Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.C([NH2:28])C1C=CC=CC=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH2:28][C@H:2]1[CH2:11][CH2:10][C@@H:9]2[C@@H:4]([CH2:5][C@@H:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1C[C@H]2C[C@@H](N)CC[C@H]2CN1C(=O)OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 174.6 %

Procedure:
To a room temperature solution of ethyl 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate (4 g, 14.1 mmol), benzylamine (1.71 g, 15.9 mmol), and acetic acid (1.27 g, 21.2 mmol) in 1,2-dichloroethane (20 ml), sodium triacetoxyborohydride (5 g, 23.3 mmol) was added. The mixture was stirred under an atmosphere of nitrogen for 15 hours at room temperature. The reaction was quenched by adding aqueous saturated sodium bicarbonate, and extracted with dichloromethane three times. The organic layer was dried over sodium sulfate and evaporated to give 7 g of the title compound. The crude material was used in next step without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:19][CH2:18][C:13]2(OCC[O:14]2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl>O1CCOCC1.[Cl-].[Na+].O.C(=O)(O)[O-].[Na+].CCOCC>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:11][CH2:12][C:13](=[O:14])[CH2:18][CH2:19]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCC(COCc2ccccc2)CC1
Temperature: 85 °C

Procedure:
To a solution of EXAMPLE 341C (43.02 g) in dioxane (500 mL) was added water (125 mL) and 2M hydrochloric acid (90 mL). The mixture was heated at 85° C. for 18 hours. Upon cooling, the reaction mixture was diluted with brine (1500 ml), saturated sodium bicarbonate solution (300 mL) and ether (1000 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified on silica gel eluting with a 5-50% ethyl acetate in hexanes step gradient to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.II.C(N(CC)CC)C.[F:21]F>S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[F:21][C:3]1[C:2]([Br:1])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: FF
Reactant: Brc1cnc2ccccc2c1
Agent: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Fc1nc2ccccc2cc1Br
Yield: 47.9 %

Procedure:
A solution containing 3-bromoquinoline (1.0 g, 4.8mmol), iodine (1.22g, 4.8mmol) and triethylamine (0.48 g, 4.8 mmol) in CF2ClCFCl2 (30 ml) was placed in a fluorination apparatus fitted with a drying tube filled with soda lime. Elemental fluorine (5 mmol) as a 10% mixture in dry nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca. 15 ml/min. After the fluorine had been added the solution was poured into 10% aqueous sodium metabisulfite solution (30 ml) and extracted with dichloromethane. The organic extracts were dried and evaporated to a brown oil (0.95 g). GC/MS analysis showed a 56% conversion of starting material. Column chromatography on silica gel with dichloromethane as eluant gave 2fluoro-3-bromoquinoline (0.52g, 85%); mp 75°-76° C. (vacuum sublimation oil bath temp. 50° C./<1 mmHg) as white needles; RF 0.69 (CH2Cl2); (Found: C, 47.5; H, 2.1; N, 6.2. C9H5NBrF requires: C, 47.8; H, 2.2; N, 6.2%); δH (400 MHz, CDCl3, Me4Si) 7.55 ppm (1H, d d, JH5,H6 =JH6,H7 8.0, H-6), 7.74 (1H, d d d, JH7,H8 8.4, JH6,H7 7.2, JH5,H7 1.2, H-7), 7.76 (1H,d, JH5,H6 8.0, H-5), 7.91 (1H, d d, JH7,H8 8.4, JH6,H8 0.8, H-8), 8.42 (1H, d, JH4,F 8.4, H-4); δC (100 MHz, CDCl3, Me4Si) 104.0 (d, 2J 43.2, C-3), 126.6 (s, C-6), 127.0 (d, 4J 2.7, C-8), 128.0 (d, 5J 1.9, C-5) 128.0 (d, 4J 2.2, C-4a), 130.9 (d, 5J 1.1, C-7), 143.5 (d, 3J, 3.7, C-4), 144.2 (d, 3J 15.1, C-8a), 157.3 (d, 1J 238.1, C-2); δF (235 MHz, CDCl3, CFCl3) -60.8ppm (s); m/z (E1+) 225 (M+, 100%), 227 (M+, 74), 146 (56), 126 (23), 101 (18), 75 (14).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([Cl:21])[C:12]=1[NH:22][NH2:23]>CCO>[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([F:19])([F:18])[F:20])[CH:14]=[C:13]([Cl:21])[C:12]=1[N:22]1[C:1]([CH3:2])=[C:4]2[CH2:8][CH2:7][CH2:6][C:5]2=[N:23]1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CC(=O)C1CCCC1=O
Solvent: CCO
Product: Cc1c2c(nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl)CCC2
Yield: 75 %

Procedure:
2-Acetyl cyclopentanone (0.12 mL, 1 mmol) and 2,6-dichloro-4-trifluoromethylphenylhydrazine (245 mg, 1 mmol) in EtOH (10 mL) was heated under reflux for 12 hr. EtOH was removed under reduced pressure and the product purified by flash chromatography on silica (10% EtOAc:Hexane): yield 75%. 1H NMR (CDCl3) δ 7.8 (s, 2H), 2.6 (m, 6H each), 2.2 (s, 3H); MS (M+) 335.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].[OH:20][CH:21]([CH:24]1[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]1)[CH2:22][NH2:23]>O1CCOCC1>[OH:20][CH:21]([CH:24]1[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]1)[CH2:22][NH:23][C:13](=[O:15])[CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:16]([F:19])([F:18])[F:17])[CH:4]=1
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Reactant: CC1(C)OCC(C(O)CN)O1
Solvent: C1COCCO1
Product: CC1(C)OCC(C(O)CNC(=O)CS(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)O1

Procedure:
Analogously to the instructions for Example 9(a), 2.21 g (7 mmol) of 2-[N-(4-fluoro-3-trifluoromethyl-phenyl)sulfamoyl] acetic acid in dioxane is reacted with 1.13 g (7 mmol) of 2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamine for about 1 hour at 90° C. After concentration by evaporation and crystallization from ethanol/ether, 2.87 g=92.3% of the theoretical yield is obtained as a crystallizate. Melting point 144°-146° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P:11](=[O:18])(OCC)[O:12][CH2:13][CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P:11]([Cl:20])(=[O:18])[O:12][CH2:13][CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(Cl)Cc1ccc([N+](=O)[O-])cc1
Temperature: 30 °C
Reaction time: 24 h
Yield: 84.3 %

Procedure:
This method is a modification of that outlined by Doak and Freedman (Ref. 178). Diethyl (p-nitrophenyl)methylphosphonate (7.16) (1.0 g, 3.6 mmol) in DCM (10 ml) was added dropwise to a solution of PCl5 (0.9 g, 4.32 mmol) in CCl4 (20 ml) under an inert atmosphere. The reaction was stirred at 30° C. and the progress of the chlorination was followed by 31P NMR which showed the reaction was complete after 24 h. Solvent and phosphoryl chloride were removed in vacuo to yield a pale yellow, moisture-sensitive oil (0.8 g, 90%) which was used without further purification. δH (250 MHz, CDCl3) 1.40 (3H, t, J 7.5 Hz, CH3), 3.60 (2H, d, 2JPH 22.5 Hz, Ar--CH2), 4.25-4.43 (2H, m, JHP 8.5 Hz, J 7.5 Hz,CH2), 7.5 (2H, d, J 7.5 Hz, Ar--H), 8.20 (2H, d, J 7.5 Hz, Ar--H); δP (101 MHz, CDCl3) 35.94 (s).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15])([O:3][CH2:4][CH3:5])=[O:2].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([O:15][C:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=1[CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:18])[CH3:17]
Reactant: CCOC(=O)CCCC1CCCCC1=O
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)CCCC1=C(OC(C)=O)CCCC1

Procedure:
Treatment of 2-(3-carbethoxypropyl)cyclohexan-1-one (Example 14) with acetic anhydride by the procedure of Example 24 is productive of the subject compound.
Reaction SMILES: COC[O:4][C:5](=[O:14])[C:6]([CH3:13])([CH3:12])[CH2:7][O:8][CH2:9][O:10][CH3:11].CO.[OH-].[Na+].Cl>C(OCC)C>[CH3:11][O:10][CH2:9][O:8][CH2:7][C:6]([CH3:13])([CH3:12])[C:5]([OH:14])=[O:4]
Reactant: COCOCC(C)(C)C(=O)OCOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: COCOCC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 96 h
Yield: 111.7 %

Procedure:
To a mixture of 3-methoxymethoxy-2,2-dimethylpropionic acid methoxymethyl ester (16.5 g) and methanol (30 mL), 5 N aqueous sodium hydroxide solution (30 mL) was added, and the resulting mixture was stirred at room temperature for 4 days. Ice was added to the mixture, and at 0° C., 5 N hydrochloric acid (35 mL) and diethyl ether (300 mL) were added thereto. The mixture was shaken and the organic layer was collected. The organic layer was washed with saturated aqueous sodium chloride solution (100 mL) and dried over anhydrous magnesium sulfate. The resulting mixture was filtered and the obtained filtrate was concentrated under reduced pressure to obtain the captioned compound (14.5 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([Br:11])[CH:9]=[CH:10][C:2]=2[F:1])[CH:18]=1)[CH3:13]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: CCOC(=O)Cc1cccc(N)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cc(Br)ccc2F)c1

Procedure:
2-Fluoro-5-bromobenzoic acid (123 mg, 0.56 mmol) was coupled with ethyl ester (6) (100 mg, 0.56 mmol) following Method C to give the title compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].CCN(CC)CC.[Br:11][CH:12]([CH2:16][CH2:17][CH2:18][Br:19])[C:13](Cl)=[O:14]>C(Cl)Cl>[Br:11][CH:12]([CH2:16][CH2:17][CH2:18][Br:19])[C:13]([N:2]([CH3:3])[CH3:1])=[O:14]
Reactant: CNC
Reactant: O=C(Cl)C(Br)CCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)C(Br)CCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To a solution of dimethylamine (0.91 ml, 7.18 mmol; 40% solution in water) and 2.75 ml (19.76 mmol) of Et3N in 6 ml of CH2Cl2 cooled at 0° C. was added dropwise a solution of 2,5-dibromo-pentanoyl chloride (1.00 g, 3.59 mmol) in 4 ml CH2Cl2. After stirring 1 h at RT, the reaction mixture was partitioned between CH2Cl2 and water. The organic phases were washed with water and brine and the aqueous layers extracted twice with CH2Cl2. The organic phases were dried over MgSO4, evaporated and purified by flash silica gel column (EtOAc/n-heptane 1:1) to afford 0.66 g (64%) of the title product as light yellow oil. MS: 288.1 (2Br, MH+).
Reaction SMILES: COP([O-])(OC)=O.[C:8]1([I+:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:21][C:22]([F:28])([F:27])[S:23]([OH:26])(=[O:25])=[O:24]>C(Cl)Cl>[O-:26][S:23]([C:22]([F:28])([F:27])[F:21])(=[O:25])=[O:24].[C:15]1([I+:14][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=S(=O)(O)C(F)(F)F
Agent: COP(=O)([O-])OC
Agent: c1ccc([I+]c2ccccc2)cc1
Solvent: ClCCl
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
Diphenyliodonium dimethylphosphate (315 mg; 1 mmol) and trifluoromethanesulfonic acid (158 mg; 1.01 mmol) were dissolved in methylene chloride (10 ml), and the resultant mixture was stirred. Half volume of the solvent was removed from the methylene chloride solution through distillation, and ether (50 ml) was added thereto. The mixture was stirred, to thereby precipitate 109 mg of the target compound as white crystals (yield: 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10]([NH2:12])[CH3:11])=[CH:4][CH:3]=1.C(N(CC)CC)C>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][CH:10]([NH2:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(N)C#Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(N)C=Cc1ccc(Cl)cc1
Reaction time: 1 h
Yield: 98.3 %

Procedure:
A mixture of 3-(4-chloro-phenyl)-1-methyl-prop-2-ynylamine (1.5 g, 8.4 mmol), triethylamine (0.12 mL, 0.86 mmol, 0.1 eq.) and Lindlar catalyst (150 mg) in 40 mL of 1:1 methanol-dichloromethane was stirred for 1 hr, filtered through a CELITE pad and concentrated to provide 1.5 g of 3-(4-chloro-phenyl)-1-methyl-allylamine.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[CH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1.[CH2:24](O)[CH3:25]>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[CH:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[C:14]([O:16][CH2:24][CH3:25])=[O:15])=[CH:9][CH:8]=1
Reactant: CCO
Reactant: O=C(O)C(=Cc1ccncc1)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(=Cc1ccncc1)c1ccc(F)cc1

Procedure:
Conc. sulfuric acid (2.2 ml) was added carefully to a suspension of 2-(4-fluorophenyl)-3-(4-pyridyl)-acrylic acid (6.7 g, 27.5 mmol) in ethanol (120 ml) and the mixture was heated at reflux for 24 h. The solvent was evaporated, the remainder was taken up in dichloromethane and the organic solution was washed with aqueous sodium hydrogencarbonate and water, followed by drying and evaporation. Flash column chromatography on silica gel (hexane-acetone=2:1) provided the pure title compound. MS (m/z): 271.8 (M+H)+; C16H14FNO2requir. 271.3 1H-NMR (CDCl3): 8.44, 6.88 (2m, each 2H, Pyrid.), 7.72 (s, 1H, CH═), 7.16, 7.06 (2m, each 2H, PhF), 4.28 (q, 2H, CH2), 1.28 (t; 3H, CH3).
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[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl[CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34]>C1COCC1>[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[N:20]=[N:19][C:18]([N:21]2[CH2:30][CH2:31][CH2:32][C:33]2=[O:34])=[CH:17][CH:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Reactant: O=C(Cl)CCCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1COc1ccc(N2CCCC2=O)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.4 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (1.0 g, 3.5 mmol) in THF (15 ml) was added triethylamine (0.59 mL, 4.3 mmol). The mixture was cooled in an ice bath and a solution of 4-chlorobutyryl chloride (0.48 mL, 4.3 mmol) in THF (5 mL) was added dropwise. After stirring for 1 h at room temperature the precipitate was filtered and the organic phase was evaporated. The residue was dissolved in methanol (20 mL), sodium bicarbonate (1 spatula) was added and the mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residue was extracted (dichloromethane/water). Then the organic phase was dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane/ethyl acetate=100:0 to 60:40) afforded the title compound (250 mg, 20%) (as the most polar component of two formed in the reaction) which was obtained as a white solid. MS: m/e=351.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([N:7]1[C:12](=[O:13])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10]([CH3:20])[O:9][CH2:8]1)([CH3:6])[C:3]([OH:5])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:41]1([NH:40][C:3](=[O:5])[C:2]([CH3:1])([N:7]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([CH3:20])[O:9][CH2:8]2)[CH3:6])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)CO1
Reactant: Nc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2ccccc2)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a suspension of 2-methyl-2-(6-methyl-5-phenyl-2,3-dihydro-4-oxo-4H-1,3-oxazin-3-yl)-propionic acid (0.83 g) in 10.4 ml of CCl4 --CH2Cl2 (1:1) was added triphenylphosphin (1.04 g), then the mixture was refluxed for 40 min. The reaction mixture was ice-cooled and aniline (0.28 g) and triethylamine (0.3 g) were slowly added, then it was stirred at room temperature for 1 h. After evaporation of the solvent, the residue was dissolved in ethyl acetate. The insolubles were filtered off and the filtrate was evaporated. The residue was purified by chromatography on a silica gel column to get the captioned compound (0.58 g).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:24]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:23]=3[Cl:22])[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Clc1ccc(N2CCNCC2)c(Cl)c1
Product: CCc1cc(NC(=O)N2CCN(c3ccc(Cl)cc3Cl)CC2)c(OC)nc1C
Yield: 72 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,4-dichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH2:11][C:12]([NH:14][CH3:15])=O)[CH:8]=2)[CH:3]=[CH:2]1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH2:11][CH2:12][NH:14][CH3:15])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CNC(=O)CC(c1cccnc1)c1ccc2cc[nH]c2c1
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNCCC(c1cccnc1)c1ccc2cc[nH]c2c1

Procedure:
[3-(1H-Indol-6-yl)-3-pyridin-3-yl-propyl]-methyl-amine CLX was prepared from 3-(1H-indol-6-yl)-N-methyl-3-pyridin-3-yl-propionamide using the procedure described above for preparation of [3-(1H-Indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (Example 4). MS (M+H)=266.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C@@H:11]([C@@H:26]1[C@:43]2([CH3:44])[C@H:29]([C@H:30]3[C@H:40]([CH2:41][CH2:42]2)[C@:38]2([CH3:39])[C:33]([CH2:34][C@@H:35]([O:52][CH:53]4[CH2:58][CH2:57][CH2:56][CH2:55][O:54]4)[CH2:36][C@@H:37]2[O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)=[CH:32][CH2:31]3)[CH2:28][CH2:27]1)[CH2:12][CH2:13][C:14]([F:25])([F:24])[C:15]([O:18][CH:19]([O:21][CH2:22][CH3:23])[CH3:20])([CH3:17])[CH3:16])C>O1CCCC1.CCOCC>[O:47]1[CH2:48][CH2:49][CH2:50][CH2:51][CH:46]1[O:45][C@@H:37]1[C@@:38]2([CH3:39])[C:33](=[CH:32][CH2:31][C@@H:30]3[C@@H:40]2[CH2:41][CH2:42][C@@:43]2([CH3:44])[C@H:29]3[CH2:28][CH2:27][C@@H:26]2[C@H:11]([CH2:10][OH:9])[CH2:12][CH2:13][C:14]([F:24])([F:25])[C:15]([O:18][CH:19]([O:21][CH2:22][CH3:23])[CH3:20])([CH3:17])[CH3:16])[CH2:34][C@@H:35]([O:52][CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][O:54]2)[CH2:36]1
Reactant: CCOC(=O)[C@H](CCC(F)(F)C(C)(C)OC(C)OCC)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(C)OC(C)(C)C(F)(F)CC[C@@H](CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.20 g (0.0053 mol) of lithium aluminum hydride and 10 mL of tetrahydrofuran at 0° C. was added 2.55 g (0.0034 mol) of [1α,3β]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluorocholest-5-en-21-oic acid ethyl ester in 35 mL of tetrahydrofuran. The mixture was heated at 50° C. for 1.5 hr, recooled to 0° C., and diluted with 120 mL of ether. The mixture was then quenched with the dropwise addition of 0.40 ml of water and 0.32 mL of 10% aqueous sodium hydroxide. The mixture was stirred at 25° C. for 1 hr and was filtered. The solids were triturated with ether and filtered. Evaporation of solvent afforded [1α,3β]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluorocholest-5-en-21ol, [α]D20 +4° (c 1, CHCl3).
Reaction SMILES: [K].[CH3:2][O:3][CH2:4][C:5]([CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:8]1=[O:22])=O.Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:36][O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1.C(=O)(O)[O-].[Na+]>C1CCCCC1.C1(C)C=CC=CC=1>[CH3:36][O:37][C:38]1[CH:44]=[CH:43][C:41]([NH:42][C:5](=[C:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:8]2=[O:22])[CH2:4][O:3][CH3:2])=[CH:40][CH:39]=1
Reactant: COc1ccc(N)cc1
Reactant: COCC(=O)C1CCN(C(=O)OCc2ccccc2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: COCC(Nc1ccc(OC)cc1)=C1CCN(C(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61 %

Procedure:
Into a 100 mL eggplant-shaped flask were added benzyl 3-(2-methoxyacetyl)-2-oxopyrrolidine-1-carboxylate potassium salt (4.94 g) [mw. 329.39, 15.0 mmol], 1 mol/L hydrochloric acid (25 mL) [25 mmol] and toluene (50 mL), and the mixture was stirred for 20 min. After partitioning, the organic layer was dried over magnesium sulfate. After filtration, to the mother liquor were added cyclohexane (30 mL), p-toluenesulfonic acid monohydrate (29.0 mg) [mw. 190.22, 0.15 mmol] and p-methoxyaniline (1.85 g) [mw. 123.15, 15.0 mmol]. Dean-Stark trap was set, and the mixture was subjected to dehydration reflux for 30 min. After cooling to 25° C., 5 w/w % aqueous sodium bicarbonate solution (25 mL) was added to allow for partitioning. The organic layer was washed with 5 w/w % aqueous acetic acid solution (25 mL), further washed with 5 w/w % aqueous sodium bicarbonate solution (25 mL), dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by basic silica gel column chromatography (silica gel amount: 100 g, eluent:toluene, Rf=0.2). The effective section was concentrated under reduced pressure. Yellow candy-like product, 3.63 g, yield 61.0%, 1H-NMR (500 MHz, CDCl3, TMS) δ2.74-2.77 (m, 2H), 3.29 (s, 3H), 3.75-3.80 (m, 5H), 3.95 (s, 2H), 5.28 (s, 2H), 6.83 (d, J=8.8 Hz, 2H), 7.04 (d, J=8.8 Hz, 2H), 7.25-7.38 (m, 3H), 7.43 (d, J=7.2 Hz, 2H), 10.41 (s, 1H).
Reaction SMILES: C([O:9][CH2:10][C:11]1[C:12]2[N:20]=[C:19]([CH:21]3[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]3)[S:18][C:13]=2[N:14]=[C:15]([CH3:17])[N:16]=1)(=O)C1C=CC=CC=1.O(C)[Na].Cl.CCOC(C)=O>CO>[CH3:27][C:24]1([CH3:28])[CH2:23][CH2:22][CH:21]([C:19]2[S:18][C:13]3[N:14]=[C:15]([CH3:17])[N:16]=[C:11]([CH2:10][OH:9])[C:12]=3[N:20]=2)[CH2:26][CH2:25]1
Reactant: Cc1nc(COC(=O)c2ccccc2)c2nc(C3CCC(C)(C)CC3)sc2n1
Agent: CO[Na]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(CO)c2nc(C3CCC(C)(C)CC3)sc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
To a mixture of [2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]methyl benzoate (13.8 g) and MeOH (250 mL) was added a 28% NaOCH3 solution (670 μL) in MeOH, followed by stirring at room temperature for 3 hours. The reaction mixture was neutralized by the addition of 4 M HCl/EtOAc (870 μL), and concentrated under reduced pressure. To the residue was added water, followed by extraction with EtOAc. To the organic layer were added MgSO4 and basic silica gel, followed by stirring. The mixture was filtered through Celite and then concentrated under reduced pressure. The residue was purified by silica gel column (hexane/EtOAc) to obtain [2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl]methanol (7.9 g).