Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:22][CH2:23][C:24]#[N:25]>CN(C)C=O.C(OCC)(=O)C>[CH3:12][C:11]1([CH3:13])[C:8]([CH3:9])([CH3:10])[O:7][B:6]([C:4]2[CH:3]=[N:2][N:1]([CH2:22][CH2:23][C:24]#[N:25])[CH:5]=2)[O:14]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#CCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CCC#N)c2)OC1(C)C
Temperature: 90 °C

Procedure:
Pyrazole-4-boronic acid pinacol ester (1 g, 1 equiv, 5.15 mmol) was dissolved in dimethylformamide (15 mL) followed by the addition of Cs2CO3 (0.86 g, 1.5 equiv, 7.73 mmol) and 3-chloropropionitrile (1.1 equiv, 5.67 mmol, 0.44 mL). The mixture was heated at 90° C. overnight. The reaction was diluted with ethyl acetate and washed with water (3×) and brine (3×). The organic phases was concentrated in vacuo onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-90:10) to return the title compound (0.11 g, 9%). 1H NMR (500 MHz, DMSO): δ 1.26 (12H, s), 3.07 (2H, t), 4.40 (2H, t), 7.65 (1H, s), 8.04 (1H, s). MS m/z 248 (M+H+)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[I:11].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:15][CH2:14]1>>[I:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:17][CH2:18]1
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccc(F)c(I)c1
Product: O=C(OCc1ccccc1)N1CCC(Nc2ccc([N+](=O)[O-])cc2I)CC1
Yield: 64 %

Procedure:
The desired compound was prepared according to the procedure of Example D83, step A, using 1-fluoro-2-iodo-4-nitrobenzene and benzyl 4-aminopiperidine-1-carboxylate as the starting materials in 64% yield. LCMS for C19H211N3O4 (M+H)+: m/z=482.0.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10](C2C=CC=CC=2)=[C:11]2[CH:19]=[CH:18][C:14](=[N+](C)C)[CH:13]=[CH:12]2)=[CH:6][CH:5]=1)[CH3:3].[Cl-].S(=O)(=O)(O)[OH:28]>>[CH3:1][N:2]([CH3:3])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:11]2[CH:19]=[CH:18][CH:14]=[CH:13][CH:12]=2)=[O:28])=[CH:6][CH:5]=1
Reactant: O=S(=O)(O)O
Reactant: CN(C)c1ccc(C(=C2C=CC(=[N+](C)C)C=C2)c2ccccc2)cc1
Agent: [Cl-]
Product: CN(C)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
Doebner, Ann. 217, 257 (1883), discloses the reaction of malachite green with sulfuric acid to give 4-(dimethylamino)-benzophenone.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:31](=[O:32])[C:30]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]5[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=5)=[CH:36][CH:35]=4)=[C:29]([CH2:48][CH2:49][CH3:50])[N:28]4[N:51]=[CH:52][N:53]=[C:27]34)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>C(OCC)(=O)C>[OH:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[C:31](=[O:32])[C:30]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=5[C:46]5[NH:3][C:4](=[O:7])[O:5][N:47]=5)=[CH:36][CH:35]=4)=[C:29]([CH2:48][CH2:49][CH3:50])[N:28]4[N:51]=[CH:52][N:53]=[C:27]34)[CH2:24][CH2:25]2)=[CH:18][CH:19]=1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(c3ccc(O)cc3)CC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCN(c3ccc(O)cc3)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
A mixture of hydroxylammonium chloride (344 mg), sodium hydrogen carbonate (554 mg) and dimethyl sulfoxide (3 mL) was stirred at 60° C. for 30 min, 4′-({4-[1-(4-hydroxyphenyl)piperidin-4-yl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (180 mg) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (65 mg) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (61 mg) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=70/30→45/55 (volume ratio)] and crystallized from a mixture of ethyl acetate and diisopropyl ether to give the title compound as colorless crystals (72 mg, 36%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:9]=[N:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[N:41]=[C:42]=[O:43].O>O1CCCC1>[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[NH:41][C:42](=[O:43])[N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[N:12]=1
Reactant: c1ccc(Nc2nnn(CCCCCCCCOC3CCCCO3)n2)cc1
Reactant: O=C=Nc1ccc(F)cc1F
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1F)N(c1ccccc1)c1nnn(CCCCCCCCOC2CCCCO2)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred, cold (-78° C.) solution of (±)N-phenyl-2-[8-[(tetrahydro-2H-pyran-2-yl) oxy]octyl]-2H-tetrazol-5-amine (0.6161 9, 0.001650 mol) in anhydrous tetrahydrofuran (20 mL) was added a 1.6M solution of n-butyl lithium in hexanes (1.0 mL, 0.0016 mol) under a nitrogen atmosphere, and the mixture was stirred. After 2.5 hours, 2,4-difluorophenyl isocyanate (0. 195 mL, 0. 00165 mol) was added dropwise, and the mixture was stirred. After 3 hours the mixture was allowed to warm to room temperature and then stirred 1.5 days. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried (Na2SO4), and rotoevaporated to an oil. The oil was chromatographed on silica gel (120 g, 230-400 mesh) using chloroform-diethyl ether (24:1, 13×100 mL) as eluent. Fractions containing product were rotoevaporated from diethyl ether to give the title compound as a yellow oil. The oil was dried in vacuo, yield 0.5406 g (64%). 1H NMR (CDC13): δ 10.4 (br s, 1H), 8.3 (m, 1H), 7.5 (m, 3H), 7.4 (d, 2H), 6.9 (m, 2H), 4.6 (m, 1H), 4.5 (t, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.5 (m, 1H), 3.4 (m, 1H), 2.0 (m, 2H), 1.5-1.9 (m, 9H), 1.3 (m, 7H).
Reaction SMILES: [CH3:1][O:2][P:3]([O-:5])[O-:4].[CH2:6]([Sn+2:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9].[CH2:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]C>>[CH2:1]([O:2][P:3]([O-:5])[O-:4])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19].[CH2:15]([Sn+2:10]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCO
Reactant: COP([O-])[O-]
Agent: CCCC[Sn+2](CCCC)CCCC
Product: CCCCCCCCCCCCOP([O-])[O-]
Temperature: 140 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
In a 500 ml four-neck round-bottom flask, as described in Example 1, 148.85 g of tributyltin oxide and 110 g dimethyl phosphite are heated with stirring to about 120° C. The reaction mixture is kept at this temperature for about 2 hours, dimethyl ether being split off. The reaction mixture is then heated with stirring under a vacuum of 20 to 5 mm Hg at 145° C, until the excess dimethyl phosphite has been distilled off. 193.3 g of tributyltin methyl phosphite are obtained. 128.5 g of tributyltin methyl phosphite and 68.7 g of lauryl alcohol are heated with stirring in a 500 ml four-neck round-bottom flask equipped with a stirrer, thermometer, standard taper glass stopper, stillhead with condenser, cooled distillate receiver and cold trap at 140° C for 5 hours, for one hour of which a vacuum (30 - 5 mm HG) is applied. Methanol is distilled off. 178 g tributyltin lauryl phosphite are obtained.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[O:13]=[C:14]1[N:20]2[CH2:21][CH2:22][C@H:19]2[C:18]2=[C:23]([C:26]([OH:28])=O)[N:24]=[CH:25][N:17]2[C:16]2[CH:29]=[CH:30][S:31][C:15]1=2.N>CN(C)C=O>[O:13]=[C:14]1[N:20]2[CH2:21][CH2:22][C@H:19]2[C:18]2=[C:23]([C:26]([NH2:3])=[O:28])[N:24]=[CH:25][N:17]2[C:16]2[CH:29]=[CH:30][S:31][C:15]1=2
Reactant: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1sccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
7.65 g (47 mmol) of 1,1'-carbonyldiimidazole were added portionwise to a suspension of 12.43 g (45 mmol) of (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carboxylic acid in 70 ml of dimethylformamide. The resulting pale brown solution was heated to 50° for 45 minutes. Subsequently, the solution was cooled to room temperature and 10.9 ml of aqueous ammonia solution were added dropwise. After stirring for a further 30 minutes the reaction mixture was poured into 100 ml of ice-water and the resulting precipitate was filtered off and rinsed with water, ethanol and subsequently with ether. After drying at 70°/10 Torr there were obtained 11.0 g (89%) of (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carboxamide as colourless crystals of m.p. >250°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=1.C(OCC)(=O)C>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:18])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCc2ccc(C#N)cc2)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
A solution of the product from Example G (1.0 g, 2.18 mmol) was dissolved in DMF and cooled to 0° C. The resulting solution treated with NaH (2.18 mmol) and was stirred for 1 hour at 0° C. and treated with α-bromo-p-tolunitrile (0.45 g, 2.30 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured into a separatory funnel containing ethyl acetate (50 mL) and water (50 mL) and shaken. The organic phase was separated and washed with brine, dried, and concentrated to give the title compound (0.76 g, 61%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[CH3:16][O:17][C:18](=[O:41])[C:19]([N:22]1[CH:26]=[C:25]([C@H:27]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[CH:31]C=2)[NH3+:28])[N:24]=[N:23]1)([CH3:21])[CH3:20].C1C=[N:46]C2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([NH:28][C@H:27]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([F:39])([F:38])[F:40])=[CH:31][N:46]=2)[C:25]2[N:24]=[N:23][N:22]([C:19]([CH3:20])([CH3:21])[C:18]([O:17][CH3:16])=[O:41])[CH:26]=2)=[O:14])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(C)(C)n1cc([C@@H]([NH3+])c2ccc(OCC(F)(F)F)cc2)nn1
Reactant: On1nnc2cccnc21
Reactant: CC(C)(C)c1ccc(CC(=O)O)cc1
Agent: [Cl-]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)n1cc([C@H](NC(=O)Cc2ccc(C(C)(C)C)cc2)c2ccc(OCC(F)(F)F)cn2)nn1
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To a solution of 0.05 g (0.26 mmol) (4-tert-butylphenyl)acetic acid in 0.50 ml CH2Cl2 was added 0.12 g (0.26 mmol) (S)-[1-(2-methoxy-1,1-dimethyl-2-oxoethyl)-1H-1,2,3-triazol-4-yl][4-(2,2,2-trifluoroethoxy)phenyl]methanaminium chloride, 0.05 g (0.34 mmol) HOAT, 0.07 g (0.34 mmol) EDC, and 0.14 ml (0.78 mmol) triethylamine. After 1 h at room temperature, the reaction mixture was diluted with CH2Cl2, and washed twice with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Purification by preparative HPLC (5->95% CH3CN/H2O over 15 min, 0.05% added TFA, C18) afforded 0.06 g (42%) methyl 2-(4-{(S)-{[(4-tert-butylphenyl)acetyl]amino}[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}-1H-1,2,3-triazol-1-yl)-2-methylpropanoate. ES-MS [M+1]+=548.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.N1(C(N2C=CN=C2)=S)C=CN=[CH:9]1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[C:28]1[NH:29][C:30]2[CH:36]=[C:35]([C:37]([NH:39][NH2:40])=[O:38])[CH:34]=[CH:33][C:31]=2[N:32]=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[C:28]1[NH:29][C:30]2[CH:36]=[C:35]([C:37]3[O:38][C:9]([NH:1][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)=[N:40][N:39]=3)[CH:34]=[CH:33][C:31]=2[N:32]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccnc1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cccc(Cl)c1-c1nc2ccc(-c3nnc(Nc4cccnc4)o3)cc2[nH]1
Temperature: 25 °C

Procedure:
Combine 3-aminopryidine (30 mg, 0.312 mmol) and di-imidazol-1-yl -methanethione (56 mg, 0.312 mmol) in DMF (0.3 mL) and stir for 2 days. Add 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (77 mg, 0.240 mmol) and dilute with DMF (1.5 mL). Heat the reaction to 80° C. for 1 hr. Add EDCI (92 mg, 0.480 mmol) and heat for 1 hr at 80° C. Allow reaction to cool to room temp and dilute the reaction with water. Collect the resulting precipitate by filtration. Purify the solid by reverse-phase HPLC (25-65% ACN/H2O+5 mM NH4OH) to afford the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.44 (dd, J=8.34, 4.80 Hz, 1 H) 7.63-7.67 (m, 1H) 7.70 (s, 1 H) 7.72 (d, J=1.77 Hz, 1 H) 7.87 (br. s., 2 H) 8.13 (ddd, J=8.40, 2.59, 1.39 Hz, 2 H) 8.25 (dd, J=4.80, 1.26 Hz, 1 H) 8.80 (d, J=2.53 Hz, 1 H) 10.98 (s, 1 H) 13.30 (br. s., 1H); MS (m/z) 423.1 (M+1).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13]OC(=O)C)[CH:11]=2)[CH:6]=[N:5]1)(=O)C.[BrH:18]>>[Br:18][CH2:13][C:10]1[CH:11]=[C:12]2[C:7]([CH:6]=[N:5][NH:4]2)=[CH:8][CH:9]=1
Reactant: CC(=O)OCc1ccc2cnn(C(C)=O)c2c1
Reactant: Br
Product: BrCc1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 46 h

Procedure:
A suspension of 1-acetyl-6-(acetoxymethyl)indazole (9.5 g, 41 mmol) (4-4) in aqueous hydrobromic acid (48% aqueous solution, 20 mL, 177 mmol) was stirred at room temperature for 46 hours. The solid was collected on a Buchner funnel and dried under vacuum for 12 hours. The filtrate was stirred at room temperature for additional 24 hours and more solid was collected. After drying under vacuum, title compound was obtained as a yellow solid (10.0 g, 84%) which was used as such without further purification. MS (electrospray) 211 (M+1 for 79Br), 213 (M+1 for 81Br); 1H N MR (CDCl3) δ 4.85 (s, 2H), 7.65 (d, 1H, J=8.4 Hz), 7.78 (d, 1H, J 8.4 Hz), 8.05 (s, 1H), 8.10 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]=[C:27]1[C:35](OCC)=[O:36])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:35]([C:27]2[N:26]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[N:28]=2)=[O:36])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CCCCCCCCCCCCCCCCCCn1c(C(=O)OCC)nc2ccccc21
Product: CCCCCCCCCCCCCCCCCCn1c(C(=O)N2CCN(C)CC2)nc2ccccc21
Temperature: 75 °C
Reaction time: 48 h
Yield: 59.6 %

Procedure:
1-Methylpiperazine (1.811 g) was added to ethyl 1-octadecyl-1H-benzimidazole-2-carboxylate (1.601 g) and the mixture was stirred for 48 hours at 75° C. The reaction mixture was purified by silica gel column chromatography (silica gel 60 g, chloroform:methanol=1:0-50:1), thereby yielding the entitled compound (1.070 g) as pale yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1([CH3:32])[C:14]2[C:9](=[CH:10][C:11]([CH2:15][NH2:16])=[CH:12][CH:13]=2)[N:8]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:19][CH2:18]2)[CH2:7]1.C(N(CC)CC)C.[OH-].[Na+]>O1CCCC1.O>[CH3:5][C:6]1([CH3:32])[C:14]2[C:9](=[CH:10][C:11]([CH2:15][NH:16][C:1](=[O:3])[CH3:2])=[CH:12][CH:13]=2)[N:8]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:19][CH2:18]2)[CH2:7]1
Reactant: CC(=O)Cl
Reactant: CC1(C)CN(C2CCN(CCc3ccc(F)cc3)CC2)c2cc(CN)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2(C)C
Yield: 73.7 %

Procedure:
Under ice cooling, acetyl chloride (0.05 ml) was added dropwise into a solution of 3,3-dimethyl-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (0.22 g) obtained above and triethylamine (0.5 ml) in tetrahydrofuran (10 ml) and the resultant mixture was stirred at room temperature for 1 hr. Then a 1 N aqueous solution (5 ml) of sodium hydroxide and water (10 ml) were added to the reaction mixture, which was extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform/methanol system) and crystallized from ethyl acetate/hexane to give the title compound (0.18 g) as a yellowish white powder (yield: 73.7%).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH:10](Cl)[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([N:21]([CH2:29][CH3:30])[CH2:22][C:23]#[C:24][C:25]([NH2:28])([CH3:27])[CH3:26])[CH3:20].[I-].[Na+]>CC(C)=O>[CH2:29]([N:21]([CH2:19][CH3:20])[CH2:22][C:23]#[C:24][C:25]([NH:28][CH:10]1[CH2:11][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[CH:9]1)([CH3:26])[CH3:27])[CH3:30]
Reactant: ClC1C=CC(c2ccccc2)(c2ccccc2)C1
Reactant: CCN(CC)CC#CC(C)(C)N
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCN(CC)CC#CC(C)(C)NC1C=CC(c2ccccc2)(c2ccccc2)C1
Yield: 59.3 %

Procedure:
A mixture of 4,4-diphenyl-2-cyclopentenyl chloride (0.60 g), 4-diethylamino-1,1-dimethyl-2-butynylamine (0.79 g) and a catalytic amount of sodium iodide in acetone (5 ml) was refluxed for 8 hours. After being cooled, the solvent was removed off under reduced pressure and the residue was purified with column chromatography on silica gel with a mixture of chloroform and methanol as an eluent to give N-[4-diethylamino-1,1-dimethyl-2-butynyl]-4,4-diphenyl-2-cyclopentenylamine (0.54 g). The free amine obtained above was dissolved in chloroform, and to the solution was added hydrogen chloride in methanol (0.18 g/ml, 1 ml). The solution was evaporated in vacuo and triturated with a mixture of ethanol and isopropyl alcohol to give its hydrochloride (0.45 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27].C(Cl)Cl>>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:25])[CH2:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCC(=O)c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCC1CCNCC1)c1ccc(F)cc1

Procedure:
A solution of 4-(4-(4-fluorophenyl)-4-oxo-butyl)-1-tert-butoxycarbonyl-piperidine (184 mg, 0.52 mmol, from Step C) in 30% TFA/CH2Cl2 was stirred for 30 min, then concentrated and dried under vacuum to provide the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][OH:35])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:35][CH2:34][C@@H:10]1[CH2:9][NH:8][CH2:12][C@H:11]1[CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)ccc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CO)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of (3S*,4R*)-3-hydroxymethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (85 mg, 0.172 mmol) in 2 mL CH2Cl2, TFA (85 μL, 2.23 mmol) is added. The mixture is stirred 4.5 h at RT, and poured into a saturated solution of NaHCO3. The layers are separated, and the aqueous one is back-extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude material is purified by flash chromatography on Isolute SPE Flash NH2 column (eluent: CH2Cl2/MeOH 100:0 to 99:1) to give the title product. MS (LC-MS): 395.1 [M+H]+; tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 3.75 min.
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]2[C:23]=1[CH:24]=[N:25][C:26]([CH3:33])=[N:27]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:21][C:22]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]3[C:23]=2[CH:24]=[N:25][C:26]([CH3:33])=[N:27]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncc2c(N)cc(F)cc2n1
Reactant: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=O)C(F)(F)F
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=Nc1cc(F)cc2nc(C)ncc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 250 mg (0.85 mmol) of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 185 mg (1.05 mmol) of 5-amino-7-fluoro-2-methylquinazoline and 0.4 ml of titanium tetraethoxide are reacted to give (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-1-[(7-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol. 430 mg of resultant crude imine are cyclized in the same way as in Example 1 at −30° C. using 8 ml (8 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-75%) yields 67 mg of product.