hours. Water (150 mL) was added, the mixture was extracted for two times with ethyl acetate, the combined organic phases were washed with saturated brine for one time and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 20:1) to afford the target compound.
Reaction SMILES: [CH2:1]([C@H:8]1[C:12](=[O:13])[O:11][C@@H:10]([CH2:14][S:15]C(=O)C)[CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[BH4-].[Na+].[C:21](O)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[CH2:1]([C@@H:8]1[CH2:9][C@H:10]([CH2:14][S:15][C:21]([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)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:11][C:12]1=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC[C@@H]1C[C@H](CSC(C)=O)OC1=O
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCC[C@@H]1C[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of the product of Example 13 in 100 mL of methanol, cooled to 0° C., was added 2.69 g (0.071 mol) of solid sodium borohydride in portions over 15 minutes. The reaction was then concentrated in vacuo, acidified with 10% HCl solution and extracted with methylene chloride. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting crude thiol was dissolved in 50 mL of trifluoroacetic acid and 5.98 g (0.023 mol) of trityl alcohol was added. After stirring at room temperature for 1 h the reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:50) to provide 5.26 g (61%) of the desired product as a colorless oil. CI Mass Spec: 473.5 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]([CH2:11][C:12]([OH:14])=[O:13])[N:9]=[N:8][N:7]=2)=[CH:2]1.[CH2:15](O)[CH2:16][CH2:17][OH:18].C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C>CN(C)C=O>[OH:18][CH2:17][CH2:16][CH2:15][O:13][C:12](=[O:14])[CH2:11][N:10]1[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][N:8]=[N:9]1
Reactant: O=C(O)Cn1nnnc1-c1ccsc1
Reactant: OCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(Cn1nnnc1-c1ccsc1)OCCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To a solution of 500 mg (2.38 mM) of [5-(3-thienyl) tetrazol-1-yl] acetic acid and 220 mg (2.85 mM) of 1,3-propanediol in 5 ml of N,N-dimethylformamide was added 540 mg (2.62 mM) of dicyclohexylcarbodiimide at room temperature. After the mixture was stirred at room temperature for 30 min, a small amount of acetic acid was added to the mixture and then was stirred for 30 min. The mixture was poured into ice-water. The precipitated crystal was filtered off and washed with water. The filtrate was extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/ethyl alcohol=60/1) for separation and purification, to give 350 mg (yield 54.8%) of [5-(3-thienyl) tetrazol-1-yl] acetic acid 3-hydroxypropyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH3:14])[C:5]=1[CH2:6]O)[CH3:2].P(Br)(Br)[Br:16]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH3:14])[C:5]=1[CH2:6][Br:16])[CH3:2]
Reactant: CCOc1cccc(OCC)c1CO
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: CCOc1cccc(OCC)c1CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of 2,6-diethoxybenzyl alcohol (1.0 g, 5.2 mmol) in THF (10 mL) was added phosphorous tribromide (0.48 mL, 5.1 mmol) dropwise. The reaction was allowed to warm to room temperature and stirred for 1 h. After quenching the reaction with water, the mixture was extracted with EtOAc. The combined organics were washed with brine and dried over Na2SO4. The solution was concentrated under reduced pressure to give 2,6-diethoxybenzyl bromide as a brown oil. Yield (1.3 g, 98%).