Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH2:40]([N:47]1[CH2:51][CH2:50][N:49]([C@@H:52]([C:56]([CH3:59])([CH3:58])[CH3:57])[C:53](O)=[O:54])[C:48]1=[O:60])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:40]([N:47]1[CH2:51][CH2:50][N:49]([C@@H:52]([C:56]([CH3:58])([CH3:57])[CH3:59])[C:53]([NH:1][C@@H:2]([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][CH:8]=2)=[O:54])[C:48]1=[O:60])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)(C)[C@@H](C(=O)O)N1CCN(Cc2ccccc2)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
A solution containing the product from Example 2C (1.09 g, 2.05 mmol) in THF (20 mL) was treated with the product from Example 70A (0.71 g, 2.45 mmol), DEPBT (1.0 g, 3.34 mmol), and N,N-diisopropylethylamine (2.0 mL, 11.5 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by 1% methanol in ethyl acetate to give the title compound (1.197g, 73% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (s, 9 H), 0.89 (s, 9 H), 1.56 (m, 2 H), 2.33 (q, J=9.2 Hz, 1 H), 2.58 (dd, J=13.6, 8.8 Hz, 1H), 2.67 (m, 2H), 2.78 (dd, J=13.6, 3.3 Hz, 1H), 2.84 (m, 1 H), 2.94 (q, J=9.2 Hz, 1 H), 3.19 (m, 1 H), 3.50 (s, 3 H), 3.67 (m, 1 H), 3.85 (d, J=9.93 Hz, 1 H), 4.09 (s, 1 H), 4.19 (m, 2 H), 4.31 (s, 2 H), 4.55 (d, J=7.72 Hz, 1 H), 6.63 (d, J=9.56 Hz, 1 H), 7.07 (m, 5 H), 7.22 (d, J=8.5 Hz, 2 H), 7.29 (m, 4 H), 7.36 (m, 2 H), 7.47 (d, J=9.56 Hz, 1 H), 7.85 (m, 3H), 7.89 (d, J=8.5 Hz, 2 H ), 8.63 (d, J=4.78 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([NH:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Nc1nc(NCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 91 %

Procedure:
2-Amino-6-benzylamino-3-nitropyridine was prepared from 2-amino-6-chloro-3-nitropyridine as follows: 2-Amino-6-chloro-3-nitropyridine (17.35 g, 0.10 mol), benzyl amine (Fluka) (10.72 g, 0.10 mol) and powdered potassium carbonate (10.4 g, 0.035 mol) in n-butanol (100 mL) were heated under reflux for 2 hours. The suspension was filtered and after cooling to room temperature the solid was collected by filtration, washed with butanol, and dried at 50 C in vacuo to give 2-amino-6-benzylamino-3-nitropyridine (22.2 g, 91%, m.p. 145-146 C).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH2:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][CH:6]([CH2:4][OH:3])[CH2:7]1)=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCC(CO)C1
Reaction time: 0.75 h
Yield: 66 %

Procedure:
Piperidine-1,3-dicarboxylic acid 1-benzyl ester 3-ethyl ester (7) (1.5 g, 5.83 mmol) was dissolved in 5.8 mL of anhydrous THF, and the reaction was stirred under N2 at −5° C. while lithium aluminum hydride dissolved in THF (7.0 mL, 1.0M) was added dropwise by addition funnel over 30 minutes. When the reaction was complete by TLC (10 min.), H2O (0.6 mL), then 10% NaOH (1.5 mL), then H2O (0.6 mL) were added, and the reaction was stirred for about 45 minutes. The salts were removed by filtration and the solution was dried with sodium sulfate, filtered, and concentrated. The crude material was purified using an ISCO CombiFlash flash column (silica, 80:20 Hexane: EtOAc to 40:60 Hexane: EtOAc) to achieve 1.24 g of pure 8 (66% yield).
Reaction SMILES: [C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:22][N:23]1[C:28]([CH3:30])([CH3:29])[CH2:27]C(O)[CH2:25][C:24]1([CH3:33])[CH3:32]>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:1]([O:20][CH:21]1[CH2:27][C:28]([CH3:30])([CH3:29])[N:23]([CH3:22])[C:24]([CH3:33])([CH3:32])[CH2:25]1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CCCCCCCCCCCCCCCCCC(=O)OC1CC(C)(C)N(C)C(C)(C)C1

Procedure:
In a 250-ml three-necked flask equipped with a KPG stirrer, internal thermometer, and short helical glass column followed by a Liebig condenser, 74.6 g methyl octadecanoate and 64.2 g 1,2,2,6,6-pentamethyl-4-piperidinol were heated 6 hr at 200° C. in the presence of 1 g tetraisopropyl titanate, with a gentle nitrogen stream being passed through the reaction mixture A 28 g amount of a distillate was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[N:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1)=[C:25]=[O:26]>CN(C)C=O.C(OCC)(=O)C>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[O:5][C:6]2[CH:18]=[CH:17][C:9]3[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=3[C:7]=2[C:19]#[N:20])=[O:26])=[CH:28][CH:29]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Nc4ccc(C(C)(C)C)cc4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.6 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (120 mg, 0.369 mmol) produced in Example 12(ii) was dissolved in N,N-dimethylformamide (1.5 mL), 1-isocyanato-4-(tert-butyl)benzene (85 μL, 0.48 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 ml), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=60/40→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from acetone/n-hexane to give the title compound (73 mg, 40%) as a white powder.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[NH2:12])[CH2:3]1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>N1C=CC=CC=1.ClCCl.ClCCl>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[C:11]([NH:12][S:29]([C:26]3[CH:25]=[CH:24][C:23]([C:19]4[S:18][CH:22]=[CH:21][CH:20]=4)=[CH:28][CH:27]=3)(=[O:30])=[O:31])[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:3]1
Reactant: COc1ccc(N)cc1N1C[C@@H](C)N[C@@H](C)C1
Reactant: O=S(=O)(Cl)c1ccc(-c2cccs2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2ccc(-c3cccs3)cc2)cc1N1C[C@@H](C)N[C@@H](C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-(cis-3,5-dimethyl-1-piperazinyl)-4-(methyloxy)aniline (D2) (117 mg, 0.5 mmol) in pyridine:dichloromethane (1:1, 4 ml) was treated with a solution 4-(2-thienyl)benzenesulfonyl chloride (WO 9827069) (143 mg, 0.55 mmol) in dichloromethane (2 ml). The solution was stirred at room temperature for 24 hours, quenched with methanol (2 ml) and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with water (×3). The organic phase was applied to a SCX cartridge (Varian bond-elute, 5 g) and washed with methanol and 2M ammonia in methanol. The combined basic fractions were concentrated in vacuo and the resulting residue was purified by column chromatography (dichloromethane to 1:4 2M ammonia in methanol:dichloromethane) to afford the title product (E11). MS (ES+) m/e 458 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[C:30]1[CH:41]=[CH:40][CH:39]=[CH:38][C:31]=1[O:32][CH2:33][C:34]([CH3:37])([OH:36])[CH3:35].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O>[OH:36][C:34]([CH3:37])([CH3:35])[CH2:33][O:32][C:31]1[CH:38]=[CH:39][CH:40]=[CH:41][C:30]=1[N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:21]=[C:12]([S:9]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]1=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Reactant: CC(C)(O)COc1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2OCC(C)(C)O)cc1
Reaction time: 1 h
Yield: 61.6 %

Procedure:
A mixture of N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (Intermediate M; 700 mg, 1.674 mmol), 1-(2-bromophenoxy)-2-methylpropan-2-ol (2.8 g, 11.722 mmol), Pd2(dba3)2 (96 mg, 0.1674 mmol), Xantphos (306 mg, 0.3349 mmol) and sodium-tert-butoxide (402 mg, 4.186 mmol) in toluene (15 mL) was degassed with nitrogen for 10 minutes. The reaction mixture was subjected to microwave for 1 h at 100° C. After completion, reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude material, which was purified by combiflash silica gel column chromatography (column size: 12 g; elution: 12% ethyl acetate in hexane) to yield 4-(2-(2-hydroxy-2-methylpropoxy)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (600 mg, 88.2%). m/z (ESI) 582.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Brc1cccs1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccs2)CCN(C)C1
Yield: 3.5 %

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.4 g, 2 mmol), 2-bromothiophene (0.347 mL, 4 mmol), K3PO4 (0.848 g, 4 mmol), CuI (38 mg, 0.2 mmol) and L-Proline (46 mg, 0.39 mmol) in dry DMF (6 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-thiophen-2-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (20 mg). 1H NMR (TFA salt, CD3OD) d (ppm): 7.50 (d, 1H), 7.30 (s, 1H), 7.15 (m, 3H), 7.05 (d, 1H), 4.78 (m, 1H), 4.39 (m, 1H), 3.80 (m, 1H), 3.58 (m, 1H), 3.15 (s, 3H), 3.05 (m, 2H), 2.42 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]([NH:19][C:20](=[O:27])[CH2:21][C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=[C:15]3[C:11]=2/[C:12](=[CH:29]/[C:30]2[NH:31][CH:32]=[CH:33][C:34]=2[O:35][CH3:36])/[C:13](=[O:28])[NH:14]3)=[CH:6][CH:5]=1.O[Li].O>C1COCC1.O>[CH3:36][O:35][C:34]1[CH:33]=[CH:32][NH:31][C:30]=1/[CH:29]=[C:12]1\[C:13](=[O:28])[NH:14][C:15]2[C:11]\1=[C:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:37])=[O:2])=[CH:9][CH:8]=1)[C:18]([NH:19][C:20](=[O:27])[CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)=[CH:17][CH:16]=2
Reactant: COC(=O)c1ccc(-c2c(NC(=O)Cc3cccs3)ccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(NC(=O)Cc3cccs3)c(-c3ccc(C(=O)O)cc3)c21
Yield: 28.6 %

Procedure:
Using Method F above, (Z)-4-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-5-[(2-thienylacetyl)amino]-1H-indol-4-yl]-benzoic acid methyl ester (70 mg, 0.14 mmol) (from Example 50 supra) was hydrolyzed with LiOH.H2O (20 mg, 0.48 mmol) in THF (3 mL) and water (2 mL) at room temperature for 3 days to yield (Z)-4-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-5-[(2-thienylacetyl)amino]-1H-indol-4-yl]-benzoic acid (yield: 20 mg, 29%).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[N:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](OC)(=[O:23])[CH2:21][SH:22]>>[CH2:15]([N:14]1[C:20](=[O:23])[CH2:21][S:22][CH:13]1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:19])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN=Cc1ccccc1OCCCN(C)C
Reactant: COC(=O)CS
Product: CCCCN1C(=O)CSC1c1ccccc1OCCCN(C)C

Procedure:
N-[[2-[3-(Dimethylamino)propoxy]phenyl]methylene]-butanamine (5.2 g) is reacted with 4.2 g of methyl thioglycolate following the procedure described in Example 1, part B, to yield 6.5 of 3-butyl-2-[2-[3-(dimethylamino)propoxy]phenyl]-4-thiazolidinone as an oil.
Reaction SMILES: F[C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[F:13].[OH:21][C:22]1[CH:23]=[C:24]([CH:38]=[CH:39][CH:40]=1)[CH2:25][NH:26][S:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:29])=[O:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:17][C:15]1[CH:14]=[C:4]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=2[F:13])[C:3]([N+:18]([O-:20])=[O:19])=[C:2]([CH:16]=1)[O:21][C:22]1[CH:23]=[C:24]([CH:38]=[CH:39][CH:40]=1)[CH2:25][NH:26][S:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1cccc(O)c1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1Nc1ccc(I)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 140.5 %

Procedure:
2.0 g of 3,5-difluoro-N-(2-fluoro-4-iodophenyl)-2-nitroaniline (Intermediate 1A; 64% pure, 3.25 mmol, 1 eq.), 0.98 g tert-butyl [(3-hydroxybenzyl)sulfamoyl]carbamate (Intermediate 2A; 3.24 mmol, 1 eq.) and 1.6 g caesium carbonate (4.9 mmol, 1.5 eq.) were suspended in 25 mL DMF and stirred in a closed vial at rt for 3 days. Additional 0.4 eq. tert-butyl [(3-hydroxybenzyl)sulfamoyl]carbamate and 0.4 eq. caesium carbonate were added and stirring was continued for 2 days. The reaction mixture was partitioned between sodium chloride solution and ether, the layers were separated and the aqueous layer was reextracted with ether. The combined organic layers were dried, filtered and concentrated in vacuo to yield 3.08 g of the crude product (as a regioisomeric mixture containing some unreacted starting material), which was used in the subsequent reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[CH:21][CH2:20][C:19]2[C:18]3[C:13](=[C:14]([NH:23][C:24](OC(C)(C)C)=O)[CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:22]=[CH:21][CH2:20][C:19]2[C:18]3[C:13](=[C:14]([NH:23][CH3:24])[CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc2c3c([nH]c12)C=C(OCc1ccccc1)C=CC3
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CNc1cccc2c3c([nH]c12)C=C(OCc1ccccc1)C=CC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A solution of 1.37 gm (3.37 mMol) 7-benzyloxy-4-(t-butyloxycarbonyl)amino-10H-cyclohepta[7,6-b]indole in 15 mL tetrahydrofuran was added dropwise over 30 minutes to a suspension of 0.47 gm (12.4 mMol) lithium aluminum hydride in 30 mL tetrahydrofuran at 0° C. After the addition was complete, the reaction mixture was stirred for 30 minutes at room temperature and then for 4 hours at reflux. The reaction mixture was cooled to room temperature and then to it was added sodium sulfate decahydrate until no more gas evolution was observed. The resulting suspension was filtered and the filter cake washed with dichloromethane. The combined filtrates were concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with 10% methanol in dichloromethane containing 0.5% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to give 0.97 gm (90%) of the desired compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:6]([OH:15])=[C:5]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:4]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:37])[CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:25][CH:24]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>O.C1COCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:37])[CH2:30][N:31]2[CH2:32][CH2:33][N:34]([CH2:2][C:3]3[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:6]([OH:15])=[C:5]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:4]=3)[CH2:35][CH2:36]2)=[CH:25][CH:24]=1
Reactant: CCCCCOc1cc(CO)cc(OCCCCC)c1O
Reactant: O=C(CN1CCNCC1)c1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCCOc1cc(CN2CCN(CC(=O)c3ccc(F)cc3)CC2)cc(OCCCCC)c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.9 %

Procedure:
To the solution of 4-hydroxymethyl-2,6-bis-pentyloxyphenol (525 mg, 1.62 mmol), 1-(4-fluorophenyl)-2-piperazine-1-yl-ethanone (432 mg, 1.94 mmol) and PPh3 (509 mg, 1.94 mmol) in drying THF (10 ml) was dropped diethyl azodicarboxylate (0.38 ml, 2.43 mmol) at 0° C. and then was stirred 15 minutes at room temperature. The solution was added with H2O, then CH2Cl2 was evaporated in vacuo and was washed with brine. The obtained organic solution was dried over anhydrous magnesium sulfate and filtered. The obtained filterate was vacuum concentrated to give the residue, which was purified by column chromatography (Hexane:EtOAc=1:10), yielding 129 mg (15%) of 1-(4-fluorophenyl)-2-[4-(4-hydroxy -3,5-bis-pentyloxybenzyl)piperizine-1-yl]ethanone as a yellow oil.
Reaction SMILES: FC1C=C(C#CC=C2CCN(C3C([N+]([O-])=O)=CC=CN=3)CC2)C=C(F)C=1OC.[CH:29](=[C:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1)[C:30]#[CH:31].Cl[C:46]1[CH:51]=[C:50]([F:52])[CH:49]=[CH:48][N:47]=1>>[F:52][C:50]1[CH:49]=[CH:48][N:47]=[C:46]([C:31]#[C:30][CH:29]=[C:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]2)[CH:51]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: C#CC=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: COc1c(F)cc(C#CC=C2CCN(c3ncccc3[N+](=O)[O-])CC2)cc1F
Product: CC(C)(C)OC(=O)N1CCC(=CC#Cc2cc(F)ccn2)CC1
Yield: 38.5 %

Procedure:
The title compound was prepared following the procedure described for the Compound of Example 199, but using Compound 2b instead of Compound 1c and 2-chloro-4-fluoropyridine instead of 4-bromo-2,6-difluoroanisole. After the usual work-up procedure, purification was carried out by automated flash liquid chromatography (Horizon™-Biotage) eluting with PE-EtOAc gradient from 95:5 to 60:40. Yield: 38.5%.
Reaction SMILES: [CH3:1][NH2:2].Cl.[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][S:12](Cl)(=[O:14])=[O:13])=[CH:6][CH:5]=1.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][NH:2][S:12]([CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][N:4]=[CH:5][CH:6]=1)(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)CCc1ccncc1
Reactant: CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNS(=O)(=O)CCc1ccncc1
Temperature: 25 °C

Procedure:
To 50 ml of a 40% solution of methylamine in methanol was added 3.0 g of 2-(pyridin-4-yl)ethanesulfonyl chloride hydrochloride as such (i.e., as a solid). After stirring for a while at room temperature, a solution of 2.1 g of sodium hydrogencarbonate in 15 ml of water was carefully added thereto. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 1.3 g of the title compound as brownish white scaly crystals.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][CH:9]([O:13][CH3:14])[CH2:10][NH:11][CH3:12].CC1OCCC1.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O>[CH2:25]([O:24][C:22](=[O:23])[N:11]([CH2:10][CH:9]([O:13][CH3:14])[O:8][CH3:7])[CH3:12])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCC(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC1CCCO1
Product: COC(CN(C)C(=O)OCc1ccccc1)OC
Temperature: 20 °C

Procedure:
K2CO3 (13.8 g, 100 mmol, 1.76 eq.) and H2O (46 mL) were mixed to form a homogeneous solution. The solution was cooled to 20° C. N-methylaminoacetaldehyde dimethylacetal (12.8 mL, 100 mmol, 1.8 eq) and MeTHF (50 mL) were added. The resulting mixture was cooled to 2° C. Benzyl chloroformate (8.1 mL, 56.7 mmol, 1.0 eq.) was added by syringe over 10 minutes (addition was exothermic). The mixture was maintained at room temperature until completion of the reaction. The layers were separated and the organic layer was washed with 1N HCl (50 mL) and used directly in the next step.