Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:5](C(O)=O)=[CH:4][N:3]=1.Cl.[CH3:16][NH:17][O:18][CH3:19].CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([N:17]([CH3:16])[O:18][CH3:19])=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: O=C(O)c1cnc(Cl)cc1C(F)(F)F
Reactant: CNOC
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CON(C)c1cnc(Cl)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a solution of 6-chloro-4-trifluoromethyl-nicotinic acid (0.9 g, 3.99 mmol) in methylene chloride were added N,O-dimethylhydroxylamine HCl (0.39 g, 1.0 eq), NMM (0.44 ml), and EDC (0.768 g) at 0° C. and the reaction mixture was stirred at 0° C. for 2 hrs. The reaction mixture was extracted with methylene chloride, and washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex/EtOAc=4/1) to give the product (0.824 g, 76.9%).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]1[CH2:19][C:17](=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1>[C].[Pd]>[CH:13]1[CH:12]=[C:11]2[CH:10]=[CH:9][C:19]3[C:6]4[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=4)[NH:7][C:17]=3[C:16]2=[CH:15][CH:14]=1
Reactant: O=C1CCCc2ccccc21
Reactant: NNc1ccccc1
Agent: [Pd]
Product: c1ccc2c(c1)ccc1c3ccccc3[nH]c21

Procedure:
1,2-benzo-3,4-dihydrocarbazole synthesized from phenylhydrazine and α-tetralone according to the method of J. Am. Chem. Soc., 69, 2910 (1947) was dehydrogenized with palladiumcarbon to obtain 1,2-benzocarbazole.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:16].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>O1CCOCC1>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:16][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:2]=1[F:1])=[O:21]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CN1CCC(Oc2cccc(N)c2F)CC1
Solvent: C1COCCO1
Product: CN1CCC(Oc2cccc(NC(=O)c3ccccc3Cl)c2F)CC1
Yield: 107.7 %

Procedure:
Heat a mixture of 2-fluoro-3-(1-methyl-piperidin-4-yloxy)-phenylamine (preparation 33, 0.26 g) and 2-chlorobenzoyl chloride (0.233 g) in 1,4-dioxane (10 mL) for 2 hrs. Evaporate and purify on a silica gel column (10 g, solvent: dichloromethane-2M NH3 in methanol, gradient) to give the title compound (0.453 g). Mass spectrum (electric spray) m/z=363 (M+1); 1H NMR (CDCl3): 8.27 (br s, 1H), 8.07 (m, 1H), 7.80 (dd, 1H), 7.42 (m, 3H), 7.07 (ddd, 1H), 6.79 (ddd, 1H), 4.31 (m, 1H), 2.70 (m, 2H), 2.30 (s, 3H), 2.28 (m, 2H), 2.00 (m, 2H), 1.89 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:14])=[C:4]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:15]([O:17][C:18]1[C:19](=O)[C:20](=[O:25])[C:21]=1[O:22]CC)C>CO>[OH:14][C:3]1[C:2]([NH:1][C:19]2[C:20](=[O:25])[C:21](=[O:22])[C:18]=2[O:17][CH3:15])=[CH:7][CH:6]=[CH:5][C:4]=1[S:8]([N:11]([CH3:12])[CH3:13])(=[O:10])=[O:9]
Reactant: CN(C)S(=O)(=O)c1cccc(N)c1O
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CO
Product: COc1c(Nc2cccc(S(=O)(=O)N(C)C)c2O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 64.3 %

Procedure:
A mixture of 0.94 g (4.10 mmol) of 3-amino-2-hydroxy-N,N-dimethylbenzenesulfonamide and 2.47 g (17.40 mmol) of 3,4-diethoxycyclobut-3-ene-1,2-dione in 20 ml of methanol was stirred at ambient temperature for 4 days. The reaction medium was concentrated. The residue (3.29 g) was chromatographed on silica gel (200 g prepacked column, 100 ml/min, eluent heptane/ethyl acetate, from 50% to 85% of ethyl acetate). 0.86 g of product was obtained in the form of a yellow solid. Yield=64%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[F:17][C:18]1[CH:19]=[C:20]([C:30](=[O:32])[CH3:31])[CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:6]([CH:10]=1)[C:7]([N:27]1[CH2:26][CH2:25][N:24]([C:23]2[CH:22]=[CH:21][C:20]([C:30](=[O:32])[CH3:31])=[CH:19][C:18]=2[F:17])[CH2:29][CH2:28]1)=[O:8]
Reactant: O=C(Cl)c1cc(Br)ccc1N1CCOCC1
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(Br)ccc3N3CCOCC3)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 5-Bromo-2-morpholin-4-yl-benzoyl chloride and 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone (94%, yellow foam, MS (m/e): 490.3 (M+, 100%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].O=C1CCC(=O)N1[O:17][C:18](=O)[CH:19]([NH:27][C:28]([O:30][CH2:31][CH:32]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[CH2:20][S:21][S:22][C:23]([CH3:26])([CH3:25])[CH3:24]>C([O-])(O)=O.[Na+].C1COCC1.CO.C(Cl)Cl>[C:23]([S:22][S:21][CH2:20][CH:19]([NH:27][C:28]([O:30][CH2:31][CH:32]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[C:18]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:17])([CH3:26])([CH3:24])[CH3:25]
Reactant: NCCCCCC(=O)O
Reactant: CC(C)(C)SSCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)SSCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-Aminohexanoic acid (0.158.g, 1.2 mmole) dissolved in 0.1M NaHCO3 (2.0 mL) was added the NHS ester 2 (0.68 g, 1.3 mmole) in 4 mL of anhydrous THF. The reaction mixture was stirred at RT for 2 hr. The solvent was completely evaporated and the dried solid residue obtained was dissolved in CH3OH/CH2Cl2 mixture and purified by silica gel column chromatography using 10% CH3OH/CH2Cl2 and obtained 3 as a white solid on evaporation the solvent. Yield: 0.5 g (77%).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[NH2:34][CH2:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:34][CH2:35][CH:36]1[CH2:39][N:38]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:37]1
Reactant: NCC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: NCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Cl)C1
Temperature: 90 °C
Reaction time: 0.42 h
Yield: 44.8 %

Procedure:
To 280 mg of N,N-dimethylformamide were added 80 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 100 mg of 3-(aminomethyl)azetidine dihydrochloride, and 200 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 25 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 42 mg of the title compound as a colorless powder.
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])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:37]([N:39]([CH2:47][CH3:48])[CH2:40][CH2:41][CH:42]([OH:46])[CH2:43][CH2:44][CH3:45])[CH3:38].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:46][CH:42]([CH2:41][CH2:40][N:39]([CH2:37][CH3:38])[CH2:47][CH3:48])[CH2:43][CH2:44][CH3:45])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: CCCC(O)CCN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(CCN(CC)CC)OC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Yield: 35.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-(diethylamino)-3-hexanol (40 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (29 mg, yield 32%).
Reaction SMILES: [C:1]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C@H:29]([NH:34][C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1)[C:30]([O:32]C)=[O:31])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].[OH-].[Na+].Cl>C1COCC1>[C:1]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C@H:29]([NH:34][C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1)[C:30]([OH:32])=[O:31])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCCC[C@H](NC(=O)c1cccnc1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCCC[C@H](NC(=O)c1cccnc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
(S)-Methyl 6-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-2-(nicotinamido)hexanoate (40 mg, 0.0695 mmol) was taken up in 2 mL of THF along with 80 μL of a 5 M NaOH solution. The resulting reaction mixture was stirred at room temperature for 2 h. It was then acidified to pH 4 with 2 N HCl and then extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford 31 mg of (S)-6-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-2-(nicotinamido)hexanoic acid. MS calculated for C34H47N3O4: 561.36. found: [M+H]+ 562.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:27]=[C:26]([C:28]([O:30]CC)=[O:29])[O:25][N:24]=4)=[CH:19][C:18]=3[CH3:33])=[CH:13][C:8]=2[C:7](=[O:34])[N:6]([CH3:35])[C:5]2[CH:36]=[CH:37][CH:38]=[N:39][C:4]1=2)[CH3:2].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[O:25][N:24]=4)=[CH:19][C:18]=3[CH3:33])=[CH:13][C:8]=2[C:7](=[O:34])[N:6]([CH3:35])[C:5]2[CH:36]=[CH:37][CH:38]=[N:39][C:4]1=2)[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc(OCCc3cnc4c(c3)C(=O)N(C)c3cccnc3N4CC)c(C)c2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3ccc(-c4cc(C(=O)O)on4)cc3C)cc2C(=O)N(C)c2cccnc21
Yield: 89 %

Procedure:
A solution of ethyl 3-{4-[2-(11-ethyl-6,11-dihydro-5-methyl-6-oxo-5H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-8-yl)ethoxy]-3-methylphenyl}-5-isoxazolecarboxylate (50.0 mg, 0.090 mmol) and aqueous 1 N NaOH solution (0.90 mL, 0.90 mmol) in THF (2 mL) and MeOH (0.5 mL) was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure, acidified with aqueous 4 N HCl solution and extracted with EtOAc (1×) and CH2Cl2 (1×). The combined organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting solid was triturated with EtOAc/Hexane to give the title compound (40 mg, 85% yield) as a pale yellow solid. A 1 N NaOH solution (78 μL, 0.078 mmol) was added to a solution of the title compound (39.0 mg, 0.078 mmol) in THF (3 mL). After 45 min, the mixture was concentrated. The residue was dissolved in water and MeCN then the solution was frozen and lyophilized to give the corresponding sodium salt of the title compound 1041 (40.5 mg, 100% yield) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19].B(F)(F)F>F>[C:18]([OH:20])(=[O:19])[CH3:17].[C:18]([OH:20])(=[O:19])[CH3:17].[OH:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=2)=[CH:6][CH:5]=1)=[O:19]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cccc(O)c1
Agent: F
Agent: FB(F)F
Product: CC(=O)O
Product: O=C(c1ccc(-c2ccc(O)cc2)cc1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
One hundred seventy grams (1 mole) of p-phenylphenol, 138 grams (1 mole) of 3-hydroxybenzoic acid, 400 mL of hydrogen fluoride (HF), and 170 grams of boron trifluoride were reacted for 15 hours at 0° C. under autogenous pressure in an autoclave. Then the contents were mixed in excess water/ice to precipitate a green solid. After filtering and washing with water to remove the remaining HF, the powder was slurried with water, neutralized with 80 grams sodium bicarbonate (NaHCO3) until pH=8, filtered, and washed with water. After drying at 25° C. in air for 10 hours, the solid was dissolved in 3000 ml ethyl acetate, stirred overnight, and precipitated in a blender with 6000 ml n-hexane by volume. The solid was separated by filtration, washed two times with n-hexane, and dried at 120° C. under vacuum. The product was 160 grams of a beige crystalline solid which was determined by NMR analysis to be the 3-hydroxy,4'(4 -hydroxyphenyl)-benzophenone. This solid was acetylated directly by refluxing 3 hours with 640 ml of acetic anhydride and one drop of concentrated sulfuric acid. The solution was cooled to 25° C. and allowed to stand overnight. The solid was filtered, washed with methanol, and dried at 90° C. under vacuum. The product was 150 grams of 100% pure 3-hydroxy, 4'-(4-hydroxyphenyl)benzophenone diacetate as determined by NMR analysis. Its melting point was 120°-121° C.
Reaction SMILES: C([N:3](CC)CC)C.[CH:8]1([O:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2/[CH:22]=[CH:23]/[C:24]2[N:28]([C:29]3[N:34]=[N:33][C:32]([C:35](O)=[O:36])=[CH:31][CH:30]=3)[C:27]3[CH:38]=[CH:39][CH:40]=[CH:41][C:26]=3[N:25]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1.ClC(OCC)=O.N>C1COCC1>[CH:8]1([O:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2/[CH:22]=[CH:23]/[C:24]2[N:28]([C:29]3[N:34]=[N:33][C:32]([C:35]([NH2:3])=[O:36])=[CH:31][CH:30]=3)[C:27]3[CH:38]=[CH:39][CH:40]=[CH:41][C:26]=3[N:25]=2)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COc1cccc(/C=C/c2nc3ccccc3n2-c2ccc(C(=O)O)nn2)c1OC1CCCC1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: COc1cccc(/C=C/c2nc3ccccc3n2-c2ccc(C(N)=O)nn2)c1OC1CCCC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
This compound was prepared by adding triethylamine (66.44 mg, 0.657 mmol) to the stirred solution of Step 1 product (200 mg, 0.43 mmol) in dry THF (5 ml) under nitrogen atmosphere. Ethyl chloroformate (71.40 mg, 0.657 mmol) was added to the reaction mixture which was cooled to −10° C., after a time interval of 30 minutes aqueous ammonia (2 ml, 25%) was added and the reaction mixture was stirred for 30 minutes. Reaction mixture was quenched with water to get off-white solid which was filtered, washed with diethylether and dried under vaccum to get 131 mg of yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][N:18]3[CH:26]=[CH:27][CH:28]=[C:17]3[CH2:16]2)=[O:14])=[CH:9][CH:8]=1)=[O:5].[Cl:33]N1C(=O)CCC1=O>O1CCCC1>[Cl:33][C:26]1[N:18]2[C:17]([CH2:16][N:15]([C:13]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:29]=[CH:30][CH:31]=[CH:32][C:2]=4[CH3:1])=[CH:12][CH:11]=3)=[O:14])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19]2)=[CH:28][CH:27]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccc(Cl)n3Cc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
To an ice-water cooled suspension of 211 mg of 2-methyl-N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H)-ylcarbonyl)-phenyl]benzamide in 5 ml of tetrahydrofuran is added 67 mg of N-chlorosuccinimide followed by continued stirring in the cold for 10 minutes. The bath is removed and stirring continued for 2.25 hours. The reaction mixture is added to ice-water and extracted with ether. The organic layer is dried and concentrated in vacuo to give a foam which is crystallized from ethyl acetate-hexane to give 157 mg of the desired product as an orange-pink solid, m.p. 185-187° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]([CH2:17][C@@H:18]([C:25]([O:27]C)=[O:26])[NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)[CH3:2].O.[OH-].[Li+].Cl>O1CCOCC1.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][C@@H:18]([C:25]([OH:27])=[O:26])[NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[CH:29][CH:30]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(CCOc2ccc(C[C@H](NC(=O)C(C)C)C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1ccc(CCOc2ccc(C[C@H](NC(=O)C(C)C)C(=O)O)cc2)cc1
Reaction time: 8 h
Yield: 102.6 %

Procedure:
Methyl O-[2-(4-ethoxyphenyl)ethyl]-N-isobutyryltyrosinate (0.25 g, 0.61 mmol) was dissolved in dioxane (4 ml). Lithium hydroxide monohydrate (0.1 g, 2.38 mmol) in water (4 ml) was added. The mixture was stirred overnight and then acidified with 1M hydrochloric acid, pH ˜3-4. Dioxane was removed by evaporation in vacuum. The residue was diluted with water and then extracted with dichloromethane. The organic phase was washed with brine and dried with sodium sulfate. The solvent was then evaporated. 0.25 g desired product was obtained, yield 100%.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:17]([S:20]([CH:23]([F:25])[F:24])(=[O:22])=[O:21])=[CH:16][C:14]=1[NH2:15]>CCOC(C)=O>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:17]([S:20]([CH:23]([F:24])[F:25])(=[O:21])=[O:22])=[CH:16][C:14]=1[NH:15][C:8]([NH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)=[O:9]
Reactant: COc1ccc(S(=O)(=O)C(F)F)cc1N
Reactant: Cc1ccc(N=C=O)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)C(F)F)cc1NC(=O)Nc1ccc(C)cc1
Reaction time: 72 h
Yield: 59.1 %

Procedure:
p-Tolyl isocyanate (0.058 mL, 0.46 mmol) was added to a solution of 2-methoxy-5-(difluoromethanesulfonyl)aniline (0.100 g, 0.42 mmol) in EtOAc (0.5 mL) and the reaction mixture was stirred at room temp. for 3 d. The resulting precipitate was filtered and washed with Et2O to provide the title compound as a white solid (0.092 g): 1H-NMR (CDCl3) δ 2.22 (s, 3H), 4.01 (s, 3H), 7.01-7.36 (m, 6H), 7.54 (dd, J=2.4, 8.6 Hz, 1H), 8.57 (s, 1H), 8.79 (d, J=2.6 Hz, 1H), 9.33 (s, 1H); EI-MS m/z 370 (M+). B1d. General Method for the Reaction of an Aryl Amine with an Aryl Isocyanate
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([O:11][CH2:12][CH:13]([CH3:15])C)=[CH2:10].[C:16](=O)([O-])[O-].[Na+].[Na+]>Cl>[CH2:1]([O:8][CH:9]([O:11][CH2:12][CH2:13][CH2:15][CH3:16])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=COCC(C)C
Reactant: OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Product: CCCCOC(C)OCc1ccccc1
Temperature: 40 °C

Procedure:
A 250 ml. round-bottom flask equipped with a magnetic stirrer, condensor, mantle, and addition funnel was charged with 52.5 g. of benzyl alcohol and 4 drops of 36% hydrochloric acid. The mixture was heated to 40° C. and 50 g. of isobutyl vinyl ether was added dropwise, over a one-half hour period. GLC analysis showed the reaction to be complete at this point. Saturated sodium carbonate solution was added to quench (10 ml.) and the organic phase was dried over sodium sulfate prior to distillation on a concentric tube column:
Reaction SMILES: CC1C=CC(CN)=CC=1.[CH3:10][C:11]1[CH:34]=[CH:33][C:14]([CH2:15][NH:16][C:17]2[C:18]([NH2:32])=[CH:19][CH:20]=[C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=3)[CH:22]=2)=[CH:13][CH:12]=1.[C:35]1(=[O:45])[C@H:43]2[C@@H:38]([CH2:39][CH2:40][CH2:41][CH2:42]2)[C:37](=O)[O:36]1>>[CH3:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[C:17]3[CH:22]=[C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=4)[CH:20]=[CH:19][C:18]=3[N:32]=[C:37]2[C@@H:38]2[CH2:39][CH2:40][CH2:41][CH2:42][C@H:43]2[C:35]([OH:45])=[O:36])=[CH:33][CH:34]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@@H]12
Reactant: Cc1ccc(CNc2cc(OCc3ccc(C)cn3)ccc2N)cc1
Agent: Cc1ccc(CN)cc1
Product: Cc1ccc(Cn2c([C@@H]3CCCC[C@H]3C(=O)O)nc3ccc(OCc4ccc(C)cn4)cc32)cc1

Procedure:
The title compound was prepared using analogous conditions described for Example 1 using p-tolylmethanamine in Step A then for Intermediate I using N1-(4-methylbenzyl)-5-((5-methylpyridin-2-yl)methoxy)benzene-1,2-diamine and racemic trans-hexahydroisobenzofuran-1,3-dione followed by the hydrolysis according to Example 111. MS (ESI): mass calcd. for C29H31N3O3, 469.24; m/z found, 470.3 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.33 (s, 1H), 7.65 (d, J=8.0, 1H), 7.47 (d, J=8.7, 1H), 7.44 (s, 1H), 7.11 (d, J=7.9, 2H), 7.03 (d, J=8.1, 2H), 6.98 (d, J=2.2, 1H), 6.95 (dd, J=8.7, 2.3, 1H), 5.44 (s, 2H), 5.12 (s, 2H), 3.15 (td, J=11.2, 4.9, 1H), 3.02-2.94 (m, 1H), 2.35 (s, 3H), 2.30 (s, 3H), 2.21 (d, J=12.2, 1H), 1.85 (d, J=11.5, 1H), 1.70 (d, J=13.3, 1H), 1.46 (dt, J=28.3, 14.0, 4H), 1.31-1.16 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:13]#[N:14])[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2.[C:15]([O:19][C:20](=[O:30])[C:21]1[CH:26]=[C:25]([Cl:27])[C:24](F)=[CH:23][C:22]=1[F:29])([CH3:18])([CH3:17])[CH3:16].CC(C)([O-])C.[K+]>CS(C)=O.C(OCC)(=O)C>[Cl:27][C:25]1[C:24]([O:1][CH2:2][C:3]2([C:13]#[N:14])[CH:4]3[CH2:12][CH:8]4[CH2:7][CH:6]([CH2:11][CH:10]2[CH2:9]4)[CH2:5]3)=[CH:23][C:22]([F:29])=[C:21]([CH:26]=1)[C:20]([O:19][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:30]
Reactant: N#CC1(CO)C2CC3CC(C2)CC1C3
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2(C#N)C3CC4CC(C3)CC2C4)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 2-(hydroxymethyl)adamantane-2-carbonitrile (0.369 g, 1.93 mmol) and tert-butyl-5-chloro-2,4-difluorobenzoate (0.96 g, 3.86 mmol) in dimethylsulfoxide (30 mL) was added potassium tert-butoxide (0.42 g, 3.76 mmol). The mixture was stirred at ambient temperature for 0.5 hour, then diluted with ethyl acetate (200 mL). The organic layer was washed with 1 M hydrochloric acid (200 mL), brine (2×150 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography with a gradient of 0-30% ethyl acetate in hexanes to afford the title compound (0.64 g, 79% yield) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=7.6 Hz, 1H), 6.65 (d, J=11.7 Hz, 1H), 4.29 (s, 2H), 2.36-2.30 (m, 4H), 2.02 (br s, 1H), 1.91-1.74 (m, 9H), 1.56 (s, 9H); MS (ES−) m/z 420.1 (M+1).