Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:18])=[O:19])=[CH:13][CH:12]=2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CC(C)S(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: CC(C)S(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
(R)-3-cyclopentyl-2-[4-(propane-2-sulfonyl)-phenyl]-propionic acid (100 mg, 0.31 mmol) was dissolved in methylene chloride (3 mL) and N,N-dimethylformamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 180 μL, 0.33 mmol) which produced gas evolution and it was then stirred at 25° C. for 15 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (3 mL) and added dropwise into a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 50 mg, 0.31 mmol), 2,6-lutidine (100 μL, 0.62 mmol) and methylene chloride (3 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 3 h. After this time, the reaction was quenched with a small amount of methanol and diluted with methylene chloride. It was then washed with 1 N aqueous hydrochloric acid solution and saturated aqueous brine solution dried over sodium sulfate and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 60% ethyl acetate/hexanes to 100% ethyl acetate) to afford (R)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(propane-2-sulfonyl)-phenyl]-propionamide (83 mg, 58%) as a white foam: [α]30589=−8.3° (c=0.18, methanol); ES-HRMS m/e calcd for C24H35N3O4S (M+H)+ 462.2421, observed 462.2421; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 3H, CH3), 1.04 (s, 3 H, CH3), 1.11 (m, 2H, CH2), 1.13 (d, J=6.9 Hz, 6H, 2×CH3), 1.35-1.80 (m, 8H, 4×CH2), 2.10 (m, 1H, CH), 3.36 (m, 1H, SO2CH), 3.86 (s, 2H, NCH2), 3.93 (m, 1H, ArCHCO), 4.65 (s, 1H, OH), 6.46 (d, J=2.4 Hz, 1H, Ar), 7.50 (d, J=2.4 Hz, 1H, Ar), 7.64 (d, J=8.4 Hz, 2H, Ar), 7.80 (d, J=8.4 Hz, 2H, Ar), 10.79 (s, 1H, NH).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[CH2:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH3:20])[CH3:19])[CH:13]=1.[OH-].[Na+]>C(O)C.O>[CH3:19][N:18]([CH3:20])[C:14]1[CH:13]=[C:12]([C:11]2[N:2]([CH3:1])[C:3](=[O:22])[C:4]3[CH:9]=[CH:8][CH:7]=[N:6][C:5]=3[CH:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CNC(=O)c1cccnc1CC(=O)c1cccc(N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)c1cccc(-c2cc3ncccc3c(=O)n2C)c1
Temperature: 70 °C

Procedure:
The crude product of Example 7 (17.2 g.). was dissolved in ethanol and 4.3 g. of gaseous hydrogen chloride were bubbled in. The reaction mixture was heated for 5 minutes at 70° C. Two crops of a solid, 12.4 g., m.p. 197°-220° C. (dec.), and 1.9 g., m.p. 224°-226° (dec.), were obtained. The two crops were combined and recrystallized from ethanol to obtain 11.8 g., m.p. 221°-232° C. (dec.). The mother liquors from each of the crystallizations and recrystallizations were combined; two additional crops, 4.9 g. (total), m.p. 193°-216° C. (dec.), were obtained therefrom. 11.5 g. of the combined crystalline materials were dissolved in water, excess sodium hydroxide solution was added, and the basic solution was extracted with methylene chloride. The methylene chloride extract was dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure. The residue was chromatographed on silica gel using ethyl acetate as the eluant. The major fractions were combined and recrystallized from acetone/pentane, 7.6 g., m.p. 118°-120° C. An analytical sample had a melting point of 120° C. A second crop (2.4 g.), m.p. 117°-119° C., was also obtained.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(Cl)(C1C=CC=CC=1)(C1C=CC(OC)=CC=1)C1C=CC(OC)=CC=1.N1C=CN=C1.[Si:47](Cl)([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]>N1C=CC=CC=1.O>[Si:47]([O:10][C@@H:9]1[C@@H:11]([CH2:12][OH:13])[O:14][C@@H:7]([N:6]2[CH:15]=[C:2]([F:1])[C:3](=[O:17])[NH:4][C:5]2=[O:16])[CH2:8]1)([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2cc(F)c(=O)[nH]c2=O)O[C@@H]1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
To a solution of 5-fluoro-2′-deoxyuridine (FDUR) (4.92 g, 20 mmol) in pyridine (100 mL) was added DMTrCl (10.16 g, 30 mmol) portion-wise at 0° C. and the solution was stirred at 0° C. for 2 h. Water (5 mL) was added and the mixture was evaporated to dryness and the residue was co-evaporated with toluene (2×20 mL). The residue was dissolved in EtOAc (200 mL) and the solution was washed with brine and dried over Na2SO4. Solvent was removed and the residue was dissolved in CH2Cl2 (100 ml). To the solution were added imidazole (4.08 g, 60 mmol) then t-butyldimethylsilylchloride (TBSCl, 4.52 g, 30 mmol) and the mixture was stirred at room temperature for overnight. Water (50 mL) was added and the mixture was evaporated to dryness. The residue was dissolved in EtOAc (300 mL) and the solution was washed with brine and dried over Na2SO4. Solvent was removed and the residue was co-evaporated with toluene twice then dissolved in CH2Cl2 (200 mL). To the solution was added trifluoroacid (TFA, 3 mL) and the solution was stirred at room temperature for 3 h. Water (5 mL) was added and the mixture was stirred for 30 min then methanol (10 mL) added. After 10 min, the solution was neutralized with 30% ammonium hydroxide. The mixture was concentrated to dryness and the residue was purified by silica gel chromatography to give product as solid (5.6 g. 78%). 1H-NMR (CDCl3): δ 8.88 (br s, 1H), 7.96 (d, J=6.4 Hz, 1H), 6.23 (m, 1H), 4.78 (m, 1H), 3.95 (m, 1H), 3.79 (m, 1H), 2.28 (m, 2H), 0.88 (s, 9H), 0.00, 0.09 (ss, 6H). LC-MS (ESI): 361 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:17])[CH2:9][C:10]3([S:16][C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:1][C:2]1[C:7]2[C:8](=[O:17])[CH2:9][C:10]3([S:16][C:6]=2[CH:5]=[C:4]([O:18][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:3]=1)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3
Reactant: O=C1CC2(CCCCC2)Sc2cc(O)cc(O)c21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cc(O)c2c(c1)SC1(CCCCC1)CC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
A mixture of 5,7-dihydroxy-spiro [2H-1-benzothiine-2,1'-cyclohexan]-4(3H)-one (prepared in Preparation 79) (0.47 g, 1.78 mmol ), ethyl bromoacetate (0.297 g, 1.78 mmol), anhydrous potassium carbonate (0.368 g, 2.67 mmol), and dry acetonitrile (5 ml) is stirred overnight at room temperature. The mixture is stirred at 35° C. for additional 5 hours. The reaction mixture is filtered to remove inorganic materials. The solvent is removed by distillation from the filtrate. The residue is placed on a silica gel column and eluted with a mixture of dichloromethane and ethyl acetate (9:1) to obtain ethyl 2-{(5-hydroxy-3,4-dihydro-4-oxospiro[2H-1-benzothiine-2,1'-cyclohexan]-7-yl)oxy}acetate as a crystalline solid (0.57 g, 91.5%). Recrystallization from diethyl ether gives a product having a melting point of 87°-88° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:25]2([OH:28])[CH2:26][CH2:27][N:22]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24]2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(Br)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CCN(Cc3ccccc3)CC2)c1
Reaction time: 1 h

Procedure:
3-Bromoanisole (50.0 g, 0.264 mol) was dissolved in 150 mL of THF and then chilled to −78° C. n-Butyllithium (1.6M, 175 mL, 0.276 mol) was then added while maintaining the reaction temperature at −70° C. or below. After complete addition, the reaction mixture was stirred for an additional 60 min. 1-Benzyl-4-piperidone in 150 mL of THF was then added at such a rate as to maintain the reaction temperature at −70° C. or below. The reaction was stirred at −70° C. for an additional 15 min, then the dry ice-acetone bath was removed, and the reaction was allowed to come to room temperature. Brine (400 mL) was added, and the organic layer was separated and washed with an additional 300 mL of brine. The organic layer was separated, dried (K2CO3), and concentrated in vacuo. 6N HCl (250 mL) was added to the oily residue which was then washed with EtOAc. The aqueous layer was separated, basified with 50% NaOH, and extracted with EtOAc. The EtOAc layer was separated, dried (K2CO3), and concentrated in vacuo to give 75.7 g of 4-(3-methoxyphenyl)-1-benzyl-4-piperidinol as an orange oil. A sample was chromatographed on silica gel using hexane/EtOAc (7:3) mixtures as the eluent to afford a yellow oil which was dissolved in ether and treated with ethereal hydrochloric acid to give 4-(3-methoxyphenyl)-1-benzyl-4-piperidinol hydrochloride as a white solid (mp 195-197° C.). 1H NMR (CDCl3) (free base) δ (ppm) 1.64-1.75 (m, 2H), 2.09-2.21 (m, 2H), 2.41-2.51 (m, 2H), 2.71-2.80 (m, 2H), 3.51 (s, 2H), 3.80 (s, 3H), 6.77-6.81 (m, 1H), 7.06-7.09 (m, 2H), 7.23-7.35 (m, 6H). Anal. Calcd for C19H23NO2 HCl.1/2 H2O: C, 66.56; H, 7.06; N, 4.09. Found: C, 66.41; H, 7.31; N, 4.33.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[N+:25]([C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1)([O-:27])=[O:26]>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:32][C:31]3[CH:34]=[CH:35][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: O=[N+]([O-])c1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1
Yield: 1.2 %

Procedure:
The title compound (0.004 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.3 g) using 4-nitrobenzyl bromide (0.3 g) in place of benzyl chloride. MS (ESI): exact mass calculated for C20H19ClN4O2, 382.12. found, m/z 383.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.23-8.19 (m, 2H), 7.51-7.47 (m, 2H), 7.45-7.47 (m, 2H), 7.32 (d, J=8.6 Hz, 2H), 5.52 (s, 2H), 2.98-2.95 (m, 4H), 2.89-2.85 (m, 2H), 2.83-2.79 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][CH2:4][OH:5].C[C:13]([OH:22])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])CC>>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][CH2:4][O:5][C:13](=[O:22])[CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CCCCCCC(C)(O)CC
Reactant: CCCCCCC(C)CCO
Product: CCCCCCC(C)CCOC(=O)C1CCCCC1

Procedure:
The procedure in Example XIX is followed except that 39 g. of 3-methylnonan-1-ol instead of 40 g. of 3-methylnonan-3-ol are brought into the reaction.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:19][C:20]([F:40])([F:39])[C:21]1([O:34][Si](C)(C)C)[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1>C1COCC1>[OH:34][C:21]1([C:20]([F:40])([F:19])[F:39])[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCCC(O[Si](C)(C)C)(C(F)(F)F)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 1.0 M solution of TBAF in THF (1 eq) was added to a solution of tert-butyl 3-(trifluoromethyl)-3-(trimethylsilyloxy)piperidine-1-carboxylate (1 eq) in THF (0.2 M). After stirring for 16 h at rt the reaction mixture was concentrated in vacuo. The resulting residue was dissolved in EtOAc, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was dissolved in CH2Cl2, loaded onto a SiO2 column, and purified by flash chromatography to give tert-butyl 3-hydroxy-3-(trifluoromethyl)piperidine-1-carboxylate. 19F NMR (282 MHz, CDCl3): δ−83.74 ppm; 1H NMR (300 MHz, CDCl3): δ 4.04-4.16 (m, 2H), 2.72-3.01 (m, 2H), 1.50-2.04 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Li][CH2:16][CH2:17]CC.ICC>>[CH3:1][C:2]1[C:14]2[CH:13]([CH2:16][CH3:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1Cc1ccccc1-2
Reactant: [Li]CCCC
Solvent: CCI
Product: CCC1c2ccccc2-c2cccc(C)c21
Yield: 95.7 %

Procedure:
The substitution reaction at the 9-position was performed according to the general procedure for the synthesis of 9-substituted fluorenes described above in item IV(i). 1-Methylfluorene (47) (3.01 g, 16.7 mmol) was used instead of fluorene, n-BuLi (8.06 ml, 20 mmol, 2.5 M in hexane), RX=1-iodoethane (3.39 g, 21.7 mmol). 48 was isolated to give a colorless oil (3.33 g, 95%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH2:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=O.O>CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]1[O:11][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)COCc1ccccc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(-c2coc(COCc3ccccc3)n2)cc1
Temperature: 130 °C
Yield: 42.9 %

Procedure:
To a solution of 2-Benzyloxy-acetamide (1.40 g, 8.56 mmol) in 4 ml of DMF was added 2-Bromo-1-(4-chloro-phenyl)-ethanone (2.0 g, 8.56 mmol) and the reaction mixture was heated at 130° C. for 6 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 10% EtOAc-Hexane) to get the desired product (1.1 g, 44%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:19]([NH2:23])[CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl.N[C@@H](CCC)[C@@H:33](C1C=CC=C(OC)C=1)[OH:34]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:24]4[CH:25]=[CH:26][CH:27]=[C:28]([O:34][CH3:33])[CH:29]=4)[C@@H:19]([NH2:23])[CH2:20][CH2:21][CH3:22])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCC[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: CCC[C@H](N)[C@H](O)c1cccc(OC)c1
Agent: Cl
Product: CCC[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(OC)c1

Procedure:
was synthesised in the same way as (91a) from (1R,2S)-2-amino-1-(3-methoxyphenyl)pentan-1-ol hydrochloride (93b, 50 mg, 0.20 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:41][S:42]([CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:44])=[O:43]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:51]3[CH2:50][CH2:49][N:48]([CH2:47][CH2:46][CH2:45][S:42]([CH3:41])(=[O:43])=[O:44])[CH2:53][CH2:52]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:31])([CH3:32])[C:33]#[N:34])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). LR-MS: 738.0 [(M+H)+]
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=[O:6].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH2:5][OH:6]
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc(Br)cc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3,5-Dibromobenzaldehyde (1.7 g, 6.3 mmol) was dissolved in methanol (100 mL) and sodium borohydride (0.250 g, 6.3 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 0° C. and then at 20° C. for another 0.5 h. The reaction mixture was concentrated in vacuo, diluted with brine (250 mL), acidified with hydrochloric acid and extracted with dichloromethane (3×50 mL). Evaporation of the organic solution gave 3,5-dibromo-benzyl alcohol as a white crystalline compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[CH2:10][CH2:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.Cl.C(OCC)C>C1COCC1>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)CCCc1cccs1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCCCc1cccs1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
A 2.5 M solution of lithium aluminum hydride in THF (10 mL) was slowly added to a solution of methyl ester 1b (7.30 g, 0.04 mol,) in 100 mL of anhydrous THF. After completion of the addition, the solution was refluxed for four hours, then cooled to room temperature. Hydrochloric acid (10%, 25 mL) was then slowly added, and the resulting mixture was heated for another 30 minutes. After cooling to room temperature, diethyl ether (100 mL) was added, the organic layer was separated and washed with brine, dried with anhydrous magnesium sulfate. Evaporation of the solvent gave the alcohol 1c (5.4 g, 90%) as a colorless oil. 1H NMR (250 MHz, 25° C., CDCl3): δ7.12 (m, 1H, Ar—H), 6.92 (m, 1H, Ar—H), 6.79 (m, 1H, Ar—H), 3.62 (t, 2H, CH2OH), 2.86 (t, 2H, Ar—CH2), 2.30 (s, 1H, OH), 2.00 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([Br:9])=[C:4](Cl)[N:3]=1.[Na].[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([Br:9])=[C:4]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: OCc1ccccc1
Reactant: Nc1nc(N)c(Br)c(Cl)n1
Agent: [Na]
Product: Nc1nc(N)c(Br)c(OCc2ccccc2)n1
Temperature: 130 °C

Procedure:
2,4-Diamino-5-bromo-6-chloropyrimidine (Phillips et. al., J. Org. Chem., 29, 1488-1490 (1963)) (2.3 g, 10 mmol) was added to a solution of sodium (0.29 g, 12.5 mmol) in benzyl alcohol (10 mL) under argon. The solution was heated in a 130° C. oil bath for 3 h and the benzyl alcohol was evaporated under reduced pressure to give a white solid. This solid was washed with water, and air dried. Crystallization from 50% aqueous ethanol gave white crystalline needles of 3f: yield, 2.32 g (76%); mp 165°-166° C. (lit. 136° C.; Kosary et. al., Acta Pharm. Hung., 49, 241-247 (1989)); UV (pH 1)) λmax 236 nm (ε=0.873×104), 291 (1.388×104); (pH 6.9) 236 (0.850×104), 277 (0.835×104); (pH 13) 234 (0.869×104), 277 (0.827×104); 1H NMR δ5.30 (s, 2H, ARCH2), 6.15 (s, 2H, NH2, exchange with D2O), 6.32 (s, 2H, NH2, exchange with D2O), 7.31-7.45 (m, 5H, ArH); MS (EI) calcd. m/z for C11H11N4O79Br 294.0115, found 294.0127; calcd. m/z for C11H11N4O81Br 296.0094, found 296.0083; Anal. (C11H11N4OBr) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:17]=1[C:18]([N:20]=[C:21]=[O:22])=[O:19]>C(OCC)(=O)C>[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:17]=1[C:18]([NH:20][C:21]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:2]([CH3:1])[N:7]=1)=[O:22])=[O:19]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Cc1nc(N)ccc1-c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc(NC(=O)NC(=O)c2c(F)cccc2F)ccc1-c1ccccc1

Procedure:
6-Methyl-5-phenyl-2-pyridylamine (500 mg) and 2,6-difluorobenzoyl isocyanate (650 mg) were reacted in 25 ml ethyl acetate. A precipitate formed which was filtered, dried, and identified as the desired product by NMR, m.p. 206°-208° C.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][C@:9]([OH:59])([C@@H:17]([C:38](=[O:58])[NH:39][C@H:40]([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]#[C:51][CH3:52])=[CH:44][CH:43]=1)/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])OCC[O:27]1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[Cl-].[Na+].O>C(#N)C>[CH2:49]([O:48][C:45]1[CH:44]=[CH:43][C:42]([CH2:41][C@H:40]([NH:39][C:38]([C@@H:17](/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](=[O:27])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C@@:9]([OH:59])([CH2:8][CH2:7][OH:6])[C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])=[O:58])[C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:47][CH:46]=1)[C:50]#[C:51][CH3:52]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@@](O)(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)C(=O)OCC)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
tert-Butyl (E)-(2S,3S)-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-ethoxycarbonyl-ethylcarbamoyl]-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-undec-4-enoate (3.92 g, 4.49 mmol) was dissolved in acetonitrile (43 mL), and an aqueous solution of 0.5 M citric acid (19 mL, 9.50 mmol) was then added. The mixture was then stirred at 60° C. for 2.5 hours. The reaction solution was cooled to room temperature, and a mixture of a saturated aqueous solution (3.0 mL) of sodium chloride and water (60 mL) was then added. The solution was extracted three times with 20% ethyl acetate/n-hexane (32 mL). The organic layers were combined, then washed twice with a saturated aqueous solution (32 mL) of sodium chloride, dried over anhydrous sodium sulfate, and filtered. The solvent was then distilled off under reduced pressure to obtain 3.24 g (4.54 mmol, quant) of No. 5328627.