Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[C:11]([NH:17][C:18](N)=[S:19])=[C:10]([CH:21]([CH3:23])[CH3:22])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC1C=CC=CC=1C>[O:1]([C:8]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[C:11]([N:17]=[C:18]=[S:19])=[C:10]([CH:21]([CH3:23])[CH3:22])[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1cc(Oc2ccccc2)cc(C(C)C)c1NC(N)=S
Solvent: Cc1ccccc1C
Product: CC(C)c1cc(Oc2ccccc2)cc(C(C)C)c1N=C=S
Yield: 89.3 %

Procedure:
315 g (1 mol) of N-(4-phenoxy-2,6-diisopropylphenyl)thiourea are suspended in 800 ml of o-xylene, and the suspension is heated for 5 hours to reflux temperature, whereupon the temperature of the reaction mixture rises to ca. 150° C. The reaction mixture is then cooled, the solvent is removed by vacuum distillation, and the crude product is purified by distillation under a high vacuum, giving 278 g (93% of theory) of 4-phenoxy-2,6-diisopropylphenylisothiocyanate as a pale yellow oil with a boiling point of 130°-140° C./0.05 mbar.
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6](=[O:8])[CH:5]=[C:4]([S:9][CH2:10][C:11]2[CH2:12][S:13][C@@H:14]3[C@H:34]([NH:35][C:36](=[O:84])/[C:37](/[C:59]4[N:60]=[C:61]([NH:64]C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[S:62][CH:63]=4)=[N:38]\[O:39]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:33](=[O:85])[N:15]3[C:16]=2[C:17]([O:19]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:18])[CH:3]=1.Cl.O.[K+].[Br-]>C(O)=O>[NH2:64][C:61]1[S:62][CH:63]=[C:59](/[C:37](=[N:38]/[OH:39])/[C:36]([NH:35][C@@H:34]2[C:33](=[O:85])[N:15]3[C:16]([C:17]([OH:19])=[O:18])=[C:11]([CH2:10][S:9][C:4]4[CH:3]=[C:2]([CH3:1])[O:7][C:6](=[O:8])[CH:5]=4)[CH2:12][S:13][C@H:14]23)=[O:84])[N:60]=1
Reactant: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)[C@H]3SC2)cc(=O)o1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: O=CO
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(N)n4)[C@H]3SC2)cc(=O)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diphenylmethyl 3-(6-methyl-2-oxo-2H-pyran-4-ylthiomethyl)-7β-[2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetamido]ceph-3-em-4-carboxylate (969 mg) was dissolved in 100% formic acid (14.9 ml) and 1N hydrochloric acid (0.825 ml) and water (0.825 ml) were added. The mixture was stirred at room temperature for 0.5 h and then concentrated hydrochloric acid (0.66 ml) was added. The mixture was stirred for 1 h and then the solid was filtered off and washed with 90% formic acid. The combined filtrates were evaporated and a 1:1 mixture of toluene and tetrahydrofuran was evaporated from the residue twice. The residue was triturated with ether and the solid filtered off and washed with ether. The solid was suspended in water and the pH adjusted to 2.6 with 0.1N sodium hydroxide solution. The resulting solid was filtered off, washed with water and dried under vacuum to give the product. υmax (KBr) 1773, 1675 and 1624cm-1 ; δ[(CD3)2SO] 2.16 (3H, s), 3.47 (1H, d, J 17.9Hz), 3.70 (1H, d, J 18.0Hz), 4.11 (1H, d, J 12.9Hz), 4.19 (1H, d, J 13.1Hz), 5.18 (1H, d, J 4.8Hz), 5.79 (1H, dd, J 4.8 and 8.2Hz), 6.00 (1H, s), 6.21 (1H, s), 6.66 (1H, s), 7.17 (2H, s), 9.48 (1H, s).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:18]2[CH2:17][CH2:16][C:15]3[CH:14]=[N:13][CH:12]=[CH:11][C:10]=3[C:9]=2[NH:8][CH:7]=1)=[O:5])C.[OH-].[K+]>C(O)C>[NH:8]1[C:9]2[C:10]3[CH:11]=[CH:12][N:13]=[CH:14][C:15]=3[CH2:16][CH2:17][C:18]=2[C:6]([C:4]([OH:5])=[O:3])=[CH:7]1
Reactant: CCOC(=O)c1c[nH]c2c1CCc1cnccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c[nH]c2c1CCc1cnccc1-2
Yield: 56 %

Procedure:
To a solution of 4,5-dihydro-1H-pyrrolo[2,3-f]isoquinoline-3-carboxylic acid ethyl ester E2 (0.165 mmol) in ethanol (3 mL), 2N KOH (20 eq) was added and the mixture was heated at 60° for 4 h. After solvent removal the solution was neutralized with 1N HCl and the precipitate was filtered and dried, providing the title compound in 56% yield.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[Cl:16].[F:17][C:18]1[CH:23]=[C:22](B(O)O)[C:21]([F:27])=[CH:20][N:19]=1.C(=O)([O-])[O-].[Na+].[Na+].B(O)O>COCCOC.O>[Cl:16][C:3]1[C:2]([C:22]2[C:21]([F:27])=[CH:20][N:19]=[C:18]([F:17])[CH:23]=2)=[N:7][C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1
Reactant: OB(O)c1cc(F)ncc1F
Reactant: Clc1ccc(NCC2CCOCC2)nc1Br
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Fc1cc(-c2nc(NCC3CCOCC3)ccc2Cl)c(F)cn1
Temperature: 105 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (0.500 g, 1.64 mmol), 2,5-difluoropyridin-4-ylboronic acid (0.260 g, 1.64 mmol), and sodium carbonate (2.45 ml, 4.91 mmol, 2 M in H2O) were dissolved in DME (7.36 ml). The solution was then degassed by sparging with argon for 5 min. It was then treated with PdCl2(dppf)CH2Cl2 adduct (0.267 g, 0.327 mmol). The reaction mixture was then heated in the microwave at 105° C. for 25 min. More boronic acid (0.260 g, 1.64 mmol) and PdCl2(dppf)CH2Cl2 adduct (0.267 g, 0.327 mmol), and H2O (˜2 ml) were added. Heating in the microwave was continued at 110° C. for 30 min. The reaction mixture was then filtered through a pad of Celite. The filtrate was then concentrated in vacuo to give 1.2090 g of crude product. The resulting residue was subjected to silica gel column chromatography. Elution using 10 EtOAc/90 heptane to 80 EtOAc/20 heptane gave 0.3584 g (65%) of 3-chloro-2′,5′-difluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine. LCMS (m/z): 340.0 (MH+), retention time=0.90 min. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.37 (qd, 3H) 1.60 (br. s., 2H) 1.68 (d, J=12.91 Hz, 3H) 1.84 (ddd, J=11.15, 7.24, 4.30 Hz, 1H) 3.21 (t, J=6.26 Hz, 2H) 3.32-3.45 (m, 3H) 4.00 (dd, J=11.15, 3.72 Hz, 2H) 4.74 (br. s., 1H) 6.45 (d, J=9.00 Hz, 1H) 6.99-7.07 (m, 1H) 7.51 (d, J=8.61 Hz, 1H) 8.12 (s, 1H).
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:4]=2[CH2:3]1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(Cl)(Cl)Cl>[CH3:19][C:16]1[CH:17]=[CH:18][C:4]2[CH2:3][CH:2]([N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[C:8]3[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:7]=3[S:6][C:5]=2[CH:15]=1
Reactant: CN1CCNCC1
Reactant: CSc1ccc2c(c1)C(Cl)Cc1ccc(C)cc1S2
Solvent: ClC(Cl)Cl
Product: CSc1ccc2c(c1)C(N1CCN(C)CC1)Cc1ccc(C)cc1S2

Procedure:
10.0 G. of 10-chloro-10,11-dihydro-3-methyl-8-methylthio-dibenzo[b,f]thiepin, 300 ml. of chloroform and 9.8 g. of N-methylpiperazine are heated at reflux for 30 hours. The mixture is evaporated under reduced pressure. The residue is worked up in an analogous manner to that described in Example 1, and there is obtained 1-(10,11-dihydro-3-methyl-8-methylthio-dibenzo[b,f]-thiepin-10-yl)-4-methylpiperazine whose dimethanesulfonate crystallizes from acetone and melts at 199°-200°C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[CH:8]=[CH:9][CH2:10]Cl)=[O:4].C([O:19][AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].Cl>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)/[CH:8]=[CH:9]/[CH2:10][OH:19])=[O:4]
Reactant: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Reactant: COC(=O)c1cccc(C=CCCl)c1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(/C=C/CO)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3-Methoxycarbonylcinnamyl chloride (24 g) was dissolved in dry tetrahedrofuran and then this solution added to lithium tri-tert-butoxyaluminohydride (63.5 g) dissolved in tetrahydrofuran (250 ml) at -78° C. The resultant clear solution was stirred at -78° C. for 30 minutes then it was added to ice and 2 M hydrochloric acid (750 ml). The two phase mixture was extracted 4 times with dichloromethane. After drying the dichloromethane was evaporated to yield the title compound as a pale yellow oil.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:14]=[C:13]([CH2:15]B2OCC(C)(C)CO2)[O:12][C:11]=1[CH3:24])(C)C)(C)(C)C.BrC1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][S:36][CH3:37])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:24][C:11]1[O:12][C:13]([C:15]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][S:36][CH3:37])=[CH:28][CH:27]=2)=[CH:14][C:10]=1[CH2:9][OH:8]
Reactant: CSCCCOc1ccc(Br)cc1
Reactant: Cc1oc(CB2OCC(C)(C)CO2)cc1CO[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CSCCCOc1ccc(-c2cc(CO)c(C)o2)cc1
Reaction time: 8 h
Yield: 88.4 %

Procedure:
A mixture of tert-butyl({5-[(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)methyl]-2-methylfuran-3-yl}methoxy)dimethylsilane (3.0 g), 1-bromo-4-[3-(methylsulfanyl)propoxy]benzene (2.8 g), tetrakis(triphenylphosphine)palladium(0) (0.5 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), 1N tetrabutylammonium fluoride in tetrahydrofuran (10 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, purified by silica gel chromatography (0% ethyl acetate/hexane to 40% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.2 g, 84%) as a white crystal.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3](O)[CH2:2]1.C(O)C>CN(C)C=O>[CH3:16][C:15]1[C:13](=[O:14])[N:12]=[C:10]2[N:9]([C@@H:1]3[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([O:11]2)[CH2:2]3)[CH:17]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1cn2c(nc1=O)O[C@H]1C[C@H]2O[C@@H]1CO
Temperature: 70 °C
Yield: 60.3 %

Procedure:
Thymidine (85.4 g; 0.353 mol) was dissolved in 500 ml dry DMF (dimethylformamide) and added to N-(2-chloro-1,1,2-trifluoroethyl)dielthylamine (100.3 g; 0.529 mol) [prepared according to the method of D. E. Ayer, J. Med. Chem. 6, 608 (1963)]. This solution was heated at 70° C. for 30 minutes then poured into 950 mL ethanol with vigorous stirring. The product precipitated from this solution and was filtered. The ethanol supernatant was refrigerated then filtered to yield a total of 47.75 g (0.213 mol; 60.3%) of 2,3'-anhydrothymidine mp=228°-230° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](I)[C:5]([Cl:9])=[CH:4][C:3]=1[OH:10].[CH:11]1([Mg]Br)[CH2:13][CH2:12]1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[CH:7]=[C:6]([CH:11]2[CH2:13][CH2:12]2)[C:5]([Cl:9])=[CH:4][C:3]=1[OH:10]
Reactant: Br[Mg]C1CC1
Reactant: Nc1cc(I)c(Cl)cc1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: Nc1cc(C2CC2)c(Cl)cc1O
Temperature: 25 °C
Yield: 63.1 %

Procedure:
To a mixture of 2-amino-5-chloro-4-iodophenol (500 mg, 1.9 mmol), PdCl2(dppf) (136 mg, 0.19 mmol) in THF (10 mL) under argon at RT, cyclopropylmagnesium bromide (16 mL, 11.4 mmol, 0.7 M in THF) was added and the mixture was stirred at reflux for 15 h. The mixture was allowed to cool to RT, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (10-20% ethyl acetate/hexanes) to afford the desired product (220 mg, 63% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.27 (s, 1H), 6.62 (s, 1H), 6.22 (s, 1H), 4.53 (s, 2H), 1.89-1.93 (m, 1H), 0.83-0.87 (m, 2H), 0.46-0.49 (m, 2H).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.[CH3:6][C:7]([O:10][C:11]([NH:13][CH2:14][CH2:15][C:16](O)=[O:17])=[O:12])([CH3:9])[CH3:8].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[N:2]1([C:16](=[O:17])[CH2:15][CH2:14][NH:13][C:11](=[O:12])[O:10][C:7]([CH3:6])([CH3:8])[CH3:9])[CH2:5][CH2:4][CH2:3]1
Reactant: C1CNC1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.3 %

Procedure:
After adding azetidine hydrochloride (2.96 g) to a solution of triethylamine (4.42 ml) in N,N-dimethylformamide, the mixture was stirred for 10 minutes at room temperature. Boc-beta-ALA-OH (5.00 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.59 g) and 1-hydroxybenzotriazole (5.35 g) were added thereto, and the mixture was stirred at room temperature for 3 days. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed with brine and dried over anhydrous sodium sulfate. It was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate, then ethyl acetate:methanol=10:1). Fractions containing the target compound were concentrated under reduced pressure to provide the title compound (5.99 g, 99.4%) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)O1>>[CH3:16][N:15]([CH3:17])[C:13]([C:4]1[CH:3]=[C:2]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:14]
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: COC(=O)Cc1ccc(Br)cc1C(=O)N(C)C
Product: COC(=O)Cc1ccc(-c2ccc(O)cc2)cc1C(=O)N(C)C
Yield: 77 %

Procedure:
According to a method similar to Example (26-3) and Example (68), from methyl {4-bromo-2-[(dimethylamino)carbonyl]phenyl}acetate (102 mg, 0.340 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (90 mg, 0.408 mol), methyl {3-[(dimethylamino)carbonyl]-4′-hydroxy-1,1′-biphenyl-4-yl}acetate was obtained (82 mg, two-step total yield: 77%).
Reaction SMILES: [CH3:1][C@H:2]([C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:15])[C@H:3]([NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[C:4]([OH:6])=[O:5].[CH3:22][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1>[CH3:1][C@H:2]([C:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH2:15])[C@H:3]([NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[C:4]([O:6][CH3:22])=[O:5]
Reactant: C=C(c1ccccc1)[C@@H](C)[C@H](NC(=O)C(F)(F)F)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: C=C(c1ccccc1)[C@@H](C)[C@H](NC(=O)C(F)(F)F)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
Carboxylic acid 14 (544.4 mg, 1.81 mmol) was placed in 1:1 CH3OH-toluene (6 mL) under N2, and trimethylsilyldiazomethane (2 M solution in hexane, 4.0 mL, 8.0 mmol) was added. The solution was stirred at ambient temperature for 16 h. The solvent was evaporated, and the residue was chromatographed (silica gel, 17 g; 9:1 hexane-EtOAc) to yield 0.46 g (81%) of 15 as a colorless oil: Rf0.54 (4:1 hexane-EtOAc); 1H NMR δ 7.33 (5H, m), 6.48 (1H, br d), 5.34 (1H, s), 5.11 (1H, d, J=0.8 Hz), 4.64 (1H, dd, J=8.7 and 4.0 Hz), 3.76 (3H, s), 3.48 (1H, m), 1.26 (3H, d, J=7.1 Hz).
Reaction SMILES: [CH2:1]1[C@@H:6]2[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[O:9][CH2:10][C@@H:5]2[CH2:4][CH2:3][NH:2]1.I[CH2:16][CH2:17][CH3:18].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:16]([N:2]1[CH2:3][CH2:4][C@H:5]2[CH2:10][O:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[C@H:6]2[CH2:1]1)[CH2:17][CH3:18]
Reactant: CCCI
Reactant: c1ccc2c(c1)OC[C@@H]1CCNC[C@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCN1CC[C@H]2COc3ccccc3[C@H]2C1

Procedure:
A solution of 0.235 g (±)-[4aR*,10bS*]-1,3,4,4a,5,10b-hexahydro-2H-[1]benzopyrano[4,3-c]pyridine in 5 ml toluene is refluxed with 200 mg iodopropane and 3 ml saturated NaHCO3 solution for 2 hours. The organic phase is separated, dried over Na2SO4, filtered, concentrated in vacuo, and flash chromatographed with CH2Cl2 /ammonia saturated methanol (95:5)to give the title compound; m.p. HCl salt 245°-247°.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][N:10]([CH2:22][CH2:23][OH:24])[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:22][CH2:23][O:24][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:25][CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN(CCO)C(=O)c2cccc3cc[nH]c23)cc1
Reactant: Oc1ccccc1C(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CN(CCOc2ccccc2C(F)(F)F)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
To a solution of 175 mg (0.5 mmol) of 1H-indole-7-carboxylic acid (4-tert-butyl-benzyl)-(2-hydroxy-ethyl)-amide, 91 mg (0.55 mmol) of 2-hydroxy-benzotrifluoride and 144 mg (0.55 mmol) of triphenyl phosphine in 5 ml THF were added dropwise 88 μl (0.55 mmol) azodicarboxylic acid diethyl ester at 0° C. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue purified by column chromatography (50 g silica gel; diethyl ether/heptane 1:1) to yield 172 mg (70%) product as a white solid. MS (ISP) 495.5 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[N:26][N:27]([CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:28]=2)O1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:31]1([CH2:30][CH2:29][N:27]2[CH:28]=[C:24]([C:2]3[CH:3]=[N:4][C:5]([C:8]4[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=4)=[N:6][CH:7]=3)[CH:25]=[N:26]2)[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
Reactant: OCc1cccc(-c2ncc(Br)cn2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: OCc1cccc(-c2ncc(-c3cnn(CCN4CCOCC4)c3)cn2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Under an argon atmosphere, 2.82 g (10 mmol) of [3-(5-bromopyrimidin-2-yl)-phenyl]methanol are dissolved in 100 ml of ethylene glycol dimethyl ether, 3.38 g (10 mmol) of 4-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]ethyl}morpholine and 4.25 g (20 mmol) of tripotassium phosphate trihydrate are added. The reaction mixture is evacuated twice and flushed with argon. 840 mg (1.2 mmol) of bis(triphenylphosphine)palladium(II) chloride are added, the mixture is again evacuated and flushed argon. The reaction mixture is stirred at 80° C. for 16 hours. The reaction mixture is diluted with dichloromethane and water and filtered through Celite. The organic phase is separated off, washed with water again, the organic phase is dried over sodium sulfate and evaporated to dryness. The residue is recrystallised from isopropanol; yield: 2.74 g, LCMS: 366 (M+H).
Reaction SMILES: C(=O)([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])=[CH:7][C:6]=1[N+:26]([O-:28])=[O:27])OC.O>C(O)C.S(=O)(=O)(O)O>[Cl:25][C:15]1[CH:16]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:18]=[C:19]([Cl:20])[C:14]=1[N:11]1[C:12]2[C:8](=[CH:7][C:6]([N+:26]([O-:28])=[O:27])=[C:5]([OH:4])[CH:13]=2)[CH:9]=[N:10]1
Reactant: COC(=O)Oc1cc2c(cnn2-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc2cnn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2cc1O
Yield: 58.8 %

Procedure:
To a solution of methyl 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-nitroindazol-6-yl carbonate (8 g) in ethanol (100 g), 30% sulfuric acid (20 ml) was added, and the resultant mixture was refluxed for 6 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with diethyl ether. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-6-hydroxy-5-nitroindazole (4.1 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.Cl[C:13]1[N:18]=[CH:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([OH:30])([CH3:29])[CH3:28])=[C:21]([O:31][CH3:32])[CH:20]=2)[C:15](=[O:33])[CH:14]=1>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:13]2[N:18]=[CH:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([OH:30])([CH3:29])[CH3:28])=[C:21]([O:31][CH3:32])[CH:20]=3)[C:15](=[O:33])[CH:14]=2)=[CH:6][CH:5]=1
Reactant: COc1cc(-n2cnc(Cl)cc2=O)ccc1OCC(C)(C)O
Reactant: OCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-n2cnc(OCc3ccc(Cl)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.2 %

Procedure:
Sodium hydride (13 mg, 0.32 mmol) was added to a solution of (4-chlorophenyl)methanol (46 mg, 0.32 mmol) in THF (1 mL) under nitrogen. The mixture was stirred at RT for 1 hour, then 6-chloro-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one Part A (35 mg, 0.108 mmol) was added and stirred for 45 min at RT. The reaction was quenched with MeOH (0.5 mL), diluted with EtOAc, washed with saturated NH4Cl, dried (Na2SO4), and concentrated. The residue was subjected to ISCO flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient). The product was then re-purified using HPLC (C18 column/10:90 to 90:10 MeOH—H2O) to afford the title compound 6-(4-chlorobenzyloxy)-3-(4-(2-hydroxy-2-methyl-propoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one H-1 (2.5 mg, 5.2% yield). LC/MS 431 (M+H)+, tR 0.91 min (method 5); 1H NMR (400 MHz, chloroform-d) δ 6.04 (1H, s), 7.38 (4H, s), 7.00 (1H, d), 6.79-6.89 (2H, m), 5.85 (1H, s), 5.27 (2H, s), 3.87 (3H, s), 3.86 (2H, s), 1.36 (6H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]3[N:10]=[CH:11][N:12]=[C:13](S(C)(=O)=O)[C:14]=3[N:15]=2)=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=[C:3]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C[N:33]1C(C2SC3N=CN=C(S(C)(=O)=O)C=3C=2)=C(C2C=CC=CC=2)N=C1>>[CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]3[N:10]=[CH:11][N:12]=[C:13]([NH2:33])[C:14]=3[N:15]=2)=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=[C:3]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Reactant: Cn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1nc2c(S(C)(=O)=O)ncnc2s1
Product: Cn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 2-(1-Methyl-2,4-diphenyl-1H-imidazol-5-yl)-7-(methylsulfonyl)[1,3]thiazolo[5,4-d]pyrimidine (Intermediate 40) in place of 6-(1-Methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 17). Yellow solid (21 mg, 91%);