Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@H:8]([CH2:9][OH:10])[C@H:6]([OH:7])[C@H:4]([OH:5])[CH:3]=[CH:2]1.[C:11](OC=C)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[C:11]([O:10][CH2:9][C@H:8]1[O:1][CH:2]=[CH:3][C@@H:4]([OH:5])[C@H:6]1[OH:7])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC[C@H]1OC=C[C@@H](O)[C@H]1O
Reactant: C=COC(=O)c1ccccc1
Solvent: O
Product: O=C(OC[C@H]1OC=C[C@@H](O)[C@H]1O)c1ccccc1

Procedure:
1.0 g (6.85 mmol) of galactal is taken up in 0.5-1.5 ml of H2O, 8 g of crushed molecular sieves are added, and the mixture is stirred with 1 g of Candida lipase AY-20 (Meito, Sangyo) or 1 g of lipase P (Amano) in 10-15 ml of vinyl benzoate at room temperature for 8-10 h. Filtering off the enzyme, concentration of the solution in vacuo, taking up the residue in ethyl acetate and extracting it with aqueous NaHCO3 solution, and subsequent chromatography on silica gel (ethyl acetate/hexane 1:1) result in 65-68% (about 1130 mg) of the desired 6-O-benzoylgalactal.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[CH3:20]C1C2C(=CC=CC=2)NC=1>>[CH3:20][C:7]1[C:6]2[C:10](=[CH:2][CH:3]=[CH:4][CH:5]=2)[NH:9][C:8]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Reactant: Cc1c[nH]c2ccccc12
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)[nH]c2ccccc12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 3-methyl-1H-indole.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.[OH-].[Na+]>O.C1COCC1>[CH:14]1([O:13][C:10]2[CH:11]=[CH:12][C:7]([B:20]([OH:25])[OH:21])=[CH:8][CH:9]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Brc1ccc(OC2CCCCC2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OB(O)c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 73.9 %

Procedure:
n-Butyllithium (1.6 M in hexane) (136 mL) was dropwised to a mixture of 1-bromo-4-(cyclohexyloxy)benzene (46.3 g) and THF (dry) (500 mL) at −78° C. and the mixture was stirred at the same temperature under nitrogen for 40 min. Triisopropyl borate (51.2 g) was dropwised to the mixture at −78° C. for 15 min and the mixture was stirred at the same temperature for 5 min. Then the mixture was warmed up to room temperature and stirred for additional 30 min. The mixture was poured into 1N NaOH aq. (250 mL) and water (750 mL) and the mixture was further stirred for 30 min. The organic layer was separated and the aqueous phase was washed with Et2O (300 mL×2) and acidified by 6N HCl aq. The mixture was extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-(cyclohexyloxy)phenylboronic acid (29.5 g) as a white powder. Tetrakis(triphenylphosphine)palladium(0) (0.656 g) was added to a suspension of 3-bromopyridin-2-amine (9.83 g), 4-(cyclohexyloxy)phenylboronic acid (15.0 g) and sodium carbonate (12.0 g) in DME (325 mL) and water (65.0 mL) and the mixture was stirred at 100° C. under nitrogen for 3 hr and at 90° C. for 12 hr. Volatiles were removed in vacuo with silica-gel. The silica-supported mixture was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (14.1 g) as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]([Cl:18])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=O)[CH:7]=1.C([SiH](CC)CC)C.CS(O)(=O)=O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH3:17])=[CH:14][CH:15]=2)[C:5]([Cl:18])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: CCc1ccc(C(=O)c2cc(Br)c(OC)cc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(Cc2cc(Br)c(OC)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.4 %

Procedure:
(5-bromo-2-chloro-4-methoxyphenyl)(4-ethylphenyl)methanone (21) (5.6 g, 69%) was dissolved in trifluoroacetic acid (40 mL). To this mixture was added triethylsilane (6.3 mL, 40 mmol) and methanesulfonic acid (0.40 mL, 6.0 mmol). The resulting solution was stirred at room temperature for 2.5 hours, after which it was partitioned between water and ethyl acetate. The organic layer was washed with water (1×25 mL), followed by saturated NaHCO3 (2×25 mL) and brine (25 mL). The organic layer was dried (Na2SO4), filtered, and evaporated. Silica gel chromatography with 0-10% ethyl acetate in hexane gave the title compound (4.7 g, 88%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.29 (s, 1H), 7.09-7.04 (m, 4H), 6.88 (s, 1H), 3.95 (s, 2H), 3.84 (s, 3H), 2.61 (q, J=7.5 Hz, 2H), 1.21 (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:19])C(=O)C1.C(Cl)Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:19][C:5]1[C:6]([C:8]([F:9])([F:11])[F:10])=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(C(F)(F)F)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Nc1cc(C(F)(F)F)c(Br)cn1
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a solution of 2-amino-4-trifluoromethylpyridine (10.0 g, 62.1 mmol) in chloroform (200 mL) was added NBS (12.0 g, 67.4 mmol). The solution was stirred in the dark for 2 hours, at which time it was added to DCM (200 mL) and 1N NaOH (200 mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated. The crude material was purified by Silica gel chromatography (0-5% EtOAc/CH2Cl2) yielding 12.0 g (80%) of 5-bromo-4-(trifluoromethyl)-2-pyridylamine: LCMS (m/z): 241/243 (MH+); 1H NMR (CDCl3): δ 8.28(s, 1H), 6.77(s, 1H), 4.78(bs, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[N+]=[N-])[CH:6]=[CH:7][CH:8]=1.COC1C=C(C=CC=1)C(=NN)C1C=CC=C(OC)C=1.[O:39]=[CH:40][C:41](=[CH2:43])[CH3:42]>ClCCl.CCCCCCC.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[CH2:42][C:41]2([CH3:43])[CH:40]=[O:39])[CH:6]=[CH:7][CH:8]=1
Reactant: C=C(C)C=O
Reactant: COc1cccc(C(=[N+]=[N-])c2cccc(OC)c2)c1
Agent: [Mn+4]
Agent: COc1cccc(C(=NN)c2cccc(OC)c2)c1
Agent: [O-2]
Solvent: ClCCl
Solvent: CCCCCCC
Product: COc1cccc(C2(c3cccc(OC)c3)CC2(C)C=O)c1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
A solution of bis(3-methoxyphenyl)diazomethane, prepared as in Example 84 from 3,3'-dimethoxybenzophenone hydrazone (18.7 g) and activated manganese dioxide (24.3 g) in dichloromethane (125 mL) was added to a solution of methacrolein (10.8 mL) in heptane (70 mL) over 10 minutes at 40° C. The mixture was stirred at 40° C. for 16 hours, and then after the dichloromethane was distilled off, at 85° C. for 1 hour. The solvent was removed in vacuo and the residue was purified by HPLC (ethyl acetate-hexane; 1:5) to yield 8.0 g of 2,2-bis(3-methoxyphenyl)1-methylcyclopropanecarboxaldehyde. Crystallization of the material from ethyl acetate-hexane provided 6.2 g of the aldehyde, mp 122°-123° C.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:16][C:17]1([CH2:25]Br)[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:7][O:6][C:4]([C:3]1[C:2]2[O:1][CH2:25][C:17]3([CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19][CH2:18]3)[CH2:16][O:12][C:11]=2[C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:5]
Reactant: COC(=O)c1ccc(OC)c(O)c1O
Reactant: CC1(C)OCC(CBr)(CBr)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OC)c2c1OCC1(CO2)COC(C)(C)OC1

Procedure:
Following the general procedure, dialkylation of compound 513 (1.19 g, 6 mmol) with compound 521 (2.0 g, 6.62 mmol) in DMSO (30 mL) in the presence of K2CO3 (2.07 g, 15 mmol) afforded compound 522 as a white solid material after purification by column chromatography (30-40% EtOAc in light petroleum). LC-MS: RT=2.99 min.; m/z 339.31 (M+H)+, 361.25 (M+Na)+. 1H NMR (CDCl3): δ 7.45 (1H, d, J 8.8), 6.59 (1H, d, J 8.8), 4.22 (2H, s), 4.18 (2H, s), 3.89 (3H, s), 3.86 (7H, s), 1.43 (6H, s).
Reaction SMILES: [C-]#N.[K+].Br[CH2:5][C:6]1[C:7]([Cl:13])=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=1.BrCC1(CBr)C=CC(Cl)=[N:18][CH:17]1Cl>O.C(O)C>[Cl:13][C:7]1[C:6]([CH2:5][C:17]#[N:18])=[CH:11][CH:10]=[C:9]([Cl:12])[N:8]=1
Reactant: ClC1=NC(Cl)C(CBr)(CBr)C=C1
Reactant: Clc1ccc(CBr)c(Cl)n1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(Cl)nc1Cl
Temperature: 40 °C
Reaction time: 16 h

Procedure:
Potassium cyanide (1.0 g) was dissolved in water by heating to 40° C. A mixture of 3-bromomethyl-2,6-dichloro-pyridine, 3,3-dibromomethyl-2,6-dichloro-pyridine, and 2,6-dichloro-3-methyl-pyridine (Example 4.1) (3.2 g) suspended in ethanol (20 ml) was added dropwise at 40° C. over a period of 30 minutes. The reaction mixture was heated to reflux for 3 hours. The reaction mixture was cooled to 40° C. and another equivalent of potassium cyanide was added. The reaction mixture was heated to reflux for a further 3 hours and then stored at ambient temperature for 16 hours. The reaction mixture was filtered to remove the solids and the solids were washed with ethyl acetate. The combined filtrates were concentrated. The residue was diluted with ethyl acetate. The organic solution washed with aqueous sodium hydrogen carbonate (saturated) and brine, dried over magnesium sulfate, and concentrated. This residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane from 3:100 to 1:1) to give slightly impure (2,6-dichloro-pyrid-3-yl)-acetonitrile (1.5 g) which solidified on standing. This material was used without further purification. 1H-NMR (400 MHz, CDCl3): 3.83 (s, 2H), 7.37 (d, 1H), 7.85 (d, 1H) ppm.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9][CH:8]=1.[Cl-].[NH4+].[Cl-].[Na+].[O:21]1CCC[CH2:22]1>CCCCCC.C(=O)=O.C(O)C.CN(C)C=O.CCOCC>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([CH:22]=[O:21])=[CH:8][N:9]=1
Reactant: Brc1cncc2ccccc12
Reactant: C1CCOC1
Agent: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCO
Solvent: CN(C)C=O
Product: O=Cc1cncc2ccccc12
Temperature: -68 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium in n-hexane (90 ml, 2.4 M) was added at room temperature to a mixture of 500 ml of anhydrous ether and 500 ml of tetrahydrofuran under nitrogen. The solution was cooled to -68° C. and there was added 20.8 g of 4-bromoisoquinoline portionwise over a period of 30 minutes while maintaining the temperature at about -67° C. When addition was complete, the dark brown solution was stirred at -68° C. for 30 minutes. Then, a solution of 73 g of dimethylformamide in 150 ml of tetrahydrofuran at -68° C. was added all at once. The temperature rose to -57° C. and the reaction turned lighter brown. The mixture was stirred in dry ice for 15 minutes and then 100 ml of chilled ethanol was added over a period of 5 minutes. This was followed by the addition of 100 ml of saturated ammonium chloride solution and then 100 ml of saturated aqueous sodium chloride solution. The solution was then warmed to room temperature, the layers separated and the aqueous layer was washed once with ether. The organic layers were combined and dried over sodium sulfate and the solvent was evaporated. The resulting orange-brown oil was then dried. The residue was recrystallized from ethanol to give 4-isoquinolinecarboxaldehyde melting at about 104°-105° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:50]=[CH:51][C:52]=1[F:53])[NH:29][C:30]1[C:39]2[C:34](=[CH:35][C:36]([O:48][CH3:49])=[CH:37][C:38]=2[O:40][CH2:41][C@@H:42]2[NH:46][CH2:45][C@@H:44]([OH:47])[CH2:43]2)[N:33]=[CH:32][N:31]=1.C(N(CC)C(C)C)(C)C.[C:63](O)(=[O:66])[CH2:64][OH:65]>C(Cl)Cl.C(=O)([O-])O.[Na+]>[Cl:25][C:26]1[CH:27]=[C:28]([CH:50]=[CH:51][C:52]=1[F:53])[NH:29][C:30]1[C:39]2[C:34](=[CH:35][C:36]([O:48][CH3:49])=[CH:37][C:38]=2[O:40][CH2:41][C@@H:42]2[N:46]([C:64](=[O:65])[CH2:63][OH:66])[CH2:45][C@@H:44]([OH:47])[CH2:43]2)[N:33]=[CH:32][N:31]=1
Reactant: COc1cc(OC[C@H]2C[C@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC[C@H]2C[C@H](O)CN2C(=O)CO)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 171 mg) was added in one portion to a stirred solution of (3S,5R)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (157 mg), N,N-diisopropylethylamine (131 μl) and glycolic acid (31 μl) in DCM (5 ml), under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 4 hours and then diluted with DCM and saturated aqueous sodium hydrogen carbonate was added. The organic layer was separated, dried (Na2SO4) and then concentrated in vacuo to leave the crude product as a yellow waxy solid. Purification by column chromatography, using 0 to 10% methanol in DCM as eluent, gave the title compound as a white solid (144 mg, 80%); NMR spectrum (DMSO-d6) 10.17 (s, 1H), 8.53 (s, 1H), 8.14 (dd, 1H), 7.74-7.69 (m, 1H), 7.47 (t, 1H), 6.92 (d, 1H), 6.83 (d, 1H), 5.14-5.10 (m, 1H), 4.71-4.67 (m, 1H), 4.50-4.44 (m, 1H), 4.40-4.38 (m, 1H), 4.28-4.23 (m, 1H), 4.06-4.03 (m, 2H), 3.95 (s, 3H), 3.53-3.48 (m, 2H), 2.05-2.02 (m, 2H); Mass spectrum MH+ 477.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH2:10])[C:6]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([F:16])[CH:4]=1.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[C:28]([F:32])[C:29](O)=[O:30])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].CCOC(OC(OCC)=O)=O>CN(C=O)C>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([CH:27]=[C:28]([F:32])[C:29]([NH:1][CH2:2][C:3]2[CH:8]=[C:7]([CH:9]=[CH2:10])[C:6]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]([F:16])[CH:4]=2)=[O:30])=[CH:25][CH:26]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: C=Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(C=C(F)C(=O)O)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: CN(C)C=O
Product: C=Cc1cc(CNC(=O)C(F)=Cc2ccc(C(C)(C)C)cc2)cc(F)c1NS(C)(=O)=O
Reaction time: 12 h
Yield: 47.8 %

Procedure:
N-(4-Aminomethyl-2-fluoro-6-vinylphenyl)methanesulfonamide (1.1 eq, 0.15 mmol, 53.24 mg), 3-(4-tert-Butylphenyl)-2-fluoroacrylic acid (1 eq, 0.14 mmol, 30 mg), DEPC (1.2 eq, 0.17 mmol, 25.49 μl), and TEA (2 eq, 0.28 mmol, 39.09 μl) were added in DMF under argon atmosphere. The reaction mixture was stirred for 12 hrs. The reaction mixture was purified according to similar procedure of Example 21 to yield title product (30.0 mg, 48%).
Reaction SMILES: [C:1]([N:8]([CH:10](O)[CH2:11][CH2:12][CH3:13])[CH3:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].CI.O.[O:20]1CCC[CH2:21]1>>[C:1]([N:8]([CH3:9])[CH2:10][CH2:11][CH2:12][CH2:13][O:20][CH3:21])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C1CCOC1
Reactant: CCCC(O)N(C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCCCCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The resulting N-Boc-N-methyl amino butanol (4.00 g) was placed in a 200-mL threeneck flask, and after nitrogen substitution, the compound was dissolved in 35 mL of anhydrous tetrahydrofuran. The solution was added with 60% sodium hydride (1.77 g), and stirred at room temperature for 30 minutes. Then, the reaction mixture was added dropwise with 1.87 mL of methyl iodide and stirred on an oil bath at 50° C. for 1.5 hours. The reaction was stopped with water, and the organic layer was extracted with ethyl acetate, washed once with water and once with saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4) to obtain 4.25 g of N-Boc-N-methyl-N-methoxybutylamine.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>CCOCC>[C:2]1([CH2:1][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: BrCc1ccccc1
Solvent: CCOCC
Product: c1ccc(CN2CCCCC2)cc1
Reaction time: 8 h

Procedure:
A mixture of 11.9 ml of benzyl bromide in 100 ml of ether was added dropwise to a solution of 29.6 ml of piperidine in 100 ml of ether. This mixture was stirred overnight, then filtered. The organic layer was washed with water, then dried and concentrated to an oil. The oil was distilled through a Kugelrohr and the fraction boiling at 75°-85° C., 1.55 mm collected, giving 16.77 g of 1-(phenylmethyl)piperidine as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[NH:5][CH:6]1[CH2:11][CH2:10][CH:9]=[C:8]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)[CH3:2].[H-].[Na+].[CH3:23]I>CN(C=O)C.C1COCC1>[CH2:1]([O:3][C:4](=[O:20])[N:5]([CH3:23])[CH:6]1[CH2:11][CH2:10][CH:9]=[C:8]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7]1)[CH3:2]
Reactant: CI
Reactant: CCOC(=O)NC1CCC=C(C#Cc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)C1CCC=C(C#Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43 %

Procedure:
22 mg (0.082 mmol) (3-phenylethynyl-cyclohex-3-enyl)-carbamic acid ethyl ester are dissolved in 2 ml DMF and 1 THF. 8 mg (0.165 mmol) of a 60% dispersion of NaH in oil is added and the mixture stirred under argon for 90 minutes at room temperature. The reaction mixture is cooled to 0°, and 16 microliters MeI in 0.5 ml THF are added dropwise. After stirring one hour at room temperature, the reaction mixture is cooled to 0° again, ice is added and the crude product extracted with ethyl acetate, washed with water and saline, dried with sodium sulfate and column chromatographed using a 4:1 mixture of petroleum ether and ethyl acetate. Yield: 43%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[C:16]([OH:29])[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2].[N:32]1([CH2:38][CH2:39][CH2:40]O)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[C:16]([O:29][CH2:40][CH2:39][CH2:38][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:30])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(O)cc(C#CCc3ccccc3)c2)cc1C
Reactant: OCCCN1CCOCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCc3ccccc3)cc(OCCCN3CCOCC3)c2)cc1C
Reaction time: 1 h

Procedure:
{4-[3-Hydroxy-5-(3-phenyl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.46 mmol), 3-morpholin-4-yl-propan-1-ol (101 mg; 0.69 mmol), tributylphosphine (0.28 mL; 1.39 mmol) and 1,1′-(azodicarbonyl)dipiperidine (0.35 g; 1.39 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. After stirring for 1 h the reaction mixture was purified by prep. HPLC (method A). Yield: 200 mg. HPLC-MS: m/z: 560.5 (M+H); Rt: 2.07 min.
Reaction SMILES: [C:1](OCC)(=S)C(N)=O.[CH:9]([C:12]1[N:13]=[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:15][CH:16]=1)([CH3:11])[CH3:10]>>[CH2:20]([O:19][C:17]([C:14]1[S:15][CH:16]=[C:12]([CH:9]2[CH2:11][CH2:1][CH2:10]2)[N:13]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)c1nc(C(C)C)cs1
Reactant: CCOC(=S)C(N)=O
Product: CCOC(=O)c1nc(C2CCC2)cs1
Yield: 64 %

Procedure:
Compound V2 (yellow oil) was synthesized from compound U2 (23.87 g, 1 eq.) and ethyl thiooxamate (21.41 g, 1 eq.) in 64% yield, following the procedure as described for compound 36.
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.[NH2:27][C:28]1[CH:33]=[C:32]([CH3:34])[C:31]([OH:35])=[C:30]([Cl:36])[CH:29]=1.[Cl:37][C:38]1[N:43]=[C:42](Cl)[C:41]([F:45])=[CH:40][N:39]=1>>[Cl:37][C:38]1[N:43]=[C:42]([NH:27][C:28]2[CH:33]=[C:32]([CH3:34])[C:31]([OH:35])=[C:30]([Cl:36])[CH:29]=2)[C:41]([F:45])=[CH:40][N:39]=1
Reactant: Cc1cc(N)cc(Cl)c1O
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: Cc1cc(Nc2nc(Cl)ncc2F)cc(Cl)c1O

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 4-amino-2-chloro-6-methylphenol and 2,4-dichloro-5-fluoropyrimidine resulted 2-chloro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-4-pyrimidineamine. The reaction of 2-chloro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-4-pyrimidineamine and 3-methoxycarbonylmethyleneoxyaniline (1.95 g, 11 mmol) gave N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (850 mg, 55%). 1H NMR (CD3OD): δ 2.22 (s, 3H), 3.76 (s, 3H), 4.52 (s, 2H), 6.50 (dt, J=2.7 and 6.3 Hz, 1H), 7.09-7.14 (m, 2H), 7.24 (t, J=1.8 Hz, 1H), 7.30 (t, J=1.2 Hz, 1H), 7.49 (d, J=2.4 Hz, 1H), 7.88 (d, J=3.9 Hz, 1H); 19F NMR (282 MHz, CD3OD): δ −168.70; LCMS: ret. time: 20.63 min.; purity: 98.56%; MS (m/e): 432.96 (MH+).
Reaction SMILES: CS(C)=O.[I-].[CH3:6][S+](C)(C)=O.[H-].[Na+].[CH3:13][CH:14]([CH3:23])[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[N:21][CH:22]=1)=[O:16]>O1CCCC1>[CH:14]([C:15]1([C:17]2[CH:22]=[N:21][CH:20]=[N:19][CH:18]=2)[CH2:6][O:16]1)([CH3:23])[CH3:13]
Reactant: C[S+](C)(C)=O
Reactant: CC(C)C(=O)c1cncnc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)C1(c2cncnc2)CO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under an atmosphere of argon, 50 ml of dimethyl sulphoxide are slowly added dropwise to 8.06 g (37 mmol) of trimethylsulphoxonium iodide and 1.47 g of sodium hydride (60%, 37 mmol). The reaction mixture is then stirred at room temperature for 15 min, and 5.00 g (33 mmol) of 2-methyl-1-(5-pyrimidinyl)-1-propanone, dissolved in 10 ml of tetrahydrofuran, are added. The reaction mixture is stirred at 50° C. for 90 min. The reaction mixture is then concentrated under reduced pressure, and saturated aqueous sodium chloride solution and ethyl acetate are added to the residue. The organic phase is separated off, dried over sodium sulphate, filtered and concentrated. This gives 1.36 g (25%) of the desired product, which is reacted without further purification.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:19]([CH:29]([NH2:31])[CH3:30])=[CH:20][C:21]([CH3:28])=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[CH:15]=[CH:16][CH:17]=1.C(N(CC)C(C)C)(C)C>C(O)C>[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:19]([CH:29]([NH:31][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH3:30])=[CH:20][C:21]([CH3:28])=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cc(C(C)N)c(-c2cccc(F)c2)c2ncccc12
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c2ncccc12

Procedure:
A mixture of 6-bromo-9H-purine (0.0712 g, 0.358 mmol), 1-[8-(3-fluorophenyl)-5-methylquinolin-7-yl]ethanamine (0.050 g, 0.18 mmol), and N,N-diisopropylethylamine (0.0623 mL, 0.358 mmol) in ethanol (0.6 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting residue was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the product. LCMS calculated for C23H20FN6 (M+H)+: m/z=399.2; Found: 399.0.