Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7](I)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1ncccc1I
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: Fc1ncccc1N1CCOCC1
Temperature: 150 °C
Yield: 67.5 %

Procedure:
A microwave reaction vessel was charged with 2-fluoro-3-iodopyridine (purchased from Maybridge™) (0.565 g, 2.53 mmol), morpholine (purchased from Aldrich™) (0.221 ml, 2.53 mmol), Pd2(dba)3 (purchased from Strem™) (0.154 g, 0.152 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (purchased from Strem™) (0.135 g, 0.304 mmol), and sodium t-butoxide (0.8 g, 7.6 mmol). The reaction mixture was stirred and heated in a Discover® model microwave reactor (CEM, Matthews, N.C.) at 150° C. for 20 min (125 watts, Powermax feature on, ramp time 5 min). Solvent was evaporated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column, eluting with a gradient of 1% to 5% MeOH in CH2Cl2, to provide 4-(2-fluoropyridin-3-yl)morpholine (0.311 g, 67.5% yield).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:22][C:23]1([CH3:30])[O:27][CH:26]([CH2:28]O)[CH2:25][O:24]1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([O:21][CH2:28][CH:26]4[CH2:25][O:24][C:23]([CH3:30])([CH3:22])[O:27]4)=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC1(C)OCC(CO)O1
Reactant: O=C(O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC1(C)OCC(COC(=O)Cc2cccc3c(=O)cc(C4=CCCCC4)oc23)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
[2-(1-Cyclohexenyl)-4-oxo-4H-[1]-benzopyran-8-yl]acetic acid (2.84 g), 2,2-dimethyl-1,3-dioxolan-4-methanol (3.96 g) and dicyclohexylcarbodiimide (2.28 g) were added to dichloromethane (30 ml) with ice cooling and then the mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (2.65 g), yield 67%, m.p. 104°-105° C. (recrystallized from ethyl acetate).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23]>C1COCC1>[CH:1]([NH:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[O:22][CH3:23])=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(N)c(OC)c1
Solvent: C1CCOC1
Solvent: O=CO
Product: COC(=O)c1ccc(NC=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Acetic anhydride (268 mL) was added dropwise to formic acid (401 mL) at room temperature, and the reaction solution was stirred at room temperature for 40 minutes. A solution of methyl 4-amino-3-methoxybenzoate (134 g) in THF (600 mL) was added dropwise to the reaction solution at room temperature, and the reaction solution was stirred for one hour. 3.8 L of ice water was added to the reaction solution, and the precipitated solid was filtered and further washed with water (2 L). The resulting solid was dried at 50° C. overnight to obtain 111 g of the title compound. The property values corresponded to the reported values (CAS #700834-18-0).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][N:6]([CH3:29])[C:7](=[O:28])[C:8]1[CH:13]=[C:12]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]2Cl)[C:11]([F:26])=[CH:10][C:9]=1[Cl:27].[C:30](OCC)(=[O:32])C.CCCCCC>CO>[CH3:4][O:5][N:6]([CH3:29])[C:7](=[O:28])[C:8]1[CH:13]=[C:12]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]2[O:32][CH3:30])[C:11]([F:26])=[CH:10][C:9]=1[Cl:27]
Reactant: CON(C)C(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)N(C)OC)c(Cl)cc1F
Reaction time: 0.17 h

Procedure:
A solution of 0.54 g of sodium methylate in 5 ml of methanol is added dropwise to a suspension of 4.14 g of N-methoxy-N-methyl-2-chloro-5-[2-chloro-4-oxo-6-trifluoromethyl-3(4H)-pyrimidinyl]-4-fluorobenzamide in 25 ml of methanol and the reaction mixture is stirred for 10 minutes. The mixture is then treated with 30 ml of ethyl acetate as well as 50 ml of n-hexane, filtered and the filtrate is evaporated. The resulting colourless, viscous crude product crystallizes from diethyl ether/n-hexane. There is obtained N-methoxy-N-methyl-2-chloro-4-fluoro-5-[2-methoxy-4-oxo-6-trifluoromethyl-3(4H)-pyrimidinyl]-benzamide, m.p. 119° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[N:7]2[C:8]3[CH:27]=[CH:26][CH:25]=[N:24][C:9]=3[O:10][C:11]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:6]2=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:28][C:2]([F:1])([F:29])[C:3]1[N:7]2[C:8]3[CH:27]=[CH:26][CH:25]=[N:24][C:9]=3[O:10][C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:6]2=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ncccc1-n1c(C(F)(F)F)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc2n1-c1cccnc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
To a solution of tert-butyl 9′-(trifluoromethyl)spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate (83 mg, 0.20 mmol) in CH2Cl2 (3 mL) was added TFA (1.0 mL, 13 mmol) and the mixture was stirred at room temperature for 15 min before being evaporated to dryness. The residue was taken up in EtOAc and sat. aq. Na2CO3, the layers were separated, and aqueous layer was extracted with EtOAc (2×). The organics were combined, washed with sat. aq. Na2CO3, brine, dried (Na2SO4) and evaporated to dryness to give 9′-(trifluoromethyl)-spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine] as a pale yellow solid (59 mg). ESI-MS m/z calc. 309.1. found 310.3 (M+1)+; Retention time: 1.32 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([C:6]([OH:13])=NC(O)=[N:9]2)=[N:4][CH:3]=1.[OH-:14].[Na+].Cl>O>[NH2:9][C:10]1[C:5]([C:6]([OH:13])=[O:14])=[N:4][CH:3]=[C:2]([CH3:1])[N:11]=1
Reactant: [OH-]
Reactant: Cc1cnc2c(O)nc(O)nc2n1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cnc(C(=O)O)c(N)n1
Temperature: 150 °C

Procedure:
7-Methyl-pteridine-2,4-diol (prepared by the procedure of ‘Synthesis of 2,6-Disubstituted pyrazines and Related Derivates.’, Sharefkin, D. M. J. Am. Chem. Soc., 1959, 345) (4 g, 22.5 mmol) is suspended in a solution of NaOH (2.17 g, 53 mmol) in H2O (20 ml), in an autoclave, and the mixture is heated to 150° C. for 3 days. The reaction mixture is cooled to room temperature and the pH is adjusted to 2.5 by the slow addition of 6M HCl (98 ml). The resulting suspension is cooled in a fridge for 1.5 hours, and the solid is then collected by filtration, washed with cold H2O, and MeOH, and dried in vacuo to yield 3-amino-5-methyl-pyrazin-2-carboxylic acid as a beige solid. [M+H]+ 154
Reaction SMILES: [C:1]([O:5]CC#C)(=[O:4])[CH:2]=[CH2:3].[CH:9]1[CH2:13][CH:12]=[CH:11][CH:10]=1.C[SiH](C)Cl>>[CH:11]12[CH2:12][CH:13]([CH:9]=[CH:10]1)[CH2:3][CH:2]2[C:1]([OH:5])=[O:4]
Reactant: C1=CCC=C1
Reactant: C#CCOC(=O)C=C
Agent: C[SiH](C)Cl
Product: O=C(O)C1CC2C=CC1C2
Temperature: 70 °C
Reaction time: 3 h

Procedure:
The propargyl ester of 2-norborn-5-ene carboxylic acid was prepared by Diels-Alder reaction of propargyl acrylate and cyclopentadiene at ambient temperature. Dimethylchlorosilane (56.4g) was added portionwise to 100 grams of this norbornene carboxylate ester and 0.16 g Karstedt catalyst under nitrogen at 70° C. After exotherming to 80° C., the mixture was stirred for 3 hours at 70° C., stripped under light vacuum and then distilled. The product, ##STR13## (84% purity by GC), distilled at 100°-105° C. at 0.07 mm.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[CH:6]1[C:15]2[C:16]3[C:25]([C:13]4[C:14]=2[C:9]([CH:10]=[CH:11][CH:12]=4)=[CH:8][CH:7]=1)=[N:24][C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17]=3>O>[CH:6]1[C:15]2[C:16]3[C:25]([C:13]4[C:14]=2[C:9]([CH:10]=[CH:11][CH:12]=4)=[CH:8][C:7]=1[S:1]([OH:3])(=[O:5])=[O:2])=[N:24][C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17]=3
Reactant: O=S(=O)(O)O
Reactant: c1cc2c3c(cccc3c1)-c1nc3ccccc3nc1-2
Solvent: O
Product: O=S(=O)(O)c1cc2c3c(cccc3c1)-c1nc3ccccc3nc1-2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
As represented by the following reaction pathway, 30% fuming sulfuric acid (2.1-liter) was added to 300 g of acenaphtho[1,2-b]quinoxaline obtained by synthesis example 1 and the mixture was stirred at room temperature for 48 hours for reaction. While keeping the obtained solution at 40° C. to 50° C., 4.5-liter of ion exchange water was added for dilution, and the resultant was further stirred for 3 hours. The precipitate was filtered to obtain acenaphtho[1,2-b]quinoxaline-2-sulfonic acid as represented by the following formula (d).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[NH3:17]>O1CCCC1>[Cl:1][C:2]1[N:11]=[C:10]([NH2:17])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: N
Solvent: C1CCOC1
Product: COc1cc2nc(Cl)nc(N)c2cc1OC
Reaction time: 48 h

Procedure:
8.6 g of 2.4-Dichloro-6,7-dimethoxy quinazoline was dissolved in 300 ml of tetrahydrofuran and NH3 -gas was introduced to the solution. After saturated with NH3 -gas, the reaction mixture was allow to stand for 2 days and the solvent was removed. The resulting precipitate was collected by filtration and recrystallized from methanol. 2.8 g of desired compound was obtained. m.p. 248° C. (decomp.)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([NH:11][CH3:12])=[O:10].[CH3:13][O:14][C:15](=[O:44])[N:16]=[C:17]([S:42][CH3:43])[C:18]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([O:39][CH2:40][CH3:41])[CH:33]=1)=[N:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[CH:22][CH:21]=1.O>CC(C)=O.C(OCC)(=O)C>[CH3:13][O:14][C:15](=[O:44])[N:16]=[C:17]([S:42][CH3:43])[C:18]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:8][C:9](=[O:10])[NH:11][CH3:12])=[C:34]([O:39][CH2:40][CH3:41])[CH:33]=1)=[N:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[CH:22][CH:21]=1
Reactant: CNC(=O)CBr
Reactant: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)ccc1OCC(=O)NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
After adding 200 mg of potassium carbonate and 78 mg of 2-bromo-N-methyl -acetamide to a solution of 154 mg of {2-(3-ethoxy-4-hydroxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 1 ml of acetone, the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layers were combined and washed with 0.5N hydrochloric acid and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (161 mg) as a yellow solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:8][CH2:7]1)=[O:5].[N:30]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][C@H:31]1[C:40](O)=[O:41].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>>[C:46]([O:45][C:43]([N:30]1[C@H:31]([C:40]([NH:2][C@H:3]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:4]([N:6]2[CH2:7][CH2:8][N:9]([C:12]3[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=3[C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:11]2)=[O:5])=[O:41])[CH2:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:39]1)=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: COC(=O)c1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared according to the procedure described in Preparation V by using methyl 2-{4-[(2R)-2-amino-3-(4-chlorophenyl)propanoyl] piperazinyl}-benzoate hydrochloride (2.6 g, 5.9 mmol), Boc-L-Tic-OH (Bachem) (1.8 g, 6.5 mmol), HOAT (Aldrich) (810 mg, 5.9 mmol), and EDC (Aldrich) (2.3 g, 12 mmol) and DIEA (Aldrich) (1.0 mL, 5.9 mmol). The title compound was isolated and purified by column chromatography (CH2Cl2 with 1.5% NH3 2M in MeOH) (2.8 g). MS (ESI, pos. ion) m/z: 661 (M+H). Calc'd for C36H41ClN4O6: 660.27.
Reaction SMILES: Cl.Cl.Cl.Cl.[N:5]1([C@H:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([C@H:21]4[CH2:26][NH:25][CH2:24][CH2:23][NH:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C.Cl[C:35]1[N:40]([CH3:41])[C:39](=[O:42])[CH:38]=[C:37]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][N:44]=2)[N:36]=1>O1CCCC1>[CH3:41][N:40]1[C:39](=[O:42])[CH:38]=[C:37]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][N:44]=2)[N:36]=[C:35]1[N:25]1[CH2:24][CH2:23][NH:22][C@@H:21]([C:18]2[CH:17]=[CH:16][C:15]([N:12]3[CH2:13][CH2:14][CH:10]([N:5]4[CH2:6][CH2:7][CH2:8][CH2:9]4)[CH2:11]3)=[CH:20][CH:19]=2)[CH2:26]1
Reactant: c1cc(N2CC[C@H](N3CCCC3)C2)ccc1[C@H]1CNCCN1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN[C@@H](c3ccc(N4CCC(N5CCCC5)C4)cc3)C2)nc(-c2ccncn2)cc1=O
Reaction time: 24 h
Yield: 66.8 %

Procedure:
To a suspension of (S)-2-(4-((S)-3-(pyrrolidin-1-yl)pyrrolidin-1-yl)phenyl) piperazine tetrahydrochloride (99 mg, 0.22 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.20 mL, 1.40 mmol) and 2-chloro-3-methyl-6-(4-pyrimidinyl)-3H-pyrimidin-4-one (45 mg, 0.20 mmol) at room temperature. After stirring for 24 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and sodium bicarbonate aqueous solution, and the solution was passed through CHEM ELUT CE1010 (manufactured by VARIAN). The filtrate was concentrated, and the resulting crystals were washed in a mixture of diisopropyl ether and ethanol to afford (S)-3-methyl-6-(4-pyrimidinyl)-2-(3-(4-(3-(pyrrolidin-1-yl)pyrrolidin-1-yl)phenyl)piperazin-1-yl)-pyrimidin-4-one (65 mg, 66%) as a pale yellow solid.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:8]([NH:9][CH2:10][CH3:11])=[CH:7][N:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:5]=1.C(N(CC)CC)C.[C:25]([O:28][CH:29]([CH3:33])[C:30](Cl)=[O:31])(=[O:27])[CH3:26]>C(Cl)Cl>[C:25]([O:28][CH:29]([CH3:33])[C:30]([N:9]([C:8]1[C:4]([Cl:3])=[N:5][N:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=1)[CH2:10][CH3:11])=[O:31])(=[O:27])[CH3:26]
Reactant: CCNc1cn(-c2cccnc2)nc1Cl
Reactant: CC(=O)OC(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(C(=O)C(C)OC(C)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine dihydrochloride (3.00 g, 10.2 mmol) in CH2Cl2 (20 mL) cooled in an ice bath were added triethylamine (5.7 mL, 40.6 mmol) followed by dropwise addition 1-chloro-1-oxopropan-2-yl acetate (1.3 mL, 10.2 mmol). The reaction mixture was stirred overnight warming to room temperature. The reaction mixture was then diluted with CH2Cl2 and washed with water. The phases were separated, and the organics were dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0%-70% acetone/hexanes to afford the title compound C12 as a tan taffy-like solid (3.2 g, 93%): 1H NMR (400 MHz, CDCl3) δ 8.99 (d, J=2.5 Hz, 1H), 8.62 (dd, J=4.8, 1.3 Hz, 1H), 8.18 (s, 1H), 8.04 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.46 (ddd, J=8.4, 4.8, 0.5 Hz, 1H), 5.01 (d, J=6.5 Hz, 1H), 3.54 (m, 2H), 2.09 (s, 3H), 1.39 (d, J=6.8 Hz, 3H), 1.17 (t, J=7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.01, 148.62, 140.57, 140.24, 135.63, 127.56, 126.33, 124.06, 122.58, 67.49, 43.74, 20.61, 16.80, 12.57 (one carbon signal not located); ESIMS m/z 336.4 ([M+H]+), 335.0 ([M−H]−).
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.S(Cl)([Cl:16])=O>C1C=CC=CC=1>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[C:1]([Cl:16])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1OC
Solvent: c1ccccc1
Product: COc1ccc(C(=O)Cl)cc1OC

Procedure:
Veratric acid (3,4-dimethoxybenzoic acid) (25 g) was suspended in dry benzene (400 ml) and treated with a large excess of thionyl chloride. This mixture was refluxed for 5 hours. The benzene was removed in vacuo and the oily residue was washed 5 times with 150 ml portions of fresh dry benzene followed by distillation of the benzene to remove excess thionyl chloride. This yielded 26.5 g of the desired acid chloride as a light brown solid, m.p. 68°-69° C. (lit. value, 70° C.).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:14]>C(Cl)Cl>[CH:13]([C:15]1[CH:16]=[CH:17][C:18]([S:21]([N:2]([CH2:3][CH2:4][OH:5])[CH3:1])(=[O:23])=[O:22])=[CH:19][CH:20]=1)=[O:14]
Reactant: CNCCO
Reactant: O=Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCO)S(=O)(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 80 h
Yield: 92.3 %

Procedure:
To an ice-cooled solution of 2-(methylamino)ethanol (0.196 mL, 2.44 mmol) and triethylamine (0.407 mL, 2.93 mmol) in DCM (10 mL) was added 4-formylbenzenesulfonyl chloride (0.500 g, 2.44 mmol). The reaction mixture was warmed slowly to RT and stirred at RT for 80 hours. The reaction mixture was diluted with DCM and was washed with 10% aqueous potassium hydrogen sulfate and dried (magnesium sulfate). The mixture filtered and the solvent evaporated at reduced pressure to afford the title compound (0.548 g, 92%).
Reaction SMILES: I[C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=1[C:9]=23.[C-:16]#[N:17].[Na+]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Cu]I>[O:15]=[C:14]1[C:8]2[C:9]3[C:10](=[C:2]([C:16]#[N:17])[NH:3][C:4]=3[CH:5]=[CH:6][CH:7]=2)[CH2:11][CH2:12][NH:13]1
Reactant: O=C1NCCc2c(I)[nH]c3cccc1c23
Reactant: [C-]#N
Agent: [Cu]I
Agent: [Pd]
Agent: [Na+]
Product: N#Cc1[nH]c2cccc3c2c1CCNC3=O
Temperature: 80 °C
Reaction time: 15 h

Procedure:
Following a procedure from JOC 1998, p. 8224, 2-iodo-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (100 mg, 0.32 mmol), sodium cyanide (31 mg, 0.64 mmol), palladium tetrakis(triphenylphosphine) (19 mg, 0.05 mmol), and copper(I) iodide were combined in a schlenk tube. The vessel was evacuated and refilled with argon gas three times. Degassed propionitrile (2 mL) was added, and the reaction was stirred at 80° C. under an argon atmosphere for 15 h. The reaction mixture was partitioned between water and 25% iPrOH/CHCl3. The layers were separated and the aqueous layer extracted thrice with 25% iPrOH/CHCl3. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The yellow solid was recrystallized from CH2Cl2/MeOH/hexanes to yield 6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indole-2-carbonitrile, 38 mg (56%) as a pale yellow solid: m.p. 315° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ3.04 (m, 2H), 3.47 (m, 2H), 7.46 (t, J=7.5 Hz, 1H), 7.64 (dd, J=8.1, 0.9 Hz, 1H), 7.81 (dd, J=7.2, 0.9 Hz, 1H), 8.24 (br t, 1H), 12.44 (br s, 1H). MS (electrospray, [M+Na]+): 234. Anal. (C12H9N3O) C, H, N.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9](/[CH:12]=[C:13](\[CH3:30])/[CH2:14][CH2:15]/[CH:16]=[C:17](\[CH3:29])/[CH2:18][CH2:19]/[CH:20]=[C:21](\[CH3:28])/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[N:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:31](C/C(/C)=C/CC/C(/C)=C/CC(Cl)=O)/C=C(/CCC=C(C)C)\C>>[CH3:30]/[C:13](/[CH2:14][CH2:15]/[CH:16]=[C:17](\[CH3:29])/[CH2:18][CH2:19]/[CH:20]=[C:21](\[CH3:28])/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:12]\[C:9]1[O:8][C:7]([C:1]2[CH:2]=[CH:3][C:4]([CH3:31])=[CH:5][CH:6]=2)=[N:11][N:10]=1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/c1nnc(-c2ccccc2)o1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC(=O)Cl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/c1nnc(-c2ccc(C)cc2)o1
Yield: 16 %

Procedure:
Similar to the preparation of 29a, the reaction of 25 with 28b afforded the desired compound 29b (20.8 mg, 16%) as oil. TLC Rf: 0.42 (20% EtOAc/petroleum ether); 1H NMR (400 MHz, CDCl3): δ 7.92 (d, 2H), 7.29 (d, 2H) 5.11-5.09 (m, 3H), 4.98 (d, 2H), 3.65 (s, 2H), 2.42 (s, 3H), 2.18-2.16 (m, 4H), 2.07-2.04 (m, 4H), 1.99-1.96 (m, 4H), 1.67 (s, 3H), 1.60 (s, 3H), 1.59 (s, 3H), 1.58 (s, 3H). LCMS: MS (m/z): 419.40 (M+H); ret. time: 8.32 min.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].CO[C:8](=[O:33])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:19][C:18]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=2)=[CH:11][C:10]=1[CH3:32]>CO>[Cl:30][C:28]1[CH:29]=[C:24]([C:18]2([C:20]([F:23])([F:21])[F:22])[O:17][N:16]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:8]([NH:2][OH:3])=[O:33])=[C:10]([CH3:32])[CH:11]=3)[CH2:19]2)[CH:25]=[C:26]([Cl:31])[CH:27]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NO
Temperature: 40 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
In a solution of 0.30 g of hydroxylamine hydrochloride in 10 ml of methanol, a solution of 0.65 g of potassium hydroxide in 5 ml of methanol was added, then a solution of 1.00 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoic acid methyl ester synthesized similarly to Steps 1 to 4 of Synthetic Example 28 in 10 ml of methanol was added, and stirred at 40° C. for 1 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, 10 ml of acetic acid aqueous solution (1:1) was added in the residue, and extracted with ethyl acetate (20 ml×2), the organic phase was dehydrated and dried with saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and the solvent was distilled under reduced pressure. Toluene was added in the residue and the remaining acetic acid was distilled off azeotropically to to obtain 1.01 g of crude 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzhydroxamic acid as white crystal.