Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.[NH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>C(N(CC)CC)C>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:5][CH2:6][CH2:7][CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: NCCCn1ccnc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(NCCCn2ccnc2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 111.4 %

Procedure:
100 ml of DMSO were introduced into a 500 ml three-necked flask and treated with 10.3 g of triethylamine, 12.8 g of 1-(3-aminopropyl)imidazole and 14.4 g of 1-fluoro-4-nitrobenzene. The mixture was stirred at 80° C. for 12 h, cooled to room temperature and subsequently poured onto 1 l of ice. A sample of the resulting oily precipitate was triturated with H2O until crystallization commenced. A sample of the mixture was seeded with the crystals thus obtained and crystallized at room temperature for 1 h. The resulting precipitate was filtered off with suction, triturated with H2O, filtered off with suction again and rewashed with H2O. For the purpose of purification, the 28 g of moist crude product thus obtained were recrystallized from 250 ml of H2O and 114 ml of ethanol. The product was dried in vacuo at 50° C.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([C:16](O)=[O:17])[CH:12]=[CH:11][C:10]=2[C:9](=[O:19])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.S(Cl)(Cl)=O.[CH3:24][C:25]1[N:29]([CH2:30][CH2:31][OH:32])[C:28]([N+:33]([O-:35])=[O:34])=[CH:27][N:26]=1>O>[CH3:24][C:25]1[NH:29][C:28]([N+:33]([O-:35])=[O:34])=[CH:27][N:26]=1.[O:1]=[C:2]1[C:15]2[CH:14]=[C:13]([C:16]([O:32][CH2:31][CH3:30])=[O:17])[CH:12]=[CH:11][C:10]=2[C:9](=[O:19])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Product: Cc1ncc([N+](=O)[O-])[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 8.9 %

Procedure:
The reaction mixture of 9,1 0-dihydro-9,10-dioxo-2-anthracenecarboxylic acid (126 mg, 0.5 mmol) and thionyl chloride (2 ml) was refluxed for 2 h. The excessive thionyl chloride was evaporated under vacuum. The residue was dissolved in 5 ml of pyridine. To this solution, metronidazole (80 mg, 0.47 mmol) was added. After the mixture was stirred at 80° C. for 2 h, water was added to this mixture. The water layer was extracted with dichloromethane (20 ml×3). The organic layer of dichloromethane was washed with 5% Na2CO3, H2O, and brine, and then dried over MgSO4. The solvent was removed, and the residue was recrystallized from C2H5OH—EtOAc to give 17 mg 2-methyl-5-nitro-1H-imidazole-1-ethyl 9,10-dihydro-9,10-dioxo-2-anthracenecarboxylate. m.p.: 223-225 ° (dec.).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][Cl:20])[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)(C)(C)C.[CH3:30][N:31]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[ClH:20].[ClH:20].[CH3:30][N:31]1[CH2:37][CH2:36][CH2:35][N:34]([CH2:19][CH2:18][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]4[CH:27]=[CH:28][CH:29]=[C:23]4[CH:22]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:33][CH2:32]1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Reactant: CN1CCCNCC1
Product: CN1CCCN(CCOc2ccc3oc(-c4cc5cccn5cn4)cc(=NO)c3c2)CC1
Product: Cl

Procedure:
6-[2-(4-methyl-[1,4]diazepan-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, dihydrochloride was prepared in 13% overall yield using the method described in example 87, starting from 6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 87B) and 1-methyl-[1,4]diazepane.
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:29]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:30])[C:20]=2[N:19]=[C:18]1[CH2:31][CH2:32][CH2:33][CH3:34].ClCCl>N1C=CC=CC=1>[NH2:30][C:21]1[C:20]2[N:19]=[C:18]([CH2:31][CH2:32][CH2:33][CH3:34])[N:17]([CH2:16][CH2:15][CH2:14][CH2:13][NH:12][S:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:10])=[O:9])[C:29]=2[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
α-Toluenesulfonyl chloride (0.5 g in 10 ml dichloromethane, 2.7 mmol) was added dropwise to a stirring solution of 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine (0.75 g, 2.4 mmol), dichloromethane (115 ml), and pyridine (1 ml). The reaction was maintained at room temperature for 4 hours and then concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 9:1 dichloromethane\methanol, Rf 0.16). The fractions containing product were combined and washed with saturated aqueous bicarbonate. The organic layer was dried (MgSO4), filtered, and concentrated. A final recrystallization from dichloromethane\diethyl ether provided 0.65 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]phenylmethanesulfonamide as a white crystalline solid, m.p. 197.0–199.5° C. 1H NMR (300 MHz, DMSO-d6) δ 8.02 (d, J=7.6 Hz, 1H), 7.62 (dd, J=8.3, 1.1 Hz, 1H), 7.42 (dt, J=7.5, 1.1 Hz, 1H), 7.35–7.23 (m, 7H), 7.12 (t, J=5.4 Hz, 1H), 6.46 (broad s, 2H), 4.49 (t, J=7.5 Hz, 2H), 4.29 (s, 2H), 2.91 (m, 4H), 1.83–1.42 (m, 8H), 0.96 (t, J=(t, J=7.4 Hz, 3H); IR (KBr) 3460, 3293, 3226, 3158, 2955, 2931, 2867, 1632, 1586, 1534, 1482, 1437, 1389, 1331, 1152, 1094, 752, 700 cm−1; MS (EI) m/e 465.2204 (465.2198 calcd for C25H31N5O2S); Anal calcd for C25H31N5O2S: C, 64.49; H, 6.71; N, 15.04Found: C, 64.15; H, 6.71; N, 15.00.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH2:23][NH:24][S:25]([CH:28]=[CH2:29])(=[O:27])=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:30][O-:31].[Na+].CO>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH2:23][NH:24][S:25]([CH2:28][CH2:29][O:31][CH3:30])(=[O:26])=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[O-]
Reactant: C=CS(=O)(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COCCS(=O)(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (6S,7R)-7-(3,4-dichlorophenyl)-6-{[(ethenylsulfonyl)amino]methyl}-1,4-oxazepane-4-carboxylate (200 mg) in methanol (1 mL) was added 28% sodium methoxide-methanol (4 mL) solution at room temperature, and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (132 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.O>ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=CC(=O)N3CCOCC3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(C=Cc1ccc(OC2CCNCC2)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.4 %

Procedure:
A solution of 3-[4-(1-t-Butyloxycarbonyl piperidin-4-yloxy)phenyl]-1-(morpholin-4-yl)prop-2-ene-1-one (29.8 grams, 0.071 moles) in dichloromethane (400 mL) was treated with trifluoroacetic acid (55.6 mL, 0.726 moles) at room temperature. The reaction mass was stirred for 6 hours at room temperature. The progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mass was poured on to chilled water (500 mL) and basified with 40% lye solution (pH˜9). The layers were separated and the aqueous layer was extracted with dichloromethane (2×200 mL) and the combined organic phase was washed with water (150 mL), brine solution (150 mL) and dried over sodium sulphate. The organic phase was concentrated on rotavacuum to afford the title compound (21.2 grams).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1.[CH3:27][N:28]1[CH:32]=[C:31]([S:33](Cl)(=[O:35])=[O:34])[N:30]=[CH:29]1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:33]([C:31]2[N:30]=[CH:29][N:28]([CH3:27])[CH:32]=2)(=[O:35])=[O:34])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2cn(C)cn2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A of Example 11o, and 1-methyl-1H-imidazole-4-sulfonyl chloride following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, 1H), 7.70 (s, 1H), 7.54 (m, 3H), 7.39 (d, 1H), 7.24 (m, 2H), 7.14 (m, 1H), 7.04-6.97 (m, 3H), 6.45 (m, 1H), 4.43 (s, 2H), 4.40 (s, 2H), 3.74 (s, 3H), 3.65 (s, 3H), 2.83 (t, 2H), 2.53 (t, 2H); MS 494 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][NH2:27])[CH:19]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[ClH:1].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][NH:27][C:2]2[N:9]=[C:8]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[CH:7]=[C:6]([CH3:17])[C:3]=2[C:4]#[N:5])[CH:19]=1
Reactant: NCCOc1cccnc1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3cccnc3)n2)n[nH]1
Product: Cl
Temperature: 130 °C
Reaction time: 20 h
Yield: 138.5 %

Procedure:
Compound A (13 g, 53 mmol), 2-(pyridin-3-yloxy)ethylamine (11 g, 80 mmol) and sodium hydrogencarbonate (45 g) were added to DMSO (130 ml), and the mixture was stirred at 130° C. for 20 hr. After stirring, the reaction mixture was added to cold water, and insoluble substance was filtrated (20 g). This was converted to hydrochloride to give the object compound of 2-(2-(pyridin-3-yloxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile dihydrochloride (15.5 g).
Reaction SMILES: [CH:1]1N=C[N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])[CH:2]=1.CC1[CH:21]=[CH:20][C:17]([CH2:18]N)=[CH:16][CH:15]=1.NC1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1>[OH-].[Na+]>[CH3:18][C:17]1[CH:16]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[NH:3][CH2:2][C:1]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(CN)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(CNC(=O)NCc2ccc(C(=O)O)cc2)cc1
Yield: 94.9 %

Procedure:
N,N-carbonyldiimidazole (1.62 g, 10 mmol), p-methyl benzyl amine (1.21 g, 10 mmol), p-aminobenzoic acid (1.52 g, 10 mmol), and 10 ml of 1 mol/L sodium hydroxide solution are used according to the method for the production of compound III in Method two to obtain 2.83 g of 4-[(4-methylbenzylureido)methyl]benzoic acid (intermediate M-33) as a white solid, with a yield of 95.0%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12]>C(O)C>[F:12][C:11]([F:14])([F:13])[C:10]1[N:1]=[C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]2[CH:9]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: Nc1cnccn1
Solvent: CCO
Product: FC(F)(F)c1cn2ccncc2n1
Yield: 12.3 %

Procedure:
2-Aminopyrazine (12.5 g, 0.13 mol) and 3-bromo-1,1,1-trifluoro-propan-2-one (27.6 g, 0.14 mol) in ethanol (150 ml) was heated at reflux for 24 hours. A further portion of 3-bromo-1,1,1-trifluoro-propan-2-one (2.51 g, 14 mmol) was added and the mixture was heated at reflux for 18 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in water (30 ml). Solid sodium hydrogen carbonate was added to bring the pH to 8 and the solution was extracted with dichloromethane (×3). The combined organic layers were washed with water (20 ml) dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by medium pressure chromatography on silica gel using methanol in dichloromethane as eluant (gradient from 2:98 to 4:96). The material isolated was further purified by chromatography on silica gel using methanol in dichloromethane as eluant (2:98). The material isolated was recrystallised from ethyl acetate/hexane to give the title compound as an orange brown solid (3 g).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH3:13])[CH2:12][CH2:11]2)=[CH:6][C:5]=1[CH3:14].CO.[OH-].[Na+].Cl>O>[CH3:14][C:5]1[CH:6]=[C:7]([C:10]2([CH3:13])[CH2:12][CH2:11]2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:15])=[O:2]
Reactant: COC(=O)c1ccc(C2(C)CC2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C2(C)CC2)ccc1C(=O)O
Temperature: 80 °C
Yield: 85.1 %

Procedure:
2-Methyl-4-(1-methyl-cyclopropyl)-benzoic acid methyl ester (2.75 g, 13.46 mmol) was treated with methanol and 5 M aqueous sodium hydroxide solution (20.46 ml, 102.32 mmol). This solution was heated to 80° C. for 4 hours. The reaction mixture was concentrated until methanol was evaporated. A white solid was obtained. The solid was dissolved in 50 ml water under heating then cooled with an ice bath; acidified with 10 ml conc. hydrochloric acid. A white precipitate was formed; filtered; washed with water; dried under high vacuum over night to yield 2-Methyl-4-(1-methyl-cyclopropyl)-benzoic acid (2.18 g, 11.46 mmol) MS (ESI) 189.1 (M−H)−
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.Cl.[N:45]1[CH:50]=[CH:49][C:48]([CH2:51][C:52](O)=[O:53])=[CH:47][CH:46]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:52](=[O:53])[CH2:51][C:48]3[CH:49]=[CH:50][N:45]=[CH:46][CH:47]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1ccncc1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (1.2 g, 7.8 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 4-pyridylacetic acid hydrochloride (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: CH3OH: CH2Cl2 3:97) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-pyridin-4-yl-acetamide (0.4 g, 50%) as white solid: mp 294-296° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=0.87 min. (98%); 1H NMR (DMSO-d6) δ 2.02-2.07 (m, 1H), 2.52-2.96 (m, 2H), 2.84-2.96 (m, 1H), 3.59 (s, 2H), 5.12-5.18 (dd, J=5.2 and 12.7 Hz, 1H), 7.31 (d, J=5.5 Hz, 2H), 7.64-7.70 (m, 1H), 7.79-7.84 (m, 2H), 8.50 (d, J=5.6 Hz, 2H), 8.77 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.90, 37.91, 41.27, 48.83, 121.96, 124.54, 127.17, 131.53, 133.30, 134.71, 138.88, 144.92, 149.37, 166.88, 167.41, 169.33, 169.78, 172.73; Anal. Calcd. for C21H18N4O5: C, 62.07; H, 4.46; N, 13.79. Found: C, 61.77; H, 4.39; N, 13.59.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][OH:28].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:26][CH2:27][OH:28])[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CCO)c2)c2ccc(F)cc21
Yield: 30.4 %

Procedure:
A solution of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 1.20 mg; 0.35 mmol), 2-bromoethanol (157 mg; 1.26 mmol) and K2CO3 (145 mg; 1.05 mmol) in MeCN (4 mL) was heated to 165° C. for 1 h in a microwave reactor. The reaction mixture was filtered and washed with MeCN. The combined filtrate was concentrated and purified by preparative TLC (petroleum ether/EtOAc=1/1) to afford 41 mg (30%) of the title compound as a yellow semi-solid.
Reaction SMILES: C(ON=O)(C)(C)C.[F:8][CH:9]([F:31])[C:10]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12](N)[C:11]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].N#N.[ClH:34]>CC#N.[Cu](Cl)Cl>[F:8][CH:9]([F:31])[C:10]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:12]([Cl:34])[C:11]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: Cl
Reactant: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1N
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Agent: N#N
Solvent: CC#N
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1Cl

Procedure:
To a mechanically stirred mixture of 11.52 g of (0.087 mol) of copper (II) chloride, and 11.18 g (0.108 mol) of t-butylnitrite in 350 ml of CH3CN, was added a solution of 25.00 g (0.070 mol) of product of Example 100 in 25 ml of CH3CN in such a rate that a slow evolution of N2 was observed. After 18 hours the mixture was poured into 3.7% HCl, and extracted with diethyl ether. The ether phase was washed with H2O, and dried (MgSO4). This was concentrated in vacuo to 24.03 g of a yellow oil. The crude product was purified by HPLC in 5% ethyl acetate/cyclohexane affording 13.2 g (50%) of product as a yellow solid; mp 35°-40° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.[CH2:20]([Cl:23])[CH2:21]Cl.C1C=[CH:26][C:27]2N(O)N=[N:30][C:28]=2[CH:29]=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:4]([NH:30][C:28]2[CH:29]=[CH:21][C:20]([Cl:23])=[CH:26][CH:27]=2)=[O:6])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: On1nnc2ccccc21
Reactant: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-chloronicotinic acid (4 g) and 4-chloroanaline (3.2 g) and DIEA (6 ml) in CH2Cl2 (200 ml) was added EDC (6 g) and HOBt (3.3 g). The reaction was stirred at RT overnight and washed with 2 N NaOH (100 ml), H2O (150 ml) and brine (100 ml). The organic layer was dried over Na2SO4 and evaporated to give (2-chloro(3-pyridyl))-N-(4-chlorophenyl)carboxamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:21]([OH:23])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(NC(C)C)(C)C.[C@H:31]1([NH2:41])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CCOC(C)=O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:21](=[O:23])[NH:41][C@H:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@@H]1CCCc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
Anhydrous DMF (20 ml) is added to a 100 ml round bottom flask containing compound 4 (325 mg, 1.014 mmol) under N2. After ten minutes diisopropylamine (0.88 ml, 5.07 mmol) is added to the flask. It is then stirred at room temperature for 1.5 hrs. (R)-1,2,3,4-Tetrahydro-1-napthylamine (149.3 mg, 1.014 mmol) is then added to the flask and stirred for 1 hr. HBTU (423.07 mg, 1.115 mmol) is added to the reaction followed by HOBT (152.1 mg, 1.126 mmol). The reaction mixture is then stirred at room temperature under N2 overnight at which point LCMS shows completion of the reaction. It is then diluted with EtOAc and washed subsequently with 1.0 M citric acid, brine, saturated sodiumbicarbonate, brine, water and brine. The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound is flash column purified using hexane and ethylacetate gradient solvent system to yield 423 mg (93%) of the desired product 6. HPLC shows this compound to be greater than 99% pure.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[N:13]1[CH2:18][CH:17]=[C:16]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1OB(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>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.C(O)C.C1(C)C=CC=CC=1>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[C:7]2[N:13]1[CH2:18][CH:17]=[C:16]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: OB(O)Oc1ccc(Cl)cc1Cl
Reactant: Cc1cc(N2CC=C(C(=O)OC(C)C)CC2)c2cccc(Br)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1cc(N2CC=C(C(=O)OC(C)C)CC2)c2cccc(-c3ccc(Cl)cc3Cl)c2n1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
Under a nitrogen atmosphere, 8-bromo-4-(4-isopropyloxycarbonyl-1,2,3,6-tetrahydropyridin-1-yl)-2-methylquinoline (5.9 g), 2,4-dichlorophenylboric acid (3.2 g) and sodium carbonate (4.8 g) were suspended in a mixed solvent of deaerated water (15 mL), toluene (7.5 mL) and ethanol (7.5 mL), followed by adding thereto tetrakis(triphenylphosphine)palladium (0.88 g), and the resulting mixture was heated under reflux for 5 hours. The reaction mixture was cooled to room temperature to be separated. After the aqueous phase was extracted with ethyl acetate, the combined organic phase was dried over anhydrous sodium sulfate. The desiccating agent was filtered off, after which the filtrate was concentrated under reduced pressure and the resultant residue was crystallized from diisopropyl ether. The crystals were collected by filtration and washed with a small amount of diisopropyl ether to obtain the title compound (5.3 g).