Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:10]([C:18](O)=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH2:44][C@@H:45]([C:48]1[CH:49]=[N:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=1)[CH2:46][OH:47].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:47][CH2:46][C@@H:45]([NH:44][C:18]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:11]=1)=[O:19])[C:48]1[CH:49]=[N:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=1
Reactant: COc1ccc([C@H](N)CO)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1ccc([C@@H](CO)NC(=O)c2cc(-c3ccc(C)cc3)cc(S(C)(=O)=O)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-(methylsulfonyl)biphenyl-3-carboxylic acid (35 mg, 0.12 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (46 mg, 0.24 mmol), 1-hydroxybenzotriazole hydrate (18 mg, 0.12 mmol), and CH2Cl2 (3 mL) were added (S)-2-amino-2-(6-methoxypyridin-3-yl)ethanol (30 mg, 0.18 mmol) and N,N-diisopropylethylamine (42 μL, 0.24 mmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-80% CH3CN-water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH:42]1([C:48](Cl)=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>O1CCCC1.CCCCCC>[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][CH2:36][CH:37]([C:48]([CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=[O:49])[C:38]([O:40][CH3:41])=[O:39])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)CCCc1ccccc1OCc1ccccc1
Reactant: O=C(Cl)C1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C(CCc1ccccc1OCc1ccccc1)C(=O)C1CCCCC1
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
To a dry ice-acetone bath cooled solution of lithium diisopropylamide, prepared from diisopropylamine (222 mg) and 1.61M hexane solution of n-butyllithium (1.24 ml) in tetrahydrofuran (5.6 ml), was added methyl 4-(2-benzyloxyphenyl)butyrate (284 mg) and the mixture was stirred for 30 minutes at the same temperature. Cyclohexanecarbonyl chloride (176 mg) was added. After being stirred for 30 minutes the reaction mixture was quenched by 1N hydrochloric acid solution and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with aqueous sodium bicarbonate solution and brine, and dried. The solvent was evaporated in vacuo and the residue was purified by preparative thin layer chromatography [silica gel, ether - n-hexane (1:4)] to afford methyl 4-(2-benzyloxyphenyl)-2-(cyclohexylcarbonyl)butyrate (190 mg).
Reaction SMILES: C(OC1C=CC(C[O:11][NH:12][C:13]([CH:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]3[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:16]2[C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=2[Cl:44])=[O:14])=CC=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:44][C:38]1[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=1[CH:16]1[CH:15]([C:13]([NH:12][OH:11])=[O:14])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[N:17]1[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[NH:32][S:33]([CH3:36])(=[O:34])=[O:35]
Reactant: CC(C)(C)Oc1ccc(CONC(=O)C2c3ccccc3C(=O)N(C3CCCCC3NS(C)(=O)=O)C2c2ccc(Cl)cc2Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NO)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a solution of 644 mg of (3RS,4RS)—N-[(4-tert-butoxybenzyl)oxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 8.4 ml of dichloromethane was added 0.94 ml of trifluoroacetic acid under ice-cooling, followed by stirring at room temperature for 1 hour. The solution was concentrated under reduced pressure and then recrystallized from ethyl acetate to obtain 363 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-hydroxy-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>C(#N)C>[Cl:12][C:4]1[CH:3]=[C:2]([NH:1][C:20]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:21])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC(=O)c1ccc(N)cc1Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 106 %

Procedure:
Methyl 4-amino-2-chlorobenzoate (407 mg, 2.2 mmol) was dissolved in acetonitrile. To the reaction mixture was added pyridine (0.3 ml, 2.4 mmol) and phenyl chloroformate (0.21 ml, 2.6 mmol) and the mixture was stirred at room temperature for 1 h under N2. TLC showed complete consumption of starting material. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to give pure compound methyl 2-chloro-4-(phenoxycarbonylamino)benzoate (713 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.O>C(Cl)Cl>[N+:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][NH:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2[N+](=O)[O-])CC1
Reaction time: 16 h
Yield: 117.3 %

Procedure:
A solution of 1-(bromomethyl)-2-nitrobenzene (13.2 g, 61 mmol) in DCM (60 ml) was added dropwise to a solution of tert-butyl 4-aminopiperidine-1-carboxylate (14.6 g, 73 mmol) and TEA (13.4 ml, 91 mmol) in DCM (100 ml), followed by stirring the reaction mixture for a further 16 hours. The reaction mixture was then poured into water, and the layers separated. The aqueous layer was then extracted with DCM (2×). The organic layers were combined, washed with water (2×), brine, dried (MgSO4) and evaporated to dryness. The residue was taken up in EtOAc and filtered through a large plug of silica. The silica was washed with EtOAc until TLC analysis show no further material was eluting. Evaporation gave the product as an orange oil (24 g, 74%). LC/MS (10% to 99%): M/Z (M+H)+ (obs)=336; tR=2.23.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]CC3C=CC=CC=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3c(ccn3Cc3ccccc3)c2)cc1
Agent: [Pd]
Product: Oc1ccc2c(ccn2Cc2ccccc2)c1
Reaction time: 72 h
Yield: 63.2 %

Procedure:
A slurry of 0.98 g (3.12 mmol) 1-benzyl-5-benzyloxy-1H-indole, 0.20 g 20% Palladium on carbon, and 1.51 g (24 mmol) NH4CHO was heated to reflux with stirring for 3 days. The reaction was allowed to cool and an additional 0.20 g 20% Palladium on carbon and 1.33 g NH4CHO was added. The reaction was refluxed for an additional 24 hours upon which time the reaction was complete by TLC. The reaction was filtered through paper and concentrated. The residue was chromatographed on silica using 25–40% EtOAc-hexane to afford 0.44 g 1-benzyl-5-hydroxy-1H-indole as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:19][C:14]2[CH2:15][NH:16][CH2:17][CH2:18][C:13]=2[CH:12]=1)=[O:10].CCN(CC)CC.[N+](C1C=CC([O:36][C:37](=O)[NH:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=CC=1)([O-])=O>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[S:19][C:14]2[CH2:15][N:16]([C:37]([NH:38][C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)=[O:36])[CH2:17][CH2:18][C:13]=2[CH:12]=1)=[O:10]
Reactant: O=C(Nc1cccnc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccc1NC(=O)c1cc2c(s1)CNCC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1cc2c(s1)CN(C(=O)Nc1cccnc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-aminophenyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxamide (1.0 eq) in DMF was added Et3N (3.0 eq.) followed by pyridin-3-yl-carbamic acid 4-nitro-phenyl ester (1.0 eq) and reaction was stirred at room temperature overnight. Reaction mixture was then quenched with water and extracted with dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the title compound.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([N:16]([C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:35]=1[OH:46])[C:17]([N:19]([CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18])=[O:15])[CH3:13])=O)C1C=CC=CC=1.Cl>[C].[Pd].CO>[NH2:11][C@H:12]([C:14]([N:16]([C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:35]=1[OH:46])[C:17]([N:19]([CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:18])=[O:15])[CH3:13]
Reactant: COc1cc(N(C(=O)[C@H](C)NC(=O)OCc2ccccc2)C(=O)N(CCC2CCCCC2)c2ccccc2)c(O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cc(N(C(=O)[C@H](C)N)C(=O)N(CCC2CCCCC2)c2ccccc2)c(O)c(C(C)(C)C)c1
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To 75 ml of a methanol solution containing 2.5 g of Compound B obtained in Example 178 (1) were added 1.5 ml of conc. hydrochloric acid and 1.0 g of 10% palladium-carbon (Pd-C). The mixture was subjected to catalytic reduction at normal temperature under normal pressure for 2 hours. After removing the catalyst by filtration, the filtrate was evaporated to dryness under reduced pressure, and the residue was crystallized by adding hexane to give 1.80 g of 2-[1-L-alanyl-3-(2-cyclohexylethyl)-3-phenylureido]-4-methoxy-6-tert-butylphenol (yield: 85%, state: powder, IR: 3500 (br), 1730, 1705 cm-1).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH2:18])=[O:17])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:3])=[O:2].[CH3:19][CH2:20][O:21][C:22]([CH:24]1[C:28](=O)[CH2:27][CH2:26][CH2:25]1)=[O:23]>>[CH2:20]([O:21][C:22]([C:24]1[CH2:28][CH2:27][CH2:26][C:25]=1[NH:18][C:16](=[O:17])[NH:15][C:12]1[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:23])[CH3:19]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CCOC(=O)c1cc(NC(N)=O)ccc1[N+](=O)[O-]
Product: CCOC(=O)C1=C(NC(=O)Nc2ccc([N+](=O)[O-])c(C(=O)OCC)c2)CCC1

Procedure:
using ethyl 2-nitro-5-ureidobenzoate and ethyl cyclopentanone-2-carboxylate there is obtained ethyl 5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-2-nitrobenzoate, m.p. 152°-155° C.,
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8](C1C=CC=CN=1)[CH3:9].C(C1C=CC=CN=1)CC.CC1C(C)=NC=CC=1.C(C1C(C)=NC=CC=1)C.CC1C=CN=C(C)C=1C.C1(C2C=CC=CN=2)C=CC=CC=1.C(C1C=CC=CN=1)C1C=CC=CC=1.[Cl-].N1C=CC=CC=1>N1C=CC=CC=1>[NH:3]1[C:2]2[C:1](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=[CH:8]1
Reactant: Cc1ccccn1
Reactant: CCc1ccccn1
Agent: CCCc1ccccn1
Agent: CCc1cccnc1C
Agent: Cc1cccnc1C
Solvent: c1ccncc1
Product: c1ccc2[nH]ccc2c1

Procedure:
pyridines, such as pyridine, methylpyridine, ethylpyridine, propylpyridine, dimethylpyridine, ethylmethylpyridine, trimethylpyridine, phenylpyridine, benzylpyridine and pyridine chloride;
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Na+]>C1COCC1>[CH:5]([C:1]1[CH:5]=[CH:4][CH2:3][CH:2]=1)=[CH:1][CH2:2][CH3:3]
Reactant: c1cc[cH-]c1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC=CC1=CCC=C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
To a solution of 25.0 g (110 mmol) 3-buten-1-tosylate prepared according to step (a) above in 200 ml THF cooled to 0° C. was added 68.9 ml of 2.0M (138 mmol) sodium cyclopentadienylide in THF. The reaction mixture was allowed to warm to room temperature and was stirred for 16 h. 100 ml concentrated aqueous saline solution was added and the product extracted with ether (3×75 ml). The combined organic fractions were dried over magnesium sulphate for 2 hours, filtered and the solvents removed under reduced pressure using a rotary evaporator to yield a dark brown oil. The crude product was distilled under reduced pressure (b.p. 50°-51° C. @ 15 mm Hg) to give 5.71 g of a colourless oil (47.6 mmol, 43.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]2)=[O:22])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([N:13]1[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]1)=[O:12])=[CH:7]2.[H-].[Na+].Br[CH:35]([CH3:37])[CH3:36]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]2)=[O:22])[CH:5]=[C:6]2[C:10]=1[N:9]([CH:35]([CH3:37])[CH3:36])[C:8]([C:11]([N:13]1[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]1)=[O:12])=[CH:7]2
Reactant: CC(C)Br
Reactant: CC(C)N1CCN(C(=O)c2cc(Cl)c3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2cc(Cl)c3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3C(C)C)CC1
Yield: 24 %

Procedure:
The title compound was synthesized in analogy to example 51, from [7-chloro-2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 232), sodium hydride and 2-bromopropane in N,N-dimethylformamide, to give the desired product as a colorless foam (24%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].C(Cl)Cl.[CH3:15][CH2:16][O:17]C(C)=O>>[O:11]1[CH2:15][CH2:16][O:17][CH:10]1[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cn1
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C2OCCO2)nc1

Procedure:
2-(1,3-Dioxolanyl)-5-nitropyridine was prepared from 5-nitropyridine-2-carboxaldehyde by the procedure employed for the synthesis of Example III. Yield: 2.0 g (84%); mp 104°-105° C.; TLC Rf 0.73 (CH2Cl2 /EtOAc, 1:1, v/v); 1H NMR (90 MHz, CDCl3) δ 4.10 (s, 4H, CH2CH2), 5.92 (s, 1H, 2-CH), 7.72 (d, 1H, 3-H, J3,4 =8 Hz), 8.50 (dd, 1H, 4-H, J3,4 =8 Hz, J4,6 =2 Hz), 9.42 (d, 1H, 6-H, J4,6 =2 Hz). Anal. (C8 H8N2O4) C, H, N.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].Br[CH2:14][CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[OH:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: OCCCBr
Reactant: COC(=O)c1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCO)c(C)c1
Temperature: 60 °C
Yield: 45.8 %

Procedure:
To a solution of methyl 4-hydroxy-3-methyl-benzoate (3.03 g, 18.2 mmol) in DMF (9 mL) was added 3-bromopropan-1-ol (3.80 g, 2.4 mL, 27.4 mmol) and cesium carbonate (17.8 g, 54.7 mmol) and the reaction mixture was heated at 60° C. for 16 hours. The reaction mixture was cooled to room temperature and then partitioned between water (250 mL) and ethyl acetate (2×100 ml). The organic layers were combined, washed with brine solution (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to yield a crude oil that was purified by silica gel column chromatography eluting with EtOAc/hexanes (10-100%) to give methyl 4-(3-hydroxypropoxy)-3-methyl-benzoate (1.87 g, 46%) as a white solid. ESI-MS m/z calc. 224.0. Found 225.0 (M+1)+; Retention time: 1.27 minutes (3 min run); 1H NMR (400 MHz, CDCl3) δ 7.94-7.77 (m, 2H), 6.85 (d, J=8.5 Hz, 1H), 4.18 (t, J=5.9 Hz, 2H), 3.98-3.82 (m, 5H), 2.24 (s, 3H), 2.10 (p, J=5.9 Hz, 2H).
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:30]2[C:35](=O)[CH2:34][CH:33]([C:37]3[CH:42]=[C:41]([O:43][CH3:44])[C:40]([O:45][CH3:46])=[C:39]([O:47][CH3:48])[CH:38]=3)[CH2:32][C:31]=2[O:49]CC)[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[O:18])=[CH:11][CH:10]=1)#[N:8].O>C(#N)C>[O:18]=[C:17]1[NH:16][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([C:7]#[N:8])=[CH:14][CH:13]=2)[C:30]2[C:31](=[O:49])[CH2:32][CH:33]([C:37]3[CH:38]=[C:39]([O:47][CH3:48])[C:40]([O:45][CH3:46])=[C:41]([O:43][CH3:44])[CH:42]=3)[CH2:34][C:35]=2[N:19]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=1
Reactant: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC(c2cc(OC)c(OC)c(OC)c2)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C2CC(=O)C3=C(C2)N(c2cccc(C(F)(F)F)c2)C(=O)NC3c2ccc(C#N)cc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium tert-butoxide (126 mg, 1.32 mmol) is added to a solution of 1-((4-cyanophenyl)-(2-ethoxy-6-oxo-4-(3,4,5-trimethoxyphenyl)cyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 19, 684 mg, 1.10 mmol) in acetonitrile (8 mL) and the mixture is stirred at room temperature for 2 h. Water is added and the mixture is extracted with ethyl acetate. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 190 mg; ESI mass spectrum [M+H]+=578, Retention time HPLC: 1.13 min, 1.14 min (1:1 mixture of diastereomers) (V011_S01).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1C(OC(C)(C)C)=O)=[N+:2]=[N-:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]([CH2:4][C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][NH:6]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1CN=[N+]=[N-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NC[C@@H]1Cc2ccccc2CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of (S)-tert-butyl 3-(azidomethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Page, D. et al., J. Med. Chem., 44:2387-2390 (2001)) (509 mg, 1.77 mmol) in CH2Cl2 (8.0 mL) was added TFA (2.7 mL, 35.3 mmol). The resulting reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with sat. aq. NaHCO3 solution (2×). The aqueous layer was extracted with CH2Cl2 (2×), and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to provide the title compound (302 mg, 91%) as a clear, colorless oil. 1H NMR (CDCl3) δ 7.17-7.13 (m, 2H), 7.12-7.08 (m, 1H), 7.07-7.02 (m, 1H), 4.14-4.05 (m, 2H), 3.55 (dd, J=12.2, 4.4 Hz, 1H), 3.45-3.39 (m, 1H), 3.16-3.09 (m, 1H), 2.82-2.75 (m, 1H), 2.70-2.60 (m, 1H), 2.02 (br s, 1H); MS(ESI+) m/z 189.1 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][NH2:3].O=[C:5]([CH2:12][CH3:13])[CH2:6][C:7](OCC)=[O:8]>CO>[CH2:12]([C:5]1[CH:6]=[C:7]([OH:8])[N:2]([CH3:1])[N:3]=1)[CH3:13]
Reactant: CCOC(=O)CC(=O)CC
Reactant: CNN
Solvent: CO
Product: CCc1cc(O)n(C)n1
Temperature: 45 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
Methylhydrazine (31.6 g, 0.687 mol) in methanol (100 mL) was added dropwise to a solution of ethyl 3-oxopentanoate (100 g, 0.694 mol) in methanol (280 mL) over a period of 45 min, during which time the temperature increased to 45° C. The reaction mixture was then allowed to stir at room temperature overnight and then evaporated, affording 84.5 g (97%) of the crude title product.
Reaction SMILES: [CH:1]1[C:14]2=[C:15]3[C:16]4[C:11]([CH:12]=[CH:13]2)=[C:10]2[CH:17]=[CH:18][CH:19]=[CH:20][C:9]2=[CH:8][C:7]=4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.C[O:22][C:23]1[N:31]=[C:30]([NH2:32])[N:29]=[C:25]2[N:26]=[CH:27][NH:28][C:24]=12.C(O)CO>CO>[CH:1]1[C:14]2=[C:15]3[C:16]4[C:11]([CH:12]=[CH:13]2)=[C:10]2[CH:17]=[CH:18][CH:19]=[CH:20][C:9]2=[C:8]([N:28]2[C:24]5[C:23](=[O:22])[NH:31][C:30]([NH2:32])=[N:29][C:25]=5[N:26]=[CH:27]2)[C:7]=4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: COc1nc(N)nc2nc[nH]c12
Reactant: c1ccc2c(c1)cc1ccc3cccc4ccc2c1c34
Agent: *CC(*)C
Solvent: CO
Solvent: OCCO
Product: Nc1nc2ncn(-c3c4ccccc4c4ccc5cccc6ccc3c4c65)c2c(=O)[nH]1
Reaction time: 0.75 h

Procedure:
While the blocking reaction is progressing, NAb (selective for BP-6-N7Gua) and BP-6-N7Gua or benzo[a]pyrene (BP) or methylguanine (Me-N7Gua) or other structures related to BP-6-N7Gua are combined in separate Eppendorf tubes (1.5 mL polypropylene tubes). MAb is diluted 1:500 to 1:5000 in TBS buffer (0.05M Tris, 0.20M NaCl, pH 7.5) containing 10% (v/v) ethylene glycol as a protein stabilizer, then 500 uL is dispensed to each Eppendorf tube seated in a thermal mixing block set at 45 degrees C. These samples are heated for 10 minutes with vortexing. BP-6-N7Gua or BP or Me-N7Gua or other structures related to BP-6-N7Gua are diluted in methanol (MtOH), then added with vortexing in 10 uL volumes to duplicate samples of heated MAb solution. MtOH, alone, is added as a control to selected Eppendorfs. The reaction mixtures are heated with vortexing for an additional 20 minutes, then the reaction mixtures are cooled by addition of 100 uL of TBS buffer with 10% ethylene glycol. The reaction mixtures are incubated an additional 45 minutes at 37 degrees C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1OCCOCCF)[N:12]=[CH:11][N:10]=[C:9]2[NH:23][C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[CH:26][C:25]=1[F:32])=[O:4].ClC1C(Cl)=CC(NC2C3C(=CC=C(N)C=3)N=C([O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][F:65])N=2)=C(F)C=1.CCN(C(C)C)C(C)C.ClCC(Cl)=O>C1COCC1>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][F:65])[N:12]=[CH:11][N:10]=[C:9]2[NH:23][C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[CH:26][C:25]=1[F:32])=[O:4]
Reactant: O=C(CCl)Nc1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCF
Reactant: Nc1ccc2nc(OCCOCCOCCOCCF)nc(Nc3cc(Cl)c(Cl)cc3F)c2c1
Agent: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)Nc1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCOCCOCCF

Procedure:
Compound 1b was prepared as described hereinabove for Compound 1a, using Compound 38b (0.085 gram, 0.16 mmol), DIPEA (0.33 mmol, 57.8 μl) and chloroacetylchloride (0.33 mmol, 26.4 μ) in THF (11 ml), as starting materials, to give 0.025 gram (26% yield) of the product.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:24][C:25](=[O:27])[CH3:26])([CH2:22][OH:23])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:12]=2)[CH2:7][CH:6]=1.[Li+].[OH-]>CO.CCOCC>[OH:23][CH2:22][C:3]([NH:24][C:25](=[O:27])[CH3:26])([CH2:2][OH:1])[CH2:4][CH:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1
Reactant: CCCCCCCCc1ccc2c(c1)CC=C2CC(CO)(CO)NC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: CCCCCCCCc1ccc2c(c1)CCC2CC(CO)(CO)NC(C)=O

Procedure:
Compound 19 (18 mg, 0.047 mmol) is dissolved in methanol (0.50 mL) and LiOH (0.04 g, 0.60 mmol) is added. The reaction is heated and maintained at reflux for 2 hours, diluted with ether (5 mL). The organic layer is washed with water (1×5 mL) and brine (1×5 mL). The combined organic layer is concentrated in vacuo then purified by silica gel chromatography eluding with 75% methanol and 25% methylene chloride.