Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:37])=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:26]4[C:21](=[C:22]([F:32])[CH:23]=[CH:24][C:25]=4[O:27][C:28]([F:31])([F:30])[F:29])[N:20]([CH2:33][CH2:34][O:35][CH3:36])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH:9]=1.[NH:38]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:39]([C:43]([NH:45][CH2:46][C:47](O)=[O:48])=[O:44])[CH:40]([CH3:42])[CH3:41].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[C:53]([O:52][C:50](=[O:51])[NH:38][C@H:39]([C:43](=[O:44])[NH:45][CH2:46][C:47](=[O:48])[NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:37])=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:26]4[C:21](=[C:22]([F:32])[CH:23]=[CH:24][C:25]=4[O:27][C:28]([F:31])([F:29])[F:30])[N:20]([CH2:33][CH2:34][O:35][CH3:36])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH:9]=1)[CH:40]([CH3:41])[CH3:42])([CH3:54])([CH3:56])[CH3:55]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: COCCn1cc(C(=O)N2CCC(c3cc(CN)ccc3F)CC2)c2c(OC(F)(F)F)ccc(F)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCCn1cc(C(=O)N2CCC(c3cc(CNC(=O)CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc3F)CC2)c2c(OC(F)(F)F)ccc(F)c21
Yield: 94.7 %

Procedure:
A solution of [4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-[7-fluoro-1-(2-methoxy-ethyl)-4-trifluoromethoxy-1H-indol-3-yl]-methanone hydrochloride (0.3 g, 0.55 mmol), BOC-Val-GlyOH (0.18 g, 0.66 mmol), EDCI (0.126 g, 0.66 mmol), HOBT (0.224 g, 1.65 mmol), and Et3N (0.23 ml, 1.65 mmol) in DMF (15 mL) was stirred at room temperature overnight. The reaction mixture was poured into EtOAc and the organic layer washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the crude product. Purification by flash chromatography on SiO2 eluting with 3% MeOH/CH2Cl2 provided the desired product (0.4 g, 95%). 1H NMR (300 MHz, CDCl3) δ 7.4 (s, 1H), 7.1 (m, 2H), 7.0-6.8 (m, 3H), 6.7 (bs, 1H), 5.1 (bs, 1H), 4.5-4.3 (m, 4H), 4.1-3.7 (m, 6H), 3.35 (s, 3H), 3.1 (m, 3H), 2.1 (m, 1H), 1.8-1.6 (m, 6H), 1.4 (s, 9H), 0.9 (m, 6H). MS m/z: [M+H]+=768.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>ClCCl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=2[C:24]([F:23])([F:34])[F:35])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
To a stirred solution of 1-Boc-piperazine (0.50 g, 2.7 mmol) and diisopropylethylamine (1.75 g, 13.5 mmol) in dichloromethane at 0° C. was added a solution of 2-trifluoromethylbenzoyl chloride (0.626 g, 3.0 mmol). The resulting mixture was stirred at room temperature for 20 h and then quenched with water (25 mL). The organic phase was washed with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield 4-(2-trifluoromethylbenzoyl)piperazine-1-carboxylic acid tert-butyl ester as a pale brown oil (0.948 g, 98% yield). 1H NMR (300 MHz, CDCl3) δ 7.69, 7.54, 7.30, 3.77, 3.51, 3.33, 3.14, 1.45.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:9]([C:16](OCC)=[O:17])=[C:10]([CH2:14][CH3:15])[CH:11]=[N:12][CH:13]=1>C1COCC1>[Cl:7][C:8]1[CH:13]=[N:12][CH:11]=[C:10]([CH2:14][CH3:15])[C:9]=1[CH2:16][OH:17]
Reactant: CCOC(=O)c1c(Cl)cncc1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cncc(Cl)c1CO
Reaction time: 1 h
Yield: 88 %

Procedure:
To a suspension of lithium aluminum hydride (LAH, 0.920 g, 24.24 mmol) in anhydrous THF (20 mL) at 0° C. was added dropwise a solution of ethyl 5-chloro-3-ethylpyridine-4-carboxylate (2.59 g, 12.12 mmol) in THF (30 mL). After stirring for 1 hour, the reaction mixture was slowly quenched with 15% aqueous NaOH and then water. Ethyl acetate was added, and the mixture was stirred for 10 minutes. The white precipitate was filtered off and washed with ethyl acetate (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to provide (3-chloro-5-ethylpyridin-4-yl)methanol as a thick oil (1.83 g, 88% yield) and used for the next step without any further purification; M+ 166.5.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[S:21](=[O:23])(=[O:22])[N:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:19](=[O:28])[CH:18]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C.[O:36]([C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O>[C:24]([N:20]1[C:19](=[O:28])[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:8][S:49]([C:46]3[CH:45]=[CH:44][C:43]([O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:48][CH:47]=3)(=[O:51])=[O:50])=[CH:12][CH:13]=2)[S:21]1(=[O:23])=[O:22])([CH3:25])([CH3:27])[CH3:26]
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)N1C(=O)C=C(c2ccc(CCN)cc2)S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C=C(c2ccc(CCNS(=O)(=O)c3ccc(Oc4ccccc4)cc3)cc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-[4-(2-Aminoethyl)phenyl]-2-tert-butylisothiazol-3(2H)-one 1,1-dioxide trifluoroacetate (36.7 mg, 0.0869 mmol) and triethylamine (36.3 μL, 0.260 mmol) were dissolved in N,N-dimethylformamide (0.15 mL). 4-Phenoxybenzenesulfonyl chloride (29.2 mg, 0.109 mmol) was added and the reaction was allowed to stir at room temperature for 30 minutes. The reaction was chromatographed on a 21.2 mm Luna C18 column using a 10–90% acetonitrile in water gradient with 0.05% trifluoroacetic acid at 12.5 mL per minute over a 15 minute period. The major fraction was evaporated to a clear glass (18 mg, 38%). 1H NMR (500 MHz, CDCl3): δ 7.75 (d, J=8.8 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H), 7.41 (t, J=8.1 Hz, 2H), 7.27 (d, J=7.8 Hz, 3H), 7.23 (t, J=7.6 Hz, 1H), 7.07 (d, J=7.8 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 3.25 (t, J=6.8 Hz, 2H), 2.87 (t, J=7.1 Hz, 2H), 1.73 (s, 9H); LCMS found for C27H32N3O6S2 (M+NH4)+: m/z 558.2.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:19]([O-])=O.[H][H].O.N>[Pd].O1CCOCC1>[NH2:19][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:2]=1)[C:6]([C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)=[O:7]
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc(Br)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: N
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(C(=O)c2cccc(N)c2)cc1
Temperature: 30 °C
Reaction time: 7 h

Procedure:
In a closed vessel equipped with a thermometer and a stirrer there are charged 105 g (0.3 moles) of 4-bromo-3,4'-dinitro benzophenone, 5 g of 5% palladium/active carbon catalyst (from Nihon-Engelhardt Co.) and 300 ml of dioxane. At 70°-80° C., with the mixture being stirred, there is introduced 41 l (1.83 moles) of hydrogen so as to be absorbed in the mixture in about 11 hours. Following cooling the mixture to 30° C., there is added 38.5 g (0.33 moles) of 30% ammonia water. Then, again with the mixture being stirred, at 30°-40° C., there is introduced an additional amount of hydrogen, 7.2 l (0.32 moles), during seven hours. The reaction liquid is filtered at 30°-40° C. to remove the catalyst and then allowed to cool giving yellow crystals of 3,4'-diamino benzophenone. The crystals are filtered, washed with 30 ml of 50% aqueous dioxane solution and dried. Yield 58 g (91%). M.P. 121°-123° C.
Reaction SMILES: [CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=S)[S-:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].C([NH+](CC)CC)C.C(N(CC)CC)C.ClC(OCC)=O>C(Cl)(Cl)Cl>[CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:13]=[CH:14][C:15]([N:18]=[C:19]=[S:20])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5]
Reactant: CCC/C=C/[C@H]1CC[C@H](c2ccc(NC(=S)[S-])cc2)CC1
Agent: CCOC(=O)Cl
Agent: CC[NH+](CC)CC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC/C=C/[C@H]1CC[C@H](c2ccc(N=C=S)cc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
428 mg of triethylammonium p-[trans-4-(trans-1-pentenyl)cyclohexyl]phenyldithiocarbamate were dissolved in 4 ml of chloroform and the solution was treated under argon with 284 μl of triethylamine. The mixture was subsequently cooled to 0° C. and treated dropwide with 194 μl of ethyl chloroformate. The mixture was stirred at 0° C. for a further 10 minutes and then at room temperature for 1 hour. The reaction mixture was subsequently partitioned between 100 ml of diethyl ether and 100 ml of water. The aqueous phase was back-extracted twice with 100 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the oily residue (450 mg) on 35 g of silica gel with ethyl acetate/petroleum ether (vol. 7:93) gave 234 mg (51%) of p-[trans-4-(trans-1-pentenyl)cyclohexyl]phenyl isothiocyanate as colourless crystals. By recrystallization from 10 ml of methanol at 0° C. there were obtained 119 mg of p-[trans-4-(trans-1-pentenyl)cyclohexyl]phenyl isothiocyanate of melting point (C--I) 61.2° C. and cl.p. (N--I) 49.0° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:3]=1.[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[N:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:3]=2)[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: Fc1ccc(-c2cc(Cl)nnc2C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc(F)cc3)c(C(F)(F)F)nn2)CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 101.7 %

Procedure:
To a stirred solution of 6-chloro-4-(4-fluorophenyl)-3-trifluoromethyl-pyridazine (D7) (0.81 g, 2.93 mmol) and N-Boc-piperazine (0.818 g, 4.39 mmol) in acetonitrile (10 ml) was added diisopropylethylamine (1 ml, 5.9 mmol) and the mixture was stirred at 80° C. for 30 min., under microwave irradiation. After this period, the reaction mixture was diluted with dichloromethane and extracted with water. The organic layer was separated, dried (MgSO4) and the solvents evaporated in vacuo to yield D8 (1.27 g, 62%). C20H22F4N4O2 requires 426; Found 427 (MH+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[C:17]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28]Br)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[I-].[Na+].O>C(#N)C>[C:20]([O:19][C:17](=[O:18])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][N:12]1[CH2:13][CH2:14][CH:9]([C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:16][CH:15]=2)[CH2:10][CH2:11]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CC(C)(C)OC(=O)NCCCCBr
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4-(4-fluorobenzoyl)piperidine hydrochloride (0.5 g, 2.01 mmol) was suspended in acetonitrile (5 mL), 4-(Boc-amino) Butyl Bromide was added (0.569 g, 2.01 mmol) and sodium iodide (0.461 g, 3.02 mmol) and the mixture was stirred at 80° C. overnight. Water was added and the aqueous phase was extracted with 30 mL dichloromethane. The combined organic phases were dried with magnesium sulfate, filtrated concentrated and purified with column chromatography on silica using dichloromethane/Methanol (95/0.5) to yield 0.830 g, (2.1 mmol, 100% yield) of the title compound as a brown solid. MS (m/e): 379.2 (M+H+).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][CH:59]1[CH2:64][CH2:63][N:62]([CH2:65][CH2:66][OH:67])[CH2:61][CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][CH:59]5[CH2:64][CH2:63][N:62]([CH2:65][CH2:66][OH:67])[CH2:61][CH2:60]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: NC1CCN(CCO)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCN(CCO)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 2-(4-aminopiperidin-1-yl)ethanol. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (m, 1 H) 1.39 (m, 3 H) 1.54-1.90 (m, 10 H) 2.02 (t, J=10.99 Hz, 2 H) 2.38 (t, J=6.32 Hz, 2 H) 2.89 (d, J=10.86 Hz, 2 H) 3.31 (s, 3 H) 3.49 (br. s., 2 H) 3.74 (m, 1 H) 3.94 (s, 3 H) 4.06 (t, J=13.39 Hz, 2 H) 4.45 (m, 2 H) 7.47 (d, J=8.0 Hz, 1 H) 7.51 (s, 1 H) 7.90 (s, 1 H) 8.14 (d, J=8.0 Hz, 1 H) 8.21 (s, 1 H) 8.26 (d, J=8.0 Hz, 1 H). [M+H] calculated for C29H39F2N7O4, 588; found 588.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=3)(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:44])(=[O:43])[N:20]=1.[OH-].[Na+:46]>O>[CH3:17][C@@:5]1([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O-:1])=[C:3]([C:19]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([NH:29][S:30]([C:33]4[CH:42]=[CH:41][C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[CH:34]=4)(=[O:32])=[O:31])=[CH:28][C:22]=3[S:21](=[O:44])(=[O:43])[N:20]=2)[C:4]1=[O:18].[Na+:46]
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4ccc5ccccc5c4)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4ccc5ccccc5c4)ccc3N2)=C([O-])c2ccccc21
Yield: 95.9 %

Procedure:
A mixture of Example 103A (10.0 mg, 0.016 mmol) and 0.998 M sodium hydroxide (0.016 mL, 0.016 mmol) in water (1 mL) was stirred at rt for 16 h. The reaction mixture was concentrated in vacuo to give the title compound (10.0 mg, quant. yield). 1H NMR (300 MHz, DMSO-d6) δ 0.40 m, 1 H) 0.65 (d, J=6.62 Hz, 3 H) 0.67 m, 3 H) 0.76 (m, 1 H) 1.27 m, 1 H) 1.34 (s, 3 H) 1.69 m, 1 H) 2.11 m, 1 H) 7.26 m, 4 H) 7.43 (m, 2 H) 7.64 m, 2 H) 7.75 (dd, J=8.46, 1.84 Hz, 1 H) 8.03 m, 4 H) 8.38 (s, 1 H) 10.54 (s, 1 H) 15.37 (s, 1 H). MS (ESI+) m/z 630.0 (M+H—Na)+, 647.1.0 (M−Na+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH3:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=O.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:21][N:18]1[CH2:19][CH2:20][N:15]([C:13]2[CH:12]=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[C:2]([NH:1][CH:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[CH:14]=2)[CH2:16][CH2:17]1
Reactant: CN1CCCCC1=O
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CN1CCC(Nc2cc(N3CCN(C)CC3)ccc2C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 26 h
Yield: 51 %

Procedure:
tert-Butyl 2-amino-4-(4-methylpiperazin-1-yl)benzoate (1.5 g, 5.15 mmol) was dissolved in dry dioxane (25 mL) under a nitrogen atmosphere. N-methylpiperidone (0.72 g, 6.18 mmol, 1.2 eq) was added, followed by trifluoroacetic acid (1.03 mL, 13.39 mmol, 2.6 eq) and sodium triacetoxyborohydride (1.72 g, 7.73 mmol, 1.5 eq). The mixture was stirred at room temperature for 26 hours. During this time extra portions of N-methylpiperidone (0.5 mL, 0.75 eq) and sodium triacetoxyborohydride (1.72 g, 7.73 mmol, 1.5 eq) were added. A saturated aqueous solution of NaHCO3 was then added and the reaction mixture was concentrated under reduced pressure. 10% ammonium hydroxide was added until pH 10 and the aqueous phase was extracted with dichloromethane. The organic phase was washed with brine, dried over Na2SO4 and evaporated under reduced pressure. After purification by chromatography over silica gel (DCM/MeOH/NH3 7% in MeOH 90:8:2) 1.025 g of title compound were obtained as off-white solid (51% yield).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:9][CH2:8][NH:7][C:6]1=[O:10])[CH2:2][CH:3]=[CH2:4].[H-].[Na+].[Cl:13][C:14]1[C:18]([N:19]([CH2:25][CH3:26])[C:20](=[O:24])[CH2:21][CH2:22]I)=[CH:17][N:16]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:15]=1.O>CN(C=O)C>[CH2:1]([CH:5]1[CH2:9][CH2:8][N:7]([CH2:22][CH2:21][C:20]([N:19]([C:18]2[C:14]([Cl:13])=[N:15][N:16]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:17]=2)[CH2:25][CH3:26])=[O:24])[C:6]1=[O:10])[CH2:2][CH:3]=[CH2:4]
Reactant: CCN(C(=O)CCI)c1cn(-c2cccnc2)nc1Cl
Reactant: C=CCCC1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCC1CCN(CCC(=O)N(CC)c2cn(-c3cccnc3)nc2Cl)C1=O
Reaction time: 0.75 h

Procedure:
To 3-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylpropan amide (0.500 g, 1.60 mmol) in acetone (8 mL) was added sodium iodide (0.359 g, 2.40 mmol). The reaction was heated to reflux for 24 hours. The reaction product was filtered and concentrated to provide N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-iodopropanamide (0.363 g, 0.898 mmol), which was used immediately without further purification. To 3-(but-3-en-1-yl)pyrrolidin-2-one (0.125 g, 0.898 mmol) dissolved in DMF (4.49 ml) was added sodium hydride (60% in mineral oil, 0.0360 g, 0.898 mmol). The reaction stirred for 45 minutes. Then, N-(3-Chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-iodopropanamide (0.363 g, 0.898 mmol) was added as a solution in DMF (2 mL). The reaction mixture was allowed to stir at room temperature overnight. The reaction product was poured into water, extracted with diethyl ether, and washed with brine. The organics were dried and concentrated to give an oil that was purified by flash column chromatography using 0-60% acetone/hexanes as eluent providing the title compound as a clear, colorless oil. (0.257 g, 69%).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:22]=3)[O:18][N:17]=2)=[CH:11][C:10]=1[CH2:34][CH3:35])(=O)=O.[CH3:36][C:37]1([CH3:44])[O:41][CH:40]([CH2:42][NH2:43])[CH2:39][O:38]1>C(#N)C>[CH:29]1([C:23]2[CH:22]=[C:21]([C:19]3[O:18][N:17]=[C:16]([C:12]4[CH:13]=[C:14]([CH3:15])[C:9]([O:8][CH2:7][CH2:6][NH:43][CH2:42][CH:40]5[CH2:39][O:38][C:37]([CH3:44])([CH3:36])[O:41]5)=[C:10]([CH2:34][CH3:35])[CH:11]=4)[N:20]=3)[CH:26]=[C:25]([O:27][CH3:28])[N:24]=2)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCOS(C)(=O)=O
Reactant: CC1(C)OCC(CN)O1
Solvent: CC#N
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCNCC1COC(C)(C)O1
Temperature: 65 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
A mixture of 2-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)ethyl methanesulfonate (195 mg, 0.389 mmol) and rac-2,2-dimethyl-1,3-dioxolane-4-methanamine (51 mg, 0.389 mmol) in acetonitrile (6 mL) is stirred at 65° C. for 16 h. The mixture is separated by prep. HPLC to give rac-2-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)ethanamine (180 mg) as a white solid. This material is dissolved in 2 N aq. HCl (1 mL) and dioxane (5 mL) and stirred at 60° C. for 1 h. The solvent is evaporated and the crude product is purified by prep. TLC eluting with DCM containing 15% of methanol followed by prep. HPLC to give the title compound (16 mg) as a white solid; LC-MS: tR=0.91 min, [M+H]+=497.11; 1H NMR (CD3OD): δ 7.82 (s, 1H), 7.80 (s, 1H), 7.48 (s, 1H), 7.22 (s, 1H), 4.00 (t, J=5.0 Hz, 2H), 3.98 (s, 3H), 3.82-3.89 (m, 1H), 3.53-3.63 (m, 2H), 3.20-3.30 (m, 1H), 3.08 (t, J=5.0 Hz, 2H), 2.88 (dd, J1=12.1 Hz, J2=3.7 Hz, 1H), 2.70-2.81 (m, 3H), 2.38 (s, 3H), 2.05-2.15 (m, 2H), 1.84-1.95 (m, 4H), 1.69-1.81 (m, 2H), 1.30 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[S:14][CH:15]=[CH:16][C:17]=2[CH:18]=[O:19])=[CH:8][CH:7]=1.[NH4+].[Cl-]>CCOCC.O>[OH:19][CH:18]([C:17]1[CH:16]=[CH:15][S:14][C:13]=1[S:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[CH:11][CH:10]=1)[CH3:1]
Reactant: C[Mg]Br
Reactant: COc1ccc(Sc2sccc2C=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(Sc2sccc2C(C)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a stirred solution of methylmagnesium bromide (20.7 ml, 0.06 mol of 2.9M solution in ether) in anhydrous ether (50 ml) cooled to -5° C. was added 2-(4-methoxyphenylthio)thiophene 3-carboxaldehyde (10.0 g, 0.04 mol) in anhydrous ether (40 ml) over a 1/2 hour period under nitrogen atmosphere. The mixture was stirred at 0° C. for 2 hours and was decomposed by adding a solution of NH4Cl (5.3 g, 0.1 mol) in water (50 ml) over a 20 minute period at 0° to 15° C. The ether layer was separated, washed with 3NHCl, saturated, NaHCO3 and water. It was dried, filtered and concentrated in vacuo at room temperature to obtain an amber oil. The product was purified by silica gel column chromatography using 50/50 hexane-ethyl acetate. This procedure gave 8.8 g of amber oil. Yield was 83%.
Reaction SMILES: [F:1][CH:2]([F:21])[C@H:3]1[CH2:8][N:7](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:6][C@@H:5]([OH:19])[C@@H:4]1[OH:20].C1(C)C(S([Cl:31])(=O)=O)=CC=CC=1>>[ClH:31].[F:21][CH:2]([F:1])[C@H:3]1[CH2:8][NH:7][CH2:6][C@@H:5]([OH:19])[C@@H:4]1[OH:20]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)N2C[C@@H](O)[C@H](O)[C@@H](C(F)F)C2)cc1
Product: Cl
Product: O[C@H]1[C@H](O)CNC[C@@H]1C(F)F

Procedure:
(3R,4R,5S)-5-(Difluoromethyl)-1-(methanesulfonyl)piperidine 3,4-diol (8b; Z=SO2; R5=Me). Following General Procedure D except that the reaction was run at room temperature and using methanesulfonyl chloride (0.16 g, 1.4 mmol), the title compound was obtained as a white solid (0.17 g, 51%). 1H NMR (DMSO-d6) 6.2 (t, 1H, J=53 Hz), 5.43 (d, 1H, ex), 5.38 (d, 1H, ex), 3.2-3.7 (m, 4H), 2.95 (s, 3H), 2.85 (m, 1H), 2.7 (t, 1H), 2.1 (br s, 1H). (3R,4R,5S)-5-(Difluoromethyl)-1-tosylpiperidine 3,4-diol (8b; Z=SO2; R5=Ph) Following General Procedure D except that the reaction was run at room temperature and using toluenesulfonyl chloride (0.26, 1.4 mmol), the title compound was obtained as a white solid (0.35 g, 67%). 1H NMR (DMSO-d6) 7.6 (d, 2H), 7.45 (d, 2H), 6.25 (t, 1H, J=53 Hz), 5.4 (2d, 2H, ex), 3.3-3.55 (m, 4H), 3.2 (m, 1H), 2.5 (m, 3H), 2.4 (t, 1H), 2.1 (m, 1H).