Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:16]([NH2:28])[CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:29][C:30](N)=[O:31]>C(O)(=O)C>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:14]3[CH:15]=[C:16]4[C:17]([C:20]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:29][C:30](=[O:31])[NH:28]4)=[CH:18][CH:19]=3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)c2ccccc2)c(N)c1
Reactant: NC(N)=O
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(-c3ccccc3)nc(=O)[nH]c2c1
Temperature: 120 °C
Reaction time: 4 h
Yield: 59.5 %

Procedure:
The mixture of 3′-Amino-4′-benzoyl-6-methyl-biphenyl-3-carboxylic acid cyclopropylamide from Example 14 (19 mg, 0.051 mmol) and urea (3.7 mg, 0.062 mmol) in 0.5 mL acetic acid was stirred at 120° C. for 4 hours. The solvents were removed under reduced pressure. The crude product was purified by preparative TLC sheet (methylene chloride:methanol=10:1) to give a colorless solid (12 mg, 59%).
Reaction SMILES: C(=O)(O[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)OC.[C:12](=O)([O:20]C1C=CC=CC=1)[O:13][C:14]1C=CC=CC=1>>[C:12]([O:13][CH3:14])(=[O:20])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Oc1ccccc1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Product: COC(=O)c1ccccc1
Yield: 39 %

Procedure:
In Example 20, the same procedures as in Example 20 were used, except that the reaction temperature was 180° C., and the contents were reacted for three hours. As a result, the yield of methyl phenyl carbonate was 18%, and the yield of diphenyl carbonate was 21%. Furthermore, methyl benzoate was produced as a by-product with a yield of 39% (the yield is given in terms of phenyl benzoate).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:7]=1)=[O:5].[CH3:21][Mg+].[Br-]>C1COCC1>[C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH:7]=1)(=[O:5])[CH3:21]
Reactant: C[Mg+]
Reactant: CON(C)C(=O)c1ccnc(NC(=O)OC(C)(C)C)c1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 4{[methoxy(methyl)amino]carbonyl}pyridin-2-ylcarbamate (16-2, 224 mg, 0.8 mmole) in dry THF (5 mL) was added MeMgBr (0.6 mL, 3 M in Et2O, 1.75 mmole) at −20° C. After 30 minutes the mixture was warmed to RT. After 30 minutes additional MeMgBr (0.3 mL) was added. After 1 hr the mixture was quenched with saturated NH4Cl and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated to give the titled compound as an off-white solid which was sufficiently pure for use in the next step. 1H-NMR (500 MHz, (CDCl3) δ8.44 (s, 1H), 8.40 (d, 1H, J=5.13 Hz), 8.02 (bs, 1H), 7.41 (d, 1H, J=5.13 Hz), 2.64 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: [NH2:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[CH:3][C:4]([O:6]CC)=O.[H-].[Na+].C1(C)C=CC=CC=1.[F:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35]>CN(C)C=O>[F:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:4](=[O:6])[CH:3]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[NH:1][C:34]1=[O:35]
Reactant: O=C=Nc1ccc(Cl)cc1F
Reactant: CCOC(=O)C=C(N)c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=c1cc(-c2ccccc2F)[nH]c(=O)n1-c1ccc(Cl)cc1F
Temperature: 0 °C
Yield: 72.4 %

Procedure:
2.1 g of this ethyl 3-amino-3-(2-fluorophenyl)-2-propenoate was added dropwise to a solution of 0.5 g of sodium hydride (purity: 55%) in 20 ml of dimethylformamide with stirring at 0° C. The resulting solution was further stirred at room temperature for 15 minutes and then cooled to -30° C. and added dropwise with 20 ml of a toluene solution of 1.7 g of 2-fluoro-4-chlorophenyl isocyanate. The resultant solution was heated to room temperature and stirred at 80° C. for 30 minutes. Then the solvent was distilled away under reduced pressure and 100 ml of water was added to the residue to dissolve it. This aqueous solution was washed twice with diethyl ether and added to a mixed solution of 50 g of ice and 20 ml of concentrated hydrochloric acid. The precipitated crystals were filtered out and dried under the reduced pressure to obtain 3.0 g of a crude product. This crude product was washed with heated diisopropyl ether and then dried to obtain 2.4 g of the objective compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:24]([OH:26])=O)[N:6]2[CH2:21][O:22][CH3:23].C[N:28](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:24]([NH2:28])=[O:26])[N:6]2[CH2:21][O:22][CH3:23]
Reactant: COCn1c(C(=O)O)cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c21
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COCn1c(C(N)=O)cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a mixture of 4-fluoro-1-(methoxymethyl)-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.41 g), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (0.21 g) and N,N-dimethylformamide (15 ml) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.26 g) at 4° C., and the mixture was stirred at room temperature for 2 days. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.41 g, yield 100%) as pale-yellow needle crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4]C2=[C:6]([CH:24]=1)CN(C)CC=C2C1C=CC2N(C)CCOC=2C=1.C(=O)([O-])[O-].[K+].[K+].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:32]2[CH2:33][CH2:34][CH2:35][CH2:36][NH:31][C:6]=2[CH:24]=1
Reactant: CN1CC=C(c2ccc3c(c2)OCCN3C)c2ccc(Br)cc2C1
Reactant: c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1ccc2c(c1)NCCCC2
Temperature: 25 °C
Yield: 65 %

Procedure:
To a solution of the dihydrobenzazepine (270 mg, 0.70 mmol) from step F above in pyridine (15 mL) were added potassium carbonate (967 mg, 7.0 mmol) and p-toluenesulfonylhydrazide (672 mg, 3.5 mmol) in batches. The reaction solution was heated under reflux for 24 hours and then cooled to room temperature. The resultant reaction mixture was filtered through Celite. The Celite bed was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue dissolved in ethyl acetate was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography (3% methanol/dichloromethane) to give the desired 8-bromotetrahydrobenzazepine (176 mg, 65%): 1H NMR (500 MHz, CDCl3) δ 7.28 (d, J=2.1 Hz, 1H), 7.19 (dd, J=8.2, 1.7 Hz, 1H), 6.64 (d, J=8.2 Hz, 2H), 6.60-6.56 (m, 2H), 4.31 (t, J=4.4 Hz, 2H), 4.12 (d, J=9.9 Hz, 1H), 3.83 (br, 1H), 3.69 (d, J=14.2 Hz, 1H), 3.26 (t, J=4.4 Hz, 2H), 3.13-3.10 (m, 1H), 2.95-2.90 (m, 1H), 2.89 (s, 3H), 2.32 (s, 3H), 2.24-2.17 (m, 1H), 2.06-2.04 (m, 1H); ESI MS m/z 387, 389 [M+H]+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.C1C=C(O)C([S:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=CC=1.[OH-].[Na+]>O.ClC1C=CC=CC=1Cl>[CH:6]1[C:1]([OH:7])=[CH:2][CH:3]=[C:4]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:5]=1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(c1ccc(O)cc1)c1ccccc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Clc1ccccc1Cl
Product: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Yield: 91.2 %

Procedure:
A mixture of 290 g (3.09 moles) of phenol, 146 g of 98% sulfuric acid and 150 g of o-dichlorobenzene is heated with stirring. When the temperature of the reaction system reaches about 150° C., the mixture begins to boil, giving off an azeotropic mixture of water and o-dichlorobenzene, which is condensed and separated into two phases, i.e., water and o-dichlorobenzene. The o-dichlorobenzene is continuously returned to the reaction mixture. With continuous heating, when the amount of the aqueous phase reaches 52 ml, the temperature of reaction mixture is about 180° C. Subsequently o-dichlorobenzene containing small amounts of water and phenol is completely distilled off over a period of 3 hours by reducing a pressure of the reaction system to produce the dried reaction mixture in a solid state, while adjusting the temperature to 175° to 185° C. When analyzed by gas chromatography, the dried reaction mixture is found to contain 0.9% by weight of 2,4'-dihydroxydiphenylsulfone based on 4,4'-dihydroxydiphenylsulfone present therein (hereinafter referred to as isomer content). A solution of 62 g of sodium hydroxide in 3.5 l of water is added to the residue, 5 g of active carbon is added to the solution, the mixture is filtered and the filtrate is neutralized with sulfuric acid. The resulting crystals are filtered off, then washed with water and dried, giving 332 g of 4,4'-dihydroxydiphenylsulfone, melting at 248° C., in a yield of 91.2% based on the sulfuric acid starting material. When analyzed by gas chromatography, the product is found to contain 0.8% of isomer content.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:17][CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)#[CH:19]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](/[CH:19]=[CH:18]/[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=1)[C:6]1[CH2:11][CH:12]3[NH:17][CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Reactant: C#Cc1cccc(C(F)(F)F)c1
Product: Cc1ccc2c(c1)c1c(n2/C=C/c2cccc(C(F)(F)F)c2)CC2CCCC1N2

Procedure:
The coupling of 2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (1132 mg, 5.0 mmol; Example 118A) and 1-ethynyl-3-(trifluoromethyl)benzene (1701 mg, 10.0 mmol; Aldrich) was performed according to the procedure described in Example 20 to afford the title compound as the major isomeric product: 1H NMR (300 MHz, methanol-d4) δ ppm 1.34-1.54 (m, 2H), 1.67-1.80 (m, 2H), 1.89-2.07 (m, 2H), 2.42 (s, 3H), 2.84 (d, J=17 Hz, 1H), 3.34-3.45 (m, 1H), 3.68 (t, J=5 Hz, 1H), 4.41 (t, J=3 Hz, 1H), 6.91 (d, J=15 Hz, 1H), 7.06 (dd, J=8, 1 Hz, 1H), 7.22 (s, 1H), 7.46-7.57 (m, 2H), 7.65 (d, J=8 Hz, 1H), 7.72-7.84 (m, 3H); MS (DCI/NH3) m/z 397 (M+H)+.
Reaction SMILES: [C:1]12(COC3C(Cl)=CC(C(OC(C)(C)C)=O)=C(F)C=3)[CH2:7][CH:6]1CCCC2.Cl[C:26]1[C:27]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][C:43]([CH3:48])([CH3:47])[CH2:42]2)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=1)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[CH:1]1([C:26]2[C:27]([O:40][CH:41]3[CH2:46][CH2:45][CH2:44][C:43]([CH3:48])([CH3:47])[CH2:42]3)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=2)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:7][CH2:6]1
Reactant: CC1(C)CCCC(Oc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)C1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCCCC2C3)cc1F
Product: CC1(C)CCCC(Oc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)C1

Procedure:
Following the procedure as described in Example 342 Step 4 and making variations as required to replace tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate with tert-butyl 5-chloro-4-((3,3-dimethyl- cyclohexyl)oxy)-2-fluorobenzoate, the title compound was obtained as an orange oil (1.29 g, 82%): MS (ES+) m/z 385.1 (M+23).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1C2C=CC(O[CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:33]4([C:37]5[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=5)[CH2:36][CH2:35][CH2:34]4)=[O:32])[CH2:26]3)=CC=2OC1>>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([C:33]2([C:31]([N:27]3[CH2:28][CH2:29][CH2:30][CH:25]([CH2:24][O:1][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)[CH2:26]3)=[O:32])[CH2:36][CH2:35][CH2:34]2)=[CH:38][CH:39]=1
Reactant: Oc1cccnc1
Reactant: O=C(N1CCCC(COc2ccc3c(c2)OCO3)C1)C1(c2ccc(Cl)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(N1CCCC(COc2cccnc2)C1)C1(c2ccc(Cl)cc2)CCC1

Procedure:
Compound 85 was synthesized from 3-hydroxypyridine (0.25 g, 2.60 mmol), cesium carbonate (1.27 g, 3.89 mmol) and compound 43 (1.0 g, 2.60 mmol), using the method described for the synthesis of compound 44 to give 0.52 g of the desired product 85. C22H25ClN2O2, LRMS (m/z)=385 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[O:24]=[C:25]1[N:29]([C@H:30]2[C@H:35]([OH:36])[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]2)[C:28](=[O:44])[CH2:27][S:26]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:27]4/[C:28](=[O:44])[N:29]([C@H:30]5[C@H:35]([OH:36])[CH2:34][CH2:33][NH:32][CH2:31]5)[C:25](=[O:24])[S:26]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:21])([F:23])[F:22])[CH:3]=1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](N2C(=O)CSC2=O)C1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CNCC[C@H]1O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-4-hydroxypiperidin-3-yl]-1,3-thiazolidine-2,4-dione was prepared from [4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 1) and 1,1-dimethylethyl trans-3-(2,4-dioxo-1,3-thiazolidin-3-yl)-4-hydroxypiperidine-1-carboxylate (from Example 270) following General Procedure F.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH2:20][CH:21]=2)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.[C].[Pd]>[C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:27])[C:23]([F:25])([F:26])[F:24])[CH2:20][CH2:21]2)=[CH:12][CH:11]=1)[CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C2=CCN(C(=O)C(F)(F)F)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C2CCN(C(=O)C(F)(F)F)CC2)cc1
Yield: 106.1 %

Procedure:
50 mg of the t-butyl((1S)-1-{4-[1-(trifluoroacetyl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}ethyl)carbamate [154-3] was dissolved in 3 mL of tetrahydrofuran, then a catalytic amount of 10% palladiumcarbon catalyst was added thereto, and stirred at room temperature for 1 hour in a hydrogen atmosphere. The insolubles were filtered through celite, the filtrate was concentrated under reduced pressure, and 53.3 mg of t-butyl((1S)-1-{4-[1-(trifluoroacetyl)piperidin-4-yl]phenyl}ethyl)carbamate [155-1] was obtained as a white solid.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[O:12].[NH2:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1>C(COC)OC>[F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1)=[O:12]
Reactant: O=C=Nc1ccccc1OC(F)F
Reactant: Nc1cnccn1
Solvent: COCCOC
Product: O=C(Nc1cnccn1)Nc1ccccc1OC(F)F
Temperature: 25 °C

Procedure:
2-(Difluoromethoxy)phenylisocyanate (1.0 g, 5.4 mmol) and aminopyrazine (0.51 g, 5.4 mmol) were reacted for 6 hours in refluxing dimethoxyethane (20 mL). The reaction mixture was cooled to room temperature to precipitate the product, which was collected by filtration, washed with ethyl acetate, and dried in vacuo (765 mg, 50%). 1H NMR (300 Mhz, d6-DMSO) δ: 10.49 (br s, 1H), 10.26 (s, 1H), 8.83 (s, 1H), 8.35-8.24 (m, 3H), 7.53-7.00 (m,4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][NH:11][C:10]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.N1C=CC=CC=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][N:11]([C:28]([CH:25]3[CH2:27][CH2:26]3)=[O:29])[C:10]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: O=C(Cl)C1CC1
Reactant: Clc1ccc2c(c1)C=Cc1cc(Br)ccc1CN2
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: O=C(C1CC1)N1Cc2ccc(Br)cc2C=Cc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
A solution of 9-Bromo-2-chloro-5,6-dihydro-dibenzo[b,f]azocine (30 mg, 0.09 mmol) (prepared in a manner analogous to that described for Example 1F) in dichloroethane was treated with pyridine (0.02 mL, 0.27 mmol) and cyclopropanecarbonyl chloride (0.011 mL, 0.12 mmol). The reaction mixture was stirred at room temperature for two hours then concentrated, diluted with MeOH and filtered. The crude product was purified by preparative reversed-phase HPLC to afford Example 326A (30 mg, 82%). HPLC Rt=4.05 min. m/z=388 (M+H+)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12]O.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][N:18]1[C:14](=[O:24])[C:15]2[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17]1=[O:19]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1ccccc1-c1nccs1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1-c1nccs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
To a stirred solution of (2-(thiazol-2-yl)phenyl)methanol (0.95 g, 5.1 mmol) in THF (15 mL) was added phthalimide (1.12 g, 7.65 mmol), triphenylphosphine (2.0 g, 7.65 mmol). The mixture was cooled in an ice-water bath and diisopropyl azodicarboxylate (3.1 g, 15.3 mmol) was added dropwise. After the addition, the mixture was stirred at 0° C. for 30 min, and at rt for 18 h. The mixture was then filtered and the filtrate was evaporated. The residue was purified by column chromatography to yield 2-(2-(thiazol-2-yl)benzyl)isoindoline-1,3-dione (1.1 g) as a white solid. To a stirred solution of 2-(2-(thiazol-2-yl)benzyl)isoindoline-1,3-dione (400 mg, 1.25 mmol) in ethanol (10 mL) was added dropwise hydrazine hydrate (160 mg, 3.1 mmol). The mixture was heated at 70° C. for 1 h. After cooling to rt, the mixture was filtered, and the filtrate was evaporated. The residue was purified by column chromatography to yield (2-(thiazol-2-yl)phenyl)methanamine (190 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][CH:6]([NH:8][C:9](=[O:14])[C:10]([O:12]C)=O)[CH2:5][C:4]([CH3:16])([CH3:15])[NH:3]1.[C:18]([C:22]1[CH:23]=[C:24]([CH2:33][CH2:34][C:35]([NH:37][NH2:38])=[O:36])[CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])([CH3:21])([CH3:20])[CH3:19]>CO>[CH3:17][C:2]1([CH3:1])[CH2:7][CH:6]([NH:8][C:9](=[O:14])[C:10]([NH:38][NH:37][C:35](=[O:36])[CH2:34][CH2:33][C:24]2[CH:25]=[C:26]([C:29]([CH3:30])([CH3:32])[CH3:31])[C:27]([OH:28])=[C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:23]=2)=[O:12])[CH2:5][C:4]([CH3:16])([CH3:15])[NH:3]1
Reactant: COC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Solvent: CO
Product: CC1(C)CC(NC(=O)C(=O)NNC(=O)CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CC(C)(C)N1

Procedure:
Into a 3-necked 100 ml flask was introduced methyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate (4.85 g, 0.02 mole) and 50 ml of methanol. The flask was equipped with a magnetic stirrer, a thermometer and a reflux condenser. The mixture was stirred until all of the solid material dissolved, following which 3-(3,5-di-t-butyl-4-hydroxyphenyl)propionhydrazide (5.85 g, 0.02 mole) was added and the mixture was refluxed for 2 hours. The solid material was filtered off and air dried. The product weighed 2.7 g and had a melting range of 255°-257° C. The infrared scan of the product contained strong carbonyl bands at 1655, 1620, 1590 and 1490 cm-1.
Reaction SMILES: [NH2:1]/[C:2](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1.BrN1C(=[O:25])CCC1=O>CO.O>[NH2:1]/[C:2](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1=[O:25]
Reactant: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CO
Product: N/C(=C1\C(=O)c2ccccc2S1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1.18 gm (4.66 mmols) of (E)-2-[(amino)phenylmethylene]-benzo[b]thiophen-3(2H)-one were dissolved in 50 ml of methanol and mixed with 0.9 gm (4.94 mmols) of N-bromo-succinimide. The mixture was stirred at room temperature for 15 hours, diluted with 500 ml of hot water (60° C.), and decanted off the residue which crystallized. After recrystallization from ethanol, 0.83 gm (66% of theory) of pale yellow crystals were obtained, m.p. 245°-247° C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=1)=[O:9].[CH3:36][OH:37]>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][C:13]([O:37][CH3:36])=[N:14][CH:15]=1)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(S(C)(=O)=O)nc1-c1ccccc1
Reactant: CO
Product: COc1ncc(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(-c2ccccc2)n1
Reaction time: 16 h
Yield: 63.6 %

Procedure:
To a suspension of of 0.4 g (0.77 mmol) 2-methylsulfonyl-4-phenyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 10 ml methanol 0.10 g (1.93 mmol) sodiummethanolat (95%) was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH2Cl2 and 50 ml H2O. The aqueous layer was extracted with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 40:1) to give 0.23 g (63%) 2-methoxy-4-phenyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a colorless solid, m.p. 101.2-102°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[CH2:23]([N:26]1[C:30](=[O:31])[C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[S:27]1(=[O:37])=[O:36])[C:24]#[CH:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:25]#[C:24][CH2:23][N:26]3[C:30](=[O:31])[C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[S:27]3(=[O:37])=[O:36])[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Reactant: C#CCN1C(=O)c2ccccc2S1(=O)=O
Product: Cc1nnc2n1-c1sc(C#CCN3C(=O)c4ccccc4S3(=O)=O)cc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was prepared by reacting 4-(2-chlorophenyl)2-iodo-9-methyl-6H-thieno[3,2-f][1,2,4]triazol[4,3-a][1,4]diazepine with 2-(2-propynyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide [ref. R. Granger and J. Giroux, French patent No. 1,273,867 February 1962] as described in Example 37. It was isolated by chromatography and crystallized from ethyl acetate to give colorless crystals with m.p. 232°-234° C.