Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.Br[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5]1
Reactant: CC1CNCC(C)O1
Reactant: CCOC(=O)CCCBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCN1CC(C)OC(C)C1

Procedure:
This intermediate (37.8 g.) was prepared using the procedure described in Example 4a except using 24.5 ml. (0.2 mole) of 2,6-dimethylmorpholine, 28.6 ml. (0.2 mole) of ethyl 4-bromobutyrate, 30.3 ml. (0.2 mole) of triethylamine, and 60 ml. of toluene and was isolated as a colorless liquid boiling 96.5°-97° C. at 4 mm of Hg.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([N:6]=[C:7](Cl)[CH3:8])[CH2:4][CH3:5].C(=O)([O-])[O-:11].[Na+].[Na+]>>[Cl:1][CH2:2][CH:3]([NH:6][C:7](=[O:11])[CH3:8])[CH2:4][CH3:5]
Reactant: CCC(CCl)N=C(C)Cl
Reactant: O=C([O-])[O-]
Agent: [Na+]
Product: CCC(CCl)NC(C)=O

Procedure:
A sample of N-[1-(chloromethyl)propyl]acetimidoyl chloride from Example 8 is treated with an excess of 10% aqueous sodium carbonate solution at room temperature. The organic material is extracted with ether and dried over MgSO4. Removal of the solvent under reduced pressure leaves N-[1-(chloromethyl)propyl]acetamide as a crystalline solid in nearly quantitative yield. An infrared spectrum shows peaks at 3300(M), 3100(W), 1650(S), and 550(S) cm-1 ; nuclear magnetic resonance (CDCl3) shows peaks 0.95 ppm (t ,3H), 1.4-1.8 ppm (m ,2H), 2.03 ppm (s ,3H), 3.67 ppm (d,2H,CH2Cl), 3.8-4.4 ppm (m ,1H).
Reaction SMILES: NC1C=C(OC2C=CC=CC=2)C=CC=1S(N)(=O)=O.C(N=C=S)(C)C.[NH2:25][C:26]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:27]=1[S:39]([NH:42][C:43]([NH:45][CH:46]([CH3:48])[CH3:47])=S)(=[O:41])=[O:40]>>[CH:46]([NH:45][C:43]1[NH:25][C:26]2[CH:31]=[C:30]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:29]=[CH:28][C:27]=2[S:39](=[O:41])(=[O:40])[N:42]=1)([CH3:48])[CH3:47]
Reactant: CC(C)NC(=S)NS(=O)(=O)c1ccc(Oc2ccccc2)cc1N
Agent: CC(C)N=C=S
Agent: Nc1cc(Oc2ccccc2)ccc1S(N)(=O)=O
Product: CC(C)NC1=NS(=O)(=O)c2ccc(Oc3ccccc3)cc2N1

Procedure:
Starting from 2-amino-4-phenoxybenzenesulfonamide and isopropyl isothiocyanate, and following a procedure analogous to the one described in Example 4a, N-(2-amino-4-phenoxybenzenesulfonyl)-N′-isopropylthiourea was prepared. The impure crude product was used without purification. Subsequent ring closure with phosgene by a procedure analogous to the one described in Example 4b gave the title compound; m.p. 250-252° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:27]C(=O)OC(C)(C)C)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:19]4[CH2:26][S:25][CH2:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[ClH:35]>C(Cl)Cl>[ClH:1].[ClH:35].[NH2:27][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:19]3[CH2:26][S:25][CH2:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3c2CSC3)CC1
Agent: Cl
Solvent: ClCCl
Product: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3c2CSC3)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of (R)-tert-butyl 3-(4-chlorophenyl)-1-(4-(5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (30 mg, 0.06 mmol) in CH2Cl2 (10 mL) was added HCl (4M in dioxane, 2 mL). The mixture was stirred at room temperature for 4 hours. The solvent was removed to afford (R)-2-amino-3-(4-chlorophenyl)-1-(4-(5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (30 mg, 99%). MS (APCI+) [M+H]+ 405.
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)C=CC=CC=1.[ClH:20]>CO>[ClH:20].[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: c1ccc(CN2CCC[C@H]2CN2CCCCC2)cc1
Agent: Cl
Solvent: CO
Product: C1CCN(C[C@@H]2CCCN2)CC1
Yield: 123 %

Procedure:
1-{[(2S)-1-(Phenylmethyl)-2-pyrrolidinyl]methyl}piperidine (710 mg, 2.747 mmol) was dissolved in a mixture of MeOH (20 mL) and 1N HCl (6 mL, 6.044 mmol), degassed and placed under argon. 10% Pd/C (213 mg) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon for 2 h. The contents were then degassed, and the Pd/C was removed by filtration through a fiberglass filter, washing with MeOH. The filtrate was concentrated in vacuo to provide pure 1-[(2S)-2-pyrrolidinylmethyl]piperidine hydrochloride (692 mg, >99%). LCMS: (M+H)+: 169.2.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([C:8]1([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].Cl.[C:22]([C:24]1[CH:37]=[CH:36][C:27]([CH2:28][N:29]2[C:33]([CH2:34]Cl)=[CH:32][N:31]=[CH:30]2)=[CH:26][CH:25]=1)#[N:23].C(N(C(C)C)CC)(C)C>C(#N)C>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:29]2[C:33]([CH2:34][N:11]3[CH2:10][CH2:9][C:8]([C:6](=[O:7])[C:5]4[CH:18]=[CH:19][CH:20]=[C:3]([CH3:2])[CH:4]=4)([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]3)=[CH:32][N:31]=[CH:30]2)=[CH:36][CH:37]=1)#[N:23]
Reactant: COC(=O)C1(C(=O)c2cccc(C)c2)CCNCC1
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(C(=O)c2cccc(C)c2)CCN(Cc2cncn2Cc2ccc(C#N)cc2)CC1

Procedure:
A solution of methyl 4-(3-methylbenzoyl)piperidine-4-carboxylate hydrochloride salt (58 mg, 0.2 mmol), l-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt (52 mg, 0.19 mmol), and diisopropylethylamine (174 μL, 1 mmol) in anhydrous acetonitrile (4 mL) was heated at 60° C. overnight. The resultant mixture was concentrated under vacuum, and the residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 2.5% methanol in ethyl acetate. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][NH2:7])[CH3:3].[CH2:8]([N:17]=[C:18]=[O:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]=[C:15]=[O:16]>C(Cl)Cl>[N:2]([CH2:4][CH2:5][CH2:6][NH:7][C:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:17][C:18]([NH:7][CH2:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])=[O:19])=[O:16])([CH3:3])[CH3:1]
Reactant: CN(C)CCCN
Reactant: O=C=NCCCCCCN=C=O
Solvent: ClCCl
Product: CN(C)CCCNC(=O)NCCCCCCNC(=O)NCCCN(C)C
Yield: 59.3 %

Procedure:
204.3 g of dimethylaminopropylamine are added dropwise to a solution of 168.2 g of hexamethylene diisocyanate in 100 ml of methylene chloride and the mixture is refluxed overnight, in the process of which crystals precipitate. The crystals are filtered with suction at room temperature, washed with CH2Cl2 and dried. Recrystallisation from a mixture of 1000 ml of acetone and 800 ml of ethanol yields 221.0 g (59.3%) of product with a melting point of 159° C. Tritration: 2 equivalents=376.7 g (theory 372.6 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C.C(OC(C)C)(C)C>[OH:16][C@H:3]1[C@H:4]([NH:15][C:25]([NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])[C:5]2=[CH:13][C:9]3[C:8]([CH:7]=[C:6]2[O:14][C:2]1([CH3:17])[CH3:1])=[N:12][O:11][N:10]=3
Reactant: O=C=Nc1ccccc1
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CC1(C)Oc2cc3nonc3cc2[C@@H](NC(=O)Nc2ccccc2)[C@@H]1O
Temperature: 25 °C
Yield: 47.9 %

Procedure:
To a solution of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole (0.25 g, 1.06 mmoles) (prepared as described in part I of Example 1) in ethanol (2.5 ml) at 60° C. was added phenyl isocyanate (0.126 g, 1.06 mmoles). The reaction was heated at reflux for three hours, cooled to room temperature and diluted with isopropyl ether (5 ml). The product slowly crystallized from solution. It was collected via suction filtration and dried under vacuum to obtain 0.18 g of the desired compound as a beige solid. The residue obtained upon evaporation of the mother liquor was chromatographed on silica gel eluting with 1:1 ethyl acetate/hexane to afford an additional 0.16 g of product. The two crops were combined and triturated with isopropyl ether to obtain 0.30 g of the title compound as an off-white solid (m.p. 215°-216° C.).
Reaction SMILES: C1CO[CH:20]2[CH:3]([CH2:4][C:5]34O[C@H:6]3[C:7](=[CH2:30])[C@@H:8]3[C@@H:17]([C@@:18]4([CH3:24])[C@@H:19]2[CH3:23])[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][C@:11]3([F:29])OCC[O:25][CH:12]32)[O:2]1.[Mg].[CH3:33]I>C1C=CC=CC=1.C(OCC)C>[F:29][C@@H:11]1[CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]2([CH3:14])[C:12]1=[O:25])[C@:18]1([CH3:24])[C:5](=[CH:4][C:3](=[O:2])[CH2:20][C@H:19]1[CH3:23])[C@H:6]([CH3:33])[C:7]3=[CH2:30]
Reactant: CI
Reactant: C=C1[C@@H]2[C@H](CC[C@]3(C)C4OCCO[C@@]4(F)C[C@@H]23)[C@@]2(C)[C@H](C)C3OCCOC3CC23O[C@@H]13
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: C=C1[C@@H](C)C2=CC(=O)C[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@H]12
Reaction time: 3 h
Yield: 80.5 %

Procedure:
3,17-bis(ethylenedioxy)-5,6α-epoxy-16α-fluoro-1β-methyl-7-methylenandrostane (431 mg) in benzene solution (40 ml), is added to a Grignard mixture prepared from magnesium (122 mg) and methyl iodide (710 mg) in diethylether (10 ml). Solvent is removed until the boiling point reaches ~78° C. Heating is then continued for a further 3 hrs. Ice and saturated ammonium chloride solution are added, the product extracted with ethyl acetate and the organic layer is evaporated in vacuo after having washed and dried it. The residue is dissolved in a 2:1 mixture of acetic acid and water (10 ml) and the solution heated for about 6 hrs at 40°-50° C. Then water is added and the product extracted with ethyl acetate. The organic layer is washed with sodium bicarbonate solution, dried and evaporated in vacuo. The residue is submitted to column chromatography thus giving pure 16α-fluoro-1β,6β-dimethyl-7-methylenandrost-4-ene-3,17-dione (275 mg).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[CH3:11][C:12]([CH3:32])([CH3:31])[CH2:13][C:14]1[N:19]=[C:18]([CH2:20][OH:21])[CH:17]=[CH:16][C:15]=1[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[F:30].[H-].[Na+].Cl>C1COCC1>[Cl:10][C:6]1[C:7]([O:8][CH3:9])=[C:2]([O:21][CH2:20][C:18]2[CH:17]=[CH:16][C:15]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=3[F:30])=[C:14]([CH2:13][C:12]([CH3:32])([CH3:31])[CH3:11])[N:19]=2)[N:3]=[CH:4][N:5]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Reactant: COc1c(Cl)ncnc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3ncnc(Cl)c3OC)nc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 4,6-dichloro-5-methoxypyrimidine (450 mg) and (6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol (760 mg) in THF (8.0 mL) was added 60% sodium hydride (200 mg) at 0° C., and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.05 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[CH:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1.[OH2:20].N>S(=O)(=O)(O)O>[CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]([NH2:10])=[O:20])=[CH:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1
Reactant: O
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccc2nccn2c1
Agent: N
Agent: O=S(=O)(O)O
Product: Cc1[nH]c(=O)c(C(N)=O)cc1-c1ccc2nccn2c1

Procedure:
In 15 ml of conc. sulfuric acid, 3 g of 1,2-dihydro-6-methyl-5-(imidazo[1,2-a]pyridin-6-yl)-2-oxo-3-pyridinecarbonitrile was stirred at 90° C. for 40 minutes. After cooling, the reaction mixture was poured into ice and conc. ammonia water was added thereto to render the mixture alkaline. Crystals prepcipitated were taken by filtration. After washing with water and drying, the crystals were recrystallized from N,N-dimethylformamide to obtain 2.5 g of 1,2-dihydro-6-methyl-5-(imidazo[1,2-a]pyridin-6-yl)-2-oxo-3-pyridinecarboxamide.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25](OCC)=[O:26])=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:32][NH2:33].ClCCl.CO>O1CCCC1>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]([NH:33][CH3:32])=[O:26])=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nc2)CC1
Reactant: CN
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nc2)CC1

Procedure:
The procedure described in Example 1 (step 1.4.) is used. Starting with 0.60 g (1.37 mmol) of 2-(ethyloxy)-2-oxoethyl 4-{6-[3-(trifluoromethyl)phenyl]-3-pyridyl}-1-piperazinecarboxylate, obtained in step 7.5., and 3.40 ml (6.86 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel, eluting with a 98/2 and then 97/3 mixture of dichloromethane and methanol, followed by washing with diisopropyl ether, 0.36 g of pure product is obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=O)[CH3:2].[NH2:13][C:14]1[C:15](=[O:24])[NH:16][C:17](=[O:23])[N:18]([CH2:21][CH3:22])[C:19]=1[NH2:20].C(N(CC)CC)C.[OH-].[Na+].Cl>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]1[NH:13][C:14]2[C:15](=[O:24])[NH:16][C:17](=[O:23])[N:18]([CH2:21][CH3:22])[C:19]=2[N:20]=1)[CH3:2]
Reactant: CCOc1ccccc1C(=O)Cl
Reactant: CCn1c(N)c(N)c(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1ccccc1-c1nc2c([nH]1)c(=O)[nH]c(=O)n2CC
Temperature: 25 °C
Reaction time: 20 h
Yield: 38.2 %

Procedure:
A solution of 2-ethoxybenzoyl chloride (12.0 g, 65 mmol) in dimethylformamide (10 mL) was added dropwise to a stirred solution of 5,6-diamino-1-ethyl-1H-pyrimidine-2,4-dione (10.4 g, 61 mmol) and triethylamine (9.8 mL, 65 mmol) in dimethylformamide (250 mL). The resulting mixture was stirred for 20 hours at room temperature, then evaporated under reduced pressure. Aqueous sodium hydroxide solution (1N, 98 mL, 98 mmol) was added and the mixture heated under reflux for 6 hours. The resulting solution was acidified with 1N hydrochloric acid and the precipitate collected and dried by suction to give 8-(2-ethoxyphenyl)-3-ethyl-3,7-dihydropurine-2,6-dione as a beige solid (7.0 g, 72%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=1[CH:11]=O.Cl.[NH2:19][OH:20].O>ClCCl>[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=1[CH:11]=[N:19][OH:20]
Reactant: NO
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: ON=Cc1c(Cl)cccc1Cl
Reaction time: 8 h
Yield: 132.9 %

Procedure:
Alternate procedure: Add triethylamine (23.1 g, 229 mmol) dropwise to a solution of 2,6-dichloro-benzaldehyde (20.0 g, 114 mmol) and hydroxylamine hydrochloride (10.3 g, 149 mmol) in dichloromethane (200 mL). Stir the reaction mixture for 8 h. Add water (200 mL). Separate the phases and extract the aqueous phase with dichloromethane (100 mL). Wash the combined organic phases with water (100 mL). Concentrate the combined organic phases to provide 28.8 g (94%) of the title compound.
Reaction SMILES: COC(=O)C1C=CC(O)=CC=1.[OH-].[K+].CC(OS(C1C=CC(C)=CC=1)(=O)=O)CCC.Cl.C[O:32][C:33](=[O:46])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([CH3:45])[CH2:42][CH2:43][CH3:44])=[CH:36][CH:35]=1.[OH-].[Na+]>CO.C(O)C.O.C1(C)C=CC=CC=1>[CH3:45][CH:41]([O:40][C:37]1[CH:36]=[CH:35][C:34]([C:33]([OH:46])=[O:32])=[CH:39][CH:38]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCCC(C)Oc1ccc(C(=O)OC)cc1
Agent: CCCC(C)OS(=O)(=O)c1ccc(C)cc1
Agent: COC(=O)c1ccc(O)cc1
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: O
Product: CCCC(C)Oc1ccc(C(=O)O)cc1

Procedure:
On the other hand, p-hydroxybenzoic acid methyl ester (28.5 g, 0.187 mol) was dissolved in methanol (120 ml), followed by adding and dissolving KOH (10.1 g, 0.187 mol), adding to the solution, optically active p-toluenesulfonic acid 1-methyl-butyl ester obtained above (50 g, 0.206 mol), keeping the mixture under reflux for 4 hours, cooling, adding toluene (200 ml) and 6N-HCl (50 ml), washing the toluene layer with 2N-NaOH aqueous solution, then with water till the washing water became neutral, and distilling off toluene to obtain as a residue, optically active p-(1-methyl-butyloxy)benzoic acid methyl ester (16.6 g, 0.070 mol), which was then dissolved in ethanol (5 ml), NaOH (4.2 g, 0.105 mol) and water (21 ml), heating under reflux for one hour, cooling, pouring the reaction solution in 6N-HCl aqueous solution (50 ml) with stirring, separating deposited crystals by filtration, and recrystallizing from ethanol to obtain optically active p-(1-methyl-butyloxy)benzoic acid having a m.p. of 67.0°~68.8° C. (9.3 g). To this product (6.5 g, 0.031 mol) was added thionyl chloride (6.0 g, 0.047 mol), followed by heating under reflux for one hour and distilling off excess thionyl chloride to obtain optically active p-(1-methyl-butyloxy)benzoic acid chloride (6.2 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.[N:29]1(OC(N(C)C)=[N+](C)C)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=N1.C(N(CC)C(C)C)(C)C.NCC1C=CC=CN=1>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:31][CH2:32][C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][N:29]=2)=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NCc1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCc2ccccn2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.5 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (228 mg, 0.71 mmol), N,N-diisopropyl ethyl amine (552 μL, 3.22 mmol) and 2-(aminomethyl)pyridine (0.77 mmol). The resulting reaction mixture was stirred for 12 h at ambient temperature. After dilution with ethyl acetate (20 mL) it was washed with water (20 mL) and aqueous sodium carbonate (saturated, 40 mL). The organic layer was dried over sodium sulfate and concentrated. Purification by chromatography ((SiO2, heptane:ethyl acetate:methanol=50:50:0 to 0:95:5) afforded the title compound (191 mg, 74%) which was obtained as a white solid. MS: m/e=401.2 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[F:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH:12]=O.O>C1C=CC=CC=1>[F:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH:12]=[N:1][C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:7][OH:8]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(C)C[C@H](N)CO
Solvent: c1ccccc1
Solvent: O
Product: CC(C)C[C@@H](CO)N=Cc1ccc(F)cc1F

Procedure:
A solution of (S)-(+)-leucinol (2.47 g, 21 mmol) and 2,4-difluorobenzaldehyde (3 g, 21 mmol) in benzene (50 mL) was heated to reflux for 4 hours during which time water was collected in a Dean-Stark trap. The solvent was evaporated in vacuum to give (2S)-2-[(2,4-difluorobenzylidene)-amino]-4-methylpentan-1-ol.
Reaction SMILES: [Na].[ClH:2].[NH2:3][CH2:4][CH2:5][SH:6].[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[CH2:8]>C(O)C>[ClH:2].[ClH:2].[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:7][CH2:8][S:6][CH2:5][CH2:4][NH2:3]
Reactant: NCCS
Reactant: C=Cc1ccccn1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NCCSCCc1ccccn1
Reaction time: 1.5 h
Yield: 46.4 %

Procedure:
To a solution of sodium (9.2 g) in ethanol (300 ml) at 5° was added 2-aminoethanethiol hydrochloride (24 g). The solution was stirred at 5°-10° for 1.5 hr, 2-ethenylpyridine (20 g) was added and the mixture refluxed for 16 hr. The cooled mixture was filtered, the filtrate evaporated to dryness and the residue extracted with ether. Excess ethereal hydrogen chloride was added and the gummy precipitate crystallised from methanol-isopropanol to give the title compound (12.5 g) m.p. 151°-154°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:31])([CH3:30])[CH2:9][C:10]([C:26]([F:29])([F:28])[F:27])([OH:25])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([CH2:23][OH:24])=[N:18]3)=[C:4]([O:32]C)[CH:3]=1.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:30])([CH3:31])[CH2:9][C:10]([C:26]([F:27])([F:29])[F:28])([OH:25])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([CH2:23][OH:24])=[N:18]3)=[C:4]([OH:32])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(C)(C)CC(O)(CNc1cccc2nc(CO)ccc12)C(F)(F)F
Agent: BrB(Br)Br
Product: CC(C)(CC(O)(CNc1cccc2nc(CO)ccc12)C(F)(F)F)c1ccc(Cl)cc1O

Procedure:
Analogously to Example 38, 110 mg (0.23 mmol) of 4-(4-chloro-2-methoxyphenyl)-1-(2-(hydroxymethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol is reacted with 4.60 ml (4.60 mmol) of a 1 M boron tribromide solution. After working-up and purification on silica gel with hexane-ethyl acetate (0-100%) as well as with ethyl acetate-methanol (0-20%), 54 mg (50% of theory) of the product is obtained.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22](Br)[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+].[C:32](OCC)(=[O:34])C>CN(C)C=O.O1CCCC1>[CH2:12]([O:19][C:20]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]([CH:21]=1)[CH:32]=[O:34])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc(C)c(Br)cc1OCc1ccccc1
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cc(C)c(C=O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A hexane solution (17 ml) of n-butyllithium was dropwise added to a tetrahydrofuran (190 ml) solution of 4-benzyloxy-2-bromo-5-methoxytoluene (7.83 g) at −78° C. over a period of 20 minutes, followed by stirring at the same temperature for 1 hour. A tetrahydrofuran (10 ml) solution of dimethylformamide (3.73 g) was dropwise added thereto at −78° C., followed by stirring at the same temperature for 1 hour. The temperature was gradually raised to room temperature, and stirring was further carried out for one night. The reaction solution was poured into an aqueous ammonium chloride solution (200 ml), and extraction with ethyl acetate (150 ml) was carried out twice. The ethyl acetate phase was washed with an aqueous sodium chloride solution (100 ml) twice and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3.14 g (yield 48%) of 5-benzyloxy-4-methoxy-2-methylbenzaldehyde (m.p. 107-109° C.), and its structure was confirmed by nuclear magnetic resonance spectrum.