Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]([S:20]([CH3:23])(=[O:22])=[O:21])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH3:19])=[N:9]1)[C:3]([OH:5])=O.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[O:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH:44]1[O:49][NH2:50].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:1][C@@:2]([S:20]([CH3:23])(=[O:22])=[O:21])([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH3:19])=[N:9]1)[C:3]([NH:50][O:49][CH:44]1[CH2:45][CH2:46][CH2:47][CH2:48][O:43]1)=[O:5]
Reactant: Cc1nn(CC[C@](C)(C(=O)O)S(C)(=O)=O)cc1-c1ccccc1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nn(CC[C@](C)(C(=O)NOC2CCCCO2)S(C)(=O)=O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a solution of (2R)-2-methyl-4-(3-methyl-4-phenyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)butanoic acid (129 mg, 0.38 mmol, 1 eq) in anhydrous DCM (7 mL) was added DIPEA (140 uL, 0.804 mmol, 2.1 eq), followed by HOBt (120 mg, 0.784 mmol, 2.05 eq) and the solution was stirred at RT for 30 minutes. The mixture was then treated with O-tetrahydro-2H-pyran-2-yl-hydroxylamine (70 mg, 0.60 mmol, 1.6 eq) followed by EDCI (110 mg, 0.574 mmol, 1.5 eq) and the reaction was allowed to stir at RT. The reaction mixture was concentrated in vacuo to give a crude white solid. The crude mixture was purified via flash chromatography using an Analogix SF15-12 g silica column eluting with ethyl acetate in heptane (0-80%) to give (2R)-2-methyl-4-(3-methyl-4-phenyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (110 mg, 66% yield). LC-MS M+H+436.1.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1)[NH2:21]>C(O)(C)C.C(=O)([O-])O.[Na+]>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:10]1[C:3]2[C:2]([NH:21][C:20]3[CH:22]=[CH:23][C:24]([O:25][C:26]4[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=4)=[C:18]([CH3:17])[CH:19]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)[CH3:16]
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reactant: CCOC(=O)Cn1ccc2ncnc(Cl)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)Cn1ccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c21
Temperature: 110 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a solution of ethyl (4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)acetate (140 mg) in isopropyl alcohol (0.6 mL) was added 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (188 mg), and the mixture was stirred in an oil bath at a temperature of 110° C. for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL) and extracted with ethyl acetate (25 mL×3). The organic layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=10/0→9/1). The object fraction was concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (210 mg) as white powder crystals.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8](=[O:11])[CH2:9][CH3:10])[C:6](=[O:12])[CH2:5][CH:4]([C:13]#[N:14])[CH2:3]1.[CH3:15][SH:16].[ClH:17]>C(OCC)C>[ClH:17].[O:12]=[C:6]1[CH:7]([C:8](=[O:11])[CH2:9][CH3:10])[C:2](=[O:1])[CH2:3][CH:4]([C:13]([S:16][CH3:15])=[NH:14])[CH2:5]1
Reactant: CCC(=O)C1C(=O)CC(C#N)CC1=O
Reactant: CS
Agent: Cl
Solvent: CCOCC
Product: CCC(=O)C1C(=O)CC(C(=N)SC)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5.0 g (0.026 mol) of 3,5-dioxo-4-propionylcyclohexanecarbonitrile and 1.37 g (0.028 mol) of methyl mercaptan were dissolved in 100 ml of dry diethyl ether. The solution was cooled to 0° C. and then a vigorous stream of dry hydrogen chloride was passed through it. After 0.5 h the gas stream was turned off, and the reaction mixture was slowly warmed to room temperature. It was again cooled to 0° C., hydrogen chloride was passed in (0.5 h) and then the cooling was removed and the mixture was left to stand overnight. The crystals which formed were filtered off with suction and dried in vacuo: 5.4 g (74% of theory) of compound 2.1 [melting point 161° C. (decomposition)].
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12](Cl)=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:21]1([CH:27]([NH2:31])[CH:28]([OH:30])[CH3:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)Cl>CC#N>[OH:30][C@H:28]([C@H:27]([NH:31][C:12]([C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:2]=1[CH3:1])=[O:13])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:29]
Reactant: CC(O)C(N)c1ccccc1
Reactant: Cc1c(-c2ccccc2)nc2ccccc2c1C(=O)Cl
Solvent: ClCCl
Solvent: CC#N
Product: Cc1c(-c2ccccc2)nc2ccccc2c1C(=O)N[C@H](c1ccccc1)[C@H](C)O

Procedure:
Prepared as described in Ex. 1, starting from 11.08 g (39.33 mmol) of crude 3-methyl-2-phenylquinoline-4-carbonylchloride, 4.87 g (32.20 mmol) of 1-phenyl-2-hydroxypropylamine and 10.33 ml (74.14 mmol) of TEA in 150 ml of a 1:1 mixture of dry CH2Cl2 and CH3CN.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](O)=[O:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O1CCCC1>C([O-])(O)=O.[Na+]>[OH:14][CH2:13][CH:10]1[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.2 %

Procedure:
To an ice cooled solution of 1-Boc-pyrrolidine-3-carboxylic acid (1 g, 4.64 mmol) in dry tetrahydrofuran (6 ml) Borane-methyl sulfide complex (2M in tetrahydrofuran) (3.48 ml, 6.96 mmol) was added dropwise the under N2 atmosphere The reaction mixture was stirred overnight at room temperature. NaHCO3 sat. sol. (20 ml) was added and the resulting mixture was stirred for 30 min. The mixture was extracted with ethylacetate (3×20 ml). Collected organics after solvent evaporation afforded the title compound (D39) (1.02 g)
Reaction SMILES: Br.Br.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:16]([N:6]1[CH2:5][CH2:4][N:3]([C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(O)cc2)CC1

Procedure:
A mixture of 33.8 parts of 4-(1-piperazinyl)phenol dihydrobromide, 11.2 parts of acetic acid anhydride, 42 parts of potassium carbonate and 300 parts of 1,4-dioxane is stirred and refluxed for 3 days. The reaction mixture is filtered and the filtrate is evaporated. The solid residue is stirred in water and sodium hydrogen carbonate is added. The whole is stirred for 30 minutes. The precipitated product is filtered off and dissolved in a diluted hydrochloric acid solution. The solution is extracted with trichloromethane. The acid aqueous phase is separated and neutralized with ammonium hydroxide. The product is filtered off and crystallized from ethanol, yielding 5.7 parts of 1-acetyl-4-(4-hydroxyphenyl)piperazine; mp. 181.3° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5]>O1CCCC1>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([C:9]2[N:8]=[CH:7][C:6]([C:4](=[O:5])[CH2:16][CH2:17][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: CON(C)C(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Solvent: C1CCOC1
Product: CCCCCCC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 0 °C
Yield: 109.9 %

Procedure:
2-(4-Trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid methoxy-methyl-amide (2.46 g, 7.936 mmol) is suspended in anhydrous tetrahydrofuran (40 mL), and cooled to 0° C. with stirring under nitrogen. N-hexyl magnesium bromide (8.0 mL, 2.0 M in diethyl ether, 16 mmol) is slowly added to the reaction over 1 h. The reaction is allowed to warm slowly to room temperature and monitored by TLC. Upon complete consumption of starting material, the reaction is carefully neutralized with 1N hydrochloric acid, extracted with diethyl ether, washed, dried, and concentrated. The 1-[2-(4-Trifluoromethyl-phenyl)-pyrimidin-5-yl]-heptan-1-one (1.47 g, 4.36 mmol) is obtained in pure form after flash column chromatography.
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[C:11]([CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.FC(F)(F)C(O)=O>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:8][C:9]1[CH:10]=[C:11]([CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13]
Reactant: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(NCc3ccccc3)n2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(N)n2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of tert-butyl 2-(benzylamino)-6-(4-methylphenyl)isonicotinate (0.37 g, 0.98 mmol) in ethanol (4.67 mL) were added palladium dihydroxide (3.42 mg, 0.024 mmol) and trifluoroacetic acid (0.08 mL, 1.08 mmol). The mixture was purged with hydrogen and stirred under hydrogen (1 atm) at 60° C. After 30 min, the mixture was cooled to ambient temperature and filtered with Celite. The filtered cake was washed with methanol and the filtrate was concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound (145 mg): LC-MS [M+1]=285.2.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[CH2:14][NH:13][C:12](=[O:15])[CH:11]3[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][C:3]=2[O:2]1.[Na].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:27]Cl>C(O)C>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:27][C:11]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[CH2:14][NH:13][C:12]1=[O:15]
Reactant: COc1ccc(CCl)cc1OC
Reactant: CCOC(=O)C1C(=O)NCC1c1ccc2c(c1)OCO2
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1(Cc2ccc(OC)c(OC)c2)C(=O)NCC1c1ccc2c(c1)OCO2
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A solution of 9.9 g of ethyl 4-(3,4-methylenedioxyphenyl)-2-oxo-3-pyrrolidinecarboxylate in 40 ml of absolute ethanol is added to a solution of 0.9 g of sodium in 50 ml of absolute ethanol at room temperature with stirring. The stirring is continued for one hour. To the mixture is added 8 g of 3,4-dimethoxybenzyl chloride. The resulting mixture is held at room temperature with stirring for one hour and then refluxed for an additional two hours. The ethanol is then removed under reduced pressure, water is added to the residue, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is recrystallized from ethanol to give 11.5 g of ethyl 3-(3,4-dimethoxybenzyl)-4-(3,4-methylenedioxyphenyl)-2-oxo-3-pyrrolidinecarboxylate, melting at 167°-168°C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[S:12][C:13]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C1COCC1>[CH3:21][C:20]1[C:16]([C:13]2[S:12][C:11]([C:9]([N:5]3[CH2:6][CH2:7][CH2:8][C@@H:3]([NH:2][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:4]3)=[O:10])=[CH:15][CH:14]=2)=[N:17][O:18][C:19]=1[C:22]([F:25])([F:24])[F:23]
Reactant: Cc1c(-c2ccc(C(=O)N3CCC[C@@H](N)C3)s2)noc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@@H](NS(C)(=O)=O)C3)s2)noc1C(F)(F)F
Reaction time: 48 h
Yield: 69.7 %

Procedure:
A suspension of ((R)-3-Amino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone, hydrochloride (Example 27, 79 mg, 0.2 mmol) in THF (2 mL) was treated with triethylamine (63 μL, 0.45 mmol) followed by methanesulfonyl chloride (19 μL, 0.24 mmol). The reaction mixture was allowed to stir 48 h, evaporated, and chromatographed on silica gel with EtOAc as eluant to afford product as a colorless foam (61 mg, 70%). 1H NMR (CDCl3) 1.68 (m, 2 H), 1.88 (m, 2 H), 2.02 (m, 1 H), 2.33 (d, J=1.8, 3 H), 2.98 (s, 3 H), 3.46 (m, 2 H), 3.57 (m, 1 H), 3.84 (m, 1 H), 4.05 (d, J=12.7, 1 H), 5.45 (d, J=7.5, 1 H), 7.39 (d, J=4.0, 1 H), 7.43 (d, J=3.5, 1 H). 13C NMR 7.9, 23.4, 31.6, 41.9, 47 (br), 52 (br), 49.9, 114.8, 118.7 (q, J=271), 128.2, 129.8, 131.8, 139.6, 155.2 (q, 40), 157.9, 163.5. 19F NMR −63.1. LC/MS 5.82 min, [M+1]+ 438.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:5]([O:7][CH3:8])=[O:6].C(O)[CH2:30][CH2:31][OH:32].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:5]([O:7][CH2:8][CH2:30][CH2:31][OH:32])=[O:6]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cc1F
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCCCO)cc1F

Procedure:
A mixture of 2.25 g of methyl 3-fluoro-4-(hexadecylamino)benzoate, 280 mg of 1,3-propanediol and 1.37 g. of p-toluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield 3-hydroxypropyl 3-fluoro-4-(hexadecylamino)benzoate.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([F:18])[C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:27])C=CC=CC=1>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:27])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([F:18])[C:7]2=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1ncc2cc(F)c(=O)n(C3CCCC3)c2n1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: CS(=O)c1ncc2cc(F)c(=O)n(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
8-Cyclopentyl-6-fluoro-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (10.5 g, 37.9 mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (11.8 g, 45.4 mmol) were combined in dichloromethane (120 ml) and stirred at room temperature for 18 hours. The mixture was evaporated to an oil, crystallized from ethyl acetate/diethyl ether, filtered and dried in vacuo to provide 8-cyclopentyl-6-fluoro-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one as a white solid (8.88 g, 79.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=[CH:12][N:11]=1.Cl.[CH3:23][N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][C:32]=2[C:40]([F:43])([F:42])[F:41])[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:25][CH2:26][CH:27]([O:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([NH:9][C:10]4[N:15]=[C:14]([C:16]5[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=5)[CH:13]=[CH:12][N:11]=4)[CH:4]=3)=[O:36])=[CH:33][C:32]=2[C:40]([F:41])([F:42])[F:43])[CH2:28][CH2:29]1
Reactant: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CN1CCC(Oc2ccc(C(=O)Cl)cc2C(F)(F)F)CC1
Agent: Cl
Product: Cc1ccc(NC(=O)c2ccc(OC3CCN(C)CC3)c(C(F)(F)F)c2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
This compound was prepared in the same manner as in Example 1, except that 4-methyl-3-[4-(3-pyridyl)pyrimidin-2-ylamino]aniline (Patent Document 1) and 4-(1-methylpiperidin-4-yloxy)-3-trifluoromethylbenzoyl chloride hydrochloride (Reference Example 11) were used.
Reaction SMILES: [C:1](=[S:3])=[S:2].OS(O[CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][NH:11]1)(=O)=O.Cl>[OH-].[Na+]>[CH2:9]1[C@@H:10]2[N:11]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:19]2)[C:1](=[S:3])[S:2]1
Reactant: O=S(=O)(O)OC[C@H]1Cc2ccccc2CN1
Reactant: S=C=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: S=C1SC[C@H]2Cc3ccccc3CN12
Reaction time: 1 h
Yield: 97.3 %

Procedure:
Carbon disulphide (14 g.) is added dropwise, with vigorous stirring, to a solution of (R)-3-hydroxysulphonyloxymethyl-1,2,3,4-tetrahydroisoquinoline (33.9 g.) in 0.6N sodium hydroxide solution (1,000 cc.). After one hour at a temperature of about 20° C., a precipitate appears; stirring is continued for 15 hours. The mixture is neutralised by adding 4N hydrochloric acid. The crystals formed are filtered off and washed with water and then with ethanol. (R)-1,5,10,10a-Tetrahydrothiazolo[3,4-b]isoquinoline-3-thione (30.0 g.) is thus obtained in the form of white crystals melting at 150° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(CC)CC)C>C(Cl)Cl>[C:31]([O:29][C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@@H]1CCCC[C@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1CCCC[C@H]1n1cnc2c(cc(Cc3ccc(Cl)nc3)c3ccccc32)c1=O
Temperature: 25 °C

Procedure:
To a solution of rac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one (0.040 g, 0.095 mmol) in 2 mL of CH2Cl2 at 0° C. was added acetic anhydride (0.011 mL, 0.11 mmol) and triethylamine (0.026 mL, 0.20 mmol). The mixture was warmed to rt and after 15 h, concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 461.9 for [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:25]([O:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:6][OH:7])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: CCCCCCCCCCCCCCCCCBr
Reactant: COC(CO)CO
Product: CCCCCCCCCCCCCCCCCOCC(CO)OC
Yield: 45 %

Procedure:
2-Methylglycerol (10.6 g) and 10.7 g of 1-bromoheptadecane were reacted and worked up in accordance with Example 5-(i) to give 5.2 g of the above-identified alcohol compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH:42]([NH:45][C:46](=[O:49])[CH2:47]Cl)([CH3:44])[CH3:43]>C1COCC1>[CH:42]([NH:45][C:46](=[O:49])[CH2:47][N:33]1[CH2:34][CH2:35][CH:30]([C:28]2[CH:27]=[CH:26][C:23]3[C:24]4[N:18]([CH:17]=[C:16]([C:15]5[N:11]([CH:8]([CH3:10])[CH3:9])[N:12]=[CH:13][N:14]=5)[N:25]=4)[CH2:19][CH2:20][O:21][C:22]=3[CH:29]=2)[CH2:31][CH2:32]1)([CH3:44])[CH3:43]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Reactant: CC(C)NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)CN1CCC(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.1 %

Procedure:
To a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt (350 mg, 0.71 mmol) in THF was added potassium carbonate (245 mg, 1.78 mmol) followed by N-isopropyl-2-chloroacetamide (106 mg, 0.78 mmol) and the reaction mixture stirred for 18 h at RT then heated at 50° C. for 2 h. The resultant mixture was concentrated in vacuo and the residue subjected to flash chromatography (SiO2, gradient 0 to 5% MeOH in DCM to give 247 as a white solid (180 mg, 53%). 1H NMR δ (ppm) (DMSO-d6): 8.28 (1 H, d, J=8.28 Hz), 7.86 (1 H, d, J=0.63 Hz), 7.85 (1 H, s), 7.40 (1 H, d, J=8.18 Hz), 7.03 (1 H, dd, J=8.36, 1.77 Hz), 6.89 (1 H, d, J=1.72 Hz), 5.88-5.79 (1 H, m), 4.48-4.41 (4 H, m), 3.89-3.83 (1 H, m), 2.89-2.79 (4 H, m), 2.13 (2 H, td, J=10.70, 4.11 Hz), 1.74-1.64 (4 H, m), 1.43 (6 H, d, J=6.60 Hz), 1.04 (6 H, d, J=6.59 Hz). 1 Proton obscured by solvent peak. LCMS: RT=2.94 min, M+H+=478
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[CH:11]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12]1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:16][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: NC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(NC1CCCC1)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a solution of 1-(4-bromophenyl)ethanone (500 mg, 2.5 mmol) in ethanol (16 mL) was added cyclopentanamine (320 mg, 3.8 mmol) and the reaction mixture was heated at 50° C. for 18 h. The reaction mixture was cooled to 0° C. and sodium borohydride (140 mg, 3.8 mmol) was added and the reaction mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was quenched with 2 M aqueous ammonium hydroxide and extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford the desired product (600 mg, 90%) as a red oil: ESI MS m/z 269 [C13H18BrN+H]+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[C:13]1(=[O:19])[O:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CCCCCC.CCOCC>[OH:19][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:18]
Reactant: Brc1cccnc1
Reactant: O=C1CCCCO1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(CCCCO)c1cccnc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution prepared by adding 497 ml (1 mole) of 2.01 molar solution of n-butyllithium in hexane into 2 l of ether at -60° C., is added dropwise with stirring under argon at -78° C. a solution of 172 g (1.09 mole) of 3-bromopyridine in 50 ml of ether over a period of 15 min. The mixture is stirred at -78° C. for an additional 30 min and a solution of 100 g(1 mole) of δ-valerolactone in 100 ml of ether is added dropwise over a period of 15 min. The mixture is stirred at -78° C. for 3 h, quenched with 500 ml of concentrated aqueous ammonium chloride, washed with water, dried (MgSO4) and evaporated to give 5-hydroxy-1-(3-pyridyl)pentan-1-one as an oil.