Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@@H:10](O)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:33]1([N:36]2[C:44]3[C:39](=[N:40][CH:41]=[CH:42][CH:43]=3)[NH:38][C:37]2=[O:45])[CH2:35][CH2:34]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([N:38]2[C:39]3=[N:40][CH:41]=[CH:42][CH:43]=[C:44]3[N:36]([CH:33]3[CH2:34][CH2:35]3)[C:37]2=[O:45])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O)C1
Reactant: O=c1[nH]c2ncccc2n1C1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3cccnc32)C1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl(cis-3-hydroxycyclobutyl)carbamate (Intermediate 71) (0.502 g, 2.68 mmol), triphenylphosphine (Sigma-Aldrich, 0.932 ml, 4.02 mmol), 1-cyclopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.47 g, 2.68 mmol) in THF (10.73 ml) cooled to 0° C. was added diisopropyl azodicarboxylate (Sigma-Aldrich, 0.791 ml, 4.02 mmol) dropwise. The ice bath was removed after 1 h of stirring to allow the mixture to warm to room temperature. After an additional 3 h stirring, the reaction mixture was diluted with EtOAc and washed with saturated NaHCO3 solution. The organic layer was directly loaded onto a Biotage samplet. Purification (0-100% EtOAc/hexane) produced the title compound that solidified upon drying, which was advanced to next step directly without further purification. M+1: 345.0.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].N1C=CC=CC=1.[CH3:14][C@@H:15]([OH:19])[CH2:16][CH2:17][CH3:18].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>C1COCC1.CCCCCCC.C(OCC)(=O)C>[CH3:14][C@@H:15]([O:19][C:2](=[O:3])[O:4][CH:5]([Cl:7])[CH3:6])[CH2:16][CH2:17][CH3:18]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCC[C@@H](C)O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: c1ccncc1
Product: CCC[C@@H](C)OC(=O)OC(C)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-chloroethyl chloroformate (1.19 mL), pyridine (1.49 mL), and THF (100 mL), (R)-(−)-2-pentanol [CSA No. 31087-44-2] (1 mL) dissolved in THF (3 mL) was added at −78° C. After stirring the mixture overnight at room temperature, ethyl acetate and heptane were added to the reaction mixture. The resulting mixture was sequentially washed with 0.5 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, water, and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure to obtain the captioned compound (1.8 g) as a crude product.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].[NH2:19][C@@:20]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][C:24](=[CH2:26])[C@@H:23]2[C@H:21]1[C@H:22]2[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[CH:17]1[C:18]2[CH:6]([CH2:5][O:4][C:2]([NH:19][C@@:20]3([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][C:24](=[CH2:26])[C@@H:23]4[C@H:21]3[C@H:22]4[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:3])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: C=C1C[C@@](N)(C(=O)OCC)[C@H]2[C@@H]1[C@@H]2C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1C[C@@](NC(=O)OCC2c3ccccc3-c3ccccc32)(C(=O)OCC)[C@H]2[C@@H]1[C@@H]2C(=O)OCC
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Add solid 9-fluorenylmethyl chloroformate (3.15 g, 12.2 mmol) portion wise over 5 minutes to a stirred solution of diethyl (1S,2S,5R,6S)-2-amino-4-methylene-bicyclo[3.1.0]hexane-2,6-dicarboxylate (2.8 g, 11.1 mmol) and sodium bicarbonate (2.04 g, 24.3 mmol) in tetrahydrofuran (28 mL) and water (8.4 mL) cooled to 0-5° C. After 1 hour, add water (10 mL) and extract with ethyl acetate (50 mL). Wash the extract with brine solution (20 mL), dry, filter and evaporate to a pale yellow oil (6.5 g). Purify by flash chromatography eluting with ethyl acetate:iso-hexane (10:90 to 20:80) to give a viscous colorless oil (4.58 g). Repurify by flash chromatography eluting with ethyl acetate:iso-hexane (20:80) to give a white semi-solid foam of title compound (4.22 g, 80%). MS (m/z): 476 (M+1).
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][C:11]2[CH:10]=[C:9]([C:14]3[N:18]=[C:17]([C:19]4[O:23][N:22]=[C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C:20]=4[C:30]([F:33])([F:32])[F:31])[O:16][N:15]=3)[CH:8]=[CH:7][C:6]=2[CH:5]1[O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])=[N+]=[N-].C(OCC)(=O)C.C(Cl)Cl.O.O.[Sn](Cl)Cl>CO>[Si:35]([O:34][CH:5]1[C:6]2[C:11](=[CH:10][C:9]([C:14]3[N:18]=[C:17]([C:19]4[O:23][N:22]=[C:21]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:20]=4[C:30]([F:31])([F:32])[F:33])[O:16][N:15]=3)=[CH:8][CH:7]=2)[CH2:12][CH2:13][CH:4]1[NH2:1])([C:38]([CH3:40])([CH3:41])[CH3:39])([CH3:36])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)OC1c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2CCC1N=[N+]=[N-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2CCC1N
Reaction time: 8 h
Yield: 96.5 %

Procedure:
Racemic 3-(6-azido-5-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-2-yl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole (500 mg, 0.86 mmol) was dissolved in MeOH (2131 μL), ethyl acetate (2131 μL), and CH2Cl2 (2131 μL). To this solution was added tin(II) chloride dihydrate (1.94 mg, 8.6 mmol) and the reaction mixture was stirred overnight. The solvent was evaporated and the residue was redissolved in CH2Cl2 and washed with 1N NaOH and brine. The organic phase was dried over MgSO4 and concentrated to afford racemic (1S*,2R*)-1-(tert-butyldimethylsilyloxy)-6-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-2-amine (46.2 mg, 0.83 mmol, 96.5%) as a pale yellow oil: LCMS=557.44 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=4)[CH:35]=[O:36])[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([CH2:35][OH:36])[CH:37]=[CH:38][CH:39]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCC[C@@H](Nc2nccc(-c3c(-c4cccc(CO)c4)nc4sccn34)n2)C1
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a mixture 3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo [2,1-b][1,3]thiazol-6-yl}benzaldehyde (0.20 g, 0.346 mmol) in anhydrous tetrahydrofuran (THF) (5.0 mL) at room temperature was added a solution of lithium aluminum hydride (LAH) (2.0 M in THF) (0.346 mL, 0.692 mmol). The mixture was stirred for one hour, then quenched with methanol (1.0 mL), diluted with dichloromethane (50 mL) and 30 mL of water. Organic layer was separated and the water layer was extracted with dichloromethane (50 mL×2). Organic layer was combined, dried over sodium sulfate and concentrated. Product was purified by flash chromatography on silica gel (methanol:dichloromethane:ethylacetate=0.5:7:2) to afford 0.142 g (71%) of the title compound as an off-white solid. M.p.=150-155° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.75 (bs, 1H), 8.12 (d, J=5.6 Hz, 1H), 7.77-7.74 (m, 2H), 7.67-7.65 (m, 2H), 7.56 (s, 1H), 7.44-7.36 (m, 4H), 7.11 (d, J=7.2 Hz, 1H), 6.39 (d, J=5.6 Hz, 1H), 5.07 (t, J=5.6 Hz, 1H), 4.55 (d, J=6.0 Hz, 2H), 3.29 (br. s, 1H), 3.73 (d, J=7.2 Hz, 1H), 3.48 (d, J=11.2 Hz, 1H), 2.5-2.43 (m, 1H), 2.35 (t, J=10.0 Hz, 1H), 1.91-1.82 (m, 2H), 1.60-1.57 (m, 1H), 1.40-1.32 (m, 1H). LCMS: 581 [M+H].
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])=[O:2].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[CH:1]([C:3]1[CH:4]=[C:5]([N+:13]([O-:15])=[O:14])[C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])=[O:2]
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=Cc1cc(C(=O)O)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
A solution of 5-formyl-2-hydroxybenzoic acid (2 g, 12.04 mmol) in concentrated sulfuric acid (5 mL) was added a mixture of concentrated nitric acid (1 mL) and concentrated sulfuric acid (1 mL) at 0° C. The resulting suspension was stirred at 0° C. for 3 h, and poured into ice water (30 mL). The solid was collected by filtration, washed with water (30 mL), and dried in vacuo to give Intermediate 55 (2.2 g, yield 86.6%).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][OH:21])=[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[C:23]([O:25][CH2:26][Cl:27])=[O:24]>C(Cl)Cl.N1C=CC=CC=1>[C:23](=[O:24])([O:25][CH2:26][Cl:27])[O:21][CH2:20][CH2:19][O:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(Cl)OCCl
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCOC(=O)OCCl
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
To a mixture of 2-(N-CBz-L-valyloxy)-ethanol (12. 0 g, 40.6 mmol) and pyridine (19.7 mL, 0.24 mmol) in CH2Cl2 (300 mL) at 0° C., was added dropwise chloromethyl chloroformate (10.5 g, 81.2 mmol). After 30 min at 0° C., the reaction mixture was washed with H2O (200 mL). The H2O phase was washed with CH2Cl2 (100 mL) and the solvent of the combined organic phases was removed under reduced pressure. The crude product was column chromatographed (silica gel, 0.5→1% MeOH in CH2Cl2), to give 8.26 g 2-(N-CBz-L-valyloxy)-ethyl chloromethyl carbonate.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[I:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>CC(N(C)C)=O.[Zn].C1CC=CCCC=C1.C1CC=CCCC=C1.[Ni].IC1C=CC(CCCCCCCCCCCCCCCCCCO)=CC=1>[I:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:26][CH:25]=1
Reactant: ClCc1ccc(I)cc1
Reactant: CCOC(=O)CCCCCCCCCCCCCCCCI
Agent: [Ni]
Agent: C1=C\CC/C=C\CC/1
Agent: OCCCCCCCCCCCCCCCCCCc1ccc(I)cc1
Solvent: C1=CCCC=CCC1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCCCCCCCCCCCCCCCCc1ccc(I)cc1
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
Zinc powder (70 mg, 1.06 mmol) was dried at 70° C. for 30 min in a sealed tube, then DMA (0.4 ml) and solid 12 (9 mg, 0.04 mmol) were added. After stirring for 10 min, a solution of ethyl 17-iodo-heptadecanoate 80 (300 mg, 0.71 mmol) in DMA (1.5 ml) was added and the reaction mixture was stirred in the sealed tube for 11 h at 70° C. In a 10-ml flask, Ni(COD)2 (10 mg, 0.04 mmol), (R)-(s-Bu)-Pybox (or (S)-(s-Bu)-Pybox) (23 mg, 0.07 mmol) and p-iodobenzyl chloride 82 (252 mg, 1 mmol) were dissolved in DMA (1.5 ml), then organozinc solution 81 was added via cannula. The mixture was stirred at room temperature for 15 h, and the reaction was quenched by addition of aqueous NH4Cl, extracted with EtOAc, the extract was dried over Na2SO4 and evaporated. Chromatography of the crude product in hexane-ether (97:3) yielded the compound 37 (276 mg, 76%).
Reaction SMILES: [CH:1]1([C:4]2[N:8](C(OC(C)(C)C)=O)[N:7]=[C:6]([NH:16][C:17]3[C:22](I)=[CH:21][N:20]=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH3:30][O:31][CH2:32]/[CH:33]=[CH:34]/B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:16][C:17]3[C:22](/[CH:34]=[CH:33]/[CH2:32][O:31][CH3:30])=[CH:21][N:20]=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]=3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)n1nc(Nc2nc(-c3ccccc3)ncc2I)cc1C1CC1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC/C=C/c1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 4.6 %

Procedure:
A mixture of tert-butyl 5-cyclopropyl-3-(5-iodo-2-phenylpyrimidin-4-ylamino)-1H-pyrazole-1-carboxylate (318 mg, 0.63 mmol, 1.0 equiv.), (E)-2-(3-methoxyprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg, 2.53 mmol, 4.0 equiv.), PdCl2(dppf2)′CH2Cl2 (155 mg, 0.19 mmol, 0.3 equiv.) and K2CO3 (348 mg, 2.53 mmol, 4.0 equiv.) in dry DMF (40 mL) was heated to 90° C. under a nitrogen atmosphere and stirred for 2 hours. Then, the reaction mixture was cooled down to room temperature and concentrated in vacuum. The residue was purified by Prep-HPLC to give the title compound (E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-(3-methoxyprop-1-enyl)-2-phenylpyrimidin-4-amine (Compound 39) (10 mg, 2%). LCMS: 348.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 0.72-0.78 (m, 2H), 0.96-0.98 (m, 2H), 1.94-2.02 (m, 1H), 3.30 (s, 3H), 4.06 (d, J=5.2 Hz, 2H), 6.33 (m, 1H), 6.46 (s, 1H), 7.02 (d, J=15.6 Hz, 1H), 7.48 (m, 3H), 8.29 (d, J=4.4 Hz, 2H), 8.53 (s, 1H), 9.26 (s, 1H), 12.15 (s, 1H).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.NC1C=CN=C(N2CCN(C3C=CC(NS(C)(=O)=O)=CC=3)CC2)C=1.Cl[C:44]1[CH:45]=[N+:46]([O-:53])[CH:47]=[CH:48][C:49]=1[N+:50]([O-:52])=[O:51].C(=O)(O)[O-].[Na+]>C(O)CCC>[N+:50]([C:49]1[CH:48]=[CH:47][N+:46]([O-:53])=[CH:45][C:44]=1[N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:3][CH2:4]1)([O-:52])=[O:51]
Reactant: CS(=O)(=O)Nc1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Cl
Agent: CS(=O)(=O)Nc1ccc(N2CCN(c3cc(N)ccn3)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCCCO
Product: CS(=O)(=O)Nc1ccc(N2CCN(c3c[n+]([O-])ccc3[N+](=O)[O-])CC2)cc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of N-[(4-piperazin-1-yl)phenyl]methanesulphonamide hydrochloride (the product of Example 11, (iii) (0.59 g), 3-chloro-4-nitropyridine-N-oxide (0.35 g) and sodium bicarbonate (0.50 g) in n-butanol (25 ml) was heated at 100° C. with stirring for 1.5 hours and then evaporated. The residue was stirred with water, filtered, and the solid was crystallised from methanol to give the title compound (0.55 g), m.p. 206°-208° C. Found: C,48.77; H,4.91; N,17.52. C16H19N5O5S requires: C,48.84; H,4.87; N,17.80%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C@@H:9]1[CH2:14][N:13]([S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:17])=[O:16])[CH2:12][CH2:11][N:10]1[C:23]1[CH:28]=[CH:27][C:26]([C@@:29]([OH:35])([CH3:34])[C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1.ClC1C=CC(Cl)=CC=1[C@H]1CN(S(C2SC=CC=2)(=O)=O)CCN1C1C=CC([C@](O)(C)C(F)(F)F)=CC=1.ClC1C=CC(Cl)=CC=1[C@@H]1CN(S(C2SC=CC=2)(=O)=O)CCN1C1C=CC([C@](O)(C)C(F)(F)F)=CC=1.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C@H:9]1[CH2:14][N:13]([S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:17])[CH2:12][CH2:11][N:10]1[C:23]1[CH:28]=[CH:27][C:26]([C@@:29]([OH:35])([CH3:34])[C:30]([F:32])([F:31])[F:33])=[CH:25][CH:24]=1
Reactant: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2c2cc(Cl)ccc2Cl)cc1)C(F)(F)F
Agent: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2c2cc(Cl)ccc2Cl)cc1)C(F)(F)F
Agent: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2c2cc(Cl)ccc2Cl)cc1)C(F)(F)F
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2c2cc(Cl)ccc2Cl)cc1)C(F)(F)F

Procedure:
(2S)-2-(4-((2R)-2-(2,5-dichlorophenyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(4-((2S)-2-(2,5-dichlorophenyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol; (2R)-2-(4-((2R)-2-(2,5-dichlorophenyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol. 1H NMR (300 MHz, CDCl3) δ 7.63 (d, J=5.0 Hz, 1H), 7.55 (dd, J=3.65, 1.0 Hz, 1H), 7.36 (d, J=8.5 Hz, 2H), 7.29 (d, J=1.8 Hz, 1H), 7.24 (s, 1H), 7.14 (dd, J=4.9, 3.9 Hz, 1H), 7.08 (dd, J=8.5, 2.5 Hz, 1H), 6.85 (d, J=8 62 Hz, 2H), 4.84 (dd, J=9.0, 3.4 Hz, 1H), 3.73-3.90 (m, 2H), 3.60 (d, J=12.3 Hz, 1H), 3.19-3.31 (m, 1H), 3.00-3.11 (m, 1H), 2.59-2.71 (m, 1H), 1.68 (d, J=3.5 Hz, 3H). m/z (ESI, +ve ion) 586.8 (M+Na)+. GK-GKRP EC50 (NADPH-coupled)=2.64 μM; GK-GKRP EC50 (LC MS/MS)=1.96 μM.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]([CH3:52])[CH2:46][C@H:47]1[CH2:51][CH2:50][CH2:49][O:48]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]([CH3:52])[CH2:46][C@H:47]2[CH2:51][CH2:50][CH2:49][O:48]2)=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CN(C[C@H]1CCCO1)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)C[C@H]2CCCO2)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 40.2 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N-[(R)-tetrahydrofuran-2-ylmethyl]acetamide (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.5 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[C:17]([C:21]([OH:23])=[O:22])([F:20])([F:19])[F:18]>C(Cl)Cl>[F:18][C:17]([F:20])([F:19])[C:21]([OH:23])=[O:22].[F:1][C:2]([F:16])([F:15])[CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(F)(F)F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)C1CCNC1

Procedure:
tert-Butyl 3-(trifluoromethyl)pyrrolidine-1-carboxylate (100 mg, 0.42 mmol) was treated with 20% CF3CO2H in CH2Cl2 at room temperature overnight. The volatiles were removed in vacuo to give the subtitled compound (106 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([OH:16])=[CH:13][CH:14]=2)[C@@H:9]([NH:17][C:18]2[N:23]=[C:22]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[C:21]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:20][N:19]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].COC(=O)[C:56](Cl)([F:58])[F:57].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH:56]([F:58])[F:57])=[CH:13][CH:14]=2)[C@@H:9]([NH:17][C:18]2[N:23]=[C:22]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:26]=3)[C:21]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)=[CH:20][N:19]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2]
Reactant: COC(=O)C(F)(F)Cl
Reactant: CCOC(=O)N1c2ccc(O)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1c2ccc(OC(F)F)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 75 °C
Reaction time: 17 h
Yield: 93.8 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-hydroxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (100 mg), cesium carbonate (55 mg) and 2-chloro-2,2-difluoroacetic acid methyl ester (44 mg) are dissolved in N,N-dimethylformamide (1 ml) and stirred at 75° C. for 17 hours. The reaction solution is cooled to room temperature, and thereto are added an aqueous citric acid solution and ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=9:1→4:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-6-difluoromethoxy-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (101 mg). MS (m/z): 705 [M+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[O:26]([C:28]1[N:29]=[N:30][C:31]([O:37][CH3:38])=[CH:32][C:33]=1B(O)O)[CH3:27].C([O-])([O-])=O.[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:27][O:26][C:28]1[N:29]=[N:30][C:31]([O:37][CH3:38])=[CH:32][C:33]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: COc1cc(B(O)O)c(OC)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(OC)nn1
Temperature: 90 °C

Procedure:
A solution of N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) (200 mg, 0.468 mmol), 3,6-dimethoxylpyridazine-4-boronic acid (129 mg, 0.702 mmol, CAS RN 1015480-87-1) and K2CO3 (194 mg, 1.404 mmol) in DMF (6 mL) in a sealed tube was degassed with argon for 30 minutes. To this mixture were added S-PHOS (96 mg, 0.234 mmol, CAS RN 657408-07-6) and Pd(PPh3)4 (44 mg, 0.046 mmol), degassed for another 15 minutes, and heated to 90° C. for 1 h in microwave. Work up and purification as described in example 25 yielded 15 mg of the title compound. Off-white solid (7%). MS (ESI): m/z=487.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:18])[C:14]=2[C:15]([OH:17])=O)=[CH:5][CH:4]=1)[CH3:2].FC1C=CC(NC2C=NN(C)C=2C(O)=O)=CC=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:9][C:10]3[CH:11]=[N:12][N:13]([CH3:18])[C:14]=3[C:15](=[O:17])[C:7]=2[CH:8]=1)[CH3:2]
Reactant: CCc1ccc(Nc2cnn(C)c2C(=O)O)cc1
Agent: Cn1ncc(Nc2ccc(F)cc2)c1C(=O)O
Product: CCc1ccc2[nH]c3cnn(C)c3c(=O)c2c1

Procedure:
The title compound was prepared according to the procedure of step 2 in EXAMPLE 1 using 4-[(4-ethylphenyl)amino]-1-methyl-1H-pyrazole-5-carboxylic acid (EXAMPLE 6, step 1), instead of 4-[(4-fluorophenyl)amino]-1-methyl-1H-pyrazole-5-carboxylic acid.