Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19](Br)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.O.[Cl-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[N:18][C:17]=3[N:16]([CH3:29])[C:14]2=[O:15])[N:3]=1
Reactant: C1CNCCN1
Reactant: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1c(N2CCNCC2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 200 °C

Procedure:
A mixture of 300 mg of 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine and 290 mg of piperazine in 5 ml of N,N-dimethylformamide is heated at 200° C. for 5 min in a microwave oven. After cooling to room temperature, the reaction mixture is treated with water and saturated sodium chloride solution and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The solid flask residue is triturated with diethyl ether, filtered off with suction and dried at 45° C. in a circulating air drying oven.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[N:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)([O:3][CH2:4][CH3:5])=[O:2].[CH2:16]([O:18][CH:19](OC(=O)C)OCC)[CH3:17].C(OCC)C>C(O)(=O)C>[C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[N:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:19][O:18][CH2:16][CH3:17])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(OCC)OC(C)=O
Reactant: CCOC(=O)c1cnc2c(c1)CC(=O)N2
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC=C1C(=O)Nc2ncc(C(=O)OCC)cc21
Temperature: 110 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
5-Carboethoxy-7-azaoxindole (0.040 g, 0.19 mmol) and diethoxymethylacetate (0.16 mL, 0.97 mmol) were combined and dissolved in acetic acid (1 mL). The reaction was warmed to 110° C. and stirred at this temperature for 1 h. The reaction was cooled to room temperature and diethyl ether was added to precipitate a beige solid that was collected by filtration (35 mg, 69% yield). 1H NMR 400 M Hz (DMSO-d6) δ 11.30 (s, 1H); 8.58 (s, 1H); 8.05 (s, 1H); 7.93 (s, 1H); 4.44 (m, 2H); 4.28 (m, 2H); 1.35 (m, 3H); 1.28 (m, 3H).
Reaction SMILES: [O-]CC.[Na+].[Br:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:14])=[C:10]([CH:13]=1)[CH:11]=O.[N:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N+:16]=[N-:17]>C(O)C.C(O)C.O1CCCC1>[N:15](/[C:18](=[CH:11]\[C:10]1[CH:13]=[C:6]([Br:5])[CH:7]=[CH:8][C:9]=1[Cl:14])/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N+:16]=[N-:17]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1cc(Br)ccc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)/C(=C/c1cc(Br)ccc1Cl)N=[N+]=[N-]
Temperature: -10 °C
Reaction time: 3 h

Procedure:
To a solution of sodium ethoxide in ethanol (15 mL) cooled to −10° C. was added dropwise a solution of 5-bromo-2-chlorobenzaldehyde (1.0 g) and ethyl 2-azidoacetate (11 mL, 18 mmol) in ethanol-tetrahydrofuran (15 mL-3 mL). The reaction mixture was stirred at −10° C. for 3 hours, allowed to warm to 10° C. over 3 hours and poured onto crushed ice. The solid was collected by filtration and dried in a vacuum oven to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:12][O:13][CH3:14]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:12][O:13][CH3:14])=[CH:6][N:7]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1000 mg (1 eq) of 6-chloropyridin-3-ol was dissolved in 50 mL of N,N-dimethylformamide, and 370 mg (1.2 eq) of sodium hydride was added thereto, followed by stirring at room temperature for 1 hour. Then, 688 uL (1.1 eq) of chloro(methoxy)methane was added slowly thereto, and the solution was stirred at room temperature for 2 hours. N,N-dimethylformamide was removed by concentrating under reduced pressure. After extracting with ethyl acetate, the extract was treated with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (developing solvent, hexane:ethyl acetate=9:1) to obtain 1200 mg of 2-chloro-5-(methoxymethoxy)pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[C:12]([CH2:13][S:14][CH2:15][C:16]([NH2:18])=[O:17])=[CH:11][CH:10]=[CH:9][C:7]=3[O:8][C:4]=2[CH:3]=1.[OH:21]O>C(O)(=O)C>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[C:12]([CH2:13][S:14]([CH2:15][C:16]([NH2:18])=[O:17])=[O:21])=[CH:11][CH:10]=[CH:9][C:7]=3[O:8][C:4]=2[CH:3]=1
Reactant: NC(=O)CSCc1cccc2oc3cc(Cl)ccc3c12
Reactant: OO
Solvent: CC(=O)O
Product: NC(=O)CS(=O)Cc1cccc2oc3cc(Cl)ccc3c12
Temperature: 50 °C
Reaction time: 24 h
Yield: 74.2 %

Procedure:
To a suspension of 2-(7-chlorodibenzofuran-1-ylmethylsulfanyl)acetamide (Example 151 2.56 g, 8.38 mmole) in acetic acid (90 mL), were added 1.4 mL of 35% hydrogen peroxide (14.4 mmole). The mixture was heated at 50° C. for 30 minutes to give a solution, then stirred at RT for 24 hours to give a thick suspension which was filtered, washed by ethanol, ether, dried in vacuum to give 2 g of white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:23][C:24]2[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=2[C:26](OCC)=[O:27])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:10]=2)=[N:6][CH:7]=1.[NH:35]1[CH2:40][CH2:39][S:38][CH2:37][CH2:36]1>>[F:1][C:2]1[C:3]([NH:23][C:24]2[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=2[C:26]([N:35]2[CH2:40][CH2:39][S:38][CH2:37][CH2:36]2)=[O:27])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: C1CSCCN1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1F
Product: O=C(c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1F)N1CCSCC1

Procedure:
Ethyl 2-{[5-fluoro-2-({3-[2-(4-morpholinyl)ethyl]phenyl}amino)-4-pyrimidinyl]amino}benzoate (200 mg, 0.51 mmoles) and thiomorpholine (2 mL) were heated at 120° C. for 48 h. The reaction mixture was concentrated to dryness under vacuum and the title compound was purified by flash chromatography on silica gel (using ethyl acetate containing 0.1% triethylamine). MS: M(C27H31FN6O2S)=522.2, (M+H)+=523.
Reaction SMILES: [CH2:1]([C@@H:3]1[C@@H:16]2[C@:7]3([CH2:19][CH2:18][N:17]([CH3:20])[C@@H:15]2[CH2:14][C:13]2[CH:12]=[CH:11][C:10]([O:21][CH3:22])=[CH:9][C:8]3=2)[CH2:6][C:5](=[O:23])[CH2:4]1)[CH3:2].[N:24]#CBr>>[C:20]([N:17]1[CH2:18][CH2:19][C@@:7]23[C:8]4[CH:9]=[C:10]([O:21][CH3:22])[CH:11]=[CH:12][C:13]=4[CH2:14][C@@H:15]1[C@@H:16]2[C@@H:3]([CH2:1][CH3:2])[CH2:4][C:5](=[O:23])[CH2:6]3)#[N:24]
Reactant: CC[C@H]1CC(=O)C[C@]23CCN(C)[C@H](Cc4ccc(OC)cc42)[C@H]13
Reactant: N#CBr
Product: CC[C@H]1CC(=O)C[C@]23CCN(C#N)[C@H](Cc4ccc(OC)cc42)[C@H]13
Yield: 73 %

Procedure:
To a rapidly stirred solution of 8β-ethyl-3-methoxy-17-methylmorphinan-6-one (prepared in Part A) was added cyanogen bromide as in Example 1B. The product, mp. 141°-145° C., was obtained in 73% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2O)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:19])=O.C(N(C(C)C)CC)(C)C.OP([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[Cl:19])=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cn2ncnc(O)c2c1C
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn2ncnc(Cl)c2c1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 10 L reactor was charged with 4-hydroxy-5-methyl-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester (155.1 g, 0.7 mol) and toluene (2.7 L). Phosphorous oxychloride (128.8 g, 78 mL, 0.84 mol) was then added followed by the addition of diisopropylethylamine (94.2 g, 127 mL, 0.7 mol). The reaction mixture was stirred for 5 min at room temperature and then heated at reflux for 20 h. HPLC analysis indicated complete disappearance of starting material. The reaction mixture was then cooled to 0° C. and cold K2HPO4 solution (527 g in 2.4 L of water) was added at a rate to maintain the internal temperature of the reaction mixture below 5° C. The final pH of the mixture was 8. The mixture was then stirred at between 0° C. to 5° C. for 20 min and then at room temperature for 1 h. The organic phase was separated and washed with K2HPO4 solution (85 g in 405 mL of water) and water (345 mL) and then filtered and concentrated in vacuo until yellow solids began to precipitate. Dimethyl formamide (1 L) was added and the remaining toluene was removed in vacuo (bath temperature=38° C., pressure=9 Torr). After concentration, approximately 4% toluene was observable by HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(#N)C>[CH2:25]([O:24][C:22](=[O:23])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])=[CH:6][CH:7]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)C(=O)CCc1ccc(N)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)C(=O)CCc1ccc(NC(=O)OCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A solution of 11.9 g (62 mmol) of crude 5-(4-amino-phenyl)-2-methyl-pentan-3-one (prepared in Example GGGGG) in 100 mL of acetonitrile was treated with 24.3 g (75 mmol) of cesium carbonate, and the mixture was stirred at 50° C. for 15 minutes. Benzyl chloroformate (10.7 mL, 75 mmol) was added all at once, and the mixture was stirred at room temperature for 90 minutes. The solvent was evaporated. The residue was partitioned between EtOAc and H2O; the organic layer was separated, washed with brine, dried (MgSO4), and concentrated. The product was chromatographed on silica gel, eluting with EtOAc:hexane (30:70), to give the title compound. 1H NMR (CDCl3) δ 1.01 (d, 6 H), 2.48-2.55 (m, 1 H), 2.67-2.82 (m, 4 H), 5.15 (s, 2 H), 6.58 (br s, 1 H), 7.08 (d, 2 H), 7.25-7.38 (m, 7 H).
Reaction SMILES: C([O:4][C@H:5]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C:7](=[C:8]([CH2:36][N:37]([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:9][C@@H:10]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:26])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:25])[CH2:20]OC(=O)C)[CH2:6]1)(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:38]([N:37]([CH2:36][C:8]1[CH2:9][C@@H:10]2[C@@H:30]([C@:31]3([CH3:34])[C:7]=1[CH2:6][C@@H:5]([OH:4])[CH2:33][CH2:32]3)[CH2:29][CH2:28][C@@:27]1([CH3:35])[C@H:11]2[CH2:12][CH2:13][C@@H:14]1[C@H:15]([CH3:26])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[CH3:25])[CH2:42][CH2:43][CH2:44][CH3:45])[CH2:39][CH2:40][CH3:41]
Reactant: CCCCN(CCCC)CC1=C2C[C@@H](OC(C)=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)COC(C)=O)CC[C@H]3[C@@H]2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCCN(CCCC)CC1=C2C[C@@H](O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]2C1

Procedure:
To a solution of approximately 10 parts of 3β-acetoxy-acetoxy-6-(dibutylaminomethyl)cholest-5-ene in 80 parts of methanol is added 10 parts of aqueous 20% potassium carbonate. The resultant mixture is heated to the boiling point under reflux for 2 hours, whereupon 100 parts of water is introduced. The oil which separates is extracted with hexane. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residual oil is taken up in benzene; and the benzene solution is chromatographed on alumina, using benzene and mixtures thereof with increasing amounts of ethanol as developing solvents. From an eluate comprising 2% ethanol in benzene, on evaporation of solvent, 6-(dibutylaminomethyl)cholest-5-en-3β-ol is obtained as the residue.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=3[F:29])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1.Br>CC(O)=O>[F:29][C:21]1[CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=[CH:25][C:20]=1[O:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:30][CH3:31])[CH:11]=2)[N:16]=[CH:15][CH:14]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
To a flask containing 7-benzyloxy-4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinoline (850 mg, 2.0 mmol) was added 20 mL of 30% HBr in AcOH. The resulted solution was stirred for 4 h at rt; at this time, a large amount of precipitate formed. The crude product was filtered, washed with Et2O and dried in air, giving 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-hydroxyquinoline (609 mg, 92% yield).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=2[CH:14]=[N:15][OH:16])=[CH:4][CH:3]=1.[OH-].[Na+].CS(C)=O.Br[CH2:26][C:27]1[CH:41]=[CH:40][C:30]([C:31]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:32])=[CH:29][CH:28]=1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:8]=2[CH:14]=[N:15][O:16][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([O:33][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:32])=[CH:40][CH:41]=2)=[CH:17][CH:18]=1
Reactant: Cc1nn(C)c(Oc2ccc(F)cc2)c1C=NO
Reactant: O=C(OC1CCCCC1)c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nn(C)c(Oc2ccc(F)cc2)c1C=NOCc1ccc(C(=O)OC2CCCCC2)cc1
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
2.0 Grams (0.008 mole) of 5-(4-fluorophenoxy)-1,3-dimethylpyrazole-4-carbaldehyde oxime and 0.5 g (0.0125 mole) of powdery sodium hydroxide were added to 50 ml of dimethyl sulfoxide, and the resulting mixture was stirred for 30 minutes. To this solution was added 2.38 g (0.008 mole) of cyclohexyl 4-bromomethylbenzoate, and reaction was carried out at from 70° to 80° C. for 6 hours. After completion of the reaction, water was added to the reaction solution which was then extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 3.0 g of the desired compound.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:36][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:28])([F:29])[F:27])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:21]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4cccc(Cl)c4)cc(C(F)(F)F)n3)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4cccc(Cl)c4)cc(C(F)(F)F)n3)cn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[6-(3-chloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.2 g) in dichloromethane (5 mL) was added TFA (5 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (3 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as a white solid (0.1 g, 14%). MS (ISP) 580.2 [(M+H)+]; mp 204.5° C.
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]#[N:30])[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.[NH4+]=[S:32]>CN(C=O)C>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29](=[S:32])[NH2:30])[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: C[C@@H]1CN2c3c(cc4c(C#N)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Solvent: CN(C)C=O
Product: C[C@@H]1CN2c3c(cc4c(C(N)=S)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2R,4S,4aS)-rel-11-fluoro-2,4-dimethyl-2′,4′,6′-trioxo-1,1′,2,3′,4,4′,4a,6′-octahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-8-carbonitrile (Example 183, 210 mg, 0.51 mmol) in DMF was added ammonium sulfide (0.35 mL, 1.02 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give product as a pale yellow solid.
Reaction SMILES: [CH:1](/[CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)=[CH:2]\[CH3:3]>CO>[CH2:1]([CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: C/C=C/C1CCc2ccccc21
Solvent: CO
Product: CCCC1CCc2ccccc21

Procedure:
A MeOH (6 mL) solution of the trans-propenylindane acid from 144b (11.8 mg, 0.18 mmol) was hydrogenated under 50 psi H2 for 1 h to give propylindane acid. MS Found: (M+Na)=317.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH:7]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)[CH2:8][NH:9][C:10]([C:12]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:18]([CH2:17][C:12]1([C:10]([NH:9][CH2:8][CH:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:6]([OH:30])=[O:5])=[O:11])[CH2:16][CH2:15][CH2:14][CH2:13]1)([OH:20])=[O:19]
Reactant: CC(C)(C)OC(=O)C(CNC(=O)C1(CC(=O)O)CCCC1)Cc1ccc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC1(C(=O)NCC(Cc2ccc(Cl)c(Cl)c2)C(=O)O)CCCC1
Reaction time: 2 h
Yield: 39 %

Procedure:
To a solution of 2-(1-(3-tert-butoxy-2-(3,4-dichlorobenzyl)-3-oxopropylcarbamoyl)cyclopentyl)acetic acid (30.6 mg, 0.067 mmol) in DCM (0.7 ml), TFA (0.257 ml, 3.34 mmol) was added. The reaction mixture was allowed to stir for 2 hr and then concentrated under reduced pressure. The obtained residue was purified by RP-HPLC (SunFire, H2O (0.1% TFA) I CH3CN), and then lyophilized to give 3-(1-(carboxymethyl)cyclopentanecarboxamido)-2-(3,4-dichlorobenzyl)propanoic acid (10.5 mg); Retention time=0.67 minutes (condition B); MS (m+1)=402.0; 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.47-1.58 (m, 6H) 1.97-2.04 (m, 2H) 2.54-2.63 (m, 2H) 2.68-2.84 (m, 3H) 3.13-3.28 (m, 2H) 7.17-7.19 (m, 1H) 7.43 (d, J=2.0 Hz, 1H) 7.52-7.54 (m, 1H) 7.61-7.63 (app t, 1H) 12.14 (br s, 2H); HRMS (ES+) m/z for C18H22Cl2NO5 [M+H]+ calcd 402.0875. found 402.0855.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH3:12])[C:6]3=[N:13][C@@H:14]4[CH2:18][CH2:17][CH2:16][C@@H:15]4[N:5]3[C:4]=2[N:3]=1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[CH3:1][C:2]1[N:10]([CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[C:9]2[C:8](=[O:11])[N:7]([CH3:12])[C:6]3=[N:13][C@@H:14]4[CH2:18][CH2:17][CH2:16][C@@H:15]4[N:5]3[C:4]=2[N:3]=1
Reactant: Cc1nc2c([nH]1)C(=O)N(C)C1=N[C@@H]3CCC[C@@H]3N12
Reactant: ClCc1ccncc1
Product: Cc1nc2c(n1Cc1ccncc1)C(=O)N(C)C1=N[C@@H]3CCC[C@@H]3N12

Procedure:
Treat 5,6a(R),7,8,9,9a(S)-hexahydro-2,5-dimethylcyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one from Example 19a with 4-chloromethyl pyridine in accordance with Example 47 to give the title compound as a powder.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([O:5][C:6]2([CH3:9])[CH3:8])=[O:4].[C:10](Cl)(=[O:13])[CH:11]=[CH2:12]>>[C:10]([O:1][CH:7]1[C:6]([CH3:8])([CH3:9])[O:5][C:3](=[O:4])[CH2:2]1)(=[O:13])[CH:11]=[CH2:12]
Reactant: CC1(C)OC(=O)C2OC21
Reactant: C=CC(=O)Cl
Product: C=CC(=O)OC1CC(=O)OC1(C)C
Yield: 87 %

Procedure:
The obtained 3-hydroxy-4,4-dimethyl-γ-butyrolactone was allowed to react with acrylyl chloride in the same manner as in Production Example 16 to thereby yield the title compound (yield: 87%).
Reaction SMILES: [CH3:1][S:2]SC.C(P(CCCC)CCCC)CCC.[F:18][C:19]([F:53])([F:52])[C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]2[O:29][CH:30]=[C:31]([CH2:33][O:34][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][N:45]4[CH:49]=[CH:48][N:47]=[C:46]4[CH2:50]O)=[CH:37][CH:36]=3)[N:32]=2)=[CH:22][CH:21]=1.[OH-].[Na+]>ClCCl.N1C=CC=CC=1>[CH3:1][S:2][CH2:50][C:46]1[N:45]([CH2:44][CH2:43][CH2:42][CH2:41][C:38]2[CH:39]=[CH:40][C:35]([O:34][CH2:33][C:31]3[N:32]=[C:28](/[CH:27]=[CH:26]/[C:23]4[CH:24]=[CH:25][C:20]([C:19]([F:53])([F:52])[F:18])=[CH:21][CH:22]=4)[O:29][CH:30]=3)=[CH:36][CH:37]=2)[CH:49]=[CH:48][N:47]=1
Reactant: CSSC
Reactant: OCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Pyridine (0.600 ml), dimethyl disulfide (0.217 ml) and tributylphosphine (0.600 ml) were added to a solution of [1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]methanol (400 mg) in dichloromethane (8 ml) at room temperature, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was combined with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1 to ethyl acetate), and recrystallized from ethyl acetate-diethyl ether-hexane to give the titled compound (213 mg) as a colorless crystal powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:36])(=[O:35])[N:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:17][CH:16]=2)[C@H:10]([OH:37])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][C@@H:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]3[OH:37])=[CH:20][CH:19]=2)(=[O:36])=[O:35])=[CH:29][CH:30]=1
Reactant: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O[C@@H]2CCNC[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.2 %

Procedure:
To a solution of (+/−)trans-4-{4-[(4-chloro-benzyl)-isobutyl-sulfamoyl]-phenoxy}-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (222 mg, 402 μmol) in DCM (8 mL) was added TFA (2 mL) and the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated and purified by SCX column eluting with 2 M NH3 in MeOH to give N-(4-chloro-benzyl)-4-((+/−)trans-3-hydroxy-piperidin-4-yloxy)-N-isobutyl-benzenesulfonamide (202 mg, 447 μmol). LCMS (m/z, Method A) ES+ 453 [M+1]+.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[CH:8][CH:7]=1)=[O:5].Cl[C:18]([O:20][CH3:21])=[O:19]>>[CH3:1][N:2]([CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:14])[F:15])=[CH:8][CH:7]=1)=[O:5])[C:18]([O:20][CH3:21])=[O:19]
Reactant: CN(C)CC(=O)c1ccc(OC(F)F)cc1
Reactant: COC(=O)Cl
Product: COC(=O)N(C)CC(=O)c1ccc(OC(F)F)cc1
Yield: 60.2 %

Procedure:
By substantially following the procedure of Example 115b using 16.8 g (73 mmole) of 2-dimethylamino-4'-difluoromethoxy-acetophenone Example 126c and 7.6 g (81 mmole) of methyl chloroformate one obtain 12 g of 2-(N-methyl-N-(methoxycarbonyl)amino)-4'-difluoromethoxyacetophenone an oil. bp 150°-190° C. at 0.7 torr.