Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][O:6][C:7]1[C:8]([N+:13]([O-:15])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K].O>CN(C)C=O>[N+:13]([C:8]1[C:7]([O:6][CH2:5][C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=2[CH2:2][N:24]2[C:23](=[O:25])[C:22]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]3[C:20]2=[O:30])=[CH:12][CH:11]=[CH:10][N:9]=1)([O-:15])=[O:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])c1ncccc1OCc1ccccc1CCl
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1COc1cccnc1[N+](=O)[O-]
Yield: 47.3 %

Procedure:
A solution of 3-(2-chloromethylbenzyloxy)-2-nitropyridine (4.09 g) and potassium phthalimide (2.99 g) in N,N-dimethylformamide (41 ml) was stirred at 50° C. for 9.5 hours. The reaction mixture was poured into water (200 ml) and extracted twice with ethyl acetate (250 ml). The combined extract was washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the resultant residue was recrystallized from ethyl acetate to give 2-nitro-3-(2-phthalimidomethylbenzyloxy)pyridine (2.7 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[CH2:17]([O:19][C:20](=[O:27])[CH2:21][C:22](OCC)=[O:23])[CH3:18].C1CCN2C(=NCCC2)CC1>>[CH2:17]([O:19][C:20]([C:21]1[C:22](=[O:23])[NH:1][C:2]2[C:3]([C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:4][C:5]([Cl:8])=[CH:6][CH:7]=2)=[O:27])[CH3:18]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Temperature: 185 °C
Reaction time: 16 h
Yield: 49.5 %

Procedure:
To a mixture of (2-amino-5-chloro-phenyl)-phenyl-methanone (5 g, 21.58 mmol) and malonic acid diethyl ester (4.565 ml, 30.21 mmol) was added DBU (0.45 ml, 3.02 mmol) under nitrogen and the mixture was stirred at 180-190° C. for 16 h. After cooling, the crude residue was purified by flash column chromatography (100-200 mesh silica, eluting with 50% ethyl acetate in hexane) to afford pure 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid ethyl ester (3.5 g, 49%) as off white solid. LC-MS: 328 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]3[B:11]([OH:14])[O:12][CH2:13][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[OH:14][B:11]1[C:10]2[CH:15]=[CH:16][C:7]([O:6][C:5]3[CH:17]=[CH:18][C:2]([NH:1][C:26](=[O:28])[CH3:27])=[CH:3][CH:4]=3)=[CH:8][C:9]=2[CH2:13][O:12]1
Reactant: Nc1ccc(Oc2ccc3c(c2)COB3O)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 20 mL scintillation vial containing 5-(4-amino-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (68 mg, 0.28 mmol, 1.0 eq.) in DCM (3.0 mL) was added Et3N (47 μL, 0.33 mmol, 1.2 eq.), followed by acetyl chloride (22 μL, 0.31 mmol, 1.1 eq.). The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenyl]-acetamide as a white solid. LCMS (m/z) 284 (M+H); 1H NMR (DMSO-d6) δ: 10.17 (s, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.58-7.63 (m, 2H), 6.94-6.99 (m, 2H), 6.88 (dd, J=8.0, 2.1 Hz, 1H), 6.84 (d, J=1.5 Hz, 1H), 4.85 (s, 2H), 3.12 (s, 1H), 2.00 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6].[BH4-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3,4-difluorobenzaldehyde (200 mg, 1.41 mmol) in methanol (4 mL) was added NaBH4 (80 mg, 2.1 mmol). The reaction mixture was stirred at rt for 10 min., then diluted with water and extracted with ethyl acetate. The organic part was separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude was used into next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:42](OC(=O)C)(=[O:44])[CH3:43]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:42](=[O:44])[CH3:43])=[CH:29][CH:28]=2)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(CN(c2ccc(CN)cc2)C2CCN(C(=O)OCc3ccccc3)CC2)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of the above amine (462 mg, 1.02 mmol) in CH2Cl2 (10 mL) were added Et3N (0.45 mL, 3.23 mmol) followed by acetic anhydride (0.20 mL, 2.12 mmol) and the mixture was stirred at room temperature overnight to afford 4-[[4-(acetylamino-methyl)-phenyl]-(3-cyano-benzyl)-amino]-piperidine-1-carboxylic acid benzyl ester as a white solid (463 mg, 91%) following work-up and purification.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([F:18])[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:19])[CH:3]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(N[C:42]([NH:44][C:45](=[O:54])[CH2:46][C:47]4[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=4)=[O:43])=CC=3F)C=2)=CC=1>>[C:13]([C:9]1[CH:8]=[C:7]([O:6][C:5]2[C:16]([F:18])=[CH:17][C:2]([NH:1][C:42]([NH:44][C:45](=[O:54])[CH2:46][C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=3)=[O:43])=[CH:3][C:4]=2[F:19])[CH:12]=[CH:11][N:10]=1)(=[O:14])[NH2:15]
Reactant: NC(=O)c1cc(Oc2c(F)cc(N)cc2F)ccn1
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Product: NC(=O)c1cc(Oc2c(F)cc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Yield: 52 %

Procedure:
4-(4-Amino-2,6-difluorophenoxy)picolinamide (104 mg, 0.39 mmol) was converted to the title compound (91 mg, 52%) in a manner similar to the preparation of Compound D of Example 112. 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.62 (s, 1H), 8.50 (d, 1H, J=5.6 Hz), 8.11 (br s, 1H), 7.72 (br s, 1H), 7.61 (m, 2H), 7.36-7.37 (d, 1H, J=2.3 Hz), 7.23-7.31 (m, 3H), 7.11 (m, 2H), 3.69 (s, 2H); HRMS (ESI+), 445.1124 (M+H)+ calcd., 445.1117 (M+H)+ found.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(N(CC)CC)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19].Cl>C(OCC)C>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:17](=[O:20])[CH:18]=[CH2:19]
Reactant: C=CC(=O)Cl
Reactant: Cc1cccc(C)c1N
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2,6-dimethylaniline (8.68 g, 0.0718 mole) and triethylamine (15.3 ml) in ethyl ether (250 ml) was cooled to +5° C. A solution of acryloyl chloride (6.47 g, 0.0716 mole) in ethyl ether (25 ml) was added dropwise with stirring over a 20 minute period. The solution was allowed to warm to room temperature and stirred for 72 hours. 10 Percent hydrochloric acid (150 ml) was added and the layers separated. The acid layer was extracted with ethyl acetate (150 ml), combined, washed with water (150 ml), dried over sodium sulfate, filtered and the solvents evaporated. The solid was taken up in hot ethyl acetate and recrystallized from hexane to yield the title compound, m.p. ca. 143.5°-145.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[I:10]I>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[I:10][C:7]1[C:2]([NH2:1])=[CH:3][CH:4]=[C:5]([O:8][CH3:9])[N:6]=1
Reactant: II
Reactant: COc1ccc(N)cn1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COc1ccc(N)c(I)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-2-methoxypyridine (10.0 g, 0.081 mol) was dissolved in EtOH (50 mL), and silver sulfate (27.6 g, 0.089 mol) and iodine (22.5 g, 0.089 mol) were added. The reaction was stirred at room temperature overnight, and then the mixture was filtered over Celite to remove solids. The filtrate was concentrated and purified on silica gel (0-50% EtOAc in hexanes) to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][NH2:13])[C:6]([O:14][CH3:15])=[N:5]2.[C:16](OCC)(OCC)(OCC)[CH2:17][CH3:18]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:16]([CH2:17][CH3:18])=[N:13][N:12]=[C:7]1[C:6]([O:14][CH3:15])=[N:5]2
Reactant: CCOC(CC)(OCC)OCC
Reactant: COc1nc2cc(Cl)ccc2nc1NN
Product: CCc1nnc2c(OC)nc3cc(Cl)ccc3n12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture consisting of 5.1 g. (0.022 mole) of 6-chloro-2-hydrazino-3-methoxyquinoxaline, the product of Preparation C(d), and 60 ml. of triethyl orthopropionate was heated with mechanical stirring in a preheated oil bath at 100° C. overnight (~16 hours). The resulting mixture was then cooled to room temperature (~20° C.), and the precipitate which formed was subsequently collected by means of suction filtration and washed with diethyl ether to ultimately afford 4.3 g. (75%) of pure 7-chloro-1-ethyl-4-methoxy-[1,2,4[4,3-a]quinoxaline, m.p. 221°-223° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.O>CC(C)=O>[CH:9]1[C:8]2[NH:7][C:6]3[C:5](=[CH:3][CH:2]=[CH:10][CH:9]=3)[C:4]=2[CH:3]=[CH:2][CH:10]=1
Reactant: Fc1ccc2[nH]ccc2c1
Solvent: O
Solvent: CC(C)=O
Product: c1ccc2c(c1)[nH]c1ccccc12
Reaction time: 0.08 h
Yield: 64 %

Procedure:
15 ml of acetone was poured into a 200 ml three-neck flask, and 1.62 g of 5-fluoroindole was dissolved therein. On the other hand, preparation of an oxidant solution was performed by dissolving 32.2 g of cupric chloride anhydrate and 12.9 g of water in 55 ml of acetone and agitating the mixture for 5 minutes. Then the prepared oxidant solution was dripped into the 5-fluoroindole solution for two hours and the resultant mixture solution was agitated for 5 hours at the temperature of 30° C. Color of the reaction solution changed from white to dark blue with slight heat generation. pH of the reaction solution was less than 1. After the end of the reaction, the reaction liquid was suction-filtered with a perforated funnel, and the filtrate was washed with acetone and then methanol and dried to obtain 1.04 g of 2,9,14-trifluoro-6,11-dihidro-5H-diindolo [2,3,-a:2′,3′-c] carbazole (5-fluoroindole trimer) (yield: 64%). The resultant trimer was pressure-molded with a tablet molding machine and the mold was cut into a piece with the diameter of 10 mm and thickness of 1 mm. A conductivity thereof was measured by the four terminal method and found to be 0.88 S/cm. The result of elemental analysis was: <C8.00H3.95N1.10F0.96Cl0.10>3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)=[CH:5][CH:4]=1.[F:21][CH:22]([F:24])Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[F:21][CH:22]([N:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:20])[N:11]=1)[F:24]
Reactant: COc1ccc(Nc2nc(C)nc3ccccc23)cc1
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(N(c2nc(C)nc3ccccc23)C(F)F)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A solution of (4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (100 mg, 0.35 mmol) in 3 mL of dimethylformamide in a 15 mL high pressure reaction vessel was cooled to −78° C. Diflurochloromethane (about 0.8 mL) was condensed into the solution, then cesium carbonate (160 mg, 0.49 mmol) was added. The reaction vessel was capped and heated at 80° C. overnight. The reaction mixture was cooled to room temperature and cooled to −78° C. and the seal tube was uncapped, warm to room temperature and allowed to stand for 2 h. The reaction mixture was diluted with 50 mL of ethyl acetate and the organic layer was washed with water (50 mL×3), followed by saturated aqueous NaCl. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by chromatography (30% ethyl acetate/hexane, 6 drops triethylamine/500 mL of solvent) to give the title compound (35 mg, 0.111 mmol, 32%). 1H NMR (CDCl3): 8.35 (dd, J=1.8, 8.1, 1H), 7.35−(m, 3H), 7.25 (t, J=72.1, 1H), 7.21-7.25 (m, 2H), 6.86-6.91 (m, 2H), 3.82 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:22][C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][C:28](=[O:35])[N:29]2[C:32]([NH2:34])=[O:33])=[CH:25][CH:24]=1>CN(C1C=CN=CC=1)C.C(O)(=O)C>[Cl:22][C:23]1[CH:31]=[C:30]2[C:26]([CH:27]([C:7]([C:4]3[CH:3]=[C:2]([Br:1])[O:6][CH:5]=3)=[O:9])[C:28](=[O:35])[N:29]2[C:32]([NH2:34])=[O:33])=[CH:25][CH:24]=1
Reactant: NC(=O)N1C(=O)Cc2ccc(Cl)cc21
Reactant: O=C(O)c1coc(Br)c1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Product: NC(=O)N1C(=O)C(C(=O)c2coc(Br)c2)c2ccc(Cl)cc21
Yield: 11 %

Procedure:
The experimental procedure used to produce the title compound was adopted from Example 55. A 750 mg (3.93 mmole) portion of 5-bromo-3-furoic acid (prepared according to Amaral, L., et al., J.O.C., 41, 2350 (1976)) was transformed into the acyl imidazole by reaction with 690 mg (4.25 mmole) of 1,1'-carbonyldiimidazole. The intermediate 5-bromo-3-furan-(1-imidazo)carboxamide coupled directly with 689 mg (3.27 mmole) of 6-chloro-2-oxindole-1-carboxamide in the presence of 1.08 g (8.83 mmole) of 4-(N,N-dimethylamino)pyridine to give 500 mg (40% yield) of crude greenish-yellow solid. Recrystallization gave 143 mg (0.37 mmole, 11% yield) of pure title compound as a greenish solid, m.p. 232°-4° C. (acetic acid).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=1)([O-:3])=[O:2].[O:19]1CCO[CH2:21][CH2:20]1.C(N(CC)CC)C.BrCCO>C(Cl)Cl.[OH-].[Na+]>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:14][CH2:15][N:16]([CH2:21][CH2:20][OH:19])[CH2:17][CH:18]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: C1COCCO1
Agent: OCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCN(CCO)CC3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.9 %

Procedure:
A suspension of 5-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.55 g, 2.261 mmol) in dry CH2Cl2:1,4-dioxane (15 mL, 2:1) was treated with triethylamine (0.636 mL, 4.52 mmol), followed by 2-bromoethanol (0.176 mL, 2.487 mmol) at room temperature. Only starting material was observed after stirring for 4 h at room temperature. The reaction was then refluxed for 24 h. The reaction was brought to room temperature, diluted with 1 N NaOH solution (25 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) to obtain 2-(4-(5-nitro-1H-indol-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanol (0.24 g, 36.9%) as a dark yellow solid. 1H NMR (DMSO-d6) δ 11.86 (s, 1H), 8.68 (d, 1H, J=2.1 Hz), 8.01 (dd, 1H, J=2.4, 9.0 Hz), 7.65 (s, 1H), 7.55 (d, 1H, J=9.0 Hz), 6.16 (s, 1H), 4.42 (t, 1H, J=5.4 Hz), 3.56 (q, 2H), 3.18 (t, 2H, J=6.3 Hz), 2.69 (t, 2H, J=5.4 Hz), 2.54-2.50 (m, 4H); ESI-MS (m/z, %): 288 (MH+, 100).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][NH:4][C@H:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([NH2:8])=[O:7].C(N(CC)CC)C.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:4]([CH2:3][C:2]([CH3:16])([CH3:15])[CH3:1])[C@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([NH2:8])=[O:7])(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)CN[C@@H](C(N)=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CN([C@@H](C(N)=O)c1ccccc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 3 %

Procedure:
(R)-2-(2,2-Dimethyl-propylamino)-2-phenyl-acetamide (700 mg, 3.2 mmol) was dissolved in dichloromethane (15 mL) and chilled in an ice bath. The solution was treated with triethylamine (553 uL, 4.0 mmol) followed by 4-chlorobenzenesulfonyl chloride (671 mg, 3.2 mmol). After heating at 50° C. for 18 h, the mixture was cooled, diluted with aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated to an oil. Purification on a silica gel flash column (40% EtOAc in hexanes, eluent) afforded the title compound in 3% yield. 13CNMR (100 MHz, CDCl3) 28.6, 33.2, 62.7, 70.0, 128.8, 129.0, 121.1, 129.2, 130.7, 133.6, 138.7, 139.0, 172.7. MS 395.1 m/z (M+1).
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1)[NH2:2].[CH3:13][C:14](=NNC1C2C(=CC=CC=2)C=NN=1)[CH:15]=C(C)C.N(C1C2C(=CC=CC=2)C(NN)=NN=1)N.C(OC(NNC1C2C(=CC=CC=2)C=NN=1)=O)C>>[NH:1]([C:3]1[N:4]=[N:5][C:6]2[CH2:13][CH2:14][CH2:15][CH2:10][CH2:9][CH2:8][C:7]=2[C:12]=1[CH3:11])[NH2:2]
Reactant: CC(C)=CC(C)=NNc1nncc2ccccc12
Reactant: NNc1nncc2ccccc12
Agent: CCOC(=O)NNc1nncc2ccccc12
Agent: NNc1nnc(NN)c2ccccc12
Product: Cc1c(NN)nnc2c1CCCCCC2

Procedure:
1-hydrazinophthalazine derivatives, e.g., 1-hydrazinophthalazine, 1-[2-(1,3-dimethyl-2-butenylidene)-hydrazino]phthalazine, 1,4-dihydrazinophthalazine or 1-(N'-ethoxycarbonylhydrazino)phthalazine.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[CH:2]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:11][CH2:10][C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1cccc(C(=O)O)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cccc(CBr)c1
Temperature: -20 °C
Reaction time: 1.25 h
Yield: 60.5 %

Procedure:
In a 1 L round bottom flask fitted with a reflux condenser, a stirred suspension of 10.00 g of m-toluic acid and 14.37 g (1.1 eq.) N-bromosuccinimide in 735 mL chloroform was sparged for 0.5 h with nitrogen. The sparging was discontinued, and the suspension was stirred and irradiated under nitrogen atmosphere using a 500 W quartz halogen lamp at 75% power, causing the solids to dissolve and the chloroform to reflux. The red color of the reaction mixture disappeared after 1.25 h, and 14.37 g of N-bromosuccinimide was added. The reaction mixture was stirred and irradiated under nitrogen atmosphere with a 500 W quartz halogen lamp at 75% power for another 1.5 h, at which time the solution became colorless. The solvent volume was reduced in vacuo to about 100 mL, and then cooled to −20° C. The resultant suspension was vacuum filtered through a bed of dry silica. The silica was washed with 800 mL of chloroform. The chloroform filtrate was reduced in vacuo to about 100 mL, and then cooled to −20° C. The resultant crystals were vacuum filtered, washed with 30 mL of chloroform followed by 50 mL of hexanes, then dissolved in 250 mL chloroform and washed in a separatory funnel with 3×300 mL volumes of water followed by one 300 mL volume of brine to remove traces of succinimide. The organic phase was dried with magnesium sulfate, vacuum filtered, and the solvent was removed in vacuo to provide 9.56 g (61%) of 3-bromomethylbenzoic acid as a white crystalline power.
Reaction SMILES: BrBr.[CH2:3]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[S-:17][C:18]#[N:19].[NH4+]>C(O)(=O)C>[NH2:19][C:18]1[S:17][C:15]2[CH:16]=[C:10]([CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:11]=[CH:12][C:13]=2[N:14]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Cc2ccccc2)cc1
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Cc3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
11.2 ml of bromine were added dropWise to a solution of 39.7 g of 4-benzylaniline and 33 g of ammonium thiocyanate in 400 ml of acetic acid at a temperature of from 12 to 18° C. After completion of the addition, the mixture was stirred at room temperature for 2 hours and then the solvent was distilled off. The residue was mixed with 600 ml of ethyl acetate and 300 ml of water and the mixture was neutralized by the addition of potassium carbonate powder The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residual solid was recrystallized from ethyl acetate to give 37.6 g of the title compound melting at 173-175° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.C(=O)(O)[O-].[Na+].[CH3:17][CH:18]([CH3:22])[C:19](Cl)=[O:20].Cl>O.COCCOC>[Cl:11][C:4]1[CH:3]=[C:2]([NH:1][C:19](=[O:20])[CH:18]([CH3:22])[CH3:17])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)C(=O)Nc1ccc(C(=O)O)c(Cl)c1
Reaction time: 2 h

Procedure:
4-Amino-2-chlorobenzoic acid was stirred in water (60 ml) and 1,2-dimethoxyethane (25 ml) with sodium bicarbonate (5.04 g) and the brown suspension cooled to 0°-5° C. 2-Methylpropionyl chloride (4.26 g) was added dropwise over 10 minutes with vigorous stirring, and the mixture was then stirred at 0°-10° C. for 2 hours. The mixture was poured into 2M hydrochloric acid and the pale brown precipitate washed with water and filtered and dried to give 2-chloro-4-(2'-methylpropionamido)benzoic acid as a pale brown crystalline solid (6.30 g), m.p. 206°-209° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O.CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:44](O)[CH2:45][CH2:46][OH:47]>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([O:31][CH2:44][CH2:45][CH2:46][OH:47])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCCCO
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1C(OCCCO)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Temperature: 140 °C
Yield: 55.6 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-(hydroxy(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide (41.8 mg, 0.100 mmol) was suspended in 2 mL of toluene containing 4-methylbenzenesulfonic acid hydrate (pTsOH, 23.8 mg, 0.125 mmol) and propane-1,3-diol (9.89 mg, 0.130 mmol). The reaction mixture was then heated to 140° C. for 5 minutes in a microwave reactor. The crude product was then filtered, evaporated to dryness, dissolved in N,N-dimethylformamide (1 mL) and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield the pure product (26.5 mg, 0.0556 mmol, 55.6%). ESI-MS m/z calc. 476.5, found 477.3 (M+1)+. Retention time 2.71 minutes.