Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn]([Cl:14])(CCCC)CCCC)CCC.[N-:15]=[N+:16]=[N-:17].[Na+].[C:19]([CH2:21][NH:22][C@@H:23]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)[C:24]([NH:26][C:27]1[N:31]([CH3:32])[N:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([NH:39][CH3:40])[CH:34]=2)[CH:28]=1)=[O:25])#[N:20]>CN(C=O)C.O>[NH:15]1[C:19]([CH2:21][NH:22][C@@H:23]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=2)[C:24]([NH:26][C:27]2[N:31]([CH3:32])[N:30]=[C:29]([C:33]3[CH:38]=[CH:37][N:36]=[C:35]([NH:39][CH3:40])[CH:34]=3)[CH:28]=2)=[O:25])=[N:20][N:17]=[N:16]1.[ClH:14]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: [N-]=[N+]=[N-]
Reactant: CNc1cc(-c2cc(NC(=O)[C@H](Cc3ccc(F)cc3)NCC#N)n(C)n2)ccn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cc(-c2cc(NC(=O)[C@H](Cc3ccc(F)cc3)NCc3nnn[nH]3)n(C)n2)ccn1
Product: Cl
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
To neat tributyltin chloride (1250 μl, 4608 μmol) was added sodium azide (271 μl, 7691 μmol). After sting at 80° C. for 30 mins, to the mixture was added a solution of 23.E (178 mg, 437 μmol) in DMF. The resulting mixture was stirred at 160° C. under N2 for 1.5 hr, cooled and diluted with water. The resulting mixture was extracted with 30% iPrOH/CHCl3 (3×10 mL), and organic solvents was removed under reduced pressure. After purification of the residue by preparative HPLC (10-90% CH3CN/water, 30 min), the combined product fractions were treated with 1.0 N HCl (0.50 ml) and concentrated to provide 23.11 HCl salt colorless solid (121 mg, 57%) as. MS ESI (positve.) m/e: 451.1 (M+H), 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J=6.65 Hz, 1H), 7.23-7.45 (m, 4H), 7.11 (t, J=8.61 Hz, 2H), 6.88 (s, 1H), 4.71 (s, 2H), 4.60 (br. s., 1H) 3.63 (s, 3H) 3.42-3.54 (m, 1H), 3.20-3.29 (m, 1H), 3.01-3.11 (m, 4H).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].Br[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.N1CCCCC1>C(OCC)(=O)C.[Pd].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>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:5]#[C:4][CH2:3][CH2:2][C:1]([OH:7])=[O:6])=[CH:10][CH:11]=1)#[N:14]
Reactant: N#Cc1ccc(Br)cc1
Reactant: C#CCCC(=O)O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: N#Cc1ccc(C#CCCC(=O)O)cc1
Temperature: 80 °C

Procedure:
A solution of 4-pentynoic acid (2.15 g, 22 mmol), 4-bromobenzonitrile (3.64 g, 20 mmol) and piperidine (40 mL) was degassed by bubbling nitrogen through the solution for 5 min prior to the addition of tetrakis(triphenylphosphine) palladium (0) (240 mg, 0.2 mmol). The reaction vial was sealed and warmed to 80° C. for 1.5 h. After cooling to 23° C., the reaction mixture was diluted with ethyl acetate (200 mL), filtered, and concentrated in vacuo. The residue was diluted with ethyl acetate (300 mL), washed with 5% HCl (2×100 mL), washed with water (1×100 mL), and extracted with 3% sodium carbonate (2×200 mL). The basic aqueous layer was treated with decolorizing carbon, filtered, and acidified to pH=2. The resultant solid was filtered, washed with water, dried, and purified by flash chromatography (gradient ethyl acetate:methylene chloride:acetic acid 1:9:0.005) and fractional recrystallization (methylene chloride-ether) to afford the title compound as a white solid: m.p. 149°-152° C.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[OH:4][CH2:3][C@H:2]([NH:1][C:40]([C:36]1[CH:35]=[C:34]2[C:39](=[CH:38][CH:37]=1)[N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:19]3[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:29][CH:28]=1)[C:32]([CH3:44])=[C:33]2[CH3:43])=[O:41])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: N[C@@H](CO)c1ccccc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](CO)c3ccccc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using (R)-2-amino-2-phenylethanol and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 519 (M+H).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]([CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][OH:16])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:21]=[C:20]([Cl:30])[C:19]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:5][N:6]=[C:7]([CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][C:19]1[C:20]([Cl:30])=[CH:21][C:22]([O:24][CH2:25][CH:26]=[C:27]([Cl:28])[Cl:29])=[CH:23][C:18]=1[Cl:17])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(COCCOCCO)=NOC(C)(C)C
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(COCCOCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NOC(C)(C)C
Yield: 67.1 %

Procedure:
To a mixture of 0.51 g of 2-(2-hydroxyethoxy)ethoxyacetone O-tert-butyloxime, 0.58 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 0.58 g of triphenylphosphine, and 20 ml of tetrahydrofuran is slowly added dropwise 0.49 g of diisopropyl azodicarboxylate with stirring under ice cooling in a stream of nitrogen gas. After stirring at room temperature for 4 hours, the reaction mixture is concentrated to give a residue. This residue is subjected to silica gel chromatography, which affords 0.68 g (yield, 68%) of 2-(2-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)ethoxy)ethoxyacetone O-tert-butyloxime, nD23.0 1.5172.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH3:18][N:19]([CH3:38])[S:20]([C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:26]1[CH:25]=[CH:24][C:23]([S:20]([N:19]([CH3:38])[CH3:18])(=[O:21])=[O:22])=[CH:28][CH:27]=1
Reactant: CN(C)S(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)N(C)C)cc1
Yield: 24.9 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (100 mg, 0.32 mmol) was reacted with N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (110 mg, 0.35 mmol) to afford the desired product (33 mg, crude) as a brown solid: ESI MS m/z 415 [C20H8N2O4S2+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:7]([O:9]CC)=[O:8])[S:5][CH:6]=1.[OH-].[Na+].Cl.O>C1COCC1.CO.O>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1
Reactant: CCOC(=O)c1scc(Br)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Br)csc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of ethyl 4-bromo-3-methyl-2-thiophenecarboxylate (5.0 g, 0.0201 mol) in THF/MeOH/H2O (4:1:1, v/v/v, 50 mL) was added NaOH (1.00 g, 0.0251 mol) and the resulting mixture was stirred at ambient temperature overnight. The mixture was acidified by adding 6 N HCl (100 mL) and water (100 mL). The resulting fine white precipitate was filtered off, washed with water and dried to give 3.80 g (86%) of 4-bromo-3-methyl-2-thiophenecarboxylic acid as a fine white solid, mp 188-189° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>CN(C=O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCc1cccnc1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCc1cccnc1
Yield: 101.2 %

Procedure:
The method described in Part A of Example 1 was used to treat 2,4-dichloro-3-nitroquinoline (10.0 g, 40.8 mmol) in DMF (100 mL) with triethylamine (8.53 mL, 61.2 mmol) and 3-aminomethylpyridine (4.16 mL, 40.8 mmol). After the precipitate was isolated by filtration, it was dried for three hours in a vacuum oven at 60° C. to provide 13.0 g of 2-chloro-3-nitro-N-(pyridin-3-ylmethyl)quinolin-4-amine as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]([S:8]([CH3:11])(=[O:10])=[O:9])([CH3:7])[CH3:6])C.O.[OH-].[Li+]>C1COCC1.O.O>[CH3:11][S:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:12])=[O:3])(=[O:10])=[O:9]
Reactant: CCOC(=O)C(C)(C)S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
To a solution of 500 mg (2.6 mmol) of 2-methanesulfonyl-2-methyl-propionic acid ethyl ester in THF/water (4/1, 5 mL) were added 270 mg (6.6 mmol) of lithium hydroxide monohydrate. The reaction was stirred at room temperature for 18 h. The reaction was further diluted with water (20 mL) and then washed with DCM (2×15 mL). The basic aqueous layer was cooled in an ice bath and acidified with 1M aqueous HCl solution to pH 2. The acidic aqueous layer was extracted with isopropanol/chloroform (1/1, 3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate under reduced pressure afforded 413 mg of 2-methanesulfonyl-2-methyl-propionic acid. The compound did not ionise under LCMS conditions, thus the structure was confirmed by 1H-NMR spectroscopy:
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:18])=O>CN(C)C=O.C(Cl)Cl>[C:1]1([CH2:11][C:12]([Cl:18])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1cccc2ccccc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1cccc2ccccc12
Reaction time: 0.5 h

Procedure:
Into 20 mL of methylene chloride, 0.250 g of the naphthyl acetic acid prepared as in Example 2 above, was dissolved. After cooling the solution in an ice bath, 0.090 mL of oxalyl chloride and a few drops of dimethylformamide were added. After 30 minutes, the ice bath was removed, and the reaction was allowed to come to room temperature over 30 minutes. The solvent of the reaction mixture was removed under vacuum, and product was redissolved in 50 mL of methylene chloride, followed by evaporation under vacuum, giving the napthylacetyl chloride as an oil. This product was redissolved in 40 mL of methylene chloride, and excess ammonia was bubbled in over 15 minutes at room temperature. After stirring overnight, the solvent of the reaction mixture was removed under vacuum. The reaction product was redissolved in ethyl acetate and washed with brine and dilute potassium carbonate. The organic solution was dried over sodium sulfate, and filtered. The solvent was removed under vacuum, and the product was redissolved in a minimum of methylene chloride. On dilution to cloudiness with hexane and after cooling, 130 mg (55%) of 4-phenoxynaphth-1-yl-acetamide was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([C:7]#[N:8])[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(C#N)c1ccc(Cl)cc1
Temperature: 37.5 °C

Procedure:
About 20% of a solution of p-chlorobenzyl cyanide (0.75 g, 4.94 mmol) and diethyl oxalate (0.87 mL, 6.4 mmol) in tetrahydrofuran (one mL) was added to a stirred suspension of sodium hydride (167 mg, 6.95 mmol) in tetrahydrofuran (4 mL). The mixture was heated at 35-40° C. until H2 evolution began. The remaining mixture was added dropwise over about ten minutes. After H2 evolution ceased, part of the solvent was removed under reduced pressure. The residue was diluted with 10 mL of water, neutralized with dilute sulfuric acid and extracted twice with ethyl acetate. The extract was water washed, dried (MgSO4) and stripped to a light brown solid. This was triturated with hexane, filtered and dried to give 1.17 g, (94%yield) of ethyl 3-(4-chlorophenyl)-3-cyano-2-oxopropanoate.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)([OH:11])=[O:10].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1](=[N:21][S:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=1)(=[O:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(S(=O)(=O)N=Cc2ccccc2)cc1

Procedure:
In the same manner as Example 2, 4.00 g (38 mmol) of benzaldehyde, 7.58 g (38 mmol) of 4-carboxybenzenesulfonamide and 20 mg of TsOH in 150 mL of toluene were heated for 36 hours to afford 7.40 g (71%) of SULF-4 as a light tan powder: IR (Nujol) 3800-2600 (br), 1685, 1600, 1283, 1155 cm-1 ; 1H NMR (DMSO-d6, TMS ext std)δ 9.05 (s, 1), 8.2-7.2 (m, 9).
Reaction SMILES: [OH-:1].[Na+].[CH3:3][O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]2[C:6]=1C[O:8][C:9]2=[O:10].[Mn]([O-])(=O)(=O)=O.[K+].[CH2:23]([OH:25])C>>[CH3:16][O:15][C:14]1[CH:13]=[C:12]([C:23]([OH:25])=[O:1])[C:11](=[CH:6][C:5]=1[O:4][CH3:3])[C:9]([OH:8])=[O:10]
Reactant: CCO
Reactant: COc1ccc2c(c1OC)COC2=O
Reactant: [OH-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: COc1cc(C(=O)O)c(C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An aqueous 2N sodium hydroxide solution of the product of above-mentioned (a) (3.0 g, 15 mmol) was added dropwise with stirring to a 6% aqueous solution of potassium permanganate (50 ml) under ice cooling, and the reaction solution was stirred overnight with gradually raising the temperature to 25° C. To the reaction solution was added ethanol and the precipitated manganese dioxide was filtered off. The filtrate was acidified with concentrated hydrochloric acid and concentrated under reduced pressure. To the residue was added methanol and stirred for 10 minutes. After the insoluble materials were filtered off, the filtrate was concentrated under reduced pressure to give 4.1 g of 4,5-dimethoxyphthalic acid.
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:14]([NH:16][CH:17]([CH:21]1[CH2:25][C:24](=[O:26])[NH:23][C:22]1=[O:27])[C:18]([OH:20])=[O:19])=[O:15])[CH3:13])=O)C1C=CC=CC=1.[H][H]>O.CO.C(O)(=O)C.[Pd]>[NH2:11][C@@H:12]([C:14]([NH:16][CH:17]([CH:21]1[CH2:25][CH:24]([OH:26])[NH:23][C:22]1=[O:27])[C:18]([OH:20])=[O:19])=[O:15])[CH3:13]
Reactant: [H][H]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)NC(C(=O)O)C1CC(=O)NC1=O
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](N)C(=O)NC(C(=O)O)C1CC(O)NC1=O
Reaction time: 0.5 h

Procedure:
In 100 ml of water-methanol-acetic acid (1:1:0.2) was dissolved 2.0 g of benzyloxycarbonyl-D-alanyl-2-(2,5-dioxopyrrolidin-3-yl)glycine, and the solution was stirred with 600 mg of palladium black in a stream of hydrogen at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 70 ml of water and, following addition of 580 mg of sodium borohydride at 0°-5° C., the mixture was stirred for 30 minutes with adjusting pH to 8.5-9.2 with 2 N hydrochloric acid. This reaction mixture was adsorbed on a column (150 ml) of Amberlite IRA-68 (OH- -form) and after the column was washed with water, elution was carried out with 0.3 N acetic acid. The eluate was concentrated to dryness under reduced pressure and the resultant powder was subjected to column chromatography on activated carbon (250 ml) and eluted with water. The eluate was concentrated under reduced pressure and lyophilized to give D-alanyl-2-(5-hydroxy-2-oxopyrrolidin-3-yl)glycine as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([CH3:19])=[C:12]2[C:3]=1[CH:4]=[CH:5][C:6]1[S:11][CH2:10][CH2:9][S:8][C:7]=12.[C:20](Cl)(=[O:24])[C:21](Cl)=O>O1CCCC1.CN(C)C=O>[CH3:1][C:2]1[CH:15]=[C:14]([C:16]([O:18][C:2]2[CH2:3][CH2:4][CH2:21][C:20](=[O:24])[CH:1]=2)=[O:17])[C:13]([CH3:19])=[C:12]2[C:3]=1[CH:4]=[CH:5][C:6]1[S:11][CH2:10][CH2:9][S:8][C:7]=12
Reactant: Cc1cc(C(=O)O)c(C)c2c3c(ccc12)SCCS3
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)OC2=CC(=O)CCC2)c(C)c2c3c(ccc12)SCCS3
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.40 g of the title compound of Step D in 25 mL of tetrahydrofuran was added 0.34 mL of oxalyl chloride (purchased from Aldrich Chemical Co.) and 2 drops of N,N-dimethylformamide. The mixture was refluxed for 2 h and was then concentrated under reduced pressure to dryness. To the resulting residue was added 25 mL of tetrahydrofuran and evaporated to dryness again. Another 25 mL of tetrahydrofuran was added to the residue and the solution was cooled to about 0° C. To this mixture was added 0.16 g of 1,3-cyclohexanedione (purchased from Aldrich Chemical Co.) followed by addition of 0.52 mL of triethylamine. The mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium bicarbonate and the mixture was extracted with methylene chloride. The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to dryness. Chromatography of the crude product on silica gel eluting with a mixture of hexanes:ethyl acetate (8:1 and then 4:1) yielded 0.21 g of the title compound of Step E as a yellow solid melting at 126°-130° C. 1H NMR (CDCl3): δ 2.18 (m, 2H), 2.49 (t, 2H), 2.64 (s, 3H), 2.72 (t, 2H), 2.90 (t, 2H), 3.06 (s, 3H), 3.52 (t, 2H), 6.07 (s, 1H), 7.50 (d, 1H), 7.62 (s, 1H), 7.70 (d, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[O:13].O>Br.C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[O:13]
Reactant: COc1ccc2c(c1)C(=O)CCO2
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCOc2ccc(O)cc21
Reaction time: 4 h
Yield: 93.2 %

Procedure:
A mixture of 50.0 g (281 mmol) of 6-methoxychroman-4-one in 350 mL 48% HBr and 350 mL acetic acid was heated to reflux under N2. After 4 hours, the reaction mixture was cooled to room temperature in a Rotovap (trademark) and 1 L H2O was added. The suspension was kept at 0° C. overnight. The mixture was filtered, and the precipitate washed two times with H2O, two times with hexanes and then dried under vacuum to give 43.0 g of the title product as a dark purple/black solid. 93% yield.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][C:7]([Sn](C)(C)C)=[CH:6][C:5]=2[N:4]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[N:3]=1.Br[C:26]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]2[C:27]=1[CH:28]=[CH:29][N:30]2[S:36]([C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)(=[O:38])=[O:37]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][C:7]([C:26]3[CH:34]=[C:33]([F:35])[CH:32]=[C:31]4[C:27]=3[CH:28]=[CH:29][N:30]4[S:36]([C:39]3[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=3)(=[O:37])=[O:38])=[CH:6][C:5]=2[N:4]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[N:3]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)n2ccc3c(Br)cc(F)cc32)cc1
Reactant: C[Sn](C)(C)c1cc(N)c2c(F)nn(S(=O)(=O)c3ccccc3)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1cc(-c2cc(F)cc3c2ccn3S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc2c1c(F)nn2S(=O)(=O)c1ccccc1
Yield: 55.1 %

Procedure:
A solution of 3-fluoro-1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (0.65 g, 1.43 mmol), 4-bromo-6-fluoro-1-[(4-nitrophenyl)sulfonyl]-1H-indole (0.69 g, 1.71 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.17 g, 0.14 mmol) in DMF (5 mL) was heated to 120° C. for 18 hr. The mixture was concentrated in vacuo and purified by silica cartridge (100 g) by Flashmaster II using a gradient of cyclohexane and ethyl acetate to give the title compound as an orange solid (0.48 g).
Reaction SMILES: [I-:1].[Na+].Cl[C:4]1[CH:9]=[C:8](Cl)[N:7]=[C:6]([S:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:22])[CH2:20][CH3:21])=[CH:14][CH:13]=2)[N:5]=1.[IH:23]>>[I:1][C:4]1[CH:9]=[C:8]([I:23])[N:7]=[C:6]([S:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:22])[CH2:20][CH3:21])=[CH:14][CH:13]=2)[N:5]=1
Reactant: I
Reactant: CCC(=O)Nc1ccc(Sc2nc(Cl)cc(Cl)n2)cc1
Reactant: [I-]
Agent: [Na+]
Product: CCC(=O)Nc1ccc(Sc2nc(I)cc(I)n2)cc1
Temperature: 70 °C
Reaction time: 10 h
Yield: 78 %

Procedure:
Sodium iodide (13.5 g, 90 mmol) was added to a solution of N-(4-(4,6-dichloropyrimidin-2-ylthio)phenyl)propionamide (5 g, 15 mmol) in 60% HI (50 ml). The reaction mixture was stirred at 70° C. for 10 h. The suspension was filtered. The recovered solid was taken up in saturated sodium bicarbonate aqueous solution (˜200 ml). Extractions were carried out with ethyl acetate (3×100 ml). The organic was washed with saturated sodium bicarbonate solution and brine. The solid was triturated in a minimum of dichloromethane to afford the title compound as a white solid (6 g, 78%). ES+ 512.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].[CH3:13][O:14][C:15](=[O:28])[CH2:16][NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[O:26][CH3:27]>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:28])[CH2:16][N:17]([S:2](=[O:4])(=[O:3])[NH:5][C:6]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[O:26][CH3:27]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)O
Reactant: COC(=O)CNc1ccc(OC)cc1OC
Solvent: ClCCl
Product: COC(=O)CN(c1ccc(OC)cc1OC)S(=O)(=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1.15 g (8.08 mmol) of chlorosulfonyl isocyanate in 10 mL of CH2Cl2 is added dropwise a solution of 598 mg (8.08 mmol) of t-butanol in 2 mL of CH2Cl2. The solution is stirred at RT for 45 min, then a solution of 1.3 g (5.8 mmol) of the title A compound, (2,4-dimethoxyphenylamino)-acetic acid methyl ester and 1.2 g (11.9 mmol) of TEA in 4 mL of CH2Cl2 is added dropwise. The mixture is stirred at RT for 90 min, then washed with water. The organic phase is dried over anhydrous Na2SO4 and the solvent is removed under reduced pressure. The residual oil is purified by chromatography using 10% EtOAc in CH2Cl2 as the eluant to give N-(t-butoxycarbonylsulfamoyl)-N-(2,4-dimethoxy-phenyl)glycine methyl ester as a thick yellow oil: 1H-NMR (CDCl3) δ 7.57 (d, J=9.19, 1H), 7.19 (s, 1H), 6.51-6.46 (m, 2H), 4.55 (br s, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 3.71 (s, 3H), 1.53 (s, 9H); [M−1]−=403.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1=[O:9].[N+:11]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)([O-:13])=[O:12].[NH2:22][C:23]1[CH:27]=[CH:26][NH:25][N:24]=1>>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5]2[NH:22][C:23]3=[CH:27][CH:26]=[N:25][N:24]3[CH:17]([C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=3)[C:4]=2[C:3]1=[O:9]
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC1(C)CCC(=O)CC1=O
Product: CC1(C)CCC2=C(C1=O)C(c1cccc([N+](=O)[O-])c1)n1nccc1N2

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione, 3-nitrobenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.