Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[C:13]#[N:14])=[CH:8][N:7]=2)=[CH:2]1.Cl.C(N(CC)CC)C.[CH:24]([S:27](Cl)(=[O:29])=[O:28])([CH3:26])[CH3:25]>C1COCC1.CO>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH:14][S:27]([CH:24]([CH3:26])[CH3:25])(=[O:29])=[O:28])=[CH:8][N:7]=2)=[CH:2]1
Reactant: CC(C#N)c1ccc(-c2ccsc2)nc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccsc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7 %

Procedure:
To an ambient temperature solution of 214 mg,(l mmol) of material prepared in step A in 5 ml of THF was added dropwise 0.11 ml of a 10 M solution borane-methyl sulfide complex (1.1 mmol) in THF. The mixture was stirred at ambient temperature for 2 h. Then, 0.1 ml of a 10 M solution borane-methyl sulfide complex (1.0 mmol) in THF were added and the mixture stirred overnight. A saturated solution of hydrochloric acid in methanol (5 ml) was added, and stirred for 10 min. The solution was concentrated in vacuo. The crude was disolved in dichloromethane (5 ml) and cooled to 0° C., triethylamine 0.44 ml (3.2 mmol) was added, followed by isopropylsulfonyl chloride (0.14 ml, 1.2 mmol). The ice-bath was removed and the solution was stirred at ambient temperature for 2 h. The organic solution was washed with 1N hydrochloric acid, sodium bicarbonate saturated solution, brine, dried over Na2SO4 filtered and concentrated in vacuo. Chromatography (50 g of silica gel, 33% ethyl acetate/hexane) of the residue afforded 25 mg (7%) of the title compound. Field Desorption Mass Spectrum: M=324.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:16][C:17]1[CH:22]=[C:21]([S:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=1F>>[Cl:16][C:17]1[CH:22]=[C:21]([S:23]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Reactant: O=S(=O)(Cc1cccc(F)c1)c1ccc(F)c(Cl)c1
Product: O=C(O)Cc1cc(Oc2ccc(S(=O)(=O)Cc3cccc(F)c3)cc2Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from step (i).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[C:17]([CH:22](O)[CH3:23])=[N:18][O:19][C:20]=2[CH3:21])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.CS(Cl)(=O)=O.[N-:37]=[N+:38]=[N-:39].[Na+]>O.CCOC(C)=O.C(Cl)Cl>[N:37]([CH:22]([C:17]1[C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])=[C:20]([CH3:21])[O:19][N:18]=1)[CH3:23])=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1onc(C(C)O)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1onc(C(C)N=[N+]=[N-])c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 74 %

Procedure:
To a round bottomed flask was added (4-chlorophenyl)(2-(3-(1-hydroxyethyl)-5-methylisoxazol-4-yl)phenyl)methanone (0.092 g, 0.269 mmol), CH2Cl2 (3.0 mL), and Et3N (0.075 mL, 0.538 mmol). The vial was cooled to 0° C. before addition of methanesulfonyl chloride (0.025 mL, 0.323 mmol) and the reaction stirred for 45 min at 0° C. before quenching with water. The layers were separated and the aqueous extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was taken up in DMF (2 mL) and sodium azide (0.053 g, 0.808 mmol) was added. The reaction was stirred at room temperature overnight before being diluted with water and EtOAc. The layers were separated and the aqueous was extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (2-(3-(1-azidoethyl)-5-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanone (0.073 g, 0.199 mmol). LC/MS m/z 389 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:30][CH2:31]OS(C)(=O)=O)[O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:48]([NH:51][C:52]1([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)(=[O:50])[CH3:49].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.CCOCC.O>[OH2:13].[ClH:1].[C:48]([NH:51][C:52]1([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH2:53][CH2:54][N:55]([CH2:31][CH2:30][C:9]2([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=[C:18]([C:26]([F:28])([F:27])[F:29])[CH:17]=3)[CH2:10]2)[CH2:56][CH2:57]1)(=[O:50])[CH3:49]
Reactant: CC(=O)NC1(c2ccccc2)CCNCC1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: CC(=O)NC1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C(=O)O2)CC1
Temperature: 80 °C
Yield: 67.5 %

Procedure:
A mixture of 1.5 g of the compound obtained in step B of EXAMPLE 21, 1.5 g of 4-acetamido-4-phenylpiperidine p-toluenesulfonate and 1.6 g of K2CO3 in 4 ml of DMF is heated at 80° C. for 3 hours. After cooling, the reaction mixture is poured into water and extracted with an AcOEt/ether mixture (50/50; v/v), the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH mixture (100/3; v/v) as the eluent. The product obtained is dissolved in DCM, a saturated solution of gaseous HCl in ether is added until the pH is 1, and the solvent is evaporated off under vacuum to give 0.66 g of the expected product after crystallization from a DCM/pentane mixture. M.p.=165°-170° C.
Reaction SMILES: N#N.Br[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[N:5]=1.[Li]CCCC.[NH4+].[Cl-].[CH3:18][CH2:19][O:20]CC>CCCCCC>[Br:10][C:6]1[N:5]=[C:4]([C:19](=[O:20])[CH3:18])[CH:9]=[CH:8][CH:7]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCOCC
Agent: N#N
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CC(=O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of commercially available 2,6-dibromopyridine (2.44 g, 10.00 mmol) in ether (25.0 mL) was treated at −78° C. with n-BuLi (4.0 mL of a 2.5M solution in hexane, 10.00 mmol). The reaction mixture was stirred for 30 min before N,N-dimethylacetaminde (1.50 mL, 16.13 mmol) was added and the solution was then allowed to warm to rt over 1 h. Sat. aq. NH4Cl was then added and the aq. layer was extracted with Et2O (2×50 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (20:1 hept-EA) gave the title compound as a white solid. TLC: rf (20:1 hept-EA)=0.25. LC-MS-conditions 02: tR=0.98 min.
Reaction SMILES: [CH:1]([C:4]1[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]=1[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:17]#[N:18])=[O:13])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[Li+].[CH2:31](Cl)[CH:32]=[CH:33][CH3:34]>CN(C=O)C>[CH2:31]([N:6]1[C:5]([C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=2)[C:17]#[N:18])=[O:13])=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[NH:8][C:7]1=[O:11])[CH:32]=[CH:33][CH3:34]
Reactant: CC=CCCl
Reactant: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC=CCn1c(C(=O)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a stirred solution of 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (Compound 1) (297 mg, 1 mmol), anhydrous powdered potassium carbonate (165 mg, 1.2 mmol), and lithium iodide (134 mg, 1 mmol) in DMF (5 mL) at room temperature, was added crotyl chloride (97 μL, 1 mmol). After stirring for overnight, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:2)) to give 300 mg (85%) of 3-(3-but-2-enyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (80) as a white solid. The product was recrystallized from chloroform-ether-hexane to afford a white solid. m.p. 177-178° C.; 1H-NMR (300 MHz, CDCl3) δ 1.12 (3H, d, J=6.6 Hz), 1.21 (3H, d, J=6.6 Hz), 1.44 (3H, d, J=5.1 Hz), 2.22 (1H, m), 2.53 (3H, s), 4.02-4.20 (2H, m), 5.19-5.43 (2H, m), 7.78 (1H, s), 7.93 (1H, s), 8.03 (1H, s), 8.95 (1H, s). m/z (EI) 351 (M+).
Reaction SMILES: Cl[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:15][O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:7]2[C:2]([O:32][C:29]3[CH:28]=[CH:27][C:26]([NH:25][C:17]4[S:16][C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=5[N:18]=4)=[CH:31][CH:30]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: COC1CCN(c2cccnc2Cl)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC1CCN(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Temperature: 120 °C

Procedure:
The mixture of 2-chloro-3-(4-methoxypiperidin-1-yl)pyridine (25.0 mg, 0.11 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (32.1 mg, 0.132 mmol), Pd2(dba)3 (5.05 mg, 5.51 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (5.15 mg, 8.27 μmol) and sodium 2-methylpropan-2-olate (26.5 mg, 0.276 mmol) in toluene (440 μL) was sparged under argon for 5 min. The mixture was heated to 120° C. in a microwave reactor for 10 min. More phenol (32 mg) was added and the reaction mixture was heated at 120° C. in microwave for another 25 min. After cooling to RT, the mixture was filtered through celite and washed with DCM. The crude product was purified by silica gel chromatography (12 g, 0-50% EtOAc-hexane) to give N-(4-(3-(4-methoxypiperidin-1-yl)pyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine as off-white solid. MS (ESI, pos. ion) m/z: 433.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([CH:22]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]=1[OH:25])[CH:10]=[C:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[S:12]1)([CH3:6])([CH3:5])[CH3:4].Cl[CH2:31][S:32]([O-:35])(=[O:34])=[O:33].[K+].Cl>CC(C)=O>[C:3]([C:7]1[CH:8]=[C:9]([CH:22]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]=1[OH:25])[CH:10]=[C:11]1[C:16](=[O:17])[N:15]([CH2:31][S:32]([OH:35])(=[O:34])=[O:33])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[S:12]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: O=S(=O)([O-])CCl
Reactant: CC(C)(C)c1cc(C=C2Sc3ccccc3NC2=O)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(C=C2Sc3ccccc3N(CS(=O)(=O)O)C2=O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of sodium hydride (60% suspension in paraffin liquid, 0.042 g) in dimethylformaldehyde (1 ml), 2-(3, 5-di-tert.-butyl-4-hydroxybenzylidene)-3,4-dihydro-3-oxo-2H-1,4-benzothiazine (0.20 g) dissolved in dimethylformalhyde (2 ml) was added, dropwise, under ice-cooling and a nitrogen atmosphere. The mixture was stirred for 40 minutes at room temperature. To the mixture, potassium (chloro)methanesulfonate (0,096 g) dissolved in dimethylformaldehyde (2 ml) was added, dropwise, and the mixture was stirred for one day at room temperature. 1N hydrochloric acid was added to the mixture and the whole was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by silica gel column chromatography to give the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])=[O:22])[C:16]=1[CH3:32].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[CH3:62][O:63][C:64]1[CH:69]=[CH:68][C:67]([NH2:70])=[C:66]([NH2:71])[CH:65]=1>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:70][C:67]2[CH:68]=[CH:69][C:64]([O:63][CH3:62])=[CH:65][C:66]=2[NH2:71])=[O:30])=[O:22])[C:16]=1[CH3:32]
Reactant: COc1ccc(N)c(N)c1
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)CCCCCNC(=O)c2c(C)[nH]c(C=NN=C3C(=O)Nc4ccc(F)cc43)c2C)c(N)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
6-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-hexanoic acid (441 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-methoxy-o-phenylenediamine (166 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (427 mg, 76% yield) as a red solid. LC-MS (m/z) 562 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:15][C:14]=3[O:25][CH3:26])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[O:27]1[CH2:32][CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH2:29][CH2:28]1>>[O:27]1[CH2:28][CH:29]=[C:30]([C:2]2[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=5)=[CH:15][C:14]=4[O:25][CH3:26])[N:10]=[CH:11][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:31][CH2:32]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Product: COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(C3=CCOCC3)c2n1

Procedure:
The title compound was prepared according to the method described for Example 91 using 8-chloro-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Example 94) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([CH2:13][OH:14])=[C:10]([Cl:12])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]1([C:7]2[N:8]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([CH3:20])=[CH:18][CH:17]=3)[C:9]([CH2:13][OH:14])=[C:10]([Cl:12])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: OCc1[nH]c(-c2ccccc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Cn2c(-c3ccccc3)nc(Cl)c2CO)cc1

Procedure:
1 g of 2-phenyl-4-chloro-5-hydroxymethylimidazole, together with 0.7 ml of p-methylbenzyl bromide and 3 g of potassium carbonate, was stirred in 10 ml of dimethylformamide at 30° C. for 2 days. The reaction solution was poured into 100 ml of water, and the precipitate deposited was chromatographed on a column of 30 g of silica gel, followed by eluting with chloroform. The initially eluted fraction was collected, and recrystallization from aqueous methanol yielded 0.5 g of 2-phenyl-4-chloro-5-hydroxymethyl-1-(4-methylbenzyl)imidazole as colorless, needle-formed crystals, m.p. 173°-175° C.
Reaction SMILES: [CH:1]1([C:4]2[C:9](=[O:10])[NH:8][C:7](=[O:11])[N:6]([CH2:12][C:13]3[CH:18]=[C:17]([F:19])[N:16]=[C:15](F)[CH:14]=3)[C:5]=2[C:21]([C:23]2[CH:24]=[C:25]([CH:28]=[C:29]([CH3:31])[CH:30]=2)[C:26]#[N:27])=[O:22])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].FC1C=C(COS(C)(=O)=O)C=C([NH:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)N=1.[I-].[Li+]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([C:4]2[C:9](=[O:10])[NH:8][C:7](=[O:11])[N:6]([CH2:12][C:13]3[CH:14]=[C:15]([NH:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=4)[N:16]=[C:17]([F:19])[CH:18]=3)[C:5]=2[C:21]([C:23]2[CH:24]=[C:25]([CH:28]=[C:29]([CH3:31])[CH:30]=2)[C:26]#[N:27])=[O:22])[CH2:2][CH2:3]1
Reactant: Cc1cc(C#N)cc(C(=O)c2c(C3CC3)c(=O)[nH]c(=O)n2Cc2cc(F)nc(F)c2)c1
Reactant: COc1ccc(CNc2cc(COS(C)(=O)=O)cc(F)n2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cc(Cn3c(C(=O)c4cc(C)cc(C#N)c4)c(C4CC4)c(=O)[nH]c3=O)cc(F)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
3-[5-Cyclopropyl-3-(2,6-difluoro-pyridin-4-ylmethyl)-2,6-dioxo-1,2,3,6tetrahydro-pyrimidine-4-carbonyl]-5-methyl-benzonitrile (16 mg, 0.054 mmol) was dissolved in 0.5 mL DMF. Potassium carbonate (7.5 mg, 1 eq.) and methanesulfonic acid 2-fluoro-6-(4-methoxy-benzylamino)-pyridin-4-ylmethyl ester (1 eq.) were added to the reaction, followed by lithium iodide (7.2 mg, 1 eq.) The reaction was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, followed by washing with brine. The organic layer was concentrated down and purified (silica gel, 20-80% EtOAc/hexane) to give light yellow oil (10 mg, 34%). LC-MS shows 540.0 (M+1). 1H NMR (300 MHz, CDCl3): δ 7.81 (s, 1H), 7.63 (s, 1H), 7.59 (s, 1H), 7.23 (s, 1H), 7.21 (s, 2H), 6.91 (s, 1H), 6.88 (s, 1H), 5.80 (s, 1H), 5.78 (s, 1H), 4.26 (d, 2H), 3.80 (s, 2H), 2.39 (s, 3H), 0.9 (m, 1H), 0.62 (m, 3H), 0.41 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O=P(Cl)(Cl)Cl.[BH4-].[Na+].O>C(#N)C.C(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH2:11][CH:12]1[C:23]2[CH:22]=[C:21]([O:24][CH3:25])[C:20]([O:26][CH3:27])=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15][NH:14]1
Reactant: COc1ccc(CCCNC(=O)Cc2ccc(OC)c(OC)c2)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CC2NCCCc3cc(OC)c(OC)cc32)cc1OC
Temperature: 0 °C

Procedure:
A mixture of 2-(3,4-dimethoxy-phenyl)-N-[3-(3,4-dimethoxy-phenyl)-propyl]-acetamide (6.16 g, 16.49 mmol) and POCl3 (4.95 ml, 54.07 mmol) in anhydrous acetonitrile (185 ml) was stirred at reflux for 4 h under nitrogen. After cooling, the reaction mixture was concentrated in vacuo and the residue was dissolved in MeOH (125 ml). The solution was cooled to 0° C. and NaBH4 (4.31 g, 113.93 mmol) was added portionwise. After stirring at 0° C. for 2 h under nitrogen, the reaction mixture was poured into H2O and extracted three times with CH2Cl2. The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (CH2Cl2/MeOH: 9/1) gave the title compound as a racemic mixture (2.29 g, 6.40 mmol, 39%, yellow oil).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CCOCC.[Cu](I)I.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].[Cl-].C12([N+]3C=CN(C45CC6CC(CC(C6)C4)C5)C=3)CC3CC(CC(C3)C1)C2>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH3:15]
Reactant: CCOC(=O)CCCBr
Reactant: C#CCCCC
Agent: Cl[Pd+]
Agent: I[Cu]I
Agent: C=C[CH2-]
Solvent: CCOCC
Product: CCCCC#CCCCC(=O)OCC
Temperature: 45 °C
Reaction time: 17 h
Yield: 72.8 %

Procedure:
1-Hexyne (43 μl, 0.38 mmol) and ethyl 4-bromobutyrate (40 μl, 0.28 mmol) were added to a suspension of 1,3-bis(1-adamantyl)imidazolium chloride (5.2 mg, 0.014 mmol), copper iodide (4.1 mg, 0.022 mmol), allylpalladium(II) chloride dimer (2.6 mg, 0.071 mmol) and cesium carbonate (127 mg, 0.390 mmol) in anhydrous ether (0.37 ml)-anhydrous DMF (0.185 ml) at room temperature in a nitrogen stream, and the mixture was stirred at 45° C. for 17 hours. The reaction mixture was extracted with pentane. The insoluble matter was removed by filtration, and the filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ether=50/1) to give dec-5-ynoic acid ethyl ester (40 mg, 73%).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[F:13][C:14]([Si](C)(C)C)([F:16])[F:15].[F-].C[N+](C)(C)C.[Cl-].[NH4+]>O1CCCC1>[OH:1][C:2]1([C:14]([F:16])([F:15])[F:13])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 3-oxoazetidine-1-carboxylate (0.50 g, 2.9 mmol) and (trifluoromethyl)trimethylsilane (0.65 mL, 4.4 mmol) in tetrahydrofuran (5 mL) at 0° C. was added tetramethylammonium fluoride (0.014 g, 0.15 mmol). The reaction mixture was warmed to room temperature. After 1 h, the reaction mixture was poured into a 0.5M aqueous ammonium chloride solution (25 mL) and extracted with diethyl ether (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to a crude oil. The crude oil was dissolved in tetrahydrofuran (5 mL). A 1M aqueous citric acid solution (5 mL) was added and the mixture was stirred for 1 h. The reaction mixture was partitioned between diethyl ether (25 mL) and water (10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to a crude oil. The residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford tert-butyl 3-hydroxy-3-(trifluoromethyl)azetidine-1-carboxylate as a white solid. 1H NMR (600 MHz, DMSO-D6) 4.17 (d, 2H); 3.91 (d, 2H); 1.43 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CC(C)=O>[CH2:26]([O:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([O:8][CH2:14][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[CH:7]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)Cc1cc(O)cc(O)c1-c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1-c1ccccc1
Yield: 168.1 %

Procedure:
Compound 1 (1.81 g, 7.00 mmol) obtained in Example 1 was dissolved in acetone (50 mL), and potassium carbonate (5.88 g, 42.6 mmol) and benzyl bromide (3.33 mL, 28.0 mmol) were added thereto and stirred with heating under reflux for 1.5 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane/ethyl acetate=20/1 to 9/1) to obtain methyl 3,5-bis(benzyloxy)-2-phenylphenylacetate (2.58 g, 84%).