Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+]>C(O)C.O>[Br:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH:21]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccccc1Br)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCC(Cc1ccccc1Br)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
p-Chlorobenzaldehyde (2.81 g., 0.02 mole) in ethanol (10 ml.) is added to a solution of 4-(o-bromobenzyl)-4-phenyl-5-oxohexanoic acid (3.0 g., 0.006 mole) and sodium hydroxide (0.56 g., 0.014 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, diluted with water (200 ml.), and extracted with ether to remove the excess p-chlorobenzaldehyde. Ether is expelled from the aqueous phase by warming. The solution is cooled, acidified with dilute hydrochloric acid (10 ml.), and the yellowish solid which precipitates is collected and air-dried to yield 3.5 g. Recrystallization from ethanol gives material with m.p. 210°-213.5°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:6][CH2:5]2.[CH3:17]I>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:17])=[C:7]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:6][CH2:5]2
Reactant: CI
Reactant: Fc1ccc2c(c1)CCC(N1CCCC1)=C2
Solvent: C1CCOC1
Product: CC1=C(N2CCCC2)CCc2cc(F)ccc21

Procedure:
To 6-fluoro-2-pyrrolidinyl-3,4-dihydronaphthalene (13 g; 60.8 mmol) in 200 ml of dry tetrahydrofuran (THF) was added methyliodide (30 ml; 482 mmol) and the mixture was refluxed for 2 hours. The reaction mixture was allowed to cool with stirring while crystallization took place. The solids were collected by filtration to afford the subtitle compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[S:10][C:3]=12.Br[CH2:15][C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH4+].[OH-]>C1COCC1.CO.C(Cl)(Cl)Cl>[NH4+:5].[OH-:18].[CH2:20]([O:19][C:17]([C:16]1[N:12]=[C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)[S:13][CH:15]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1cc2nccc(Cl)c2s1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1csc(-c2cc3nccc(Cl)c3s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a solution of 7-Chloro-thieno[3,2-b]pyridine-2-carbothioic acid amide (5.00 g, 21.9 mmol) in 60 mL of THF was added ethyl bromopyruvate (4.11 mL, 32.8 mmol). The reaction mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was cooled to 0° C., and 30 mL trifluoroacetic anhydride was added. The reaction was stirred at room temperature for four hours then cooled to 0° C. The reaction was treated with 30 mL of concentrated NH4OH followed by removal of THF under reduced pressure. The dark, oily residue was partitioned between water and ethyl acetate. The aqueous layer was separated and washed with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure to give a brown oily residue. Chromotography (99.5:0.45:0.05 CHCl3:CH3OH:NH4OH) over silica gel gave a 67% of 2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-thiazole-4-carboxylic acid ethyl ester (3.42 g) as a pale yellow solid. C13H9ClN2O2S2: APCI m/z 325.0/327.0 (MH+); 232.9/325.9 (neg.); 1H NMR (d6-DMSO): δ 8.67 (d, 1H, J=5.0 Hz), 8.37 (s, 1H), 7.62 (d, 1H, J=5.0 Hz), 3.98 (q, 2H, J=7.0 Hz), 1.13 (t, 3H, J=7.0 Hz) ppm.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[N+:14]([O-])=O)[C:3](O)=[O:4]>CCO.[Pt]>[NH2:1][CH:2]1[CH2:6][C:7]2[C:8](=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[NH:14][C:3]1=[O:4]
Reactant: NC(Cc1ccc(Cl)cc1[N+](=O)[O-])C(=O)O
Agent: [Pt]
Solvent: CCO
Product: NC1Cc2ccc(Cl)cc2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
To a solution of 152A (1.0 g, 4.1 mmol) in 50% aqueous EtOH (40 mL), 10% Pt/C (100 mg) was added under argon and the mixture was hydrogenated at 35 psi for 1 h. The reaction mixture was filtered via a pad of celite and the filtrate was concentrated. The residue was dissolved in conc. HCl (10 mL) and stirred at RT for 6 h. The mixture was then concentrated and dissolved in 100 mL of saturated aqueous sodium bicarbonate. The white solid was filtered and dried to afford 0.44 g of 152B.
Reaction SMILES: [CH2:1]([C:3]1[S:43][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:8](=[O:23])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=O)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Cl.[NH2:45][O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.N1C=CC=CC=1.Cl>O.C(Cl)(Cl)Cl.C(O)C>[CH2:47]([O:46][N:45]=[C:13]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[CH2:12][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:43][C:6]=2[N:7]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:42])[O:39][N:38]=3)=[CH:27][CH:26]=2)[C:8]1=[O:23])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: NOCc1ccccc1
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n(CC(=NOCc3ccccc3)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.2 g), [(aminooxy)methyl]benzene hydrochloride (0.066 g), pyridine (10 mL) and ethanol (10 mL) was stirred at 100° C. for 16 hr. To the reaction mixture were added chloroform and water, and the mixture was adjusted to pH 4 with 1N hydrochloric acid. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a stereoisomer mixture (0.12 g, 51%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:10]=[C:11](Br)[C:12](=[O:21])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)=[O:8].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12](=[O:21])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)=[O:8]
Reactant: O=C(c1cc(Br)c(=O)n(-c2ccccc2)c1)c1ccccn1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1cc(-c2ccccc2)c(=O)n(-c2ccccc2)c1)c1ccccn1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
A mixed liquid of 10 mg of 5-(2-pyridinecarbonyl)-1-phenyl-3-bromo-1,2-dihydropyridin-2-one, 10 mg of phenylboronic acid, 40 mg of cesium carbonate, 6 mg of tetrakistriphenylphosphine palladium and 1 ml of dimethylformamide was stirred at 130° C. for 2 hours in nitrogen atmosphere. After cooling to room temperature, ethyl acetate was added thereto. The extract was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/hexane), to give 6 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[F:5][C:6]([F:25])([CH:11]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[CH:12]=[CH2:13])[CH2:7][CH2:8][CH:9]=[O:10]>O1CCCC1>[OH:10][CH:9]([CH2:8][CH2:7][C:6]([F:5])([F:25])[CH:11]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[CH:12]=[CH2:13])[CH:1]=[CH2:2]
Reactant: C=C[Mg]Br
Reactant: C=CC(N1C(=O)c2ccccc2C1=O)C(F)(F)CCC=O
Solvent: C1CCOC1
Product: C=CC(O)CCC(F)(F)C(C=C)N1C(=O)c2ccccc2C1=O
Temperature: -70 °C

Procedure:
Under an atmosphere of nitrogen, vinyl magnesium bromide (1 ml of 1M solution in tetrahydrofuran) is added to 4,4-difluoro-5-phthalimido-6-hepten-1-al (274 mg, 0.93 mmoles), dissolved in dry tetrahydrofuran (5 ml) previously cooled to -70° C. The temperature is allowed to rise to -5° C., and the reaction mixture is quenched with a saturated solution of ammonium chloride, diluted with ether, and the layers are separated. The alcohol obtained as an oil (300 mg) is purified by chromatography on silica (ethyl acetate/petroleum ether: 70/30, RF: 0.61): 148 mg (49%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:19]CC2C=CC(OC)=C(OC)C=2)=[N:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].FC(F)(F)C(O)=O>>[NH2:19][C:3]1[C:2]([Cl:1])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[N:4]=1
Reactant: COC(=O)c1cc(Cl)c(NCc2ccc(OC)c(OC)c2)nc1-c1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)c(N)nc1-c1cccc(F)c1
Yield: 76.7 %

Procedure:
A solution of methyl 5-chloro-6-[(3,4-dimethoxybenzyl)amino]-2-(3-fluorophenyl)nicotinate (0.11 g, 0.26 mmol) in trifluoroacetic acid (4 mL, 50 mmol) was heated at 60° C. for 22 hours. The reaction mixture was concentrated, diluted with methanol, and filtered. The filtrate was concentrated and purified via RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (56 mg, 75%). LCMS calculated for C13H11ClFN2O2 (M+H)+: m/z=281.0. found: 280.8.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CS(C)=O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]([CH2:39][OH:40])=[C:27]([CH:36]([CH3:38])[CH3:37])[O:28][C:29]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:21][C:20]=1[O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)CC)C>ClCCl>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]([CH:39]=[O:40])=[C:27]([CH:36]([CH3:38])[CH3:37])[O:28][C:29]=2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:21][C:20]=1[O:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC(C)c1oc(-c2ccccc2)c(-c2ccc(F)c(Oc3ccccc3)c2)c1CO
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CS(C)=O
Product: CC(C)c1oc(-c2ccccc2)c(-c2ccc(F)c(Oc3ccccc3)c2)c1C=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 13.8 ml (97 mmol) of trifluoroacetic anhydride in 90 ml of dichloromethane is added dropwise at -70° C. to -65° C. to 9.2 ml (130 mmol) of dimethyl sulphoxide in 70 ml of anhydrous dichloromethane and the mixture is stirred at this temperature for 10 minutes. 26.1 g (665 mmol) of the compound from Example 24, dissolved in 500 ml of dichloromethane, are then added dropwise and the mixture is stirred for 1 more hour at -65° C. 26.9 ml (195 mmol) of triethylamine are now added and the mixture is held at the same temperature for a further 10 minutes. After warming to RT, the mixture is washed with saturated bicarbonate solution and sodium chloride solution and dried over sodium sulphate, and the solvent is removed in vacuo. After boiling the residue with ethanol, 17.6 g (68%) of colorless solid remain of m.p.: 137° C. By cooling the ethanolic solution, a further 5.6 g (21%) are produced of m.p.:138° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([B:10]([OH:12])[OH:11])[CH:7]=[CH:8][CH:9]=1.[NH:15]([CH2:19][CH2:20]O)[CH2:16][CH2:17]O>>[F:14][C:2]([F:1])([F:13])[O:3][C:4]1[CH:5]=[C:6]([B:10]2[O:12][CH2:20][CH2:19][NH:15][CH2:16][CH2:17][O:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: OCCNCCO
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: FC(F)(F)Oc1cccc(B2OCCNCCO2)c1
Yield: 86 %

Procedure:
The title compound (86%, crystals) was prepared from 3-trifluoromethoxyphenylboronic acid and diethanolamin.
Reaction SMILES: C[O:2][C:3](=[O:44])[C@:4]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:30]=4[CH:31]=3)=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH:6]([CH3:8])[CH3:7])[NH2:5].[Li+].[OH-].O.Cl>C1COCC1.CO.C(OCC)(=O)C>[CH2:37]([O:36][C:32]1[C:30]2[CH:31]=[C:27]([C:25]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([C:15]4[CH:16]=[CH:17][C:12]([S:9]([C@@:4]([C:3]([OH:44])=[O:2])([CH:6]([CH3:8])[CH3:7])[NH2:5])(=[O:11])=[O:10])=[CH:13][CH:14]=4)=[CH:19][CH:20]=3)=[O:26])[O:28][C:29]=2[CH:35]=[CH:34][CH:33]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COC(=O)[C@@](N)(C(C)C)S(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4c(OCc5ccccc5)cccc4o3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)[C@](N)(C(=O)O)S(=O)(=O)c1ccc(-c2ccc(NC(=O)c3cc4c(OCc5ccccc5)cccc4o3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
2-{4′-[(4-Benzyloxy-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonyl}-L-valine methyl ester (0.24 mmol) was dissolved in THF and MeOH (2:1) (0.6 mL). A 5 M solution of LiOH in water (5.0 equiv.) was then added. The reaction was stirred at room temperature overnight. The reaction was diluted with ethyl acetate and acidified with 1N hydrochloric acid. The organic layer was washed with brine (2×), dried (magnesium sulfate), filtered and concentrated to afford 55 mg of the pure 2-{4′-[(4-benzyloxy-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonyl}-L-valine. LCMS MH+ (m/z) 599. 1H NMR (300 MHz, DMSO-d6): δ 10.55 ppm (s, 1H), 8.08 ppm (d, 1H, J=9.2 Hz), 7.97-7.76 ppm (m, 8 H), 7.58-7.28 ppm (m, 7H), 7.02 ppm (d, 1H, J=8.0 Hz), 5.31 ppm (s, 2H), 3.94 ppm (s, 2H), 3.58-3.52 ppm (m, 1H), 1.96-1.90 ppm (m, 1H), 0.84 ppm (d, 3H, J=7.0 Hz), 0.81 ppm (d, 3H, J=7.0 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19](O)=[O:20])[CH2:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([N:24]1[CH:28]=[C:27]([CH2:29][NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=2)[CH:26]=[N:25]1)[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([C:19]([N:30]([CH2:29][C:27]1[CH:26]=[N:25][N:24]([CH2:22][CH3:23])[CH:28]=1)[C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH3:38])[CH3:39])=[CH:33][CH:32]=1)=[O:20])[CH2:14][CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Reactant: O=C(O)C1CCCc2cc(OCc3ccccc3)ccc21
Product: CCn1cc(CN(C(=O)C2CCCc3cc(OCc4ccccc4)ccc32)c2ccc(C(C)C)cc2)cn1
Yield: 64.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 4 using 6-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.56 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.49 g) as starting materials, 6-benzyloxy-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.65 g) was obtained. melting point: 122-124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[C:10]1[CH:36]=[C:35]([CH3:37])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[CH:21][CH:20]=3)[N:16]=[N:17][C:12]=2[CH:11]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:10]1[CH:36]=[C:35]([CH3:37])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([S:25]([N:28]4[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]4)(=[O:26])=[O:27])=[CH:23][CH:24]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(S(=O)(=O)N5CCN(C)CC5)cc4)nnc3c2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(-c2cc(O)ccc2Cl)cc2nnc(Nc3ccc(S(=O)(=O)N4CCN(C)CC4)cc3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
[7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-amine (1.0 equiv., 0.339 mmol) was dissolved in 10 mL anhydrous DCM, purged of air via house vacuum, then blanketed with argon. Neat BBr3 (4.0 equiv., 1.355 mmol) was added via syringe dropwise and allowed to stir at room temperature for 2 h. The reaction was quenched with saturated NaHCO3; the precipitate was filtered and rinsed with Et2O to afford crude orange solid. The compound was purified by prep. HPLC using 10-50-75 gradient, collecting peaks for 9-14 minutes. A yellow solid was recovered (70.5 mg, 40% yield). 1H NMR (DMSO-d6): δ 1.98 (s, 3H), 2.37 (bs, 4H), 2.72 (s, 3H), 2.90 (bs, 4H), 6.88 (dd, J=2.94 Hz, 8.81 Hz, 1H), 6.95 (d, J=2.92 Hz, 1H), 7.41 (d, J=8.79 Hz, 1H), 7.78 (d, J=8.89 Hz, 2H), 7.92 (m, 1H), 8.21 (d, J=1.35 Hz, 1H), 8.28 (d, J=8.88 Hz, 2H), 11.47 (s, 1H). MS (ES+): m/z=526 LC retention time: 2.30 minutes.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:10]=[C:11]([CH:19](OC(=O)C)[C:20]([Cl:23])([Cl:22])[Cl:21])[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13].[O-]C1C=CC=CC=1>O1CCCC1.CCOCC.O>[CH2:10]=[C:11]([CH:19]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:20]([Cl:21])([Cl:23])[Cl:22])[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13]
Reactant: C=C(C(=O)OCCCC)C(OC(C)=O)C(Cl)(Cl)Cl
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: C=C(C(=O)OCCCC)C(Oc1ccccc1)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Phenol (2.0 g) in 15 ml of tetrahydrofuran (THF) was slowly added to sodium hydride (1.0 g, 60% in oil) suspended in 5 ml THF at 0° C. Fifteen minutes later, 3.0 g of butyl 2-methylene-3-acetoxy-4,4,4-trichlorobutyrate (crude, GC: 86%) in 10 ml THF was slowly dropped into the phenoxide solution. The reaction was stirred at 0° C. for 3 hours and then permitted to warm to room temperature. The reaction was worked up by addition of 50 ml of water and 50 ml of ether. The organic layer was separated and the solvents were removed by vacuum. The resulting yellow oil was transferred to an alumina column and the product was eluted out with hexanes. A slightly yellow oil was obtained after removal of the hexanes, 3.1 g. The product was confirmed by NMR spectroscopy to be butyl 2-methylene-3-phenoxy-4,4,4-trichlorobutyrate.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15]1.O>ClCCl>[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[CH:20][CH:21]=2)[C:16]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:15]1
Reactant: Cn1ccc2cc([N+](=O)[O-])ccc21
Reactant: O=S(=O)(O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cn1cc(S(=O)(=O)Cl)c2cc([N+](=O)[O-])ccc21
Reaction time: 0.5 h
Yield: 10.4 %

Procedure:
A solution of chlorosulfonic acid (1.9 mL, 28 mmol) and Na2SO4 (403 mg, 2.8 mmol) in dichloromethane (17 mL) was treated with a solution of 1-methyl-5-nitro-1H-indole (500 mg, 2.8 mmol) in dichloromethane (11 mL) over 1 hour, stirred for 30 minutes, and decanted to provide a thick brown oil. The oil was slowly treated with water (20 mL), stirred for 10 minutes, and filtered. The filtrate was dried in a vacuum oven to provide 80 mg of the desired compound which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:16]([N:23]3[CH2:31][C:30]4[C:25](=[C:26]([N+:32]([O-])=O)[CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:35])[CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[C:24](=[O:35])[N:23]([CH:16]([C:8]1[CH:9]=[CH:10][C:11]([O:12][CH:13]([F:14])[F:15])=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH:7]=1)[CH2:17][C:18]([N:20]([CH3:21])[CH3:22])=[O:19])[CH2:31]2
Reactant: CN(C)C(=O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1Cc2cccc([N+](=O)[O-])c2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)C(=O)CC(c1ccc(OC(F)F)c(OCC2CC2)c1)N1Cc2cccc(N)c2C1=O
Yield: 97.4 %

Procedure:
To a solution of 3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-(7-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-N,N-dimethyl-propionamide (330 mg, 0.67 mmol) in ethyl acetate (100 ml) was added 10% Pd on carbon (100 mg). The suspension was shaked under about 50 psi hydrogen atmosphere at room temperature overnight. The suspension was filtered through a pad of celite. The solvent was removed and the resulted oil was purified by HPLC(CH3CN:water=40:60) to give 3-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-N,N-dimethyl-propionamide as a white solid (300 mg, 65%): mp 70-72° C.; 1HNMR (CDCl3): δ 0.31-0.37 (m, 2H), 0.58-0.65 (m, 2H), 1.21-1.28 (m, 1H), 2.90 (s, 3H), 3.05 (dd, J=6.3, 15.8 Hz, 1H), 3.09 (s, 3H), 3.52 (dd, J=8.5, 15.3 Hz, 1H), 3.85 (d, J=7 Hz, 2H), 4.20 (d, J=16.8 Hz, 1H), 4.35 (d, J=16.8 Hz, 1H), 5.20 (broad, 2H), 5.56 (dd, J=6.3, 8.5 Hz, 1H), 6.52-6.63 (m, 2H), 6.59 (t, JH-F=75 Hz, 1H), 6.90-6.98 (m, 1H), 7.09-7.26 (m, 3H); 13C NMR (CDCl3): δ 10.8, 36.2, 37.0, 38.1, 49.8, 54.3, 114.0, 114.9, 116.3, 116.9, 120.1, 121.0, 123.3, 133.4, 139.4, 140.5, 143.4, 146.6, 151.3, 170.4, 170.9; Anal. Calcd. for C24H27F2N3O4+0.18H2O: C, 62.30; H, 5.96; N, 9.08; H2O, 0.7. Found: C, 62.30; H, 5.89; N, 9.02; H2O, 0.7.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:14]([O:16][C:17]([C:19]12[CH2:26][CH2:25][C:22]([NH:27][CH2:28][C:29]([N:31]3[CH2:35][C@@H:34]([F:36])[CH2:33][C@H:32]3[C:37]([NH2:39])=O)=[O:30])([CH2:23][CH2:24]1)[CH2:21][CH2:20]2)=[O:18])[CH3:15].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:14]([O:16][C:17]([C:19]12[CH2:26][CH2:25][C:22]([NH:27][CH2:28][C:29]([N:31]3[CH2:35][C@@H:34]([F:36])[CH2:33][C@H:32]3[C:37]#[N:39])=[O:30])([CH2:23][CH2:24]1)[CH2:21][CH2:20]2)=[O:18])[CH3:15]
Reactant: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C(N)=O)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
Trifluoroacetic anhydride (80 μL) was added to a solution of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]ac etyl]-4-fluoropyrrolidine-2-carboxamide (100 mg) in tetrahydrofuran (1 mL). The mixture was stirred at room temperature for 2 hours and then at 40° C. for 1.5 hours. Subsequently, additional trifluoroacetic anhydride (40 μL) was added and the mixture was further stirred for 30 minutes. A saturated aqueous sodium bicarbonate solution (5 mL) was then added and the reaction mixture was extracted with ethyl acetate (2×10 mL). The ethyl acetate extracts were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on an aminated silica gel column (eluant=ethyl acetate:methanol=30:1) to give (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]ac etyl]-4-fluoropyrrolidine-2-carbonitrile as a colorless solid (63.7 mg, 67% yield). This compound was identical to the compound obtained in Example 7.