Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])[NH:4][N:3]=1.[CH3:13][C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:18][C:17]1[N:1]([C:2]2[CH:6]=[C:5]([C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])[NH:4][N:3]=2)[C:14]([CH3:13])=[CH:15][CH:16]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CON(C)C(=O)c1cc(N)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CON(C)C(=O)c1cc(-n2c(C)ccc2C)n[nH]1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A 250-mL round-bottomed flask equipped with a magnetic stirrer and a Dean-Stark trap was charged with 150b (11.0 g, 1.0 eq., 64.7 mmol), hexane-2,5-dione (11.1 g, 1.5 eq., 97.2 mmol), p-toluenesulfonic acid monohydrate (558 mg, 0.05 eq., 3.24 mmol), and toluene (100 mL). The reaction mixture was refluxed overnight. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 1:2 petroleum ether/ethyl acetate to afford 150c (10.4 g, 65%) as a white solid. MS-ESI: [M+H]+ 249.0
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][C@@H:24]4[CH2:26][O:25]4)=[C:17]([CH2:27][CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:2].[CH3:32][O-:33].[Na+]>CO.CC(=O)OCC>[CH2:30]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH2:23][C@@H:24]([OH:25])[CH2:26][O:33][CH3:32])=[C:17]([CH2:27][CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:31]
Reactant: C[O-]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@@H]1CO1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@@H](O)COC

Procedure:
A solution of diethyl-{4-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridin-2-yl}-amine (100 mg, 0.229 mmol) in 5.4 M NaOMe in methanol (5 mL) is stirred at 70° C. for 72 h. The mixture is diluted with EA and washed with water and brine. The org. extract is dried over Na2SO4, filtered and concentrated. The crude product is purified on prep. TLC plates with heptane:EA 1:1 to give the title compound (91 mg) as a yellow solid; LC-MS*: tR=1.21 min, [M+1]+=455.09; 1H NMR (CDCl3): δ 1.25 (t, J=7.0 Hz, 6H), 1.33 (t, J=7.5 Hz, 3H), 2.41 (s, 3H), 2.50 (s, 3H), 2.58 (d, J=5.0 Hz, 1H), 2.77 (q, J=7.8 Hz, 2H), 3.47 (s, 3H), 3.59-3.70 (m, 6H), 3.92 (d, J=5.3 Hz, 2H), 4.19-4.27 (m, 1H), 7.01 (s, 1H), 7.10 (s, 1H), 7.87 (s, 1H), 7.88 (s, 1H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([C@@H:30]2[CH2:34][CH2:33][CH2:32][NH:31]2)[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:20]4[C@H:27]([CH3:28])[CH2:26][C@@H:25]([OH:29])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1.[CH:35](N(C(C)C)CC)([CH3:37])[CH3:36].CC(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([C@@H:30]2[CH2:34][CH2:33][CH2:32][N:31]2[CH:35]([CH3:37])[CH3:36])[C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[C:20]4[C@H:27]([CH3:28])[CH2:26][C@@H:25]([OH:29])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH2:17][CH2:18]2)=[O:12])=[CH:6][CH:5]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4)[C@@H]4CCCN4)CC3)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(C)=O
Product: CC(C)N1CCC[C@H]1[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
(S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone di-hydrochloride (0.074 g, 0.1399 mmol) was dissolved in 1,2-dichloroethane (0.50 mL) and treated with diisopropylethylamine (0.04874 mL, 0.2798 mmol), propan-2-one (0.03082 mL, 0.4197 mmol) and sodium triacetoxyborohydride (0.1483 g, 0.6996 mmol). The mixture was stirred at 40° C. for 18 hours. The reaction was quenched with 3N HCl and stirred for 30 minutes. The reaction was neutralized to a pH of about 8 to about 8.5 with slow addition of saturated NaHCO3. The reaction was diluted with methylene chloride and separated. The aqueous layer was washed with methylene chloride (2×), and the combined organics were dried over Na2SO4 and concentrated in vacuo. The material was subjected to chromatography on SiO2 eluting with 5% MeOH/1% NH4OH/methylene chloride. The recovered free base (51.2 mg) was dissolved in dioxane (1 mL) and treated with 4N HCl in dioxane (1.5 mL). After stirring for 5 minutes, the mixture was concentrated in vacuo. The mixture was re-dissolved and re-concentrated in vacuo three times from MeOH. The mixture was re-dissolved in MeOH (0.5 mL+0.25 mL wash) and added dropwise to stirred Et2O (30 mL). The resultant solid was stirred for 30 minutes. The solid was then filtered, washed with Et2O and dried under a blanket of nitrogen. (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-1-isopropylpyrrolidin-2-yl)ethanone dihydrochloride was recovered as a solid (0.026 g, 59%). MS (ESI+) [M+H] 498.2/500.1. 1H NMR (CD3OD, 400 MHz) δ 8.56 (s, 1H), 7.44 (dd, 4H), 5.29 (t, J=8.1 Hz, 1H), 4.56 (d, J=10.3, 1H), 4.44-4.35 (m, 1H), 4.29-4.06 (m, 3H), 3.87-3.75 (m, 3H), 3.72-3.62 (m, 1H), 3.60-3.35 (m, 5H), 2.31-2.25 (m, 1H), 2.23-2.08 (m, 2H), 2.07-1.95 (m, 1H), 1.90-1.78 (m, 1H), 1.78-1.68 (m, 1H), 1.39 (d, 3H), 1.32 (d, 3H), 1.18 (d, 3H).
Reaction SMILES: [NH2:1][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[Cl:7][C:8]1[C:9]([F:16])=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O.O>ClCCl>[Cl:7][C:8]1[C:9]([F:16])=[C:10](/[CH:11]=[N:1]/[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])[CH:13]=[CH:14][CH:15]=1
Reactant: C[Si](C)(C)CN
Reactant: O=Cc1cccc(Cl)c1F
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)C/N=C/c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a solution of (aminomethyl)trimethylsilane (Fluka) (1.03 g, 10 mmol) in dichloromethane (50 mL) was added 3-chloro-2-fluoro-benzaldehyde (Oakwood) (1.6 g, 10 mmol). The reaction mixture was stirred at room temperature for 3 h. Water was added. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated to give [1-(3-chloro-2-fluoro-phenyl)-meth-(E)-ylidene]-trimethylsilanylmethyl-amine as a colorless oil (2.4 g, 99%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](NN)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Br:12]Br>C(Cl)(Cl)Cl.CCOCC.CCCCCC>[Br:1][C:2]1[S:6][C:5]([S:7]([Br:12])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: NNS(=O)(=O)c1ccc(Br)s1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CCCCCC
Product: O=S(=O)(Br)c1ccc(Br)s1

Procedure:
To a slurry of 6.43 g (0.025 mol) of 5-bromo-2-thiophenesulfonyl hydrazine and some crushed ice in 100 ml of chloroform was added 8.0 g (0.05) of bromine dropwise with stirring. After the addition was complete and all of the bromine color had disappeared, the chloroform layer was separated and dried over anhydrous magnesium sulfate. The chloroform was removed in vacuo, leaving an orange oil. The oil was dissolved in ether/hexane and cooled to crystallize 3.67 g of the title compound as off-white crystals, mp 48°-50°.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:12]=[CH:11][CH:10]=[CH:9][C:4]=1/[C:5](=[N:7]/[NH2:8])/[NH2:6].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:28](=O)[CH:29]=O)[CH:20]=[C:21]([N+:25]([O-:27])=[O:26])[C:22]=1[O:23][CH3:24]>C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:28]2[N:6]=[C:5]([C:4]3[C:3]([C:2]([F:13])([F:1])[F:14])=[N:12][CH:11]=[CH:10][CH:9]=3)[N:7]=[N:8][CH:29]=2)[CH:20]=[C:21]([N+:25]([O-:27])=[O:26])[C:22]=1[O:23][CH3:24]
Reactant: COc1cc(C(=O)C=O)cc([N+](=O)[O-])c1OC
Reactant: N/N=C(\N)c1cccnc1C(F)(F)F
Solvent: CCO
Product: COc1cc(-c2cnnc(-c3cccnc3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Temperature: 25 °C

Procedure:
To a stirred solution of (Z)-2-(trifluoromethyl)nicotinohydrazonamide (1.02 g, 5 mmol) in ethanol (30 mL) was added 2-(3,4-dimethoxy-5-nitrophenyl)-2-oxoacetaldehyde (1.19 g, 5 mmol). The reaction mixture was heated to reflux for 5 hours. It was then cooled to room temperature and the solvent was removed by evaporation. The residue was dissolved in dichloromethane (30 mL) and the organic phase was washed with water and dried over anhydrous magnesium sulphate, filtered and evaporated. The crude product was recrystallized from isopropanol to give 5-(3,4-dimethoxy-5-nitrophenyl)-3-(2-(trifluoromethyl)pyridin-3-yl)-1,2,4-triazine, 1.628 g (80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[N+:13]([CH3:16])([O-:15])=[O:14].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[CH:16][N+:13]([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)c(OC)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1ccc(C=C[N+](=O)[O-])c(OC)c1

Procedure:
A mixture of 100 g of 2,4-dimethoxybenzaldehyde, 102 ml of nitromethane, 46.4 g of ammonium acetate and 500 ml of glacial acetic acid was heated at reflux for 2 hours and quenched in 700 ml of water. The crude precipitate was recrystallized from ethanol to give 105.57 g of 1-(2,4-dimethoxyphenyl)-2-nitroethylene as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.[Cl:12][C:13]1[C:22]2[C:17](=[C:18]([F:23])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>>[ClH:12].[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:13]1[C:22]3[C:17](=[C:18]([F:23])[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][CH:14]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2
Reactant: Cc1ccc2[nH]c(C)cc2c1
Reactant: Fc1cccc2c(Cl)ccnc12
Product: Cc1ccc2[nH]c(C)c(-c3ccnc4c(F)cccc34)c2c1
Product: Cl

Procedure:
The sub-title compound was prepared by the method of Example 15 step a, using 2,5-dimethylindole and 4-chloro-8-fluoroquinoline.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.F[C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:20]2[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH:28]([CH3:30])[CH3:29])=[CH:22][N:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[H-].[Na+]>CS(C)=O>[CH2:31]([N:19]([C:20]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH:28]([CH3:30])[CH3:29])=[CH:22][N:21]=1)[S:16]([C:13]1[CH:14]=[CH:15][C:10]([O:8][CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:11][CH:12]=1)(=[O:18])=[O:17])[CH:32]([CH3:34])[CH3:33]
Reactant: OCC1CCOCC1
Reactant: COc1cc(C(C)C)cnc1N(CC(C)C)S(=O)(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(C(C)C)cnc1N(CC(C)C)S(=O)(=O)c1ccc(OCC2CCOCC2)cc1
Reaction time: 96 h

Procedure:
To a solution of (tetrahydro-2H-pyran-4-yl)methanol (14.29 mg, 0.123 mmol) and 4-fluoro-N-isobutyl-N-(5-isopropyl-3-methoxypyridin-2-yl)benzenesulfonamide (46.8 mg, 0.123 mmol) in dimethyl sulfoxide (DMSO) (200 μL) stirred in air at room temperature was added sodium hydride (4.92 mg, 0.123 mmol, 60% wt in mineral oil). The reaction mixture was stirred for 4 days then carefully quenched with isopropanol (1 mL) and evaporated in vacuo. The crude sample was purified by mass directed autoprep (formic acid modifier) to give the title product, 42.9 mg. LCMS (2 min, formic) Rt 1.36 min, m/z (ES+) 477 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10].[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)=[C:6]([CH:21]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: CCN(Cc1cc(Br)ccc1OCC1CCCC1)c1ccc(C(=O)OC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1cc(Br)ccc1OCC1CCCC1)c1ccc(C(=O)O)cn1
Temperature: 40 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
A solution of methyl 2-[N-(5-bromo-2-(cyclopentylmethoxy)benzyl)-N-ethylamino]pyridine-5-carboxylate (see reference example 5) (0.37 g, 0.83 mmol) in THF (4 ml) and methanol (4 ml) was treated with IN aqueous sodium hydroxide solution (4 ml). The reaction was heated at 40° C. for 18 hours. The solvents were evaporated at reduced pressure and the residue was acidified with 1N acetic acid (4 ml) and allowed to stir for 2 days. The precipitate was filtered, washed with water and dried in vacuo at 45° C. to give the title compound as a white solid (0.32 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:13][C:14]=2[N+:15]([O-])=O)=[CH:5][CH:4]=1.[Cl-].[NH4+]>C(O)C.C1COCC1.O>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:13][C:14]=2[NH2:15])=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(SCc2ccc(OC)cc2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(N)c(SCc2ccc(OC)cc2)c1
Yield: 80.3 %

Procedure:
Under stirring, a solution of ethyl 3-(4-methoxybenzylthio)-4-nitrophenylacetate (3.33 g, 9.92 mmol), ammonium chloride (542 mg, 10.1 mmol) and reduced iron powder (2.57 g, 46.1 mmol) in ethanol/THF/water (2:2:1, 75 ml) was heated and refluxed for 1.5 hours. After the reaction mixture was cooled, the insoluble matter was filtered off. The filtrate was distilled under reduced pressure to remove the solvent. The residue was neutralized by pouring therein a saturated aqueous solution of sodium bicarbonate, followed by extraction with a chloroform-methanol mixture. The extract was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform-ethyl acetate (20:1) eluate fractions, ethyl 3-(4-methoxybenzylthio)-4-aminophenylacetate (2.64 g, 86%) was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][C:28]1([CH3:40])[O:32][CH:31]([CH2:33][N:34]2[CH:38]=[C:37]([NH2:39])[CH:36]=[N:35]2)[CH2:30][O:29]1.CCN(C(C)C)C(C)C>O1CCOCC1.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:21]=[CH:22][N:23]=[C:24]([NH:39][C:37]4[CH:36]=[N:35][N:34]([CH2:33][CH:31]5[CH2:30][O:29][C:28]([CH3:40])([CH3:27])[O:32]5)[CH:38]=4)[N:25]=3)[CH2:16][CH2:15]2)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCC(Cn2cc(N)cn2)O1
Reactant: Clc1ncnc(N2CCN(c3ncc(Cc4ccccc4)cn3)CC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1(C)OCC(Cn2cc(Nc3ncnc(N4CCN(c5ncc(Cc6ccccc6)cn5)CC4)n3)cn2)O1
Temperature: 25 °C
Yield: 126.1 %

Procedure:
A solution of 2-(4-(5-benzylpyrimidin-2-yl)piperazin-1-yl)-4-chloro-1,3,5-triazine (110 mg, 0.3 mmol), 1((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-amine (90 mg, 0.45 mmol) and Hunig's base (80 mg, 0.6 mmol) in 1,4-dioxane (4 mL) was stirred at 60° C. for 5 h. LCMS showed the reaction was completed. The reaction mixture was cooled to RT and diluted with ethyl acetate (40 mL). The organic phase was washed with water (40 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated to give 4-(4-(5-benzylpyrimidin-2-yl)piperazin-1-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-1,3,5-triazin-2-amine (200 mg, crude) as a yellow solid, which was directly used in the next step without further purification. MS (ES+) C26H30N10O2 requires: 528, found: 529 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])(C(F)(F)F)[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[CH:14]=[CH:13]2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10](=[O:27])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[CH:14]=[CH:13]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1C(C)(C)CC(=O)Cn1ccc(=O)c2ccccc21
Temperature: 120 °C
Yield: 56.7 %

Procedure:
To a solution of 1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one (2.25 g, 5.14 mmol) in DMF (40 mL) was added potassium carbonate (2.13 g, 15.4 mmol) followed by heating to 120° C. in a sealed reaction vessel for 14 hours. The solution was diluted with 300 mL of diethyl ether, washed with one 200 mL portion of saturated aqueous sodium bicarbonate, three 100 mL portions of water, one 100 mL portion of brine, dried over anhydrous sodium sulfite (Na2SO3), and concentrated in vacuo. The crude material was purified by flash column chromatography (5% MeOH/CH2Cl2) to give 1-[4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxopentyl]-1H-quinolin-4-one as a brown foam (1.07 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][CH2:24][C:19]=5[N:20]([CH3:23])[C:21]=4[CH:22]=3)[C:10](=[O:36])[CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[CH2:28][NH:27][CH2:26][CH2:25][CH2:24][C:19]=5[N:20]([CH3:23])[C:21]=4[CH:22]=3)[C:10](=[O:36])[CH:9]=2)=[CH:37][CH:38]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5)cc4=O)cc31)CNCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To a solution of tert-butyl 8-(4-(4-chlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (100 mg, 0.19 mmol) in dichloromethane (20 mL) was trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA). The clean fractions were combined and concentrated under reduced pressure. The trifluoracetate salt was converted to the HCl salt by dissolving in 1.25 M HCl in methanol and concentrating the resulting solution to dryness. This process was repeated three times afforded the title compound (35 mg, 39%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 7.64 (d, J=8.0 Hz, 2H), 7.48-7.42 (m, 5H), 7.07 (dd, J=8.0, 2.0 Hz, 1H), 6.37 (dd, J=7.5, 2.5 Hz, 1H), 6.17 (d, J=3.0 Hz, 1H), 5.20 (s, 2H), 4.55 (s, 2H), 3.77 (s, 3H), 3.59-3.57 (m, 2H), 3.22-3.19 (m, 2H), 2.26-2.18 (m, 2H); ESI MS m/z 434 [M+H]+.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[C:25]1([CH2:31][CH:32]=O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:32][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: O=CCc1ccccc1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2CCc2ccccc2)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was reductively aminated with phenyl acetaldehyde in analogy to experiment L3 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-phenethyl-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 458.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14].OO.C(O)(=[O:20])C>C1(C)C=CC=CC=1.C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:20]
Reactant: Cc1cc(O)c(SCCC(C)C)c(=O)o1
Reactant: CC(=O)O
Agent: OO
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1cc(O)c(S(=O)CCC(C)C)c(=O)o1
Temperature: 25 °C

Procedure:
4-Hydroxy-3-isopentylthio-6-methyl-2-pyrone (4.5 g., 0.020 mol), 30% hydrogen peroxide (2.44 g., 0.0220 mol), and 35 ml. glacial acetic acid were combined and stirred over night at room temperature. The clear solution was diluted with a mixture of toluene and ethanol and the acetic acid was removed by codistillation in vacuo. A yellow liquid was recovered which solidified upon cooling. The compound was recrystallized from n-hexane to recover 2.5 g. (51 percent) of shiny yellow platelets. One additional recrystallization from n-hexane gave the pure compound as tiny white crystalline needles: m.p. 80°-81°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[O:12][CH:13]=[C:14]([CH2:16]Cl)[N:15]=1.[CH3:18][S:19]([CH2:22][C:23]1[N:24]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH:25]=[CH:26][N:27]=1)(=[O:21])=[O:20].[H-].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[O:12][CH:13]=[C:14]([CH2:16][O:38][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][N:24]3[CH:25]=[CH:26][N:27]=[C:23]3[CH2:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:37][CH:36]=2)[N:15]=1
Reactant: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(F)cc3Cl)n2)cc1
Yield: 68.9 %

Procedure:
Using 2-[(E)-2-(2-chloro-4-fluorophenyl)ethenyl]-4-(chloromethyl)-1,3-oxazole (243 mg), 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol (250 mg) and 65% sodium hydride (32.9 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (304 mg) as colorless needle crystals.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[F:8][C:9]([F:39])([F:38])[C:10]1[CH:11]=[C:12]([C@H:20]([O:22][C@@H:23]2[C@@H:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:27]([C:35]([OH:37])=[O:36])[CH2:26][CH2:25][O:24]2)[CH3:21])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>CO.C1(C)C=CC=CC=1>[F:39][C:9]([F:38])([F:8])[C:10]1[CH:11]=[C:12]([C@H:20]([O:22][C@@H:23]2[C@@H:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:27]([C:35]([O:37][CH3:1])=[O:36])[CH2:26][CH2:25][O:24]2)[CH3:21])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C[C@@H](O[C@H]1OCC[C@@H](C(=O)O)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)[C@@H]1CCO[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Yield: 73 %

Procedure:
Trimethylsilyldiazomethane (2.0M in hexanes, 3.5 mL, 7 mmol) was added in portions over 1 hour to a solution of (2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-carboxylic acid (WO 00/56727A1; 3.2 g, 6.9 mmol) in a mixture of methanol (10 mL) and toluene (7 mL). The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane (80:20), to give the title compound as a colorless solid (2.4 g, 73%).