Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.O[N:6]=[CH:7][C:8]1[N:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:11]=[CH:10][C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].CCOCC>O>[C:7]([C:8]1[N:12]([C:13]([CH3:15])([CH3:16])[CH3:14])[N:11]=[CH:10][C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:6]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1C=NO
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1cnn(C(C)(C)C)c1C#N
Reaction time: 16 h
Yield: 83.5 %

Procedure:
Thionyl chloride (6.6 ml., 0.092 mole) was added to a cold solution of 5-(hydroxyiminomethyl)-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester (11 grams, 0.046 mole) in 75 ml. of ether. The solution was stirred in the cold for thirty minutes, then at room temperature for 16 hours. Water was added to the reaction mixture to neutralize the remaining thionyl chloride, then the reaction mixture was poured into a separatory funnel. The phases were separated and the organic phase was washed with water and dried using sodium sulfate and filter paper. The solvent was removed in vacuo, yielding 8.5 grams of 5-cyano-1-tert-butyl-1H-pyrazole-4-carboxylic acid, ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[O:22][C:21]([CH:23]=[N:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[OH:8])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)([O-:11])=[O:10]
Reactant: O=Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: Nc1ccccc1O
Product: O=[N+]([O-])c1ccc(-c2ccc(C=Nc3ccccc3O)o2)cc1

Procedure:
Using 2-aminophenol and 5-(4-nitrophenyl)furan-2-carbaldehyde, 3.62 g of 2-{[5-(4-nitrophenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][NH2:8].I.CS[C:16]1[NH:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1>C(#N)C.C(O)(C(F)(F)F)=O>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:24][NH:25][C:16]=1[NH:8][CH2:7][CH2:6][O:5][C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: CSC1=Nc2ccccc2CN1
Reactant: COc1ccccc1OCCN
Agent: I
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1OCCNC1=Nc2ccccc2CN1
Temperature: 80 °C
Yield: 61.4 %

Procedure:
2-(2-Methoxy-phenoxy)-ethylamine (42 mg, 0.25 mmol) was added to a solution of 2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (70 mg, 0.23 mmol) in acetonitrile (1 ml), and the mixture was heated overnight (80° C.) in a screw-capped vial. The title compound (42 mg, 62%) was then isolated from the reaction mixture by preparative, reverse-phase HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[O:26]1[CH2:29][C:28]([CH2:32][NH2:33])([CH2:30][NH2:31])[CH2:27]1>>[NH2:31][CH2:30][C:28]1([CH2:32][NH:33][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:29][O:26][CH2:27]1
Reactant: NCC1(CN)COC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(CN)COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.04 (d, J=1.8 Hz, 1 H), 7.90 (d, J=1.9 Hz, 1 H), 7.81 (s, 1 H), 7.67 (t, J=3.6 Hz, 1 H), 7.57 (d, J=2.1 Hz, 1 H), 7.52 (t, J=3.8 Hz, 1 H), 7.43 (d, J=2.1 Hz, 1 H), 6.21 (s, 1 H), 5.26 (s, 2 H), 4.63 (s, 4 H), 4.55 (brs, 2 H), 3.82 (s, 2 H), 3.67 (t, J=2.4 Hz, 2 H), 3.45 (brs, 2 H), 2.46 (s, 3 H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=3)[N:15]=[C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])C>[OH-].[Na+]>[F:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH:13]=[C:12]2[N:9]1[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCN(c2cc(-c3ccccc3)nc3ccc(F)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CCN(c2cc(-c3ccccc3)nc3ccc(F)cc23)CC1
Yield: 100.8 %

Procedure:
From 6.0 g of 1-[6-fluoro-2-phenyl-4-quinolinyl]-4-piperidinecarboxylic acid ethyl ester and 10 ml of 3N sodium hydroxide, treated in a manner similar to that described in Example 1C, there was obtained 5.6 g of product as yellow needles, mp 255°-260° dec.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH:9]=O)[C:3]=1F.[NH2:12][NH2:13]>CCCCO>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[CH:9]=[N:12][NH:13][C:3]=12
Reactant: NN
Reactant: O=Cc1ncc(F)c(Cl)c1F
Solvent: CCCCO
Product: Fc1cnc2cn[nH]c2c1Cl
Temperature: 110 °C

Procedure:
To a solution of 4-chloro-3,5-difluoropicolinaldehyde (533 mg, 3.0 mmol) in n-BuOH (15 mL) was added hydrazine (0.113 mL, 3.60 mmol) and the reaction was heated at 110° C. for 22 hours. The reaction mixture was cooled, concentrated and the residue was dissolved in EtOAc (100 mL) and washed with saturated Na2CO3 solution, dried over Na2SO4, and evaporated to give a residue which was purified by silica gel column chromatography eluted with hexanes/EtOAc (0-100%) to give the title compound. MS [M+H] found 172.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[N:17]=[C:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:19][C:20]=3[C:21]([F:24])([F:23])[F:22])=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH:31]1[C:35]([CH:36]2[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38][CH2:37]2)=[N:34][N:33]=[N:32]1>>[NH:34]1[C:35]([CH:36]2[CH2:37][CH2:38][CH:39]([C:42]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]4[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]5[N:17]=[C:18]([C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[O:19][C:20]=5[C:21]([F:22])([F:23])[F:24])=[O:15])=[CH:11][CH:12]=4)[CH2:3][CH2:2]3)=[O:43])[CH2:40][CH2:41]2)=[N:31][N:32]=[N:33]1
Reactant: O=C(O)C1CCC(c2nnn[nH]2)CC1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1ccc(C2CCN(C(=O)C3CCC(c4nnn[nH]4)CC3)CC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a procedure similar to example 1,2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-{1-[4-(1H-tetrazol-5-yl)-cyclohexanecarbonyl]-piperidin-4-yl}-phenyl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (212 mg, 0.51 mmol) and 4-(1H-tetrazol-5-yl)-cyclohexanecarboxylic acid (100 mg, 0.51 mmol) as an off white solid (147 mg, 49%). LCMS calcd for C30H30F3N7O3 (m/e) 593, obsd 594 (M+H).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.C([Li])CCC.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>CCOCC>[CH2:25]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1)[CH2:26][CH2:27][CH3:28]
Reactant: Brc1coc2ccccc12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1coc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.3 %

Procedure:
A solution of bromine (4.49 g, 28.09 mmol) in chloroform (5 mL), was added slowly to a stirred mixture of benzofuran (1.58 g, 13.38 mmol) and potassium acetate (2.69 g, 27.42 mmol) in chloroform (20 mL) at room temperature. After the addition was complete, the reaction mixture was warmed to 50° C. and stirred at this temperature for 5 h. The solution was then allowed to cool, and washed with 5% NaHSO3, then brine, then dried through MgSO4, filtered and evaporated to give trans-2,3-dihydro-2,3-dibromo-benzofuran as a pale-yellow solid (2.88 g). The pale-yellow solid (2.18 g, 7.84 mmol) was dissolved in anhydrous ethanol (20 mL) then sodium ethoxide (1.33 g, 19.60 mmol) was added and the resulting mixture was heated to 50° C. and stirred at this temperature for 5 h. The solution was allowed to cool, then brine added, and the solution was extracted with ether. The ether layer was washed with water and brine, dried through MgSO4, and the solvent was evaporated to give a brown oily residue. Purification by flash chromatography using a gradient of ammoniated methanol in chloroform gave 3-bromo-benzofuran as a light-brown oil (1.50 g). Under nitrogen, the 3-bromobenzofuran (450 mg, 2.28 mmol) was then dissolved in anhydrous ether, (10 mL) and stirred at −78° C. n-Butyllithium (1.6M, 2.3 mL, 3.65 mmol) was added, and stirring was continued at −78° C. After 15 min, tri-n-butylstannyl chloride (668 mg, 2.05 mmol) was added, then the solution was allowed to warm to room temperature, and stirring was continued for another 1 h. The mixture was quenched, and washed with 1N sodium hydroxide, dried through MgSO4, and then the solvent was evaporated to give a brown oily residue. Purification by flash chromatography using a gradient of ammoniated methanol in chloroform as the eluant gave the sub-title compound as a yellow oil (570 mg).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:9]([OH:11])=O)=[C:5]([CH2:7][CH3:8])[N:6]=1.C(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([C:9]([Cl:14])=[O:11])=[C:5]([CH2:7][CH3:8])[N:6]=1
Reactant: CCc1nc(C)sc1C(=O)O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1nc(C)sc1C(=O)Cl

Procedure:
In a similar apparatus to Example 1, 8.6 g (0.05 mole) of 2-methyl-4-ethylthiazole-5carboxylic acid were suspended in 200 ml of toluene. Under heating and reflux, phosgene was blown at a rate of 340 ml/hr for 12 hours (0.18 mole). After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 9.2 g of 2-methyl-4-ethylthiazole-5-carboxylic acid chloride. Its purity and yield were 96.0% and 96.6%, respectively. NMR (δCDCl 3/TMS, ppm): 1.25(3H,t,J=8Hz), 2.46(3H,s), 3.06(2H,q,J=8Hz).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[C:11]2[C:6](=[CH:7][C:8]([Cl:18])=[CH:9][C:10]=2[Cl:17])[N:5]=1)([OH:3])=[O:2].[CH3:19]O>>[C:14]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([Cl:18])=[CH:9][C:10]=2[Cl:17])[N:5]=[C:4]([C:1]([O:3][CH3:19])=[O:2])[CH:13]=1)([OH:16])=[O:15]
Reactant: CO
Reactant: O=C(O)c1cc(C(=O)O)c2c(Cl)cc(Cl)cc2n1
Product: COC(=O)c1cc(C(=O)O)c2c(Cl)cc(Cl)cc2n1
Reaction time: 1 h

Procedure:
2,4-Dicarboxy-5,7-dichloroquinoline was added to methanol (presaturated with dry hydrogen chloride) (500 ml) and the solution left at room temperature for 1 h. After this time the volume of solvent was reduced to approximately 100 ml and the white solid that precipitated was collected by filtration and dried in a vacuum oven at 100° C. (20 mm Hg) for 2 h to give the title compound (18.5 g, m.p. 260°-262° C.); δ (250 MHz, DMSO) 3.98 (3H, s, CH3), 8.11 (1H, s, 3-H), 8.15 (1H, d, J=2.1 Hz, 6-H or 8-H), 8.36 (1H, d, J=2.1 Hz, 6-H or 8-H); m/e 299 (M+) 241 (100%, M-CO2CH3 +H); Found: C, 47.58; H, 2.42; N, 4.62. C12H7Cl2NO4. 0.2 H2O requires C, 47.46; H, 2.46; N, 4.61%.
Reaction SMILES: C(N1C2C=CC=CC=2C([N+]([O-])=[O:15])=CC2C=CC=CC1=2)#N.B(F)(F)F.[C:25]([N:28]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[C:32]([N+]([O-])=O)=[CH:31][C:30]2[CH:42]=[CH:43][CH:44]=[CH:45][C:29]1=2)(=[O:27])[NH2:26]>ClC1C=CC=CC=1.C(O)(=O)C>[C:25]([N:28]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[C:32](=[O:15])[CH2:31][C:30]2[CH:42]=[CH:43][CH:44]=[CH:45][C:29]1=2)(=[O:27])[NH2:26]
Reactant: N#CN1c2ccccc2C=C([N+](=O)[O-])c2ccccc21
Reactant: NC(=O)N1c2ccccc2C=C([N+](=O)[O-])c2ccccc21
Agent: FB(F)F
Solvent: Clc1ccccc1
Solvent: CC(=O)O
Product: NC(=O)N1c2ccccc2CC(=O)c2ccccc21

Procedure:
31.5 g (0.12 mole) of 5-cyano-10-nitro-5H-dibenz[b,f]azepine are suspended in 340 ml of chlorobenzene and 98 ml of a solution of 10% by weight of BF3 in acetic acid are quickly added. By heating to 30° dissolution occurs and shortly after that the BF3 adduct of 5-carbamoyl-10-nitro-5H-dibenz[b,f]azepine begins to precipitate. The mixture is left to crystallise for 2 hours in an ice-bath, suction-filtered and washed with benzine. The dry intermediate is dissolved in a mixture of 200 ml of acetic acid and 35 ml of water. 50 g of iron powder are added in portions over a period of 30 minutes and the temperature is maintained at approximately 60° by cooling. The mixture is stirred for a further hour at 50°, filtered and then washed with acetic acid. The filtrate is concentrated by evaporation in vacuo and the residue is taken up in 500 ml of water. The precipitated product is suction-filtered, washed neutral with water and dried in vacuo at 50°. 5-Carbamoyl-10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine is obtained, which according to the IR spectrum is identical to authentic material.
Reaction SMILES: C[O-].[Na+].C(O[C:9]([C:11]1[N:12]=[CH:13][C:14]2[C:19]([C:20]=1[OH:21])=[CH:18][CH:17]=[C:16]([O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])=[CH:25][CH:24]=1)[CH:15]=2)=[O:10])CCC.[NH2:40][CH2:41][C:42]([OH:44])=[O:43].Cl>CO>[OH:21][C:20]1[C:19]2[C:14](=[CH:15][C:16]([O:22][C:23]3[CH:24]=[CH:25][C:26]([NH:29][S:30]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)(=[O:32])=[O:31])=[CH:27][CH:28]=3)=[CH:17][CH:18]=2)[CH:13]=[N:12][C:11]=1[C:9]([NH:40][CH2:41][C:42]([OH:44])=[O:43])=[O:10]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1ncc2cc(Oc3ccc(NS(=O)(=O)c4ccc(C)cc4)cc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc4c(O)c(C(=O)NCC(=O)O)ncc4c3)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1.85 ml of 0.5 M sodium methoxide in methanol was added 42 mg of 4-Hydroxy-7-[4-(toluene-4-sulfonylamino)-phenoxy]-isoquinoline-3-carboxylic acid butyl ester and 70 mg of glycine. The resultant mixture was heated at reflux temperature for 24 hours and then cooled to room temperature. The reaction was poured into a 0.2 N HCl aqueous solution and then extracted three times with ethyl acetate. The organic fractions were dried over anhydrous sodium sulfate and concentrated to 41 mg of a white solid; MS (+): m/z 508.10 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:25]=[CH:24][C:13]3[N:14]([CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:15](=[O:18])[N:16]([CH3:17])[C:12]=3[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[C:26]1([Mg]Cl)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH3:22][C:20]([CH3:21])([CH3:23])[CH2:19][N:14]1[C:13]2[CH:24]=[CH:25][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:1]([OH:3])([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH3:2])[CH:5]=3)=[CH:11][C:12]=2[N:16]([CH3:17])[C:15]1=[O:18]
Reactant: Cl[Mg]c1ccccc1
Reactant: CC(=O)c1cccc(-c2ccc3c(c2)n(C)c(=O)n3CC(C)(C)C)c1
Solvent: C1CCOC1
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(C(C)(O)c4ccccc4)c3)cc21
Reaction time: 1 h

Procedure:
A solution of 5-(3-acetylphenyl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (1-17, 170 mg, 0.51 mmol) in anhydrous THF (5 ml) was cooled to −78 deg C. and treated with Phenyl magnesium chloride (1.8 M in THF, 365 μL, 0.66 mmol, 1.3 eq). The reaction mixture was warmed to 0 deg C. and stirred for 1 h. The reaction was only ˜30% complete, so more of the Grignard reagent (1.8 M in THF, 365 μL, 0.66 mmol, 1.3 eq) was added at 0 deg C. and the reaction was maintained there for 30 min. The completed reaction was partitioned between EtOAc (50 ml) and water (55 ml) and the cloudy, white precipitate present which was removed via filtration. The filtrate was separated in a separatory funnel and the aqueous layer was re-extracted with EtOAc (50 ml). The combined organic layers were dried over Na2SO4, concentrated, then purified via flash column chromatography (SiO2: 100% Hex to 50:50 Hex/EtOAc), affording the title compound, 1-(2,2-dimethylpropyl)-5-[3-(1-hydroxy-1-phenylethyl)phenyl]-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (10-1) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.48-7.45 (m, 3H), 7.40-7.31 (m, 4H), 7.27-7.24 (m, 2H), 7.12 (s, 1H), 7.05 (d, 1H, J=8.15 Hz), 3.67 (s, 2H), 3.45 (s, 3H), 2.02 (s, 3H), 1.05 (s, 9H). LRMS m/z: Calc'd for C27H30N2O2(M+H) 415.2, found 415.5.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[NH:25]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:25]4[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: OC1CCNC1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CCC(O)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, and pyrrolidin-3-ol. 1H NMR (400 MHz, DMSO-d6): δ 8.74 (t, J=5.62 Hz, 1H), 7.72 (d, J=9.61 Hz, 1H), 7.52 (dd, J=9.21, 8.20 Hz, 2H), 6.96 (d, J=9.23 Hz, 1H), 4.97-5.01 (m, 1H), 3.55-3.61 (m, 4H), 3.22-3.25 (m, 2H), 2.02-2.04 (m, 3H), 1.73-1.94 (m, 6H), 1.15-1.32 (m, 2H). m/z: 424.2 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:28])[C@H:9]([C:25]([OH:27])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:40][C@@H:41]([C:43]([O:45]CC1C=CC=CC=1)=[O:44])[CH3:42].C1N2CCN(CC2)C1.C1CCC(N=C=NC2CCCCC2)CC1>CCOCC.CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:28])[C@H:9]([C:25]([NH:40][C@@H:41]([C:43]([OH:45])=[O:44])[CH3:42])=[O:27])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](N)C(=O)OCc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CN2CCN1CC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)N(C)C(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
To 30 ml. of DMF were added 2.73 grams (7.1 mmoles) of Nα -t-butyloxycarbonyl-Nα -methyl-O-benzyl-L-tyrosine (prepared by acidification of 3.6 grams of the product from Part A and extraction into ether). The solution was cooled to 0° C., and 2.26 grams (7.1 mmoles) of the tosylate salt of D-alanine, benzyl ester, were added followed by 0.794 grams (7.1 mmoles) of triethylenediamine. The mixture was stirred at 0° C. for five minutes, and 0.96 grams of HBT and 1.46 grams (7.1 mmoles) of DCC were added. The mixture was stirred at 0° C. for two hours and then at room temperature for 24 hours. The mixture then was cooled to 0° C. and filtered. The filtrate was concentrated in vacuo to an oil, and then the oil was dissolved in ethyl acetate and extracted successively with 1 N aqueous sodium bicarbonate, water, 1.5 N citric acid, and water. The organic phase was dried over magnesium sulfate and concentrated in vacuo to an oil. The oil was dissolved in 60 ml. of ethanol, and 1.5 grams of 5% palladium on carbon were added to the mixture as a water slurry. Nitrogen was bubbled into the reaction mixture through a gas dispersion tube for five minutes followed by hydrogen gas for 24 hours. The mixture was flushed with nitrogen, and the catalyst was removed by filtration. The reaction mixture was concentrated in vacuo to an amorphous solid to give 2.5 grams (99 percent) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[S:9][C:10]([Br:28])=[CH:11][C:12]=1[S:13](=[O:27])(=[O:26])[N:14]([CH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[OH:18])[CH3:15])([CH3:4])([CH3:3])[CH3:2].[C:30](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:29])[N:7]([C:8]1[S:9][C:10]([Br:28])=[CH:11][C:12]=1[S:13](=[O:26])(=[O:27])[N:14]([CH2:16][CH:17]([C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[OH:18])[CH3:15])[CH3:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1cc(Br)sc1NC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)c1sc(Br)cc1S(=O)(=O)N(C)CC(O)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a solution of (5-bromo-3-{[2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-sulfamoyl}-thiophene-2-yl)-carbamic acid t-butyl ester (the compound of Preparation Example 97) (1 g) and potassium carbonate (278 mg) in N,N-dimethylformamide was added methyl iodide (0.75 mL). After stirred for 2 hours, ethyl acetate was added, and insoluble matter was removed by filtration. The residue resulting form evaporating the filtrate in vacuo was purified by silica gel column chromatography (hexane/ethyl acetate), and a colorless oily matter (958 mg) was obtained.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Solvent: CC(=O)O
Product: O=C1CCCc2cc(O)ccc21

Procedure:
A mixture of 6-methoxy-1-tetralone (5 g, 28.4 mmol) in acetic acid (50 ml) and 48% bromhydric acid (25 ml) was heated at reflux for 7 hours. After extraction with CH2Cl2 and evaporation, the residue was purified by flash chromatography (AcoEt/petroleum ether 45/55) to give 6-hydroxy-1-tetralone as a foam (3.9 g; 84.7%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][C@@H:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](=[O:19])[NH:47][C@@H:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH3:39])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:37][CH:38]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Oc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: C[C@@H](N)c1ccccc1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@H](C)c4ccccc4)ccc3Oc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 84 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenoxy)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 411D) and R-(+)-α-methylbenzylamine: yield 84%.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.[CH2:18]([N:21]=[C:22]=[O:23])[CH2:19][CH3:20]>>[CH2:18]([NH:21][C:22]([N:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]2[C:9](=[O:12])[N:10]([CH3:11])[C:2]([CH3:17])([CH3:1])[N:3]=[C:4]12)=[O:23])[CH2:19][CH3:20]
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Reactant: CCCN=C=O
Product: CCCNC(=O)N1C2=NC(C)(C)N(C)C(=O)N2c2ccccc21

Procedure:
The title compound was prepared from 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one (Example 1 (B)) and n-propyl isocyanate according to the procedure of Example 10. The confirmatory elemental analysis for the product, mp 85°-87° C., is shown in Table III.