Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C@@H:5]([CH:13]([CH3:15])[CH3:14])[N:6]=[C:7]([O:10][CH2:11][CH3:12])[CH2:8][N:9]=1)[CH3:2].[Li]CCCC.CCCCCC.Br[CH2:28][C@@H:29]([CH:45]([CH3:47])[CH3:46])[CH2:30][C:31]1[CH:39]=[C:38]2[C:34]([CH:35]=[N:36][N:37]2[CH2:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:33][CH:32]=1>C1COCC1>[CH2:11]([O:10][C:7]1[C@H:8]([CH2:28][C@@H:29]([CH:45]([CH3:47])[CH3:46])[CH2:30][C:31]2[CH:39]=[C:38]3[C:34]([CH:35]=[N:36][N:37]3[CH2:40][CH2:41][CH2:42][O:43][CH3:44])=[CH:33][CH:32]=2)[N:9]=[C:4]([O:3][CH2:1][CH3:2])[C@@H:5]([CH:13]([CH3:15])[CH3:14])[N:6]=1)[CH3:12]
Reactant: CCOC1=N[C@H](C(C)C)C(OCC)=NC1
Reactant: COCCCn1ncc2ccc(C[C@@H](CBr)C(C)C)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC1=N[C@H](C(C)C)C(OCC)=N[C@H]1C[C@H](Cc1ccc2cnn(CCCOC)c2c1)C(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a stirred solution of (R)-3,6-diethoxy-2-isopropyl-2,5-dihydropyrazine (480 mg, 2.3 mmol) in anhydrous THF (7 mL) at −78° C. was added dropwise 2.5 M n-BuLi in hexane (0.9 mL, 2.3 mmol). After stirring for 2 h at −78° C., a solution of (R)-6-(2-(bromomethyl)-3-methylbutyl)-1-(3-methoxypropyl)-1H-indazole (530 mg, 1.5 mmol) in THF (2 mL) was added dropwise. The mixture was stirred for 1 h at −78° C., then warmed to rt and stirred for 12 h. The reaction mixture was quenched with satd aq NH4Cl and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, evaporated, and purified by flash chromatography on silica gel to give 6-((S)-2-(((2S,5R)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazin-2-yl)methyl)-3-methylbutyl)-1-(3-methoxypropyl)-1H-indazole (493 mg, 68%). MS: 485 (M++1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[OH:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1cccc(O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1C
Temperature: 110 °C

Procedure:
In a 20 mL microwave vial 2-chloro-5-nitropyridine (500 mg, 3.15 mmol), 2,3-dimethylphenol (385 mg, 3.15 mmol) and potassium carbonate (1308 mg, 9.46 mmol) were dissolved in N,N-Dimethylformamide (10 mL) to give a dark brown suspension. The reaction vessel was sealed and heated in Biotage Initiator at 110° C. for 1 h. After cooling the reaction was diluted with 25 mL of Et2O. The organic phase was washed with 3×25 mL of water, 10 mL of brine, dried over sodium sulphate, filtered and evaporated under vacuum to afford the title compound as a pale orange oil. (640 mg). 1H NMR (400 MHz, CDCl3): δ ppm 9.07 (1H, d), 8.50 (1H, dd), 7.24-7.19 (1H, m), 7.18-7.14 (1H, m), 7.04 (1H, d), 6.95 (1H, d), 2.38 (3H, s), 2.09 (3H, s); UPLC: 0.81 min, 245 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[S:6]1(=[O:23])=[O:22].[CH3:24][CH:25]1[CH2:30][NH:29][CH2:28][CH:27]([CH3:31])[NH:26]1>>[F:21][C:16]1[CH:15]=[C:14]([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:5]([CH2:4][CH2:3][CH2:2][N:29]3[CH2:28][CH:27]([CH3:31])[NH:26][CH:25]([CH3:24])[CH2:30]3)[S:6]2(=[O:23])=[O:22])[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: O=S1(=O)N(CCCBr)c2ccccc2N1c1ccc(F)c(F)c1
Reactant: CC1CNCC(C)N1
Product: CC1CN(CCCN2c3ccccc3N(c3ccc(F)c(F)c3)S2(=O)=O)CC(C)N1
Yield: 85.3 %

Procedure:
In an analogous manner as general procedure V, 1-(3-bromopropyl)-3-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.2, 0.51 mmol) was treated with 2,6-dimethylpiperazine (0.21 g, 1.8 mmol) to provide 1-(3,4-difluorophenyl)-3-[3-(3,5-dimethylpiperazin-1-yl)propyl]-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.19 g, 85%) as a white solid:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:9][C:10]=1[CH2:11]O.C(N(CC)CC)C.CS([Cl:36])(=O)=O>ClCCl>[Cl:36][CH2:11][C:10]1[O:9][C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:7][C:6]=1[CH2:5][O:4][CH2:3][C:2]([F:24])([F:23])[F:1]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1oc(-c2ccc(C(F)(F)F)cc2)nc1COCC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(F)COCc1nc(-c2ccc(C(F)(F)F)cc2)oc1CCl
Temperature: 25 °C

Procedure:
422 mg [4-(2,2,2-Trifluoro-ethoxymethyl)-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol were dissolved in 5 ml dichloromethane and cooled in an ice bath. 247 μl triethylamine were added, followed by the addition of 110 μl methanesulfonylchloride. The ice bath was removed and the resulting mixture stirred at room temperature over night. 50 ml dichloromethane were added and the reaction mixture was then washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to obtain 509 mg 5-chloromethyl-4-(2,2,2-trifluoro-ethoxymethyl)-2-(4-trifluoromethyl-phenyl)-oxazole as an oil which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]3[CH:41]=[CH:40][C:22]([CH2:23][NH:24][C:25]4[CH:30]=[C:29]([F:31])[C:28]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[C:27]([F:39])[CH:26]=4)=[CH:21][C:20]=3[O:42][CH:43]([CH3:45])[CH3:44])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]3[CH:41]=[CH:40][C:22]([CH2:23][NH:24][C:25]4[CH:30]=[C:29]([F:31])[C:28]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[C:27]([F:39])[CH:26]=4)=[CH:21][C:20]=3[O:42][CH:43]([CH3:45])[CH3:44])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1c(F)cc(NCc2ccc(Cn3nc(-c4ccccc4)cc3-c3ccccc3)c(OC(C)C)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)Oc1cc(CNc2cc(F)c(CCC(=O)O)c(F)c2)ccc1Cn1nc(-c2ccccc2)cc1-c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a solution of ethyl 3-[4-({4-[(3,5-diphenyl-1H-pyrazol-1-yl)methyl]-3-isopropoxybenzyl}amino)-2,6-difluorophenyl]propanoate (0.431 g, 0.710 mmol) in a mixture of ethanol (5 mL) and tetrahydrofuran (8 mL) was added 1 N sodium hydroxide (2.12 mL, 2.12 mmol) and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from diethyl ether-hexane to give the title compound (0.310 g, yield 75%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:20])[C:14]([C:16]([O:18]C)=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:21].Cl.C(O)(=O)C>O>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:20])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:21]
Reactant: COC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CN1CCc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 75.8 %

Procedure:
29.1 g of methyl ester (6) obtained in Example 2 (1) was added to 80 ml of concentrated hydrochloric acid and 320 ml of acetic acid, and the solution was heated under reflux for 3.5 hours. After air-cooled, 500 ml of water was added to the solution, and the solid was filtered off and washed consecutively with water, ethanol and ether to obtain 23.2 g of crude solid. The obtained crude solid was recrystallized from ethanol and chloroform to obtain 21 g of subject compound (8) in a 80% yield. The result of the analysis of this compound was as follows.
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[Cl-].[Al+3].[Cl-].[Cl-].[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:22]([C:16]1[CH:17]=[CH:18][C:19]([C:7]([C@@H:2]2[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]2[C:10]([OH:9])=[O:11])=[O:8])=[CH:20][CH:21]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCc1ccccc1
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCCCCc1ccc(C(=O)[C@@H]2CCCC[C@H]2C(=O)O)cc1

Procedure:
The procedure described in Example 23 is followed using trans-1,2-cyclohexanedicarboxylic anhydride (20.0 g), 1-phenylnonane (200 ml), and anhydrous aluminum chloride (38.1 g). Work-up as described provided trans-2-(4-n-nonylbenzoyl)cyclohexane1-carboxylic acid (28.5 g, m.p. 84°-86° C).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:8]=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)[C:10]3[N:15]=[CH:14][S:13][C:11]=3[N:12]=2)[CH2:3]1.[CH3:27][O:28][C:29]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][N:32]=1)=[O:30].CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([NH:16][C:9]2[C:10]3[N:15]=[CH:14][S:13][C:11]=3[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][CH:2]([NH:1][C:35]([C:34]4[CH:38]=[CH:39][C:31]([C:29]([O:28][CH3:27])=[O:30])=[N:32][CH:33]=4)=[O:36])[CH2:3]3)[N:8]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: COC(=O)c1ccc(C(=O)O)cn1
Reactant: COc1ccc(Nc2nc(N3CCC(N)C3)nc3scnc23)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NC2CCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.4 %

Procedure:
To a solution of 5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (80 mg, 0.22 mmol) and 6-(methoxycarbonyl)nicotinic acid (39 mg, 0.22 mmol) in dichloromethane (15 mL) was added the solution of 1-methyl-1H-imidazole (71 mg, 0.88 mmol) and EDCI (164 mg, 0.88 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 15 hours, the solid was collected by filtration and washed with MeOH to afford methyl 5-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)picolinate (90 mg, 80.3%) as a off-white solid. 1H NMR (300 MHz, DMSO): δ 9.57 (s, 1H), 9.07 (s, 1H), 8.99 (d, 1H, J=6.3 Hz), 8.79 (s, 1H), 8.36 (dd, 1H, J1=8.1 Hz, J2=2.1 Hz), 8.11 (d, 1H, J=8.1 Hz), 7.86 (s, 1H), 7.45 (s, 1H), 6.90 (d, 1H, J=8.7 Hz), 4.60-4.58 (m, 1H), 3.89 (s, 3H), 3.75 (s, 3H), 3.71 (s, 3H), 3.64 (brs, 4H), 2.28-2.24 (m, 1H), 2.11-2.06 (m, 1H). LC-MS: 536 [M+H]+, tR=1.37 min. HPLC: 95.95% at 214 nm, 96.44% at 254 nm, tR=4.85 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:18](=[CH:19][C:20]=3[F:21])[N:17]([CH3:22])[N:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][C:25]1=[O:30]>>[F:23][C:13]1[C:12]([CH2:11][C:8]2[N:6]3[N:7]=[C:2]([N:27]4[CH2:28][CH2:29][NH:24][C:25](=[O:30])[CH2:26]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[C:20]([F:21])[CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[CH3:22]
Reactant: O=C1CNCCN1
Reactant: Cn1ncc2c(F)c(Cc3cnc4ccc(Cl)nn34)c(F)cc21
Product: Cn1ncc2c(F)c(Cc3cnc4ccc(N5CCNC(=O)C5)nn34)c(F)cc21

Procedure:
The title compound was prepared in analogy to Example 52 using 6-chloro-3-((4,6-difluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine (Intermediate T, (100 mg, 0.300 mmol) and piperazin-2-one (90 mg, 0.899 mmol) (tR 3.47 min (conditions 4), MH+=398, 1H-NMR in DMSO-d6: 8.13 (s, 1H); 8.11 (s, 1H); 7.81 (d, 1H); 7.45 (d, 1H); 7.27 (s, 1H); 7.09 (d, 1H), 4.27 (s, 2H); 3.98 (m, 5H); 3.67 (m, 2H), 3.29 (m, 2H)).
Reaction SMILES: [ClH:1].[C:2]1([C@H:8]2CCC[C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=CC=1.Cl.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][CH2:18][CH:17]1[NH2:21]>>[ClH:1].[NH:13]1[CH2:9][CH2:8][CH2:2][CH2:7][CH2:6][C:5]1=[N:21][CH:17]1[CH2:18][CH2:19][CH2:20][C:16]1([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:15]
Reactant: NC1CCCC1(O)c1ccccc1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Agent: Cl
Product: OC1(c2ccccc2)CCCC1N=C1CCCCCN1

Procedure:
Following the procedure described in Example 1, only substituting for cis-2-phenylcyclopentylamine hydrochloride an appropriate amount of 2-hydroxy-2-phenylcyclopentylamine hydrochloride and employing a reaction time of 47 days the desired product was obtained, M.P.261°-262° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=O)[C:6]2[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[C:8]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:7]=2)[CH2:3][CH2:2]1.B.CSC>C1COCC1>[CH3:21][O:20][CH2:19][CH2:18][CH2:17][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=1)[CH2:5][NH:4][CH:1]1[CH2:2][CH2:3]1
Reactant: COCCCc1cc(CCCOC)cc(C(=O)NC2CC2)c1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: COCCCc1cc(CCCOC)cc(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of N-cyclopropyl-3,5-bis(3-methoxypropyl)benzamide (1 eq.) from the previous step in THF (0.18 M) at 80° C. was added borane-dimethylsulfide (10 eq.). The reaction was distilled to about half volume and heated under reflux for 3 h. Then, the reaction was cooled to rt and slowly quenched with 10% HCl aqueous solution. The reaction was heated to reflex again and stirred for 45 min. After cooling to rt, the reaction was diluted with EtOAc and basified with aqueous NaOH solution (pH >10). The organic extract was washed with saturated aqueous NaHCO3, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 25% EtOAc in Hex plus 3% Et3N) to afford the title compound amine 3 as an oil.
Reaction SMILES: N1C=CC=C(CN)C=1.[CH3:9][C:10]1[CH:14]=[C:13]([CH2:15][NH2:16])[NH:12][N:11]=1.[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[S:29][C:30]([C:34](O)=[O:35])=[C:31]([CH3:33])[N:32]=3)[C:24]2=[O:37])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[S:29][C:30]([C:34]([NH:16][CH2:15][C:13]4[NH:12][N:11]=[C:10]([CH3:9])[CH:14]=4)=[O:35])=[C:31]([CH3:33])[N:32]=3)[C:24]2=[O:37])=[CH:20][CH:19]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1cc(CN)[nH]n1
Agent: NCc1cccnc1
Product: Cc1cc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)nc2C)[nH]n1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with (3-methyl-1H-pyrazol-5-yl)methanamine to react 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid instead of (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as an off-white solid (0.04 g, 12%): mp 225-226° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.30 (t, J=5.0 Hz, 1H), 7.38-7.34 (m, 2H), 7.23-7.17 (m, 2H), 5.89 (s, 1H), 4.42 (s, 2H), 4.29 (d, J=5.7 Hz, 2H), 4.02-3.97 (m, 2H), 2.48-3.42 (m, 2H), 2.46 (s, 3H), 2.16 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.6, 161.5 (d, 1JC-F=243 Hz), 157.3, 155.0, 150.5 (br), 132.6 (d, 4JC-F=3 Hz), 129.9 (d, 3JC-F=8 Hz), 118.2, 115.4 (d, 2JC-F=21 Hz), 102.5, 46.1, 41.9, 41.5, 36.8 (br), 17.0, 10.6 (br); MS (ES+) m/z 428.9 (M+1).
Reaction SMILES: [CH2:1]([S:4]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16](Cl)=[O:17])[CH:13]=[CH2:14].O1CCCC1>C(N(CC)CC)C>[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[N:8]1)=[O:17])[CH:13]=[CH2:14]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCCS(=O)(=O)c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)(=O)CCC)n1

Procedure:
A mixture of 5.25 g. 3-propylsulphonyl-1,2,4-triazole, 5.3 g. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 6 ml. dry triethylamine was refluxed under anhydrous conditions for 1.5 hours. The reaction mixture was worked up as described in Example 1 to give a solid product which was recrystallized from petroleum ether (b.p. 60° - 80° C.) to give 1-diallylcarbamoyl-3-propylsulphonyl-1,2,4-triazole, m.p. 41° - 42° C. Elemental analysis satisfactory.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Na+].[Na+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29].Cl>O.C(OCC)(=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:2]2[CH2:6][CH2:5][CH2:4][C@H:3]2[C:7]([O:9][CH3:10])=[O:8])(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
At 0° C., a solution of 0.647 g (3.9 mmol) of methyl (S)-pyrrolidine-2-carboxylate hydrochloride in 6 ml of water was added to 0.83 g of sodium carbonate (7.8 mmol, 2 eq), followed portionwise by 1.0 g (3.9 mmol) of 4-chloro-3-nitrobenzenesulfonyl chloride. The medium was stirred at 0° C. for 4 hours. The reaction medium was diluted with ethyl acetate and brought to pH 5-6 with 2 N HCl. After extraction, the aqueous phase was basified with sodium bicarbonate and extracted twice with ethyl acetate. The organic phases were combined, washed with a saturated sodium chloride solution, dried over magnesium sulfate and evaporated. 1.22 g (90%) of product were obtained. Yield=90%.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[S:12]([O-:15])([O-:14])=[O:13].[Na+:16].[Na+]>CO.O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:12]([O-:15])(=[O:14])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+:16]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(CS(=O)(=O)[O-])cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
A suspension of 100g (463 mmol, 1.0 equiv.) of 4-nitrobenzyl bromide and 64.2 g (509 mmol, 1.1 equiv.) of sodium sulfite in 500 mL of methanol and 500 mL of water was heated to reflux. The progress of the reaction was monitored by TLC. When the bromide was consumed, the reaction mixture was allowed to cool to room temperature. The product precipitated and was collected by filtration. It was thoroughly dried for sixteen hours at 65° C. at 0.05 mm Hg to give 100 g (90%) of sodium 4-nitrobenzyl sulfonate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Si:7]([CH3:10])([CH3:9])[CH3:8].C([Li])(C)(C)C.CCCCC.[CH3:21][Si:22](C[Li])([CH3:29])[C:23]1C=CC=CN=1.Cl[Si](C)(C)C.Cl>C(OCC)C>[CH3:8][Si:7]([CH3:10])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH2:9][Si:22]([CH3:29])([CH3:23])[CH3:21]
Reactant: C[Si](C)(C)c1ccccn1
Reactant: [Li]C[Si](C)(C)c1ccccn1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: C[Si](C)(C)C[Si](C)(C)c1ccccn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
After dissolving 151 mg (1.0 mmol) of (2-pyridyl)trimethylsilane in 2 ml of dry diethyl ether, 0.67 ml (1.1 mmol) of a t-butyllithium/pentane solution (the concentration: 1.64 M) was added dropwise at an inner temperature of −78° C., whereby the reaction solution turned orange indicating the formation of [dimethyl(2-pyridyl)silyl]methyllithium. After that, the mixture was continued to be stirred at an inner temperature of −78° C. for 30 minutes, and then 130 mg (1.2 mmol) of chlorotrimethylsilane was added to the mixture, which was subsequently stirred at an inner temperature of −78° C. overnight. To the resulting reaction solution was added 5 ml of 1N hydrochloric acid, and the mixture was separated to the organic and aqueous layers. The organic layer was extracted with four portions of 5 ml of 1N hydrochloric acid. The resulting aqueous layers were combined together, and neutralized by the addition of sodium hydroxide pellets. The neutralized aqueous layer was extracted with three portions of 10 ml of diethyl ether. The resulting organic layers were combined together and dried over magnesium sulfate. The solvent was evaporated to give 208 mg of dimethyl(2-pyridyl)(trimethylsilylmethyl)silane (yield: 93%; NMR purity: 95% or more).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=3)=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[CH:46][N:47]=[CH:48][CH:49]=3)=[CH:40][CH:39]=2)[C:35]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=2)=[O:37])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1ccccn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(-c2ccncc2)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(-c2ccncc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of triphenylphosphine (59 mg, 0.22 mmol) in methylene chloride (1 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (39 mg, 0.22 mmol). The reaction mixture was stirred at 0° C. for 20 min and then treated with 3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-propionic acid (55 mg, 0.19 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C., where it was stirred for 20 min. The reaction mixture was then treated with 2-aminopyridine (39 mg, 0.41 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 20/1 methylene chloride/methanol) to afford impure 3-cyclopentyl-N-pyridin-2-yl-2-(4-pyridin-4-yl-phenyl)-propionamide as a yellow solid. Repurification by flash chromatography (Merck Silica gel 60, 230-400 mesh, 100% ethyl acetate) afforded pure 3-cyclopentyl-2-(4-pyridin-4-yl-phenyl)-N-thiazol-2-yl-propionamide (10 mg, 14%) as a yellow solid: mp 165-167° C.; EI-HRMS m/e calcd for C24H25N3O (M+) 371.1998, found 371.1998.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][C@@H:13]2[CH2:15][C@@H:14]2[CH:16]2[CH2:21][CH2:20][N:19]([C:22]#[N:23])[CH2:18][CH2:17]2)=[CH:8][C:7]=1[F:26])(=[O:5])=[O:4])[CH3:2].[OH:27][NH:28][C:29](=N)[CH2:30][O:31][CH3:32]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH2:1]([S:3]([C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][C@H:13]2[CH2:15][C@H:14]2[CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[O:27][N:28]=[C:29]([CH2:30][O:31][CH3:32])[N:23]=3)[CH2:18][CH2:17]2)=[CH:8][C:7]=1[F:26])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C#N)CC2)cc1F
Reactant: COCC(=N)NO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(OCC[C@H]2C[C@H]2C2CCN(c3nc(COC)no3)CC2)cc1F
Temperature: 25 °C

Procedure:
To a solution of 4-((1R,2S)-2-{2-{4-(ethylsulfonyl)-3-fluorophenoxy]ethyl}cyclopropyl)piperidine-1-carbonitrile (Step D; 100 mg, 0.27 mmol) and N-hydroxy-2-methoxyacetimidamide (38 mg, 0.37 mmol) in tetrahydrofuran (5 mL) was added zinc chloride (0.8 mL, 0.5 M in tetrahydrofuran, 0.4 mmol). The mixture was refluxed for 2 h, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in 2 mL of 4N HCl ethanol and water (1:1). The solution was refluxed for 30 min, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (5 mL), neutralized by the addition of excess potassium carbonate, mixed silica gel (2 g), and concentrated to dryness under reduced pressure. The residue was loaded on a silica gel column (10 g of silica gel) and eluted with a gradient of dichloromethane/CMA, 19:1, 500 mL; 4:1, 500 mL to provide the title compound. MS (ESI) m/z 468 [M+H]+.