Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:14](=[O:29])[N:15]([CH:26]([CH3:28])[CH3:27])[C:16]1[CH:25]=[CH:24][C:19]2[N:20]=[C:21]([SH:23])[S:22][C:18]=2[CH:17]=1)=[CH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)#[N:2].[CH2:30]([NH2:34])[CH:31]([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:30]([NH:34][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[C:3]([C:1]#[N:2])[C:14](=[O:29])[N:15]([CH:26]([CH3:27])[CH3:28])[C:16]2[CH:25]=[CH:24][C:19]3[N:20]=[C:21]([SH:23])[S:22][C:18]=3[CH:17]=2)=[CH:13][CH:12]=1)[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)CN
Reactant: CC(C)N(C(=O)C(C#N)=Cc1ccc(C(=O)O)cc1)c1ccc2nc(S)sc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)CNC(=O)c1ccc(C=C(C#N)C(=O)N(c2ccc3nc(S)sc3c2)C(C)C)cc1
Reaction time: 2 h

Procedure:
Combined 4-{2-Cyano-2-[isopropyl-(2-mercapto-benzothiazol-6-yl)-carbamoyl]-vinyl}benzoic acid (50 mg, 0.118 mmol), isobutylamine (13 μl, 0.130 mmol), HATU (58 mg, 0.153 mmol), and N,N-diisopropylethylamine (27 μl, 0.153 mmol) in anhydrous THF (1.1 ml). The mixture was stirred 2 hours, filtered through celite and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1 M aqueous citric acid. The organic extract was dried over magnesium sulfate and purified by preparative TLC (10% methanol, 90% dichloromethane) to yield 28 mg (50%). 1H NMR (CDCl3) δ0.93 (d, 6H), 1.18 (d, 6H), 1.86 (m, 1H), 3.25 (t, 1H), 4.95 (m, 1H), 6.39 (t, 1H), 7.13 (dd, 1H), 7.24 (m, 3H), 7.72 (app q, 4H), 7.91 (s, 1H); ESIMS: m/z 477 (M-H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@@H:3]([NH:2][C:31]([C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:21])=[CH:30][CH:29]=3)=[O:32])[C:4]([N:6]2[CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]2)=[O:5])=[CH:19][CH:18]=1
Reactant: N[C@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Product: O=C(N[C@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
(R)-2-Amino-3-(4-fluoro-phenyl)-1-(4-hydroxy-piperidin-1-yl)-propan-1-one hydrochloride (0.6 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.6 mmol) were coupled according to Procedure A and the crude product purified by chromatography on silica gel eluted with 50, 75 and 100% ethyl acetate in hexanes. Yield 171 mg, 765%; HPLC (60/40) 4.23 minutes (97%); MS 444/446 (MH+, 100%); TSPMS 444/446 (MH+, 100%);
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([S:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1.[CH3:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][C:4]2[N:3]=[C:2]([N:22]3[C:21]([CH3:20])=[CH:25][C:24]([CH3:26])=[N:23]3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH3:11])=[CH:14][CH:15]=1
Reactant: Cn1cnc2c(Sc3ccc(Cl)cc3)nc(Cl)nc21
Reactant: Cc1cc(C)[nH]n1
Product: Cc1cc(C)n(-c2nc(Sc3ccc(Cl)cc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 6 from 2-chloro-6-(4-chloro-phenyl-sulfanyl)-9-methyl-9H-purine and 3,5-dimethylpyrazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1Cl.[F:9][C:10]([F:15])([F:14])[C@@H:11]([OH:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:13][C@@H:11]([CH3:12])[C:10]([F:15])([F:14])[F:9]
Reactant: C[C@H](O)C(F)(F)F
Reactant: Clc1ccncc1Br
Product: C[C@H](Oc1ccncc1Br)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 78a, using 3-bromo-4-chloropyridine (CAN 36953-42-1) and (S)-1,1,1-trifluoropropan-2-ol (CAN 3539-97-7) as starting materials and isolated (28 g, 82%) as a yellow oil; MS (ESI, m/z): 270.4 (M+H+).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35]([N:39]=[C:40]=[O:41])[CH:36]=[CH:37][CH:38]=1>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([F:31])([F:42])[F:43])[CH:34]=4)=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 40.0 mg (0.21 mmol) of 3-trifluoromethylphenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 51 mg (89% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.Cl.CN.[CH:31]([N:34](C(C)C)CC)(C)C.CCCP(=O)=O>O1CCCC1>[CH3:31][NH:34][C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:26]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), methanamine hydrochloride (186 mg, 2.76 mmol), diisopropylethylamine (627 μl, 3.59 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7.00 ml) is stirred for 4 hours at 70° C. and then over the weekend at 25° C. under nitrogen atmosphere. The solvent is evaporated and to the residue is added sat. aqueous sodium hydrogencarbonate solution. The mixture is stirred for 20 minutes while a white solid precipitates. The solid is collected by filtration, washed with diethylether and dried affording N4,1-dimethyl-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (69 mg, 66.6%) as a white solid. mp.: >250° C. MS: m/z=376.2 (M+H+).
Reaction SMILES: [OH-].[Li+].[C:3]1([C:9]2[N:10]=[C:11]([N:14]3[CH2:18][CH2:17][CH:16]([C:19]([O:21]C)=[O:20])[CH2:15]3)[S:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1.O>[C:3]1([C:9]2[N:10]=[C:11]([N:14]3[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=[O:20])[CH2:15]3)[S:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C1CCN(c2nc(-c3ccccc3)cs2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCN(c2nc(-c3ccccc3)cs2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
Lithium hydroxide (10 mg, 0.39 mmol) was added to a solution of methyl 1-(4-phenylthiazol-2-yl)pyrrolidine-3-carboxylate (75 mg, 0.26 mmol) in THF-H2O (3 mL, 7:3 v/v) at 0° C. The reaction mixture was allowed to warm up to room temperature, stirred for 1 h, concentrated under reduced pressure, and then diluted with water. The aqueous layer was washed with EtOAc. The pH of the aqueous layer was adjusted to ˜3 using 1.5N HCl and the organic product was extracted with EtOAc. The combined extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 1-(4-phenylthiazol-2-yl)pyrrolidine-3-carboxylic acid (40 mg, yield 56%) as off-white solid, which was carried through without further purification. MS (ESI) m/z: Calculated for C14H14N2O2S: 274.08. found: 275.0 (M+H)+
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=2[N:3]=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:25])[C:18]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:25])[C:18]=1[N:19]1[CH2:24][CH2:23][N:22]([C:2]2[NH:6][C:5]3[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=3[N:3]=2)[CH2:21][CH2:20]1
Reactant: Cc1ccc2nc(Cl)[nH]c2c1
Reactant: Clc1cncc(Cl)c1N1CCNCC1
Product: Cc1ccc2nc(N3CCN(c4c(Cl)cncc4Cl)CC3)[nH]c2c1

Procedure:
The benzoimidazole from step (b) above (0.287 g, 1.73 mmol) and 1-(3,5-dichloropyridin-4-yl)piperazine (0.4 g, 1.73 mmol, Maybridge) reacted under the conditions of Example 1d to give the title compound as a white solid. M.p. 251-254° C. MS (ESI, pos. ion) m/z: 362 (M+1).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br.Br[CH2:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:42][C:43]4[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=4)[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1cccnc1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4cccnc4)c4ccc(OC(F)F)cc34)nc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
In a 25 ml round-bottomed flask, 2-(5-difluoromethoxy-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (120 mg, 0.23 mmol) was dissolved in DMF (1.7 ml). The light yellow solution was cooled to 0° C. and sodium hydride (60% in mineral oil, 37 mg, 0.93 mmol) was added. The reaction was stirred at 0° C. for 15 min then 3-(bromomethyl)pyridine hydrobromide (91 mg, 0.36 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h then quenched with water and diluted with petroleum ether. The suspension was filtered, washed with water and petroleum ether and the product collected was dried under high vacuum to afford 126 mg (90%) of 2-(5-difluoromethoxy-1-pyridin-3-ylmethyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide as a yellow powder.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH:5]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][P:7]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:8])C>[OH-].[Na+]>[CH2:15]([CH:5]([CH2:6][P:7]([O:9][CH2:10][CH3:11])([O:12][CH2:13][CH3:14])=[O:8])[C:4]([OH:22])=[O:3])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(Cc1ccccc1)CP(=O)(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOP(=O)(CC(Cc1ccccc1)C(=O)O)OCC

Procedure:
The ester from stage (a) (3.28 g) was saponified at pH 11.3 (pH stat) for 4 hr with 1 N. NaOH (10 ml). The reaction mixture was extracted with ether (30 ml), the aqueous phase acidified to pH 2.0 with cHCl and extracted with ethyl acetate (3×30 ml). The combined extracts were dried (MgSO4) and evaporated in vacuo to a viscous oil (2.7 g). The structure was confirmed by NMR.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][OH:6])[CH2:3][CH2:2]1.ClCCl.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>C(OCC)(=O)C.O>[CH3:10][S:11]([O:6][CH2:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)(=[O:13])=[O:12]
Reactant: OCCC1CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)OCCC1CC1
Yield: 101 %

Procedure:
To a mixture of 2-cyclopropylethanol (5.35 g, 62.1 mmol) and dichloromethane (107 mL) were added methanesulfonyl chloride (5.29 mL, 68.3 mmol) and triethylamine (13.1 mL, 93.1 mmol) in that order while stirring on ice, and the resulting mixture was stirred for 1 hour. Water and ethyl acetate were then added to the reaction mixture. After thoroughly shaking the mixture, the organic layer was separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was then filtered, and the solvent in the filtrate was distilled off under reduced pressure to obtain the title compound (10.3 g, 62.7 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C@H:8]([CH2:28][C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=1[F:37])[CH2:9][C:10](=O)[NH:11][NH:12][C:13]1[C:18]2[N:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[N:21]=[CH:22][C:17]=2[CH2:16][CH2:15][N:14]=1)([CH3:4])([CH3:3])[CH3:2]>COCCO>[C:1]([O:5][C:6](=[O:38])[NH:7][C@H:8]([CH2:28][C:29]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=1[F:37])[CH2:9][C:10]1[N:14]2[CH2:15][CH2:16][C:17]3[C:18](=[N:19][C:20]([C:23]([F:24])([F:26])[F:25])=[N:21][CH:22]=3)[C:13]2=[N:12][N:11]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NNC1=NCCc2cnc(C(F)(F)F)nc21)Cc1cc(F)c(F)cc1F
Solvent: COCCO
Product: CC(C)(C)OC(=O)N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2n1CCc1cnc(C(F)(F)F)nc1-2

Procedure:
A mixture of 63 mg (0.115 mmol) of tert-butyl((1R)-3-oxo-1-(2,4,5-trifluorobenzyl)-3-{2-[2-(trifluoromethyl)-5,6-dihydropyrido[3,4-d]pyrimidin-8-yl]hydrazino}propyl)carbamate and 2 mL of 2-methoxyethanol was stirred at reflux for 5.5 h and then concentrated. Purification of the residue by preparative HPLC (C18 reverse phase column, 30-80% acetonitrile in water containing 0.05% trifluoroacetic acid) afforded the title compound as a white solid. LC-MS 529 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Cl)=[N:11][C:12]2[C:17]([C:18]=1[Cl:19])=[CH:16][C:15]([C:20]([C:32]1[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=1)([C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1)[OH:21])=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][O-:40].[Na+]>CO>[CH2:1]([O:8][C:9]1[C:10]([O:40][CH3:39])=[N:11][C:12]2[C:17]([C:18]=1[Cl:19])=[CH:16][C:15]([C:20]([C:32]1[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=1)([C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)[OH:21])=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(OCc3ccccc3)c(Cl)c2c1
Agent: [Na+]
Solvent: CO
Product: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1OCc1ccccc1
Temperature: 65 °C

Procedure:
To a mixture of (3-(benzyloxy)-2,4-dichloroquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (2.46 g, 4.4 mmol, Intermediate 11: step d) in methanol (24.6 mL) was added NaOMe (0.5 M in MeOH, 8.8 mL, 4.4 mmol) and the resulting suspension heated to 65° C. for 8 hours. The mixture was then cooled to room temperature and concentrated to dryness. Water was added and the mixture acidified with 2 N aqueous HCl to ˜pH 2. The aqueous was then extracted with EtOAc. The organics were combined and washed with water, saturated aqueous NaHCO3 and brine. The organics were then dried (MgSO4), filtered and concentrated to dryness to afford the title compound which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[F:25][C:4]1[CH:3]=[C:2]([N:29]2[CH2:30][CH2:31][N:27]([CH3:26])[C:28]2=[O:32])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1C
Reactant: CN1CCNC1=O
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3F)CC2)nc1C
Yield: 8 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (203 mg) described in Preparation Example 128 and 1-methylimidazolidin-2-one (60 mg) and by the reaction and treatment in the same manner as in Example 511, the title compound (17 mg) was obtained.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>N1C=CC=CC=1>[C:1]1([S:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:22](=[O:23])[O:24][CH2:25][CH3:26])=[CH:11][C:10]=2[O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cl
Reactant: CCCCOc1cc(N)ccc1S(=O)c1ccccc1
Solvent: c1ccncc1
Product: CCCCOc1cc(NC(=O)OCC)ccc1S(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
4-(Phenylsulfinyl)-3-butoxybenzenamine (0.1 mole) and pyridine (50 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and are cooled to about 5° C. Ethyl chloroformate (0.125 mole) is added, with stirring, at about 5° C. Stirring is continued for a period of about 30 minutes at about 5° C., then for an additional 16 hours at room temperature. The mixture is then washed with 2 portions of water (50 ml), dried and the solvent is then removed to yield the desired product ethyl [4-(phenylsulfinyl)-3-butoxyphenyl]carbamate.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[CH:7]([CH2:8][C@@H:9]([O:33][C:34](=[O:36])[CH3:35])[C@@H:10]3[C@@H:26]2[CH2:25][C@H:24]([OH:31])[C@@:23]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2].Cl[O-].[Na+]>>[C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[CH:7]([CH2:8][C@@H:9]([O:33][C:34](=[O:36])[CH3:35])[C@@H:10]3[C@@H:26]2[CH2:25][C:24](=[O:31])[C@@:23]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](OC(C)=O)CC4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: [Na+]
Agent: [O-]Cl
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](OC(C)=O)CC4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3CC(=O)[C@]12C

Procedure:
wherein the oxidation reaction of the methyl 3α,7α-diacetoxy-12α-hydroxycholanate intermediate on the hydroxyl group in position 12, takes place by means of the sodium hypochlorite, to give the methyl 3α,7α-diacetoxy-12-ketocholanate intermediate.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C@H:3]([OH:16])[CH2:4][N:5]([CH3:15])[C:6](=[O:14])[O:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11].N1C=CC=CC=1.[Si:30](Cl)([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[NH2:1][C@@H:2]([CH2:17][CH:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)[C@H:3]([O:16][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH2:4][N:5]([CH3:15])[C:6](=[O:14])[O:7][CH2:8][CH2:9][Si:10]([CH3:12])([CH3:13])[CH3:11]
Reactant: C[Si](C)(C)Cl
Reactant: CN(C[C@@H](O)[C@@H](N)CC1CCOCC1)C(=O)OCC[Si](C)(C)C
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CN(C[C@@H](O[Si](C)(C)C)[C@@H](N)CC1CCOCC1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
A 100 mL flask was charged with 2-(trimethylsilyl)ethyl (2R,3S)-3-amino-2-hydroxy-4-(tetrahydro-2H-pyran-4-yl)butyl(methyl)carbamate (100 mg, 0.29 mmol) dissolved in THF (10 mL), pyridine (68 mg, 0.87 mmol) was added at 0° C. Me3SiCl (94 mg, 0.87 mmol) was added and the mixture was stirred for 2 h at rt. The mixture was quenched with 1% aq HCl and extracted with EtOAc (3×15 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography to give 2-(trimethylsilyl)ethyl (2R,3S)-3-amino-4-(tetrahydro-2H-pyran-4-yl)-2-(trimethylsilyloxy)butyl(methyl)carbamate (110 mg, 92%)
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:4][CH2:3]1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[F:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]([C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)Cl)=[CH:39][CH:38]=1.[I-].[K+]>O1C=CCCC1>[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH:43]([C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=2)[N:2]2[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:4][CH2:3]2)=[CH:41][CH:42]=1
Reactant: OCCCCC1CCNCC1
Reactant: Fc1ccc(C(Cl)c2ccc(F)cc2)cc1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Product: OCCCCC1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
20 g (103 mmol) 4-piperidin-4-yl-butan-1-ol hydrochloride are suspended in 70 ml 3,4-dihydro-2H-pyrane and added to 1.0 g pyridinium tosylate. The mixture is stirred for two days at RT. After addition of 5 g potassium carbonate, this is concentrated under vacuum to dryness. The resulting 4-[4-tetrahydropyran-2-yloxy)-butyl)-piperidine is dissolved without further purification in 100 ml acetonitrile and added to 25.1 g (105 mmol) bis-(4-fluorophenyl)-chloromethane, 30 g (217 mmol) potassium carbonate and 5.0 g (30 mmol) potassium iodide and stirred for four days at RT. The mixture is filtered and the solvent is removed under vacuum. The resulting 1-[bis-(4-fluorophenyl)-methyl]-4-[4-(tetrahydropyran-2-yloxy)-butyl]-piperldine is dissolved without further purification in 150 ml methanol, added to enough 6 M methanolic hydrochloric acid until the pH of the mixture is acidic and left to stand for two days at RT. Subsequently, the solvent is drawn off under vacuum and the residue is dispersed between sodium hydroxide solution and acetic acid ethyl ester. The aqueous solution is extracted three times with acetic acid. The combined organic phases are dried over sodium sulfate and the residue is chromatographically purified over silica gel with CH2Cl2/CH3OH(99/1 to 94/4). Yield: 23.8 g (63%).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[N:32]=1>CN(C)C=O>[F:37][C:33]1[N:32]=[C:31]([CH2:30][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:15]3[CH:14]=[C:13]([C:12]4[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=4)[O:17][N:16]=3)=[CH:20][CH:21]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Fc1cccc(CCl)n1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4cccc(F)n4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 14.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (40 mg, 0.14 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (28.3 μL, 0.14 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. To a suspension of this solid in N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of 2-chloromethyl-6-fluoro-pyridine (52.7 mg, 0.36 mmol) described in manufacturing Example 45-1-1, which was stirred for 14 hours at room temperature. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:2), and then further purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (7.8 mg, 11%) as a trifluoroacetic acid salt.