Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][CH2:14]3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:19]N1C(=O)CCC1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O.CS(C)=O>[Br:19][C:13]1[CH2:14][C:15]2[C:11]([CH:12]=1)=[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[CH:18]=[CH:17][CH:16]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1ccc(-c2cccc3c2C=CC3)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)c1ccc(-c2cccc3c2C=C(Br)C3)cc1
Yield: 94.3 %

Procedure:
Into a 500-ml glass reaction vessel, 15.4 g of 4-(4-i-propylphenyl)-indene (67 mmol), 7.2 ml of distilled water and 200 ml of DMSO were added. Then, 17 g (93 mmol) of N-bromosuccinimide was gradually added and the resultant mixture was stirred for 2 hours at room temperature. The reaction liquid was poured into 500 ml of distilled water, and the resultant mixture was extracted with 100 ml of toluene for 3 times. The resultant toluene layer was washed with saturated brine. Then, 2 g (11 mmol) of p-toluenesulfonic acid was added to the washed toluene layer and refluxed under heating while removing water. The reaction liquid was left to cool, washed with saturated brine and dried over sodium sulfate. Then, the sodium sulfate was removed by filtration and the resultant filtrate was evaporated under reduced pressure to remove the solvent. The resultant residue was purified by silica gel column chromatography to thereby obtain 19.8 g of 2-bromo-4-(4-i-propylphenyl)-indene as yellow liquid (yield: 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21](OC)=[O:22])=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[CH3:26][O:27][CH:28]1[CH2:31][N:30]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39][NH:40][CH3:41])=[CH:35][CH:34]=2)[CH2:29]1.C[Al](C)C>ClCCCl>[CH3:26][O:27][CH:28]1[CH2:31][N:30]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([CH3:41])[C:21]([C:19]3[O:20][C:16]([CH2:15][N:13]([S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:25])(=[O:12])=[O:11])[CH3:14])=[N:17][N:18]=3)=[O:22])=[CH:35][CH:34]=2)[CH2:29]1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Reactant: CNCc1ccc(CN2CC(OC)C2)cc1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N(C)Cc3ccc(CN4CC(OC)C4)cc3)o2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (30 mg, 0.08 mmol), 1-{4-[(3-methoxyazetidin-1-yl)methyl]phenyl}-N-methylmethanamine (30 mg, 0.14 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (5 mL). A portion of the crude product was purified using prep method D to afford the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[F:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1>>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][C:26]([CH2:25][C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:34][CH:33]=3)([OH:32])[CH2:31][CH2:30]2)=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC1(Cc2ccc(F)cc2)CCNCC1
Reactant: BrCCCOc1ccc(OCc2ccccc2)cc1
Product: OC1(Cc2ccc(F)cc2)CCN(CCCOc2ccc(OCc3ccccc3)cc2)CC1

Procedure:
The title compound, MS: m/e=450.5 (M+H+), was prepared from 1-(3-bromopropoxy)-4-(benzyloxy)-benzene and 4-(4-fluor-benzyl)-piperidin-4-ol.
Reaction SMILES: Br[CH2:2][O:3][C:4]1[C:5]([O:10][CH3:11])=[CH:6][CH:7]=[CH:8][CH:9]=1.[NH2-].[Na+].[CH2:14]([O:16][C:17]([O:19][CH2:20][CH3:21])=[CH2:18])[CH3:15].O>C1(C)C=CC=CC=1>[CH2:14]([O:16][C:17]1([O:19][CH2:20][CH3:21])[C:9]2[C:8](=[CH:7][CH:6]=[C:5]([O:10][CH3:11])[C:4]=2[O:3][CH3:2])[CH2:18]1)[CH3:15]
Reactant: C=C(OCC)OCC
Reactant: COc1ccccc1OCBr
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC1(OCC)Cc2ccc(OC)c(OC)c21
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
24 g (107 mmol) of bromoveratrol is poured onto 8.4 g (215 mmol)/2 eq.) of sodium amide in 10 mL of toluene, followed by 25 g (215 mmol/2 eq.) of 1,1diethoxyethylene. Heating is carried out at 80° C. for 4 hours 30 minutes; cooling to −10° C. is carried out and 50 mL of water and then 50 mL of toluene are poured in. The phases are separated and the aqueous phase is extracted again with toluene. The combined toluene phases are washed with water to neutral pH and are then concentrated. The residue is chromatographed over 600 g of silica (eluant: dichloromethane) to yield the desired product.
Reaction SMILES: [C:1]([C:5]([C:8]([C:11]([O:14][CH2:15][C:16]([C:19]([OH:21])=[O:20])([F:18])[F:17])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].[NH3:22].[OH-].[Na+]>>[C:1]([C:5]([C:8]([C:11]([O:14][CH2:15][C:16]([C:19]([O-:21])=[O:20])([F:18])[F:17])([F:12])[F:13])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].[NH4+:22]
Reactant: N
Reactant: O=C(O)C(F)(F)COC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])C(F)(F)COC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: [NH4+]

Procedure:
An aqueous solution of CF3CF2CF2CF2OCH2CF2COONH4 was prepared in the same manner as in Synthesis Example 1 except that the CF3CF2CF2CF2OCH2CF2COOH prepared in Synthesis Example 3 was neutralized to pH 7 using aqueous ammonia in lieu of the aqueous solution of sodium hydroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]1[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]1[NH:23][C:24](=[O:27])[CH2:25]I)=[O:12])=[CH:5]2.C(=O)([O-])[O-:29].[Na+].[Na+].O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][CH:14]1[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]1[NH:23][C:24](=[O:27])[CH2:25][OH:29])=[O:12])=[CH:5]2
Reactant: O=C(CI)NC1c2ccccc2CC1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(CO)NC1c2ccccc2CC1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Yield: 86.8 %

Procedure:
5-Chloro-N-{1-[(iodoacetyl)amino]-2,3-dihydro-1H-inden-2-yl}-1H-indole-2-carboxamide (Method 7a; 60 mg, 0.12 mmol) and sodium carbonate (100 mg) were dissolved in 1:1 dioxane:water (5 mL) and heated to reflux for 20 hours. The reaction was cooled, water (10 mL) added, filtered and the filter cake washed with water (3×1 mL) and dried to give the title compound (40 mg, 85%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:17])[CH3:16])(Cl)[CH2:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.NC1C=CC(C2C=CC=C(Cl)C=2)=CC=1[C:39](=[O:41])C.C([Mg]Br)C1C=CC=CC=1.[Cl:51]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:18]([C:15]1([CH3:16])[O:17][C:39](=[O:41])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([Cl:51])[CH:9]=3)=[CH:4][C:3]1=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)(Cc1ccccc1)C1(Cl)CC(c2ccccc2)=CC=C1N
Reactant: CC(=O)c1cc(-c2cccc(Cl)c2)ccc1N
Agent: Br[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(Cc2ccccc2)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Yield: 30 %

Procedure:
A mixture of 1-(4-amino-3-chloro-biphenyl-3-yl)-1-benzyl-ethanol (prepared from 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone and benzylmagnesium bromide according to procedure described previously, 0.14 g, 0.42 mmol) and triphosgene (0.04 g, 0.14 mmol) in dry THF (10 mL) was stirred under a blanket of nitrogen for 10 minutes. THF was removed and the residue purified via flash chromatography (silica gel, 35% ethyl acetate/hexane) to give 4-benzyl-6-(3-chloro-phenyl)-4-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.045 g, 30%) as an off-white solid: mp 187-188° C.; 1H-NMR (DMSO-d6) δ 10.1 (s, 1H), 7.70 (t, 1H, J=2.3 Hz), 7.6 (d, 1H, J=8.0 Hz), 7.58-7.53 (m, 2H), 7.46 (t, 1H, J=8.0 Hz), 7.38 (d, 1H, J=8.0 Hz), 7.22-7.17 (m, 3H), 7.06-7.0 (m, 2H), 6.84 (d, 1H, J=9.14 Hz), 3.24 (d, 1H, J=14.3 Hz), 3.06 (d, 1H, J=14.3 Hz), 1.68 (s, 3H); MS (ESI) m/z 364 ([M+H]+, 100%); Anal. Calcd. For C22H18C1NO2: C, 72.63; H, 4.99; N, 3.85. Found: C, 71.82; H, 5.09; N, 3.58.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.C([N-]C(C)C)(C)C.[Li+].[C:23]1(=[O:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>O1CCCC1.C(OCC)(=O)C>[OH:30][C:23]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCCCC1
Reactant: N#Cc1ccc(Cc2ncc[nH]2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C(c2ncc[nH]2)C2(O)CCCCCC2)cc1
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
10 g of 4-[1-(imidazolyl)methyl]benzonitrile is dissolved in 270 ml of tetrahydrofuran and combined at -50° with 40 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour at -60°, combined with 6.5 g of cycloheptanone, stirred further for 1 hour, and heated to 25°. Then water is added, the mixture is diluted with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus producing 16 g of crude 4-[1-hydroxycyclohept-1-yl-1-(imidazolyl)methyl]benzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:28])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:27])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.CC(C)=O.[Cr](O)(O)(=O)=O.[OH-].[Na+]>O>[O:27]=[C:19]1[N:18]([CH:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][CH2:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:28])[CH2:13][CH2:14]2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20]1
Reactant: O=c1[nH]c2ccccc2n1C1CCN(CCCC(O)c2ccc(F)cc2)CC1
Agent: O=[Cr](=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a stirred mixture of 4 g of 1-(p-fluorophenyl)-4-[4-(2-oxo-1-benzimidazolinyl)piperidino]-1-butanol and 100 ml of acetone was added dropwise a chromic acid solution (prepared from 2 g of chromic anhydride, 5 ml of water and 2 ml of sulfuric acid) under cooling with ice. The mixture was stirred over night at room temperature, poured into 600 ml of cold water and made alkaline by addition of a 10% aqueous sodium hydroxide solution. The basic material which was separated was extracted twice with each 100 ml of chloroform and the combined extracts were washed with water and evaporated to dryness. Recrystallization of the solid residue from aqueous acetone gave γ-[4-(2-oxo-1-benzimidazolinyl)-piperidino]-p-fluorobutyrophenone, melting at 171° - 172°C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Cl:10][C:11]1[CH:19]=[C:18]([Cl:20])[C:17]([F:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[Cl:10][C:11]1[C:19]([N+:1]([O-:4])=[O:2])=[C:18]([Cl:20])[C:17]([F:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(F)c(Cl)cc1Cl
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Temperature: 25 °C

Procedure:
40 ml of concentrated nitric acid are added dropwise to 34 ml of concentrated sulphuric acid, while cooling with ice and stirring. 20.9 g of 2,4-dichloro-5-fluorobenzoic acid or introduced in portions into this nitration mixture, whereupon the temperature rises to 45°-50° C. The mixture is then heated at 90°-100° C. for a further 3 hours, the mixture is cooled to room temperature and poured onto 350 ml of ice-water and the precipitate is filtered off with suction and washed with water. The moist crude product is dissolved hot in 30 ml of methanol, and 150 ml of H2O were added to the solution. The precipitate is filtered off cold with suction, washed with CH3OH/H2O and dried in vacuo at 80° C. 21.2 g of crude 2,4-dichloro-5-fluoro-3-nitro-benzoic acid are obtained. The compound is sufficiently pure for the subsequent reactions. A sample recrystallized from toluene/petroleum ether gives crystals of melting point 192° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24]Cl>C(#N)C>[CH3:22][O:23][CH2:24][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: O=c1ccc2cc(O)ccc2o1
Reactant: COCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc2oc(=O)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
Equip a 3-L, three-neck, round-bottom flask equipped with a large blade mechanical stirrer, a thermocouple, a Claisen adapter, an addition funnel, and a reflux condenser. Add 2,5-dimethoxycinnamic acid (102.8 g, 493 mmol, 1.0 equiv) and dichloroethane (1.5 L). Add boron tribromide (247.4 g, 987 mmol, 2.0 equiv) dropwise over 45 min while keeping the temperature below 40° C. Rapidly stir the resulting mixture and heat gradually to 83° C. over 45 min, monitoring the temperature increase and gas evolution, Stir for 6 h at reflux then for 15 h at 76° C. Cool the resulting mixture to room temperature and quenched carefully with water (450 mL). Filter the solid, wash with heptane and dry under vacuum to afford 6-hydroxy coumarin (95 g) as a light brown solid which is used without further purification. Equip a 2-L, three-neck, round-bottom flask with a magnetic stir bar and a thermocouple. Add 6-hydroxy coumarin (39.8 g, 245 mmol, 1.0 equiv), anhydrous acetonitrile (700 mL) and N,N-diisopropylethylamine (200 mL, 1.15 mol, 4.7 equiv). Add chloromethyl methyl ether (40.0 mL, 527 mmol, 2.1 equiv) dropwise over 30 min while keeping the temperature below 40° C. Stir the resulting mixture at room temperature for 3 h, then add an additional equiv of chloromethyl methyl ether. Stir at room temperature for 15 h, then quench the reaction mixture with saturated aqueous ammonium chloride (500 mL) and extracted with ethyl acetate. Combine the organic extracts and dry over anhydrous magnesium sulfate, filter and concentrate under reduced pressure. Purify the residue by column chromatography on silica gel (30-50% ethyl acetate/heptane) to afford a light yellow solid. Suspend the solid in a mixture of ethyl acetatefleptane (150 mL, 10:90), filter and dry to afford 6-methoxymethoxy coumarin 17a (25.6 g, 50%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=7.8 Hz, 1H), 7.30-7.12 (m, 3H), 6.41 (d, J=7.8 Hz, 1H), 5.20 (s, 2H), 3.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.2, 154.0, 149.5, 143.5, 121.6, 119.6, 118.1, 117.3, 113.8, 95.3, 56.4; IR (KBr) 1714 (s), 1570 (s), 1491 (m), 1447 (m), 1266 (s), 1154 (s), 1070 (s), 1017 (s) cm−1; ESI MS m/z 207 [C11H10O4+H]+.
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6](N[C@H](C2N(C3C=NC=C(F)C=3)C3C=C(F)C=CC=3N=2)C)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-:31].[K+].[K+].OO.O>CS(C)=O>[N:5]1[CH:6]=[C:7]([C:8]([NH2:9])=[O:31])[CH:2]=[N:3][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1cncc(F)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cncnc1
Reaction time: 2 h

Procedure:
To a solution of (S)-4-amino-6-(1-(6-fluoro-1-(5-fluoropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethylamino)pyrimidine-5-carbonitrile (0.040 g, 0.10 mmol) in DMSO (1.02 mL) was added potassium carbonate (0.017 g, 0.122 mmol) followed by hydrogen peroxide (31% in water, 0.635 mL, 6.42 mmol). After stirring for 2 h the solution was poured into water and extracted with EtOAc. Organic extracts were concentrated and purified by MPLC (eluted with 0-100% (1:10:90 NH4OH:MeOH:DCM) in DCM) to afford 4-amino-6-4(1S)-1-(6-fluoro-1-(5-fluoro-3-pyridinyl)-1H-benzimidazol-2-yl)ethyl)amino)-5-pyrimidinecarboxamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (d, J=6.85 Hz, 3H) 5.34 (quin, J=6.94 Hz, 1H) 6.57 (s, 2H) 7.04-7.22 (m, 2H) 7.43 (br. s., 2H) 7.67-7.80 (m, 2H) 7.92 (d, J=7.63 Hz, 1H) 8.21 (dt, J=9.29, 2.10 Hz, 1H) 8.71 (s, 1H) 8.81 (d, J=2.74 Hz, 1H). LC-MS (ESI) m/z 411.0 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@@H:40]2[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]2)=[O:37])=[O:30])[CH2:3]1.[CH2:46]=O>>[OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@@H:40]2[CH2:45][CH2:44][CH2:43][N:42]([CH3:46])[CH2:41]2)=[O:37])=[O:30])[CH2:3]1
Reactant: C=O
Reactant: O=C(NC[C@@H]1CCCNC1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CN1CCC[C@@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2C[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared by a method similar to Step 3 of Example 17, using (2R)-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-N-((3R)-3-piperidylmethyl)pyrrolidine-2-carboxamide and 37% aqueous formaldehyde solution. The compound was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.S(Cl)([Cl:17])=O>CN(C)C=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([Cl:17])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2ccccc2c1O
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2ccccc2c1O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Dry 1-hydroxy-2-naphthoic acid (50 gms., 0.266 mole) was suspended in 350 ml. dry benzene in a flame-dried 1 liter 1-neck round bottom flask under an air condenser and drying tube. Thionyl chloride (31.7 gms., 0.266 mole) was added in one portion followed by 1.5 ml. dry N,N-dimethylformamide. The reaction mixture was stirred magnetically 2-3 days at room temperature. Insoluble material (6.5 gms.) was removed by filtration, and the yellow-tan filtrate was evaporated to dryness to give pale yellow 1-hydroxy-2-naphthoyl chloride, m. p. 87°-88° C. Chilled anhydrous methanol (100 ml.) was added quickly to the solid chloride in an exothermic reaction. The partial solution was heated about 5 minutes on the steam bath under a drying tube then allowed to cool. The suspension was chilled and the solid was collected to give 43 gms. (92% by weight) of 1-hydroxy-2-methyl naphthoate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:25][O:26][CH3:27]>CN(C=O)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:25][O:26][CH3:27])[C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: COCCl
Reactant: N#Cc1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCN(c1nccs1)S(=O)(=O)c1ccc(C#N)cc1
Reaction time: 4 h
Yield: 82 %

Procedure:
To a suspension of 4-cyano-N-thiazol-2-yl-benzenesulfonamide (10 mmol) and potassium carbonate (15 mmol) in DMF (30 mL) was added chloro-methoxy-methane (10 mmol) and the mixture was stirred for 4 h. The reaction mixture was diluted with water (30 mL) and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography to give 4-cyano-N-methoxymethyl-N-thiazol-2-yl-benzenesulfonamide (8.2 mmol) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.[NH:21]1[C:25]([CH:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)=[N:24][N:23]=[N:22]1.C([O-])([O-])=O.[K+].[K+].Cl>CN1CCCC1=O.O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[CH:3]=[C:2]([N:28]2[CH2:29][CH2:30][CH2:31][CH:26]([C:25]3[N:21]=[N:22][NH:23][N:24]=3)[CH2:27]2)[N:7]=[C:6]([O:8][CH3:9])[N:5]=1
Reactant: C1CNCC(c2nnn[nH]2)C1
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(N2CCCC(c3nn[nH]n3)C2)n1
Temperature: 140 °C
Yield: 74.9 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine [300 mg, 0.9 mmol], 3-(1H-tetrazol-5-yl)-piperidine [383 mg, 2.25 mmol] and K2CO3 (373 mg, 2.7 mmol) in N-methylpyrollidinone (5 mL) is heated at 140° C. for 16 hours. The mixture is diluted with water (50 mL), acidified to pH 3 with 10% HCl and extracted three times with EtOAc (40 mL). The organic extracts from the acidic layer are combined and dried over magnesium sulfate, filtered and concentrated. The residue is subjected to chromatography on silica gel eluting with 15% ethyl methanol:DCM to afford an oil which is diluted with water (20 mL). A solid is formed and collected by filtration to afford [2-(2,4-dichloro-phenyl)-ethyl]-{2-methoxy-6-[3-(2H-tetrazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-amine [303 mg, 75%, Example 96] as a solid. LCMS: RT=1.95 minutes, MS: 449 (M+H). IC50=5 nM
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH:10]2[N:22](C(OCC3C=CC=CC=3)=O)[CH2:23][CH2:24][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH:10]2[NH:22][CH2:23][CH2:24][CH:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)c(F)c2)C2C1CCN2C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)c(F)c2)C2NCCC21
Reaction time: 3 h
Yield: 102.8 %

Procedure:
A mixture of compound 21 (3.8 g, 8.0 mmol) and 10% Pd-on-carbon (wet, 500 mg) in MeOH/EtOAc (1:1, 100 mL) was pressurized to 50 PSI H2 and shaken for 3 h using a Parr apparatus. The reaction mixture was filtered through a pad of celite and the solids were washed with EtOAc. The clarified filtrate was concentrated in vacuo to give 22 (2.8 g, 100%). The crude product was used without further purification. Mass spectrum, m/z [341.1] (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].N1C=CN=C1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16]>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Cl)c(Br)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a stirred solution of 3-bromo-4-chlorophenol (25.0 g, 120.5 mmol) in dichloromethane at 0° C. was added imidazole (9.0 g, 132.5 mmol) and t-butyldimethylchlorosilane (TBSC1) (19.0 g, 126.5 mmol). The solution was stirred at 0° C. for 30 min, then at room temperature for 14 h. The reaction mixture was diluted with deionized water, extracted with dichloromethane (2×200 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-10% ethyl acetate in hexanes) to afford (3-bromo-4-chlorophenoxy)-t-butyldimethylsilane as colorless oil (37.0 g, 115.0 mmol, 98%). MS: (ES) m/z calculated for C12H19BrClOSi [M+H]+ 321.0. found 321.