Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[CH2:6])(=[O:3])[CH3:2].[CH3:13]C([O-])(C)C.[K+].C(Cl)(=O)CC>O1CCCC1>[C:1]([O:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[CH2:6])(=[O:3])[CH2:2][CH3:13]
Reactant: C=C(OC(C)=O)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: CCC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(OC(=O)CC)c1ccccc1
Reaction time: 1 h
Yield: 14 %

Procedure:
A solution of 8.11 g (50 mmol) of 1-phenylvinyl acetate (prepared as described in Example 1) in 80 ml of anhydrous tetrahydrofuran was placed in a 500 ml round bottomed flask and cooled to −75°. A solution of 6.16 g (55 mmol) of potassium tert-butylate in 60 ml of anhydrous tetrahydrofuran was slowly added (40′) and the mixture was stirred for 1 h at −75°. A solution of propionyl chloride (55 mmol) in 20 ml of anhydrous tetrahydrofuran was slowly added (20′) and, after 2 h at −75°, the cooling bath was removed and 60 ml of a saturated solution of NaHCO3 was rapidly added. The temperature rose rapidly to −10° and the mixture was extracted with ether. After usual workup, the product was purified by flash chromatography (SiO2, pentane/ether 8/2), bulb-to-bulb distillation and preparative GC using a 1.2 m×6 mm column loaded with 10% SE-30 on Supelcoport® 80–100 mesh, vector gas: helium at 30 ml/min. The product was obtained in 14% yield.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>C1COCC1>[S:26]([N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cc[nH]c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cccc2)cc1
Reaction time: 0.08 h
Yield: 97.6 %

Procedure:
In a 1-liter three-neck flask, 8.65 cm3 of freshly distilled pyrrole (125 mmoles) was introduced together with 100 cm3 of THF and 1 cm3 of a 40% aqueous solution of tetrabutylammonium hydroxide. 125 cm3 of a 50% aqueous NaOH solution was added and the mixture was then vigorously stirred. After 5 minutes, a solution of 38 g of tosylchloride (200 mmoles) in 100 cm3 of THF was dropwise added. The obtained adduct was maintained under stirring until the temperature reached a maximum and then again during some 30 minutes more. After decantation, the aqueous layer was extracted with ethyl acetate, and the combine organic layer was concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with water, dried over magnesium sulfate and evaporated. 27 g of a white solid compound was obtained (1) (M=221, yield: 97.6%). Recrystallization in methanol. F (° C)=92. Elemental analysis: calc.: C 59.73; H 4.98; N 6.33; found: C 59.59; H 4.67; N 6.32. NMR: (CDCl3) ppm 7.7 d J(Hz) 8 2H; 7.2 4H; 6.25 2H; 2.33 s 3H.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([N:11]([CH3:13])[CH3:12])[N:10]=[C:4]2[CH:3]=1.[C:14](=[O:21])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[NH2:15].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:12][N:11]([CH3:13])[C:9]1[N:10]=[C:4]2[CH:3]=[C:2]([NH:15][C:14](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=[CH:6][N:5]2[N:8]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: CN(C)c1nc2cc(Br)ccn2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN(C)c1nc2cc(NC(=O)OC(C)(C)C)ccn2n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
To an argon purged solution of 7-bromo-N,N-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-amine (300 mg, 1.24 mmol) in dioxane (11 ml) are added tert-butyl carbamate (175 mg, 1.49 mmol), cesium carbonate (568 mg, 1.74 mmol), tris(dibenzylideneacetone)dipalladium(0) (22.8 mg, 24.9 μmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (28.8 mg, 49.8 μmol). The resulting mixture is stirred for 18 hours at 100° C. under argon atmosphere. The crude material is loaded on silicagel and purified by chromatography on a 20 g silica column using heptane/ethyl acetate 10-70% as eluent affording tert-butyl 2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridine-7-ylcarbamate (310 mg, 89.8%) as a yellow foam. MS: m/z=278.3 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[C:9]([NH2:10])=[C:8]([N+:11]([O-:13])=[O:12])[C:7]([N+:14]([O-])=O)=[C:6]([N+:17]([O-:19])=[O:18])[C:5]=1[N+:20]([O-])=O)([O-:3])=[O:2].N>C1C=CC=CC=1.C(Cl)Cl>[C:9]1([NH2:10])[C:8]([N+:11]([O-:13])=[O:12])=[C:7]([NH2:14])[C:6]([N+:17]([O-:19])=[O:18])=[C:5]([NH2:20])[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Nc1c([N+](=O)[O-])c([N+](=O)[O-])c([N+](=O)[O-])c([N+](=O)[O-])c1[N+](=O)[O-]
Agent: N
Solvent: c1ccccc1
Solvent: ClCCl
Product: Nc1c([N+](=O)[O-])c(N)c([N+](=O)[O-])c(N)c1[N+](=O)[O-]

Procedure:
According to this invention, the 4-nitro group or trinitrotoluene (TNT) is selectively reduced by H2S in p-dioxane to produce 4-amino-2,6-dinitrotoluene. This latter compound is then nitrated with HNO3 in H2SO4 to produce pentanitroaniline. Finally the pentanitroaniline is reacted with NH3 in benzene, methylene chloride or another suitable solvent to produce a quantitative yield of TATB. The method of this invention is easily carried out and all reactants are inexpensive.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9]Br)[C:3]=1[F:11].O.C(=O)([O-])[O-:14].[Ca+2].Cl>O1CCOCC1>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH2:9][OH:14])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(Br)c(F)c1CBr
Agent: Cl
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: OCc1c(F)ccc(Br)c1F
Yield: 114.3 %

Procedure:
1-Bromo-3-(bromomethyl)-2,4-difluoro-benzene (45.2 g, 0.158 M) was dissolved in dioxane (800 mL), water (800 mL) and calcium carbonate (80 g, 0.80 M) were added and the mixture was refluxed for 16 h. The mixture was cooled, acidified with 2N HCl and extracted with dichloromethane. Organic phases were pooled, dried with Na2SO4 and and evaporated to yield a brownish oil (40.3 g). The residue was purified by column chromatography (silica gel; n-hexane/ethyl acetate 9:1) to yield 31.2 g (88%) of the title compound as a colorless solid. MS (EI): 224.0 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][NH:37][C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1.C(N(CC)CC)C>>[CH3:23][N:24]1[CH2:25][CH2:26][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][N:37]([C:20]([C:17]5[CH:18]=[CH:19][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[N:12]([CH3:13])[CH:11]=[N:10][CH:9]=7)=[CH:7][C:2]=6[CH3:1])=[CH:15][CH:16]=5)=[O:21])[C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:28][CH2:29]1
Reactant: Cc1cc(-c2cncn2C)ccc1-c1ccc(C(=O)O)cc1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cncn2C)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1
Reaction time: 18 h
Yield: 38.6 %

Procedure:
2'-Methyl-4'-(1-methylimidazol-5-yl)biphenyl-4-carboxylic acid (D93, 300 mg, 1.0 mmol) was heated at reflux in thionyl (15 ml) for 1 hour, cooled and evaporated in vacuo. The residue was redissolved in dry THF (10 ml) and treated with 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8, 250 mg, 1.0 mmol) and triethylamine (143 ul, 1.0 mmol) then stirred for 18 hours. The reaction mixture was evaporated in vacuo, partitioned between water and CHCl3 (3 times) and the organic extracts combined. The organics were dried over Na2SO4 and evaporated in vacuo to an orange gum. The gum was purified by flash silica gel chromatography (eluting with 3% MeOH/CHCl3) to yield the title compound as a pale yellow gum (200 mg, 38%) which was converted to the hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[O:12]=[S:13]1(=[O:19])[CH2:17][CH2:16][C@H:15](N)[CH2:14]1.C([O-])([O-])=O.[K+].[K+].CCN(CC)CC>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:15]2[CH2:16][CH2:17][S:13](=[O:19])(=[O:12])[CH2:14]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: N[C@H]1CCS(=O)(=O)C1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)ccc1N[C@H]1CCS(=O)(=O)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a mixture of 4-chloro-2-nitro-phenylamine (1.2 g, 6.8 mmol) and (S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-ylamine (0.97 g, 5.7 mmol) and K2CO3 (13.6 mmol) in DMF (8 mL) was added Et3N (13.6 mmol). The mixture was stirred at 100° C. for 2 h. After cooled to RT, the reaction mixture was poured into water, extracted with EtOAc. The organic phase was washed with saturated NH4Cl, aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4. The nitro compound (1.1 g, yield: 66%) was obtained as yellow solid by flash column (ethyl acetate/petroleum ether=1/1). MS obsd. MS obsd. (ESI+) [(M+H)+] 291.0.
Reaction SMILES: [C:1]1([C:7]23[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[S:17](=[O:25])(=[O:24])[CH2:16][C:10]4([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]4)[CH:8]2[O:9]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[H][H]>[Pd].C(Cl)Cl>[OH:9][C@@H:8]1[C:10]2([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:16][S:17](=[O:25])(=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S1(=O)CC2(CCCCC2)C2OC2(c2ccccc2)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: O=S1(=O)CC2(CCCCC2)[C@@H](O)[C@H](c2ccccc2)c2ccccc21
Yield: 40.1 %

Procedure:
A mixture of 0.5 g (1.4 mmoles) of 58, 20 ml of ethanol, 10 ml of methylene chloride and 0.4 g of 10% Pd/C catalyst was hydrogenated with 70 psi hydrogen for 3 h at room temperature. The crude reaction slurry was filtered through Celite and evaporated to dryness. The residue was purified by HPLC (10% EtOAc-Hexane, 25% EtOAc-Hexane). The first fraction was 300 mg (60%) as a white solid, mp 99-100° C. Proton NMR showed this was a trans isomer. The second fraction gave 200 mg of solid which was impure cis isomer.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[CH:22]1([CH:28]=O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:15])[CH2:10][N:9]1[CH2:28][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:7])#[N:3]
Reactant: O=CC1CCCCC1
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1CC1CCCCC1

Procedure:
L4. (2S,4R)-4-Benzenesulfonyl-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride prepared in analogy to experiment K1 was reductively aminated with cyclohexanecarbaldehyde in analogy to experiment L3 to give (2S,4R)-4-benzenesulfonyl-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a white solid. MS: 390.4 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][N:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH3:16])=[CH:8][CH:7]=1.[OH-].[K+].O.Cl>C(O)C>[CH2:17]([N:15]([CH2:14][CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:29])=[O:2])=[CH:7][CH:8]=1)[CH3:16])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)O)cc1
Temperature: 22 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A solution of 3-[4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl]propanoic acid methyl ester (2.30 g, 5.69 mmol) in ethanol (25 ml) was treated with potassium hydroxide (0.64 g, 11.4 mmol) and water (5 ml) and stirred at 22° C. for 2 h. The reaction mixture was then acidified to pH 4 with 1M hydrochloric acid and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure to give a white solid. Recrystallization from ethyl acetate gave 2.20 g (89%) of 3-[4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl]propanoic acid as white crystals.
Reaction SMILES: [ClH:1].[CH:2]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:27][CH2:26][C:14]3([N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:17][CH2:16][CH:15]3[OH:25])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)([CH3:4])[CH3:3].[H-].[Na+].[CH3:30]OS(OC)(=O)=O>CN(C)C=O>[ClH:1].[CH:2]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:12][CH2:13][C:14]3([N:18]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:17][CH2:16][CH:15]3[O:25][CH3:30])[CH2:26][CH2:27]2)[CH2:7][CH2:6]1)([CH3:4])[CH3:3]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)[C@H]1CC[C@@H](N2CCC3(CC2)C(O)CCN3c2ccccc2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCN(c2ccccc2)C12CCN([C@H]1CC[C@@H](C(C)C)CC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
RS)-8-(cis-4-Isopropyl-cyclohexyl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol hydrochloride (0.3 mmol) was dissolved in dimethylformamide (15 ml), sodium hydride (1.2 mmol) was added and the mixture stirred for 1 h at room temperature. Dimethylsulfate (0.9 mmol) was added and stirring continued for 5 h. The mixture was quenched with ice-water (10 ml) and saturated sodiumbicarbonate solution (10 ml) and extracted three times with dichloromethane. The organic phases were pooled, dried with Na2SO4 and concentrated. Chromatography on silica gel (ethyl acetate) yielded the desired product which was crystallized as its HCl-salt from ethanol. 55 mg (44%) (RS)-8-(cis-4-isopropyl-cyclohexyl)-4-methoxy-1-phenyl-1,8-diaza-spiro[4.5]decane hydrochloride (1:1) as a colorless solid, m.p. 214-215° C. and MS: m/e=371.4 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[OH:21][CH:22]1[CH:31]([OH:32])[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:33](O)=[O:34])[CH:29]=2)[O:24][C:23]1([CH3:37])[CH3:36]>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:33]([C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[O:24][C:23]([CH3:37])([CH3:36])[CH:22]([OH:21])[CH:31]2[OH:32])=[O:34]
Reactant: CC1(C)Oc2ccc(C(=O)O)cc2C(O)C1O
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1ccc2c(c1)C(O)C(O)C(C)(C)O2

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 3,4-Dihydroxy-2,2-dimethyl-chroman-6-carboxylic acid. MS: 494.6 (M+H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:31])[CH:14]([NH:18][CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[C:22]([F:30])[CH:23]=[C:24]([F:29])[CH:25]=3)[CH2:20]2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH3:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[OH:2][CH2:3][C:4]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:31])[CH:14]([NH:18][CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[C:22]([F:30])[CH:23]=[C:24]([F:29])[CH:25]=3)[CH2:20]2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:5])[CH3:6]
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)C(=O)OC)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CO)cn1

Procedure:
2-{4-[2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoylamino]-imidazol-1-yl}-2-methyl-propionic acid methyl ester was reduced using LAH to afford the title compound: mixture of diasteromers C13 NMR (100 MHz, CDCl3) 14.1, 14.2, 14.4, 19.4, 19.5, 21.2, 22.7, 24.7, 24.8, 24.9, 28.1, 28.3, 28.8, 28.9, 29.6, 29.7, 36.4, 52.1; 52.7, 59.3, 60.0, 60.6, 60.7, 70.5, 100.8, 101.0, 101.3, 104.6, 110.5, 110.6, 110.7, 110.8, 117.9, 118.1, 118.4, 118.6, 131.2, 131.3, 137.3, 137.4, 139.5, 139.6, 139.7, 139.8, 139.9, 139.9, 159.7, 159.8, 159.9, 162.1, 162.2, 162.3, 172.4, 172.6; MS m/z 421.4 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:17]1[C:18]([CH3:24])=[CH:19][C:20]([F:23])=[N:21][CH:22]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:17]4[CH:22]=[N:21][C:20]([F:23])=[CH:19][C:18]=4[CH3:24])[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Cc1cc(F)ncc1Br
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(F)ncc1N1CCN(c2ccc3ncsc3c2)C1=O
Yield: 28.9 %

Procedure:
1-Benzothiazol-6-yl-imidazolidin-2-one (I-84b: 150 mg, 0.6849 mmol) was reacted with 5-bromo-2-fluoro-4-methyl-pyridine (130 mg, 0.6849 mmol), 1,4-dioxane (5 mL), copper iodide (13 mg, 0.06849 mmol), trans -N,N′-dimethyl-cyclohexane-1,2-diamine (32.3 mL, 0.2054 mmol) and potassium phosphate (362.9 mg, 1.7122 mmol) to afford the crude product. Purification by column chromatography on silica gel (60% ethylacetate in hexane) afforded 65 mg of the product (28.9% yield).
Reaction SMILES: C(C1C=NC=CC=1)(=O)C.[C:10]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)(=[O:12])[CH3:11]>>[N:16]1[CH:17]=[CH:18][C:13]([C@H:10]([OH:12])[CH3:11])=[CH:14][CH:15]=1
Reactant: CC(=O)c1ccncc1
Agent: CC(=O)c1cccnc1
Product: C[C@@H](O)c1ccncc1

Procedure:
Example 1 was repeated except that 3-acetylpyridine used in Example 1 was replaced by 4-acetylpyridine to obtain (R)-1-(4-pyridyl)ethanol. [a]D25 =+32.4° (c=1.0, EtOH). Its optical purity was 99% ee or higher according to a high-speed liquid chromatography using an optical resolution column (CHIRAL CEL OB made by Daicel K. K.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:30][CH2:31][CH2:32][OH:33])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([OH:29])[N:24]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:34]C([Si](Cl)(C)C)(C)C.[H-].[Na+].CI.[N+](CC)(CC)(CC)CC.[F-]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:30][CH2:31][CH2:32][OH:33])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][N:26]([CH3:34])[C:25](=[O:29])[N:24]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(-c2ccnc(O)n2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Agent: [H-]
Solvent: CI
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)n2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2-hydroxypyrimidin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one by treatment with (i) TBSCl, (ii) NaH, MeI and (iii) Et4NF. LC-MS Method 2 tR=1.079 min, m/z=466.2; 1H NMR (CD3OD) 1.20 (m, 3H), 1.49 (d, 3H), 1.78-1.91 (m, 2H), 2.08 (s, 1H), 2.14 (m, 1H), 2.28 (m, 1H), 2.39 (m, 1H), 3.07 (m, 1H), 3.36 (m, 3H), 3.50 (s, 3H), 4.50 (s, 2H), 5.49 (m, 1H), 6.90 (d, 1H), 6.95-7.08 (m, 4H), 7.21 (m, 2H), 7.80 (d, 2H), 8.06 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[C:9]1=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:37])C(=O)C1>C(O)(=O)C.C(Cl)(Cl)Cl.C(Cl)Cl>[Br:37][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:11]2[N:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:9](=[O:29])[CH:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][CH2:13][C:12]=2[CH:15]=1
Reactant: COc1ccc2c(c1)N(Cc1cccc(F)c1)C(=O)C(C(=O)OC(C)(C)C)CC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1Br)CCC(C(=O)OC(C)(C)C)C(=O)N2Cc1cccc(F)c1
Temperature: 25 °C

Procedure:
A suspension of 3-tert-butoxycarbonyl-1-(3-fluorobenzyl)-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (1.00 g, 2.503 mmol) and NBS (0.49 g, 2.754 mmol) in acetic acid (0.8 mL) and chloroform (8 mL) was heated at reflux for 4 hrs. The reaction mixture was allowed to cool to room temperature, diluted with DCM (30 mL), washed with saturated aqueous sodium bicarbonate solution, dried over Na2SO4. Filtration and evaporation of the organic layer gave a solid residue, which was purified by flash chromatography on silica column eluted with ethyl acetate/n-hexane (25% of ethyl acetate in n-hexane). The title compound was obtained as a white powder (0.400 g, 33%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C@H:10]([CH:31]([CH3:33])[CH3:32])[NH:11][CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][N:23]=1)[CH2:13][CH:14]=[CH2:15].O.S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1>[O:24]1[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:12]([NH:11][CH:10]([CH:31]([CH3:33])[CH3:32])[CH2:9][OH:8])[CH2:13][CH:14]=[CH2:15])=[N:23]1
Reactant: C=CCC(N[C@H](C(=O)OC)C(C)C)c1ccccc1-c1noc2ccccc12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(NC(CO)C(C)C)c1ccccc1-c1noc2ccccc12
Temperature: -10 °C
Reaction time: 16 h

Procedure:
Under an atmosphere of nitrogen, 5.6 g of lithium aluminum hydride were added to 500 ml of dry tetrahydrofuran. The mixture was cooled to -10° C. and a solution of 30 g of (S)-N-[1-[2-(1,2-benzisoxazol-3-yl)phenyl]-3-butenyl]-L-valine methyl ester in 500 ml of dry tetrahydrofuran was added slowly. The mixture was stirred at -10° C. for 16 h, after which 22 ml of water was slowly added. After stirring at room temperature for 0.5 h, magnesium sulphate was added. The solids were filtered off and the filtrate was evaporated to dryness under reduced pressure to yield 25 g of [S-(R*,R*)]-2-[[1[2-(1,2-benzisoxazol3-yl)phenyl]-3-butenyl]amino]-3-methyl-1-butanol.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[H-].[Na+].[CH3:22]I.O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:22])[C:10](=[O:19])[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COc1ccc(C(=O)Nc2cccc(C#N)c2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)N(C)c2cccc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 mg (1.9 mmol) N-(3-Cyano-phenyl)-4-methoxy-benzamide were dissolved in 25 ml THF and 150 mg sodium hydride (60% in oil, 3.7 mmol) were added. The reaction was stirred for 1 h at room temperature, 172 μl (2.8 mmol) methyl iodide were added and the mixture was stirred for 2 h at 60° C. To the reaction mixture water was added and subsequently extracted with ethyl acetate, dried over Na2SO4 and evaporated to dryness.