Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:14]2[S:15][CH:16]([CH3:18])[CH2:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH3:24][O:25][CH2:26]Br.Cl>O1CCCC1.CCCCCC>[C:1]([NH:5][S:6]([C:9]1[C:14]2[S:15][CH:16]([CH3:18])[CH2:17][C:13]=2[CH:12]=[CH:11][C:10]=1[CH2:24][O:25][CH3:26])(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCBr
Reactant: CC1Cc2cccc(S(=O)(=O)NC(C)(C)C)c2S1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCc1ccc2c(c1S(=O)(=O)NC(C)(C)C)SC(C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7.14 g of N-t-butyl-2,3-dihydro-2-methylbenzo[b]thiophene-7-sulfonamide in 175 ml of dry tetrahydrofuran was added 34 ml of a 1.6M hexane solution of n-butyl lithium at -40° C. to -30° C. under an inert atmosphere. The mixture was allowed to warm and was stirred at room temperature for 30 minutes. It was recooled to -30° C. and was contacted with 2.2 ml of bromomethyl methyl ether. The mixture was allowed to come to room temperature overnight and was acidified with 10 ml of 6N hydrochloric acid. The organic layer was separated, was dried over magnesium sulfate, and was concentrated to give 7.4 g of the title compound as a brown oil.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH2:11]O)[CH:3]=1.C([O-])(O)=O.[Na+].O=S(Cl)[Cl:20]>>[Cl:20][CH2:11][C:4]1[CH:3]=[C:2]([F:1])[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(F)c2c(c1)OCO2
Agent: O=C([O-])O
Agent: [Na+]
Product: Fc1cc(CCl)cc2c1OCO2
Temperature: 25 °C
Yield: 92 %

Procedure:
To SOCl2 (20 mL) was added (7-fluoro-benzo[1,3]dioxol-5-yl)-methanol (0.80 g, 4.7 mmol) in portions at 0° C. The mixture was warmed to room temperature over 1 h and then was heated at reflux for 1 h. The excess SOCl2 was evaporated under reduced pressure to give the crude product, which was basified with saturated aqueous NaHCO3 to pH ˜7. The aqueous phase was extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to give 6-chloromethyl-4-fluoro-benzo[1,3]dioxole (0.80 g, 92%), which was directly used in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Br[CH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])O.[Na+]>ClCCl>[NH2:1][C:2]1[CH:3]=[C:4]([S:8][CH2:17][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(S)c1
Reactant: COC(=O)c1sccc1CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1sccc1CSc1cccc(N)c1
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of 3-aminothiophenol (2.3 g, 18.7 mmol) and triethylamine (3.12 ml, 22.4 mmol) in dichloromethane (30 ml) was slowly added methyl 3-bromomethylthiophene-2-carboxylate (6.24 g, 22.4 mmol) under ice-cooling, followed by stirring for 30 minutes. After the reaction was completed, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (hexane/ethyl acetate=7/1) to give oily methyl 3-(3-aminophenylthiomethyl)thiophene-2-carboxylate (4.82 g, 92%).
Reaction SMILES: C[Al](C)C.[Cl-].[NH4+:6].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23]CC)=O)=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH2:6])=[O:23])=[CH:19][CH:20]=2)=[CH:11][C:10]=1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OC)c(-c3cccc([N+](=O)[O-])c3)c2)cc1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(C(N)=O)cc2)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A solution of trimethylaluminium in toluene (10 mL of 2.0 M) is added over 30 minutes to a stirred suspension of ammonium choride (1.07 g 20 mmol) in toluene (20 mL) at 5° C. under an argon atmosphere. The mixture is stirred at 20° C. for 2 h, treated with a solution of 4′-methoxy-3′-(3-nitrophenyl)-[1,1′-biphenyl]-4-carboxylic acid, ethyl ester (1.65 g, 4.3 mmol) in toluene (40 mL) and stirred at 60° C. for 18 h. The cooled mixture is washed with hydrochloric acid (50 mL of 0.5 M) followed by saturated aqueous sodium chloride (50 mL), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by crystallisation from ethyl acetate-t-butylethyl ether to give 4′-methoxy-3′-(3-nitrophenyl)-[1,1′-biphenyl]-4-carboxamide as a colourless crystalline solid, m.p. 201-205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1>O1CCCC1>[Cl:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])=[N:13]2)=[CH:18][CH:17]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1ccccc1Cl
Solvent: C1CCOC1
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccccc1Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
N,N'-Carbonyldiimidazole (12.9 g) is added to a solution of 2-chlorobenzoic acid (12.5 g) in anhydrous tetrahydrofuran (250 cc). The mixture is stirred for 2 hours at a temperature in the region of 20° C., until the evolution of gas has ceased. 2-Amino-7-chloro-1,8-naphthyridine (8.9 g) is then added and the mixture is heated under reflux for 22 hours. The reaction mixture is poured into distilled water (2000 cc), and the precipitate formed is separated by filtration, washed with water and dried in the air. On recrystallization from ethanol (180 cc) of the product thereby obtained, N-(7-chloro-1,8-naphthyridin-2-yl)-2-chlorobenzamide (6.9 g), m.p. 180° C., is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)(=O)C>C(O)C.[Pt]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]2[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(O)CC2)CC1
Reaction time: 6 h
Yield: 13.7 %

Procedure:
1-tert-Butoxycarbonyl-4-piperidone (3 g, 0.0151 mol, 1 eq) and 4-hydroxypiperidine (1.56 g, 0.0154 mol, 1 eq) were stirred at room temperature in ethanol (10 ml) and acetic acid (1 ml) for 30 minutes. To the solution was added 0.4 g of 5% platinum on carbon type 117 Johnson Matthey catalyst. The reaction was then hydrogenated under a pressure of 3 bar at room temperature for 6 hours. The reaction was filtered through CELITE™ and washed with ethanol (40 ml). The 4-(hydroxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester (13.7% purity by HPLC area %) was not isolated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([F:16])[CH:11]=[C:12]([F:15])[CH:13]=2)[C:8]([S:17]([CH2:20][C:21]([OH:23])=O)(=[O:19])=[O:18])=[CH:7]1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.ClC(Cl)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([F:16])[CH:11]=[C:12]([F:15])[CH:13]=2)[C:8]([S:17]([CH2:20][C:21]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[O:23])(=[O:18])=[O:19])=[CH:7]1
Reactant: O=C(O)CS(=O)(=O)c1cn(Cc2cccc(Br)c2)c2cc(F)cc(F)c12
Reactant: Nc1ccccn1
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CS(=O)(=O)c1cn(Cc2cccc(Br)c2)c2cc(F)cc(F)c12)Nc1ccccn1

Procedure:
2-((1-(3-bromobenzyl)-4,6-difluoro-1H-indol-3-yl)sulfonyl)acetic acid (30 mg, 0.68 mmol) from Step D, 2-amino-pyridine (13 mg, 0.135 mmol), PyClu (45 mg, 0.135 mmol), and DIEA (29 μL, 0.169 mmol) were added to dichloroethane (3 mL) and microwave irradiated at 110° C. for 30 minutes. The solvent was removed in vacuo and the remaining residue was purified on a Gilson reverse phase HPLC system with a Phenomenex, Luna 50×21.2 mm, 5 uM C18 column (5%-95% water:acetonitrile over 6 min) to yield the desired product. LCMS>99% 215 nm, RT=0.78 min, m/z=520 ([79Br]m+1), 522 ([81Br]m+1). 1H NMR (400 MHz, DMSOD6) 10.89 (s, 1H), 8.47 (s, 1H), 8.41 (d, J=4.0 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.86 (t, J=8.4 Hz, 1H), 7.66 (s, 1H) 7.59 (d, J=8.4 Hz, 2H), 7.38-7.34 (m, 2H), 5.61 (s, 2H), 4.64 (s, 2H), 2.16 (s, 3H). HRMS found 520.0142; calculated for C22H17N3O3SBrF2, 520.0142.
Reaction SMILES: [C:1]1([C@@H:7]([CH2:9]O)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](=[S:13])=[S:12]>[OH-].[K+].O>[C:1]1([C@H:7]2[CH2:9][S:13][C:11](=[S:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C=S
Reactant: N[C@H](CO)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: S=C1N[C@@H](c2ccccc2)CS1
Temperature: 110 °C
Yield: 8.7 %

Procedure:
To a solution of (S)-(+)-2-Phenylglycinol(1.40 g, 10 mmol) in 1N KOH/H2O (10 ml) at room temperature, was added carbon disulfide (3 ml, 50 mmol). The resulting solution was heated by a pre-heated oil-bath (110° C.) to reflux for 20 h after which the reaction mixture was cooled to room temperature and extracted with CH2Cl2 (3×30 ml), dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by column chromatography over silica gel with 1:1 hexane/CH2Cl2 followed by CH2Cl2 as the eluting system (Rf=0.09, CH2Cl2:hexane=7:3) to obtain 4(S)-phenyl-thiazolidine-2-thione (170 mg, 9%).
Reaction SMILES: [C:1]([S:5](/[N:7]=[C:8](/[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)\[CH2:9][CH2:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:26][Mg]Br.C(OCC)C>C(Cl)Cl>[C:1]([S:5]([NH:7][C@@:8]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)([CH3:26])[CH2:9][CH2:10][C:11]([CH3:16])([CH3:17])[C:12]([O:14][CH3:15])=[O:13])=[O:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(C)(C)CC/C(=N\S(=O)C(C)(C)C)c1cc(F)cc(F)c1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C(C)(C)CC[C@](C)(NS(=O)C(C)(C)C)c1cc(F)cc(F)c1
Reaction time: 0.25 h

Procedure:
To a solution of methyl (5E)-5-[(tert-butylsulfinyl)imino]-5-(3,5-difluorophenyl)-2,2-dimethylpentanoate (342 mg, 0.920 mmol) in CH2Cl2 (6 mL) at 0° C., was added dropwise over five minutes methyl magnesium bromide as a 3M solution in diethyl ether (0.61 mL, 1.83 mmol). After 15 minutes the reaction was determined to be complete by LCMS analysis. The reaction was quenched by the dropwise addition of 1M HCl (5 mL), followed by 5 mL of water. The aqueous layer was extracted once with CH2Cl2 (10 mL) and the organics were combined and washed once with brine (15 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of EtOAc:Hexanes—10:90 to 55:45, to give the title compound. MS: m/z=390 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH3:9])[CH:3]=1)[CH2:8][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(Br)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: Cc1cc(Br)cc(CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
5-Bromo-m-xylene (10.0 g; 54.0 mmol), N-bromosuccinimide (9.63 g; 54.0 mmol), and benzoyl peroxide (150 mg) were added to benzene (100 ml), and the mixture was heated under reflux for 2.5 hours. The resultant mixture was left to cool to room temperature, and insoluble matter was filtered off, followed by washing with benzene. The filtrate was evaporated under reduced pressure, and the residue was taken up in n-hexane. The mixture was left to stand for 30 minutes, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:0→20:1), to thereby yield 9.44 g of the target compound (yield: 66.3%).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[F:5][C:6]([F:17])([F:16])[C:7]1[CH:8]=[C:9]([C:13](=O)[CH3:14])[CH:10]=[CH:11][CH:12]=1>C(O)C.N1C=CC=CC=1>[CH3:3][O:2][N:4]=[C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:6]([F:5])([F:16])[F:17])[CH:8]=1)[CH3:14]
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(C)c1cccc(C(F)(F)F)c1
Yield: 93 %

Procedure:
Methoxylamine hydrochloride (2.33 g) is added to a solution of 3′-(trifluoromethy)-acetophenone (1.5 g) in ethanol (20 mL) and pyridine (2 mL). The solution is heated at reflux for 45 minutes. The reaction mixture is then cooled, concentrated under reduced pressure and partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the desired product as a colorless oil (1.61 g).
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=[CH:4]1)=O.[F:13][C:14]1[CH:22]=[CH:21][C:20]2[NH:19][C:18]3[C:23](=[O:37])[N:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:25]=[C:26]([CH2:27][C:28]([OH:30])=O)[C:17]=3[C:16]=2[CH:15]=1.CNC.O>O1CCCC1>[F:13][C:14]1[CH:22]=[CH:21][C:20]2[NH:19][C:18]3[C:23](=[O:37])[N:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:25]=[C:26]([CH2:27][C:28]([N:3]([CH3:4])[CH3:1])=[O:30])[C:17]=3[C:16]=2[CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1nn(-c2ccccc2)c(=O)c2[nH]c3ccc(F)cc3c12
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)Cc1nn(-c2ccccc2)c(=O)c2[nH]c3ccc(F)cc3c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
A suspension of 1.7 g (10.5 mmol) of 1,1′-carbonylbis-1H-imidazole and of 3 g (8.9 mmol) of 8-fluoro-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid in 300 ml of tetrahydrofuran is stirred at 40° C. for 3 h. The mixture is cooled to room temperature, 10 ml of liquefied dimethylamine are added and the mixture is stirred for 2 h. After standing overnight, 300 ml of water are added and the precipitate is collected by filtration and recrystallized from dimethylformamide. 0.8 g (2.2 mmol) of solid is obtained.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39](=[O:47])[C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[N:42][CH:41]=1>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([C:39]([C:40]2[CH:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=2)=[O:47])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Reactant: CON(C)C(=O)c1ccc(C)nc1
Product: Cc1ccc(C(=O)c2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(N3C[C@@H](C)O[C@@H](C)C3)c(Cl)c2F)cn1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42) and N-methoxy-6,N-dimethyl-nicotinamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([O:23][CH3:24])[CH:5]=1.[CH3:26][C:27]1[N:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1.CCOC(C)=O>CN1C(=O)CCC1>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:33][C:30]2[CH:29]=[N:28][C:27]([CH3:26])=[CH:32][N:31]=2)=[O:13])=[C:6]([O:23][CH3:24])[CH:5]=1
Reactant: Cc1cnc(N)cn1
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(OC)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(NC(=O)Nc2cnc(C)cn2)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 3-methoxy-4-(4-nitro-phenoxycarbonylamino)-benzoic acid methyl ester (11.7 g, 33.8 mmol) in 34 mL NMP at room temperature under nitrogen was added 5-methyl-2-aminopyrazine (3.69 g, 33.8 mmol) and the reaction was immersed in an 85° C. oil bath. After 6 hours the reaction was allowed to cool to room temperature and a precipitate formed. EtOAc (200 mL) was added and the precipitate was isolated by filtration (4.7 g, 44%). 1H-NMR (400 MHz, d6-DMSO) 6 8.79 (br s, 1H), 8.36 (d, 1H), 8.23 (s, 1H), 7.60 (d, 1H), 7.52 (s, 1H), 3.98 (s, 3H), 3.81 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][CH:8]=[CH:9][C:2]=12.[Br:10]Br>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Br:10][C:9]1[C:2]2[C:3](=[N:4][CH:5]=[CH:6][N:1]=2)[NH:7][CH:8]=1
Reactant: BrBr
Reactant: c1cnc2[nH]ccc2n1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c[nH]c2nccnc12
Reaction time: 1.5 h

Procedure:
7-Bromo-5H-pyrrolo[2,3-b]pyrazine (4) is prepared by dissolving 5H-pyrrolo[2,3-b]pyrazine (3) in chloroform and slowly adding Br2 in carbon tetrachloride at 0° C. After stirring for 1-2 hours, the reaction may be quenched in aqueous hydrochloric acid. Isolation by conventional means (e.g. extraction and silica gel chromatography) provides compound 4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)[CH3:2].Cl.[CH2:14]([O:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH2:14]([O:21][NH:22][C:6]1[N:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccnc1NOCc1ccccc1
Yield: 52.3 %

Procedure:
2-Chloro-nicotinic acid ethyl ester (4.55 g, 24.6 mmol), O-benzylhydroxyamine hydrochloride (7.85 g, 49.2 mmol) and N,N-diisopropylethylamine (6.36 g, 49.2 mmol) in 10 mL 1,4-dioxane were reacted in a sealed tube at 120° C. for 48 hours. The reaction mixture was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The aqueous layer was re-extracted with ethyl acetate (2×50 mL). The organic layers were combined and dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane and ethyl acetate (9:1) to provide the title compound (3.5 g, 53%). MS (DCI) m/z 273 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3].[Br:12]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.O>C1C=CC=CC=1>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:12])=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N=[N+]=[N-])c(Cl)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: c1ccccc1
Product: [N-]=[N+]=Nc1ccc(CBr)cc1Cl
Yield: 57.6 %

Procedure:
4-Azido-3-chlorotoluene (17.14 g, 0.1 mol) was dissolved in dry benzene (80 ml) and thereto were added N-bromosuccinimide (19.6 g, 0.11 mol) and AIBN (1.64 g, 0.01 mol). The resulting mixture was refluxed in the shade in a nitrogen stream for 10 hr. Water (100 ml) was added and the mixture was filtrated. The aqueous layer of the filtrate was taken and extracted with ether. The organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained brown oil was purified by silica gel column chromatography (eluent; hexane) to give the title compound (14.2 g, yield 58%). m.p.: 75-77° C.
Reaction SMILES: FC(F)(F)C([O:5][C:6](=[O:11])[C:7](F)(F)F)=O.[N+:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=C2)([O-:16])=[O:15].O>CN(C)C=O>[N+:14]([C:17]1[CH:25]=[C:24]2[C:23](=[CH:19][CH:18]=1)[NH:22][CH:21]=[C:7]2[C:6]([OH:5])=[O:11])([O-:16])=[O:15]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1c[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C

Procedure:
Trifluoroacetic anhydride (21.37 g) was added dropwise to a chilled solution of 5-nitro-1H-indole (15.0 g) in dry dimethylformamide (150 ml) under a dry N2 atmosphere. The solution was allowed to warm to room temperature, and was then heated at reflux for 24 hours. The reaction mixture was cooled and poured into water (500 ml) and the resulting dark brown precipitate was filtered, suspended in water (200 ml) containing sodium hydroxide (50.0 g), and heated at reflux for 3 hours. The dark brown solution was cooled to room temperature, extracted with ether (4×100 ml), acidified to pH2 and the title compound filtered and dried (19 g), m.p. 256°-258° C. δH (360 MHz, DMSO-d6) 7.71 (1H, d, J=7.2 Hz, H-7), 8.9 (1H, dd, J=7.2, 1.0 Hz), 8.27 (1H, s, H-2), 8.89 (1H, d, J= 1.0 Hz, H-4); m/z 206 (M+, 70), 163 (10), 138 (20), 123 (100, 106 (15), 81 (10%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]([Cl:13])=[C:7]2[C:3]=1[CH2:4][N:5]([CH:14]([CH:32]([CH3:34])[CH3:33])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=1)=[O:16])[CH2:6]2.ClC1C(Cl)=C(Cl)C(Cl)=C2C=1[CH2:38][N:39](C(C(C)C)C(O)=O)C2.[OH-].[K+].S(OC(C#N)C1C=CC=C(OC2C=CC=CC=2)C=1)(=O)(=O)C>C(O)C.O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]([Cl:13])=[C:7]2[C:3]=1[CH2:4][N:5]([CH:14]([CH:32]([CH3:34])[CH3:33])[C:15]([O:17][CH:18]([C:38]#[N:39])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=1)=[O:16])[CH2:6]2
Reactant: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)c1)N1Cc2c(Cl)c(Cl)c(Cl)c(Cl)c2C1
Reactant: CC(C)C(C(=O)O)N1Cc2c(Cl)c(Cl)c(Cl)c(Cl)c2C1
Agent: CS(=O)(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)N1Cc2c(Cl)c(Cl)c(Cl)c(Cl)c2C1

Procedure:
The ester, m-phenoxybenzyl 2-(4,5,6,7-tetrachloro-2-isoindolinyl)-3-methylbutanoate is hydrolyzed to 2-(4,5,6,7-tetrachloro-2-isoindolinyl)-3-methylbutanoic acid using KOH in ethanol/water, which is reacted with α-cyano-m-phenoxybenzyl mesylate to yield α-cyano-m-phenoxybenzyl 2-(4,5,6,7-tetrachloro-2-isoindolinyl)-3-methylbutanoate.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:5]1[CH:10]=[C:9]([CH:11]=O)[CH:8]=[CH:7][C:6]=1[N:13]=[C:14]1[S:18][CH2:17][C:16]2([CH2:22][CH2:21][CH2:20][CH2:19]2)[N:15]1[CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH3:4].[CH3:28][C:29]#[N:30]>>[CH2:3]([C:5]1[CH:10]=[C:9]([CH:11]=[CH:28][C:29]#[N:30])[CH:8]=[CH:7][C:6]=1[N:13]=[C:14]1[S:18][CH2:17][C:16]2([CH2:22][CH2:21][CH2:20][CH2:19]2)[N:15]1[CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH3:4]
Reactant: CC#N
Reactant: CCc1cc(C=O)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Agent: [K+]
Agent: [OH-]
Product: CCc1cc(C=CC#N)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Reaction time: 4 h

Procedure:
To a solution of KOH (0.024 g, 0.36 mmol) in CH3CN (20 ml) at the reflux temp. was added 2-(2-ethyl-4-formylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane (Method D11a; 0.127 g, 0.36 mmol). The reaction mixture was heated at the reflux temp. for 4 h, cooled to room temp., and concentrated under reduced pressure The residue was diluted with water (15 mL) and extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with a saturated NaCl solution and dried (Na2SO4). The resulting material was purified by preparative TLC (30% EtOAc/hex) to give 2-(2-ethyl-4-(2-cyanovinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane as 1:3 cis/trans mixture of isomers (0.050 g): TLC (30% EtOAc/hex) Rf0.56.