Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([C:12]1[CH:25]=[CH:24][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=2)=[C:14]([CH2:26][CH2:27][CH3:28])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].ClC1C=CC=[C:34]([C:38]([O:40]O)=[O:39])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[C:38]([O:40][CH2:23][C:19]1[CH:18]=[C:17]([O:16][C:15]2[CH:24]=[CH:25][C:12]([C:3]([O:8][CH2:9][O:10][CH3:11])([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:29])[F:30])=[CH:13][C:14]=2[CH2:26][CH2:27][CH3:28])[CH:22]=[CH:21][N:20]=1)(=[O:39])[CH3:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccnc(C)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccnc(COC(C)=O)c1
Temperature: 140 °C
Yield: 55.6 %

Procedure:
To a solution of 4-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)-2-methylpyridine (780 mg, 1.78 mmol) in chloroform (2 mL), m-chloroperbenzoic acid (2.05 g) was added at room temperature and the resultant mixture was stirred. After completion of the reaction, the reaction solution was added with an aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and then dried using sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The obtained residue was added with acetic anhydride and heated at a surrounding temperature of 140° C. After completion of the reaction, the reaction solution was added with methanol (4 mL) at room temperature, then neutralized by adding a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (490 mg, yield 56%) was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[CH2:12][C:13]#[N:14].[NH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[CH:22]=O.[OH-].[Na+]>CCO.CCOC(C)=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13]([NH2:14])=[N:15][C:16]2[C:17]([CH:22]=1)=[CH:18][N:19]=[CH:20][CH:21]=2
Reactant: Nc1ccncc1C=O
Reactant: N#CCc1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1nc2ccncc2cc1-c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 23.4 %

Procedure:
A solution of 2,6-dichloro-3-nitrophenyl-acetonitrile (1.02 g, 4.42 mmol), 4-amino-pyridine-3-carbaldehyde (0.4 g, 3.28 mmol) and NaOH (52 mg, 1.31 mmol) in EtOH (2.0 mL) is heated to 105° C. for 24 hours. The reaction mixture is diluted with EtOAc (50 ml) and washed with saturated K2CO3 and brine. The organic layer is dried, filtered and concentrated to give crude product. Flash silica gel column purification eluting with CH2Cl2 (100%) gradient to CH2Cl2/MeOH (2N NH3) (100/6) affords the titled intermediate as a solid (257 mg, 23.4%).
Reaction SMILES: [Si:1]([O:18][CH:19]([C:21]1[CH:25]=[N:24][N:23]([CH2:26][C@@H:27]2[C@H:30]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29](=[O:42])[N:28]2CC2C=CC(OC)=CC=2OC)[N:22]=1)[CH3:20])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OP([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[Si:1]([O:18][CH:19]([C:21]1[CH:25]=[N:24][N:23]([CH2:26][C@@H:27]2[C@H:30]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29](=[O:42])[NH:28]2)[N:22]=1)[CH3:20])([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2ncc(C(C)O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n2)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 67.8 %

Procedure:
To a solution of benzyl ((2R,3S)-2-((4-(1-((tert-butyldiphenylsilyl)oxy)ethyl)-2H-1,2,3-triazol-2-yl)methyl)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-3-yl)carbamate (2.50 g, 3.41 mmol) in ACN/water (2:1, 45 mL) at room temperature was added K2S2O8 (1.57 mg, 5.79 mmol) and K2HPO4 (949 mg, 5.45 mmol). The mixture was heated to 90° C. under nitrogen with stirring for 6 h. The reaction mixture was concentrated in vacuo to remove ACN. To the resulting slurry was added EtOAc and water. The organic layer was separated and the aqueous layer was extracted with EtOAc (2×). The organic portions were combined, dried with Na2SO4, filtered and concentrated in vacuo. Purification of the crude residue via silica gel chromatography (EtOAc-Heptane, 30-60%) afforded the title compound (1.35 g, 68%). LCMS: Rt=1.18 min, m/z=584.3 (M+1) Method 2m_acidic.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([N:17]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:22]([O:35][CH2:36][CH:37]([CH3:39])[CH3:38])[N:21]=3)[CH3:18])[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([N:17]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=4[F:34])=[C:22]([O:35][CH2:36][CH:37]([CH3:39])[CH3:38])[N:21]=3)[CH3:18])[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cc(N(C)Cc2ccc(-c3cc(OC)ccc3F)c(OCC(C)C)n2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(CN(C)c3cc(C(CC(=O)O)C4CC4)ncn3)nc2OCC(C)C)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-(((5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methyl)(methyl)amino)pyrimidin-4-yl)propanoate (30 mg) in methanol (3.0 mL) was added 1N aqueous sodium hydroxide solution (0.17 mL), and the mixture was stirred at 50° C. for 3 hr. 1N Hydrochloric acid was added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from hexane/diethyl ether to give the title compound (20 mg) as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:9][C:10]([OH:12])=O.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[CH2:16]([O:15][C:13]([N:7]1[CH2:8][CH2:9][C:10](=[O:12])[C:3]2[CH:4]=[CH:5][O:1][C:2]=2[CH2:6]1)=[O:14])[CH3:17]
Reactant: CCOC(=O)N(CCC(=O)O)Cc1ccco1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)N1CCC(=O)c2ccoc2C1
Temperature: 0 °C
Yield: 41.4 %

Procedure:
3-[(Furan-2-ylmethyl)(ethoxycarbonyl)amino]propionic acid (3.6 g) prepared in the step 4 was dissolved in 300 mL of methylene chloride, then 2.66 g of thionyl chloride and 5 drops of DMF were added thereto and the mixture was heated to reflux for 3 hours. The reaction solution was cooled, 20.0 g of aluminum chloride was added thereto and the mixture was heated to reflux again for 30 minutes. The reaction solution was poured over 300 mL of ice water, the organic layer was separated, washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo therefrom. The residue was purified by silica gel column chromatography to give 1.38 g of the objective compound as yellow liquid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:32])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C[Sn](C)(C)[C:35]1[S:36][CH:37]=[CH:38][N:39]=1>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:35]3[S:36][CH:37]=[CH:38][N:39]=3)[CH:3]=2)=[O:32])=[CH:12][CH:13]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: C[Sn](C)(C)c1nccs1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(I)c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(-c3nccs3)c2)cc1
Yield: 19.5 %

Procedure:
A mixture of 10 g of N-[3-iodophenyl)-4-(tetradecyloxy)benzeneacetamide, 4.96 g of 2-(trimethylstannyl)thiazole, and 638.62 mg of dichlorobis(triphenylphosphine)palladium (II) in 100 ml of tetrahydrofuran is refluxed under argon for 6 hours. The solvent is evaporated and the residue is partitioned between chloroform and 1N sodium hydroxide. The organic layer is dried and evaporated to a yellow solid residue. The residue is purified by chromatography on silica gel using chloroform. A total of 3.5 g of starting material is recovered as well as impure product which is crystallized from hexane:carbon tetrachloride to give 1.8 g of the desired product as a tan solid, m.p. 128°-131° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2I)=[O:16])[CH2:4][O:3]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1([CH3:25])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)=[O:16])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@H](NC(=O)Nc2ccccc2I)[C@H](c2ccccc2)O1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC1(C)OC[C@H](NC(=O)Nc2ccccc2-c2cccnc2)[C@H](c2ccccc2)O1
Temperature: 80 °C
Yield: 36.1 %

Procedure:
To a reaction flask charged with 10.8 mg (0.0094 mmol) of tetrakis(triphenylphosphine)palladium(0) in ethylene glycol dimethyl ether (1.8 mL) under nitrogen was added 107 mg (0.24 mmol) of the product from Example 6. The resulting yellow solution was stirred for 15 min before the addition of 34.0 mg (0.28 mmol) of pyridine-3-boronic acid dissolved in ethanol (0.4 mL) and ethylene glycol dimethyl ether (0.2 mL), and the subsequent addition of 0.23 mL (0.47 mmol) of a 2 M sodium carbonate aqueous solution. The reaction mixture was heated at 80° C. for ˜20 h and then cooled to room temperature. The liquid was separated from the solid residue, and the residue was rinsed with dichloromethane, which was subsequently combined with the isolated liquid. The solvent was evaporated, and the crude product was partitioned between brine (˜4 mL) and dichloromethane (˜4 mL). The organic layer was washed with additional brine, dried over magnesium sulfate, and filtered. The solvent was evaporated, and the residue, an orange oil, was purified by column chromatography (hexane/ethyl acetate) to yield 35 mg (36%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN1CCOCC1.ClC(OCC(C)C)=O.C(OC([NH:39][CH2:40][C:41]([NH:43][C@H:44]1[CH2:49][CH2:48][C@@H:47]([N:50]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH:51]([CH3:53])[CH3:52])[CH2:46][C@H:45]1[C:61]([O:63][CH:64]([CH3:66])[CH3:65])=[O:62])=[O:42])=O)C1C=CC=CC=1>C1COCC1.O>[C:57]([O:56][C:54]([N:50]([CH:51]([CH3:53])[CH3:52])[C@H:47]1[CH2:46][C@@H:45]([C:61]([O:63][CH:64]([CH3:66])[CH3:65])=[O:62])[C@@H:44]([NH:43][C:41](=[O:42])[CH2:40][NH:39][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=2)[CH2:49][CH2:48]1)=[O:55])([CH3:59])([CH3:58])[CH3:60]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)OC(=O)[C@@H]1C[C@H](N(C(=O)OC(C)(C)C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)OC(=O)[C@@H]1C[C@H](N(C(=O)OC(C)(C)C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 0.08 h
Yield: 63.6 %

Procedure:
A solution of 3-Trifluoromethyl-benzoic acid (0.23 g, 0.0012 mol) in THF was cooled in an ice bath and treated with N-methylmorpholine(0.13 g, 0.0013 mol) and then drop-wise with isobutyl chloroformate (0.16 g, 0.0012 mol). The resulting mixture was stirred for 5 min and then treated with a solution of isopropyl (1R,2S,5R)-2-(2-aminoacetamido)-5-(tert-butoxycarbonyl-isopropyl-amino)cyclohexanecarboxylate (0.45 g, 0.0011 mol; See Example 8b, Step 4) in THF. The resulting mixture was stirred for 30 minutes and then diluted with water and extracted into CH2Cl2. The extract was washed with dilute NaOH, water, and brine and then concentrated under vacuum. The residue was chromatographed on silica gel (elution 55% ethyl acetate/hexane) to give 0.4 g of isopropyl(1R,2S,5R)-5-(tert-butoxycarbonyl-isopropyl-amino)-2-(2-(3-trifluoromethyl-benzamido)acetamido)cyclohexanecarboxylate as a white solid, MS found: (M+H)+=572.4.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[C:3]([CH:16]=[O:17])[CH:2]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.[OH-].[Ca+2].[OH-]>C(Cl)Cl>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6](=[O:26])[C:5]=2[CH:4]=[C:3]([CH:16]=[O:17])[CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1ccc2c(c1)Sc1ccccc1CC2
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)S(=O)c1ccccc1CC2
Reaction time: 2 h

Procedure:
Mix 2.84 g (11.83 mmole) of 10,11-dihydrodibenzo[b,f]thiepin-3-carboxaldehyde with 90 ml methylene chloride at 0° C. Add 2.3 g (11.33 mmoles) of 85% m-chloroperbenzoic acid, followed by the addition of 100 ml methylene chloride. Stir for 2 hours, and then add 4.6 g calcium hydroxide to the resulting clear solution at room temperature. After stirring the suspension for 15 minutes, filter to remove the inorganic solid, and evaporate the filtrate containing the dissolved product to dryness, producing as a residue a dry solid comprising the title product. Purify by recrystallization from acetonitrile, m.p. 158.5°-160° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:23]=[CH:22][C:13]([O:14][CH2:15][CH:16]3[O:20][C:19]([NH2:21])=[N:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:3]1.C1O[C@H]1CCl.CC1(C)CC(C)(C)C[CH:33]([C:39]2C=C[C:42]([OH:45])=[CH:41][CH:40]=2)C1.C(OCC)(=O)C#CCC>C(O)C>[CH2:39]([C:40]1[N:18]2[CH2:17][C@@H:16]([CH2:15][O:14][C:13]3[CH:12]=[CH:11][C:10]([CH:4]4[CH2:5][C:6]([CH3:8])([CH3:9])[CH2:7][C:2]([CH3:24])([CH3:1])[CH2:3]4)=[CH:23][CH:22]=3)[O:20][C:19]2=[N:21][C:42](=[O:45])[CH:41]=1)[CH3:33]
Reactant: CC1(C)CC(c2ccc(O)cc2)CC(C)(C)C1
Reactant: CC1(C)CC(c2ccc(OCC3CN=C(N)O3)cc2)CC(C)(C)C1
Agent: CCC#CC(=O)OCC
Agent: ClC[C@H]1CO1
Solvent: CCO
Product: CCc1cc(=O)nc2n1C[C@@H](COc1ccc(C3CC(C)(C)CC(C)(C)C3)cc1)O2
Temperature: 25 °C

Procedure:
To a solution of 5-[4-(3,3,5,5-tetramethyl-cyclohexyl)-phenoxymethyl]-4,5-dihydro-oxazol-2-ylamine (0.15 g, 0.454 mmol), prepared in accordance with the procedures described in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 4-(3,3,5,5-tetramethyl-cyclohexyl)-phenol (prepared using the same procedure as in step 1 of Example 74), in ethanol (5 mL) was added ethyl 2-pentynoate (0.086 g, 0.681 mmol). The reaction mixture was heated at reflux for 14 hrs and then cooled to room temperature. The reaction mixture was concentrated, loaded onto a silica gel column, and eluted with 4% methanol/methylene chloride to afford 23 mg of (S)-5-ethyl-2-[4-(3,3,5,5-tetramethyl-cyclohexyl)-phenoxymethyl]-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[S:14]([Cl:18])(=O)(=[O:16])[OH:15].O=S(Cl)Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([C:9](=[O:11])[CH3:10])[CH3:12])[CH:5]=[CH:6][C:7]=1[S:14]([Cl:18])(=[O:16])=[O:15]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)C(C)(C)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CC(=O)C(C)(C)c1ccc(S(=O)(=O)Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of 3-(3-chlorophenyl)-3-methylbutan-2-one (15 g, 76 mmol) in CHCl3 (100 mL) was added chlorosulfuric acid (101 mL, 20 eq) at 0° C. over 2 h. Next SOCl2 (20 mL) was added dropwise to the reaction mixture over 30 min under nitrogen. The reaction mixture was slowly warmed to room temperature and stirred overnight. The mixture was slowly added to ice-water and then extracted with EtOAc. The combined extracts were washed with brine, dried over MgSO4 and evaporated. The residue was purified by chromatography (silica, Hex/EtOAc=9:1 to 4:1) to give 2-chloro-4-(2-methyl-3-oxobutan-2-yl)benzene-1-sulfonyl chloride as a yellow solid (9.8 g, 43%). 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J=8.4 Hz, 1H), 7.54 (s, 1H), 7.37 (d, J=2.2 Hz, 1H), 2.03 (s, 3H), 1.56 (s, 6H).
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.S(Cl)([Cl:14])=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(OC)(C)(C)C>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][Cl:14]
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(CO)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: COc1cccc(CCl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
24.79 g (158.75 mmol) of 2-fluoro-3-methoxybenzyl alcohol is dissolved in 35 ml of dichloromethane. While being cooled slightly, 58.4 ml of thionyl chloride is added in drops, and the batch is then stirred overnight at room temperature. The reaction mixture is spun in until a dry state is reached, the residue is dissolved in methyl tert-butyl ether, and it is shaken twice with semi-saturated potassium carbonate solution. The aqueous phase is extracted once with methyl tert-butyl ether. The combined organic extracts are worked up as usual. The residue that is obtained is incorporated in crude form into the next stage.
Reaction SMILES: CO[C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1.[NH2:33]C1C=CC(C#N)=CN=1>>[C:3]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1)#[N:33]
Reactant: COC(=O)c1ccc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Reactant: N#Cc1ccc(N)nc1
Product: COc1ccc(CN2C(=O)C(C)=C(C)C2SCC(=O)Nc2ccc(C#N)cn2)cc1

Procedure:
The product from Example 1, Part C (160 mg, 0.5 mmol) and 6-aminonicotinonitrile (89 mg, 0.75 mmol) were reacted as described in Example 5. After evaporation of the reaction solvent the residue was partitioned between water and EtOAc, the aqueous phase was washed with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered, and evaporated. The title compound was obtained by silica gel chromatography (30 mg, 14%). 1H NMR (400 MHz, CDCl3) δ 8.84 (br s, 1H), 8.55 (d, J=2 Hz, 1H), 8.30 (d, J=9 Hz, 1H), 7.95 (dd, J=9 Hz, 2 Hz, 1H), 7.21 (d, J=9 Hz, 2H), 6.83 (d, J=9 Hz, 2H), 5.07 (d, J=15 Hz, 1H), 4.63 (s, 1H), 4.12 (d, J=15 Hz, 1H), 3.77 (s, 3H), 2.96 (m, 2H), 1.94 (s, 3H), 1.84 (s, 3H). MS: m/z (MNa+) 445.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([OH:11])[CH:7]1[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH3:16])=[O:4]>C(Cl)Cl>[CH3:1][O:2][C:3]([CH2:5][CH:6]1[CH2:10][CH2:9][C:8](=[O:11])[CH:7]1[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH3:16])=[O:4]
Reactant: CC/C=C\CC1C(O)CCC1CC(=O)OC
Solvent: ClCCl
Product: CC/C=C\CC1C(=O)CCC1CC(=O)OC
Temperature: 18 °C
Reaction time: 12 h

Procedure:
A 150 mg quantity of 3-methoxycarbonylmethyl-2-(cis-2-pentenyl)-cyclopentanol is dissolved in 10 ml of methylene chloride. A 2 ml quantity of chromic acid solution of 2 M concentration is added dropwise to the solution. The mixture is stirred at about 18° C. for 12 hours and thereafter extracted with ethyl acetate. The extract is washed with aqueous solution of sodium chloride, dried and concentrated. The residue is purified with a silica gel column and distilled in a vacuum, affording 3-methoxycarbonylmethyl-2-(cis-2-pentenyl)-cyclopentanone (compound (4), R2 =CH3) in a yield of 88%, b.p. 92°-96° C./2.7 mm Hg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[C:21]([S:23][CH3:24])[N:20]=[C:19]([C:25](O)=[O:26])[CH:18]=3)[CH2:13][CH2:12]2)=[O:9])[NH:5][C:6]=1[CH3:7].[NH3:28]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[C:21]([S:23][CH3:24])[N:20]=[C:19]([C:25]([NH2:28])=[O:26])[CH:18]=3)[CH2:13][CH2:12]2)=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: CSc1nc(C(=O)O)cc(N2CCC(NC(=O)c3cc(Br)c(C)[nH]3)CC2)n1
Reactant: N
Solvent: CO
Product: CSc1nc(C(N)=O)cc(N2CCC(NC(=O)c3cc(Br)c(C)[nH]3)CC2)n1

Procedure:
Title compound was synthesized by an analogous method to Example 8 by coupling 6-(4-{[(4-bromo-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-(methylthio) pyrimidine-4-carboxylic acid (Example 35) with 2 M ammonia in MeOH (commercially available).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH:18]1[CH2:20][CH2:19]1>>[CH:18]1([CH2:17][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[CH2:20][CH2:19]1
Reactant: BrCC1CC1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Product: Cc1cc(C#Cc2cn(CC3CC3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=252.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and bromomethyl-cyclopropane.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18](O)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[C:17]([CH:21]=2)[C:18]([NH:40][C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccc(OC)cc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccc(OC)cc3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.5 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(4-methoxyphenyl) benzoic acid (100 mg, 0.2369 mmol) was dissolved in methylene chloride (20 ml), then p-anisidine (58 mg, 0.4715 mmol), triethylamine (48 mg, 0.4752 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (80 mg, 0.4733 mmol) were added thereto at room temperature and the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer silica gel (hexane:ethyl acetate=1:1) to give the title compound (78 mg, 0.1480 mmol, 62%).