Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:16]([C:17]([F:20])([F:19])[F:18])=[C:15]([C:21]([O:23]CC3C=CC=CC=3)=[O:22])[CH:14]=[N:13]2)[CH2:8][C@@H:7]1[CH3:31])=[O:5])[CH3:2].[CH2:32]([O:34][C:35]([C@@H:37]1[CH2:42][CH2:41][C@@H:40]([N:43]2[C:47]([C:48]([F:51])([F:50])[F:49])=[C:46]([C:52]([O:54]CC3C=CC=CC=3)=[O:53])[CH:45]=[N:44]2)[CH2:39][C@H:38]1[CH3:62])=[O:36])[CH3:33].CCO>[Pd].CCOC(C)=O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:16]([C:17]([F:18])([F:19])[F:20])=[C:15]([C:21]([OH:23])=[O:22])[CH:14]=[N:13]2)[CH2:8][C@@H:7]1[CH3:31])=[O:5])[CH3:2].[CH2:32]([O:34][C:35]([C@@H:37]1[CH2:42][CH2:41][C@@H:40]([N:43]2[C:47]([C:48]([F:49])([F:50])[F:51])=[C:46]([C:52]([OH:54])=[O:53])[CH:45]=[N:44]2)[CH2:39][C@H:38]1[CH3:62])=[O:36])[CH3:33]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)OCc3ccccc3)c2C(F)(F)F)C[C@@H]1C
Reactant: CCOC(=O)[C@@H]1CC[C@@H](n2ncc(C(=O)OCc3ccccc3)c2C(F)(F)F)C[C@H]1C
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CC[C@@H](n2ncc(C(=O)O)c2C(F)(F)F)C[C@H]1C
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)O)c2C(F)(F)F)C[C@@H]1C
Temperature: 21 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
A pressurized vial was charged with palladium 10 wt. % on activated carbon (0.103 g, 0.097 mmol) while under a stream of nitrogen gas. Then a solution of benzyl 1-((1R,3R,4R)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate compound with benzyl 1-((1S,3S,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (1:1) (D43-3) (0.4258 g, 0.971 mmol) in a 1:1 mixture of EtOH (2.428 ml)/EtOAc (2.428 ml) was added into the vial. The reaction atmosphere was purged with hydrogen gas (3 times). The reaction was stirred vigorously under hydrogenation (33 psi) at 21° C. After 3 h, LCMS (ESI) showed that the reaction was complete. The reaction mixture was purged with nitrogen gas for 30 min. The mixture was filtered through a pad of celite and the filter cake was rinsed with EtOAc. The filtrate was concentrated in vacuo to give 1-((1R,3R,4R)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid compound with 1-((1S,3S,4S)-4-(ethoxycarbonyl)-3-methylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (1:1) (D43) (0.3224 g, 0.926 mmol, 95% yield) as light-yellow solid:
Reaction SMILES: [S:1]([O-:6])(O[O-])(=O)=[O:2].[K+].[K+].[C:9](#N)C.O.[F:13][C:14]([F:53])([F:52])[C:15]1[CH:16]=[C:17]([C@H:25]2[O:29][C:28](=[O:30])[N:27]([CH2:31][C:32]3[C:37]([C:38]4[C:39]([O:47][CH3:48])=[N:40][CH:41]=[C:42]([CH:44]([CH3:46])[CH3:45])[CH:43]=4)=[CH:36][N:35]=[C:34](SC)[N:33]=3)[C@H:26]2[CH3:51])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1>C(OC)(C)(C)C>[F:23][C:21]([F:22])([F:24])[C:19]1[CH:18]=[C:17]([C@H:25]2[O:29][C:28](=[O:30])[N:27]([CH2:31][C:32]3[C:37]([C:38]4[C:39]([O:47][CH3:48])=[N:40][CH:41]=[C:42]([CH:44]([CH3:45])[CH3:46])[CH:43]=4)=[CH:36][N:35]=[C:34]([S:1]([CH3:9])(=[O:6])=[O:2])[N:33]=3)[C@H:26]2[CH3:51])[CH:16]=[C:15]([C:14]([F:13])([F:53])[F:52])[CH:20]=1
Reactant: CC#N
Reactant: COc1ncc(C(C)C)cc1-c1cnc(SC)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Product: COc1ncc(C(C)C)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium peroxymonosulfate (4.08 g, 6.63 mmol) was added to an acetonitrile (12 mL) and water (8 mL) suspension of title compound from step A above (1.66 g, 2.76 mmol). This was then stirred for 2 hours at 25° C., at which time LCMS showed complete conversion to product. The reaction was diluted with methyl t-butyl ether (50 mL) and poured into water (100 mL). The organic layer was washed twice with 100 mL aqueous NaCl, then dried over sodium sulfate, filtered and the filtrate concentrated to give a white solid, which can be used without further purification. LCMS (M+H)+: 633.4. 1H NMR (CDCl3, 500 MHz) δ 8.75 (s, 1H), 8.24 (d, J=2.2 Hz, 1H), 7.92 (s, 1H), 7.80 (s, 2H), 7.49 (d, J=2.2 Hz, 1H), 5.89 (d, J=8.3 Hz, 1H), 4.93 (d, J=17.7 Hz, 1H), 4.59 (m, 1H), 4.26 (d, J=17.7 Hz, 1H), 3.98 (s, 3H), 3.43 (s, 3H), 3.02 (m, 1H), 1.33 (d, J=6.9 Hz, 6H), 0.80 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.O.[NH2:21][NH2:22]>C(O)COCCO>[NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4](=[N:21][NH2:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12]
Reactant: NN
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Solvent: OCCOCCO
Solvent: O
Product: NN=C(c1cc([N+](=O)[O-])ccc1N)c1ccccc1Cl

Procedure:
In the manner given in Preparation 1, 2-amino-2'-chloro-5-nitrobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 2-amino-2'-chloro-5-nitrobenzophenone hydrazone.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].[NH4+].[OH-]>O>[C:27]([N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[C:11]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)(=[O:29])[CH3:28]
Reactant: CCOC(=O)C1(Nc2cccc(F)c2)CCN(Cc2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C1(N(C(C)=O)c2cccc(F)c2)CCN(Cc2ccccc2)CC1

Procedure:
A solution of 0.2 g (0.56 mmol) ethyl 1-benzyl-4-[(3-fluorophenyl)amino]piperidine-4-carboxylate in 2.6 mL (28 mmol) acetic anhydride (neat) was heated to 120° C. for 20 hr, then poured into 50 mL of a 1:1 mixture of water and concentrated NH4OH, extracted with 100 mL EtOAc, washed with water then brine, dried over MgSO4, filtered, and concentrated. Purification by automated flash chromatography (40 g silica gel cartridge 0-5% MeOH/CH2Cl2) over 15 min) afforded ethyl 4-[acetyl(3-fluorophenyl)amino]-1-benzylpiperidine-4-carboxylate. 1H NMR (CDCl3, 400 MHz) δ 7.39 (m, 1H); 7.20-7.31 (m, 4H); 7.06-7.15 (m, 4H); 4.25 (q, J=7.14 Hz, 2H); 3.46 (s, 2H); 2.59 (br m, 2H); 2.30-2.48 (m, 3H); 2.22 (m, 2H); 1.72 (s, 3H) 1.63 (m, 2H); 1.31 (t, J=7.15, 3H). Electrospray mass spectrum M+H=399.2
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:11][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:20]=3[NH:19][C:18](=[O:21])[CH2:17]4)[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-:22].[Na+].[O:24]1CCOCC1>O>[NH2:3][C:4]1[C:9]([CH2:10][C:2]([OH:1])=[O:22])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH2:17][C:18]([OH:21])=[O:24])[C:20]=1[NH2:19]
Reactant: O=C1Cc2cccc(Oc3cccc4c3NC(=O)C4)c2N1
Reactant: [OH-]
Reactant: C1COCCO1
Agent: [Na+]
Solvent: O
Product: Nc1c(CC(=O)O)cccc1Oc1cccc(CC(=O)O)c1N

Procedure:
A mixture of bis(2-oxoindolin-7-yl)ether (2.4 g.), sodium hydroxide (1.35 g.), dioxane (10 ml.) and water (50 ml.) was refluxed under heating for 7 hours with stirring. After cooling, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure. The residue was dissolved in water and washed with ethyl acetate. Ethyl acetate was added to the solution and adjusted to pH 4 to 5 with 5% sulfuric acid. The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate and then evaporated under reduced pressure. The residue was washed with a mixture of ethyl acetate and diethyl ether to give bis(2-amino-3-carboxymethylphenyl)ether (1.6 g.). mp22 240° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.CCN(CC)CC.[Cl:29][C:30]1[C:31]([CH3:57])=[C:32]([NH:38][C@H:39]([C:53]([OH:56])([CH3:55])[CH3:54])[C:40]([NH:42][NH:43][C:44](=[O:52])[C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)=O)[CH:33]=[CH:34][C:35]=1[C:36]#[N:37]>C(Cl)Cl.C1COCC1>[Cl:29][C:30]1[C:31]([CH3:57])=[C:32]([NH:38][C@@H:39]([C:40]2[O:52][C:44]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)=[N:43][N:42]=2)[C:53]([OH:56])([CH3:55])[CH3:54])[CH:33]=[CH:34][C:35]=1[C:36]#[N:37]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)cc2)C(C)(C)O)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(F)cc3)o2)C(C)(C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of triphenylphosphine (5.35 g, 20.4 mmol) in DCM (100 mL) was added I2 (5.18 g, 20.4 mmol) at 0° C. After all the Iodine was dissolved completely, Et3N (5.7 mL, 40.9 mmol) was added, followed by a solution of (R)—N′-(2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoyl)-4-fluorobenzohydrazide (4.27 g, 10.2 mmol) in DCM (20 mL) and THF (20 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for additional 30 min. The reaction was quenched with saturated aq. sodium thiosulfate (20 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with water, brine and dried over Na2SO4. After the solvent was removed, the residue was purified by flash chromatography to provide the title compound (R)-2-chloro-4-(1-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxy-2-methylpropylamino)-3-methylbenzonitrile (3.31 g, 81%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.06 (dd, J=5.3, 9.0 Hz, 2H), 7.47 (d, J=8.6 Hz, 1H), 7.33 (t, J=9.0 Hz, 2H), 6.79 (d, J=8.6 Hz, 1H), 5.70 (d, J=8.7 Hz, 1H), 5.09 (d, J=8.7 Hz, 1H), 2.39 (s, 3H), 1.52 (s, 3H), 1.36 (s, 3H).
Reaction SMILES: [C:1]1([CH:7](OS(C2C=CC(C)=CC=2)(=O)=O)[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH2:32][CH2:31]1
Reactant: Cc1ccc(S(=O)(=O)OC(C(=O)OCc2ccccc2)c2ccccc2)cc1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(C(=O)OCc2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A THF (75 mL) solution of benzyl 2-phenyl-2-(tosyloxy)acetate (6.0 g, 15.1 mmol), 1-methylpiperazine (3.36 mL, 30.3 mmol) and N,N-diisopropylethylamine (13.2 mL, 75.8 mmol) was heated at 65° C. for 7 hours. The reaction was allowed to cool to ambient temperature and the volatile component was removed in vacuo. The residue was partitioned between ethylacetate and water, and the organic layer was washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting crude material was purified by flash chromatography (silica gel, ethyl acetate) to provide benzyl 2-(4-methylpiperazin-1-yl)-2-phenylacetate as an orangish-brown viscous oil (4.56 g). Chiral HPLC analysis (CHIRALCEL® OD-H) indicated that the sample is a mixture of stereoisomers in a 38.2 to 58.7 ratio. The separation of the stereoisomers were effected as follow: the product was dissolved in 120 mL of ethanol/heptane (1:1) and injected (5 mL/injection) on chiral HPLC column (Chiracel OJ, 5 cm ID×50 cm L, 20 μm) eluting with 85:15 Heptane/ethanol at 75 mL/min, and monitored at 220 nm. Stereoisomer-1 (1.474 g) and stereoisomer-2 (2.2149 g) were retrieved as viscous oil. 1H NMR (CDCl3, δ=7.26, 500 MHz) 7.44-7.40 (m, 2H), 7.33-7.24 (m, 6H), 7.21-7.16 (m, 2H), 5.13 (d, J=12.5, 1H), 5.08 (d, J=12.5, 1H), 4.02 (s, 1H), 2.65-2.38 (app br s, 8H), 2.25 (s, 3H). RT=2.10 (Condition III); >98% homogeneity index; LC-MS: Anal. Calcd. for [M+H]+ C20H25N2O2: 325.19. found 325.20.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]([O:24][Si](C)(C)C)=[C:21]([CH3:23])[CH3:22].CN(C=O)C.O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[F-].[Zn+2].[F-].C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:7][C@H:8]([C:10]1[CH:11]=[C:12]([C:21]([CH3:23])([CH3:22])[C:20]([O:19][CH3:18])=[O:24])[CH:13]=[CH:14][CH:15]=1)[CH3:9])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Br)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)c1cccc([C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 1 g of tert-butyl[(1S)-1-(3-bromophenyl)ethyl]carbamate, 18 mg of bis(tri-tert-butylphosphine)palladium (0), 180 mg of zinc fluoride, 1 ml of [(1-methoxy-2-methylpropa-1-en-1-yl)oxy](trimethyl)silane, and 10 ml of DMF was stirred at 80° C. overnight and at 100° C. for 5 hours. 25 mg of bis(tri-tert-butylphosphine)palladium (0) and 0.34 ml of [(1-methoxy-2-methylpropa-1-en-1-yl)oxy](trimethyl)silane were added thereto, followed by stirring at 80° C. for 3 days. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 281 mg of methyl 2-(3-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)-2-methylpropanoate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:13]([O:15][CH3:16])=[O:14])[CH3:12])=[CH:7][C:6]=1[S:17]([NH2:20])(=[O:19])=[O:18])=[O:4].S(Cl)(Cl)=O.N1C=CC=CC=1.[C:31](Cl)(Cl)=[O:32]>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:13]([O:15][CH3:16])=[O:14])[CH3:12])=[CH:7][C:6]=1[S:17]([N:20]=[C:31]=[O:32])(=[O:19])=[O:18])=[O:4]
Reactant: COC(=O)c1ccc(N(C)C(=O)OC)cc1S(N)(=O)=O
Reactant: O=C(Cl)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N(C)C(=O)OC)cc1S(=O)(=O)N=C=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5.0 g of 2-methoxycarbonyl-5-(N-methoxycarbonyl-N-methylamino)benzenesulfonamide are suspended in 17 ml of 1,2-dichloroethane. 4 ml of thionyl chloride are added and the reaction mixture is heated at boiling for 5 h. The reaction mixture is cooled to room temperature, 0.3 ml of pyridine is added, phosgene is passed into the reaction mixture, and the solution is heated at reflux for 4 h. The reaction mixture is concentrated to give 6.3 g of an oil which is employed directly in the subsequent reaction (Examples m, n, o).
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH2:6][CH2:7][C:8](=[O:36])[N:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[O:23][C:24](=[O:35])[C:25]3[C:30]4[CH2:31][CH2:32][CH2:33][CH2:34][C:29]=4[S:28][C:26]=3[N:27]=2)[CH:17]=1)[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:3]([OH:5])=[O:4].[CH3:38]N(C=O)C.CI.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:37][C:2]([CH3:1])([CH2:6][CH2:7][C:8](=[O:36])[N:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[O:23][C:24](=[O:35])[C:25]3[C:30]4[CH2:31][CH2:32][CH2:33][CH2:34][C:29]=4[S:28][C:26]=3[N:27]=2)[CH:17]=1)[CH:10]([CH2:11][CH3:12])[CH2:13][CH3:14])[C:3]([O:5][CH3:38])=[O:4]
Reactant: CN(C)C=O
Reactant: CCC(CC)N(Cc1cccc(-c2nc3sc4c(c3c(=O)o2)CCCC4)c1)C(=O)CCC(C)(C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CCC(CC)N(Cc1cccc(-c2nc3sc4c(c3c(=O)o2)CCCC4)c1)C(=O)CCC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4.81 g of 2,2-dimethyl-5-oxo-5-{[3-(4-oxo-5,6,7,8-tetrahydro-4H-[1]benzothieno[2,3-d][1,3]oxazin-2-yl)benzyl](pentan-3-yl)amino}pentanoic acid and 50 mL of DMF were added 2.59 g of methyl iodide and 3.16 g of potassium carbonate, followed by stirring for 1 hour at room temperature. Water was added to a reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was recrystallized from ethanol, thereby obtaining 3.24 g of methyl 2,2-dimethyl-5-oxo-5-{[3-(4-oxo-5,6,7,8-tetrahydro-4H-[1]benzothieno[2,3-d][1,3]oxazin-2-yl)benzyl](pentan-3-yl)amino}pentanoate as a yellowish white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([F:15])([F:14])[C:4]([F:13])([F:12])[C:5]([F:11])([F:10])[S:6]([O-:9])(=[O:8])=[O:7].[OH:18][C:19]1[CH:24]=[CH:23][C:22]([S+:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1.[F:38][C:39]([F:54])([S:50](Cl)(=[O:52])=[O:51])[C:40]([F:49])([F:48])[CH:41]1[CH2:46][CH:45]2[CH2:47][CH:42]1[CH2:43][CH2:44]2.C(N(CC)CC)C.O>ClCCl>[F:17][C:2]([F:1])([F:16])[C:3]([F:14])([F:15])[C:4]([F:12])([F:13])[C:5]([F:10])([F:11])[S:6]([O-:9])(=[O:8])=[O:7].[F:54][C:39]([F:38])([S:50]([O:18][C:19]1[CH:24]=[CH:23][C:22]([S+:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)(=[O:52])=[O:51])[C:40]([F:48])([F:49])[CH:41]1[CH2:46][CH:45]2[CH2:47][CH:42]1[CH2:43][CH2:44]2
Reactant: O=S(=O)(Cl)C(F)(F)C(F)(F)C1CC2CCC1C2
Reactant: Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1)C(F)(F)C(F)(F)C1CC2CCC1C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54.2 %

Procedure:
30 g of 4-hydroxyphenyl diphenylsulfonium nonafluoro-n-butanesulfonate was dissolved in 300 g of dichloromethane in a reaction flask, in which the atmosphere was replaced with nitrogen. 30.6 g of 1,1,2,2-tetrafluoro-2-(norbornan-2-yl)ethanesulfonyl chloride and 10.5 g of triethylamine were added in this order. The mixture was stirred for 20 minutes at room temperature. After the addition of 100 g of ion-exchanged water, the mixture was transferred to a separatory funnel, shaken, and allowed to stand still. The water layer was removed. After the addition of 300 ml of distilled water, the solution was shaken and allowed to stand still. The water layer was removed. The resulting dichloromethane solution was dried using anhydrous magnesium sulfate and filtered. After evaporating dichloromethane from the dichloromethane solution, the residual liquid was dried under reduced pressure to obtain 23.5 g of 4-[1,1,2,2-tetrafluoro-2-(norbornan-2-yl)ethanesulfonyloxy]phenyl diphenylsulfonium nonafluoro-n-butanesulfonate. This compound is indicated as “acid generator (A-3)”.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:22])([F:21])[CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)C(C)C)(C)C.[F:32][C:33]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][N:42]=[C:41]([CH3:45])[CH:40]=2)[CH:36]=[CH:35][C:34]=1[CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>ClCCl>[F:32][C:33]1[CH:38]=[C:37]([C:39]2[CH:44]=[CH:43][N:42]=[C:41]([CH3:45])[CH:40]=2)[CH:36]=[CH:35][C:34]=1[CH2:46][N:47]1[CH2:48][CH2:49][N:50]([C:5]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:11])[CH2:51][CH2:52]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(-c2ccc(CN3CCNCC3)c(F)c2)ccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2ccc(CN3CCN(C(=O)OC(C(F)(F)F)C(F)(F)F)CC3)c(F)c2)ccn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 131.7 %

Procedure:
A 25 mL round-bottom flask was purged with and maintained under an inert atmosphere of nitrogen then charged with triphosgene (55.0 mg, 0.190 mmol, 0.35 equiv), 1,1,1,3,3,3-hexafluoropropan-2-ol (143 mg, 0.530 mmol, 1.00 equiv) and dichloromethane (3 mL). N,N-Di-isopropylethylamine (205 mg, 1.59 mmol, 3.02 equiv) was added dropwise at 0° C. The resulting solution was stirred for 2 h at 0° C. 1-[[2-Fluoro-4-(2-methylpyridin-4-yl)phenyl]methyl]piperazine (150 mg, 0.530 mmol, 1.00 equiv) in dichloromethane (2 mL) was added dropwise at 0° C. The resulting solution was stirred for 5 h at 0° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (10 mL). The resulting solution was extracted with dichloromethane (3×10 mL) and the organic layers were combined, washed with (2×10 mL) of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (300 mg) was purified by preparative HPLC using the following gradient conditions: 30% CH3CN/70% Phase A increasing to 70% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 30% CH3CN over 0.1 min, and holding at 30% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 120 mg (48% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-fluoro-4-(2-methylpyridin-4-yl)phenyl]methyl]piperazine-1-carboxylate as yellow oil. 1H NMR 400 MHz (CDCl3) δ 8.59 (d, J=5.2 Hz, 1H), 7.44-7.54 (m, 1H), 7.38-7.44 (m, 1H), 7.32-7.37 (m, 3H), 5.74-5.80 (m, 1H), 3.61-3.70 (m, 6H), 2.67 (s, 3H), 2.51-2.58 (m, 4H). LCMS (ESI, m/z): 480 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.BrC1C=C(C(NC2C(C(NC(C)C)=O)=CC([Cl:38])=CC=2C)=O)N(C2C(Cl)=CC=CN=2)N=1.BrC1C=C(C(NC2C(C(NC)=O)=CC(Cl)=CC=2C)=O)N(C2C(Cl)=CC=CN=2)N=1>>[Cl:38][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: Cc1cc(Cl)cc(C(=O)NC(C)C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Agent: CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Product: O=C(O)c1cc(Cl)nn1-c1ncccc1Cl

Procedure:
The following Example 13 illustrates an alternative preparation of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid, which can be used to prepare, for example, 3-bromo-N-[4-chloro-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide and 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide, by further steps illustrated in Examples 10 and 11.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([C:14](=[O:34])[N:15]([CH:31]2[CH2:33][CH2:32]2)[CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:20]=[C:19]([O:29][CH3:30])[CH:18]=2)[CH2:11][C@H:10]([NH2:35])[CH2:9]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.[Cl:45][C:46]1[CH:51]=[C:50](Cl)[N:49]=[CH:48][N:47]=1>CN(C=O)C>[CH:31]1([N:15]([CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:20]=[C:19]([O:29][CH3:30])[CH:18]=2)[C:14]([C@@H:12]2[CH2:11][C@H:10]([NH:35][C:50]3[CH:51]=[C:46]([Cl:45])[N:47]=[CH:48][N:49]=3)[CH2:9][NH:8][CH2:13]2)=[O:34])[CH2:32][CH2:33]1
Reactant: Clc1cc(Cl)ncn1
Reactant: COCCCOc1cc(CN(C(=O)[C@@H]2C[C@H](N)CN(C(=O)OC(C)(C)C)C2)C2CC2)cc(OC)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCCOc1cc(CN(C(=O)[C@H]2CNC[C@@H](Nc3cc(Cl)ncn3)C2)C2CC2)cc(OC)c1
Reaction time: 16 h

Procedure:
To a solution of (3S*,5R*)-3-Amino-5-{cyclopropyl-[3-methoxy-5-(3-methoxy-propoxy)-benzyl]-carbamoyl}-piperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.10 mmol) in DMF (0.5 mL) are added i-Pr2NEt (26 uL, 0.15 mmol) and 4,6-dichloropyrimidine (23 mg, 0.15 mmol). After stirring for 16 h, the reaction mixture is quenched by H2O (30 mL) and extracted with EtOAc/Et2O (c.a. 1:1, 60 mL). The organic phase is successively washed with 5% KHSO4aq, 5% NaHCO3aq, H2O, and brine, then dried over Na2SO4. The solution is filtered and the solvent is evaporated in vacuo. The residue is purified by silica gel column chromatography to give Boc protected title compound. MS: 604 (Cl35) [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.88 min. The Boc protected compound is treated with 4N HCl-1,4-dioxane to give the title compound as a white amorphous solid. MS: 504 (Cl35) [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 2.66 min.