Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([OH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11](O)(=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[N+:14]([O-:18])[CH:13]=1>>[C:11]([O:10][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[N+:14]([O-:18])[CH:13]=1
Reactant: O=C(O)c1ccc[n+]([O-])c1
Reactant: CCCCCCCCO
Agent: Cl
Product: CCCCCCCCOC(=O)c1ccc[n+]([O-])c1
Yield: 81.6 %

Procedure:
Hydrogen chloride was bubbled through cold octanol (25 g, 190 mmol) until a weight gain of 4.2 g had registered. Nicotinic acid N-oxide (5.29 g, 38 mmol) was then added and the resulting mixture was stirred and heated at 95°-100° C. for 3 hours and 40 minutes. The excess octanol was then removed by distillation at reduced pressure, and the residue of the distillation was taken up in dichloromethane. The dichloromethane solution was washed with aqueous sodium bicarbonate and then with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallized from ligroine to give 7.73 g (31 mmol) of octyl nicotinate N-oxide, mp 69.5°-71° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:17])=O)C.C(O)(=O)C.[CH:22](N)=[NH:23]>C(O)C>[C:11]1([C:10]2[C:6]3[C:4](=[O:3])[NH:23][CH:22]=[N:17][C:7]=3[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N=CN
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2scc(-c3ccccc3)c12
Temperature: 25 °C

Procedure:
A stirred mixture of 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester (350.43 g, 1.535 mol), formamidine acetate (799.13 g, 7.7 mol) and ethanol (1500 ml) was heated under reflux for 18 hours then allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with a little cold ethanol, then crystallised from ethanol to give 5-Phenyl-3H-thieno[2,3-d]pyrimidin-4-one as a yellow solid which was used without further purification.
Reaction SMILES: C(N(CC)CC)C.O[C@@H]([C@@H:11]1[C@@H:14]([CH2:15][C:16](=[O:31])[CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[NH:13][C:12]1=[O:32])C.C(C1C=CC(S([N:45]=[N+:46]=[N-])(=O)=O)=CC=1)(O)=O>C(#N)C>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18]([C:17](=[N+:45]=[N-:46])[C:16](=[O:31])[CH2:15][CH:14]2[NH:13][C:12](=[O:32])[CH2:11]2)=[O:19])=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(C(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: [N-]=[N+]=C(C(=O)CC1CC(=O)N1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (263 mg, 2.6 mmol) is added by syringe to a mixture of (3S,4R)-3-[(R)-1-hydroxyethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl]azetidin-2-one (253 mg, 0.72 mmol) and p-carboxybenzene sulfonylazide (196 mg, 0.84 mmol) in dry acetonitrile (6 ml) at 0° C. When addition is complete the cooling bath is removed and the reaction mixture is stirred at room temperature for 1 hour. The mixture is then diluted with ethyl acetate (50 ml) and filtered. The filtrate is concentrated in vacuo and the residue is chromatographed on a short silica gel column (ethyl acetate) to yield 222 mg, (81% overall from (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyl dimethylsilyloxy)ethyl]-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxopropyl]azetidin-2-one) of (3S,4R)-3-(R)-1-hydroxyethyl)-4-[3-(4-nitrobenzyl)oxycarbonyl-2-oxo-3-diazopropyl]azetidin-2-one as a white solid m.p. (dec.) 163° C. IR(CHCl3, CM-1) 3410, 2132, 1756, 1718, 1650, 1350, 1280, 1120; n.m.r. (CDCl3) δ7.9(2d-aromatic,4), δ5.4(s,2), δ6.2(brs,1), δ4.1(m,2), δ2.6-3.6(m,4), δ1.32(d,3,J=6.2).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].Cl[C:20]1C=CC(S(C)(=O)=O)=CC=1C(O)=O.N1CCCCC1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:20]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Solvent: C1CCNCC1
Product: CS(=O)(=O)c1ccc(N2CCCCC2)c(C(=O)O)c1
Yield: 78 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid (Example Y) from 2-Chloro-5-methanesulfonyl-benzoic acid and piperidine and obtained in 78% yield. MS (m/e): 282.0 (M−H+ 100%)
Reaction SMILES: [Br:1][CH:2]([CH3:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH2:13]([OH:17])[CH2:14][C:15]#[CH:16].CCN(CC)CC>ClCCl.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>[Br:1][CH:2]([CH3:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:16]#[C:15][CH2:14][CH2:13][OH:17])=[CH:7][CH:6]=1
Reactant: CC(Br)COc1ccc(I)cc1
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Br)COc1ccc(C#CCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a solution of 4-(2-Bromopropoxy)-1-iodobenzene (10 g, 29 mmol), 3-butyn-1-ol (26 mL, 37 mmol), Cul (980 mg, 5.2 mmol) and dichlorobis(triphenylphosphine)palladium(II) (3.6 g, 5.2 mmol) in dichloromethane (40 mL) was added Et3N (6.0 mL, 44 mmol) dropwise. The reaction was stirred overnight at room temperature under Ar. The solvent was evaporated under reduced pressure and ethyl acetate was added to dissolve the compound, the solution was filtered over celite to remove most of the Pd. The crude product was purified by silica gel chromatography, eluted with hexane/ethyl acetate (2:1). 2.6 g of the title compound were obtained as a light brown solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[Na+].[I-].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:31])=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=1>CC(C)=O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:31])=[C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][N:5]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]3=[O:15])[CH2:29][CH2:30]2)[CH:24]=1
Reactant: Cc1ccc(Cl)cc1N1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ccc(Cl)cc1N1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.7 %

Procedure:
A mixture of 2-(3-bromopropyl)isoindoline-1,3-dione (2.68 g, 10 mmol) and NaI (20 mmol) in acetone was refluxed for 5 h, then to it was added 1-(5-chloro-2-methylphenyl)piperazine (2.11 g, 10.0 mmol). The reflux was continued for 12 h. Reaction was then cooled to room temperature, filtered through celite and concentrated.. The crude product was recrystalized from acetone to give the title compound as a white solid (3.21 g. 81%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=C)=[CH:18][CH:17]=4)=[CH:7][C:6]=1[C:26]([F:29])([F:28])[F:27])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:34]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]3[C:16]4[C:21]([CH2:22][CH2:23][C:12]=23)=[CH:20][C:19]([CH:24]=[O:34])=[CH:18][CH:17]=4)=[CH:7][C:6]=1[C:26]([F:28])([F:27])[F:29])([CH3:3])[CH3:2]
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(OC(C)C)c(C(F)(F)F)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2onc3c2CCc2cc(C=O)ccc2-3)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 33 %

Procedure:
To 3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 14B, 0.18 g, 0.451 mmol) in THF (2 mL) was added N-methylmorpholine-N-oxide (50% in water) (0.093 mL, 0.451 mmol) followed by osmium tetroxide (0.071 mL, 9.01 μmol) in one portion at room temperature. The contents were stirred at room temperature for 14 h. LCMS indicated formation of a major peak corresponding to the diol intermediate. Sodium periodate (0.145 g, 0.676 mmol) dissolved in 2 mL of water was added in one portion at room temperature. The milky heterogeneous solution was stirred at room temperature for 45 min. The reaction mixture was concentrated and partitioned between ethyl acetate (15 mL) and water (10 mL). The ethyl acetate layer was dried over sodium sulfate, concentrated and purified by silica gel column chromatography (hexane/ethyl acetate) to yield 3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (0.06 g, 0.149 mmol, 33.2% yield) as a white solid. LC/MS M+1=402.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)\[CH3:7])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[CH:10]=1)\[CH2:7][Br:20])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)Oc1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1cccc(C(F)(F)F)c1
Yield: 56.6 %

Procedure:
To a stirred mixture of (E)-3-(3-trifluoromethyl-phenoxy)-but-2-enoic acid ethyl ester (5.33 g, 0.019 mol) in carbon tetrachloride (30 mL) under a nitrogen atmosphere was added N-bromosuccinimide (5.20 g, 0.029 mol) and benzoyl peroxide (470 mg, 0.002 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(3-trifluoromethyl-phenoxy)-but-2-enoic acid ethyl ester (3.80 g, 55%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][CH3:9])[C:3]=1[C:10]#[N:11].[CH3:12][N:13]=[C:14]=[O:15]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.O1CCCC1>[CH3:12][NH:13][C:14]([NH:1][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][CH3:9])[C:3]=1[C:10]#[N:11])=[O:15]
Reactant: CCSc1nsc(N)c1C#N
Reactant: CN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Product: CCSc1nsc(NC(=O)NC)c1C#N
Reaction time: 48 h

Procedure:
A solution of 35.0 g of 5-amino-4-cyano-3-(ethylthio)-isothiazole, 11.9 g of methyl isocyanate, 50 drops of dibutyltin diacetate in 175 ml of dried tetrahydrofuran was heated under reflux during 15 hours. Thin-layer chromatographic analysis of the reaction mixture indicated the reaction was 50% complete. An additional 11 ml of methyl isocyanate and 10-15 drops of dibutyltin diacetate were added. The reaction mixture was heated with stirring for 2 days. Thin-layer chromatographic analysis of the reaction mixture indicated the reaction to be complete. The reaction mixture was cooled, and the solid collected by filtration. The filtrate was evaporated to give a second crop, which was recrystallized from ethanol/dimethylformamide. The total yield of pure 1-methyl-3-(4-cyano-3-(ethylthio)-5-isothiazolyl)urea was 37.6 g; m.p. 246° (phase change) - 263°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17](/[CH:22]=[CH:23]/[C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=3)=[N:18][NH:19]2)=[CH:15][CH:14]=1)=O>>[O:10]=[C:2]1[NH:1][C:9]2[C:4](/[C:3]/1=[CH:11]/[C:13]1[CH:21]=[C:20]3[C:16]([C:17](/[CH:22]=[CH:23]/[C:24]4[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=4)=[N:18][NH:19]3)=[CH:15][CH:14]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: COC(=O)c1ccc(/C=C/c2n[nH]c3cc(C=O)ccc23)cc1
Reactant: O=C1Cc2ccccc2N1
Product: COC(=O)c1ccc(/C=C/c2n[nH]c3cc(/C=C4\C(=O)Nc5ccccc54)ccc23)cc1
Yield: 47.5 %

Procedure:
The title compound (40 mg, 83%) was synthesized as an orange solid according to the method described for Example A67 (oil temp 75° C., reflux 150 min) using indolin-2-one (26.6 mg, 0.2 mmol) and (E)-methyl 4-(2-(6-formyl-1H-indazol-3-yl)vinyl)benzoate (61.2 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.60 (s, 1H), 10.70 (s, 1H), 9.00 (s, 1H), 8.29 (d, J=8.0 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.98 (d, J=8.0 Hz, 2H), 7.88 (d, J=8.0 Hz, 2H), 7.77 (d, J=8.4 Hz, 1H, partially overlapping with the doublet at 7.74), 7.74 (d, J=17.2 Hz, 1H, partially overlapping with the doublet at 7.77), 7.63 (d, J=17.2 Hz, 1H), 7.23 (t, J=7.6 Hz, 1H), 7.01 (t, J=7.6 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 3.86 (s, 3H); MS ESI 422.3 [M+H]+, calcd for [C26H19N3O3+H]+ 422.1.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[O:6]=[C:7]1[CH2:10][CH:9]([C:11]([OH:13])=O)[CH2:8]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:5][O:4][N:3]([CH3:2])[C:11]([CH:9]1[CH2:8][C:7](=[O:6])[CH2:10]1)=[O:13]
Reactant: CNOC
Reactant: O=C1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CC(=O)C1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
To a mixture of N,O-dimethylhydroxylamine hydrochloride (5.2 g, 0.054 mol), and 3-oxocyclobutanecarboxylic acid (4.0 g, 0.035 mol) in dichloromethane (30 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10.0 g, 0.052 mol), 1-hydroxybenzotriazole (7.1 g, 0.052 mol) followed by triethylamine (34 mL, 0.24 mol) at 0° C. The mixture was stirred at rt over night, then quenched with water. The mixture was extracted with EtOAc. The organic layers were dried over MgSO4, concentrated and purified with Combiflash (silica gel, 0-5% for 30 min followed by 5-20% EtOAc/Hex) to give the desired product (4.3 g, 78%) as light yellow oil. LCMS calculated for C7H12NO3(M+H)+: 158.1. Found: 158.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.I[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C([O-])([O-])=O.[K+].[K+].O>CC(=O)CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCI
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Yield: 94.8 %

Procedure:
A mixture of 4′-bromobiphenyl-4-ol (8.41 g, 33.8 mmol), 1-iodododecane (10 g, 33.8 mmol) and K2CO3 (18.64 g, 135 mmol) in butanone (100 mL) was heated at reflux. After 16 h the mixture was poured into water (200 mL), extracted with DCM (3×100 mL), washed with NaOH (2 M, 100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was washed with hot MeOH to give the title compound (13.37 g, 95%) as a colourless powder.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[O:15]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([CH3:10])[CH:8]=1)[C:3](=[O:14])[N:27]([CH2:26][C:25]1[CH:28]=[CH:29][C:22]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:23][CH:24]=1)[CH2:12]2
Reactant: NCc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)c1c(C)cc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(Oc3ccccc3)cc1)C2
Yield: 67.2 %

Procedure:
4-Bromo-2-bromomethyl-6-methylbenzoic acid methyl ester (762 mg, 2.37 mmol), 4-phenoxy benzylamine (0.543 mL, 3.56 mmol) and K2CO3 (981 mg, 7.10 mmol) were stirred in toluene (10 mL) at 95° C. for 12 hours. The reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine and dried over anhydrous Na2-SO4. The solvent was removed under reduced pressure and the product was purified by column chromatography (10-25% EtOAc/Hexanes) to afford a yellow oil (650 mg). 1H NMR (300 MHz, CDCl3): δ 7.35-7.38 (m, 4H), 7.32 (s, 1H), 7.26-7.29 (m, 1H), 7.15 (t, 1H), 6.99 (t, 4H), 4.74 (s, 2H), 4.23 (s, 2H), 2.75 (s, 3H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[N:11]=[C:10](Cl)[C:9]([N:13]([CH3:18])[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:8][N:7]=1.C(N(CC)CC)C>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4].C(Cl)Cl>[Cl:5][C:6]1[N:7]=[C:8]2[C:9]([N:13]([CH3:18])[C:14](=[O:17])[CH2:15][CH2:16][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[CH:10][N:11]=1
Reactant: NC1CC1
Reactant: C=CC(=O)N(C)c1cnc(Cl)nc1Cl
Agent: [Ti+4]
Agent: CC[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)CCN(C2CC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.5 %

Procedure:
Cyclopropylamine (Aldrich; 150 μL, 2.18 mmol), N-(2,4-dichloropyrimidin-5-yl)-N-methyl-prop-2-enamide (Intermediate 113; 337 mg, 1.45 mmol) Triethylamine (404 μL, 2.9 mmol), Titanium Tetra-ethoxide (152 μL, 0.725 mmol) and DCM (5 mL) were combined and stirred at room temp for 1 hr, heated at 40° C. for 4 hrs then cooled to room temperature. The reaction mixture was washed with water then gravity filtered through a PTFE cup, the aqueous layer containing the titanium emulsion was washed with further DCM (3×10 mL) and the combined organic solutions gravity filtered through a PTFE cup and solvents evaporated. The residue was dissolved in DCM and purified by chromatographic separation on silica eluting with a shallow gradient (25 column volumes) of 10-50% Ethyl Acetate/iso-hexane. Product containing fractions were combined and evaporated to give the title compound as a cream solid (42 mg, 11%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([S:23](=[O:26])(=[O:25])N)=[CH:19][CH:18]=2)[N:7]=1)=[O:5])[CH3:2].Cl.[CH3:28]S(C1C=CC(NN)=CC=1)(=O)=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:28])(=[O:26])=[O:25])=[CH:19][CH:18]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Agent: Cl
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccc(S(C)(=O)=O)cc2)n1
Yield: 82 %

Procedure:
Compound 3a was synthesized in a manner similar to the synthesis of 3b using 4-(methylsulfonyl)phenylhydrazine hydrochloride (10 g, 44.7 mmol) to give 3a (13.6 g, 82% yield) as a white solid. mp 199.4-202.9° C. 1H NMR (300 MHz, DMSO-d6): δ 7.99 (d, J=9 Hz, 2H), 7.58 (d, J=9 Hz, 2H), 7.43-7.38 (m, 3H), 7.34-7.27 (m, 2H), 7.17 (s, 1H), 4.34 (q, J=7, 2H), 3.27 (s, 3H), 1.31 (t, J=7, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:19][C@@H:20]1[CH2:22][O:21]1>CN(C=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH2:19][C@H:20]([OH:21])[CH3:22])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2ccc(O)cc2n1
Reactant: C[C@@H]1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc2ccc(OC[C@@H](C)O)cc2n1
Temperature: 80 °C
Yield: 86.4 %

Procedure:
To a stirred mixture of 2-methylquinolin-7-ol (0.400 g, 2.51 mmol), Cs2CO3 (2.46 g, 7.54 mmol) and DMF (16 mL) was added (R)-2-methyloxirane (0.438 g, 7.54 mmol). The reaction mixture was heated at 80° C. for 2 hours. After cooling, the reaction mixture was partitioned between ether and water. The aqueous layer was extracted with ether. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1% MeOH in EtOAc) to give (R)-1-(2-methylquinolin-7-yloxy)propan-2-ol (0.471 g, 86%).
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4].N1C=CC=CC=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(Cl)Cl>[S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=1)([O:21][CH2:1][CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4])(=[O:36])=[O:35]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(C)CCCC(C)CCCC(C)CCCC(C)C)cc1
Yield: 138.7 %

Procedure:
Under a nitrogen atmosphere, 29.16 g (97.67 mmol) of phytanol and 9.27 g (117.2 mmol) of pyridine were dissolved in 220 ml of dry methylene chloride, and 20.48 g (107.4 mmol) of p-toluenesulfonyl chloride was added little by little under ice cooling, in order to prevent the liquid temperature from exceeding 10° C. After the completion of addition, agitation was continued for 12 hours until phytanol disappeared, the resulting reaction solution was successively washed with 200 ml of water, 200 ml of 2N hydrochloric acid, and 200 ml of a saturated sodium bicarbonate water, and dried over anhydrous magnesium sulfate. After the filtration, the resultant was concentrated under reduced pressure to obtain 61.31 g of phytanyl tosylate.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH2:11]([O:13][C:14](=[O:22])[CH:15]([C:19](=O)[CH3:20])[C:16](=O)[CH3:17])[CH3:12].N1C=CC=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[C:16]([CH3:17])=[N:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Br:2])[CH:4]=2)[C:19]=1[CH3:20])=[O:22])[CH3:12]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNc1cccc(Br)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2cccc(Br)c2)c1C

Procedure:
Similar to Example 1, equimolar amounts of 3-bromophenylhydrazine hydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis showed that the resulting solid was the named product (m.p. 34° C.–35° C.).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[C:13]3[NH:20][CH:19]=[C:18]([C:21]([OH:23])=O)[C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:3][CH2:2]1.[C:24]([O:28][C:29](=[O:38])[NH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29](=[O:38])[NH:30][C@H:31]1[CH2:32][CH2:33][C@H:34]([NH:37][C:21]([C:18]2[C:14]3[N:15]=[CH:16][N:17]=[C:12]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:13]=3[NH:20][CH:19]=2)=[O:23])[CH2:35][CH2:36]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)c1c[nH]c2c(-c3ccccc3OCC3CC3)ncnc12
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A78) and trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.