Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][NH:5][C:4]2[C:11](=[O:19])[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:3]1=2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1>CN(C)C=O>[O:1]=[C:2]1[C:7]([C:8]([NH:33][C:34]2[NH:38][N:37]=[N:36][N:35]=2)=[O:9])=[CH:6][NH:5][C:4]2[C:11](=[O:19])[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:3]1=2
Reactant: O=C(O)c1c[nH]c2c(=O)oc3ccccc3c2c1=O
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1c[nH]c2c(=O)oc3ccccc3c2c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.9 %

Procedure:
A mixture of 1,5-dihydro-1,5-dioxo-4H-1-benzopyrano[3,4-b]pyridine-2-carboxylic acid (2.57 g, 0.01 mole) and 1,1'-carbonyldiimidazole (1.95 g, 0.012 mole) in dimethylformamide is heated at 100 for 60 minutes under nitrogen. The reaction mixture is cooled and stirred at room temperature for 15 minutes. 5-Aminotetrazole monohydrate (1.24 g, 0.012 mole) is added and the resulting mixture is heated at 100 for 60 minutes, cooled, and filtered. The product is recrystallized from dimethylformamide to give white crystals (1.1 g, 34%), m.p. above 300.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[O:26][CH3:27])=O)(=O)OC.O.[NH2:29][NH2:30]>>[F:25][C:23]1[CH:22]=[CH:21][C:20]([O:26][CH3:27])=[C:19]([C:17]2[CH:16]=[C:3]3[C:2]([CH:1]4[CH2:7][CH:4]3[CH2:5][CH2:6]4)=[N:30][N:29]=2)[CH:24]=1
Reactant: COc1ccc(F)cc1C(=O)CP(=O)(OC)OC
Reactant: O=C1C(=O)C2CCC1C2
Reactant: NN
Solvent: O
Product: COc1ccc(F)cc1-c1cc2c(nn1)C1CCC2C1

Procedure:
yellow solid. MS (ESI): 271.1 (MH+). Prepared from bicyclo[2.2.1]heptane-2,3-dione, [2-(5-Fluoro-2-methoxy-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[CH:20]=[C:19]([OH:21])[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].[CH2:41]=O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:41][N:38]4[CH2:39][CH2:40][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:34])[CH2:36][CH2:37]4)=[C:19]([OH:21])[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2cc(O)c(-c3ccccc3)cc21
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(-c3ccccc3)cc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
A solution of (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxy-5-phenylbenzofuran-3(2H)-one (0.035 g, 0.10 mmol) in methanol (3.0 mL) was added with 1-tert-butoxycarbonylpiperazine (0.021 g, 0.11 mmol), and 37% aqueous formaldehyde (0.011 g, 0.15 mmol), and the mixture was stirred overnight at 40° C. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-5-phenyl-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.031 g, 56%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]([C:14]2[C:15]3[CH:22]=[CH:21][N:20]([S:23]([C:26]4[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:54][C:55]1[CH:56]=[C:57]([NH:62][CH2:63][C:64](O)=[O:65])[CH:58]=[C:59]([Cl:61])[CH:60]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:54][C:55]1[CH:56]=[C:57]([NH:62][CH2:63][C:64]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]([C:14]3[C:15]4[CH:22]=[CH:21][N:20]([S:23]([C:26]5[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=5)(=[O:25])=[O:24])[C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2]2)=[O:65])[CH:58]=[C:59]([Cl:61])[CH:60]=1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)CN(c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1)[C@@H]1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1)[C@@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of (R)-ethyl 2-(piperidin-3-yl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)acetate (0.2 g, 0.44 mmol) in DMF (2 mL) was added EDCI (0.13 g, 0.66 mmol), HOBt (89 mg, 0.7 mmol), 2-(3,5-dichlorophenylamino)acetic acid (0.1 g, 0.5 mmol) and DIEA (0.12 mL, 0.66 mmol) at 0° C. The solution was stirred at rt overnight, diluted with EtOAc and washed with water, brine, dried over Na2SO4 and concentrated in vacuo to give a residue which was purified by column chromatography (silica gel gradient methanol in chloroform) to afford (0.09 g, 31%) the titled compound. LCMS [M+1]: 659.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[Cl:9][C:10]1[C:11]([CH3:22])=[C:12](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=1>CS(C)=O>[Cl:9][C:10]1[C:11]([CH3:22])=[C:12]([C@@H:16]2[CH2:2][C@H:17]2[C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=1
Reactant: C[S+](C)(C)=O
Reactant: COC(=O)/C=C/c1cccc(Cl)c1C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1C[C@H]1c1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
To a solution of trimethylsulfoxonium iodide (0.157 g, 0.712 mmol) in 1 mL DMSO was added NaH (60% in mineral oil) (0.032 g, 0.807 mmol) portion-wise. The mixture was stirred at room temperature for 30 min, and then a solution (E)-methyl 3-(3-chloro-2-methylphenyl)acrylate (0.1 g, 0.475 mmol) in 1 mL DMSO was added in one portion. The reaction was stirred at room temperature for 16 h. The mixture was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried (MgSO4) and concentrated. The crude material was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (0.042 g, 39% yield) as a clear colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.29-7.24 (d, J=7.8 Hz, 1H), 7.06 (t, J=7.8 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 3.79-3.75 (m, 3H), 2.55 (ddd, J=9.1, 6.7, 4.5 Hz, 1H), 2.45 (s, 3H), 1.81 (dt, J=8.4, 4.9 Hz, 1H), 1.64-1.57 (m, 1H), 1.30 (ddd, J=8.4, 6.7, 4.4 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[NH2:35][C@H:36]([CH:55]([CH3:57])[CH3:56])[C:37]([N:39]1[CH2:44][CH2:43][C@@:42]([C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=2)([OH:45])[C:41]([CH3:54])([CH3:53])[CH2:40]1)=[O:38]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:35][C@H:36]([CH:55]([CH3:57])[CH3:56])[C:37]([N:39]2[CH2:44][CH2:43][C@@:42]([C:46]3[CH:47]=[CH:48][C:49]([Cl:52])=[CH:50][CH:51]=3)([OH:45])[C:41]([CH3:53])([CH3:54])[CH2:40]2)=[O:38])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(C(=O)O)n1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](NC(=O)c1cccc(N)n1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a suspension of 6-aminopicolinic acid (33 mg, 0.24 mmol) in DMF (2 mL) was added EDC (45.9 mg, 0.24 mmol), HOBt (32.3 mg, 0.24 mmol). The mixture was stirred at rt for 0.5 h, then was added DIPEA (0.083 mL, 0.48 mmol) and (R)-2-amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one hydrochloride (90 mg, 0.239 mmol). The mixture was stirred at rt overnight. The reaction was quenched with NaHCO3 (aq) and stirred at rt for 1 h, extracted by EtOAc, washed with brine and dried over Na2SO4. After concentrating in vacuo, the residue was triturated with CH2Cl2 and filtered to give a yellow solid as 6-amino-N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)picolinamide (86 mg, 0.187 mmol, 78% yield).
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6]2[S:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3]1.CI.[C:14](O)(=O)C>[OH-].[Na+]>[CH3:14][S:1][C:2]1[NH:3][C:4](=[O:11])[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: CC(=O)O
Reactant: O=c1[nH]c(=S)[nH]c2sccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Product: CSc1nc2sccc2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-thioxo-2,3-dihydro-1H-thieno[2,3-d]pyrimidin-4-one (25.4 g, 0.138 mol) in 1N aqueous NaOH (600 mL) at room temperature was added methyl iodide (10.3 mL, 1.2 eq). The resulting mixture was stirred vigorously for about 2.5 hours. The reaction mixture was cooled to 0° C. and acetic acid was added (about 80 mL) until about pH=4.5 was reached. A fine precipitate was filtered and dried overnight to afford the title compound as a fine tan powder (24.8 g) (M+=198, M.P.=231.6-235.0° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([I:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([C@H:17]([OH:22])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([I:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1I
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1I
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
To a stirred yellow solution of methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (1.7 g, 3.40 mmol) in anhydrous toluene (100 mL) was added 1.1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (1.236 mL, 1.360 mmol). The mixture was cooled to −35° C. and a solution of catechoborane/toluene (1.166 mL, 4.76 mmol) was added over 5 min. After 30 min, the reaction mixture was slowly warmed to −15° C. and stirred for additional 2 h. and diluted with EtOAc (600 mL) and sat. Na2CO3 (100 mL). The mixture was stirred vigorously for 30 min, and the organic phase washed with sat Na2CO3 (2×100 mL), dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel chromatography (5-100% EtOAc/hexane) to afford desired (S)-methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (1 g, 1.992 mmol, 58.6% yield) as off-white solid. 1H NMR (500 MHz, CDCl3) δ: 8.21 (t, J=1.7 Hz, 1H), 7.96 (dt, J=7.8, 1.2 Hz, 1H), 7.59-7.55 (m, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.09 (s, 1H), 5.78 (s, 1H), 3.87 (s, 3H), 3.54 (br. s., 1H), 2.61 (s, 3H). LCMS (M+H)=504.05.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C@H:8]2[CH2:10][C@H:9]2[C:11](O)=[O:12])=O)=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>C(O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[CH:8]3[CH:9]([C:11](=[O:12])[NH:17][N:18]=2)[CH2:10]3)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccc(Cl)cc1)[C@H]1C[C@H]1C(=O)O
Solvent: O
Solvent: CCO
Product: O=C1NN=C(c2ccc(Cl)cc2)C2CC12
Yield: 79.8 %

Procedure:
6.0 g (26.7 millimoles) of cis-2-(p-chlorobenzoyl)-cyclopropanecarboxylic acid, 1.47 g (29.4 millimoles) of hydrazine hydrate and 150 ml of ethanol are refluxed for 6 hours. The mixture is concentrated to about 20 ml and the product is filtered off at 0° C. and recrystallized from methanol. 4.7 g (80% of theory) of 2-(p-chlorophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as colorless crystals, of melting point 199°-200° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[N:16][N:17]([CH:19]4[CH2:25][CH2:24][C:23]5[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=5[N:21]([CH2:30][C:31]([F:34])([F:33])[F:32])[C:20]4=[O:35])[CH:18]=3)=[CH:10][C:9]=2[O:36][CH3:37])[CH:5]=[CH:4][N:3]=1.[CH2:38]([Mg]Br)[CH3:39]>C1COCC1.CN1C(=O)CCC1>[CH2:38]([C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[N:16][N:17]([CH:19]4[CH2:25][CH2:24][C:23]5[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=5[N:21]([CH2:30][C:31]([F:34])([F:33])[F:32])[C:20]4=[O:35])[CH:18]=3)=[CH:10][C:9]=2[O:36][CH3:37])[CH:5]=[CH:4][N:3]=1)[CH3:39]
Reactant: COc1cc(-c2cn(C3CCc4ccccc4N(CC(F)(F)F)C3=O)nn2)ccc1-c1ccnc(Cl)c1
Reactant: CC[Mg]Br
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCc1cc(-c2ccc(-c3cn(C4CCc5ccccc5N(CC(F)(F)F)C4=O)nn3)cc2OC)ccn1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 3-{4-[4-(2-chloropyridin-4-yl)-3-methoxyphenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (50 mg, 0.095 mmol), previously prepared, and ferric acetylacetonate (3.34 mg, 9.47 μmol) in THF (852 μl) and NMP (95 μl) at 0° C. was added ethyl magnesium bromide (1M in THF, 189 μl, 0.189 mmol). The reaction was held at 0° C. and stirred for 15 minutes. The reaction was quenched at 0° C. with a small addition of 1 mL of a saturated NH4Cl aq. solution. The reaction was diluted with 50 mL of H2O and was extracted with 3×50 mL portions of DCM. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo Analytically pure material was obtained by purification by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% Formic Acid. Lyophilisation afforded 3-{4-[4-(2-ethylpyridin-4-yl)-3-methoxyphenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1 benzazepin-2-one.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[N+:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33])([O-:28])=[O:27]>O1CCCC1>[N+:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([NH:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6])=[O:33])([O-:28])=[O:27]
Reactant: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CC(NC(=O)c1cccc([N+](=O)[O-])c1)c1ccc(OC)c(OC)c1
Yield: 95.3 %

Procedure:
To an ice bath cooled stirred suspension of methyl 3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride (1.38 grams, 5.00 mmol) and triethylamine (1.5 milliliters, 10.8 mmol) in 10 milliliters of tetrahydrofuran was added 3-nitrobenzoyl chloride (0.928 grams, 5.00 mmol) in a single portion. A thick slurry resulted. The cooling bath was removed after 15 minutes, the mixture diluted with 10 milliliters of tetrahydrofuran and the mixture stirred for an additional hour. The reaction mixture was diluted with 50 milliliters of water and then partially concentrated in vacuo to remove the tetrahydrofuran. The reaction slurry was filtered, the solid washed with copious amounts of water, air-dried, and dried in vacuo (60° C., <1 mm) to afford 1.85 grams (95%) of the product as an off white powder: 1H NMR (CDCl3, 250 MHz) δ 8.63 (t, J=1.9 Hz, 1 H), 8.35 (m, 1 H, Ar), 8.20 (m, 1 H, Ar), 7.77 (d, J=8 Hz, 1 H, NH), 7.63 (t, J=8.0 Hz, 1 H), 6.95-6.75 (m, 3 H, Ar), 5.86 (m, 1 H, CHCO), 3.85 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 3.68, (s, 3 H, CO2CH3), 3.01 (m, 2 H, CH2); 13C NMR (CDCl3) δ 172.0, 164.1, 149.1, 148.6, 148.2, 135.8, 133.1, 132.7, 129.8, 126.1, 122.0, 118.2, 111.2, 109.9, 55.9, 55.8, 52.0, 50.2, 39.5.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[F:5][C:6]([F:17])([F:16])[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1.CCN(C(C)C)C(C)C>ClCCl>[F:5][C:6]([F:17])([F:16])[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH:4][CH2:1][CH:2]=[CH2:3])=[CH:10][CH:9]=1
Reactant: C=CCN
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCNCc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of allylamine (17.8 g; 312 mmol) in 200 ml of dichloromethane was added 4-trifluoromethoxybenzyl bromide (16 g; 62.4 mmol) and DIEA 8.88 g; 68.4 mmol). After stirring at rt overnight the reaction mixture was extracted with one volume of water. The organic phase was dried over sodium sulfate and concentrated to afford N-[4-(trifluoromethoxy)benzyl]prop-2-en-1-amine (14 g; 97% crude yield), which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:20][CH3:21])=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]3[CH2:16][CH2:17][CH2:18][C:11]=3[C:10]=2[CH:19]=1.Cl.Cl.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.C(O)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O>[CH3:21][O:20][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:34][CH2:33][N:32]([C:29]3[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=3)[CH2:37][CH2:36]2)=[CH:19][C:10]2[C:11]3[CH2:18][CH2:17][CH2:16][C:12]=3[C:13](=[O:15])[O:14][C:9]=2[CH:8]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCl)CCC3
Agent: Cl
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Solvent: CCO
Product: COc1ccc(N2CCN(CCCOc3cc4c5c(c(=O)oc4cc3OC)CCC5)CC2)cc1
Yield: 45 %

Procedure:
Method A (60 h at 40° C.); starting materials: 8-(3-chloropropoxy)-2,3-dihydro-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 83) and 1-(4-methoxyphenyl)piperazine dihydrochloride; yield 45%; fusion point 155°-156° C. (from ethanol). Fumarate: method E; yield 96%; fusion point 207°-210° C. (from acetone).
Reaction SMILES: CN1C(NC(=O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15][C:16]2[CH:24]=[C:23]3[C:19](/[C:20](=[CH:26]/O)/[C:21](=[O:25])[NH:22]3)=[CH:18][CH:17]=2)=CC(C)=N1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=2)[CH2:33][CH2:32]1>C1COCC1>[CH3:23][NH:22][C:21](=[O:25])[C:12]1[CH:13]=[CH:14][CH:9]=[C:10]([S:15][C:16]2[CH:24]=[C:23]3[C:19]([C:20](=[CH:26][NH:43][C:40]4[CH:41]=[CH:42][C:37]([N:34]5[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]5)=[CH:38][CH:39]=4)[C:21](=[O:25])[NH:22]3)=[CH:18][CH:17]=2)[CH:11]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1cc(NC(=O)c2ccccc2Sc2ccc3c(c2)NC(=O)/C3=C\O)n(C)n1
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(Sc2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCN(C)CC3)cc2)c1
Temperature: 68 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
A 1 mL vial was charged with N-(2,5-Dimethyl-2H-pyrazol-3-yl)-2-{3-[1-hydroxy-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indol-6-ylsulfanyl}-benzamide (as prepared below; 55 mg, 0.135 mmol), 4-(4-methyl-piperazin-1-yl)-phenylamine (25.8 mg, 0.138 mmol), and THF (1 mL). This reaction mixture was stirred for 24 h at 68° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was re-suspended in EtOAc (5 mL) and extracted with H2O (˜5 mL). The organic layer was concentrated in vacuo and the residue was chromatographed via flash silica gel chromatography (gradient of 1-10% MeOH in CHCl3) afforded the title compound in 35% yield (27 mg, 0.047 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([NH:12]/[N:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[S:11].[C:37](=O)([O-])[O-].[K+].[K+].ICI>CC(=O)CC.C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[CH2:37][S:11]/[C:10]/1=[N:12]/[N:13]=[CH:14]\[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:35])([F:34])[F:36])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cccc(F)c1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [K+]
Solvent: ICI
Solvent: CCC(C)=O
Solvent: ClCCl
Product: Fc1cccc(F)c1N1CS/C1=N/N=C\c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 55 °C
Reaction time: 48 h
Yield: 16.7 %

Procedure:
To a mixture of (E)-N-(2,6-difluorophenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (0.50 g, 0.96 mmol) and potassium carbonate (0.53 g, 3.9 mmol) in butanone (10 mL) in a 25 mL vial equipped with a magnetic stir bar was added diiodomethane (0.093 ml, 1.2 mmol). The reaction was heated to 55° C. and stirred for two days. The reaction mixture was diluted with DCM, washed with water, and the phases separated. The aqueous phase was extracted with DCM and the combined organic phases were dried by passing through a phase separator cartridge and then concentrated. Purification by flash column chromatography provided a yellow oil which crystallized upon standing. The solid was slurried in diethyl ether and hexanes and collected by vacuum filtration. The solid was washed with hexanes and dried to provide the title compound (0.086 g, 0.16 mmol, 17%) as a light yellow solid: mp 144-146° C.; 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.34 (s, 1H), 8.20 (d, J=8.3 Hz, 2H), 7.81 (d, J=8.8 Hz, 4H), 7.40 (d, J=8.3 Hz, 2H), 7.31-7.23 (m, 1H), 7.03-6.97 (m, 2H), 5.05 (s, 2H); ESIMS m/z 532 (M+H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[CH2:6][C:7](Cl)=[O:8].[CH3:10][C:11]([C:13]1[C:14]([OH:20])=[CH:15][CH:16]=[CH:17][C:18]=1[OH:19])=[O:12].C(OCC)(=O)C>[N+](C1C=CC=CC=1)([O-])=O>[C:11]([C:13]1[C:14]2[O:20][CH2:6][C:7](=[O:8])[C:15]=2[CH:16]=[CH:17][C:18]=1[OH:19])(=[O:12])[CH3:10]
Reactant: CC(=O)c1c(O)cccc1O
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1c(O)ccc2c1OCC2=O
Temperature: 0 °C
Yield: 71 %

Procedure:
The synthesis was performed with reference to the known literature (Journal of the Pharmaceutical Society of Japan (Yakugaku Zasshi), Vol. 88, p. 589, 1968). A suspension of aluminum chloride (3.5 g, 26 mmol) in nitrobenzene (10 mL) was stirred at 0° C. under an argon atmosphere. This suspension was added with chloroacetyl chloride (1.1 g, 9.9 mmol), and then the mixture was added dropwise with a suspension of 2,6-dihydroxyacetophenone (1.0 g, 6.6 mmol) in nitrobenzene (6.0 mL). After completion of the addition, the reaction mixture was stirred at 50° C. for 17 hours. The reaction mixture was added with ethyl acetate and ice water, the mixture was stirred at room temperature for 1 hour, and then the organic layer was separated. The organic layer was extracted with 1 N aqueous sodium hydroxide, and the aqueous layer was made acidic with 3 N hydrochloric acid to precipitate solid. The precipitated solid was collected by filtration and dried to obtain 7-acetyl-6-hydroxybenzofuran-3(2H)-one (0.90 g, 71%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][S:6]1(=[O:16])=[O:15].[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[S:6]1(=[O:16])=[O:15]
Reactant: O=S1(=O)Nc2ccccc2CN1CCCCl
Reactant: OB(O)c1ccc(F)cc1
Product: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1ccc(F)cc1

Procedure:
In an analogous manner to Example 1 step 7, 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (417 mg) was coupled to p-fluorophenylboronic acid to provide 3-(3-chloropropyl)-1-(4-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (67 mg):