Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:3]1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[N:5]=[N:6][N:2]([CH3:1])[N:3]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(-c2nnn(C)n2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nnc(-c2ccc(CBr)cc2)n1

Procedure:
A stirred solution of 45 grams (0.258 mole) of 2-methyl-5-(4-methylphenyl)-1,2,3,4-tetrazole (known compound), 46 grams (1 equivalent) of N-bromosuccinimide, and a catalytic amount of benzoyl peroxide in 200 mL of carbon tetrachloride was irradiated with light during a 3.5 hour period. The mixture was then cooled in an ice bath and filtered to collect 35.1 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1F)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][NH:29][CH3:30].C(N(CC)CC)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:29]([CH3:30])[CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)c1ccc([N+](=O)[O-])cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 103 %

Procedure:
A mixture of the compound (1.0 g) obtained in Example 263, dimethylamine hydrochloride (485 mg), triethylamine (0.8 ml) and dimethylformamide (10 ml) was heated at 80° C. for 5.5 h. The reaction mixture was distilled under reduced pressure and water and 2 N HCl were added to the residue; after extraction with ethyl acetate, the organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 1.1 g of the titled compound quantitatively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:25])=[C:10]([C:23]#[N:24])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH:20]([CH3:22])[CH3:21])=[C:4]([CH:26]([CH3:28])[CH3:27])[CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:25])=[C:10]([C:23]3[NH:31][N:30]=[N:29][N:24]=3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH:20]([CH3:22])[CH3:21])=[C:4]([CH:26]([CH3:28])[CH3:27])[CH:3]=1
Reactant: Cc1c(C#N)sc(-c2ccc(Cl)cc2C(C)C)c1-c1ccc(Cl)cc1C(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Product: Cc1c(-c2nnn[nH]2)sc(-c2ccc(Cl)cc2C(C)C)c1-c1ccc(Cl)cc1C(C)C
Temperature: 130 °C
Yield: 91 %

Procedure:
A round-bottomed flask was charged with 4,5-bis(4-chloro-2-isopropylphenyl)-3-methylthiophene-2-carbonitrile (190.5 mg, 0.44 mmol), zinc bromide (338 mg, 1.50 mmol) and sodium azide (97.5 mg, 1.50 mmol). After degassed, DMF (3 mL) was added. The reaction mixture was heated to 130° C. and stirred at this temperature until complete. The reaction was cooled to rt and 30 mL of 0.1 N aqueous HCl was added. The reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography (hexane:EtOAc:AcOH=30:10:1). 188.7 mg (90%) of product was obtained as a white solid, 1H NMR (CDCl3, 500 MHz) δ 7.25-7.22 (m, 2H), 7.18 (dd, J1=8.18 Hz, J2=2.13 Hz, 1H), 7.09-7.06 (m, 2H), 7.02 (d, J=8.20 Hz, 1H), 3.04 (sep, J=6.75 Hz, 1H), 2.74 (sep, J=6.80 Hz, 1H), 2.37 (s, 3H), 1.12 (d, J=6.80 Hz, 3H), 1.05 (d, J=6.80 Hz, 6H), 0.90 (d, J=6.80 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 150.32, 149.87, 141.11, 140.81, 140.72, 135.33, 134.47, 132.72, 132.02, 131.51, 129.01, 126.30, 126.20, 125.84, 125.52, 30.35, 30.10, 24.76, 23.60, 23.13, 15.78.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[F:21][C:4]1[CH:3]=[C:2]([C:28]2[CH:27]=[CH:26][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:30][CH:29]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-Trifluoromethoxybenzene boronic acid. MS (M+H) 437.1
Reaction SMILES: [BH4-].[Na+].[C:3]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=O)(OCC1C=CC=CC=1)=O.OS(O)(=O)=O>C1COCC1.CCOCC>[CH3:18][C:14]1[CH:15]=[C:15]([C@@H:14]2[CH2:18][CH2:19][CH2:20][N:13]2[CH3:3])[O:17][N:13]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc([C@@H]2CCCN2C)on1
Temperature: 0 °C
Yield: 88 %

Procedure:
To a stirred suspension of sodium borohydride (7.59 g, 200 mmol) in 100 mL of THF cooled to 0° C. was added a solution of 20 g (80.28 mmol) of N-Cbz-L-proline, from step 24a above, in 50 mL of ether. To this solution was added dropwise a solution of 5 mL of H2SO4 in 20 mL of ether, with stirring and while maintaining the temperature below 20° C. The reaction mixture was warmed to room temperature and stirred for 16 hr. The reaction was quenched by the addition of 100 mL of methanol dropwise. The solvents were removed, 30 mL of 4N NaOH was added, and the mixture was extracted with ethyl acetate. The organic extract was dried over Na2SO4 and concentrated to afford the title product; 16.61 g (88% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([F:19])=[C:14]([F:18])[C:15]=2[F:17])[C:10](=[O:20])[C:9]([C:21]([O:23]CC)=[O:22])=[CH:8]1>S(=O)(=O)(O)O.C(O)(=O)C.O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([F:19])=[C:14]([F:18])[C:15]=2[F:17])[C:10](=[O:20])[C:9]([C:21]([OH:23])=[O:22])=[CH:8]1
Reactant: CCOC(=O)c1cn(Cc2nccs2)c2c(F)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(Cc2nccs2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
A mixture of 6.0 g of ethyl(2,3,4,5-tetrafluorobenzoyl)acetate, 5.8 g of ethyl orthoformate and 6.3 g of acetic anhydride was refluxed for 2 hours. After distillation under reduced pressure, the residue was dissolved in 50 ml of ethanol. To this solution, 2.8 g of 2-aminomethylthiazole was added, followed by stirring for 2 hours, while ice cooling. The reaction product was added to 100 ml of ice water, and the resulting crystal was collected by filtration and dried. The 8.0 g crystal obtained was dissolved in 50 ml of dimethylformamide, and 2.0 g of 60% oily sodium hydride was added, followed by heating and stirring at 100 to 110° C. for 2 hours. The reaction product was added to 100 ml of ice water and extracted with dichloromethane (100 ml ×3). The extract was washed with water and dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure, to yield 5.4 g of ethyl 1-(thiazol-2-yl)methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate. Next, 5.0 g of this ester was dissolved in a mixture of 3 ml of sulfuric acid, 20 ml of acetic acid and 18 ml of water, followed by stirring at 110° to 120° C. for 1.5 hours. The reaction product was added to 100 ml of ice water to cause crystallization. The resulting crystal was collected by filtration, washed with water and dried to yield 4.4 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:26])=[C:4]([C:22]([F:25])=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:18]2[CH:17]=[N:16][C:15]([C:19](O)=[O:20])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.Cl.[CH3:28][O:29][NH2:30]>>[Cl:1][C:2]1[C:3]([F:26])=[C:4]([C:22]([F:25])=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:18]2[CH:17]=[N:16][C:15]([C:19]([NH:30][O:29][CH3:28])=[O:20])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: O=C(O)c1cc2c3ccccc3n(Cc3c(F)ccc(Cl)c3F)c2cn1
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cc2c3ccccc3n(Cc3c(F)ccc(Cl)c3F)c2cn1

Procedure:
The title compound is prepared by coupling of 9-(3-chloro-2,6-difluorobenzyl)-9H-β-carboline-3-carboxylic acid and O-methyl hydroxylamine hydrochloride under conditions similar to those provided in step (b) of example 7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH2:10][C:11]2([CH2:22][CH3:23])[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH2:9])[CH:5]=[CH:6][CH:7]=1.O.O.O.C([O-])(=[O:29])C.[Na+].C(OO)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([O:29][CH2:9]2)[CH2:10][C:11]2([CH2:22][CH3:23])[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)[O-]
Reactant: C=C(CC1(CC)C(=O)c2ccccc2C1=O)c1cccc(Cl)c1
Agent: CC(=O)OO
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC1(CC2(c3cccc(Cl)c3)CO2)C(=O)c2ccccc2C1=O
Yield: 149.1 %

Procedure:
To the mixture of 1.62 g of 2-[2-(3-chlorophenyl) propen 3-yl]-2-ethylindan-1,3-dione, 0.34 g of sodium acetate trihydrate and 10 ml of chloroform was added-2.85 g of 40% peracetic acid. After refluxing for 3 hours, excess peroxide was decomposed with 10% sodium thiosulfate aqueous solution, and the organic layer was washed with water, neutralized with a saturated sodium bicarbonate aqueous solution, washed with water and with a saturated saline solution, and dried over anhydrous magnesium sulfate. After the solvent was evaporated, the residue was separated and purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=4/1) to obtain 1.27 g of the compound No. 53 shown in Table 2.
Reaction SMILES: [C:1]([C:9]1[CH:29]=[CH:28][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([N+:25]([O-])=O)=[C:18]([N:20]([CH3:24])[C:21](=[O:23])[O-:22])[CH:19]=2)=[CH:11][C:10]=1[OH:30])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.O1CCCC1.[Pd]>[NH2:25][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:28]=[CH:29][C:9]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([OH:30])[CH:11]=2)=[CH:19][C:18]=1[N:20]([CH3:24])[C:21](=[O:23])[O:22][C:2]([CH3:7])([CH3:3])[CH3:1]
Reactant: CN(C(=O)[O-])c1cc(Oc2ccc(C(=O)c3ccccc3)c(O)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Cc3ccccc3)c(O)c2)ccc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 166.1 %

Procedure:
A mixture of a solution of N-[5-(4-benzoyl-3-hydroxyphenoxy)-2-nitrophenyl]-N-methylcarbamate (2.1 g) in methanol/tetrahydrofuran=5/3 (80 ml) and palladium on carbon (20%, 0.5 g) was stirred at ambient temperature under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated to give the title compound (1.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[CH3:39][NH:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[NH:49][CH2:50][CH2:51][CH2:52][N:53]=2)=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:40]([CH3:39])[CH2:41][C:42]3[CH:43]=[CH:44][C:45]([C:48]4[NH:53][CH2:52][CH2:51][CH2:50][N:49]=4)=[CH:46][CH:47]=3)=[O:23])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: CNCc1ccc(C2=NCCCN2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(C4=NCCCN4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AE using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.16 mmol), CDI (48 mg, 0.29 mmol), N-methyl-1-[4-(1,4,5,6-tetrahydropyrimidin-2-yl)phenyl]methanamine dihydrochloride (42 mg, 0.15 mmol) and DIPEA (0.17 mL, 0.97 mmol) in DCE (2 mL).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20].CN(C1C=CC=CN=1)C>CCOC(C)=O.C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cccc(N)c1
Agent: CN(C)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(NC(=O)Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To THF (15 mL) was added 3-tert-butylaniline (447 mg, 3 mmol), potassium carbonate (828 mg, 6 mmol), phenyl chloroformate (1.13 mL, 9 mmol), and dimethylaminopyridine (36 mg, 0.30 mmol) and the reaction stirred at room temperature overnight. The mixture was diluted with EtOAc, filtered, concentrated in vacuo, and purified by silica gel column chromatography (5-15% EtOAc/hexanes) to give phenyl 3-tert-butylphenylcarbamate (458 mg, 1.70 mmol, 57%). 1H NMR (300 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.59 (s, 1H), 7.49-7.10 (m, 7H), 7.08 (d, 1H), 1.25 (s, 9H); LC-MS (ESI) m/z 270 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[N:5]([CH:17]([CH3:25])[C:18](=[O:24])[N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:6]2[C:11]([C:12]=1[C:13]([O:15]C)=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2>O1CCCC1.C1(C)CCC(C(C)C)C(O)C1.O>[CH3:3][C:4]1[N:5]([CH:17]([CH3:25])[C:18](=[O:24])[N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:6]2[C:11]([C:12]=1[C:13]([OH:15])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COC(=O)c1c(C)n(C(C)C(=O)N2CCCC2)c2ccccc12
Agent: CC1CCC(C(C)C)C(O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)c2ccccc2n1C(C)C(=O)N1CCCC1
Temperature: 70 °C
Reaction time: 10 h
Yield: 94.2 %

Procedure:
To a solution of sodium hydroxide solution (50 mg, 1.2 mmol) in tetrahydrofuran, menthol and water (20 mL, 3:1:1, V/V) was added methyl 2-methyl-1-(1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)-1 H-indole-3-carboxylate (100 mg, 0.318 mmol). The reaction mixture was stirred at 70° C. for 10 hours. The mixture was quench with 10% hydrochloric acid aqueous (2 mL), extracted with dichloromethane and menthol (60 mL, 10:1). The combine organic layer was dried by anhydrous sodium sulfate, filtered and concentrated to give 2-methyl-1-(1-oxo-1-(pyrrolidin-1-yl)propan-2-yl)-1H-indole-3-carboxylic acid (90 mg, 92%). LCMS (M+H+) m/z: calcd 300.15. found 300.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[N:4]([CH2:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH2:19])=[O:18])[N:3]=1.[Br:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1.CS(C)=O>N1C=CC=CC=1>[Br:23][C:24]1[S:28][C:27]([S:29]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[O:11][CH3:12])[N:4]([CH2:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([NH2:19])=[O:18])[N:3]=2)(=[O:31])=[O:30])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: COc1cccc2c1c(N)nn2Cc1cccc(C(N)=O)c1
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Br)s1)nn2Cc1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 12 %

Procedure:
3-{[3-Amino-4-(methyloxy)-1H-indazol-1-yl]methyl}benzamide (for a preparation see Intermediate 12) (22 mg, 0.07 mmol) was dissolved in pyridine (1.6 mL) and added to 5-bromo-2-thiophenesulfonyl chloride (27 mg, 0.1 mmol). The reaction mixture was shaken at room temperature for 5 min and then stood overnight at room temperature. DMSO (0.2 mL) was added to the reaction mixture and purified by MDAP on Atlantis column using Acetonitrile Water with a Formic acid modifier. The solvent was evaporated in vacuo using the Genevac to give the title compound (4.6 mg, 12%) LCMS (System A) RT=1.04 min, ES+ve m/z 521/523 (M+H)+.
Reaction SMILES: [Na].O=[C:3]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:15][C:16]1[C:25]2[NH:24]C(=O)[O:22][C:21](=O)[C:20]=2[CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:21]2[OH:22]
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: O=c1[nH]c2c(Cl)cccc2c(=O)o1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc2c(Cl)cccc2c(O)c1C(=O)OCC
Temperature: 130 °C
Yield: 43.8 %

Procedure:
To a stirred mixture of diethyl oxosuccinate sodium salt (2.31 g, 11.0 mM) in dimethylformamide (20 mL) under a nitrogen atmosphere was added 8-chloro-2H-3,1-benzoxazine-2,4(1H)-dione (2.17 g, 11.0 mM). The resulting mixture was heated slowly to 130° C. and maintained at this temperature for 2.5 hr. After cooling, the reaction mixture was poured into water and the resulting mixture was then extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried (MgSO4), filtered and concentrated to obtain an oily solid (1.55 g). This material was chromatographed (eluant: CH2C12 /CH3OH; 98/2) over silica gel to provide the title compound as an oil which slowly crystallized to a tan solid (0.700 g, 19.7%). A 0.150 g portion of this material was recrystallized from toluene/hexane to provide an analytical sample (0.050 g) of the title compound as a tan solid, mp 98°-99° C.; MS(CI): 324 (M+H). Analysis for C15H14NO5Cl·0.1 C6H14Calculated: C, 56.38; H, 4.67; N, 4.21 Found: C, 56.38; H, 4.83; N, 4.19
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:17])([CH3:16])[CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:42](O)(=[O:50])[C:43]1[C:44](=[CH:46][CH:47]=[CH:48][CH:49]=1)[OH:45].CCN(C(C)C)C(C)C>CC#N>[OH:45][C:44]1[CH:46]=[CH:47][CH:48]=[CH:49][C:43]=1[C:42]([NH:2][C:3]([CH3:17])([CH3:16])[CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:50]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(C)(N)CNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(CNC(=O)OCc1ccccc1)NC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.7 %

Procedure:
The HCl salt of benzyl 2-amino-2-methylpropylcarbamate (1.0 g, 3.87 mmol) was taken up in CH3CN (15 mL) along with HATU (1.60 g, 4.2 mmol), salicylic acid (535 mg. 3.87 mmol) and DIEA (2.0 mL, 11.6 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by chromatography (30% EtOAc/pentane) to afford benzyl 2-(2-hydroxybenzamido)-2-methylpropylcarbamate (340 mg, 26%). Mass calculated for C19H22N2O4: 342.16; found: [M+H]+=343.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[C:13](Cl)([Cl:15])=[O:14].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:10])([F:11])[F:12])[C:13]([Cl:15])=[O:14]
Reactant: CNc1ccccc1C(F)(F)F
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CN(C(=O)Cl)c1ccccc1C(F)(F)F
Yield: 82.6 %

Procedure:
A mixture of 1.00 g (5.71 mmole) of 2-(methylamino)benzotrifluoride, 9 mL (17.3 mmole) of 1.93M phosgene in toluene, and 10 mL of toluene was stirred under N2 for a hour and then treated with 20 mL of 2.5N sodium hydroxide (aqueous). The layers were separated, and the organic phase was concentrated in vacuo to yield 1.12 g (83%) of the title compound as a clear oil, which eventually solidified after prolonged standing: mp 44°-46° C.; homogeneous by TLC in 3:1 hexane-EtOAc; IR spectrum νCO 1750 cm-1 ; FAB-MS m/e 237 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:4]=2[O:3]1.[F:27][CH2:28][C:29](Cl)=[O:30]>C(Cl)Cl>[CH3:1][C:2]1([CH3:26])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:29](=[O:30])[CH2:28][F:27])[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(CNc3ccccc3Oc3ccccc3)c2O1
Reactant: O=C(Cl)CF
Solvent: ClCCl
Product: CC1(C)Cc2cccc(CN(C(=O)CF)c3ccccc3Oc3ccccc3)c2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a solution of N-(2,2,-Dimethyl-2,3-dihydrobenzofuran-7-ylmethyl)-N-(2-phenoxy phenyl)amine (0.20 g, 0.58 mmol) dissolved in DCM (2 mL) was added TEA (0.24 g, 2.32 mmol, 0.32 mL). The reaction was cooled to 0° C. and fluoroacetyl chloride (0.11 g, 1.16 mmol, 0.08 mL) was added. The mixture was stirred at room temperature for 1 h. The solvents were removed in vacuo, the residue quenched with water (10 mL), extracted with DCM (2×20 mL), dried over MgSO4, filtered and solvents removed in vacuo. The crude material was purified by silica gel chromatography eluting with DCM (A) and MeOH (B) (1% B, 80 g, 2 CV, 60 mL/min) to afford 170 mg (72%) of N-(2,2,-Dimethyl-2,3-dihydrobenzofuran-7-ylmethyl)-2-Fluoro-N-(2-phenoxy phenyl)acetamide as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[N+:22]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29])([O-:24])=[O:23]>>[N+:22]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:29])([O-:24])=[O:23]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3cccc([N+](=O)[O-])c3)CC1)O2

Procedure:
Compound 56 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-nitrobenzoyl chloride and conditions outlined in procedure N. M.p.=160-162° C.; 300 MHz 1H NMR (DMSO-d6) δ 8.30 (m, 2H), 7.92 (m, 3H), 7.77 (t, 2H), 760 (m, 1H), 4.40 (m, 1H), 3.52 (brm, 2H), 3.24 (m, 1H), 3.12 (s, 2H), 2.08 (m, 1H), 1.90 (m, 3H); LCMS: 451 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([O:15][CH3:16])=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17]COCC.CN(CCN(C)C)C.[Li]CCCC.IC>>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([O:15][CH3:16])=[N:11][CH:12]=[CH:13][C:14]=1[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ncccc1NC(=O)OC(C)(C)C
Reactant: CCOCC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CI
Product: COc1nccc(C)c1NC(=O)OC(C)(C)C
Temperature: -10 °C

Procedure:
To a stirred solution of 1.12 g (5 mmol) of 3-(tert-butoxycarbonylamino)-2-methoxypyridine in 25 mL of dry ether containing 1.8 mL, (12 mmol) of TMEDA at -78° C. under an argon atmosphere was added 4.8 mL (12 mmol) of a 2.5M solution of nBuLi in hexanes. The mixture was then warmed to -10° C. for 2 h. Recooling to -78° C. and treatment with iodomethane (0.99 g, 7 mmol) followed by warming to room temperature for 1 h produced the desired product which was purified by quenching with water, washing the ether layer with 0.1N HCl, drying (MgSO4), concentration and flash chromatography (9:1 hexanes:EtOAc). Yield: 1.00 g (84%). Recrystallization from heptane provided further purification. m.p.: 93°-95° C.