Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[N-:20]=[N+:21]=[N-].[Na+]>O>[N:1]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[N+:20]=[N-:21]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
4-aminobenzoic acid (500 mg, 3.65 mmol) was dissolved in 2.5 mL of water and concentrated sulfuric acid (98%, 0.75 mL) and additional water (0.75 mL) were added. The suspension was cooled to 0° C. and a solution of NaNO2 (265 mg, 3.84 mmol) in 0.75 mL of water was added under constant stirring. Sodium azide (293 mg, 4.5 mmol) was added to the brown solution. After additional 15 min of stirring at 0° C. the precipitate was filtered and washed several times with water. The solid was dried to afford 4-azidobenzoic acid (594 mg, 3.64 mmol, 100%) as a white solid. 1H NMR (CD3OD, 500 MHz) δ (ppm): 7.13 (dd, J=1.9, 8.6 Hz, 2H), 8.02 (dd, J=1.9, 8.6 Hz, 2H).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:11]1[C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([NH2:22])[C:15]=2[CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:22][CH:21]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:16]=2[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: NC1CCCCc2ccccc21
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CCCCC2Nc1nc2ccccc2[nH]1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and racemic 6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ylamine (prepared by Procedure B from 1-benzosuberone) by Procedure A (reflux in toluene for 2 days). The product was isolated from the reaction mixture by preparative LCMS to give the title compound as the free base and as a mixture of enantiomers (white solid, mp 203-205° C.). MS(ES+) m/z 278 ([M+1]+, 100). 1NMR (DMSO-d6) δ 1.28-1.39 (m, 1H), 1.65-2.02 (m, 5H), 2.83-2.97 (m, 2H), 5.03 (t, 1H), 6.77-6.89 (m, 2H), 7.05-7.29 (m, 7H), 10.6 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:13])[CH3:3].N1C2C(=CC=CC=2)CC1=O.[CH3:24][S:25]C1(CC2C=CC=CC=2)C2C(=CC=CC=2)NC1=O>CC(C)=O>[CH3:3][CH:2]([C:4]1([S:25][CH3:24])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:13])[CH3:1]
Reactant: CC(C)C1C(=O)Nc2ccccc21
Reactant: CSC1(Cc2ccccc2)C(=O)Nc2ccccc21
Agent: O=C1Cc2ccccc2N1
Solvent: CC(C)=O
Product: CSC1(C(C)C)C(=O)Nc2ccccc21

Procedure:
Prepared from 3-(1-methylethyl)-1,3-dihydro-2H-indol-2-one (prepared from 1,3-dihydro-2H-indol-2-one and acetone by the method of Daisley and Walker, J. Chem. Soc. (C) (1971) page 1373) by the method described above for 3-methylthio-3-phenylmethyl-1,3-dihydro-2H-indol-2-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.CS(O)(=O)=O.[CH2:22]=[C:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16][C:23]([CH3:25])([CH3:24])[CH3:22])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C=C(C)C
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 0.03 h
Yield: 93.9 %

Procedure:
A 100-ml flask was charged with 5 ml of toluene and 2.12 g (10 mmol) of 4′-methyl-2-biphenylcarboxylic acid, and they were vigorously stirred. To this mixture was added 0.32 ml (5 mmol) of methanesulfonic acid, and isobutene gas (98 mmol) was introduced thereto at a flow rate of 1.2 liter/min for 2 minutes. The resulting mixture was stirred at room temperature for 20 minutes. After having confirmed that almost all of the peaks ascribed to 4′-methyl-2-biphenylcarboxylic acid disappeared by HPLC, the reaction solution was washed with a 1.5 M aqueous sodium hydroxide, and dried over anhydrous magnesium sulfate. Thereafter, the solution was concentrated by distilling off toluene by using a rotary evaporator, to give 2.52 g of tert-butyl 4′-methyl-2-biphenylcarboxylate as crystals (yield: 94% based on 4′-methyl-2-biphenylcarboxylic acid, purity by HPLC: 99.9%). Incidentally, the obtained compound had the same physical properties as those of the compound obtained in Example II-1.
Reaction SMILES: [S:1](Cl)(Cl)=O.[C:5]([OH:15])(=[O:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1>>[S:1]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:7]=[C:6]1[C:5]([OH:15])=[O:14]
Reactant: O=C(O)CCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(O)c1cc2ccccc2s1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (5 eq.) was added dropwise to a round-bottom flask containing a mixture of hydrocinnamic acid (1 eq.) and pyridine (0.1 eq.) heated to 150° C. TLC after 3 h showed complete consumption of starting material. The reaction mixture was cooled to it and water (10 vol), 35% HCl (1 vol.), and THF (15 vol) were added and the mixture heated at 60° C. for 30 minutes. After 30 minutes, the THF was removed in vacuo and the obtained precipitate was filtered, dissolved in a 3:1 water:ethanol mixture (20 vol) and heated at 90° C. for 1 hr. After 1 h, the solution was cooled to it and allowed to stir overnight. The separated solid was filtered and recrystallized from toluene to get the corresponding benzothiophene-2-carboxylic acid. The results for various substituted chlorobenzothiophene carboxylic acids are given in Table 1.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH2:24][CH3:25])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[BH4-].[Na+].CO.C(O)(=O)C>COC(C)(C)C.O1CCCC1.O>[CH2:9]([O:8][C:6]([NH:5][CH:4]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH2:24][CH3:25])[CH2:3][OH:2])=[O:7])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOc1ccccc1C[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CCOc1ccccc1CC(CO)NC(=O)OCc1ccccc1
Reaction time: 5 h

Procedure:
7.9 g (22 mmol) of N-benzyloxycarbonyl-3-[2-ethoxyphenyl]-alanine-methyl ester (Example b) is dissolved in 63 ml of tert-butyl methyl ether and mixed with 1.1 g (30.1 mmol) of sodium borohydride. At 5° C., 15 ml of methanol is added, and it is stirred for five hours at constant temperature. Then, 1.5 ml of acetic acid, dissolved in 5 ml of tetrahydrofuran, is added, mixed with 9 ml of water and stirred for ten minutes at room temperature. The organic phase is separated, washed with water and dried on sodium sulfate. The drying agent is suctioned off, the filtrate is concentrated by evaporation and the residue is chromatographed for purification on silica gel.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.[CH3:26][C:27]1([CH3:41])[CH2:32][C:31](=[O:33])[CH2:30][C:29]([CH3:35])([CH3:34])[N:28]1[CH2:36][C:37]([F:40])([F:39])[F:38]>>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C:18]([C:4]2[CH:3]=[C:2]([C:31]3([OH:33])[CH2:30][C:29]([CH3:35])([CH3:34])[N:28]([CH2:36][C:37]([F:38])([F:39])[F:40])[C:27]([CH3:41])([CH3:26])[CH2:32]3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[CH:19][CH2:20]1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: CC1(C)CC(=O)CC(C)(C)N1CC(F)(F)F
Product: CC1(C)CC=C(c2cc(C3(O)CC(C)(C)N(CC(F)(F)F)C(C)(C)C3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g) and 2,2,6,6-tetramethyl-1-(2,2,2-trifluoro-ethyl)-piperidin-4-one (as prepared above). 1H-NMR (CD3OD; 400 MHz): δ 8.22 (d, 1H, J=8.4 Hz), 7.98 (s, 1H), 7.43 (dd, 1H, J=8.4, 2.0 Hz), 7.33 (d, 1H, J=2.0 Hz), 5.73 (br s, 1H), 4.18 (m, 2H), 2.28-2.36 (m, 4H), 2.08 (m, 4H), 1.73 (s, 6H), 1.58 (m, 2H), 1.42 (m, 6H), 1.08 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C30H38F3N5O2, 558.3 (M+H). found 558.0.
Reaction SMILES: [O:1]1[C@H:3]2[C:4](=[O:30])C=C3[C@:27](C)([C@@H:2]12)[C@@H]1[C@H]([C@H]2[C@](C)(CC1)[C@@H]([C@H](C)CCCC(O)(C)C)CC2)C=C3.C([O:34][C:35](=[O:37])[CH3:36])(=O)C.N1C=CC=CC=1>>[CH3:27][C:2]([CH2:3][C:4]([CH2:36][C:35]([OH:34])=[O:37])=[O:30])=[O:1]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: CC(=O)CC(=O)CC(=O)O

Procedure:
The cholest-5-ene from Example 4 (c) was acetylated with acetic anhydride/pyridine to yield the triacetate which was subjected to bromination with dibromodimethylhydantoin followed by dehydrobromination with trimethylphosphite according to the procedure of Example 3 (b) to yield, after chromatography on silver nitrate impregnated silica gel, 1α,3β,25-triacetoxycholesta-5,7-diene (m.p. 96°-101°; αD -24° in CHCl3 ; λmaxEt2O 262 (7,900), 271 (11,500), 282 (12,400), 294 (7,300) nm.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5][N:4]=1)=O.[B-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH2:30]([O:37][C:38]1[CH:43]=[CH:42][C:41]([C@@H:44]2[CH2:46][C@H:45]2[NH2:47])=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[BH4-].[Na+]>ClC(Cl)C>[CH2:30]([O:37][C:38]1[CH:39]=[CH:40][C:41]([C@@H:44]2[CH2:46][C@H:45]2[NH:47][CH2:1][C:3]2[O:7][C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[N:5][N:4]=2)=[CH:42][CH:43]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: N[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1nnc(C=O)o1
Agent: CC(=O)O[B-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1nnc(CN[C@@H]2C[C@H]2c2ccc(OCc3ccccc3)cc2)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 15.4 %

Procedure:
Tert-butyl (5-formyl-1,3,4-oxadiazol-2-yl)carbamate (Intermediate O, 220 mg, 1.041 mmol) and sodium triacetoxy borohyride (441 mg, 2.08 mmol) was added to a solution of Trans-2-[4-(benzyloxy)phenyl]cyclopropanamine (Intermediate B, 250 mg, 1.041 mmol) in dry Dichloro ethane (2.5 mL) at 0° C. and stirred at RT for 24 h, then the solvent was evaporated. The residue was taken in MeOH (2.5 mL) and NaBH4 (116 mg, 3.138 mmol) was added at 0° C. and stirred for 2 h at RT. After completion, the solvent was evaporated, the residue was taken in water (10 mL) and extracted with EtOAc (4×10 mL) Combined extracts were washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by column chromatography (SiO2) using MeOH:CHCl3 (1:99) to get tert-butyl (5-((((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)amino)methyl)-1,3,4-oxadiazol-2-yl)carbamate (70 mg, 15.3%) as pale green liquid.
Reaction SMILES: O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[NH:16][N:15]=1.Br[C:33]1[S:37][C:36]([N:38]([CH2:42][C@@H:43]([N:51]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)C(=O)C)=[N:35][CH:34]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:51][C@@H:43]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:42][NH:38][C:36]1[S:37][C:33]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH3:13])=[CH:34][N:35]=1
Reactant: Cc1n[nH]c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CC(=O)N(C[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O)c1ncc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1n[nH]c2ccc(-c3cnc(NC[C@@H](N)Cc4ccccc4)s3)cc12
Temperature: 150 °C
Yield: 26.6 %

Procedure:
To a solution of 1.0 mL dioxane, 0.5 mL distilled water and sodium carbonate (35.0 mg, 0.33 mmol) in a 5 mL microwave tube, were added 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (32.0 mg, 0.124 mmol) and (S)—N-(5-bromothiazol-2-yl)-N-(2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropyl)acetamide (40.0 mg, 0.0826 mmol). The reaction mixture was degassed by bubbling nitrogen into the microwave tube for 30 seconds. Subsequently, tetrakis(triphenylphosphine)palladium(0) (10.0 mg, 0.0083 mmol) was added to the tube, and the mixture was heated at 150° C. in a Smith microwave synthesizer. After heating for 25 minutes, the reaction mixture was filtered through a pad of Celite and washed with MeOH. The filtrate was evaporated off, and the resulting residue was diluted with 1.5 mL MeOH, 1.5 mL water, and 1.5 mL hydrazine. The resulting mixture was transferred to a 5 mL microwave tube and heated at 150° C. After heating for 33 minutes, silica gel (10.0 g) was added to the reaction mixture, and the mixture was concentrated to dryness. The resulting solid was directly loaded on a silica gel column and chromatography separation was performed with DCM:MeOH (97:3) as the eluant to afford the desired compound N—((S)-2-amino-3-phenylpropyl)-5-(3-methyl-1H-indazol-5-yl)thiazol-2-amine as a colorless solid (8.0 mg, 26.6%). HRMS Theoretical (M+H) 364.15904, found 364.15915.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[P:6]([O:11][CH2:12][CH3:13])(=[O:10])[O:7][CH2:8][CH3:9].C([N-]C(C)C)(C)C.[Li+].[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>C1COCC1>[CH2:31]([Sn:26]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:27][CH2:28][CH2:29][CH3:30])[C:5]1[O:1][C:2]([P:6]([O:7][CH2:8][CH3:9])(=[O:10])[O:11][CH2:12][CH3:13])=[CH:3][CH:4]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCOP(=O)(OCC)c1ccco1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(P(=O)(OCC)OCC)o1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of diethyl 2-furanphosphonate (1 mmol) in 2 mL THF was cooled to −78° C. and added to a solution of lithium diisopropylamide (LDA) (1 mmol) in 5 mL THF at −78° C. over 20 min. The resulting mixture was stirred −78° C. for 20 min and added into a solution of tributyltin chloride (1 mmole) in 1 mL TEF at −78° C. over 20 min. The mixture was then stirred at −78° C. for 15 min, and at 25° C. for 1 h. Extraction and chromatography gave diethyl 5-tributylstannyl-2-furanphosphonate as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(O)C.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([C:36]([N:38]=[C:39]=[S:40])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:39]([NH:38][C:36](=[O:37])[C:33]2[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:35][CH:34]=2)=[S:40])=[C:18]([F:23])[CH:17]=1
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc([N+](=O)[O-])cc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-nitro-1-benzenecarbonyl isothiocyanate (30 mg) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (75 mg, yield 90%).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23]O)[CH:19]=[CH:20][C:21]=1[CH3:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH:19]=[CH:20][C:21]=1[CH3:22]
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: Cc1ccc(CO)cc1Cl
Product: Cc1ccc(COc2ccnn2-c2cc(C#N)ccn2)cc1Cl

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-chloro-4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.38 (3H, s), 5.18 (2H, s), 5.73 (1H, d, J=1.6 Hz), 7.19-7.25 (2H, m), 7.41 (1H, dd, J=1.2, 4.8 Hz), 7.44 (1H, s), 7.57 (1H, d, J=1.6 Hz), 8.03 (1H, s), 8.71 (1H, d, J=5.2 Hz). [M+H] Calc'd for C17H13ClN4O, 325; Found, 325.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[N:12]([O-])=O.[Na+].O.O.[Sn](Cl)Cl.[OH-].[Na+]>Cl.O>[F:11][C:2]([F:1])([F:10])[C:3]1[N:8]=[CH:7][C:6]([NH:9][NH2:12])=[CH:5][CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(C(F)(F)F)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(6-(Trifluoromethyl)pyridin-3-yl)hydrazine was prepared as follows: A 250-mL round bottomed flask containing a solution of 6-(trifluoromethyl)pyridin-3-amine (5.76 g, 35.5 mmol) in 50 mL of 4 N HCl was cooled to 0° C. in an ice bath and a solution of sodium nitrite (2.57 g, 37.3 mmol) in 5 mL of water was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and added to a solution of tin(II) chloride dihydrate (16.8 g, 74.6 mmol) in 60 mL of 4 N HCl at 80° C. The reaction mixture was stirred at 80° C. for 3 h, cooled to room temperature, and made basic by the addition of 10 N NaOH. The aqueous phase was extracted with EtOAc (4×). The combined organic extracts were concentrated and the crude material was absorbed onto silica gel. Purification by flash column chromatography on silica gel (10% to 100% EtOAc in hexanes) gave 1-(6-(trifluoromethyl)pyridin-3-yl)hydrazine.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]3[C:29]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[N:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[N:21]=3)=[CH:14][CH:13]=2)=[N:4][N:3]=[N:2]1.[H-].[Na+].C1(C(Cl)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[CH2:57][C:58]([O:60][CH3:61])=[O:59].Cl>CN(C=O)C.O.O1CCOCC1>[CH3:61][O:60][C:58](=[O:59])[CH2:57][N:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[NH:1][N:2]=[N:3][N:4]=2)=[CH:13][CH:14]=1)[C:20]1[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[N:23]=[C:22]([C:30]([F:32])([F:33])[F:31])[N:21]=1
Reactant: COC(=O)CBr
Reactant: FC(F)(F)c1nc2c(c(NCc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)n1)CCCC2
Agent: Cl
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)CN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1nc(C(F)(F)F)nc2c1CCCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 0° C. solution of 0.01 mmol of 5,6,7,8-tetrahydro-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-2-(trifluoromethyl)-4-quinazolinamine in 10 mL of anhydrous DMF was added 0.01 mmol of NaH. The resulting solution was stirred at 0° C. for 30 minutes at which time 0.01 mmol of triphenylmethylchloride was added. The reaction mixture was stirred at room temperature for 18 hours and 0.01 mmol of methyl bromoacetate was added. After 24 hours the reaction mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The organic phase was extracted with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield a residue which was treated with 2N HCl in dioxane. The solvents were evaporated and the resulting residue was purified on silica to yield the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]1([F:31])[CH2:27][NH:26][C@H:25]([C:28]([NH2:30])=[O:29])[CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([N:26]3[CH2:27][C:23]([F:31])([F:22])[CH2:24][C@H:25]3[C:28]([NH2:30])=[O:29])=[O:20])=[N:8][C:9]=2[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Reactant: NC(=O)[C@@H]1CC(F)(F)CN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)[C@@H]1CC(F)(F)CN1C(=O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 5 g)) was reacted with (S)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 426844-51-1) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=404.5 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>>[CH:18]1([C:21]([N:15]2[CH2:14][CH2:13][N:12]([CH:9]3[C:10]4[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=4)[CH2:7][CH2:8]3)[CH2:17][CH2:16]2)=[O:22])[CH2:20][CH2:19]1
Reactant: COc1ccc2c(c1)C(N1CCNCC1)CC2
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc2c(c1)C(N1CCN(C(=O)C3CC3)CC1)CC2
Reaction time: 6 h
Yield: 75 %

Procedure:
A mixture of (6-methoxy-indan-1-yl)piperazine (3.0 g, 15.5 mmol), cyclopropane-carbonyl chloride (1.6 g, 15.5 mmol), and excess powdered potassium carbonate was stirred for 6 hr. The insoluble material was removed and the solution concentrated in vacuo. The residue was dissolved in ether and washed with 1N HCl. The acid washes were made basic with NaOH solution and the mixture was extracted with methylene chloride. The extracts were dried and concentrated in vacuo. The residue was converted to the hydrochloride salt with ethereal HCl to give a solid (75%, mp: 187°-188° C.). Calc'd for C18H24N2 O2.HCl: C, 64.18%; H, 7.48%; N, 8.32%. Found: C, 63.96%; H, 7.18%; N, 8.18%.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=2)[C:21]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=O)[CH2:13][CH2:12]1)[CH3:3].C1(C)C=CC=CC=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:48]2)=CC=1.[OH-].[Na+].[ClH:63]>>[ClH:63].[CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[C:20]([CH:29]=[CH:30][CH:31]=2)[C:21]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[S:48])[CH2:13][CH2:12]1)[CH3:3]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)Oc1ccccc1N1CCN(Cc2cccc(C(=O)N3CCCCC3)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccccc1N1CCN(Cc2cccc(C(=S)N3CCCCC3)c2)CC1
Temperature: 90 °C

Procedure:
A solution of 1-[3-[[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]methyl]benzoyl]piperidine (CP #36, 3.86 g, 0.0092 mol) and toluene (50 mL) was treated with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (2.22 g, 0.0055 mole) and the resulting mixture was heated at 90° C. for 1 h. The reaction was cooled followed by the addition of toluene (50 mL), and mixed thoroughly with excess 3N sodium hydroxide solution. The organic layer was separated, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to an oily residue. Chromatography of this material on flash silica, using 1.5-2.5% methanol in methylene chloride, afforded CP #1 which was converted to its hydrochloride salt in ethereal hydrochloric acid, 3.61 g (77%), m.p. 221°-224° C. (dec, uncorrected). The structural assignment was supported by 1H NMR, chemical-ionization MS, and IR data.