Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[C:20](I)=[N:21][NH:22][C:16]=2[CH2:15]1)=[O:13].ClC1C(C(F)(F)F)=CC=CC=1C([N:37]1CCC2C(I)=N[N:45]([CH:46]3[CH2:51]CCCO3)[C:39]=2[CH2:38]1)=O.C([Sn](CCCC)(CCCC)C1C=NC=CN=1)CCC.[Cl-].[Li+]>O1CCOCC1.O.CCOC(C)=O.[F-].[K+].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>[Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2=[C:20]([C:39]3[CH:38]=[N:37][CH:51]=[CH:46][N:45]=3)[NH:21][N:22]=[C:16]2[CH2:15]1)=[O:13]
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(I)n[nH]c2C1
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(I)nn(C3CCCCO3)c2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(n[nH]c2-c2cnccn2)C1
Temperature: 170 °C
Reaction time: 3 h

Procedure:
To a solution of 6-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-iodo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (Intermediate 57) (47 mg, 0.103 mmol) in 1,4-dioxane (1 mL) was added 2-tributylstannylpyrazine (0.041 mL, 0.124 mmol), lithium chloride (4 mg, 0.103 mmol) and tetrakis(triphenylphosphine)palladium(0) (119 mg, 0.103 mmol). The reaction was allowed to stir overnight at 110° C. and an additional 3 h in a microwave reactor at 170° C. The reaction was diluted with water and EtOAc and 50% potassium fluoride on Celite© (1 g) was added. After stirring for 1 h, the solution was filtered and the layers in the filtrate were separated. The organic layer was concentrated in vacuo and the residue was purified by HPLC (Agilent prep system, Waters XBridge, C18, 5 μm, 30×100 mm column, 5-99% MeOH/20 mM NH4OH over 18 min at 30 mL/min) to give the desired product. (3 mg, 8%). MS (ESI) mass calcd. C18H13ClF3N5O, 407.1. m/z found 408.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.88 (br s, 1H), 8.60-8.50 (m, 2H), 7.82-7.75 (m, 1H), 7.57-7.41 (m, 3H), 5.20-5.13 (m, 0.5H), 4.95-4.87 (m, 0.5H), 4.52 (d, J=15.7 Hz, 0.5H), 4.41 (d, J=15.8 Hz, 0.5H), 4.34-4.27 (m, 0.5H), 4.10-3.97 (m, 0.5H), 3.60-3.53 (m, 1H), 3.16-3.12 (m, 1H), 2.98 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([OH:11])[C:8]([OH:12])=[C:7]([OH:13])[CH:6]=1)[CH3:2].Br[CH2:16][CH2:17]Br>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]([OH:11])[C:8]2[O:12][CH2:16][CH2:17][O:13][C:7]=2[CH:6]=1)=[O:14])[CH3:2]
Reactant: CCOC(=O)c1cc(O)c(O)c(O)c1
Reactant: BrCCBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(O)c2c(c1)OCCO2
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 3,4,5-trihydroxy-benzoic acid ethyl ester (5.00 g, 24.2 mmol) in DMF (70 mL) are added 1,2-dibromoethane (2.13 mL, 24.2 mmol) and CsCO3 (16.9 g, 50.9 mmol) and the mixture is stirred overnight at room temperature and for 5 hrs at 60° C. Extractive work-up with diethyl ether, washing of the organic phase with brine and evaporation gives the crude product as brown oil which is purified by silica gel chromatography (hexane/AcOEt 3:2). The title compound is obtained as a white solid. TLC, Rf (hexane/AcOEt 1:1)=0.27. MS: 223.0 [M−H]+. 1H-NMR (CDCl3): δ 1.40 (t, 3H), 4.3-4.42 (m, 6H), 5.45 (s, 1H), 7.23 (s, 1H), 7.29 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][CH:12]=[C:11]([C:14]([OH:16])=O)[C:10]=1[CH3:17].C(Cl)(=O)C(Cl)=O.Cl.[CH3:25][S:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].CCN(C(C)C)C(C)C>ClCCl.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][CH:12]=[C:11]([C:14]([NH:33][C:32]2[CH:31]=[CH:30][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:35][CH:34]=2)=[O:16])[C:10]=1[CH3:17]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: Cc1c(C(=O)O)c[nH]c1-c1ccc(F)cc1Cl
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c[nH]c1-c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a suspension of 5-(2-chloro-4-fluorophenyl)-4-methyl-1H-pyrrole-3-carboxylic acid (0.61 g, 2.4 mmol) in dichloromethane (30 ml) was added oxalyl chloride (0.41 ml, 4.8 mmol). The mixture was stirred at room temperature for 2.0 h, after which time the solvent was removed on a rotary evaporator. To this brown residue was added THF (40 ml), 4-(methanesulfonyl)aniline hydrochloride (495 mg, 2.38 mmol), and DIEA (1.6 ml, 9.5 mmol). The solution was stirred at room temperature for 20 h. The reaction mixture was concentrated on a rotary evaporator and 2N HCl (30 ml) was added to the residue. The solid was filtered and washed with 2N HCl, water and IPE to give the title compound (812 mg, 84%) as a brown solid.
Reaction SMILES: [C:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10](Cl)=[O:11].[C:14]([C:16]1[CH:38]=[CH:37][C:19]([NH:20][C:21](=[O:36])[C:22]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH2:23][S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:18][C:17]=1[C:39]([F:42])([F:41])[F:40])#[N:15]>N1C=CC=CC=1>[C:14]([C:16]1[CH:38]=[CH:37][C:19]([NH:20][C:21](=[O:36])[C:22]([O:35][C:10]([CH:2]2[CH2:3][CH:4]3[C:7]([CH3:9])([CH3:8])[C:1]2([CH3:13])[CH2:6][CH2:5]3)=[O:11])([C:31]([F:32])([F:33])[F:34])[CH2:23][S:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:18][C:17]=1[C:39]([F:41])([F:42])[F:40])#[N:15]
Reactant: CC1(C)C2CCC1(C)C(C(=O)Cl)C2
Reactant: N#Cc1ccc(NC(=O)C(O)(CSc2ccccc2)C(F)(F)F)cc1C(F)(F)F
Solvent: c1ccncc1
Product: CC1(C)C2CCC1(C)C(C(=O)OC(CSc1ccccc1)(C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1)C(F)(F)F)C2
Temperature: 95 °C

Procedure:
(-)-Camphanoyl chloride (4.33 g.) was added portionwise during 5 minutes to a solution of 4-cyano-3-trifluoromethyl-N-(2-hydroxy-3-phenylthio-2-trifluoromethylpropionyl)aniline (5.8 g.) in pyridine (35 ml.) and the mixture was heated at 95° C. for 150 minutes and then evaporated to dryness. Toluene (50 ml.) was added and the mixture was again evaporated to dryness. The residue was dissolved in ethyl acetate (200 ml.) and the solution was washed with water (30 ml.) and then twice with saturated aqueous sodium chloride solution (20 ml. each time), dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was dissolved in methylene chloride (10 ml.) and the solution was flash chromatographed on silica gel (Merck 9385) using methylene chloride as eluant. There were thus obtained the two disastereoisomers of 4-cyano-3-trifluoromethyl-N-[2-(-)-camphanoyloxy-3-phenylthio-2-trifluoromethylpropionyl)aniline, the less polar isomer having m.p. 121°-123° C. and the more polar isomer having m.p. 140°-143° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[C@H:4]([CH2:16][OH:17])[CH2:3]1.CC(C)([O-])C.[K+].[Cl-].[Cl-].[Ca+2]>CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[C@H:4]([CH2:16][OH:17])[CH2:3]1
Reactant: CN1CC[C@H](c2ccc(Cl)c(Cl)c2)[C@H](CO)C1
Agent: CC(C)(C)[O-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CN1CC[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CO)C1

Procedure:
A solution of (5) (10.0 g, 36 mmol) and potassium tert-butoxide (12.0 g, 1.08 mmol) in dimethylformamide (75 ml) was stirred over night. CaCl2 (75 ml, 3M) was added and the reaction mixture was extracted with ethyl acetate (2×200 ml). The combined organic phases was dried with sodium sulfate and evaporated to dryness. The residue was recrystallized from ethyl acetate (7 ml). Yield 6.3 g (63%) of (7), mp 137-139° C., [α]D25=+39°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>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.C1(C)C=CC=CC=1.C(O)C>[CH:12]([N:11]1[C:5]2[CH:4]=[CH:3][C:2]([C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)=[CH:25][CH:26]=3)=[CH:18][C:6]=2[CH:7]=[C:8]([C:14]([O:16][CH3:17])=[O:15])[CH2:9][CH2:10]1)=[O:13]
Reactant: [O-]B([O-])Oc1ccc(N2CCOCC2)cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2N(C=O)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 82 %

Procedure:
To a mixture of methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (3.51 g), 4-morpholinophenyl borate (3.51 g) and potassium carbonate (3.75 g) was added a mixture of water (20 ml), ethanol (20 ml) and toluene (100 ml), and the mixture was stirred under argon atmosphere at room temperature for 40 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.52 g), and the mixture was refluxed under argon atmosphere for 12 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-formyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (3.64 g) as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:13][CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C([Li])(C)(C)C.CCCCC.[B:25](OC)([O:28]C)[O:26]C>O1CCCC1>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([B:25]([OH:28])[OH:26])[CH:3]=[C:4]([CH2:13][CH3:14])[C:5]=2[O:9][CH2:8]1
Reactant: CCc1cc(Br)cc2c1OCC2(C)C
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCc1cc(B(O)O)cc2c1OCC2(C)C

Procedure:
Following General Procedure A and using 5-bromo-3,3-dimethyl-7-ethyl-2,3-dihydro-benzofuran (Intermediate 14, 0.76 g, 3 mmol), 15 mL of anhydrous tetrahydrofuran, 1.7M solution of t-butyllithium in n-pentane (3.53 mL, 6 mmol) and trimethyl borate (0.75 mL, 7 mmol), the title compound was obtained as a foam that was used as such for the next step without purification and characterization.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].C(N(CC)CC)C.[CH2:20]=[C:21]([C:26](OS(F)(=O)=O)([F:28])[F:27])[C:22]([F:25])([F:24])[F:23]>C(OCC)C>[CH2:20]=[C:21]([C:26]([O:8][C:7]1[C:6]([F:9])=[C:5]([F:10])[C:4]([F:11])=[C:3]([F:12])[C:2]=1[F:1])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C=C(C(F)(F)F)C(F)(F)OS(=O)(=O)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(C(F)(F)F)C(F)(F)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
Pentafluorophenol (7.5 g, 0.040 mole) and triethylamine (4.5 g, 0.044 mole) in dry ethyl ether (7 ml) are added gradually to CH2═C(CF3)CF2OSO2F (11 g, 0.045 mole) in ethyl ether (14 ml) at 20° C. The reaction mixture is agitated at 20° C. for 30 minutes and washed in turn with water, dilute aqueous HCl, water, sodium bicarbonate solution, and water and the resulting ether solution is dried over MgSO4. Distillation of the dried mixture gives CH2═C(CF3)CF2OC6F5 (9.8 g, 73% yield, b.pt. 86-88° C. at 20 mm Hg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]#[N:10])=[C:4]([O-:11])[CH:3]=1.[Na+].C([O-])([O-])=O.[K+].[K+].[C:19]1(Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([O:11][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:5]([C:9]#[N:10])=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(N)cc([O-])c1C#N
Reactant: BrC1=CCCCC1
Agent: [Pd]
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1nc(N)cc(OC2CCCCC2)c1C#N
Reaction time: 14 h

Procedure:
To a mixture of sodium 6-amino-3-cyano-2-methylpyridin-4-olate (300 mg, 1.75 mmol) and K2CO3 (485 mg, 3.51 mmol) in DMF (6 ml) was added Cyclohexenylbromide (0.213 ml, 1.84 mmol) and the reaction mixture was stirred at it for 14 h. NaHCO3 (100 ml) was added and the mixture was extracted with EA (5×30 ml). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The resulting product was dissolved in n-PrOH (10 ml), and hydrogenated (1 atm H2, rt) for 1 h over Pd/C (93 mg, 0.088 mmol). The reaction mixture was filtered and the filtrate was adsorbed on celite. Purification by column chromatography (CombiFlash Companion, 10 g SiO2, DCM to DCM:MeOH 9:1) afforded the desired product. LCMS RtM=1.63 min, [M+H]+=232.6.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:20]=[CH:19][C:9](/[CH:10]=[CH:11]/[C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=O)=[CH:8][CH:7]=2)=[CH:4][C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]1=2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[S:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][CH2:12][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)=[CH:19][CH:20]=2)=[CH:4][C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]1=2
Reactant: O=C(/C=C/c1ccc(-c2cc3ccccc3s2)cc1)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2sc(-c3ccc(CCCN4CCCC4)cc3)cc2c1
Yield: 52 %

Procedure:
A solution of 1.2 g (3.6 mmol) of 1-[trans-4-(benzo[b]thiophen-2-yl)cinnamoyl]pyrrolidine (Part B) in 15 mL of THF was treated with 75 mg (2.0 mmol) of LiAlH4 at −15° C. After complete consumption of starting material, the reaction was cautiously quenched with H2O. The mixture was extracted with EtOAc and the combined organic layers were evaporated in vacuo. Chromatography afforded 600 mg (1.9 mmol; 52% yield) of the desired product.
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[C:6]([S:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)[CH2:2][CH3:3].O>C(O)C.[Ni]>[CH2:1]([C:4]1[N:5]=[C:6]([S:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[S:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(SCCCC(=O)OCC)sc1Cc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: CCCc1nc(SCCCC(=O)OCC)sc1Cc1ccc(N)cc1
Yield: 21.6 %

Procedure:
3 g of ethyl 4-[[4-propyl-5-(4-nitrobenzyl)thiazol-2-yl]mercapto]butyrate in 50 ml of ethanol are hydrogenated at normal pressure and room temperature in the presence of Raney nickel. After filtration of the catalyst and concentration of the filtrate, the brown oil obtained is taken up with acidified water. The aqueous phase is extracted with chloroform, rendered basic with dilute sodium hydroxide and extracted with ether. The ether solution is dried and concentrated to give a yellow oil, which is purified on a silica column (eluent: 7/3 cyclohexane/ethyl acetate) to give 0.6 g of ethyl 4-[[4-propyl-5-(4-aminobenzyl)thiazol-2-yl]mercapto]butyrate in the form of a pink oil.
Reaction SMILES: C(OC(=O)C)(=O)C.[BrH:8].C([NH:19][CH2:20][C:21]([NH:23][C:24]([C:32]([OH:34])=[O:33])=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22])(OCC1C=CC=CC=1)=O>C(O)(=O)C>[BrH:8].[NH2:19][CH2:20][C:21]([NH:23][C:24]([C:32]([OH:34])=[O:33])=[CH:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:22]
Reactant: O=C(CNC(=O)OCc1ccccc1)NC(=Cc1ccccc1)C(=O)O
Agent: Br
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: NCC(=O)NC(=Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
0.2 g (0.002 mole) of acetic anhydride was added to 3 ml of 32% hydrogen bromide in acetic acid, and the resulting mixture was allowed to stand at room temperature for 30 minutes. Thereto, 0.336 g (0.001 mole) of the azlactone of N-carbobenzoxyglycyldehydrophenylalanine was added and the resulting solution was stirred at room temperature. After 30 minutes, glyclydehydrophenylalanine hydrobromid precipitated. It was filtered and washed with anhydrous ether. Recrystallization from methanol-ethyl acetate yielded 0.290 g (91%) of glycyldehydrophenylalanine hydrobromide, mp 221°-223° (decomp.). The product was identical to that obtained from Example 9 (c)
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:11]([O:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH:5]=[CH:6][O:1]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCC1CCC=CO1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C1=COC(COCc2ccccc2)CC1
Reaction time: 17 h
Yield: 95 %

Procedure:
3,4-Dihydro-2H-pyran-2-ylmethanol (5.0 g) was dissolved in tetrahydrofuran (100 ml). 55% Sodium hydride (2.3 g) and benzyl bromide (8.2 g) were added under ice-cooling, followed by stirring for 17 hours. A saturated aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate and washing with brine. The organic layer was dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (8.5 g) as a pale yellow oil.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].N1C=CC=CC=1>CCOCC>[CH3:7][S:8]([O:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCCC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CS(=O)(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
A round-bottomed flask (1,000 cc) equipped with a mechanical stirrer was charged with cyclopentyl alcohol (51.2 g, 0.595 mol) and methanesulfonyl chloride (75.1 g, 0.656 mol), followed by the addition of pyridine (200 mL) under ice cooling to form a solution. The solution was stirred for 6 h as it was warmed gradually to room temperature. After completion of the reaction, the reaction mixture was poured into ice water (300 mL) and extraction was conducted with ether (200 mL×3). The organic layers were washed with water, 1N HCl and saturated brine and dried with anhydrous magnesium sulfate. Distilling off the solvent under vacuum gave cyclopentyl methanesulfonate as a colorless oil (75.2 g, 0.458 mol; yield=77.0%). 1H-NMR(CDCl3,TMS,ppm): δ1.54-2.03(8H,m), 3.01(3H,s), 5.19(1H,m).
Reaction SMILES: CS[C:3]1[C:9]2=[CH:10][C:11]3[C:16]([N:8]2[CH2:7][C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.[N:21]1([CH2:27][CH2:28][CH2:29][OH:30])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(Cl)Cl>[CH:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]1[N:8]2[CH2:7][C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[N:4]=[C:3]1[N:24]1[CH2:25][CH2:26][N:21]([CH2:27][CH2:28][CH2:29][OH:30])[CH2:22][CH2:23]1
Reactant: CSC1=Nc2ccccc2Cn2c1cc1ccccc12
Reactant: OCCCN1CCNCC1
Solvent: ClCCl
Product: OCCCN1CCN(C2=Nc3ccccc3Cn3c2cc2ccccc23)CC1

Procedure:
A mixture of 5.39 g of 12-methylthio-6H-indolo[2,1-c][1,4]benzodiazepine, the product of Example 1c., and 17 g of 1-piperazinepropanol in a pressurized bottle was heated to 220° C. overnight. The reaction mixture was dissolved in CH2Cl2 and then was washed with water. Removal of solvent in vacuo followed by recrystallization from EtOH gave the title compound, a colorless solid, mp 174°-175° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:32][CH2:33]SC)[C:13]([NH:15][C@H:16]1[CH2:22][CH2:21][C@@H:20]2[CH2:23][C@H:17]1[C:18](=[O:31])[N:19]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>IC.CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:32][CH2:33][N:15]([C@H:16]2[CH2:22][CH2:21][C@@H:20]3[CH2:23][C@H:17]2[C:18](=[O:31])[N:19]3[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:13]1=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1CC[C@@H]2C[C@H]1C(=O)N2C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.3 %

Procedure:
(1R,2S,5R)-tert-Butyl 2-((S)-2-(benzyloxycarbonylamino)-4-(methylthio)butanamido)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (5.1 g) was dissolved in iodomethane (40 mL). The resulting solution was stirred at rt for 12 h before being concentrated in vacuo. The residue was dissolved in methylene chloride, and the resulting solution was concentrated; this was repeated to afford the salt. This material was dissolved in DMF (30 mL) and the solution was charged with Cs2CO3 (6.6 g). After 12 h, the reaction was partitioned between EtOAc and brine. The organic phase was dried (MgSO4), filtered, and concentrated. The resulting residue was purified by flash chromatography to afford (1R,2S,5R)-tert-butyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (2.0 g). MS found: (M+H)+=458.6.
Reaction SMILES: [Mg].C[Si](Cl)(C)C.[Cl:7][C:8]1[CH:9]=[C:10]([C:17]([CH3:26])([CH3:25])[CH2:18][C:19](=[O:24])[C:20](F)([F:22])[F:21])[C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([C:17]([CH3:26])([CH3:25])[CH2:18][C:19](=[O:24])[CH:20]([F:21])[F:22])[C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Agent: C[Si](C)(C)Cl
Agent: [Mg]
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)C(F)F)c1cc(Cl)cc2c1OCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
A mixture of magnesium turnings (204 mg, 8.40 mmol) and trimethylsilyl chloride (2.13 mL, 16.8 mmol) in 10 mL of DMF was treated with 4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-one (1.23 g, 4.00 mmol) in 10 mL of DMF at 0° C. The resulting mixture was stirred at room temperature overnight. The mixture was filtered and concentrated in vacuo. The residue was suspended in 20 mL of THF and treated with TBAF (1 M in THF, 4.0 mL) at room temperature. After 15 minutes, the reaction was quenched with 25 mL of saturated aqueous ammonium chloride solution and diluted with 50 mL of diethyl ether. The phases were separated and the aqueous layer was extracted with three 50 mL portions of diethyl ether. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on SiO2 (100% hexanes to 10% diethyl ether in hexanes, gradient) afforded 550 mg of the title product (48% yield).