Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]([F:35])([F:34])[C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]4[CH:33]=[CH:32][C:24]([O:25][CH2:26][C:27]([O:29]CC)=[O:28])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH2:13][CH2:14][C:9]2=[N:8][N:7]=1.O.CO>C1COCC1>[F:35][C:5]([F:4])([F:34])[C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]4[CH:33]=[CH:32][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH2:13][CH2:14][C:9]2=[N:8][N:7]=1
Reactant: CCOC(=O)COc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
Lithium hydroxide monohydrate (381 mg, 9.08 mmol) was added to ethyl 2-[4-[1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetate (820 mg, 1.82 mmol) in a mixture of THF (20 mL), water (10 mL) and MeOH (5 mL). The resulting mixture was stirred at ambient temperature for 16 hours. The solvents were evaporated then the residue was suspended in water and acidified to pH 4 with 1M citric acid. The resulting precipitate was collected by filtration, washed with water and dried to afford 2-[4-[1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetic acid (575 mg, 74.8%) as a solid.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19]C)=[CH:13][CH:12]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:7]([C:4]2[CH:3]=[C:2]([Br:1])[S:6][CH:5]=2)=[O:9])=[CH:13][CH:12]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: CNCCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(NCCc1ccc(F)cc1)c1csc(Br)c1
Reaction time: 1.5 h

Procedure:
To a solution of 5-bromo-thiophene-3-carboxylic acid (5 g) and [2-(4-fluorophenyl)-ethyl]methyl-amine (the compound of Preparation Example 14) (3.7 g) in dichloromethane (150 mL) was added 1-Ethyl-3-(3-dimethylamino propyl)-carbodiimide.hydrochloride (5.1 g) was added. After stirring for 1.5 hours, the residue resulting from evaporation of the reaction solution in vacuo was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (6 g) was obtained as a colorless oily matter.
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)(O)=[O:2].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>>[Cl:26][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:25])[C:19]=1[NH:18][C:16]([C:10]1[C:9]2[CH:5]([CH2:4][C:1]([NH:34][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)=[O:2])[CH2:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:17]
Reactant: COc1ccc(CN)cc1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Product: COc1ccc(CNC(=O)CC2COc3c(OC)ccc(C(=O)Nc4c(Cl)cncc4Cl)c32)cc1
Yield: 85 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.20 g) obtained in Example 9 and 4-methoxybenzylamine to give Compound 28 (0.28 g, 85%) as a white solid.
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)=[CH:4][N:3]=[CH:2]1.C([Li])CCC.CON(C)[C:31](=[O:43])[CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1>C1COCC1.CCCCCC>[CH3:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][O:33][CH2:32][C:31]([C:2]2[S:1][C:5]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)=[CH:4][N:3]=2)=[O:43])=[CH:36][CH:37]=1
Reactant: COc1ccc(COCC(=O)N(C)OC)cc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cncs3)ncnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(COCC(=O)c2ncc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)s2)cc1
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
To a solution of 4-(1,3-thiazol-5-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (2.12 g, 6.38 mmol) in THF (70 mL) at −78° C. was added 2.5 M n-butyllithium in hexane (3.06 mL) slowly dropwise. After stirring for 30 minutes, N-methoxy-2-[(4-methoxybenzyl)oxy]-N-methylacetamide (2.29 g, 9.56 mmol) was added. The reaction was continued for 30 minutes following the addition, at −78° C., then the cooling bath was removed and the reaction was quenched with saturated ammonium chloride and extracted with ether. The extracts were dried with sodium sulfate and concentrated in vacuo. The crude mixture was purified by flash column chromatography (ethyl acetate/hexanes) to afford desired product (2.16 g, 66%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C@H:14]([CH:18]([CH3:20])[CH3:19])[C:15]([OH:17])=O)(=[O:12])=[O:11])=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[C:46]([O:50][NH2:51])([CH3:49])([CH3:48])[CH3:47].Cl.CN(CCCN=C=NCC)C>C(Cl)Cl.O>[C:46]([O:50][NH:51][C:15](=[O:17])[C@H:14]([N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1)(=[O:11])=[O:12])[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH:18]([CH3:19])[CH3:20])([CH3:49])([CH3:48])[CH3:47]
Reactant: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)O)C(C)C)cc1
Reactant: CC(C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)NOC(C)(C)C)C(C)C)cc1
Reaction time: 8 h

Procedure:
2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoic acid hydrochloride (5.0 g, 12.06 mmol), 1-hydroxybenzotriazole (1.63 g, 12.06 mmol), 4-methylmorpholine (6.6 mL, 60.31 mmol), and O-t-butylhydroxylamine hydrochloride (54.55 g, 36.19 mmol) are dissolved in methylene chloride (200 mL). N-[Dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (3.01 g, 15.68 mmol) is added, and the reaction is stirred overnight. The reaction is then diluted with water and extracted with methylene chloride. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (2% methanol/methylene chloride) to give N-(t-butyloxy)-2(R)-[[4-methoxybenzenesulfonyl]-(3-picolyl)amino]-3-methylbutanamide.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][OH:4].CCN(C(C)C)C(C)C.[S:18](Cl)([C:21]1[C:33]([CH3:34])=[C:32]2[C:26]([O:27][C:28]([CH2:31]2)([CH3:30])[CH3:29])=[C:24]([CH3:25])[C:22]=1[CH3:23])(=[O:20])=[O:19]>C(Cl)(Cl)Cl>[NH:1]([S:18]([C:21]1[C:33]([CH3:34])=[C:32]2[C:26]([O:27][C:28]([CH2:31]2)([CH3:30])[CH3:29])=[C:24]([CH3:25])[C:22]=1[CH3:23])(=[O:19])=[O:20])[C@H:2]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][OH:4]
Reactant: COC(=O)[C@@H](N)CO
Reactant: Cc1c(C)c(S(=O)(=O)Cl)c(C)c2c1OC(C)(C)C2
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CO)NS(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2
Reaction time: 8 h
Yield: 82.7 %

Procedure:
H-Ser-OMe, 3.5 g (22.6 mmol), was suspended in (40 mL) of chloroform. Under ice cooling, DIEA (8.7 mL, 49.7 mmol) and Pbf-Cl (5.86 g, 20.3 mmol) were sequentially added and stirred overnight while gradually elevating to room temperature. After the reaction was stopped by adding satd. citric acid aqueous solution, chloroform was distilled off under reduced pressure and the whole was extracted with AcOEt. The organic layer was washed sequentially with satd. citric acid aqueous solution, satd. sodium bicarbonate aqueous solution and satd. sodium chloride aqueous solution, and then dried over anhydrous MgSO4. After concentration under reduced pressure, flash chromatography was performed using AcOEt:n-hexane=1:1 to give Pbf-Ser-OMe (6.94 g, 82.7%).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:10]([CH2:12]O)[CH:11]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([O:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:10]([CH2:12][Cl:3])[CH:11]=1
Reactant: OCc1cc(Br)ccc1OCCN1CCCC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: ClCc1cc(Br)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mL (2.20 mmol) of thionyl chloride was added at −10° C. to a solution of 0.60 g (2.00 mmol) of [5-bromo-2-(2-pyrrolidin-1-ylethoxy)phenyl]methanol and 0.42 mL (3.00 mmol) of triethylamine in 30 mL of THF and the mixture was stirred for 16 hours at RT. Ice and dilute aqueous sodium bicarbonate solution was added to the reaction mixture and the phases were separated. The aqueous phase was exhaustively extracted with DCM, and the combined organic phases were washed with water, dried over magnesium sulfate, and evaporated down in vacuo. Yield: 0.39 g (62% of theoretical); C13H17BrClNO (M=318.637); calc.: molpeak (M+H)+: 318/320/322 (BrCl); found: molpeak (M+H)+: 318/320/322 (BrCl); HPLC-MS: 5.84 minutes (method A).
Reaction SMILES: O=[C:2]1[CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][C:16](=O)[NH:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[O:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:2][NH:3][CH2:4][CH2:5]1
Reactant: O=C1COCCOCCOCC(=O)NCCOCCOCCOCCN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1COCCOCCOCCNCCOCCOCCOCCN1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 30 g. of the diamide obtained in Example 15 in 200 ml. anhydrous tetrahydrofurane is slowly added to a mixture of 50 ml. anhydrous tetrahydrofurane and 18 g. LiAlH4 while stirring and heating at the reflux temperature. After the addition is completed, the mixture is stirred under reflux and under a nitrogen atmosphere for 24 hours. After cooling to room temperature the reducing agent is destroyed by adding a mixture of water and THF (1:2). The mixture is filtered and the filtrate is evaporated to dryness. The residue is dissolved in benzene and the solution is passed through a column of Al2O3 with benzene as eluant. The solution is evaporated to dryness and the desired product is obtained as a colourless oil which crystallizes at low temperatures. m.p. = 15°C
Reaction SMILES: [CH2:1](Br)[CH3:2].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12](=[O:25])[NH:13][C:14]([S:23][CH3:24])=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=1.[H-].[Na+].C(O)(=O)C>CN(C)C=O>[CH2:1]([N:13]1[C:12](=[O:25])[C:11]([C:8]2[CH:7]=[CH:6][C:5]([F:4])=[CH:10][CH:9]=2)=[C:16]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:15]=[C:14]1[S:23][CH3:24])[CH3:2]
Reactant: CCBr
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCn1c(SC)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reaction time: 8 h

Procedure:
Ethyl bromide (600 ml, 8.03 mmol) was added to a stirred mixture of 5-(4-fluorophenyl)-2-methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone (1.8 g, 5.97 mmol) and sodium hydride (60% oily suspension, 320 mg, 8 mmol) in N,N-dimethylformamide (60 ml) at room temperature. More ethyl bromide (2×600 ml, 2×8.03 mmol) was added after 2 and 3.5 h. After 8 h, the reaction mixture was neutralized with acetic acid and evaporated. The remainder was taken up in dichloromethane, the organic solution was washed with water, dried and evaporated. Flash chromatography on a column of silica gel (hexane-acetone=3:1, 2:1). provided in the second main fraction the title compound as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:49])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:37]=4[C:38]([NH2:40])=[O:39])[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][C@H:7]1[CH3:48])=[O:5].[OH-].[Na+].[Na+].[Cl-]>O1CCOCC1.CCOC(C)=O>[CH3:1][N:2]([CH3:49])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:37]=4[C:38]([NH2:40])=[O:39])[N:17]=3)[CH:13]=2)[CH2:8][C@H:7]1[CH3:48])=[O:5]
Reactant: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)[C@H](C)C2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CN(C)C)[C@H](C)C2
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of 2-({2-{[(2R)-1-(N,N-dimethylglycyl)-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (246 mg, 0.358 mmol) in dioxane (10 mL) and a 2M aqueous NaOH solution (2 mL) was heated at 80° C. for 5 h. The resulting mixture was allowed to cool to rt, diluted with EtOAc (50 mL) and a saturated NaCl solution (10 mL). The organic layer was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to afford 2-[(2-{[(2R)-1-(N,N-dimethylglycyl)-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide as a yellow solid (143 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (d, J=5.49 Hz, 3H), 2.27 (s, 6H), 2.60 (d, J=15.57 Hz, 1H), 3.08 (d, J=14.28 Hz, 1H), 3.26-3.48 (m, 2H), 3.80 (s, 3H), 4.71-4.86 (m, 1H), 6.24 (dd, J=3.11, 1.65 Hz, 1H), 6.89 (t, J=9.25 Hz, 1H), 6.98 (s, 2H), 7.23-7.43 (m, 1H), 7.56 (s, 1H), 8.03 (s, 1H), 8.11 (s, 1H), 8.49 (d, J=8.24 Hz, 1H), 8.63 (s, 1H), 10.53 (s, 1H), 11.33 (s, 1H); ESIMS (M+H)+=533.36; Optical rotation +14.4 (1 mg/mL MeOH, rt).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:13]=[O:14])=[CH:3][CH:4]=1
Reactant: O=Cc1ccccc1B(O)O
Reactant: Brc1ccc(Br)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=Cc1ccccc1-c1ccc(Br)c2ccccc12
Temperature: 25 °C
Yield: 67.9 %

Procedure:
Under the atmosphere of argon, 230 g of 1,4-dibromonaphthalene, 121 g of 2-formylphenylboronic acid and 18.5 g of tetrakis(triphenylphosphine)palladium(0) were placed in a flask. To the resulting mixture, 2.4 L of dimethoxyethane (DME) and 1.2 L of an aqueous 2M sodium carbonate solution were added, followed by stirring under reflux for 8 hours. After cooling to the room temperature, an aqueous phase was removed, and an organic phase was washed with water and saturated saline, and dried with magnesium sulfate. After filtering off magnesium sulfate, the organic phase was concentrated. The residues were purified by silica gel column chromatography, whereby 170 g (yield 67%) of 1-bromo-4-(2-formylphenyl)naphthalene as an intended product was obtained.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(Cl)(=O)C(Cl)=O.[CH:31]1[CH:36]=[CH:35][CH:34]=CC=1>>[C:1]([O:24][CH2:34][CH:35]1[CH2:31][CH2:36]1)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OCC1CC1

Procedure:
In a 500 ml. flask is stirred 3.2 g. of docosanoic acid in 250 ml. of dry benzene until most of acid dissolves. Oxalyl chloride (3.5 g.) is added and mixture stirred for 2 hours at room temperature under nitrogen. Solvent is removed in vacuo and fresh benzene added and 1.3 g. of cyclopropylmethyl alcohol. The reaction product is worked up by washing with water and brine, drying over calcium sulfate and evaporation of solvent to yield cyclopropylmethyl docosanoate m.p. 44°, which can be further purified by recrystallization from methanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:8]=[C:7]([CH3:16])[CH:6]=1)[CH3:2].Cl.[Cl:19][C:20]1[CH:21]=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:6]=[C:7]([CH3:16])[CH:8]=[C:9]([S:11][C:12]2[C:23]3[C:22](=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:13]=2[CH3:14])[CH:10]=1)[CH3:2]
Reactant: NNc1cccc(Cl)c1
Reactant: CCOC(=O)c1cc(C)cc(SCC(C)=O)c1
Agent: Cl
Product: CCOC(=O)c1cc(C)cc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 3-Methyl-5-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: Cl[C:2]([F:26])([F:25])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([O:18][CH2:19][CH3:20])[C:4]=1[C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C>C(O)C.[Pd]>[F:26][CH:2]([F:25])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([O:18][CH2:19][CH3:20])[C:4]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1OCC
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1OCC
Reaction time: 18 h
Yield: 47.8 %

Procedure:
A mixture of 5.0 g (0.012 mol) of product of Example 19, 1.72 ml (0.012 mol) of triethylamine and 0.75 g of 10% Pd-C in 65 ml of ethanol was hydrogenated at 40° C. under 522 kPa of H2 pressure for 18 hours. The reaction mixture was filtered through celite and concentrated. The residue was taken up in ether, washed with 10% HCl (aq), dried (MgSO4) and concentrated in vacuo to 3.28 g of yellow solid, which was recrystallized in hot hexane to give 2.13 g (47.4%) of product as a light yellow solid, mp 59°-61° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#N)=[CH:6][N:5]=[CH:4][CH:3]=1.Cl.[OH-:11].[Na+].[CH3:13]COCC>>[C:8]([C:7]1[CH:6]=[N:5][CH:4]=[CH:3][C:2]=1[CH3:1])(=[O:11])[CH3:13]
Reactant: [OH-]
Reactant: Cc1ccncc1C#N
Reactant: CCOCC
Agent: Cl
Agent: [Na+]
Product: CC(=O)c1cnccc1C
Temperature: 50 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of compound (14)(2.0 g, 16.9 mmol) in ether (13 ml) was added a methylmagnesium iodide-ether solution (18.2 ml, 27.4 mmol) under ice-cooling. The reaction mixture was heated to 50° C. and stirred overnight. The reaction mixture was again ice-cooled and 5% hydrochloric acid (400 ml) was added. The reaction mixture was neutralized with a 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was combined and dried (MgSO4) and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give a yellow oil (1.26 g, 55%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH2:10][C:11](Cl)=[O:12])[CH:3]=1.[CH:14]1[CH:15]=[CH:16][N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[NH:20][CH2:19][C:18]=12.C(N(CC)CC)C.[Cl:35]CCl>>[Cl:35][C:7]1[CH:2]=[CH:3][C:4]([O:9][CH2:10][C:11]([N:20]2[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[CH2:23][N:17]3[CH:16]=[CH:15][CH:14]=[C:18]3[CH2:19]2)=[O:12])=[C:5]([CH3:8])[CH:6]=1
Reactant: Cc1ccc(Cl)cc1OCC(=O)Cl
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1OCC(=O)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-o-tolyloxyacetic acid chloride of step A (17.4 mmol) in dichloromethane (25 mL) was added a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (17.4 mmol) and triethylamine (19.14 mmol) in dichloromethane (25 mL) in a rapid dropwise fashion. The mixture was stirred for one hour at room temperature. The reaction mixture was washed with 0.1 N hydrochloric acid (2×) and water (1×), dried over anhydrous sodium sulfate and evaporated. The product was isolated by crystallization from hot ethyl acetate/t-butyl methyl ether (2/1), m.p. 166-167° C. MS [(+)ESI, m/z]: 367 [M+H]+ Anal. Calcd for C21H19CIN2O2: C, 68.76; H, 5.22; N, 7.64. Found: C, 68.53; H, 5.18; N, 7.53.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][N:8]2[CH2:16][C:15]3[C:14]([OH:17])=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:25][N:26]([CH3:30])[C:27](=[O:28])[O:17][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][N:8]([NH:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[CH2:9]2
Reactant: CN(C)C(=O)Cl
Reactant: Oc1cccc2c1CN(Nc1ccncc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)Oc1cccc2c1CN(Nc1ccncc1)C2
Temperature: 25 °C
Yield: 60.5 %

Procedure:
To a mixture of 2,3-dihydro-2-(4-pyridinylamino)-1H-isoindol-4-ol (1.20 g), triethylamine (1.18 g) and chloroform (35 ml), was added dimethylcarbamyl chloride (0.68 g) with stirring, at ambient temperature, under nitrogen. The reaction mixture was heated under reflux for 3 hrs, poured into dilute sodium bicarbonate solution (100 ml), and the layers were separated. The aqueous phase was extracted with chloroform, and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica, eluting with 10-15% methanol/dichloromethane. The appropriate fractions were collected and concentrated to give 953 mg (60%) of product. Recrystallization from dichloromethane-heptane gave the analytical sample, mp 183-185° C.
Reaction SMILES: C(OC(=O)[N:7]([C:23]1[C:32]2[C:27](=[N:28][C:29]([S:33][CH2:34][CH3:35])=[N:30][CH:31]=2)[N:26]=[CH:25][N:24]=1)[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[S:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(C)(C)C.[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.BrCC#N>>[CH2:37]([O:22][C:19]1[CH:20]=[CH:21][C:16]([S:15][C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[NH:7][C:23]2[C:32]3[C:27](=[N:28][C:29]([S:33][CH2:34][CH3:35])=[N:30][CH:31]=3)[N:26]=[CH:25][N:24]=2)=[CH:17][CH:18]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCSc1ncc2c(N(C(=O)OC(C)(C)C)c3cc(C)ccc3Sc3ccc(O)cc3)ncnc2n1
Reactant: BrCc1ccccc1
Agent: N#CCBr
Product: CCSc1ncc2c(Nc3cc(C)ccc3Sc3ccc(OCc4ccccc4)cc3)ncnc2n1
Yield: 29 %

Procedure:
The product from Example 164 was reacted with benzyl bromide according to the procedure from Example 165 substituting benzyl bromide for bromo-acetonitrile to provide the crude product which was purified by silica gel chromatography using 98/2 dichloromethane/methanol as eluent to provide the title compound (15 mg, 29%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.20 (t, J=7.35 Hz, 3H), 2.27 (s, 3H), 3.08 (q, J=7.35 Hz, 2H), 5.44 (s, 2H), 6.74 (d, J=8.46 Hz, 2H), 6.95 (m, 3H), 7.20 (d, J=8.46 Hz, 2H), 7.35 (m, 5H), 8.77 (s, 1H), 9.42 (s, 1H), 9.81 (s, 1H); MS (ESI+) m/z 512 (M+H)+.