Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]([OH:29])[C@H:14]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@@H:15]([CH3:20])[CH2:16][N:17]=[N+:18]=[N-:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[Si:38](OS(C(F)(F)F)(=O)=O)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]>CCOC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]([O:29][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[C@H:14]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[C@@H:15]([CH3:20])[CH2:16][N:17]=[N+:18]=[N-:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CN=[N+]=[N-])cc1
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 75 %

Procedure:
To a solution of (2R,3R,4S)-5-azido-3-(tert-butyldimethylsilyloxy)-2-hydroxy-4-methylpentyl 4-methylbenzenesulfonate (1.0 equiv.) and 2,6-lutidine (3.4 equiv.) was added TBDMSOTf (1.7 equiv.) at 0° C. The solution was stirred for 7 hours as it warmed to rt. The solution was diluted with EtOAc, washed with 10% CuSO4, H2O, Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (2.5-5-10-20% EtOAc/n-heptanes) yielding (2R,3R,4S)-5-azido-2,3-bis(tert-butyldimethylsilyloxy)-4-methylpentyl 4-methylbenzenesulfonate (75%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:10][N:11](C)[C:12](=O)OC(C)(C)C)=[N:4][N:5]([CH3:9])[C:6]=1[C:7]#[N:8].Cl.O1CCOCC1>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:10][NH:11][CH3:12])=[N:4][N:5]([CH3:9])[C:6]=1[C:7]#[N:8]
Reactant: CN(Cc1nn(C)c(C#N)c1Br)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNCc1nn(C)c(C#N)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 117.9 %

Procedure:
To a 0° C. solution of compound 47 (1.0 g, 3.0 mmol) in DCM (15 mL) was added 4 N HCl in dioxane (3.8 mL, 15 mmol). Allowed to stir at room temperature for 3 hours, then concentrated under vacuum to give compound 109 (810 mg, quantitative) as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([O:10][CH2:11][C:12]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH3:9])[CH:5]=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=1.C[Si](C)(C)[C:37]([F:40])([F:39])[F:38].[F-].[K+].CN1CCCC1=O>CN(C)C=O.[Cu]I>[C:25]1([C:12]2([CH2:11][O:10][CH:8]([C:6]3[CH:5]=[C:4]([C:31]([F:34])([F:33])[F:32])[CH:3]=[C:2]([C:37]([F:40])([F:39])[F:38])[N:7]=3)[CH3:9])[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc(Br)n1
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: CC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)n1
Temperature: 110 °C
Yield: 18 %

Procedure:
Tert-butyl 4-((1-(6-bromo-4-(trifluoromethyl)pyridin-2-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (100 mg, 0.18 mmol), trimethyl(trifluoromethyl)silane (70 mg, 0.46 mmol), potassium fluoride (70 mg, 1.2 mmol) and Copper(I) Iodide (100 mg, 0.525 mmol) were combined in dry dimethylformamide (1 mL) and dry N-Methyl-2-pyrrolidinone (1 mL) in a sealed tube. The mixture was heated to 110° C. for 2 hours. After cooling the reaction mixture was quenched with the addition of ammonia hydroxide (6M, 15 mL). The reaction was diluted with ether, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting oil was redissolved in methanol (2 mL) and treated with HCl (g) for 30 seconds. The solvent was evaporated and preparatory HPLC afforded 14 mg (15%) of desired product as the TFA salt. 1H-NMR (CD3OD, 400 MHz) δ 7.92 (s, 1H), 7.24-7.57 (m, 6H), 4.54 (q, 1H), 3.91 (d, 1H), 3.57 (m, 1H), 2.82-3.03 (m, 2H), 2.51-2.77 (m, 2H), 2.34-2.48 (m, 2H), 2.03-2.22 (m, 2H), 1.38 (d, 3H). LC: Tr=1.785 min, HPLC Method 1. Mass spec.: 433.35 (MH)+.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1([C:36]([O:38]CC)=[O:37])[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[O:23][N:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])C>C(O)C.O1CCCC1>[F:34][C:32]([F:33])([F:35])[C:29]1[CH:30]=[CH:31][C:26]([C:24]2[O:23][N:22]=[C:21]([C:18]3[CH:17]=[CH:16][C:15]([CH2:14][N:11]4[CH2:10][CH2:9][C:8]([C:36]([OH:38])=[O:37])([C:6]([OH:7])=[O:5])[CH2:13][CH2:12]4)=[CH:20][CH:19]=3)[N:25]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CCN(Cc2ccc(-c3noc(-c4ccc(C(F)(F)F)cc4)n3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1(C(=O)O)CCN(Cc2ccc(-c3noc(-c4ccc(C(F)(F)F)cc4)n3)cc2)CC1

Procedure:
An aqueous solution (10 mL) of sodium hydroxide (0.86 g, 0.0215 mol) is added to a stirred solution of 1-{4-[5-(4-trifluoromethylphenyl)-1,2,4-oxadiazol-3-yl]benzyl}piperidine-4,4-dicarboxylic acid diethyl ester (2.3 g, 0.004 mol) in a mixture of ethanol (50 mL) and tetrahydrofuran (10 mL). The reaction mixture is refluxed for 20 hrs, then is concentrated under reduced pressure. The residue is acidified with 3N HCl to pH ˜2. The solid thus formed is filtered, washed with a mixture of methanol:ether (30 mL, 10:90), then tetrahydrofuran (20 mL) and dried to furnish 1-{4-[5-(4-trifluoromethylphenyl)-1,2,4-oxadiazol-3-yl]benzyl}-piperidine-4,4-dicarboxylic acid (e.g. 14).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:28][CH3:29])[CH2:22][C:23]([CH3:27])([CH3:26])[C:24]#[N:25])[C:11](=[O:30])[C@:10]([CH2:32][CH:33]3[CH2:37][O:36]C(C)(C)[O:34]3)([CH3:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.O.[Na+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:28][CH3:29])[CH2:22][C:23]([CH3:26])([CH3:27])[C:24]#[N:25])[C:11](=[O:30])[C@:10]([CH2:32][CH:33]([OH:34])[CH2:37][OH:36])([CH3:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CC(C)(C)C#N)N1C(=O)[C@@](C)(CC2COC(C)(C)O2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@@H](CC(C)(C)C#N)N1C(=O)[C@@](C)(CC(O)CO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (4S)-4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)-2,2-dimethylhexanenitrile prepared above in Step G (77 mg, 0.135 mmol) in THF (2.69 mL) was added 3 N hydrochloric acid in water (1.35 μL, 4.04 mmol) at rt. After being stirred at rt for 4 h, the reaction was diluted (sat. aq. NaCl) and extracted (2×EtOAc). The combined organic layers were washed (sat. aq. NaCl solution), dried (Na2SO4), and concentrated under reduced pressure to provide the title compound as a colorless foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li].[CH2:9](I)[CH3:10].[NH4+].[Cl-]>CN1C(=O)N(C)CCC1.C1COCC1.COC(C)(C)C>[CH2:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:10]
Reactant: Nc1ccccc1
Reactant: CCI
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: COC(C)(C)C
Product: CCNc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of aniline 22 (386 mg, 0.474 mmol, 1.0 eq.) in DMPU (1.6 mL) at 0° C. was added lithium hexamethyldisalazide (0.950 mL, 0.950 mmol, 2.0 eq., lithium hexamethyldisalazide 1.0 M in THF). The resulting mixture was stirred at 0° C. during 30 min and added ethyl iodide (0.230 mL, 2.88 mmol, 6.1 eq.). The reaction mixture was stirred 10 min at 0° C. then allowed to warm up to rt and stirred at that temperature during 1 h. A saturated solution of NH4Cl, methyl-t-butyl ether and n-hexanes were added. Layers were separated and the aqueous one was extracted twice with methyl-t-butyl ether/hexane (1:1 mixture). The combined organic layers were washed with brine/water (1:1 mixture), then with brine, dried with sodium sulfate, filtered and concentrated to dryness. The resulting foam was purified by chromography on silica gel 230-400 Mesh using the following solvent gradient: 15% and 20% ethyl acetate/hexane to elute. This procedure afforded N-ethyl-aniline 39, 349 mg, white foam, 87% yield.
Reaction SMILES: [N:1]1[N:5]2[C:6](=[O:14])[C:7]3[CH:13]=[CH:12][CH:11]=[N:10][C:8]=3[NH:9][C:4]2=[CH:3][CH:2]=1.[OH-].[K+].[CH3:17]O>>[CH3:17][N:9]1[C:8]2[N:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6](=[O:14])[N:5]2[N:1]=[CH:2][CH:3]=[C:4]12
Reactant: O=c1c2cccnc2[nH]c2ccnn12
Reactant: CO
Agent: [K+]
Agent: [OH-]
Product: Cn1c2ncccc2c(=O)n2nccc12
Reaction time: 0.5 h

Procedure:
1.8 g. of pyrazolo[1,5 -a]pyrido[2,3-d]pyrimidin-9(4H)-one are suspended in 10 ml. of methanol. 0.6 g. of potassium hydroxide are added and the mixture is stirred for 30 minutes. After this time, the potassium salt is filtered off and, after drying, suspended in 20 ml. of diethyleneglycol dimethyl ether. 2.5 g. of methyl iodide are added with stirring. After 20 minutes, 4-methylpyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-9(4H)-one is filtered off, washed with water and recrystallized from methanol, yield: 1.1 g. (55%); m.p. 249.2°.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].[OH-].[Na+].[BH4-].[Na+].Cl>O.CO>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([OH:13])=[C:10]([C:11]([CH3:16])([CH3:15])[CH2:12][OH:14])[CH:17]=1)(=[O:4])=[O:3]
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(CO)c1cc(OS(C)(=O)=O)ccc1O
Yield: 90 %

Procedure:
2,3-Dihydro-2-hydroxy-3,3-dimethylbenzofuran-5-yl methane sulphonate (129 parts) was added to a solution of sodium hydroxide (120 parts) in water (1200 parts) and methanol (320 parts). Sodium borohydride (19 parts) was added portionwise with vigorous stirring at 15°-20° C. The mixture was stirred for three hours, then acidified with hydrochloric acid and filtered to give 4-hydroxy-3-(2-hydroxy-1,1-dimethylethyl)phenyl methanesulphonate (117 parts, 90% yield). Recrystallisation from 1,2-dichloroethane gave the pure product, melting point 122°-124° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]1([CH:20]([NH:23][C:24]([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][CH:30]=[CH:29]3)=[O:25])[CH2:21][CH3:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:31]2[C:32]3[C:28](=[CH:27][C:26]([C:24]([NH:23][CH:20]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:21][CH3:22])=[O:25])=[CH:34][CH:33]=3)[CH:29]=[CH:30]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCC(NC(=O)c1ccc2[nH]ccc2c1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: CCC(NC(=O)c1ccc2c(ccn2S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1)c1ccccc1

Procedure:
The title compound was prepared following the same general protocol as described in Example 28, using 4-nitrophenylsulfonyl chloride and N-(1-phenylpropyl)-1H-indole-5-carboxamide. LC-MS 464 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH:10]([CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1(C(N2C=CN=C2)=O)C=CN=C1.Cl.[CH3:31][O:32][NH:33][CH3:34]>C(Cl)Cl>[CH3:31][O:32][N:33]([CH3:34])[C:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH:10]1[CH3:17])=[O:16]
Reactant: CNOC
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-3-methylpiperidine-4-carboxylic acid (3.00 g, 12.3 mmol) in CH2Cl2 (200 mL) was added di(1H-imidazol-1-yl)methanone (2.19 g, 13.6 mmol) portionwise. After the bubbling ceased (˜60 minutes), N-methoxymethanamine hydrochloride (1.32 g, 13.6 mmol) was added in one portion. The mixture was allowed to stir overnight at ambient temperature, then was washed with water, 1N HCl, and saturated sodium bicarbonate. The organic layer was dried, filtered, and concentrated to give the desired product (2.29 g, 64.8% yield) as a colorless oil.
Reaction SMILES: C(O)=O.[NH2:4][C:5]1[C:10]([OH:11])=[CH:9][N:8]=[C:7]([C:12]2[C:13]3[CH2:27][CH2:26][CH2:25][C:14]=3[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:16]=2)[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[C:36]1[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][N:39]=[CH:38][CH:37]=1>CN(C=O)C>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:15]1[C:14]2[CH2:25][CH2:26][CH2:27][C:13]=2[C:12]([C:7]2[N:6]=[C:5]([NH:4][C:36]3[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:40][N:39]=[CH:38][CH:37]=3)[C:10]([OH:11])=[CH:9][N:8]=2)=[N:16]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3c2CCC3)ncc1O
Reactant: CCOC(=O)c1cnccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=CO
Product: CCOC(=O)c1cnccc1Nc1nc(-c2nn(Cc3ccccc3F)c3c2CCC3)ncc1O
Temperature: 50 °C

Procedure:
3.00 g of formic acid—4-amino-2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]pyrimidin-5-ol (1:1) 1-8-1 (9.22 mmol, 1.00 eq.) were dissolved in 300 mL DMF, 6.37 g potassium carbonate (46.1 mmol, 5.00 eq) were added and under nitrogen atmosphere 2.05 g ethyl 4-chloronicotinate hydrochloride (1:1) (9.22 mmol, 1.00 eq.) were added. The reaction mixture was stirred at 50° C. over night, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography twice to provide 100 mg (0.21 mmol, 2.2%) of analytically pure target compound.
Reaction SMILES: N=[C:2]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:4](=[S:19])[N:3]1[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=1.C[OH:33].O>Cl>[O:33]=[C:2]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:4](=[S:19])[N:3]1[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=1
Reactant: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=N)C23CCCCC3)cc1
Reactant: CO
Agent: Cl
Solvent: O
Product: Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCCCC3)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixture of 9b (0.035 g, 0.08 mmol) in HCl aq., 2N (1 ml) and methanol (3 ml) was heated to reflux for 2 h. After being cooled to room temperature, the reaction mixture was poured into cold water (5 ml) and extracted with ethyl acetate (6 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane) to yield 4-(4-oxo-2-thioxo-1-(4-methylphenyl)-1,3-diazaspiro[4.5]dec-3-yl)-2-trifluoromethylbenzonitrile, 9c, [RD48] (0.034 g, 0.076 mmol, 95%) as a white powder.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:19]O>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([O:10][CH3:19])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: CO
Product: COC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
In a 500 cc 1-necked, round bottom flask, fitted with a condenser and stirring bar, were placed under nitrogen: 37.55 g. (0.15 mole) 3,5-di-tert.-butyl-4-hydroxybenzoic acid, 7.5 g. Amberlyst 15 catalyst, and 300 cc (7.43 moles) methanol. The solution was refluxed 15 hours, after which time the hot solution was filtered, concentrated, and cooled to afford 31.9 g. (81%) white crystals which were washed with hexane and dried. The melting point was 165.0° -166.5° C. The infrared and NMR spectra of the product were consistent with those expected from methyl 3,5-di-tert. butyl-4-hydroxybenzoate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(N(C(C)C)C(C)C)C.[C:18]1([O:28][CH2:29][C@H:30]2[CH2:34][CH2:33][CH2:32][NH:31]2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.O>C(O)(C)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:31]2[CH2:32][CH2:33][CH2:34][C@@H:30]2[CH2:29][O:28][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:4][N:3]=1
Reactant: c1ccc2c(OC[C@H]3CCCN3)cccc2c1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(C)O
Product: Clc1nccc(N2CCC[C@@H]2COc2cccc3ccccc23)n1
Temperature: 80 °C
Yield: 64.4 %

Procedure:
327 mg of 2,4-dichloropyrimidine are dissolved in 20 ml of isopropanol, and 0.8 ml of N-ethyldiisopropylamine and 500 mg of (R)-2-(naphthalen-1-yloxymethyl)pyrrolidine are added. This mixture is warmed at 80° C. for 6 h. After cooling, the batch is poured into 40 ml of water and 40 ml of ethyl acetate. After phase separation, the organic phase is dried, evaporated and chromatographed on silica gel, giving 480 mg of 2-chloro-4-[(R)-2-(naphthalen-1-yloxymethyl)pyrrolidin-1-yl]pyrimidine as colourless oil;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]2[NH:11][CH2:10][CH2:9]1.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>>[C:34]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)=[CH:22][CH:21]=3)[C:16]([C:17]([NH2:19])=[O:18])=[C:12]2[NH:11][CH2:10][CH2:9]1)(=[O:37])[CH:35]=[CH2:36]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)cc2)nn2c1NCCC2c1ccccc1N
Reactant: C=CC(=O)Cl
Product: C=CC(=O)Nc1ccccc1C1CCNc2c(C(N)=O)c(-c3ccc(Oc4ccc(F)cc4)cc3)nn21

Procedure:
The desired product was prepared from 7-(2-aminophenyl)-2-(4-(4-fluorophenoxyl)phenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carboxamide and acryloyl chloride using the procedure similar to that for compound 8. 1H NMR (400 MHz, CD3OD-d4) δ 7.47 (d, J=8.4 Hz, 2H), 7.39 (t, J=7.6 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.12-7.00 (m, 6H), 6.81 (d, J=8.0 Hz, 1H), 6.53-6.46 (m, 1H), 6.39-6.35 (m, 1H), 5.87-5.76 (m, 1H), 5.73-5.69 (m, 1 H), 3.36-3.30 (m, 1H), 3.22-3.17 (m, 1H), 2.45-2.39 (m, 1 H) and 2.17-2.14 (m, 1H). MS (ESI) m/e [M+1]+ 497.9.
Reaction SMILES: [ClH:1].[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.[CH3:20][S:21]([O:24][C:25]1[CH:26]=[CH:27][C:28]2[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:35][CH:34]=3)[S:30][C:29]=2[CH:44]=1)(=[O:23])=[O:22]>>[ClH:1].[CH3:20][S:21]([O:24][C:25]1[CH:26]=[CH:27][C:28]2[C:32]([C:15](=[O:17])[C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][N:5]4[CH2:4][CH2:3][O:2][CH2:7][CH2:6]4)=[CH:19][CH:18]=3)=[C:31]([C:33]3[CH:34]=[CH:35][C:36]([O:39][S:40]([CH3:43])(=[O:41])=[O:42])=[CH:37][CH:38]=3)[S:30][C:29]=2[CH:44]=1)(=[O:22])=[O:23]
Reactant: CS(=O)(=O)Oc1ccc(-c2cc3ccc(OS(C)(=O)=O)cc3s2)cc1
Reactant: O=C(O)c1ccc(OCCN2CCOCC2)cc1
Agent: Cl
Product: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCN3CCOCC3)cc2)cc1

Procedure:
The process of Example 7 was used to prepare the above product, starting with 7.2 g. of 4-(2-morpholinoethoxy)benzoic acid, hydrochloride, and 5 g. of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)benzo[b]thiophene. A yield of 4.25 g. of recrystallized product was obtained, of which 1.25 g. was purified by chromatography as explained in Example 7 above to obtain 0.9 g. of highly purified product, m.p. 197°-200°.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[C:7]([Cl:25])=[CH:6][CH:5]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[Cl:3][C:4]1[C:12]2[N:11]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[C:7]([Cl:25])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(Cl)ccc(Cl)c3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3c(Cl)ccc(Cl)c31)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.42 h
Yield: 97.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.85 g, 21 mmol) was added to a solution of tert-butyl 7,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (5.0 g, 14 mmol) in DMF (75 mL). After 25 min, ethyl bromoacetate (3.1 mL, 28 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 3 h and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography with heptane/EtOAc (3:1) to give 6.0 g (96%) of a white foam: mp 118.5-119.5° C.; IR (diffuse reflectance) 2976, 1747, 1674, 1477, 1457, 1420, 1405, 1370, 1366, 1344, 1254, 1200, 1165, 1111, 930 cm−1; MS (EI) m/z 440 (M+), 386, 384, 339, 310, 305, 300, 298, 224,57, 56; Anal. Calcd for C21H26Cl2N2O4: C, 57.15; H. 5.94; N, 6.35; found: C, 57.27; H, 6.01; N, 6.22.
Reaction SMILES: C(OC([O:6][CH2:7][CH2:8][N:9]1[C:14]([C:15](OCC)=[O:16])=[CH:13][C:12]2[CH:20]=[CH:21][S:22][C:11]=2[S:10]1(=[O:24])=[O:23])C)C.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].Cl>CCOCC.CC(C)=O>[OH:6][CH2:7][CH2:8][N:9]1[C:14]([CH2:15][OH:16])=[CH:13][C:12]2[CH:20]=[CH:21][S:22][C:11]=2[S:10]1(=[O:24])=[O:23]
Reactant: CCOC(=O)C1=Cc2ccsc2S(=O)(=O)N1CCOC(C)OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=S1(=O)c2sccc2C=C(CO)N1CCO
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a solution of the product from Step C (8.77 g, 23.4 mmol) in anhydrous ether (100 mL) at 0° C. was added diisobutylaluminium hydride (1M solution in hexanes, 70.2 mmol). The reaction mixture was stirred for 1 h, a solution of potassium sodium tartrate (28.2 g in 100 mL water) was added, and the resulting mixture stirred for 2 h. The aqueous layer was separated and extracted with ethyl acetate (2×100 mL). The combined extracts were dried over magnesium sulfate, filtered and evaporated to give an oil which was dissolved in acetone (100 mL) and treated with 100 mL of 2 N HCl for 4 h. The acetone was evaporated and the remaining aqueous mixture was extracted with ethyl acetate (2×100 mL) The combined extracts was dried and evaporated to give a solid (4.82 g, 79%); Recrystallization from EtOAc/Hex gave a crystalline solid: mp 81°-83° C.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][C:14]2=O.[Cl-].[NH4+]>O1CCCC1>[C:5]1(=[C:14]2[C:15]3[C:10](=[C:9]([O:8][CH3:7])[CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:12][CH2:13]2)[CH2:2][CH2:1]1
Reactant: COc1cccc2c1CCCC2=O
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc2c1CCCC2=C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
Under ice-cooling, to an anhydrous tetrahydrofuran (200 ml) solution of (3-bromopropyl)triphenylphosphinium bromide (19.8 g), potassium t-butoxide (9.58 g) was added, followed by stirring at room temperature for 1.5 hours. To the reaction mixture, 5-methoxy-1-tetralone (5.0 g) was added, followed by stirring at room temperature for 5 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated saline, dried with anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to thereby obtain the title compound (5.66 g) having the following physical data.