Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.[CH3:13]S(O)(=O)=O>CO>[CH3:13][O:11][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:12]
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CS(=O)(=O)O
Solvent: CO
Product: COC(=O)c1n[nH]c2ccccc12
Yield: 60 %

Procedure:
A stirred mixture of indazole-3-carboxylic acid (5.00 g, 0.0309 mole), methanesulfonic acid (1 ml), and methanol (100 ml) was heated at reflux temperature for 5 hours and then concentrated to a volume of 30 ml and treated with excess saturated aqueous sodium bicarbonate solution. Water was added to give a volume of 200 ml and the suspended solid was collected by filtration. The wet solid was dissolved in methylene chloride (200 ml), and the solution separated from a small amount of water and some insoluble material. The methylene chloride solution was dried (magnesium sulfate) and concentrated to yield 3.25 g (60%) of indazole-3-carboxylic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[O:24][N:23]=[C:22]([CH:25]([CH3:27])[CH3:26])[N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[C:4]([F:28])[C:3]=1[CH2:29][C:30]([OH:32])=O.Cl.[NH:34]1[CH2:37][CH:36]([OH:38])[CH2:35]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:28][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[O:24][N:23]=[C:22]([CH:25]([CH3:26])[CH3:27])[N:21]=3)[CH2:16][CH2:15]2)[CH:7]=[C:2]([F:1])[C:3]=1[CH2:29][C:30]([N:34]1[CH2:37][CH:36]([OH:38])[CH2:35]1)=[O:32]
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)O)c(F)c3)CC2)n1
Reactant: OC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)N4CC(O)C4)c(F)c3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of [(2,6-difluoro-4-{2-[(1S,2R)-2-{1-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}cyclopropyl]ethoxy}phenyl)acetic acid (35.0 mg, 0.078 mmol) (from example 2, step B) in 1 ml anhydrous DMF at RT was added azetidin-3-ol hydrochloride salt (8.53 mg, 0.078 mmol) and N,N-diisopropylethylamine (0.041 ml, 0.234 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (59.2 mg, 0.156 mmol) was added into the solution and stirred at RT for 4 hrs. The reaction mixture was filtered and purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 35-95% acetonitrile in 0.1% formic acid in water gradient) to give the title compound. LC/MS (m/z): 505.4 (M+H)+. GPR119 Human EC50: 0.96 nM
Reaction SMILES: O=[CH:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].Cl.[CH3:16][O:17][NH2:18].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[CH3:16][O:17][N:18]=[CH:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14]
Reactant: CON
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CON=CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.1 %

Procedure:
0.560 g (2.96 mmol) of N-(2-oxoethyl)phthalimide was dissolved in 20 ml of ethanol and to the solution was added 0.330 g (3.95 mmol) of O-methylhydroxylamine hydrochloride. To this suspension was added 10 ml of 0.35M aqueous sodium carbonate solution, followed by being stirred at room temperature for 3 days. The reaction mixture was poured into 100 ml of water and extracted with chloroform (20 ml×3), and the combined organic layer was dried over magnesium sulfate. Chloroform was distilled off and the residual solids were washed with petroleum ether to give 0.291 g (yield 45%) of the titled compound as colorless crystals.
Reaction SMILES: [C:1]1([S:11]([N:14]2[CH:18]([C:19](O)=[O:20])[CH2:17][CH:16]3[CH2:22][CH2:23][CH2:24][CH:15]23)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.C(N1CCOCC1)C.C[Si]([NH:43][OH:44])(C)C>CN(C=O)C>[OH:44][NH:43][C:19]([CH:18]1[N:14]([S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:13])=[O:12])[CH:15]2[CH2:24][CH2:23][CH2:22][CH:16]2[CH2:17]1)=[O:20]
Reactant: C[Si](C)(C)NO
Reactant: O=C(O)C1CC2CCCC2N1S(=O)(=O)c1cccc2ccccc12
Agent: CCN1CCOCC1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Product: O=C(NO)C1CC2CCCC2N1S(=O)(=O)c1cccc2ccccc12
Temperature: 80 °C

Procedure:
200 mg (0.56 mmol) of 1-(naphthaline-1-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 10 ml of DMF, after which 0.61 mmol of ethyl chloroformate, 1.23 mmol of N-ethylmorpholine and 1.68 mmol of trimethylsilylhydroxylamine were added. After the mixture had been heated at 80° C. for 6 h, the solvent was removed under reduced pressure and the crude product was purified using chromatographic methods.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10]C(C)C)([CH3:3])[CH3:2].[CH3:14][C:15]([CH3:17])=O>>[CH:15]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=1[OH:10])([CH3:17])[CH3:14]
Reactant: CC(C)Oc1ccccc1C(C)C
Reactant: CC(C)=O
Product: CC(C)c1cccc(C(C)C)c1O
Temperature: 150 °C

Procedure:
To 15 g of isopropyl (2-isopropylphenyl) ether was added 8 g of 1% fluorided alumina. The mixture was placed in a 300 cc stirred autoclave and the system was flushed with nitrogen and left under a nitrogen atmosphere. The autoclave was heated to 150° C. for 1 hour with stirring during which time the pressure reached 200 psig. The cooled reaction mixture was taken up in acetone, filtered, and the solvent was removed on a rotary evaporator. The residue was analyzed by gas-liquid phase chromatography (glpc) which showed the presence of 2-isopropylphenol (10%), isopropyl(2-isopropylphenyl) ether (28%), 2,6-diisopropylphenol (60%), and 2,4,6-triisopropylphenol (2%). Thus, the 2,6-diisopropylphenol was formed with 83% selectivity.
Reaction SMILES: [CH:1]1([C@@H:7]([NH2:9])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][C:11]([C@@H:13]1[CH2:18][C@@H:17]2[O:19][C@:16]2([CH3:20])[CH2:15][CH2:14]1)=[CH2:12]>O>[CH:1]1([C@@H:7]([NH:9][C@@H:15]2[CH2:14][C@@H:13]([C:11]([CH3:12])=[CH2:10])[CH2:18][CH2:17][C@@:16]2([CH3:20])[OH:19])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H](N)C1CCCCC1
Reactant: C=C(C)[C@H]1CC[C@@]2(C)O[C@H]2C1
Solvent: O
Product: C=C(C)[C@H]1CC[C@@](C)(O)[C@H](N[C@@H](C)C2CCCCC2)C1
Temperature: 25 °C
Reaction time: 109.75 h
Yield: 33.7 %

Procedure:
A 100-mL, single-neck flask equipped with a magnetic stirring bar and a reflux condenser fitted with a nitrogen bubbler was charged with 4.75 g (0.037 mol) of (S)-(−)-1-cyclohexylethylamine, 23.00 g (0.151 mol) of (S)-(−)-limonene oxide, and 2.0 mL of deionized water. The mixture was heated to reflux and held there for 109.75 h. The reaction mixture was cooled to room temperature and filtered to remove an insoluble white solid. The excess limonene oxide was then distilled off at reduced pressure leaving an orange oil that crystallized upon standing over night. The solid was recrystallized from approximately 20 mL of n-heptane to give 3.48 g of (1R,2R,4S)-2-((1S)-1-cyclohexylethylamino)-1-methyl-4-(1-methylethenyl) cyclohexanol, as a white solid, mp 63-64° C.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][OH:27])=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.[C:43]([O:47][C:48]([NH:50][C@@H:51]([CH:55]([CH3:57])[CH3:56])[C:52](O)=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44].C1CCC(N=C=NC2CCCCC2)CC1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:43]([O:47][C:48]([NH:50][C@@H:51]([CH:55]([CH3:57])[CH3:56])[C:52]([O:27][CH2:26][CH2:25][O:24][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([C:10]3[N:8]4[CH:9]=[C:4]([C@@H:3]([N:28]5[CH2:32][CH2:31][C@H:30]([NH:33][C:34]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:40])[CH2:29]5)[C:2]([F:1])([F:41])[F:42])[CH:5]=[CH:6][C:7]4=[N:12][N:11]=3)=[N:14]2)=[CH:19][C:18]=1[F:23])=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)c(OCCO)cc5n4)n3c2)C(F)(F)F)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCOc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
To a stirred solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-(2-hydroxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (Example 123, Step A; 100 mg, 0.169 mmol) and (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (44.1 mg, 0.203 mmol) in DCM (2 mL) was added DMAP (41.4 mg, 0.339 mmol) and DCC (41.9 mg, 0.203 mmol) under nitrogen. The reaction mixture was stirred at ambient temperature for 4 hours and then poured into water. The mixture was extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO3 solution and brine, dried, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (5-95% acetonitrile/water) to give (S)-2-(2-(6-((R)-1-((S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro quinolin-7-yloxy)ethyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate (110 mg, 82%).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][CH2:33][S:34][C:35]#[N:36])[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.I.N1C=CC=CC=1.[C:44]([O:47][CH2:48][C:49]1[CH2:50][S:51][C@@H:52]2[CH:72]([NH2:73])[C:71](=[O:74])[N:53]2[C:54]=1[C:55]([O:57][CH:58]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])(=[O:46])[CH3:45].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:44]([O:47][CH2:48][C:49]1[CH2:50][S:51][C@@H:52]2[CH:72]([NH:73][C:27](=[O:28])[C:26]([C:24]3[N:25]=[C:21]([NH:20][C:1]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[S:22][CH:23]=3)=[N:30][O:31][CH2:32][CH2:33][S:34][C:35]#[N:36])[C:71](=[O:74])[N:53]2[C:54]=1[C:55]([O:57][CH:58]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])(=[O:46])[CH3:45]
Reactant: N#CSCCON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: I
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCCSC#N)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 16 °C
Reaction time: 0.08 h

Procedure:
A mixture of 1.69 g of the product of Step A, 0.685 g of pyridine hydroiodide, 1.16 g of benzhydryl 3-acetoxymethyl-7-amino-ceph-3-eme-4-carboxylate and 1.36 g of dicyclohexylcarbodiimide was admixed with 17 ml of dimethylformamide and the mixture was cooled to 16° C. for 30 minutes and was then vacuum filtered. 400 ml of ether were added to the filtrate and the mixture was stirred for 5 minutes and allowed to stand for one hour. The mixture was decanted and the gum was washed with ether and was added to 50 ml of ether. The mixture was kneaded until concretization and was vacuum filtered. The product was washed with ether and dried to obtain 1.92 of raw product which was chromatographed over silica gel. Elution with a 91-9 chloroform-acetonitrile mixture yielded 790 mg of amorphous syn isomer of benzhydryl 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(2-thiocyanatoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=1.C([Li])CCC.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27]>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2([OH:27])[C:8]1[C:3]([O:2][CH3:1])=[N:4][C:5]([O:9][CH3:10])=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1cccc(OC)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(O)C(=O)Nc3ccc(Cl)cc32)c(OC)n1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a stirred solution of 2,6-dimethoxypyridine (50 mmol, 6.61 mL) in THF (100 mL) was added slowly a 1.6 M solution of n-butyllithium in hexanes (55 mmol, 34.4 mL) at −78° C. The mixture was allowed to warm slowly to 10° C. and kept at this temperature for 30 min. The reaction mixture was re-cooled to −78° C. and a slurry of 5-chloroisatin (20 mmol, 3.63 g) in THF (150 mL) was added portionwise, keeping the temperature below −60° C. The reaction was allowed to come to room temperature. The mixture was quenched with 10% aqueous ammonium chloride solution and extracted several times with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate and evaporated in vacuo. Recrystallization from ethyl acetate yielded 4.56 g (71%) of the desired intermediate as a white crystalline solid (71%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9](Cl)(=[O:18])[C:10]1[C:11]([O:16][CH3:17])=[CH:12][CH:13]=[CH:14][CH:15]=1>N1C=CC=CC=1>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([O:8][C:4]1[CH:3]=[C:2]([O:1][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH:7]=[CH:6][N:5]=1)=[O:18]
Reactant: O=c1cc(O)cc[nH]1
Reactant: COc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Product: COc1ccccc1C(=O)Oc1ccnc(OC(=O)c2ccccc2OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 2 %

Procedure:
A 2.00 g quantity of 4-hydroxy-2-pyridone was suspended in 60 ml of pyridine, and 5.52 g of 2-anisoyl chloride was added to the suspension. The mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated and the concentrate was washed with benzene and extracted with ethyl acetate. The extract was concentrated and the concentrate was subjected to a silica gel column chromatography using chloroform-acetone (30:1) as an eluent, giving 120 mg of the title compound in a yield of 2%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:15])=[CH:9][CH:8]=1.ClC1C=CC=C(C(OO)=[O:42])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(Cl)(Cl)Cl>[O-:42][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:15])=[CH:9][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(-c4ccccn4)cc2)CCO3)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(-c4cccc[n+]4[O-])cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 70 h
Yield: 14.5 %

Procedure:
To a suspension of N-[4-(2-pyridyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (400 mg) in dichloromethane (10 ml) was added 3-chloro-perbenzoic acid (70%, 0.25 g) at 0° C. and the mixture was stirred at room temperature for 70 hours. To the mixture was added sodium thiosulfate solution, and the mixture was stirred for minutes. The mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, and dried with magnesium sulfate. The mixture was concentrated, purified with column chromatography (ethanol/ethyl acetate=1:1) to give crystals, which were dissolved in chloroform. The mixture was concentrated, and to the residue was added ethanol. Precipitated crystal was collected by filtration to give crystals, which were washed with ethanol to give N-[4-(1-oxidopyridin-2-yl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 160) (60 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@@H:6]([CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[O:5][C@:4]([C@@H:15]2[CH2:19][S:18][C:17](=[O:20])[N:16]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)([O:13][CH3:14])[CH2:3]1.[C:30](=O)([O:41]CCCC=C)[O:31][C:32]1C=[CH:36][C:35]([N+]([O-])=O)=[CH:34][CH:33]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:14][O:13][C@:4]1([C@@H:15]2[CH2:19][S:18][C:17](=[O:20])[N:16]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:3][C@H:2]([NH:1][C:30](=[O:41])[O:31][CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH2:7][C@@H:6]([CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[O:5]1
Reactant: C=CCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C=CCCC[C@@H]1C[C@@H](N)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCCOC(=O)N[C@@H]1C[C@@H](CCCC=C)O[C@@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)C1
Reaction time: 24 h
Yield: 83 %

Procedure:
A solution of the title compound from Example 67 (113 mg, 0.269 mmol) in dichloromethane (2 mL) was treated with a solution of 4-nitrophenyl pent-4-enyl carbonate (88 mg, 0.35 mmol) in dichloromethane (0.8 mL), diisopropylethylamine (0.061 mL, 0.35 mmol), and a catalytic amount of DMAP (0.2 mg). The mixture was stirred for 24 h, after which it was chromatographed directly on silica gel, eluting with ethyl acetate/dichloromethane, to give the title compound (119 mg, 83%) as an oil.
Reaction SMILES: [C:1]1([NH:7][C:8](=O)[CH2:9][CH:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCOCC1>[C:1]1([NH:7][C:8](=[S:35])[CH2:9][CH:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CC(Sc1ccccc1)Sc1ccccc1)Nc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: S=C(CC(Sc1ccccc1)Sc1ccccc1)Nc1ccccc1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
To N-phenyl-3,3-bis(phenylthio)propionamide (0.90 g) were added Lawesson's reagent (2.0 g) and 1,4-dioxane (20 mL), and the mixture was heated to reflux for 1.5 hours. The reaction mixture was left to cool to room temperature, and then concentrated under reduced pressure. The residue was isolated and purified by medium pressure preparative liquid chromatography (YAMAZEN SI-40B, hexane:ethyl acetate=3:1) to obtain N-phenyl-3,3-bis(phenylthio)thiopropionamide (0.69 g) as an orange oil.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])(OCC)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:1]([N:8]1[C:18](=[O:19])[C:17]2[C:16](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
Benzylamine (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (1.00 g) was dissolved in purified water (20 ml) and then added with N-carbethoxyphthalimide (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (3.06 g) and sodium carbonate (2.47 g), followed by stirring at room temperature for 3 hours. After completion of the reaction, the solution was filtered and the residue was washed with purified water and then dried under vacuum at 60° C., thereby obtaining the subject compound (1.82 g) as a white solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2.[CH:8]([CH:10]=[CH2:11])=[O:9]>C1(C=CC(O)=CC=1)O>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]1[CH:2]2[O:9][CH:8]=[CH:10][CH2:11]1
Reactant: C=CC=O
Reactant: C1=CC2CCC1C2
Agent: Oc1ccc(O)cc1
Product: C1=COC2C3CCC(C3)C2C1
Yield: 50 %

Procedure:
56.4 g of norbornene, 16.8 g of acrolein and 0.5 g of hydroquinone were heated 15 hours at 190° in a stainless steel autoclave (pressure about 15 atm.). After evaporation a fractional distillation of the residue gave 22.5 g (yield 49%) of 3-oxa-tricyclo[6.2.1.02,7 ]undec-4-ene; b.p. 35°-7°/0.5 Torr.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])=[O:8])[CH:2]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]([C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])[C:10]1=[O:18])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Nc2ccccc2C1C(=O)c1cccnc1
Product: CC(=O)N1C(=O)C(C(=O)c2cccnc2)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 476 mg (2.0 mmole) of 3-(3-pyridylcarbonyl)-2-oxindole and 4 ml of acetic anhydride was heated under reflux for 30 minutes The reaction mixture was cooled to room temperature, the bulk of the acetic anhydride was removed by evaporation in vacuo and the residue was triturated under 15 ml of water. The solid was recovered by filtration, dried and triturated under isopropanol. The residue (158 mg) was recrystallized from acetonitrile giving 64 mg of the title compound as red-orange crystals, m.p. 142.5°-143.5° C. A second crop of title compound (40 mg) was obtained from the mother liquors from the recrystallization. The two crops were the same by thin-layer chromatography. The first crop was subjected to elemental analysis.
Reaction SMILES: [NH2:1][C:2]1[N:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([C:6]1[N:7]=[C:8]([N:16]2[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5].[ClH:34]>O1CCOCC1>[ClH:34].[ClH:34].[N:16]1([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=[C:6]([C:4]([C:3]3[C:2]([NH2:1])=[N:33][CH:32]=[CH:31][CH:30]=3)=[O:5])[N:7]=2)[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc(C(=O)c3cccnc3N)cc3ccccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ncccc1C(=O)c1cc2ccccc2c(N2CCCNCC2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
To a suspension of tert-butyl 4-(3-(2-aminonicotinoyl)isoquinolin-1-yl)-1,4-diazepane-1-carboxylate (18 mg, 0.04 mmol) in 1,4-dioxane (1 ml) was added 4 M HCl in 1,4-dioxane (0.5 ml). The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated to dryness to leave title compound as a solid (16.6 mg, 98% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH2:11][C:9]1[S:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:12])[N:8]=1
Reactant: CCOC(=O)c1sc(C)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(CBr)nc1C
Yield: 41.4 %

Procedure:
A mixture of 5-ethoxycarbonyl-2,4-dimethylthiazole (926 mg), N-bromosuccinimide (890 mg) and benzoyl peroxide (8 mg) in carbon tetrachloride (11 ml) was heated at reflux. After 11/2 h the reaction mixture was allowed to cool and filtered. The filtrate was evaporated and the residual oil diluted with petrol (b.p. 40°-60° C.)-ethyl acetate, 4:1, (5 ml) resulting in the precipitation of a solid. After 1 h the suspension was filtered and the filtrate evaporated to an orange oil. Petrol (2 ml) was added to the oil resulting in the formation of a solid which after cooling was collected to give crystals of 2-bromomethyl-5-ethoxycarbonyl-4-methylthiazole (546 mg), m.p. 48°-58° C., λmax (EtOH) 266 nm (ε 8,640).