Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]=2[C:4]=1[OH:18])=[O:2].[OH-].[K+].S(OC)(O[CH3:25])(=O)=O.Cl>C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:9]([CH3:14])([CH3:15])[CH2:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]=2[C:4]=1[O:18][CH3:25])=[O:2]
Reactant: Cc1cc(C=O)c(O)c2c1C(C)(C)CCC2(C)C
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1c(C=O)cc(C)c2c1C(C)(C)CCC2(C)C
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 81.3 %

Procedure:
Methylation. 2-Formyl-1-hydroxy-4,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (42 g, 0.17 mol) was stirred with toluene (656 mL), and potassium hydroxide 85% (16.8 g, 0.255 mol) was added in one portion. The mixture was heated to 40° C., dimethyl sulfate (32.13 g, 0.255 mol) added at 40°-45° C. during 0.5 h, and the heating continued at 50° C. for an additional 1.5 h. The mixture was cooled to 20° C., neutralized with 5% HCl solution, then washed with water (20 mL), and finally washed with brine (25 mL). The solvent was removed by distillation and the residue distilled to give 2-formyl-1-methoxy-4,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (36 g), bp 140°-142° C./1.5 mm, GLC purity 95%. Crystallization from hexane gave 28 g material, GLC purity 99%. 1H-NMR (CDCl3) δ10.23 (2H, s), 7.41 (1H, s), 3.89 (3H, s), 2.52 (3H, s), 1.63 (4H, s), 1.42 (6H, s), 1.40 (6H, s). 13C-NMR (CDCl3) δ189.9 (1C, d), 162.3 (1C, s), 153.1 (1C, s), 139.9 (1C, s), 132.7 (1C, s), 131.3 (1C, d), 126.5 (1C, s), 66.0 (1C, q), 39.4 (1C, t), 38.2 (1C, t), 36.4 (1C, s), 35.6 (1C, s), 30.0 (2C, q), 28.9 (2C, q), 23.7 (1C, q). IR (KBr) 1683, 1235 cm-1, MS (m/e) 260.3 (M+, 46.3), 245.2 (100.0), 175 (38.5), 128 (31.1).
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:3]=1[CH2:4][O:5][C@H:6]1[C@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[C@@H:17]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[Cl:39])[S:16][CH:7]1SCC1C=CC=CC=1.[C:45]([OH:48])(=[O:47])[CH3:46]>C(Cl)Cl>[Cl:1][C:2]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:3]=1[CH2:4][O:5][C@H:6]1[C@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[C@@H:17]([CH2:29][O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[Cl:39])[S:16][CH:7]1[O:47][C:45](=[O:48])[CH3:46]
Reactant: CC(=O)O
Reactant: Clc1ccc(COC[C@H]2SC(SCc3ccccc3)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@H]2OCc2ccc(Cl)cc2Cl)c(Cl)c1
Solvent: ClCCl
Product: CC(=O)OC1S[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@H]1OCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of mercuric acetate in acetic acid is added compound 1-4 from Step D and the resulting reaction mixture is stirred at room temperature for 2-3 h. The mixture is then diluted with CH2Cl2, washed with water, saturated aqueous sodium bicarbonate and 5% KCN solution. The organic layer is dried over anhydrous sodium sulfate, filtered, and evaporated. The residue is purified on a silica gel column using a mixture of cyclohexane and ethyl acetate as eluent. The appropriate fractions are combined and concentrated to give the title compound 1-5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][C:10]=2[F:32])[CH:5]=[CH:4][N:3]=1.[C:33]1([O:39][C:40](Cl)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.N1C=CC=CC=1.C(Cl)Cl>[CH3:24][N:21]1[C:22]([CH3:23])=[C:18]([C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:40](=[O:41])[O:39][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:7]=3)=[C:10]([F:32])[CH:11]=2)=[O:17])[C:19](=[O:31])[N:20]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
A suspension of N-(4-((2-aminopyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (500 mg, 1.10 mmol) in DCM/pyridine (50 mL/25 mL) was cooled to 0° C., then a solution of phenylcarbonochloridate (450 mg, 2.90 mmol) in DCM (5 mL) was added to the mixture slowly over 0.5 hour. The reaction was stirred at rt for 2 hours, then diluted with DCM (250 mL). The mixture was washed with water (150 mL×3), followed by washing with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=150/1) to give the title compound as a white solid (352 mg, 46%).
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH:16]=[CH:17][C:18](=[N:20][OH:21])[CH3:19])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([O-])(O)=O.[Na+]>O.C1COCC1.OS([O-])=O.[Na+]>[CH3:19][C:18]1[CH:17]=[C:16]([C@@H:12]2[CH2:13][CH2:14][CH2:15][N:11]2[C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[O:21][N:20]=1
Reactant: CC(C=C[C@@H]1CCCN1C(=O)OCc1ccccc1)=NO
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc([C@@H]2CCCN2C(=O)OCc2ccccc2)on1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
A 169 mg sample (0.59 mmol) of the product from step 23d above, 344 mg (2.07 mmol) of Kl, 156 mg ((0.61. mmol) of 12, and 198 mg (2.36 mmol) of NaHCO3 were dissolved in 3 mL of water and 3 mL of THF. The mixture was heated at reflux for 6 hr, then cooled to room temperature. The mixture was diluted with 20 mL of 1.7 M NaHSO3 solution, then extracted with ether. The combined extracts were washed with brine and dried over MgSO4, then concentrated to give 143 mg of crude product. Chromatography on silica gel, eluting with 20% ethyl acetate in hexane afforded 102 mg of the title compound after removal of the solvent.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:19][C@@H:20]1[O:25][CH2:24][CH2:23][NH:22][CH2:21]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[CH3:19][C@@H:20]1[O:25][CH2:24][CH2:23][N:22]([C:2]2[C:3]3[C:10]([C:11]4[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=4)[C:14]#[N:15])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:21]1
Reactant: N#Cc1cccc(-c2c[nH]c3ncnc(Cl)c23)c1
Reactant: C[C@H]1CNCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2ncnc3[nH]cc(-c4cccc(C#N)c4)c23)CCO1
Temperature: 100 °C

Procedure:
To a solution of 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (C14) (100 mg, 0.393 mmol) and (2S)-2-methylmorpholine (54 mg, 0.53 mmol) in n-butanol (20 mL) was added N,N-diisopropylethylamine (152 mg, 1.18 mol), and the reaction mixture was heated at 100° C. for 18 hours. The reaction mixture was then concentrated in vacuo; purification via preparative HPLC (Column: Phenomenex Gemini C18, 8 μm; Mobile phase A: ammonia in water, pH 10; Mobile phase B: acetonitrile; Gradient: 27% to 47% B) provided the product as a white solid. Yield: 17.5 mg, 54.8 μmol, 14%. LCMS m/z 320.2 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 10.71 (br s, 1H), 8.53 (br s, 1H), 7.73-7.89 (m, 2H), 7.51-7.69 (m, 2H), 7.28 (s, 1H, assumed; partially obscured by solvent peak), 3.56-3.77 (m, 3H), 3.39-3.54 (m, 2H), 2.86-2.98 (m, 1H), 2.53-2.65 (m, 1H), 0.93-1.03 (m, 3H).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH3:5][C:6]1[C:12]([CH3:13])=[C:11]([OH:14])[CH:10]=[C:9]([C:15](=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O>[CH2:1]([O:8][C:7]1[C:9]([C:15](=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:10][C:11]([OH:14])=[C:12]([CH3:13])[C:6]=1[CH3:5])[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: CCCCCCCCCCCCCC(=O)c1cc(O)c(C)c(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: C=CCOc1c(C(=O)CCCCCCCCCCCCC)cc(O)c(C)c1C
Temperature: 30 °C
Reaction time: 9 h

Procedure:
43 g of allyl bromide were dropwise added with gentle boiling within 2 h to a mixture of 105 g of the ketone of step 1, 63 g of potassium carbonate and 1200 ml of methyl ethyl ketone. After 9 h of boiling the mixture was cooled to 30° C. and 200 ml of water were added. The aqueous layer was separated. Then the organic layer was shaken once with a 25% by weight sodium chloride solution and filtered off, whereupon the solvent was distilled. The residue was stirred into 1 l of methanol and filtered with suction.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:9][C:10]1[C:11](=[O:18])[CH:12]=[C:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.Cl.C(OCC)(=O)C>C1COCC1>[OH:18][C:11]1([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:12]=[C:13]([CH3:17])[C:14](=[O:16])[CH:15]=[C:10]1[CH3:9]
Reactant: CC1=CC(=O)C(C)=CC1=O
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(O)C=C(C)C(=O)C=C1C
Yield: 87 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.45 g (3.33 mmol) of 2,5-dimethyl-p-benzoquinone in 3 mL of THF was added 15 dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3, 1/2) afforded 0.65 g of the desired product (yield 87%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]([F:29])([F:28])[C:14]1[N:19]=[CH:18][C:17]([C:20]2([CH2:26][NH2:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][N:15]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][CH2:26][C:20]1([C:17]2[CH:18]=[N:19][C:14]([C:13]([F:29])([F:28])[F:12])=[N:15][CH:16]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:6]
Reactant: NCC1(c2cnc(C(F)(F)F)nc2)CCOCC1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: O=C(NCC1(c2cnc(C(F)(F)F)nc2)CCOCC1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and (4-(2-(trifluoromethyl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)methanamine. LCMS (MH+): m/z=418.1, tR (minutes, Method F)=2.24
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=C[C:17]=2OC)[C:10]1=[O:24].C([NH:28]C1C=NC=CC=1)C=C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:17]=[N:28][CH:19]=[CH:20][CH:21]=2)[C:10]1=[O:24]
Reactant: COc1ccccc1N1CCCC[C@H](N)C1=O
Reactant: C=CCNc1cccnc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCCCN(c2cccnc2)C1=O

Procedure:
(S)-3-Amino-1-(pyridin-3-yl)azepan-2-one trifluoroacetate (36 mg, 0.11 mmol) was synthesized as described for the preparation of Intermediate 62 using N-allylpyridin-3-amine in step A. Anal. Calcd. for C11H15N3O m/z 205.2. found: 206.1 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.Cl[C:25]1[N:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[N:26]=1>>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:25]5[N:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[N:26]=5)[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: Cc1cc(C)nc(NC2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)n1

Procedure:
Using a procedure similar to that described in Example 86 except starting with 4-amino-1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)piperidine (prepared as described in Example 8b) and 2-chloro-4,6-dimethylpyrimidine the hydrochloride salt of the title compound was obtained as a white solid (55%), mp 205°-207° C.; MS(CI): 411 (M+H); NMR (250 MHz, DMSO-d6): 10.07(br s, 1H), 8.40(br m, 1H), 7.38-7.31(m, 4H), 7.03-6.94(m, 4H), 6.72(s, 1H), 4.46(s, 1H), 4.35-4.33(m, 2H), 4.21-3.97(br m, 1H), 3.60-3.48(m, 4H), 2.74(s, 2H), 2.37(s, 6H), 2.13-1.94(m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][N:43]1[CH:47]=[C:46]([S:48](Cl)(=[O:50])=[O:49])[N:45]=[C:44]1[CH3:52]>C(#N)C>[CH3:42][N:43]1[CH:47]=[C:46]([S:48]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:50])=[O:49])[N:45]=[C:44]1[CH3:52]
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nc(S(=O)(=O)Oc2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cn1C
Yield: 51.1 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0316 g, 0.0685 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0570 mL, 0.411 mmol) and 1,2-dimethylimidazole-4-sulfonyl chloride (0.0400 mL, 0.205 mmol) to obtain 4-(1,2-dimethylimidazol-4-ylsulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0217 g, yield 51%).
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:7]=[C:8]([CH:42]=[CH:43][CH:44]=2)[C:9]([NH:11][C:12]2[S:13][C:14]3[CH2:41][CH2:40][CH2:39][CH2:38][C:15]=3[C:16]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)=[CH:22][CH:21]=2)=[O:18])=[O:10])[CH2:3][CH2:2]1.Cl[C:46]1[N:51]=[CH:50][C:49]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:48][N:47]=1>>[CH:1]1([N:4]([CH2:5][C:6]2[CH:44]=[CH:43][CH:42]=[C:8]([C:9](=[O:10])[NH:11][C:12]3[S:13][C:14]4[CH2:41][CH2:40][CH2:39][CH2:38][C:15]=4[C:16]=3[C:17](=[O:18])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]4[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=4)=[CH:22][CH:21]=3)[CH:7]=2)[C:46]2[N:47]=[CH:48][C:49]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:50][N:51]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CNC5CC5)c4)sc4c3CCCC4)cc2)cc1
Reactant: CCOC(=O)c1cnc(Cl)nc1
Product: CCOC(=O)c1cnc(N(Cc2cccc(C(=O)Nc3sc4c(c3C(=O)Nc3ccc(CCc5ccc(C(=O)OC)cc5)cc3)CCCC4)c2)C2CC2)nc1
Yield: 98.5 %

Procedure:
By using 250 mg of methyl 4-{2-[4-({[2-({3-[(cyclopropylamino)methyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate and 153 mg of ethyl 2-chloropyrimidine-5-carboxylate as starting materials, the reaction similar to Preparation Example 30 was performed, thereby obtaining 307 mg of ethyl 2-{cyclopropyl[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl}-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)benzyl]amino}pyrimidine-5-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([OH:11])[C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[C@@:21]12(O)[N:28](C)[C@@H:25]([CH2:26][CH2:27]1)[CH2:24][CH:23]=[CH:22]2.[Na]>>[F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)([OH:11])[C:7]([O:9][C@@:10]23[N:28]([CH3:21])[C@@H:25]([CH2:26][CH2:27]2)[CH2:24][CH:23]=[CH:22]3)=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Agent: [Na]
Product: CN1[C@@H]2CC=C[C@@]1(OC(=O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1)CC2

Procedure:
11.13 g (0.04 mol) of methyl 4,4′-difluorobenzilate 3d and 5.57 g (0.04 mol) of tropenol are reacted with 0.09 g sodium analogously to Example 3, step 3.2. The product is recrystallized from acetonitrile. Yield: 10.43 g (62% of theory); melting point: 233-235° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[C:14]([C:19](O)=[O:20])=[N:15][N:16]([CH3:18])[CH:17]=3)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:60][C:61]1([CH3:66])[CH2:65][CH2:64][CH2:63][NH:62]1>CN(C=O)C>[CH:1]1([C:4]2[N:9]=[C:8]([C:10](=[N:12][C:13]3[C:14]([C:19]([N:62]4[CH2:63][CH2:64][CH2:65][C:61]4([CH3:66])[CH3:60])=[O:20])=[N:15][N:16]([CH3:18])[CH:17]=3)[OH:11])[C:7]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[N:25][CH:24]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)O)n1
Reactant: CC1(C)CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cn1cc(N=C(O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)N2CCCC2(C)C)n1
Reaction time: 8 h
Yield: 7.2 %

Procedure:
To stirred solution of 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid (70 mg, 0.18 mmol) in DMF were sequentially added N-methylmorpholine (0.12 ml, 0.9 mmol), HBTU (210 mg, 0.55 mmol), and 2,2-dimethylpyrrolidine (35 mg, 0.36 mmol) at rt, and the reaction mixture was allowed to stirr overnight. The solvent was removed in vacuo, and the residue was dissolved in EtOAc (10 ml), and was washed with aqueous NaHCO3 solution and water. The aqueous layer was back-extracted with EtOAc, and the combined organic layer was dried (Na2SO4), filtered, and evaporated in vacuo. The crude product was purified by prep. HPLC (column: Gemini C18 (250×21.2 mm, 5μ); elution with a gradient of 0.05% aqueous TFA solution/acetonitrile) to give the title compound (6 mg, 6%) as sticky yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.Cl.[CH2:11]([NH2:13])[CH3:12].CCN(CC)CC>C(O)CCC>[NH2:8][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([NH:13][CH2:11][CH3:12])[N:7]=1
Reactant: Nc1cc(Cl)nc(Cl)n1
Reactant: CCN
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCNc1nc(N)cc(Cl)n1
Temperature: 90 °C

Procedure:
A mixture of 2,6-dichloro-4-aminopyrimidine 18-1 (Avocado; 4.8 g, 29.3 mmol), ethylamine hydrochloride (7.0 g, 85.8 mmol), Et3N (20 mL, 144 mmol) and n-butanol (150 mL) was heated to 90° C. for 6 hours. After cooling, the solvent was removed in vacuo and the residue partitioned between saturated Na2CO3 solution and EtOAc. The EtOAc layer was washed with brine, dried (MgSO4) and concentrated to give an orange solid. Purification by column chromatography (EtOAc/hexane 1:1) gave the title compound 18-2 as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.O[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[O:6][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13](=[O:14])[CH:12]=1
Reactant: O=C(O)c1ccccc1F
Reactant: O=C(CO)c1ccccc1
Product: O=c1cc(-c2ccccc2F)oc2ccccc12

Procedure:
9 is prepared from 2-fluorobenzoic acid and 2-hydroxyacetophenone by the procedures of Examples 7 and 8. The crude material is purified by vacuum column (gradient elution using 10% ethyl acetate in hexane, 20% ethyl acetate in hexane, and 30% ethyl acetate in hexane). The material is then recrystallized from hexane/ethyl acetate, yielding 9 with a melting point of 98°-100° C.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([Cl:17])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCC[C@H](C(O)=O)C1)(=O)C1C=CC=CC=1.S(Cl)(Cl)=O>ClCCl>[C:1]([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([Cl:17])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CCCN(C(=O)c2ccccc2)C1
Agent: O=C(O)[C@H]1CCCN(C(=O)c2ccccc2)C1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)[C@H]1CCCN(C(=O)c2ccccc2)C1

Procedure:
The reaction was run in the same manner as 1-benzoyl-3-piperidinecarbonyl chloride, starting with (S)-1-benzoyl-3-piperidinecarboxylic acid (6.30 g; 27.0 mmols), thionyl chloride (16.06 g, 135 mmol), and dry dichloromethane (150 ml), giving (S)-1-benzoyl-3-piperidinecarbonyl chloride as a light yellow oil, which was used without further purification. MS (in CH3CN) m/z (positive ion) 503 (40), 485 (42), 467 (40), 254 (60), 252 (MH+; 100), 234 (68).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>ClCCl>[CH2:20]([O:19][C:17]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 4-hydroxymethylpiperidine (2.0 g, 17.4 mmol) in dry dichloromethane (DCM, 100 mL) was cooled to 0° C., treated with triethylamine (4.8 mL, 34.8 mmol) followed by benzyl chloroformate (3.7 mL, 34.8 mmol), allowed to warm to room temperature and stirred for two hours. The mixture was partitioned between DCM (50 mL) and water (30 mL). The layers were separated and the aqueous phase was extracted with DCM (2×50 mL). The combined organic phases were washed with brine (1×30 mL), dried over Na2SO4 and evaporated to a residue, that was purified by column chromatography using a gradient of 70 to 100% EtOAc in hexanes as eluant to give 3.85 g (89%) of E-12 as clear oil: 1H NMR (CDCl3) δ 1.17 (m, 2H), 1.72 (m, 3H), 2.15 (br s, 1H), 2.78 (t, 2H, J=12.24), 3.47 (d, 2H, J=6.04), 4.20 (d, 2H, J=11.68), 5.12 (s, 2H), 7.33 (m, 5H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].N1C=CC=CC=1.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C(Cl)Cl>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[C:2]([F:10])([F:11])[F:1])(=[O:29])=[O:28])=[CH:25][CH:26]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.4 %

Procedure:
A solution of 2-(trifluoromethyl)aniline (1.51 g, 9.37 mmol) and pyridine (1.08 mL, 13.38 mmol) in DCM (30 mL) was treated with 4-nitrobenzenesulfonyl chloride (1.48 g, 6.69 mmol) and stirred at room temperature for 18 hours. The mixture was diluted with DCM, washed with 1 M aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Trituration with pentane gave 4-nitro-N-(2-trifluoromethyl-phenyl)-benzenesulfonamide (1.91 g, 82%). 1H NMR (300 MHz, CDCl3) δ 8.31-8.23 (m, 2H), 7.95-7.85 (m, 3H), 7.64-7.50 (m, 2H), 7.31 (t, J=7.7 Hz, 1H), 6.89 (br s, 1H). LCMS (m/z, Method A) ES+ 347.1 [M+1]+.