Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(C)(C)C)(=O)C=C.C(O[C:18]([N:20]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]([CH2:32][CH3:33])[CH:24]=1)C)=O)C1C=CC=CC=1.C(OC(N(CC1C2C(=CC=CC=2)N(CC2C=CC=CC=2)C=1)C)=O)C1C=CC=CC=1>>[CH2:32]([N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([CH2:22][NH:20][CH3:18])=[CH:24]1)[CH3:33]
Reactant: CCn1cc(CN(C)C(=O)OCc2ccccc2)c2ccccc21
Agent: C=CC(=O)OC(C)(C)C
Agent: CN(Cc1cn(Cc2ccccc2)c2ccccc12)C(=O)OCc1ccccc1
Product: CCn1cc(CNC)c2ccccc21
Yield: 94.8 %

Procedure:
According to the procedure of Preparation 17 (c), except substituting 3-[N-(benzyloxycarbonyl)-N-methylaminomethyl]-1-ethyl-1H-indole (0.90 g, 2.80 mmole) for the 3-[N-(benzyloxycarbonyl)-N-methylaminomethyl]-1-benzyl-1H-indole, the title compound (0.50 g, 94%) was prepared as a white solid: MS (ES) n/e 189 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[N:3]=1.[CH3:24][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([OH:10])[CH3:24])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[N:3]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc(Cl)c1C=O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1c(Cl)nc(Cl)nc1Nc1ccccc1S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 2,4-dichloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidine-5-carbaldehyde (797 mg, 2.14 mmol) in THF (10 mL) was added methyl magnesium bromide (3.0 M in diethyl ether, 6.4 mL, 19.3 mmol) at −78° C. under nitrogen atmosphere. The reaction mixture was warmed to room temperature gradually, and stirred overnight. The reaction mixture was poured into 20 mL of saturated aqueous NH4Cl at 0° C., and partitioned between EtOAc (30 mL×2) and brine (10 mL×2). The collected organic extracts were dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography (EtOAc/Hexanes: 30/70) to afford 1-(2,4-dichloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidin-5-yl)ethanol. MS (ES+): 390.0 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:34])[C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15]([C:17]1[CH:18]=[CH:19][C:20]([N:23]([CH3:34])[C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:21][CH:22]=1)=[O:16]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: CN(C(=O)CCc1ccccc1)c1ccc(C(=O)NN)cc1
Solvent: CC(=O)O
Product: CN(C(=O)CCc1ccccc1)c1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 56 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3dione in acetic acid was added N-[4(hydrazinocarbonyl)phenyl]-N-methyl-3-phenylpropanamide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH and water and drying under vacuo at 60° C. overnight gave the title compound (226 mg, 56%) as an orange solid in 96.7% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([CH:11]([C:19]2[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=2)[C@@H:6]([CH3:32])[CH2:5]1)[CH:2]=[CH2:3].[CH:33](OCC)=[O:34]>>[CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([CH:11]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([N:25]([CH2:26][CH3:27])[CH2:28][CH3:29])=[O:24])=[CH:30][CH:31]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH:33]=[O:34])[CH:13]=2)[C@@H:6]([CH3:32])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: CCOC=O
Reactant: C=CCN1C[C@H](C)N(C(c2ccc(C(=O)N(CC)CC)cc2)c2cccc(N)c2)C[C@H]1C
Product: C=CCN1C[C@H](C)N(C(c2ccc(C(=O)N(CC)CC)cc2)c2cccc(NC=O)c2)C[C@H]1C
Yield: 51 %

Procedure:
(±)-4-(α-(trans-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-aminobenzyl) -N,N-diethylbenzamide (0.42 g, 0.97 mmol) (Example 32, infra) was dissolved in 15 mL of ethyl formate and heated at reflux overnight under nitrogen. The reaction was concentrated to dryness and purified by chromatography on silica gel with ethanol (0-10%) in dichloromethane to give 0.23 g (51%) of (±)-trans-4-(α-(4-allyl-2,5-dimethyl-1 -piperazinyl)-3-formamidobenzyl)-N,N -diethylbenzamide. NMR (300 MHz, CDCl3): δ1.0 (m, 3H); 1.2 (d, m, 9H); 1.8-2.2 (m, 3H); 2.4-2.9 (m, 5H); 3.2-3.6 (m, 5H); 5.1-5.3 (m, 3H) 5.8 (m, 1H); 6.7-7.8 (m, 8H); 7.9-8.1 (m, 1H), 8.6-8.9 (m, 1H). The amine was dissolved in ethanol and converted to the monohydrochloride salt by titration with ethanolic hydrogen chloride. The solution was concentrated to dryness. The resulting foam was dissolved in a minimal amount of ethanol and precipitated with diethyl ether to give 0.96 g of the hydrated monohydrochloride salt as an off-white solid. Calc. for C28H38N4O2HCl 1.5 H2O: C, 63.92; H, 8.05; N, 10.65; Cl, 6.74. Found: C, 64.21; H, 7.96; N, 10.77; C! , 6.92.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.N1C=CC=CC=1.[CH3:30][C:31]1([CH3:44])[CH2:43][O:42][C:34]2([CH2:38][C@@H:37]([C:39](O)=[O:40])[CH2:36][CH2:35]2)[O:33][CH2:32]1>ClCCl.CC(C)=O>[CH3:30][C:31]1([CH3:44])[CH2:32][O:33][C:34]2([CH2:38][C@@H:37]([C:39]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:40])[CH2:36][CH2:35]2)[O:42][CH2:43]1
Reactant: CC1(C)COC2(CC[C@H](C(=O)O)C2)OC1
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC1(C)COC2(CC[C@H](C(=O)OCc3ccccc3)C2)OC1
Temperature: 27.5 °C
Reaction time: 24 h
Yield: 82.1 %

Procedure:
Benzyl alcohol (7.28 ml, 70.0 mmol), DCC (0.43 g, 2.1 mmol) and a catalytic amount of 4-dimethylammino pyridine (0.20 g, 1.68 mmol) were successively added to a solution of (S)-8,8-dimethyl-6,10-dioxaspiro[4.5]decane-2-carboxylic acid (Synthesized following procedure as described in DE4312832 and US20080161564, 3 g, 14.00 mmol) in anhydrous Dichloromethane (50 ml). The reaction mixture was stirred for 24 h at 25-30° C. and then acetone (10 ml) was added. The resulting suspension was filtered and subsequently concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate in hexane as eluents to obtain (S)-benzyl 8,8-dimethyl-6,10-dioxaspiro[4.5]decane-2-carboxylate (3.5 g, 82%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])[CH:25]=[CH:26][CH:27]=2)=[CH:16][C:15]=1[CH3:34])[CH2:2][CH2:3][CH3:4].[Li+].[OH-]>C1COCC1.CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:25]=[CH:26][CH:27]=2)=[CH:16][C:15]=1[CH3:34])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(OC)cc1-c1ccc(COc2cccc(CCC(=O)OC)c2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1ccc(OC)cc1-c1ccc(COc2cccc(CCC(=O)O)c2)cc1C
Temperature: 23 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 4.3 (0.0241 g, 0.0521 mmol) in THF/MeOH (2/1) (1.5 mL) was added LiOH (0.50 mL, 0.500 mmol). The resulting mixture was stirred overnight at 23° C., quenched with excess 1N HCl, and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The crude residue was purified by combiflash (0 to 40% EtOAc/hexanes) to afford 4 (0.0166 g, 71.0% yield). MS ESI (neg.) m/e: 393.1 (M−H)+. 1H NMR (400 MHz, CDCl3) δ ppm 7.32 (1H, s), 7.20-7.29 (4H, m), 6.83-6.92 (5H, m), 6.74 (1H, d, J=2.9 Hz), 5.07 (2H, s), 3.83 (2H, t, J=6.6 Hz), 3.79 (3H, s), 2.97 (2H, t, J=7.8 Hz), 2.68-2.73 (2H, m), 2.19 (3H, s), 1.53-1.60 (2H, m), 1.22-1.31 (2H, m), 0.83 (3H, t, J=7.3 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]([F:21])([F:20])[C:11]([F:19])([F:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K].CN(C)C=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:9]([C:10]([F:21])([F:20])[C:11]([F:19])([F:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:26]1[C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]2[C:22]1=[O:32]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1c(CBr)cccc1C(F)(F)C(F)(F)c1ccccc1
Agent: [K]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1c(CN2C(=O)c3ccccc3C2=O)cccc1C(F)(F)C(F)(F)c1ccccc1

Procedure:
A mixture of 8.02 g. (0.022 mole) of 2-methyl-3-(α,α,β,β-tetrafluorophenethyl)-benzyl bromide, 4.10 g. (0.022 mole) of potassium phthalimide, and 40 ml. of dimethylformamide is stirred 30 minutes at room temperature, 4 hours at 95° C., and 3 hours at reflux. The cooled mixture is diluted with 100 ml of chloroform and washed with 150 ml. of water. After re-extraction of the aqueous layer with chloroform, the combined organic extracts are washed with 0.1 N. sodium hydroxide, water, dried over anhydrous magnesium sulfate, and evaporated to dryness in vacuo. Recrystallization of the residual solid from isopropyl alcohol affords the white crystalline product, m.p. 135°-137° C.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([NH:18][CH:19]([CH:27]([OH:54])[CH:28]([NH:36][C:37](=[O:53])[C@H:38]([CH:50]([CH3:52])[CH3:51])[NH:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cl:55][CH2:56][C:57]1[CH:58]=[C:59]([CH:63]=[CH:64][CH:65]=1)[C:60](Cl)=[O:61].N1C=CC=CC=1>C(Cl)(Cl)Cl.C(Cl)Cl.CO>[Cl:55][CH2:56][C:57]1[CH:58]=[C:59]([CH:63]=[CH:64][CH:65]=1)[C:60]([O:54][CH:27]([CH:19]([NH:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:28]([NH:36][C:37](=[O:53])[C@H:38]([CH:50]([CH3:52])[CH3:51])[NH:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:61]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(OC(=O)c1cccc(CCl)c1)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 65 h
Yield: 29.7 %

Procedure:
The resultant compound of Example 70 (769 mg, 1.04 mmol) was combined with 3-(chloromethyl)benzoyl chloride (395 mg, 2.09 mmol) and pyridine (165 mg, 2.09 mmol) in 10 mL of freshly distilled methylene chloride. The reaction mixture was stirred at ambient temperature under nitrogen for approximately 65 h and then diluted with 150 mL of chloroform. The chloroform solution was washed with 75 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue (1.59 g) was taken up in ~10 mL of methylene chloride and applied to a 1.5×45 cm column of 40 mesh silica gel. The column was eluted @ ~5 p.s.i. sequentially with 200 mL of methylene chloride, 200 mL of 0.5% methanol in methylene chloride and 200 mL of 1% methanol in methylene chloride to give 275 mg (30% yield) of the title compound; FAB MS M/Z: 889 (M+H)+. The 300 MHz 1H NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH:22]=[O:23])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:30][Mg]Cl>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH:22]([OH:23])[CH3:30])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: C[Mg]Cl
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(C=O)cn2)cc1Cl
Solvent: CCOCC
Product: CC(O)c1cnc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-formyl-pyrazin-2-yl)-propionamide (prepared as in Example 18, 218 mg, 0.5 mmol) in diethyl ether (15 mL) at 0° C. was slowly treated with 3.0M solution of methylmagnesium chloride in diethyl ether (0.35 mL, 1.05 mmol). After complete addition, the reaction mixture was stirred at 0° C. for 1 h. The reaction was then quenched by the dropwise addition of a 1N aqueous hydrochloric acid solution. The reaction was then diluted with water (25 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (2×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/7 to 7/3 ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(1-hydroxy-ethyl)-pyrazin-2-yl]-propionamide (140 mg, 62%) as a white solid: LC-MS m/e 451 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH2:45][CH3:46])(=[O:44])=[O:43])=[CH:38][C:37]=1[C:47]([F:50])([F:49])[F:48]>CN(C=O)C>[CH2:45]([S:42]([C:39]1[CH:40]=[CH:41][C:36]([CH2:35][N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[C:6]2[CH3:14])=[C:37]([C:47]([F:49])([F:48])[F:50])[CH:38]=1)(=[O:43])=[O:44])[CH3:46]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: CCS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)O)c3cccnc32)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (0.77 g, 3.78 mmol) in dry DMF (12 ml) under an inert atmosphere of Argon is added dropwise, BEMP (1.75 ml, 6.04 mmol). The mixture was allowed to stir at room temperature for 1 hour and then treated with 1-bromomethyl-4-ethanesulfonyl-2-trifluoromethyl-benzene (2 g, 6.04 mmol). Stirring continues for a further 2 hours after which time, the reaction mixture is partitioned between ethyl acetate/diethyl ether (80 ml of a 1:1 mixture) and water (100 ml). The organic portion is separated and washed with brine and concentrated in vacuo. Purification of the crude by chromatography on silica eluting with iso-hexane/ethyl acetate (3:1 increasing to 2:1) yields the titled product. (MH+ 455)
Reaction SMILES: I[C:2]1[C:9](=[O:10])[N:5]2[CH2:6][CH2:7][CH2:8][N:4]2[C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1.C([Mg]Cl)(C)C.[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=[O:28]>C1COCC1>[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]([OH:28])[C:2]1[C:9](=[O:10])[N:5]2[CH2:6][CH2:7][CH2:8][N:4]2[C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=1
Reactant: O=Cc1ccccc1Cl
Reactant: CSc1nccc(-c2c(I)c(=O)n3n2CCC3)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CSc1nccc(-c2c(C(O)c3ccccc3Cl)c(=O)n3n2CCC3)n1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a cold (−40° C.) suspension of 2-iodo-3-(2-methylsulfanyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 21, (0.40 g, 1.07 mmol) in THF (3 mL) is added dropwise isopropyl-magnesium chloride (0.59 mL of a 2M solution in THF, 1.18 mmol). After stirring for 30 min at −40° C., a solution of 2-chlorobenzaldehyde (0.16 mL, 1.40 mmol) is added dropwise. The reaction mixture is allowed to warm to 0° C. over 1 h period. The mixture is quenched by pouring into aqueous saturated NH4Cl. The aqueous phase is extracted three times with EtOAc and the combined organic phases are dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified over silica (10% MeOH/chloroform) to afford 240 mg (58% yield) of desired product. 1H NMR (300 MHz, CDCl3) δ 8.56 (d, J=5.1 Hz, 1H), 7.78 (dd, J=7.2, 1.8 Hz, 1H), 7.34-7.18 (m, 2H), 7.01 (d, J=5.1 Hz, 1H), 6.21 (s, 1H), 4.20-4.01 (m, 5H), 2.80-2.70 (m, 2H), 2.58 (s, 3H); ESI+ MS: m/z (rel intensity) 371.1 (100, M++H).
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.Br[C:9]1[N:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][C:26]([CH:32]4[CH2:34][CH2:33]4)=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1>>[CH:29]1([C:28]2[C:23]([N:20]3[CH2:19][CH2:18][N:17]([C:15]([C:12]4[CH:11]=[CH:10][C:9]([N:6]5[CH:2]([CH3:1])[CH2:3][CH2:4][C:5]5=[O:7])=[N:14][CH:13]=4)=[O:16])[CH2:22][CH2:21]3)=[N:24][CH:25]=[C:26]([CH:32]3[CH2:34][CH2:33]3)[CH:27]=2)[CH2:30][CH2:31]1
Reactant: CC1CCC(=O)N1
Reactant: O=C(c1ccc(Br)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: CC1CCC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cn1
Yield: 2987.4 %

Procedure:
Using 5-methylpyrrolidin-2-one (99 mg) and (6-bromopyridin-3-yl) [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (4.27 mg) described in Preparation Example 143 and by the reaction and treatment in the same manner as in Example 1, the title compound (133 mg) was obtained.
Reaction SMILES: CCN(CC)CC.II.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:29]([O:33][C:34](=[O:63])[NH:35][CH2:36][C:37]1([C:40]([NH:42][NH:43][C:44]([CH:46]2[CH2:52][CH2:51][C@@H:50]3[CH2:53][N:47]2[C:48](=[O:62])[N:49]3[O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=O)=[O:41])[CH2:39][CH2:38]1)([CH3:32])([CH3:31])[CH3:30]>C(Cl)Cl>[CH2:55]([O:54][N:49]1[C:48](=[O:62])[N:47]2[CH2:53][C@H:50]1[CH2:51][CH2:52][CH:46]2[C:44]1[O:41][C:40]([C:37]2([CH2:36][NH:35][C:34](=[O:63])[O:33][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:38][CH2:39]2)=[N:42][N:43]=1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)NNC(=O)C2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC1(c2nnc(C3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
Et3N (8.3 g, 0.082 mol) was added to a 0° C. solution of I2 (10.43 g, 0.041 mol), PPh3 (10.76 g, 0.041 mol) in CH2Cl2 (250 mL). The mixture was allowed to warm to rt. After stirring at rt for 0.5 hr, tert-butyl(1-(2-((5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonyl)cyclopropyl)methylcarbamate (10 g, 0.0205 mol) was added. The mixture was stirred at rt for another 1 hr. The mixture was concentrated, EtOAc (250 mL) was added, and the mixture was filtered to remove Ph3PO. The filtrate was concentrated and the residue was purified by silica gel column chromatography (gradient elution 33˜50% EtOAc/petroleum ether) to afford tert-butyl (1-(5-((5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)cyclopropyl)methylcarbamate (8 g, 83%) as a white solid. ESI-MS (EI+, m/z): 470.3 [M+H]+.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([F:27])=[CH:29][CH:30]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(F)cc1

Procedure:
The title compound, light yellow solid (92 mg, 82%), MS (ISP) m/z=449.3 [(M+H)+], mp 193° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-fluoro-benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:13]3[N:14]=[CH:15][C:16]([CH:18]4[CH2:20][O:19]4)=[CH:17][C:12]=3[C:11]3=[N:21][CH:22]=[N:23][N:10]3[C:9]2=[O:24])=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[OH:19][CH:18]([C:16]1[CH:15]=[N:14][C:13]2[N:8]([CH2:7][C:6]3[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:9](=[O:24])[N:10]3[N:23]=[CH:22][N:21]=[C:11]3[C:12]=2[CH:17]=1)[CH2:20][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: C1COCCN1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C4CO4)cnc32)cc1
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(O)CN4CCOCC4)cnc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
6-(4-Methoxybenzyl)-9-(oxiran-2-yl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (118 mg, 0.337 mmol) was treated with morpholine (0.50 mL) and stirred for 16 h at room temperature. The mixture was concentrated under vacuum, re-dissolved in DMSO, and filtered. Purification (HPLC, elution with 20 to 80% acetonitrile in water) afforded the title compound (63 mg, 26%) as the TFA salt as a white powder. 1H NMR (400 MHz, CDCl3) δ 3.11 (br s, 4H), 3.26 (dd, J=13.30, 2.89 Hz, 1H), 3.35 (dd, J=13.30, 10.67 Hz, 1H), 3.76 (s, 3H), 4.12 (br s, 4H), 5.65-5.71 (m, 1H), 5.73 (s, 2H), 6.82 (d, J=8.78 Hz, 2H), 7.58 (d, J=8.66 Hz, 2H), 8.35 (s, 1H), 8.69 (d, J=2.26 Hz, 1H), 8.90 (d, J=2.26 Hz, 1H). [M+H]=437.2.
Reaction SMILES: [BH4-].[Na+].[F:3][CH:4]([F:18])[O:5][CH2:6][C:7]1[N:12]=[C:11]([C:13](OCC)=[O:14])[CH:10]=[CH:9][CH:8]=1>CCO>[F:18][CH:4]([F:3])[O:5][CH2:6][C:7]1[N:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1cccc(COC(F)F)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cccc(COC(F)F)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 79.6 %

Procedure:
NaBH4 (377 mg, 9.96 mmol) was added to a solution of ethyl 6-difluoromethoxymethylpyridine-2-carboxylate (2.30 g, 9.96 mmol) in EtOH (50 mL) at 0° C., the mixture was warmed to 80° C. and stirred for 5 h. The mixture was cooled to 0° C., quenched with sat. aq. NH4Cl, concentrated in vacuo and partitioned between EtOAc and brine. The organic layer was separated, dried (MgSO4), filtered and evaporated to give the title compound (1.50 g, 80%) as a colorless oil; NMR δH (400 MHz, CDCl3) 7.73 (1H, t, J 8.0 Hz), 7.35 (1H, d, J 8.0 Hz), 7.19 (1H, d, J 8.0 Hz), 6.39 (1H, t, J 74.0 Hz), 5.02 (2H, s), 4.76 (2H, s); (M+H)+ 190.