Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1.S(Cl)(Cl)=O.COC1C(C(F)(F)F)=CC(C(Cl)=O)=CC=1.[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[S:43][C:44]3[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:45]=3[N:46]=2)=[CH:38][CH:37]=1>N1C=CC=CC=1>[F:13][C:12]([F:15])([F:14])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=1[C:7]([NH:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[S:43][C:44]3[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:45]=3[N:46]=2)=[CH:40][CH:41]=1)=[O:9]
Reactant: COc1ccc(C(=O)O)c(C(F)(F)F)c1
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Agent: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)Nc2ccc(-c3nc4ccc(OC)cc4s3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 45.9 %

Procedure:
A stirred mixture of 4-methoxy-2-trifluoromethylbenzoic acid (0.50 g, 2.27 mmol) and thionyl chloride (9 ml) was heated under reflux for 4 h. After cooling to room temperature, the excess reagent was removed under reduced pressure to give crude acid chloride. The amide was prepared as described in the Amide Coupling section using the crude 4-methoxy-5-trifluoromethylbenzoyl chloride and 2-(4-aminophenyl)-6-methoxybenzo thiazole (0.58 g, 2.27 mmol) in dry pyridine (15 ml) to give the title compound (0.478 g, 46%) as pale yellow needles after work-up and recrystallisation from acetic acid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:18][CH2:17]1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH2:20][CH2:21]2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(CN2CCOCC2)CC1
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](CN2CCOCC2)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{[4-(morpholinomethyl)cyclohexyl]-amino}-1,5-naphthyridin-3-yl)ethanone (85 mg, 0.21 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (91 mg, 0.31 mmol) to afford the desired product (59 mg, 53%) as an orange solid: 1H NMR (500 MHz, CDCl3) δ 11.18-11.16 (m, 1H), 8.95 (s, 1H), 8.21 (d, J=8.8 Hz, 1H), 7.99 (s, 2H), 7.94 (d, J=8.8 Hz, 1H), 5.51-5.42 (m, 1H), 3.71 (t, J=4.7 Hz, 4H), 2.70 (s, 3H), 2.41-2.43 (m, 4H), 2.34-2.32 (m, 2H), 2.23-2.22 (m, 2H), 2.02-1.95 (m, 2H), 1.62-1.58 (m, 1H), 1.46-1.39 (m, 2H), 1.28-1.15 (m, 2H); ESI MS m/z 529 [M+H]+; HPLC 98.2% (AUC), tR=9.93 min.
Reaction SMILES: O[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1)[CH3:3].S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[Cl:17][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1)[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)NCc1ccc(C(C)O)cc1
Solvent: ClC(Cl)Cl
Product: CC(=O)NCc1ccc(C(C)Cl)cc1

Procedure:
A solution of N-{[4-(1-hydroxyethyl)phenyl]methyl}acetamide (5.7 g) and thionyl chloride (2.6 ml) in chloroform (50 ml) was refluxed under heating for 1.5 hr. The solvent was evaporated to give a brown oil (6.7 g). The obtained brown oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=20:1) to give the title compound (5.5 g) as a pale-brown oil.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.Cl.N1C=CC=CC=1.[CH2:20]=[C:21]1[O:25][C:23](=[O:24])[CH2:22]1>ClC=C(Cl)Cl>[C:23]([NH:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])(=[O:24])[CH2:22][C:21]([CH3:20])=[O:25]
Reactant: C=C1CC(=O)O1
Reactant: CC(C)C(N)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC=C(Cl)Cl
Product: CC(=O)CC(=O)NC(=O)C(C)C
Yield: 83.6 %

Procedure:
Isobutyramide (8.7 g, 0.1 mole), pyridine (0.40 g, 0.005 mole), pyridine hydrochloride (1.73 g, 0.015 mole), diketene (8.4 g, 0.1 mole) and trichloroethylene (100 ml) were placed in a 250 ml, 3-neck flask equipped with a magnetic stirrer, a thermometer, a condenser, a drying tube and a heating mantle. The mixture was slowly heated to 80°, and the temperature range of 75°-81° was maintained for 1 hour. The slightly cooled reaction mixture was poured into a 500 ml, r.b. flask and the solvent was stripped off to give an orange oil. Crude N-acetoacetylisobutyramide thus obtained was dissolved in toluene (100 ml) and placed in a 250 ml, 3-neck flask equipped similarly as in Example 1. After addition of acetic acid (3 g, 0.05 mole), ammonia gas was bubbled in as the reaction mixture was heated at reflux for 1 hour and was further refluxed for 1 hour after the ammonia was turned off. Chloroform (~50 ml) was added to the cooled reaction mixture and the insoluble solid was filtered and washed with chloroform (~ 50 ml). The solvent of the filtrate was stripped off and 15.51 g (81.9%, by weight, of oxypyrimidine) of yellow crystals having m.p. 148°-160° were obtained. The yield was 83.6%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]=[C:10]2[CH3:34])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:36][CH:37]1[CH2:39][CH2:38]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH:37]1([CH2:36][O:8][C:7]2[CH:6]=[CH:5][C:4]([N:9]3[C:14](=[O:15])[C:13]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][CH:18]=4)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]=[C:10]3[CH3:34])=[CH:3][C:2]=2[F:1])[CH2:39][CH2:38]1
Reactant: CCCc1nc(C)n(-c2ccc(O)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OCC3CC3)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 4′-{[1-(3-fluoro-4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and (bromomethyl)cyclopropane (0.64 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.5 g), and the mixture was stirred at 80° C. for 48 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.95 g, 85%).
Reaction SMILES: [CH:1]([C:4]1[CH2:5][CH2:6][C:7](=[O:10])[NH:8][N:9]=1)([CH3:3])[CH3:2].BrBr>C(O)(=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:10])[NH:8][N:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)C1=NNC(=O)CC1
Agent: BrBr
Solvent: CC(=O)O
Product: CC(C)c1ccc(=O)[nH]n1
Temperature: 100 °C

Procedure:
4,5-Dihydro-6-isopropyl-3 (2H)-pyridazinone (3.10 g) was dissolved in acetic acid (30.0 ml), and bromine (3.50 g, 22.0 mmol) was added dropwise to the solution over 10 minutes under heating at 100° C. with stirring. After the reaction solution was heated for 1 hour under reflux, the acetic acid was distilled away under reduced pressure, and water (100 ml) was added to the residues which were then extracted 5 times with ethyl acetate. The extracts were combined, dried over anhydrous magnesium sulfate and concentrated to give a crude product of 6-isopropyl-3 (2H)-pyridazinone. The yield was 3.30 g.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[C:11]([O:14][CH2:15][CH:16](Br)[CH3:17])(=[O:13])[CH3:12]>>[C:11]([O:14][CH2:15][CH2:16][CH2:17][O:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1)(=[O:13])[CH3:12]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CC(=O)OCC(C)Br
Product: CC(=O)OCCCOc1ccc2c(c1)OCO2

Procedure:
3-(Benzo[d][1,3]-dioxol-5-yloxy)propyl acetate (43A) was prepared following a similar procedure as that described in example 39, except sesamol was used instead of 3-(dimethylamino)phenol and 2-bromopropyl acetate was used instead of 2-bromoethyl acetate in step 1 of example 39.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)(C)[C:14](O)=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[Pb](=O)=O>C1(C)C=CC=CC=1>[O:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:20]=[CH:19][C:18]([C:13]([C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:8][CH:9]=3)=[CH2:14])=[CH:23][CH:22]=2)[CH2:25][CH2:26]1
Reactant: CC(C(=O)O)(c1ccc(N2CCOCC2)cc1)c1ccc(N2CCOCC2)cc1
Agent: O=[Pb]=O
Solvent: Cc1ccccc1
Product: C=C(c1ccc(N2CCOCC2)cc1)c1ccc(N2CCOCC2)cc1
Reaction time: 1 h
Yield: 46.4 %

Procedure:
Into 200 ml of toluene was dissolved 10 g of 2,2-bis(4-morpholinophenyl)propionic acid. Thereto was added 7.2 g of lead dioxide and the mixture was reacted at reflux temperature with stirring for one hour. The lead compound was removed by filtration and the toluene layer was extracted with 200 ml of 3% aqueous solution of sodium hydroxide to recover the unreacted starting material. The remained toluene solution was concentrated at a reduced pressure to obtain crystals. The crystal was recrystallized from n-propanol to obtain 4.1 g (yield 46.3%) of 1,1-bis(4-morpholinophenyl)ethylene, having a melting point of 203°~205° C. The starting 2,2-bis(4-morpholinophenyl)propionic acid was recovered in an amount of 3.8 g.
Reaction SMILES: [CH:1](=[O:3])[CH3:2].Cl.O1[CH2:9][CH2:8][CH2:7][CH2:6]1>O>[C:1]1(=[O:3])[C:9]2[C:8](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:7]=[CH:6][CH2:2]1
Reactant: CC=O
Reactant: C1CCOC1
Agent: Cl
Solvent: O
Product: O=C1CC=Cc2ccccc21
Yield: 52.1 %

Procedure:
The acetaldehyde intermediate (4) (2.1 g, 10 mmol) was taken up in tetrahydrofuran (200 mL), and water (0.5 mL) and concentrated hydrochloric acid (1.0 mL) were added. The solution was heated at reflux for 5 hrs., then diluted with water (20 mL) and evaporated at reduced pressure to remove most of the tetrahydrofuran. The residual aqueous solution was extracted with ether (3×200 mL), and the combined ether extracts were successively washed with saturated sodium bicarbonate solution (20 mL), brine (50 mL), then dried and concentrated to give a semisolid. Recrystallization from benzene hexane provided 1.0 g (52.1%) of compound (5). mp 86°-91° C., 1H NMR (CDCl3) δ7.04-6.78 (m, 1H), 6.12-5.84 (m, 1H), 2.60-1.0 (m, 11H), 2.16 (s, 3H); mass spectrum, m/z 192 (M+).
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH2:16][CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:25])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:32].[Na+].O1CCCC1>CO.C(#N)C>[NH2:32][CH:1]([C:4]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[CH2:16][CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:25])[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)N(C)C)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)N(C)C)CC1
Temperature: 65 °C

Procedure:
A mixture of 4-(7-acetyl-5-chloroquinolin-8-yl)-N,N-dimethylpiperazine-1-carboxamide (0.027 g, 0.075 mmol) and ammonium acetate (0.0576 g, 0.747 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.19 mL, 0.19 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C15H25ClN5O (M+H)+: m/z=362.2; Found: 362.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([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)[CH3:2].CC(C)([O-])C.[K+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[CH3:36]>CS(C)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[CH3:36])[CH3:2]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Cl)ccc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(Cl)cc1C)N=C(c1ccccc1)c1ccccc1
Reaction time: 0.33 h
Yield: 50.1 %

Procedure:
To a solution containing (Benzhydrylidene-amino)-acetic acid ethyl ester (2.3 g, 8.6 mmol) in 50 mL of DMSO under a nitrogen atmosphere was added potassium t-butoxide (1.2 g, 11 mmol) After stirring for 20 minutes, 1-Bromomethyl-4-chloro-2-methyl-benzene (1.89 g, 8.6 mmol) was added and the reaction allowed to stir at room temperature overnight. The reaction was diluted with ethyl acetate and washed with brine. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 20% ethyl acetate/hexanes gave 2-(Benzhydrylidene-amino)-3-(4-chloro-2-methyl-phenyl)-propionic acid ethyl ester (1.75 g, 50%) as a yellow oil. LCMS (APCI+) m/z 406 [M+H]+; Rt: 4.16 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[CH:10]=[C:9]([CH:17]([CH2:27][CH:28]3[CH2:36][CH2:35][C:30]4([O:34]CCO4)[CH2:29]3)[C:18]([NH:20][C:21]3[CH:25]=[CH:24][N:23]([CH3:26])[N:22]=3)=[O:19])[CH:8]=[CH:7][C:6]=1[S:5]2(=[O:38])=[O:37].CN1C2C=C(C[C:55]([O:57][CH2:58][CH3:59])=[O:56])C=CC=2S(=O)(=O)C2C1=CC=CC=2.CN1C=CC(N)=N1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)C.CS(C)=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:16][N:12]1[C:13]2[CH:14]=[CH:15][C:2]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:3][C:4]=2[S:5](=[O:37])(=[O:38])[C:6]2[C:11]1=[CH:10][C:9]([CH:17]([C:18](=[O:19])[NH:20][C:21]1[CH:25]=[CH:24][N:23]([CH3:26])[N:22]=1)[CH2:27][CH:28]1[CH2:36][CH2:35][C:30](=[O:34])[CH2:29]1)=[CH:8][CH:7]=2
Reactant: CCOC(=O)Cc1ccc2c(c1)N(C)c1ccccc1S2(=O)=O
Reactant: CN1c2cc(C(CC3CCC4(C3)OCCO4)C(=O)Nc3ccn(C)n3)ccc2S(=O)(=O)c2cc(Br)ccc21
Agent: Cn1ccc(N)n1
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)S(=O)(=O)c1ccc(C(CC3CCC(=O)C3)C(=O)Nc3ccn(C)n3)cc1N2C
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A solution of 445 mg of 2-(7-bromo-10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-3-(1,4-dioxaspiro[4.4]non-7-yl)-N-(1-methyl-1H-pyrazol-3-yl)propionamide (prepared analogously to Example 1 from ethyl (10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)acetate, T-iodomethyl-1,4-dioxa-spiro[4.4]nonane and commercially available 1-methyl-1H-pyrazole-3-amine) is dissolved in 8 ml of anhydrous ethanol and 8 ml of DMSO, and 0.74 ml of triethylamine and 76 mg of 1,3-bis(diphenylphosphino)propane are added under argon. The reaction solution is flushed with argon, and 35 mg of palladium acetate are then added. The reaction mixture is stirred at 70° C. and 1 bar of CO for three hours. The cooled reaction mixture is diluted by addition of 200 ml of ethyl acetate and washed with in each case 100 ml of water and saturated sodium chloride solution, dried over MgSO4 and then concentrated under reduced pressure. The residue is dissolved in 25 ml of acetone, and 3 ml of 10% strength hydrochloric acid are added. The reaction mixture is stirred at room temperature for three hours. The reaction mixture is then washed with saturated NaHCO3 solution, dried over MgSO4 and then concentrated under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=1:1=>ethyl acetate=>ethyl acetate:methanol=99:1. This gives 844 mg of ethyl 10-methyl-8-[1-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2-(3-oxocyclopentyl)-ethyl]-5,5-dioxo-5,10-dihydrophenothiazine-3-carboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[S:18][C:19]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=2)=[O:24])=[C:20]([CH3:22])[N:21]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[S:18][C:19]([C:23]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)=[O:24])=[C:20]([CH3:22])[N:21]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccc(F)c(F)c1
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1ccc(F)c(F)c1
Yield: 85 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 4-(benzyloxy)pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with 2-bromo-N-(3,4-difluorobenzyl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 85% yield: mp 225-227° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.67 (d, J=7.9 Hz, 1H), 7.43-7.35 (m, 5H), 7.17-7.05 (m, 3H), 6.35-6.19 (m, 2H), 6.05 (s, 1H), 5.03 (s, 2H), 4.52 (s, 2H), 2.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.4, 162.3, 162.0, 153.5, 152.6, 152.1, 151.5, 148.8, 135.0, 134.5, 131.5, 128.8, 127.7, 123.7, 121.8, 117.6, 116.9, 104.1, 97.3, 70.8, 42.9, 17.3; MS (ES+) m/z 468.3 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CCCCCC.CCOC(C)=O>[N:17]1([C:7]([C:6]2[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:9])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCNCC1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)N1CCCCC1

Procedure:
Prepared from 3-nitro-5-trifluormethyl-benzoic acid and piperidine (TPTU, CH2Cl2/CH3CN, Et3N): MS: [M+1]+=303; TLC Rf=0.27 (hexane/AcOEt 7:3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O1CCCC1.Cl.Cl.[N:31]1([CH2:36][CH2:37][CH2:38][NH2:39])[CH:35]=[CH:34][N:33]=[CH:32]1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:39][CH2:38][CH2:37][CH2:36][N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: NCCCn1ccnc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1ccc(F)cc1)NCCCn1ccnc1
Reaction time: 18 h

Procedure:
A mixture of 1.54 g. of 4-fluorophenylacetic acid, 1.62 g. of 1,1'-carbonyldiimidazole and 30 ml. of tetrahydrofuran was stirred for 2 hours, then 1.98 g. of 1H-imidazole-1-propanamine dihydrochloride was added. Stirring was continued at room temperature for an additional 18 hours, then at reflux temperature for 5 hours, 5 ml. of water was added, the mixture was heated for 30 minutes and then concentrated to remove the volatile material. The residue was diluted with methylene chloride and 25 ml. of 1N sodium hydroxide and the layers separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated, giving the desired product as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=S.[Cl:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:30])[CH2:24][CH2:25][C:26]([NH:28][NH2:29])=[O:27])[CH2:18][CH2:17]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:27][C:26]([CH2:25][CH2:24][C:23]([NH:22][CH:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:14]3[CH:31]=[CH:32][C:33]([Cl:34])=[C:12]([Cl:11])[CH:13]=3)[CH2:17][CH2:18]2)=[O:30])=[N:28][N:29]=1
Reactant: S=C=Nc1ccccc1Cl
Reactant: NNC(=O)CCC(=O)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Solvent: CN(C)C=O
Product: O=C(CCc1nnc(Nc2ccccc2Cl)o1)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Chloro-2-isothiocyanato-benzene (0.112 g) and N-[1-(3,4-dichlorobenzyl)-piperidin-4-yl]-3-hydrazinocarbonyl-propionamide (0.20 g) were stirred together in dimethylformamide (2 ml) at ambient temperature for 2 hours. AM resin (0.324 g, Novabiochem, 2% DVB 1.57 mmol/g) was added and the resulting mixture was stirred at ambient temperature for 16 hours. N-Cyclohexylcarbodiimide N-methyl polystyrene HL (0.638 g, Novabiochem, 1.69 mmol/g) was added and the resulting mixture was stirred at 80° C. for 24 hours, then allowed to cool. The reaction mixture was then filtered, washing with dimethylformamide (2×2 ml). The combined filtrates were evaporated and the residue was purified by reverse phase HPLC to give the title compound as a white solid. (0.028 g, m.pt. 154-156° C., MS [M+H]+ (APCI+) 508/510).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][C:17]([C:23]([O:25]C)=[O:24])=[CH:16][C:15]=3[CH:27]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>COCCOC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:20](=[O:21])(=[O:22])[CH2:19][CH2:18][C:17]([C:23]([OH:25])=[O:24])=[CH:16][C:15]=3[CH:27]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1=Cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2S(=O)(=O)CC1
Agent: Cl
Solvent: COCCOC
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 70 °C
Reaction time: 55 h
Yield: 94.1 %

Procedure:
To a solution of methyl 7-(4-tert-butylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg) in 1,2-dimethoxyethane (20 ml) was added 6N hydrochloric acid (10 ml), and the mixture was stirred at 70° C. for 55 hours, cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were collected by filtration and washed with hexane to give pale yellow crystals of 7-(4-tert-butylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (362.7 mg).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][C@@H:15]3[C@@H:17]([NH2:20])[CH2:18][CH2:19][C@@H:14]3[CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40])([O-:32])=[O:31]>ClCCl>[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH:20][C@@H:17]1[C@@H:15]2[C@@H:14]([CH2:13][N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=3)(=[O:10])=[O:11])[CH2:16]2)[CH2:19][CH2:18]1)(=[O:41])=[O:40])([O-:32])=[O:31]
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(3aR,4S,6aS)-2-(4-(Trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine (300 mg, 0.897 mmol) from Step A of Example 256 and triethylamine (0.313 mL, 2.243 mmol) were combined in dichloromethane (20 mL). 2-Nitrobenzene-1-sulfonyl chloride (258 mg, 1.166 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with water, and the organic layer was separated and concentrated. The resulted crude material was triturated with 50% diethyl ether/hexane, collected by filtration, washed with water then hexane to yield a solid. The crude solid was purified using a 12 g silica gel cartridge with a gradient of 10-100% ethyl acetate/hexane over 20 minutes to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 9.69 (s, 1H), 8.31 (dd, J=6.0, 3.3, 1H), 8.12 (d, J=8.2, 2H), 7.92 (dd, J=8.6, 2.1, 3H), 7.67 (dd, J=5.9, 3.3, 2H), 4.94 (s, 2H), 3.84 (dd, J=15.0, 6.2, 1H), 3.58 (dd, J=10.0, 2.4, 1H), 3.17 (dd, J=9.7, 2.7, 1H), 2.94 (dd, J=10.0, 7.7, 1H), 2.87 (dd, J=9.6, 7.7, 1H), 2.71 (td, J=9.3, 2.4, 1H), 2.60-2.50 (m, 1H), 1.94-1.80 (m, 2H), 1.71-1.58 (m, 1H), 1.23 (tt, J=10.5, 6.5, 1H); MS (ESI+) m/z 518 (M+H)+.