Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=2[O:23][CH3:24])=[CH:5][CH:4]=1)#[N:2].S(Cl)([Cl:29])=O.CN(C)C=O>ClCCl>[C:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([Cl:29])=[O:19])=[CH:16][C:15]=2[O:23][CH3:24])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C(=O)O)ccc1OCCCCCOc1ccc(C#N)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)Cl)ccc1OCCCCCOc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
4-[5-(4-cyanophenoxy)pentoxy]-3-methoxybenzoic acid (3600 g, 10.13 mol) is suspended in dichloromethane (36 L) and to this is added thionyl chloride (1345 g, 11.30 mol) dropwise over 20 minutes followed by dimethylformamide (74.4 g, 10.0 mol). The reaction mixture is stirred at room temperature for 21 hours; after 6 hours a complete solution is obtained. The solution is concentrated in vacuo (50° C., 3 mm Hg) to give 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxybenzoyl chloride as a solid, which is then redissolved in dichloromethane (36 L) without further purification and cooled to 5° C. with an ice bath. Diisopropylamine (3077 g, 30.40 mol) is added dropwise over a period of 1 hour. The reaction mixture is stirred at 20° C. for 3 hours and then, N,N-dimethylethylenediamine (80.3 g, 0.91 mol) is added. The reaction is followed by TLC (2:1 ethyl acetate/hexanes, silica plates) until no more byproduct (bis-anhydride of 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxybenzoic acid) is detected. The reaction mixture is then stirred overnight at room temperature. Water (18 L) is added, stirred and the layers separated. The organic layer is washed with hydrochloric acid (1.0N, 23 L), water (18 L), ammonium hydroxide (0.5N, 2×23 L), water (18 L) and brine solution (18 L). The separated dichloromethane solution is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo (50° C., 3 mm Hg) to give 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxy-N,N-bis(1-methylethyl)-benzamide as a solid. The solid is dissolved in 2 B ethanol (21.5 L) by warming and to the solution is added water (8.6 L). The product is allowed to crystallize overnight in an ice bath. The product is filtered, washed with EtOH/H2O (5:2, 2×2 L) and dried in vacuo (54° C., 3 mm Hg) to give 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxy-N,N-bis(1-methylethyl)-benzamide, mp 90°-92° C. HPLC indicates a purity of >99.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:28])[C:12]2[C:13]([N:27]=1)=[C:14]([CH:25]=O)[CH:15]=[C:16]1[C:21]=2[C:20](=[O:22])[NH:19][C:18]([CH3:23])=[C:17]1[CH3:24].[CH2:29]([CH2:31][NH2:32])[OH:30].[BH3-]C#N.[Na+]>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:11]([CH3:28])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH3:23])=[C:17]([CH3:24])[C:16]=3[CH:15]=[C:14]([CH2:25][NH:32][CH2:31][CH2:29][OH:30])[C:13]=2[N:27]=1
Reactant: Cc1[nH]c(=O)c2c(cc(C=O)c3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Reactant: NCCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1[nH]c(=O)c2c(cc(CNCCO)c3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.2 %

Procedure:
A suspension of the product of Example 23 (30 mg, 0.07 mmol) in MeOH (5 mL) was treated with ethanolamine (44 μL, 0.72 mmol) and NaBH3CN (14 mg, 0.22 mmol), and stirred at room temperature for 16 h. The resulting mixture was concentrated and the residue was diluted with water. The precipitated solid was filtered to give the title compound (12 mg, 36%). mp decomp. above 250° C.; MS (CI) 460 (MH+).
Reaction SMILES: C[N:2]([C:23]([O:25][C:26]12[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2)=[O:24])[C:3]([CH3:22])([C:19]([OH:21])=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.O.[OH-].[Li+]>>[CH3:22][C:3]([C:19]([OH:21])=[O:20])([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[NH:2][C:23]([O:25][C:26]12[CH2:27][CH:28]3[CH2:29][CH:30]([CH2:31][CH:32]([CH2:34]3)[CH2:33]1)[CH2:35]2)=[O:24]
Reactant: CN(C(=O)OC12CC3CC(CC(C3)C1)C2)C(C)(Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(Cc1ccc(OCc2ccccc2)cc1)(NC(=O)OC12CC3CC(CC(C3)C1)C2)C(=O)O

Procedure:
The title compound was prepared from methyl α-methyl-O-(phenylmethyl)-N-[(tricyclo[3.3.1.13,7 ]dec-1-yloxy)carbonyl]-DL-tyrosine (200 mg, 0.418 mmol) and lithium hydroxide monohydrate (26.3 mg, 0.628 mmol, 1.5 eq) using the procedure described in Example 47, Step C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[C:21]([F:24])([F:23])[F:22].C(O)(=O)C>CC(N(C)C)=O.ClCCl>[CH2:3]([O:10][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[C:21]([F:22])([F:23])[F:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 44.4 %

Procedure:
Sodium hydride (1.8 g, of a 60% dispersion in oil, 45 mmol) was added in portions to a stirred solution of benzyl alcohol (10.8 g, 100 mmol) in DMA (100 ml) with vigorous stirring under an atmosphere of nitrogen at ambient temperature. After warming to 45° C. for 30 minutes the mixture was cooled to ambient temperature and added dropwise to a stirred solution of 2-chloro-5-nitro-trifluoromethylbenzene (11.3 g, 50 mmol) in DMA (30 ml), keeping the temperature below 10° C. The mixture was stirred at 25° C. for 1 hour, then acidified with acetic acid and evaporated to give a yellow solid. The residue was dissolved in dichloromethane, washed with water then dried (MgSO4), and evaporated. The residue was suspended in a mixture of hexane (70 ml) and diethyl ether (10 ml) and the resulting solid filtered off to give 2-benzyloxy-5-nitro-trifluoromethylbenzene (6.6 g, 49%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13]OS(C)(=O)=O)[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:27]3[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH2:25][CH2:26]3)[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCN1CCNCC1
Reactant: CS(=O)(=O)OCC1CCN(c2cccc(Br)c2)C1=O
Product: COCCN1CCN(CC2CCN(c3cccc(Br)c3)C2=O)CC1

Procedure:
The title compound was prepared from 1-(3-bromophenyl)-3-mesyloxymethyl-2-pyrrolidinone and 1-(2-methoxyethyl)piperazine, in the same manner as in Preparation Example 1(8).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:8]([F:10])[F:9])=[N:4][NH:5][C:6]=1[CH3:7].C(Cl)(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1>>[Br:1][C:2]1[C:3]([CH:8]([F:10])[F:9])=[N:4][N:5]([CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][O:27]2)[C:6]=1[CH3:7]
Reactant: Cc1[nH]nc(C(F)F)c1Br
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1c(Br)c(C(F)F)nn1C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromo-3-(difluoromethyl)-5-methyl-1H-pyrazole (1.40 g, 6.63 mmol) in chloroform (30.0 mL, 0.375 mol) was added p-toluenesulfonic acid monohydrate (0.13 g, 0.66 mol) at 0° C. Dihydropyran (0.91 mL, 0.010 mol) was added and stirred at 25° C. for 2 h. The reaction was extracted with ethyl acetate and the organic extracts were washed with NaHCO3, water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The compound was chromatographed on silica gel using 10% EtOAc/hexanes to give the desired product. 1H NMR (CDCl3): δ 6.51-6.78 (t, 1H), 5.31 (dd, 1H), 4.01(m, 1H), 3.65 (m, 1H), 2.40 (m, 1H), 2.35 (s, 3H), 2.21 (m, 1H), 1.95 (m, 1H), 1.50-1.70 (m, 3H).
Reaction SMILES: Br[CH:2]([C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)[CH2:3][CH:4]([O:10][C:11](=[O:13])[CH3:12])[CH2:5][O:6][C:7](=[O:9])[CH3:8].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:11]([O:10][CH:4]([CH2:5][O:6][C:7](=[O:9])[CH3:8])[CH:3]=[CH:2][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OCC(CC(Br)c1cnccn1)OC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(=O)OCC(C=Cc1cnccn1)OC(C)=O
Yield: 66.2 %

Procedure:
7.0 g of 2-(1-bromo-3,4-diacetoxybutyl)pyrazine (4102 and 4103) was dissolved in 100 ml of toluene, 3.3 g of 1,8-diazabicyclo [5.4.0]undec-7-ene added under an argon atmosphere and the solution heated overnight at 65°-70°. It was then cooled, the toluene solution decanted and concentrated in vacuo. The residue was chromatographed on silica gel (hexane/ethyl acetate) to yield 3.5 g of 2-(3,4-diacetoxy-1-butenyl)pyrazine (4104) as a pale yellow oil. UV EtOH max: 240 (4.14), 292 (3.85), 298 (3.86).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.[C:11]1([CH2:17][O:18][C:19]([NH:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C12CCCC(CCC1)B12[H]B2(C3CCCC2CCC3)[H]1.[OH-].[Na+]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].OO>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([CH2:24][CH2:23][CH2:22][NH:21][C:19]([O:18][CH2:17][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20])=[CH:3][C:4]=1[F:10])#[N:7]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: C=CCNC(=O)OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: OO
Product: N#Cc1ccc(CCCNC(=O)OCc2ccccc2)cc1F

Procedure:
Scheme IIIb, step A: 4-Bromo-2-fluorobenzonitrile (3 g, 15 mmol), (phenylmethoxy)-N-prop-2-enylcarboxamide (3.44 g, 18 mmol), 9-BBN dimer (2.93 g, 12 mmol), [1,1′bis(diphenylphosphino)ferrocene] dichloropalladium (II), PdCl2(dppf) (0.61 g, 0.75 mmol), 3N sodium hydroxide (10 mL), and pH=7 buffer: hydrogen peroxide (2:1, 20 mL) are combined in a manner analogous to the procedure described in example 6 to provide the intermediate title compound, N-[3-(4-cyano-3-fluorophenyl)propyl](phenylmethoxy)carboxamide, (4.18, 89%). Electron spray M.S. 313 (M*+H).
Reaction SMILES: [C:1]([CH2:3][N:4]([CH2:9][CH2:10][C:11]#[N:12])[CH2:5][CH2:6][CH2:7][OH:8])#N.N.[H][H]>[Ni].C(O)C>[OH:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][CH2:11][NH:12][CH2:1][CH2:3]1
Reactant: N#CCCN(CC#N)CCCO
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: OCCCN1CCCNCC1

Procedure:
100 grams (0.598 mole) of cyanomethyl-(2-cyano-ethyl)-(3-hydroxy-propyl)-amine, 800 ml of ethanol, 67 grams of ammonia and 26 grams of Raney-nickel were heated in an autoclave during 2 hours under 80 to 100 bar hydrogen pressure at 70° C. (at the beginning) to 120° C. (toward the end). Subsequently the reaction mixture was worked up as described under (b). There were obtained 52 grams (55% of theory) as a final product.
Reaction SMILES: [C:1]1(=[N:7][OH:8])CCC[CH2:3][CH2:2]1.[N+:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)([O-:11])=[O:10].O>C(Cl)Cl>[N:7]([CH:1]([O:18][CH2:16][C:15]1[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:20][CH:19]=1)[CH2:2][CH3:3])=[O:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: ON=C1CCCCC1
Solvent: ClCCl
Solvent: O
Product: CCC(N=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A solution of cyclohexanone oxime (3.11 g, 42.58 mmol) in methylene chloride (50 mL) was added dropwise with stirring to a solution of LTA (18.88 g, 42.58 mmol) and 4-nitrobenzoic acid (71.16 g, 425.8 mmol) in methylene chloride (300 mL) at 0° C. A blue color gradually appeared with the addition of the oxime. After 1 h at 0° C., the reaction mixture was warmed to room temperature. After 3 h at room temperature, water (50 mL) was added and the organic layer was extracted with water (2×50 mL) and 3% sodium bicarbonate solution (2×50 mL). The organic layer was dried over Na2SO4, the solvent evaporated and the residue was recrystallized in diethyl ether/petroleum ether (1:1) in a −5° C. freezer to give 1-Nitroso-1-para-nitrobenzoxypropane as bright blue crystals (25-30% yield): Rf 0.5 (pentane/ethyl acetate=20:1); 1H NMR (300 MHz, CDCl3) δ 1.69 (s, 6H), 8.31-8.48 (d, 4H); 13C NMR (300 MHz, CDCl3) δ 21.1 (2CH3), 122.6 (O—C—N), 124.0 (2Ph-CH), 131.4 (2Ph-CH), 135.6 (Ph-C), 151.2 (Ph-C), 162.9 (C═O).
Reaction SMILES: [CH2:1]([CH:6]([CH2:9][OH:10])[CH2:7][OH:8])[CH2:2][CH2:3][CH2:4][CH3:5].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH:15]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.C(Cl)(Cl)Cl.C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:1]([CH:6]1[CH2:9][O:10][CH:15]([C:14]2[CH:17]=[CH:18][C:19]([F:20])=[C:12]([F:11])[CH:13]=2)[O:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: CCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCC1COC(c2ccc(F)c(F)c2)OC1

Procedure:
Four solutions were prepared by dissolving 11.8 g (0.10 mol) of 2-pentylpropane-1,3-diol (prepared in Example 1 following the procedures of Steps 1-2), 14.2 g (0.10 mol) of 3,4-difluorobenzaldehyde, and 0.9 g (0.005 mol) of p-toluenesulfonic acid in methylene chloride (b.p. 40° C.), chloroform (b.p. 60° C.), benzene (b.p. 80° C.) and toluene (b.p. 111° C.), respectively. The solutions were treated following the procedures of Step 3 of Example 1 to yield mixtures of the cis and trans isomers of 5-pentyl-2-(3',4'-difluorophenyl)-1,3-dioxane. The yields of each mixture from its respective solvent and the ratio of the trans isomer to the cis isomer of each mixture are shown in Table 1.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[CH:6]=[C:5]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:3][CH2:2]1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH2:31][CH2:32][NH2:33].C(N(CC)CC)C>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([NH:33][CH2:32][CH2:31][NH:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[C:12]=3[F:14])[C:7](=[O:18])[CH:6]=[C:5]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:2][CH2:3]1
Reactant: NCCNc1ccccn1
Reactant: CCOC(=O)c1cc(=O)c2c(F)c(F)c(F)c(F)c2n1C1CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(=O)c2c(F)c(F)c(NCCNc3ccccn3)c(F)c2n1C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
A solution ethyl 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-2-carboxylate (688 mg, 2.09 mmol), N-2-pyridyl-1,2-ethanediamine (570 mg, 4.16 mmol) and triethylamine (0.87 mL, 6.24 mmol) in DMSO (20 mL) was stirred at 70° C. After 1 h, the reaction mixture was poured into ice water and the resulting solution was extracted with EtOAc, and the organic layer washed with water, brine, and then dried. The solvent was removed and the crude product was purified by column chromatography (Hexane:EtOAc 1:1) to yield ethyl 1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-2-carboxylate (773 mg, 83%) as yellow solid.
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12]([O:16][C:17]([NH:19][CH:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Br:30])[CH:26]=2)[CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=[O:38])[CH:32]=1>O1CCCC1>[C:12]([O:16][C:17]([NH:19][CH:20]1[CH2:29][CH2:28][C:27]2[CH2:26][C:25]([CH:37]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)[OH:38])([Br:30])[CH:24]=[CH:23][C:22]=2[CH2:21]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=Cc1cccnc1
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(Br)ccc2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NC1CCC2=C(C=CC(Br)(C(O)c3cccnc3)C2)C1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
8.8 ml of a solution of n-butyl lithium in hexane (2.5 mol) was dropped to a solution of 3.25 g of 2-tert.butoxycarbonylamino-6-bromo-1,2,3,4-tetrahydro-naphthaline in 50 ml of absolute tetrahydrofurane cooled to -70° C. and stirring was continued for 1.5 hours at -50° C. Subsequently, 1.1 g of pyridine-3-aldehyde were dropped into the mixture at -70° C. After stirring for one hour, the reaction mixture was poured on ice and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated. The obtained residue was recrystallised from cyclohexane/ethyl acetate.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[N:15][OH:16])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([I:13])[C:7]=2F)[CH2:3][CH2:2]1>C1COCC1>[CH:1]1([NH:4][C:5]2[C:6]3[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([I:13])[C:7]=3[O:16][N:15]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=NO)NC2CC2)c(F)c1I
Solvent: C1CCOC1
Product: Cc1ccc2c(NC3CC3)noc2c1I
Temperature: 150 °C

Procedure:
1,8-Diazabicyclo(5.4.0)-7-undecene (0.25 mL, 1.65 mmol) was added to N-cyclopropyl-2-fluoro-N′-hydroxy-3-iodo-4-methylbenzamidine (500 mg, 1.5 mmol) in anhydrous THF (2.0 mL) then heated in a microwave at 150° C. for 70 min. The solvents were evaporated and the residue was loaded on an ISCO column (40 g, eluted with 25-75% ethyl acetate in Hexanes) to provide the title compound as an off-white crystalline solid. MS (ESI, pos. ion) m/z: 315.0 (M+1).
Reaction SMILES: [CH:1]1([CH:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[CH:29][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][S:23][CH3:24])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:44]OS([O-])=O.[K+]>CO.O>[CH:1]1([CH:7]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:34])=[CH:29][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:24])=[O:44])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2cc(-c3ccc(OCCCSC)cc3)oc2C)C2CCCCC2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2cc(-c3ccc(OCCCS(C)=O)cc3)oc2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
Ethyl 3-{[(4-{[cyclohexyl(2-methyl-5-{4-[3-(methylsulfanyl)propoxy]phenyl}furan-3-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (0.37 g) synthesized in Example 259 (1) was dissolved in methanol (9 mL) and water (1 mL), OXONE (221 mg) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 100% ethyl acetate/hexane) to give the title compound (283 mg, 91%) as an oil.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3C(C)=NN=[C:10]3[CH2:9][N:8]=[C:7](C3C=CC=CC=3F)[C:6]=2[CH:23]=1>CN(C)C=O.C(Cl)(=O)C>[NH:11]1[C:5]2[CH:4]=[CH:3][CH:2]=[CH:23][C:6]=2[CH:7]=[N:8][CH:9]=[CH:10]1
Reactant: Cc1nnc2n1-c1ccc(F)cc1C(c1ccccc1F)=NC2
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: C1=CNc2ccccc2C=N1

Procedure:
In the manner given in Example 1, a solution of 8-fluoro-1-methyl-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide, N,N,N',N'-tetrapropyldiaminomethane and acetyl chloride (in 0.5 molar excess compared to the N,N,N',N'-tetrapropyldiaminomethane) are reacted together to give 8-fluoro-1[2-(dipropylamino)ethyl]-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4-benzodiazepine
Reaction SMILES: [C:1]1([CH3:34])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:24])[CH3:23])[CH2:13][CH:12]([NH:25]C(OC(C)(C)C)=O)[C:11]2=[O:33])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1>Cl.O1CCOCC1>[C:1]1([CH3:34])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:24])[CH3:23])[CH2:13][CH:12]([NH2:25])[C:11]2=[O:33])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)N1CC(NC(=O)OC(C)(C)C)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N1CC(N)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
1-(2-Toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-acetyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.00 g) was suspended in 4N HCl-dioxane (10 ml), the suspension was stirred for one hour at 50° C. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, washed with diethyl ether, alkalified with saturated aqueous sodium bicarbonate, and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, to thereby obtain 820 mg of the titled compound (Yield: 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@:5]([CH3:9])([CH:7]=O)[CH2:4][O:3]1.Cl.[NH2:12][OH:13].C([O-])([O-])=O.[Na+].[Na+]>O.CO>[CH3:1][C:2]1([CH3:10])[O:6][C@:5]([CH3:9])([CH:7]=[N:12][OH:13])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@](C)(C=O)O1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(C)OC[C@@](C)(C=NO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
(S)-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde (5.8 g, 40 mmol) was dissolved in 1:1 methanol water (100 mL) and hydroxylamine hydrochloride (2.8 g, 40 mmol) and Na2CO3 (2.1 g, 20 mmol). The reaction was stirred at ambient temperature overnight, then concentrated in vacuo. The aqueous layer was extracted with CH2Cl2, and the organic layer was dried over sodium sulfate, filtered and concentrated to afford (R)-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde oxime (4.8 g, 30 mmol, 75% yield).
Reaction SMILES: Br[C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:12][C:5]1[CH:4]=[CH:3][C:2]([C:19]2[CH:18]=[CH:17][C:16]([O:15][C:14]([F:13])([F:25])[F:26])=[CH:21][CH:20]=2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)ccc1O
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)ccc1O
Temperature: 50 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Methyl 5-bromosalicylate (5 g, 21.6 mmol), 4-(trifluoromethoxy)phenylboronic acid (4.43 g, 21.6 mmol), potassium carbonate (10 g) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (800 mg, 1.09 mmol) were combined in 10 mL DMF. 5 mL water was added and the mixture was stirred at 50° C. for 60 minutes. The reaction mixture was diluted with 300 mL ethyl acetate, washed with water and brine and evaporated under vacuum. Flash chromatographic purification on 120 g silica gel with 0-100% ethyl acetate in hexane gave methyl 4-hydroxy-4′-(trifluoromethoxy)-[1,1′-biphenyl]-3-carboxylate (5.7 g, 18.3 mmol).