Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH2:5].[CH3:8][C:9]1[NH:10][CH:11]=[C:12]([CH3:17])[C:13]=1[C:14](=[O:16])[CH3:15]>I.[PH2](O)=O>[CH3:8][C:9]1[NH:10][C:11]([CH2:3][CH2:4][NH2:5])=[C:12]([CH3:17])[C:13]=1[C:14](=[O:16])[CH3:15]
Reactant: COC(CN)OC
Reactant: CC(=O)c1c(C)c[nH]c1C
Agent: I
Agent: O=[PH2]O
Product: CC(=O)c1c(C)[nH]c(CCN)c1C
Reaction time: 4 h

Procedure:
Aminoacetaldehyde dimethyl acetal (0.75 ml) was added to a stirred solution of 2,4-dimethyl-3-acetyl-pyrrole (0.548 g) in 10 ml of hydriodic acid and 2 ml of hypophosphorous acid. The solution was stirred for 4 hr. at 35° then evaporated in a shallow dish in a vacuum disiccator, finally at 0.1 mm, and the residue twice slurried and filtered with acetone. The clarified solution of the solid in water (5 ml) was made strongly alkaline with KOH, saturated with potassium carbonate, and extracted repeatedly with ether. The ether solution (125 ml) was concentrated, adding n-pentane toward the end, to precipitate the product (29%) as pale yellow prisms, m.p. 106.5°-107.5°. Anal. Calc. for C10H16N2O: C, 66.63; H, 8.95; N, 15.54; neut. equiv. 180. Found: C, 66.51; H, 8.89; N, 15.62; neut. equiv. 182.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22][CH2:23][CH2:24][CH2:25][S:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[C:29]([OH:36])[C:28]=2[CH2:37][CH2:38][CH3:39])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:48])C=1>C(Cl)Cl>[C:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([CH2:19][CH2:20][CH3:21])[C:7]([O:22][CH2:23][CH2:24][CH2:25][S:26]([C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[C:29]([OH:36])[C:28]=2[CH2:37][CH2:38][CH3:39])=[O:48])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCCc1c(SCCCOc2ccc(C(C)=O)c(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCc1c(S(=O)CCCOc2ccc(C(C)=O)c(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Reaction time: 2 h
Yield: 63.2 %

Procedure:
To a mixture of ethyl 4-[6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyrate (1.2 g) in methylene chloride (40 ml) was added m-chloroperbenzoic acid (0.51 g) on ice-water bath and was subjected to stirring at the same temperature for 2 hours. The obtained organic layer was washed twice with a cooled aqueous solution of potassium carbonate, then with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated. The resultant residue was purified through silica-gel column chromatography (eluting with benzene:ethyl acetate=1:1) to give the title compound (0.78 g, 63.2%) as colorless crystal, mp 74-76° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.N1C=CC=CC=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl.C(OCC)(=O)C>[C:18]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[CH:3]=[CH:2]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1ccc2cc[nH]c2c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)n1ccc2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To a solution of 1H-indole-6-carboxaldehyde (300 mg, 2.07 mmol) in 6.2 mL of dry dichloromethane were added pyridine (0.34 mL, 4.2 mmol), acetic anhydride (1.77 mL, 18.7 mmol), and N,N-dimethylaminopyridine (60 mg, 0.49 mmol) at room temperature, successively. After being stirred at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid was rinsed with diethyl ether/hexane to obtain the title compound as a pale orange powder (267 mg, 69%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2(C)[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:25]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:20]2[CH:21]=[C:16]3[CH2:15][CH:14]([CH:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]4)[O:23][C:17]3=[CH:18][N:19]=2)[CH2:37][CH2:36]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3cc(Cl)ncc3O2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(N4CCN(C(=O)OCc5ccccc5)CC4)ncc3O2)CC1
Temperature: 105 °C
Reaction time: 4 h

Procedure:
4-(5-Chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (530 mg) is added to a mixture of piperazine-1-carboxylic acid benzyl ester (460 μL), Pd2(dba)3 (360 mg), Xantphos (700 mg), and potassium tert-butylate (270 mg) in toluene (16 mL) under an argon atmosphere. The reaction mixture is stirred in an oil bath at 105° C. for 4 h. The reaction mixture is concentrated in vacuo and chromatographed on silica gel (cyclohexane/ethyl acetate 70:30→35:65) to give the title compound. LC (method 10): tR=1.68 min; Mass spectrum (ESI+): m/z=523 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[CH2:10][OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc([N+](=O)[O-])c1)C(=O)O
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-3-(3-nitrophenyl)propanoic acid (562 mg, 1.8 mmol) in THF (9 ml) stirred at 0° C. under N2 atmosphere, 10 M solution of BH3.DMS (0.5 ml, 5.27 mmol) was slowly added, after addition was completed the final mixture was warmed to room temperature and stirred for further 6 h. Cooled down to 0° C., quenched with water, diluted with DCM and washed with 10% K2CO3 solution in water; dried over MgSO4, filtered and concentrated to afford 432mg (80% yield) of an oil which was submitted to the next step without further purification. MS: m/z=319.1 (MH+)
Reaction SMILES: [C:1]1([C:7](O)([C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(O)[CH3:10])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS([O-])(=O)=O.[K+]>>[C:1]1([C:7]([C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH2:10])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)(c1ccccc1)C(C)(O)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: C=C(C(=C)c1ccccc1)c1ccccc1

Procedure:
A mixture of 50 parts of 2,3-diphenyl-2,3-dihydroxybutane and 0.5 part of freshly dehydrated KHSO4 is distilled for 50 minutes at 11 Torr and 200° C. bath temperature. The fraction which is collected within the boiling range of 150°-180° C./11 Torr yields 43.8 parts of crude 2,3-diphenyl-1,3-butadiene. The product is stirred direct with 21.5 parts of acrylic acid and 2 parts of hydroquinone under a nitrogen atmosphere for 3 hours at 130° to 140° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:22][O:23][CH2:24][C:25](O)=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C.O>[CH3:22][O:23][CH2:24][C:25]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)(=[O:13])=[O:14])[CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:26]
Reactant: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Reactant: COCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: COCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-aminobenzothiazol-6-yl ester (intermediate 16) (101.2 mg, 0.312 mmol), methoxyacetic acid (84.3 mg, 0.936 mmol), HBTU (355 mg, 0.936 mmol) and N,N-diisopropylamine (326 μl, 1.872 mmol) in 5 ml of dimethylformamide in a test tube, equipped with a magnetic bar, is stirred for 20 hours at room temperature. 100 ml of water are added and the reaction medium is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated. The residue obtained is taken up in ethyl acetate and purified on a Varian flash cartridge containing 5 g of silica of porosity 15-35μ, with a mixture of 1% methanol in dichloro-methane. After evaporating off the solvent, 89 mg of 4-fluorobenzenesulfonic acid 2-but-3-enoylaminobenzothiazol-6-yl ester are obtained (yellow oil) in a yield of 72%. LC/MS (method A1): [M+H]+: 397.11, retention time: 3.59 min.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([Cl:24])[C:14]=2[N:13]=[C:12]1[CH2:25][O:26][CH2:27][CH3:28])[CH:9]=[CH2:10].[OH:29][N:30]=[C:31](Cl)[CH3:32]>ClCCl>[Cl:24][C:15]1[C:14]2[N:13]=[C:12]([CH2:25][O:26][CH2:27][CH3:28])[N:11]([CH2:8][CH:9]3[O:29][N:30]=[C:31]([CH3:32])[CH2:10]3)[C:23]=2[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: C=CCn1c(COCC)nc2c(Cl)nc3ccccc3c21
Reactant: CC(Cl)=NO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1CC1CC(C)=NO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
Triethylamine (1.04 mL, 7.46 mmol) was added to a 0° C. solution of 1-allyl-4-chloro-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline (1.50 g, 4.97 mmol) and N-hydroxyethanimidoyl chloride (581 mg, 6.21 mmol) in dichloromethane (80 mL). The reaction solution was allowed to warm slowly to room temperature and stir overnight under a nitrogen atmosphere. After 20 hours, the solution was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, elution with 98:2 dichloromethane/methanol) to yield 4-chloro-2-(ethoxymethyl)-1-[(3-methyl-4,5-dihydroisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.34 g) as a white solid.
Reaction SMILES: [CH2:1]([C@@H:3]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17]CC2C=CC=CC=2)[CH:12]=1)[C@@H:4]([CH3:10])[C:5]([N:7]([CH3:9])[CH3:8])=[O:6])[CH3:2]>CO.[Pd]>[CH2:1]([C@@H:3]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)[C@@H:4]([CH3:10])[C:5]([N:7]([CH3:8])[CH3:9])=[O:6])[CH3:2]
Reactant: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)C(=O)N(C)C
Agent: [Pd]
Solvent: CO
Product: CC[C@@H](c1cccc(O)c1)[C@@H](C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
The product of Example 5 (3.0 g, 9 mmol) was dissolved in methanol, 5% Pd—C (300 mg) was added therein, after it was purged with hydrogen for three times, the reaction was carried out with stirring at room temperature for 1 hr. Then the reaction solution was filtered to remove Pd—C, the residue was washed with methanol for 3 times, and the organic phases are combined and concentrated to give the target 2.0 g, yield: 95%. 1HNMR (300 MHz, CDCl3): δ 7.2 (1H, m), 6.7-6.8 (3H, m), 2.8-2.9 (1H, m), 2.7-2.8 (1H, m), 2.6 (3H, s), 2.5 (3H, s), 1.8-1.9 (1H, m), 1.4-1.6 (1H, m), 1.1 (3H, d, J=6.2), 0.8 (3H, t, J=6.8, 14.1). ESI-MS: 236.4 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Br[CH2:45][C:46](=[O:49])[CH2:47][CH3:48]>>[CH3:43][O:42][C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:29]([CH2:45][C:46](=[O:49])[CH2:47][CH3:48])[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: CCC(=O)CBr
Reactant: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Product: CCC(=O)Cn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 35.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and 1-bromo-butan-2-one to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([O:8]C)=[O:7])#[N:2].CO.[Li+].[OH-].Cl>C1COCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(OC)c(C#N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a stirred solution of methyl 3-cyano-4-methoxybenzoate (1.1 g, 5.70 mmol) in a mixture of THF (70 mL), MeOH (70 mL) and water (5 mL) was added LiOH (0.97 g, 23.01 mmol) at RT and the reaction mixture was then stirred at RT for 1 h. The reaction mixture was acidified to pH ˜2 with 2 N HCl and the aqueous layer was extracted with DCM (3×100 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford 3-cyano-4-methoxybenzoic acid (1.0 g, 100%) as a solid.
Reaction SMILES: Cl.Cl[C:3]1[C:4]2[CH2:18][CH2:17][N:16]([C@@:19]3([CH3:31])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]3)[C:5]=2[N:6]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:8]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][C:43]([NH2:46])=[N:44][CH:45]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:46][C:43]1[N:44]=[CH:45][C:40]([C:3]2[C:4]3[CH2:18][CH2:17][N:16]([C@@:19]4([CH3:31])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:20]4)[C:5]=3[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]3[CH3:15])[N:8]=2)=[CH:41][N:42]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1nc(Cl)c2c(n1)N([C@@]1(C)CCN(C(=O)OC(C)(C)C)C1)CC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)c2c(n1)N([C@@]1(C)CCN(C(=O)OC(C)(C)C)C1)CC2
Temperature: 120 °C
Yield: 91.4 %

Procedure:
To a vial containing tert-butyl(3S)-3-{4-chloro-2-[(3S)-3-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-3-methylpyrrolidine-1-carboxylate hydrochloride (3796 mg, 8.68 mmol) in 1,4-dioxane (41.2 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (2492 mg, 11.28 mmol), and 1 M aqueous Na2CO3 (26 mL). Nitrogen was bubbled through the suspension for a few minutes before PdCl2(dppf)-DCM (516 mg, 0.632 mmol) was added and the mixture was heated in a microwave reactor at 120° C. for 30 min. The mixture was filtered through a pad of Celite® rinsing with EtOAc, and the filtrate was concentrated. The residue was purified by ISCO (80 g cartridge) using a gradient of 25-100% EtOAc/heptanes to give the title compound (3.94 g, 91%) as a yellow foamy solid. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 2 H), 6.60 (s, 2 H), 4.64-4.54 (m, 1 H), 4.23 (dd, J=13.5, 2.3 Hz, 1 H), 3.89 (dd, J=11.2, 3.4 Hz, 1 H), 3.79-3.35 (m, 8 H), 3.33-3.24 (m, 1 H), 3.19-3.05 (m, 3 H), 2.44-2.30 (m, 1 H), 2.10-1.95 (m, 1 H), 1.42 (s, 9 H), 1.32 (s, 3 H), 1.21 (d, J=6.7 Hz, 3 H). m/z (APCI+) for C25H36N8O3 497.6 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][C@@H:14]([NH:20][C:21](=[O:34])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:15][CH2:16][C:17](=O)[NH2:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][C@@H:14]([NH:20][C:21](=[O:34])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:15][CH2:16][C:17]#[N:18])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)CC[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: N#CCC[C@@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
To a stirred solution of (64) (171 mg, 0.35 mmol) in pyridine (9 mL) was added phosphoryl chloride (65 μl) at 0° under argon. After 10 minutes the mixture was brought to room temperature and stirring was continued for 1.5 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (10 mL), dried, filtered and evaporated under reduced pressure to yield the crude product (101 mg) which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])[N:19]=[C:18]([C:28]([C:34]([F:37])([F:36])[F:35])([C:30]([F:33])([F:32])[F:31])[OH:29])[CH2:17]3)[CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:38][Mg]Cl>O1CCCC1>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:20]1[CH:16]([C:12]2[CH:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:38])[CH3:2])=[CH:9][CH:8]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:17][C:18]([C:28]([C:34]([F:37])([F:36])[F:35])([C:30]([F:31])([F:32])[F:33])[OH:29])=[N:19]1
Reactant: CC(=O)c1ccc(-c2cccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c2)cc1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(-c2cccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)c2)cc1
Temperature: -78 °C
Reaction time: 5 h
Yield: 71.8 %

Procedure:
To a mixture of 5-(4′-acetyl-biphenyl-3-yl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (25.0 mg, 0.05 mmol) prepared in Example 225 in tetrahydrofuran (1.0 mL), was slowly added methylmagnesium chloride (in 3.0 M tetrahydrofuran, 77.0 uL, 0.23 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred at −78° C. for 5 hours, quenched with a saturated solution of ammonium chloride at 0° C., and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 20.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([CH2:26][O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:12][CH2:13][N:14]1[CH2:17][CH:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:15]1)C1C=CC=CC=1>CO>[C:28]([O:27][CH2:26][C@@H:11]([NH2:10])[CH2:12][CH2:13][N:14]1[CH2:15][CH:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:17]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC[C@H](CCN1CC(Oc2ccc(F)cc2)C1)NC(=O)OCc1ccccc1
Solvent: CO
Product: CC(C)(C)OC[C@@H](N)CCN1CC(Oc2ccc(F)cc2)C1

Procedure:
A solution of {(S)-1-tert-butoxymethyl-3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-carbamic acid benzyl ester (0.2 g, 0.45 mmol) in methanol containing 10% palladium on carbon (66 mg) is stirred under an atmosphere of hydrogen for 3 hours, then filtered through a celite™ filter The filtrate is evaporated and the residue taken up in ethyl acetate, washed with aqueous NaHCO3 solution and brine, dried over MgSO4 and evaporated to afford (S)-1-tert-butoxymethyl-3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propylamine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][OH:13].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[CH2:12][O:13][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(C(F)(F)F)ccc1Br
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.2 %

Procedure:
To a solution of (2-bromo-5-(trifluoromethyl)phenyl)methanol (from Preparation 2, 10 g, 39 mmol) in DMF (20 mL) was added imidazole (5.87 g, 86.3 mmol) followed by t-butyldimethylsilyl chloride (7.11 g, 47.2 mmol) and the reaction was stirred at room temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+M Biotage silica column (eluted with 0-20% ethyl acetate in heptane) (5CV), 20% (1 CV) to afford a colorless oil (14 g, 97%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 0.15 (s, 6H) 0.98 (s, 9H) 4.75 (s, 2H) 7.36 (m, 1H) 7.60 (d, J=8.3 Hz, 1H) 7.84 (s, 1H)). GCMS: 311 (M-57, t-bu).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[NH:21][C:22]([C:24]1[S:25][C:26]3[CH2:27][NH:28][CH2:29][CH2:30][C:31]=3[N:32]=1)=[O:23])=[O:13])=[CH:6]2.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>CN(C)C=O>[C:40]([N:28]1[CH2:29][CH2:30][C:31]2[N:32]=[C:24]([C:22]([NH:21][C@@H:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C@@H:15]3[NH:14][C:12]([C:7]3[NH:8][C:9]4[C:5]([CH:6]=3)=[CH:4][C:3]([Cl:2])=[CH:11][CH:10]=4)=[O:13])=[O:23])[S:25][C:26]=2[CH2:27]1)(=[O:42])[CH3:41]
Reactant: O=C(N[C@H]1CCCC[C@H]1NC(=O)c1nc2c(s1)CNCC2)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound (100 mg) obtained in Example 34 was dissolved in N,N-dimethylformamide (3 mL), triethylamine (84 μl) and acetic anhydride (29 μl) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride and 1N hydrochloric acid were added to the residue for partitioning the mixture. The resultant organic layer was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride:methanol=100:3) to give the title compound (86 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C.O>C(Cl)Cl.CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:18]2[CH2:19][CH2:20][CH:15]([OH:14])[CH2:16][CH2:17]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCC(O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a solution of 4-nitrobenzenesulfonyl chloride (512 mg, 2.31 mmol) in CH2Cl2 (8 mL) at room temperature, 4-hydroxypiperidine (404 mg, 4.00 mmol) was added. Triethylamine (0.400 mL, 2.88 mmol) was also added. The mixture was stirred at room temperature overnight. Water and EtOAc were added. The organic phase was separated, washed with 1N HCl, dried over Na2SO4, concentrated in vacuo to give 1-(4-nitrophenylsulfonyl)piperidin-4-ol as a solid (559 mg).