Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.CO.[CH3:12][NH2:13]>C(Cl)Cl.CO>[CH3:12][NH:13][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=1
Reactant: O=Cc1cccc(O)c1
Reactant: CN
Solvent: ClCCl
Solvent: CO
Product: CNCc1cccc(O)c1
Yield: 79 %

Procedure:
10.0 g of 3-hydroxybenzaldehyde and 9.55 g of a 40% methanol solution of methylamine were mixed, and then the solvent was evaporated. The resulting Schiff base was dissolved in 50 ml of ethanol, and with stirring under ice cooling, 10.0 g of sodium borohydride was added The mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate and a saturated aqueous sodium chloride solution. The organic layer was separated, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography [Wakogel C-100, 100 g; eluting solvent: methylene chloride/methanol=10/1→5/1to give 8.88 g (yield 79%) of N-methyl-3-hydroxybenzylamine as pale yellow crystals having a melting point of 138° to 140° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[C:5]([O:12][CH3:13])=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[NH4+].[Cl-]>CO.O.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([O:12][CH3:13])=[C:4]([CH:3]=1)[CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=1
Reactant: COc1c(COc2ccc([N+](=O)[O-])cc2)cc(Br)cc1C(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COc1c(COc2ccc(N)cc2)cc(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 134.5 %

Procedure:
step 3 To a solution of 116 (0.19 g, 0.49 mmol) in MeOH-water (1:1, 20 mL) was added NH4Cl (0.26 g, 4.9 mmol) and iron powder (0.14 g, 2.5 mmol). The resulting mixture was heated at reflux and stirred for 1 h. After cooling to RT, the mixture was filtered through a pad of diatomaceous earth which was washed with MeOH. The filtrate was concentrated under reduced pressure and the resulting aqueous fraction was extracted with EtOAc. The extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane to afford 0.24 g (64%) of 4-(5-bromo-3-tert-butyl-2-methoxybenzyloxy)phenylamine (118) as a yellow oil.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH2:6]([N:13]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[NH:15][C:14]1([CH3:29])Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)(=O)C.O>CN(C)C=O>[C:1]([O:4][CH2:29][C:14]1[N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)C1=C(C(=O)OCC)N(Cc2ccccc2)C(C)(Br)N1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(COC(C)=O)n(Cc2ccccc2)c1C(=O)OCC
Temperature: 40 °C
Yield: 60.4 %

Procedure:
1.11 g of sodium acetate were added to a solution of 2.67 g of diethyl 1-benzyl-2-bromomethylimidazole-4,5-dicarboxylate [prepared as described in Preparation 42(ii)] in 30 ml of dimethylformamide, and the resulting mixture was heated at 40° C. for 5 hours. At the end of this time, the reaction solution was mixed with ethyl acetate and water, and then the ethyl acetate layer was separated. The resulting ethyl acetate extract was washed with an aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.52 g of the title compound as a syrup.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[C:32]([NH:31][C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][CH:28]=1)[N:22]([C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[CH:4][CH:3]=1)[CH:23]=[CH:24]2)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: CC(C)(C)C(=O)Nc1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(NC(=O)C(C)(C)C)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-27, using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate and N-(1H-indol-5-yl)pivalamide; MS: 437.6 (M−56).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:20])[NH:4][CH2:3]1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1([CH3:21])[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:20])[NH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)C(C)(C)CNC3=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CNC(=O)c2cc3ccc(C(=O)O)cc3n21
Temperature: 65 °C
Yield: 87.4 %

Procedure:
To a suspension of ethyl 4,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indole-7-carboxylate (2.7 g, 9.3 mmol) in methanol (30 mL) is added 3N NaOH solution (15.5 mL, 46.5 mmol). The reaction mixture is heated at 65° C. for 16 h. The reaction mixture is diluted with water and acidified to pH 2 using 2N HCl solution at 0° C. The resulting white solid is filtered, rinsed with water and dried to afford the title compound (2.1 g, 88%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([CH2:37][CH2:38][NH:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[CH2:15][CH2:16][CH2:17][C@H:18]([N:22](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:19]([OH:21])=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[NH2:22][C@@H:18]([CH2:17][CH2:16][CH2:15][N:14]([CH2:37][CH2:38][NH:39][C:40]([O:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)=[O:41])[CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:19]([OH:21])=[O:20]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCN(CCNC(=O)OCc1ccccc1)CCNC(=O)OCc1ccccc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCCN(CCNC(=O)OCc1ccccc1)CCNC(=O)OCc1ccccc1)C(=O)O
Yield: 90.1 %

Procedure:
A solution of (2S)-5-[bis(2-{[(benzyloxy)carbonyl]amino}ethyl)amino]-2-{bis[(tert-butoxy)carbonyl]amino}pentanoic acid (1.82 g, 3.14 mmol) in TFA (20 mL) was stirred overnight. The TFA was removed under reduced pressure to give (2S)-2-amino-5-[bis(2-{[(benzyloxy)carbonyl]amino}ethyl)amino]pentanoic acid XXXII as a light brown foam (1.70 g, 2.83 mmol, 90% yield). ESIMS found for C25H34N4O6 m/z 487 (M+H).
Reaction SMILES: [N:1]1[S:2][CH:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH:10]3[NH:14]C(=O)N[C:11]3=[O:16])=[CH:6][C:5]=12.[OH-:17].[Li+]>O>[NH2:14][CH:10]([C:7]1[CH:8]=[CH:9][C:4]2=[CH:3][S:2][N:1]=[C:5]2[CH:6]=1)[C:11]([OH:16])=[O:17]
Reactant: [OH-]
Reactant: O=C1NC(=O)C(c2ccc3csnc3c2)N1
Agent: [Li+]
Solvent: O
Product: NC(C(=O)O)c1ccc2csnc2c1

Procedure:
16.5 g (0.071 mole) of 10d are heated under reflux analogously to Example 3e with 17.0 g (0.71 mole) of lithium hydroxide in 250 ml of water for 20 hours.
Reaction SMILES: [C:1]([CH2:5][N:6]1[C:12](=[O:13])[CH:11]([N:14]([C:24]([O:26]CC)=[O:25])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][S:9][CH2:8][CH2:7]1)([O:3]C)=[O:2].O>CO.[OH-].[Na+]>[C:1]([CH2:5][N:6]1[C:12](=[O:13])[CH:11]([N:14]([C:24]([OH:26])=[O:25])[CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][S:9][CH2:8][CH2:7]1)([OH:3])=[O:2]
Reactant: CCOC(=O)N(CCCc1ccccc1)C1CSCCN(CC(=O)OC)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CN1CCSCC(N(CCCc2ccccc2)C(=O)O)C1=O
Yield: 94.8 %

Procedure:
4-[Carbomethoxymethyl]-6-[carboethoxy-3-phenyl propylamino]-perhydro-1,4-thiazepin-5-one (0.1 g) is dissolved in 1.5 ml of methanol and 0.5 ml of 1M sodium hydroxide. At the end of 4 hours at room temperature, 2 ml of water is added. The resulting solution is loaded onto a column of Dowex-50 resin (on the proton cycle). After thorough washing with water, the column is developed with 5% pyridine. The eluent is lyophilized to yield the product as a white solid (0.085 g). The sample analyzes for C17H23N2O5S.1/2H2O.
Reaction SMILES: [O:1]1[CH2:23][CH:2]1[CH2:3][CH:4]([CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CO>[OH:1][CH:2]([CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[CH2:3][CH:4]([CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6]
Reactant: CC(C)(C)OC(=O)C(Cc1cccc2ccccc12)CC1CO1
Reactant: C1COCCN1
Solvent: CO
Product: CC(C)(C)OC(=O)C(Cc1cccc2ccccc12)CC(O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.6 %

Procedure:
A mixture of 2 g (6.4 mmole) of t-butyl 4,5-epoxy-2-(1-naphthylmethyl)pentanoate (prepared as described in Preparation 11), 0.84 ml of morpholine and 50 ml of methanol was stirred at room temperature for 6 hours and then allowed to stand overnight. The reaction mixture was then concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent: a 10 : 90 by volume mixture of methanol and methylene chloride), to afford 1.96 g (76.6%) of the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:20]Br>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:20][C:19]2[CH:22]=[CH:23][C:24]([F:25])=[C:17]([F:16])[CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: Fc1ccc(CBr)cc1F
Product: N#Cc1ccc(N(Cc2ccc(F)c(F)c2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 3,4-difluorobenzyl bromide
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>C(Cl)(Cl)Cl.O>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:13])[F:14])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)=[O:29]
Reactant: O=C(Cl)CCCCBr
Reactant: Nc1ccnc2cc(C(F)(F)F)ccc12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(CCCCBr)Nc1ccnc2cc(C(F)(F)F)ccc12
Temperature: 20 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
4-Amino-7-trifluoromethylquinoline (120 mg, 0.56 mmol), triethylamine (170 mg, 1.7 mmol) and CHCl3 (4 mL) were charged in a 10 ml round-bottomed flask equipped with a magnetic stirrer. 5-Bromovaleryl chloride (140 mg, 0.7 mmol in CHCl3 (2 mL) were added and the reaction mixture was stirred for 15 h at 20° C. The reaction mixture was poured in 10 mL of H2O and extracted with CH2Cl2 (100 mL). The organic layer was washed with brine (2×10 mL), dried over MgSO4, filtered and evaporated at 30° C. to dryness. The crude compound was purified by column chromatography (SiO2; CH2Cl2:MeOH=99.5:0.5 to 98:2) to give after evaporation 5-bromo-N-(7-(trifluoromethyl)quinolin-4-yl)pentanamide 32 (190 mg, 90% yield) as a beige solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][C:10]=2[OH:12])[CH:5]=[C:4]([S:17]([OH:20])(=[O:19])=[O:18])[CH:3]=1.[CH3:21][N:22](C)C=O>O.[Cu+].[Cu]>[C:21]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][C:10]=2[OH:12])[CH:5]=[C:4]([S:17]([OH:20])(=[O:19])=[O:18])[CH:3]=1)#[N:22]
Reactant: CN(C)C=O
Reactant: O=S(=O)(O)c1cc(O)c2c(Br)cc(S(=O)(=O)O)cc2c1
Agent: [Cu+]
Agent: [Cu]
Solvent: O
Product: N#Cc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(O)c12
Yield: 67 %

Procedure:
1-Bromo-8-hydroxynaphthalene-3,6-disulfonic acid (51% strength, 15.0 g, 0.02 mol, prepared as in Example 31, stage 1) was stirred in N,N-dimethylformamide (100 mls). Copper (I) cyamide (2.0 g, 0.022 mol) was added and the mixture boiled under reflux until HPLC analysis indicated complete reaction. In this example 5 hours was required. If necessary further copper cyamide could be added during the reaction. The reaction mixture was cooled down and a small amount of insoluble material removed by filtration. The solvent was removed from the filtrate under vacuum to leave a brown tar. This was slurried in water and a small amount of solid removed by filtration. The filtrate was concentrated to 100 mls and the product precipitated by the addition of solid sodium chloride. The product was recovered by filtration, washed with brine and dried. The dried product (8.9 g) contained 50% sodium chloride. Yield 67%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][O:6][C:7]1[N:12]=[C:11]([NH2:13])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:9]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:8]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][O:6][C:7]1[N:12]=[C:11]([NH:13][C:33](=[O:35])[CH3:34])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:9]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Product: CC(=O)Nc1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
The title compound was obtained by treating 2-(3,4-difluorobenzyloxy)-4-amino-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (Example 33) with acetic anhydride and catalytic DMAP by the same general procedure described in Example 34. Workup and flash column chromatography on silica gel (eluted with 80/20 hexanes/ethyl acetate) afforded the desired product. HPLC/MS: m/e=536 (M++1); Rt=4.5 min. 1H-NMR 500 MHz (CDCl3): δ 2.56 (s, 3H), 5.45 (s, 2H), 7.03-7.27 (m, 9H), 7.38 (d, J=2 Hz, 1H), 8.05 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[C:11]([N:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:21]2[CH2:22][CH2:23][CH2:24][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19][CH2:20]2)=[S:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCN(C(=S)Nc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-chlorophenyl isothiocyanate (5.0 g, 29.95 mmol), and BOC-homopiperazine (6.0 g, 29.95 mmol) in ethanol (50 mL) was stirred at room temperature for 2 hours. The mixture was evaporated under reduced pressure, the residue was partitioned between ethyl acetate and water and the layers were separated. The organic phase was dried over MgSO4 and evaporated under reduced pressure to give the title compound as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])=[CH:19][CH:18]=1.[Br:33]N1C(=O)CCC1=O>CN(C=O)C>[Br:33][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Solvent: CN(C)C=O
Product: COc1cc(Br)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Yield: 30 %

Procedure:
Following General Procedure I, tert-butyl 1-(4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)ethylcarbamate (1.0 g, 2.2 mmol) was reacted with N-bromosuccinimide (0.45 g, 2.5 mmol) in DMF (10 mL) to afford the desired product (0.35 g, 29%) as a brown solid: ESI MS m/z 529 [C25H25BrN2O4S+H]+.
Reaction SMILES: [F:1][C:2]([F:56])([F:55])[C:3]1[CH:4]=[C:5]([CH:52]=[CH:53][CH:54]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:49]=[CH:50][CH:51]=2)[CH2:34][N:35]2[CH2:41][CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]2)=[O:30])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[N:35]1([CH2:34][C:33]2[CH:32]=[C:31]([CH:51]=[CH:50][CH:49]=2)[C:29]([NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][N:13]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:52]=[CH:53][CH:54]=[C:3]([C:2]([F:55])([F:56])[F:1])[CH:4]=2)=[O:9])=[O:30])[CH2:41][CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CN3CCCNCC3)c2)c1
Temperature: 15 °C
Reaction time: 3 h
Yield: 149.1 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 4-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzyl)-1,4-diazepane-1-carboxylate (100 mg, 0.13 mmol, 1.00 equiv) in dichloromethane (15 mL), and trifluoroacetic acid (147.9 mg, 1.30 mmol, 10.00 equiv). The resulting solution was stirred for 3 h at 15° C. The resulting mixture was concentrated under vacuum to yield 130 mg of crude product as a red solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[NH:8][CH2:7]/[C:6]/2=[CH:16]\[C:17]([OH:19])=O.[NH2:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[NH:8][CH2:7]/[C:6]/2=[CH:16]\[C:17]([NH:20][C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])=[O:19]
Reactant: COC(=O)c1ccccc1N
Reactant: COc1cc2c(cc1OC)/C(=C/C(=O)O)CNC2=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(=O)/C=C1\CNC(=O)c2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
To a stirred solution of (Z)-2-(6,7-dimethoxy-1-oxo-2,3-dihydroisoquinolin-4(1H)-ylidene)acetic acid (789 mg, 3 mmol), methyl 2-aminobenzoate (544 mg, 3.6 mmol), HOBt (587 mg, 3.6 mmol), EDCl (688 mg, 3.6 mmol) and DMAP (439 mg, 3.6 mmol) in dry DMF (30 mL) was added Et3N (2 mL, 15 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature overnight then the reaction was quenched with water and extracted with DCM. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated to give the crude product which was purified by flash chromatography using DCM/MeOH 40:1 (v:v) as eluent to give (Z)-methyl 2-(2-(6,7-dimethoxy-1-oxo-2,3-dihydroisoquinolin-4(1H)-ylidene)acetamido)benzoate (280 mg, 80%) LC-MS (ES-API); rt 8.39 min; m/z calculated for C21H20N2O6 [M+Na]+ 419.1, found 419.1.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:6]=[CH:7][CH:8]=1.NN>[Pd].C(O)C>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([C:23]#[N:24])=[C:10]2[NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=1
Reactant: CSc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: CSc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Reaction time: 4 h
Yield: 98.4 %

Procedure:
A mixture of 4.55 g (13.5 mmol) 4-[(3-methylsulfanylphenyl)amino]-6-nitro-3-quinolinecarbonitrile, 250 ml ethanol, 0.46 g 10% palladium on carbon, and 1.06 ml (33.8 mmol) anhydrous hydrazine was heated to reflux. At 4 hours, added 0.5 equivalents of hydrazine, and at 5 hours, filtered the hot mixture through celite. Stripped the solvent and dried in vacuo, giving 4.068 g brown solid: mass spectrum (electrospray m/e): M+H=307.1.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.O.[NH2:17][NH2:18]>C(O)C>[CH3:13][O:12][C:11]1[C:2]([NH:17][NH2:18])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([O:14][CH3:15])=[CH:6][CH:5]=2
Reactant: COc1ccc2nc(Cl)c(OC)nc2c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc2nc(NN)c(OC)nc2c1
Temperature: 50 °C

Procedure:
A mixture consisting of 5 g. (0.022 mole) of 2-chloro-3,6-dimethoxyquinoxaline and 2.8 g. (0.056 mole) of hydrazine hydrate (2.7 ml.) in 75 ml. of ethanol was heated at 50° C. overnight. Upon completion of this step, a further 1.0 ml. of hydrazine hydrate was added to the mixture and the resulting mixture was heated at 50° C. for a period of six hours. At this point, another 1.0 ml. of hydrazine hydrate was added and the final reaction mixture was heated at 50° C. overnight prior to being cooled to room temperature. The spent mixture was then filtered and the recovered precipitate washed with ethanol to ultimately afford 4.1 g. (85%) of pure 3,6-dimethoxy-2-hydrazinoquinoxaline, m.p. 128°-130° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[N+:12]([CH3:15])([O-:14])=[O:13].C([O-])(=O)C.[NH4+].O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:15][N+:12]([O-:14])=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1F
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C=C[N+](=O)[O-])cc1F

Procedure:
A solution of 3-fluoro-4-methoxybenzaldehyde [5.05 g, Intermediate (1)], nitromethane (5.3 mL) and ammonium acetate (6.3 g) in glacial acetic acid (60 mL) is heated at 110° C. for 16 hours, allowed to cool and poured into water (300 mL). The aqueous solution is extracted twice with EtOAc (200 mL). The combined extracts are washed with sodium bicarbonate solution (10%), with water, dried over sodium sulfate and evaporated affording 2-fluoro-1-methoxy-4-(2-nitro-vinyl)benzene [4.2 g, Intermediate (2)]. MS: 198 (M+H); 1H NMR (CDCl3): δ 7.9 (1H, d, J=10 Hz); 7.5 (1H, d, 10 Hz); 7.3 (2H, m); 6.95-7.15 (1H, m); 4 (3H, s).