Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>>[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34](=[O:35])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:20])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH3:19])=[CH:13][CH:12]=1)([CH3:22])[CH3:23]
Reactant: CCCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCCc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 36.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-dimethylaminophenyl)methyl](4-propylphenyl)amine (0.80 g) and 2,6-diisopropylphenyl isocyanate (0.72 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-(4-propylphenyl)urea (0.51 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6]2.[C:21]1([NH:27]N)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C2C(=CC=CC=2)C=C1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[NH:27][C:21]3[C:26]([C:14]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:7]=[CH:6]2
Reactant: NNc1ccccc1
Reactant: CCCCCCC(=O)c1ccc2cc(OC)ccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1ccc2[nH]ccc2c1
Solvent: CCO
Product: CCCCCc1c(-c2ccc3cc(OC)ccc3c2)[nH]c2ccccc12
Yield: 102.6 %

Procedure:
To a stirred suspension of the 1-(6-methoxy-2-naphthyl)heptan-1-one (81.5 g, 301.44 mmol) in ethanol (2000 mL) under N2 was added phenylhydrazine (35.857 g, 331.58 mmol) and p-toluene sulfonic acid monhydrate (120.41 g, 633.02 mmol). The mixture was refluxed. Warming gave a homogenous solution. (A modification of this Fisher indole reaction to incorporate varied substitution on the indole ring utilizes an N-arylhydrazone in place of the aryl hydrazine-details of hydrazone preparation in a recent JACS, S. Wagaw; B. H. Yang; S. L. Buchwald. JACS, 121, 1999, 10251-10263). After 92 h reflux, heating was stopped and the reaction mixture cooled and rotovap'd to a residue. The residue was partitioned between EtOAc (1700 mL) and 1 N HCl (500 mL). The layers were shaken, separated, and the organic layer washed with 1 N HCl (2×300 mL), sat. aq. NaHCO3 (3×250 mL), H2O (3×250 mL), brine (2×250 mL), dried over Na2SO4, filtered, rotovap'd and dried in vacuo to give a dark viscous oil (106.2 g). The residue was triturated with hexane to give an off-white solid which was collected, rinsed and dried in vacuo to give the product as an off-white solid (95.9 g, 279.21 mmol, 93%) which dec. 93-96° C. 400 mg of the crude indole was recrystallized from hexane to give the product as a white solid (298 mg) with mp 95-97°C.; 1H NMR (DMSO-d6) δ 0.82 (t, J=7.0 Hz, 3H), 1.31 (m, 4H), 1.66 (m, 2H), 2.89 (t, J=7.6 Hz, 2H), 3.90 (s, 3H), 6.98-7.02 (m, 1H), 7.07-7.10 (m, 1H), 7.21 (dd, J=2.4, 8.9 Hz, 1H), 7.34-7.37 (m, 2H), 7.54 (d, J=7.94 Hz, 1H), 7.73 (dd, J=1.5, 8.6 Hz, 1H), 7.88 (d, J=9.00 Hz, 1H), 7.93 (d, J=8.55 Hz, 1H), 8.03 (s, 1H), 11.17 (s, 1H); IR (solid) 3350, 2960, 2920, 2840, 1600, 1200, 740, cm−1; mass spectrum [ESI], m/z 344 (M+H)+;
Reaction SMILES: S(Cl)(Cl)=O.O(C(CC)C(O)=O)C1C=CC=CC=1.O(C(CC)C(Cl)=O)C1C=CC=CC=1.[O:31]([CH:38]([CH2:44][CH3:45])[C:39]([N:41]=[C:42]=[S:43])=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl:46][C:47]1[CH:48]=[C:49]([CH:51]=[CH:52][C:53]=1[O:54][C:55]1[C:64]2[C:59](=[CH:60][C:61]([O:67][CH3:68])=[C:62]([O:65][CH3:66])[CH:63]=2)[N:58]=[CH:57][CH:56]=1)[NH2:50]>C(O)C.C1(C)C=CC=CC=1>[Cl:46][C:47]1[CH:48]=[C:49]([NH:50][C:42]([NH:41][C:39](=[O:40])[CH:38]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:44][CH3:45])=[S:43])[CH:51]=[CH:52][C:53]=1[O:54][C:55]1[C:64]2[C:59](=[CH:60][C:61]([O:67][CH3:68])=[C:62]([O:65][CH3:66])[CH:63]=2)[N:58]=[CH:57][CH:56]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: CCC(Oc1ccccc1)C(=O)N=C=S
Agent: CCC(Oc1ccccc1)C(=O)Cl
Agent: CCC(Oc1ccccc1)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCC(Oc1ccccc1)C(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(Cl)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2-phenoxybutanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2-phenoxybutanoyl isothiocyanate was prepared using the resultant 2-phenoxybutanoyl chloride as a starting compound according to the description of the literature. 2-Phenoxybutanoyl isothiocyanate thus obatined was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 16 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (25 mg, yield 27%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][C:43](O)=[O:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:46]([NH2:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][C:43](=[O:44])[NH:53][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CC(=O)NCc4ccccc4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 50.0 mg of (2S,4R,5R)-2-carboxymethyl-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (from example 9b) are reacted with benzylamine to afford the title compound as yellow oil. Rf=0.50 (dichlormethane-methanol 9:1); Rt=5.17.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([OH:7])[C:4]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:3][CH:2]=1.[Na+:12].[C:13]1(=[O:29])[N:17]([CH:18]([CH3:23])[CH2:19][C:20](Cl)=[O:21])[C:16](=[O:24])[C:15]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:14]12>C1(C)C(C)=CC=CC=1>[C:16]1(=[O:24])[N:17]([CH:18]([CH3:23])[CH2:19][C:20]([O:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[S:8]([O-:11])(=[O:9])=[O:10])=[O:21])[C:13](=[O:29])[C:14]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:15]12.[Na+:12]
Reactant: O=S(=O)([O-])c1ccccc1O
Reactant: CC(CC(=O)Cl)N1C(=O)c2ccccc2C1=O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC(CC(=O)Oc1ccccc1S(=O)(=O)[O-])N1C(=O)c2ccccc2C1=O

Procedure:
148.0 g (755 mmol) of anhydrous sodium phenolsulfonate and 190.0 g (755 mmol) of γ-phthalimidobutanoyl chloride are reacted in 200 g of xylene at 140° C. for 4 hours and the mixture is worked up as in Example 1. The crude product is recrystallized from methanol and the white crystalline product is dried at 40° C. under a water pump vacuum.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([C:22](=[O:32])[C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH2:14][CH2:13][C:12]=1[CH:33]=O>CN(C)C=O>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([C:22]([N:15]2[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:11]3[S:3][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:33][C:12]=3[CH2:13][CH2:14]2)=[O:32])=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: CCOC(=O)CS
Reactant: O=CC1=C(Cl)c2ccccc2N(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(s1)-c1ccccc1N(C(=O)c1ccc([N+](=O)[O-])cc1)CC2
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
To a slurry of 0.240 g (6.01 mmol) of sodium hydride (60% in oil) in 20 ml of N,N-dimethylformamide, chilled in an ice bath, is added 0.656 ml (6.01 mmol) of ethyl 2-mercaptoacetate. The mixture is stirred for 10 minutes and a slurry of 2.14 g (6.01 mmol) of 2,3-dihydro-5-chloro-1-(4-nitrobenzoyl)-1H-1-benzazepine-4-carboxaldehyde in 6 ml of N,N-dimethylformamide is added dropwise. The mixture is stirred at room temperature overnight and then concentrated under high vacuum. The residue is partitioned between chloroform and water and the organic layer separated. The aqueous layer is extracted (twice) with chloroform and the organic layer and extracts combined and dried (Na2SO4). The solvent is removed and the residue chromatographed on silica gel with dichloromethane as eluent (2 liter) and then with 4% ethyl acetate in dichloromethane as eluent. Fractions containing product are combined and the solvent removed under vacuum to give 2.1 g of ethyl 4,5-dihydro-6-(4-nitrobenzoyl)-6H-thieno[3,2-d][1]benzazepine-2-carboxylate as a yellow foam.
Reaction SMILES: [CH2:1]([CH:4]1[C:8](=[O:9])[CH:7]=[CH:6][CH2:5]1)[CH:2]=[CH2:3].[C:10](=[O:17])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[NH2:11].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.CCCCCCC>[CH2:1]([CH:4]1[C:8](=[O:9])[CH2:7][CH:6]([NH:11][C:10](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)OC(N)=O
Reactant: C=CCC1CC=CC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CCCCCCC
Solvent: ClCCl
Product: C=CCC1CC(NC(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.2 %

Procedure:
A stirred solution of 5-allylcyclopent-2-enone (2.20 g, 18 mmol), t-butyl carbamate (4.70 g, 40 mmol), and tetra-n-butylammonium bromide (6.45 g, 20 mmol) in anhydrous dichloromethane (40 mL) under nitrogen was cooled in an ice bath (3° C.) and treated dropwise with boron trifluoride etherate (2.22 mL, 18 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 h. Saturated aqueous sodium bicarbonate (40 mL) was added and then mixture stirred for 15 min and separated. The aqueous solution was extracted with dichloromethane (2×20 mL) and the combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each), dried (Na2SO4), and concentrated in vacuo. The residue was dissolved in minimum dichloromethane and added to a column of silica gel (˜300 cc) and eluted first with 85:15 heptane/ethyl acetate to afford recovered starting material (0.35 g), then with 4:1 heptane/ethyl acetate to afford a mixture of t-butyl carbamate and subject compound. This mixture was warmed in heptane and filtered to remove most of the t-butyl carbamate, then the filtrate was added to a column of silica gel (˜300 cc) and eluted with 6:3:1 heptane/dichloromethane/ethyl acetate to afford tert-butyl 3-allyl-4-oxocyclopentylcarbamate 1.17 g (27%) as a pale amber solid. NMR (CDCl3): δ 5.60-5.75 (m, 1 H), 4.90-5.05 (m, 2 H), 4.50 (br s, 1 H), 4.00-4.25 (m, 1 H), 2.30-2.80 (m, 3 H), 2.20-2.30 (m, 1 H), 1.85-2.15 (m, 3 H), 1.38 (s, 9 H). MS (M+1): 240.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].CCN(C(C)C)C(C)C.[C:19](Cl)(=[O:21])[CH3:20].C(OC(=O)C)C.O>C1COCC1>[C:5]([C:4]1[CH:7]=[CH:8][N:9]=[C:2]([NH:1][C:19](=[O:21])[CH3:20])[CH:3]=1)#[N:6]
Reactant: CC(=O)Cl
Reactant: N#Cc1ccnc(N)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(C#N)ccn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
8 mmol of 2-Amino-isonicotinonitrile were dissolved in THF. 2 eq of DIPEA were added. The reaction mixture was cooled to 0° C. and 1.0 eq of acetylchloride in THF added dropwise and the reaction stirred for 2 h. The product was isolated by extraction from ethylacetate/water.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[C:5]([CH3:14])[CH:4]=1.CCN(CC)CC.[CH3:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[CH2:32][NH:33][CH3:34].C1C=CC2N(O)N=NC=2C=1.O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(Cl)Cl>[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:33]([CH3:34])[CH2:32][C:24]2[N:23]([CH3:22])[C:31]3[C:26]([CH:25]=2)=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:13])=[C:5]([CH3:14])[CH:4]=1
Reactant: CNCc1cc2ccccc2n1C
Reactant: Cc1cc(N)ncc1/C=C/C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(N)ncc1/C=C/C(=O)N(C)Cc1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
To a stirred solution of (E)-3-(6-amino-4-methylpyridin-3-yl)acrylic acid HCl salt (0.70 g, 3.3 mmole) in 1:1 DMF/CH2Cl2 (30 mL) was added Et3N (0.42 mL, 3 mmole), 1-methyl-2-(methylaminomethyl)indole (0.50 g, 2.9 mmole), HOBt.H2O (0.41 g, 3 mmole), and DCC (0.70 g, 3 mmole). After stirring at RT for 16 hr the reaction was concentrated under vacuum. The residue was taken up in ethyl acetate and filtered. The filtrate was washed with 1.0 N Na2CO3 then with brine, dried (Na2SO4), and concentrated under vacuum. Purification by flash chromatography on silica gel (4% methanol/CHCl3) gave the title compound (0.74 g, 74%) as a pale yellow solid: LCMS (ES) m/e 335.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
In 80 ml of dimethylformamide was dissolved 12.22 g of p-hydroxybenzaldehyde, and 17.66 g of anhydrous potassium carbonate and 13.0 ml of benzyl bromide were added to the solution and the mixture was stirred at room temperature in a nitrogen current for 1 hour. After the reaction, water was added to the reaction mixture and the formed precipitate was recovered by filtration and recrystallized from a dichloromethane/hexane mixed solvent to obtain 20.07 g (yield=94.6%) of 4-benzyloxybenzaldehyde in the form of a colorless needle.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:27]=[C:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:29]=[CH:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][O:5][C:30]1[CH:29]=[C:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:26][CH:31]=1
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: Cc1cccc(C)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)Cc1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2,6-Dimethylbenzyl alcohol (5.25 g, 38.6 mmol) and diisopropyl azodicarboxylate (DIAD, 8.49 g, 42 mmol) in THF (30 ml) was added drop wise to a solution of Ethyl 3-hydroxyphenylacetate (6.66 g, 37 mmol) and triphenylphosphine (11 g, 42 mmol) in THF (100 ml). The reaction mixture was stirred at room temperature for 4 hours, diluted with ether and washed with water and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[O:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH2:12][C:6]=2[CH:5]=1)([O-])=O.C(OCC)(=O)C>[Pt]=O.C(O)C>[NH2:1][C:4]1[CH:19]=[CH:18][C:7]2[O:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH2:12][C:6]=2[CH:5]=1
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2Oc2ccccc21
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)CC(=O)c1ccccc1O2

Procedure:
52.5 G. of 10,11-dihydro-2-nitro-dibenz[b,f]oxepin-10-one are suspended in 900 ml. of ethyl acetate and 450 ml. of ethanol and hydrogenated in the presence of 300 mg. of platinum oxide at room temperature and normal pressure. The catalyst is removed by filtration, the filtrate evaporated in vacuo. The residue is crystallized from benzene/hexane, and there is obtained 2-amino-10,11-dihydro-dibenz[b,f]oxepin-10-one having a melting point of 116°-117° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11](O)=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:44][C:45]1([CH3:53])[O:49][CH:48]([CH2:50][O:51][NH2:52])[CH2:47][O:46]1.[NH4+].[Cl-]>C(Cl)Cl>[CH3:44][C:45]1([CH3:53])[O:49][CH:48]([CH2:50][O:51][NH:52][C:11]([C:4]2[C:3]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])=[C:2]([F:1])[C:7]3[N:8]=[N:9][S:10][C:6]=3[CH:5]=2)=[O:12])[CH2:47][O:46]1
Reactant: O=C(O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Reactant: CC1(C)OCC(CON)O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)OCC(CONC(=O)c2cc3snnc3c(F)c2Nc2ccc(I)cc2F)O1
Reaction time: 1 h

Procedure:
To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylic acid (210 mg, 0.48 mmol) in CH2Cl2 (10 mL) was added HOBt (105 mg, 0.72 mmol) followed by EDCI (138 mg, 0.72 mmol). The mixture was stirred for 1 h and O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (108 mg, 0.74 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH4Cl (aq.). The resultant mixture was extracted with CH2Cl2 (15 mL×3). The combined organic extracts was washed by water (10 mL) and brine (10 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. The crude product (229 mg) was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[CH:8][N:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:6]2[CH:5]=[C:4]1[C:14](O)=O)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:41]([O:45][C:46](=[O:67])[NH:47][C@@H:48]1[CH2:53][CH2:52][CH2:51][N:50]([C:54](=[O:66])[C:55]2[CH:60]=[CH:59][C:58]([NH:61][CH3:62])=[C:57]([N+:63]([O-])=O)[CH:56]=2)[CH2:49]1)([CH3:44])([CH3:43])[CH3:42].CCN(C(C)C)C(C)C.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CN(C=O)C.O.C1(C)C=CC=CC=1>[C:41]([O:45][C:46](=[O:67])[NH:47][C@@H:48]1[CH2:53][CH2:52][CH2:51][N:50]([C:54]([C:55]2[CH:60]=[CH:59][C:58]3[N:61]([CH3:62])[C:14]([C:4]4[N:3]([CH2:1][CH3:2])[C:7]5=[CH:8][N:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:6]5[CH:5]=4)=[N:63][C:57]=3[CH:56]=2)=[O:66])[CH2:49]1)([CH3:44])([CH3:42])[CH3:43]
Reactant: CCn1c(C(=O)O)cc2cc(OC)ncc21
Reactant: CNc1ccc(C(=O)N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)ccc3n2C)cc2cc(OC)ncc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.9 %

Procedure:
1-Ethyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (200 mg, 0.908 mmol, reported in WO 2010/118208) and HATU (380 mg, 0.999 mmol) were dissolved in DMF (2 mL) and stirred at rt for 5 min. To this was added a solution of (R)-tert-butyl(1-(4-(methylamino)-3-nitrobenzoyl)piperidin-3-yl)carbamate (316 mg, 0.908 mmol) and DIPEA (0.476 ml, 2.72 mmol) in DMF (2 ml), and the resulting mixture stirred under nitrogen at rt for 3.5 hr. The reaction mixture was diluted with water (40 ml) and partitioned with ether (50 ml). The organic layer was isolated then the aqueous layer re-extracted with ether (2×50 ml). Combined organic layers were washed with water (2×30 ml) then dried over sodium sulfate then passed through a hydrophobic frit and concentrated under reduced pressure to give the crude amide intermediate as a blue solid. The solid was dried under reduced pressure overnight then dissolved in toluene (12.5 ml). Acetic acid (0.052 ml, 0.908 mmol) was added to the reaction mixture which was refluxed for 5 hr. Sodium bicarbonate (40 ml) was added to the reaction mixture and the organic layer isolated. The aqueous layer was reextracted with toluene (2×40 ml) and combined organic layers were concentrated under reduced pressure to give 238 mg of the crude product as a red-brown gum. The crude material was purified with column chromatography (eluted with 100% EtOAc) then further purified by high pH MDAP (Method E) to give the title compound as an off-white solid (106 mg, 22%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[C:4]([CH3:14])[CH:3]=1.[CH3:15][C:16]1[N:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])[C:18]([CH3:24])=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22].C([O-])([O-])=O.[K+].[K+].CNCCNC>CCOC(C)=O.[Cu]I.C1(C)C=CC=CC=1>[CH3:12][N:11]([CH3:13])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:23][C:21]([C:20]2[CH:19]=[C:18]([CH3:24])[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:33])([F:32])[F:34])[C:16]=2[CH3:15])=[O:22])=[CH:3][C:4]=1[CH3:14])(=[O:10])=[O:9]
Reactant: Cc1cc(C(N)=O)c(C)n1-c1ccccc1C(F)(F)F
Reactant: Cc1cc(Br)ccc1S(=O)(=O)N(C)C
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)c2cc(C)n(-c3ccccc3C(F)(F)F)c2C)ccc1S(=O)(=O)N(C)C
Temperature: 120 °C
Yield: 79246.7 %

Procedure:
An oven-dried, argon-sparged vial was charged with 4-bromo-2,N,N-trimethyl-benzenesulfonamide (70 mg, 0.25 mmol), 2,5-dimethyl-1-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxamide (85 mg, 0.30 mmol), anhyd K2CO3 (69 mg, 0.50 mmol), and copper (I) iodide (10 mg, 0.05 mmol), and then briefly sparged with argon. To the vial under argon was added anhyd toluene (0.5 mL) and N,N′-dimethyl-ethylenediamine (11 μL, 0.10 mmol), then capped and heated at 120° C. After 24h the reaction mixture was cooled, diluted with EtOAc, filtered through Celite and concentrated under reduced pressure. The crude material was chromatographed (silica, EtOAc/Hex, 0:100 to 50:50) to afford the title compound (95 g, 79%) as a white solid. 1H-NMR (DMSO-d6) δ 9.74 (1H, s), 8.01 (1H, d, J=7.8), 7.92 (1H, app t, J=7.8), 7.78-7.86 (3H, m), 7.71 (1H, d, J=8.3), 7.51 (1H, d, J=7.8), 6.65 (1H, s), 2.69 (6H, s), 2.53 (3H, s), 2.14 (3H, s), 1.88 (3H, s); MS (ESI): 480 (MH+).