Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>CCOCC>[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C=Cc1ccc(O)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCOC(=O)C=Cc1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 30 ml of anhydrous ether solution containing 5 g of ethyl 4-hydroxycinnamate was added 7.1 ml of dihydropyran and 50 mg of p-toluenesulfonic acid were added, the mixture was stirred at a room temperature for 2 hours, the reaction mixture was neutralized with 1%-sodium hydroxide solution, washed with water, and dried with anhydrous sodium sulfate. The solvent was removed by evaporation to yield 6.8 of ethyl 4-(2-tetrahydropyranyloxy)cinnamate. Colorless indefinite form crystals. Melting point: 52°-53° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[C:21]2[S:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:22][CH3:23])[C:13]([CH2:27][CH2:28][OH:29])([CH2:24][CH2:25][OH:26])[C:12]=2[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:23][O:22][C:18]1[C:19]2[S:20][C:21]3[C:12](=[CH:11][CH:10]=[CH:9][C:8]=3[O:7][CH3:6])[C:13]([CH2:24][CH2:25][O:26][S:2]([CH3:1])(=[O:4])=[O:3])([CH2:27][CH2:28][O:29][S:2]([CH3:1])(=[O:4])=[O:3])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1Sc1c(OC)cccc1C2(CCO)CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1Sc1c(OC)cccc1C2(CCOS(C)(=O)=O)CCOS(C)(=O)=O

Procedure:
Methanesulphonyl chloride (1.71 ml.) is added dropwise over 5 minutes at 5° C. to a solution of 4,5-dimethoxy-9,9-bis(2'-hydroxyethyl)thioxanthene (3.46 g.), and triethylamine (4.18 ml.) in dry methylene chloride (70 ml.) with stirring. The mixture is stirred for 15 minutes, diluted with methylene chloride (70 ml.) and washed successively with water, 10% aqueous HCl, a saturated solution of NaHCO3 and brine. The solution is dried over MgSO4 and evaporated to dryness. The solid residue is recrystallised from ethanol to give 4,5-dimethoxy-9,9-bis(2'-methanesulphonyloxyethyl)thioxanthene, m.p. 176°-178° C.
Reaction SMILES: NCC(N1C2C(=CC(/C=C/[CH:16](C3C=C(Cl)C(F)=C(Cl)C=3)[C:17]([F:20])([F:19])[F:18])=CC=2)C=C1)=O.[Cl:30][C:31]1[CH:32]=[C:33]([CH:39]([C:62]([F:65])([F:64])[F:63])/[CH:40]=[CH:41]/[C:42]2[CH:43]=[C:44]3[C:48](=[CH:49][CH:50]=2)[N:47]([C:51](=[O:61])[CH2:52][NH:53][C:54](=[O:60])OC(C)(C)C)[CH:46]=[CH:45]3)[CH:34]=[C:35]([Cl:38])[C:36]=1[F:37].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:39]([C:62]([F:65])([F:63])[F:64])/[CH:40]=[CH:41]/[C:42]2[CH:43]=[C:44]3[C:48](=[CH:49][CH:50]=2)[N:47]([C:51](=[O:61])[CH2:52][NH:53][C:54](=[O:60])[CH2:16][C:17]([F:20])([F:19])[F:18])[CH:46]=[CH:45]3)[CH:34]=[C:35]([Cl:38])[C:36]=1[F:37]
Reactant: CC(C)(C)OC(=O)NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Reactant: NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CC(F)(F)F)NCC(=O)n1ccc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(E)-2-Amino-1-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl)ethanone (BI23): To a stirred solution of (E)-tert-butyl 2-(5-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-1H-indol-1-yl)-2-oxoethylcarbamate (0.05 g, 0.09 mmol) in CH2Cl2 (5.0 mL) was added TFA (0.01 mL) and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution, water and brine solution. The separated CH2Cl2 layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude title compound which was used in the next step without further purification (50 mg).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11](O)[CH:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(Cl)(=O)=O.C(N(CC)CC)C.[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32]>CN(C)C=O.C(OCC)(=O)C.O>[C:31]([NH:35][CH:10]1[CH2:11][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[CH:9]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: OC1C=CCC1(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)N
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC1C=CC(c2ccccc2)(c2ccccc2)C1
Reaction time: 1 h

Procedure:
To a solution of 5,5-diphenyl-2-cyclopenten-1-ol (0.20 g) in N,N-dimethylformamide (1 ml) were added methanesulfonyl chloride (0.35 ml) and triethylamine (0.60 ml) at 5° to 10° C. After being stirred for 1 hour, t-butylamine (1.78 ml) was added to the reaction mixture at 5° to 12° C. The reaction mixture was stirred for 3 days at room temperature. To the reaction mixture were added water and ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of chloroform and methanol as an eluent to give N-t-butyl-4,4-diphenyl-2-cyclopentenylamine (0.11 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([CH2:19][C:20]#[C:21][CH3:22])([CH2:15][C:16]#[C:17][CH3:18])[C:12](O)=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25]>>[OH:25][NH:24][C:12](=[O:13])[C:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([CH2:19][C:20]#[C:21][CH3:22])[CH2:15][C:16]#[C:17][CH3:18]
Reactant: NO
Reactant: CC#CCC(CC#CC)(C(=O)O)S(=O)(=O)c1ccc(F)cc1
Agent: Cl
Product: CC#CCC(CC#CC)(C(=O)NO)S(=O)(=O)c1ccc(F)cc1
Yield: 77 %

Procedure:
2-(4Fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4-fluoro-benzenesulfonyl)-2-but-2-ynyl-hex-4-ynoic acid (0.26 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.21 g of the product was isolated. Yield 77%; white solid; mp 161-163° C.; MS:338.1(M+H)+; 1H NMR (300 MHz, DMSO-d6) 5 1.67(s, 6H), 2.80-3.10 (m, 4H), 7.51 (dd, J=9.0, 9.0 Hz, 2H), 7.87 (m, 2H), 9.26 (brs, 1H), 10.95 (brs, 1H); IR (KBr, cm−1): 3336s, 3245m, 1681s, 1589m, 1493m;
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([CH2:15][S:16][CH3:17])[C:6]=1[F:18])(=[O:4])=[O:3].[OH-].[Na+]>CO>[CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH2:15][S:16][CH3:17])[C:6]=1[F:18])(=[O:3])=[O:4]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(F)c1CSC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSCc1c(C(=O)O)ccc(S(C)(=O)=O)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
20 g (0.07 mol) of methyl 4-methylsulfonyl-3-fluoro-2-methylthiomethylbenzoate were dissolved in 400 ml of methanol, and 10.95 g (0.27 mol) of a 2N NaOH solution were added. The solution was stirred at RT for 4 h. The methanol was removed. The residue was taken up in water and acidified with 2N HCl. This was followed by extraction with CH2Cl2 and the organic phase was dried over MgSO4 and concentrated to completion.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[CH:34][CH:33]=1>C1COCC1>[N:38]1([C:35]2[CH:34]=[CH:33][C:32]([NH:31][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]6[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:37][CH:36]=2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCOCC4)cc3)cc2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 35.9 %

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.248 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (48.7 mg, 0.248 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 36% (50 mg, 0.089 mmol) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH:17]([O:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH3:27])=[CH:20][CH:19]=1)[N:5]([CH3:16])SC1C=CC=CC=1[N+]([O-])=O.C1(S)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH:17]([O:28][C:29](=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH3:27])=[CH:20][CH:19]=1)[NH:5][CH3:16]
Reactant: COCOc1ccc(C(OC(=O)c2ccccc2)[C@@H](C(=O)OC)N(C)Sc2ccccc2[N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: Sc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](C(=O)OC)C(OC(=O)c1ccccc1)c1ccc(OCOC)cc1
Reaction time: 0.5 h
Yield: 9.1 %

Procedure:
To a solution of O-methoxymethyl-N-methyl-N-(2-nitrophenylthio)-β-benzoyloxytyrosine methyl ester (threo isomer) (4.94 g) in dichloromethane (50 ml) were added thiophenol (4.8 ml) and trifluoroacetic acid (2.5 ml) at 0° C. After stirring for 30 minutes, sodium bicarbonate aqueous solution was added to the mixture. The organic layer was washed with sodium bicarbonate aqueous solution and brine. After evaporating, the residue was put on a column of silica gel (MERCK 7734, 100 g) and eluted with 5% methanol in chloroform to give O-methoxymethyl-N-methyl-β-benzoyloxytyrosine methyl ester (threo isomer) (0.32 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](C2C=NN(C)C=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:17][C:18]1[N:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]2[CH:22]=[N:23][C:18]([CH3:17])=[CH:19][CH:20]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(B(O)O)cn1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Product: Cc1ccc(-c2ccc(C)nc2)c(C(=O)O)c1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid in Example A1, using (6-methylpyridin-3-yl)boronic acid. ESI-MS (m/z): 228 [M+1]+.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[S:22])[CH2:15][CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:9][CH:8]=1.II.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]=[C:14]2[CH2:15][CH2:16][CH2:17][C:18](=[C:19]([CH3:20])[CH3:21])[S:22]2)=[CH:11][CH:12]=1
Reactant: CC(C)=CCCCC(=S)Nc1ccc(Cl)cc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: II
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=C1CCCC(=Nc2ccc(Cl)cc2)S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
In a tetrahydrofuran (40 ml) solution of 6-methyl-5-heptenethioic acid (4-chloro-phenyl)-amide (2.0 g), a tetrahydrofuran (15 ml) solution of iodine (2.3 g) was added dropwise at 0° C. The temperature was raised to room temperature, followed by stirring overnight. After cooling to 0° C., a tetrahydrofuran (5 ml) solution of diazabicycloundecene (2.9 g) was added dropwise. After raising the temperature to room temperature and further stirring for 1 hour, water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.1 g of the target compound.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][CH2:10][N:11](CC2C=CC=CC=2)[CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[N:1]1([CH2:8][CH2:9][CH2:10][NH:11][CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(CCCN1CCCCCC1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNCCCN1CCCCCC1

Procedure:
3-(Azepan-1-yl)-N-benzyl-N-methylpropan-1-amine (100 mg) was dissolved in MeOH (20 mL) and to the solution was added 10% Pd/C (50 mg). The reaction mixture was shook under 50 psi hydrogen atmosphere for 2 h. The catalyst was filtered over Cellite and washed with methanol. The filtrated was evaporated to give 3-(azepan-1-yl)-N-methylpropan-1-amine, used without further purification.
Reaction SMILES: [C:1](OC1C=CC(C#CC(C2CCCC2)(O)CC2OC(C)(C)OC(=O)C=2)=CC=1COC(=O)C)(=O)C.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)C#CC2C=CC(C(C)(C)C#N)=C(F)C=2)CCCC1.[CH:66]1([C:71]2([CH2:79][CH2:80][C:81]3[CH:86]=[CH:85][C:84]([OH:87])=[C:83]([CH2:88][OH:89])[CH:82]=3)[O:76][C:75](=[O:77])[CH2:74][C:73](=[O:78])[CH2:72]2)[CH2:70][CH2:69][CH2:68][CH2:67]1>>[CH:66]1([C:71]2([CH2:79][CH2:80][C:81]3[CH:86]=[CH:85][C:84]([OH:87])=[C:83]([CH2:88][O:89][CH3:1])[CH:82]=3)[O:76][C:75](=[O:77])[CH2:74][C:73](=[O:78])[CH2:72]2)[CH2:70][CH2:69][CH2:68][CH2:67]1
Reactant: CC(=O)OCc1cc(C#CC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)ccc1OC(C)=O
Reactant: O=C1CC(=O)OC(CCc2ccc(O)c(CO)c2)(C2CCCC2)C1
Agent: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C(C)(C)C#N)c(F)c2)C2CCCC2)O1
Product: COCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O

Procedure:
The title compound was prepared analogously to step 4 from Example A(97) where Acetic acid 2-acetoxy-5-[3-cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl) -3-hydroxy-but-1-ynyl]-benzyl ester (from step 2 below) was substituted in place of 2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile. The product was obtained together with Example A(195) 6-Cyclopentyl-6-[2-(4-hydroxy-3-hydroxymethyl -phenyl)-ethyl]-dihydro-pyran-2,4-dione below. 1H NMR (400 MHz, CDCl3): δ 1.48–1.82 (m, 8H), 1.87–2.09 (m, 3H), 2.22–2.28 (m, 1H), 2.55–2.61 (m, 2H), 2.76 (s, 2H), 3.41 (s, 2H), 3.45 (2, 3H), 4.62 (2, 2H), 6.78–6.82 (m, 1H), 6.96–6.99 (m, 1H), 7.38 (s, 1H). ESIMS (MH−): 345.
Reaction SMILES: [C:1]1(=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][C:3](=[O:8])[CH2:2]1.O.[C:11]1(C)C=CC(S(O)(=O)=O)=C[CH:12]=1.C(O)C>C1(C)C=CC=CC=1>[CH2:11]([O:8][C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:1](=[O:9])[CH:2]=1)[CH3:12]
Reactant: O=C1CCCCC(=O)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC1=CC(=O)CCCC1
Yield: 93 %

Procedure:
A solution of 22.3 g. (0.177 mole) of cycloheptan-1,3-dione and 600 mg. (3.16 mmoles) of p-toluenesulfonic acid monohydrate in 86 ml. of ethanol and 250 ml. of toluene was heated at reflux for B 18 hours. A soxhlet extractor filled with molecular sieves (3 A) was used to remove water from the reaction. The reaction was cooled, added to 800 ml. saturated sodium chloride and extracted with four 800 ml. portions of ether. The combined organic extract was dried over magnesium sulfate and evaporated to an oil. Distillation of the crude oil gave 25.3 g. (93%) of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18](SC)[N:17]=3)=[CH:14][N:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[OH-].[NH4+:26]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH2:26])[N:17]=3)=[CH:14][N:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: COc1ccc(Nc2ncncc2-c2nc(C)nc(SC)n2)cn1
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(Nc2ncncc2-c2nc(C)nc(N)n2)cn1
Yield: 79 %

Procedure:
A glass microwave reaction vessel was charged with N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrimidin-4-amine (14 mg, 0.041 mmol), ammonium hydroxide, 28.0-30.0% (0.5 mL, 12.84 mmol) and dioxane (1 mL). The reaction mixture was stirred and heated at reflux in an oil bath for 1 h. The solid formed was filtered off and washed with EtOAc to give 4-(4-(6-methoxypyridin-3-ylamino)pyrimidin-5-yl)-6-methyl-1,3,5-triazin-2-amine (10 mg, 0.032 mmol, 79% yield). 1H NMR (300 MHz, d6-DMSO) δ 11.78 (s, 1H); 9.37 (s, 1H); 8.65 (s, 1H); 8.48 (s, 1H); 8.10 (d, J=8.33 Hz, 1H); 7.94 (s, 1H); 7.79 (s, 1H); 6.88 (d, J=8.77 Hz, 1H); 3.87 (s, 3H); 2.43 (s, 3H). m/z (ESI, +ve ion) 311.1 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[Cl:12].N1C=CC=CC=1.[C:20]1([O:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.C(OC(=O)C)C>[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([NH:11][C:27]([O:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])[CH:8]=[CH:7][C:6]=1[Cl:12]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC(=O)c1cc(N)ccc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC(=O)Oc2ccccc2)ccc1Cl
Temperature: 25 °C
Yield: 52.3 %

Procedure:
To a stirred mixture of 5-amino-2-chloro-benzoic acid methyl ester hydrochloride (1.110 g, 5.0 mmol) and pyridine (0.79 g, 10.0 mmol) in anhydrous THF (15 mL) at 0° C. was added phenylchloroformate (0.95 g, 6.0 mmol). After warming to room temperature, the reaction mixture was diluted with ethylacetate (50 mL), washed sequentially with 10% HCl, water and brine and dried over sodium sulfate. Removal of solvent under vacuum and purification of the product by flash chromatography (10% ethyl acetate in hexanes) yielded 0.8 g (53%) of a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ3.9 (s, 3H), 7.0 (br s, 1H), 7.18 (m, 2H), 7.4 (m, 3H), 7.6 (m, 1H), 7.9 (d, J=2.5 Hz, 1H). Mass Spectrum (M−H): 3:1 ratio of 304 and 306.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]([CH3:13])[C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Br:26][CH:27]([CH3:31])[C:28](Cl)=[O:29]>O>[Br:26][CH:27]([CH3:31])[C:28]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[C:8]([CH3:13])=[CH:9][CH:10]=[C:11]([CH3:12])[C:2]=1[CH3:1])=[O:29]
Reactant: CC(Br)C(=O)Cl
Reactant: Cc1ccc(C)c(NCC=O)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(C)c(N(CC=O)C(=O)C(C)Br)c1C
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2,3,6-trimethylanilino)-acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0°C and α-bromopropionyl cloride (0.11 mole) is incrementally added with stirring. After addition is is competed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-bromopropionyl-2,3,6-trimethylanilino)acetaldehyde.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C(=O)=O.CC(C)=O.[CH:15]1([C:18](=[O:29])[C@@H:19]([NH:21][C:22](=[O:28])OC(C)(C)C)[CH3:20])[CH2:17][CH2:16]1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH:15]1([C@@:18]2([OH:29])[C@H:19]([CH3:20])[NH:21][C:22](=[O:28])[CH2:1]2)[CH2:16][CH2:17]1
Reactant: CC(C)NC(C)C
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)C1CC1
Agent: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C[C@@H]1NC(=O)C[C@@]1(O)C1CC1
Reaction time: 0.33 h
Yield: 62.1 %

Procedure:
A solution of diisopropylamine (4.06 g) in tetrahydrofuran (40 mL) was ice-cooled under a nitrogen atmosphere, and 1.6 mol/L n-butyllithium-hexane solution (24.6 mL) was added. The mixture was stirred at the same temperature for 20 min, and the reaction solution was cooled with dry ice/acetone. Ethyl acetate (3.88 ml) was added to the reaction solution, the mixture was stirred at the same temperature for 30 min, and a solution of tert-butyl [(1S)-2-cyclopropyl-1-methyl-2-oxoethyl]carbamate (3.65 g) in tetrahydrofuran (10 mL) was added. The mixture was stirred at the same temperature for 7 hr, saturated aqueous ammonium chloride solution (100 mL) was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→30%), the obtained oil was dissolved in 4 mol/L hydrogen chloride-ethyl acetate solution (30 mL), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (80 mL), and diisopropylethylamine (8.09 mL) was added. The reaction solution was refluxed under heating for 4 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol/ethyl acetate=0→5%), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound as colorless crystals (yield: 1.65 g, 71%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([CH:10]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.C(Cl)Cl>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)([CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[OH:9])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Yield: 91.8 %

Procedure:
A solution of 31.2 g (0.079 mole) of α,α-bis-(4-fluorophenyl)-1-(phenylmethyl)-4-piperidinemethanol in 400 ml of absolute ethanol was hydrogenated at 50 psi and 70° C. over 5% palladium on carbon over the weekend. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a gum as residue. Methylene chloride was added to the residue and the gum crystallized. The mixture was diluted with petroleum ether and the solid was collected by filtration, washed with petroleum ether, and dried to yield 22 g (92%) of white solid which was recrystallized from isopropyl ether-2-propanol, m.p. 159.5°-160.5° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]1)=O)(C)(C)C.[OH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[OH:17][CH:18]1[CH2:23][CH2:22][N:21]([CH:10]2[CH2:9][NH:8][CH2:11]2)[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: OC1CCNCC1
Product: OC1CCN(C2CNC2)CC1
Temperature: 110 °C

Procedure:
A mixture of 1-(t-butoxycarbonyl)-3-methanesulphonyloxyazetidine (see International Patent Application Publication no WO93/19059) (1.2 g, 4.78 mmol) and 4-hydroxypiperidine (2.89 g, 6 mol equivalent) was heated at 110° C. for sixteen hours. The mixture was cooled to room temperature and partitioned between ethyl acetate (100 ml) and 5% aqueous sodium bicarbonate solution (100 ml). The layers were separated and the aqueous phase was extracted with a further portion of ethyl acetate (100 ml). The combined organic layers were dried over anhydrous magnesium sulphate. The solution was filtered, the solvent removed from the filtrate under reduced pressure and the crude product purified by column chromatography using silica gel eluting with methanol:dichloromethane (1:9, by volume) to give 1-butoxycarbonyl)-3-(4-hydroxypiperidyl)azetidine (1.4 g). TLC Rf=0.3 (silica, methanol:dichloromethane, 1:9, by volume). 1H-NMR (CDCl3): δ=1.35-1.5(m,1OH), 1.55-1.65(m,2H), 1.9-2.1(m,4H), 2.6-2.7(m,2H), 3.0-3.1 (m,1H), 3.7-3.95(m,5H)ppm.