Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:20]([O-])=O)=[C:11]([C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[C:12]([NH2:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>CCO.[Fe]>[NH2:20][C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=[C:15]([O:18][CH3:19])[C:11]=1[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1C(N)=O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(OCc2ccccc2)c(N)c1C(N)=O
Temperature: 90 °C

Procedure:
A mixture of 3-(benzyloxy)-6-methoxy-2-nitrobenzamide (10, 0.34 g. 1.1 mmol), iron powder (0.44 g, 7.7 mmol) and concentrated hydrochloric acid (80 mL) in EtOH (4 mL)/water (0.4 mL) was heated at 90° C. for 75 min. The reaction mixture was cooled to room temperature, filtered through Celite and concentrated. The residue was dissolved in EtOAc washed with saturated NaHCO3 solution, dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography eluting with 0-10% MeOH in CH2Cl2 afforded the title compound along with its regioisomer (0.267 g, 87%) as a tan solid: 1H NMR (500 MHz, CDCl3) δ 7.83 (br s, 1H), 7.47-7.32 (m, 5H), 6.77 (d, J=8.8 Hz, 1H), 6.60 (br s, 2H), 6.06 (d, J=8.8 Hz, 1H), 5.51 (br s, 1H), 5.04 (s, 2H), 3.85 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(Cl)c23)cc1OC
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc(C)c(Cl)c23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2,5-dichloro-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-chloro-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[OH-].[Na+]>O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:12][CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCCCCBr
Reactant: OCCCCOc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCCOc1ccccc1

Procedure:
4-Phenoxy-1-butanol (4 g), 1,6-dibromohexane (6.7 ml), TAB (0.8 g) and sodium hydroxide (9.4 g in 18 ml water) were stirred at room temperature under nitrogen for 20 h. Water (80 ml) was added and the mixture extracted with diethyl ether (3×100 ml). The combined organic extracts were washed with water (50 ml), brine (50 ml), dried and evaporated to give a colourless liquid. This was applied to an FCC column and eluted with cyclohexane (2 l) and then with System A (1:40). The resulting oil was distilled to give the title compound (3.4 g) as a colourless oil b.p. 150°/3.5 mmHg T.l.c. (System A 1:6) Rf 0.3.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.[CH3:28][C@@H:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][NH:36][C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:28])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: O=CC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: C[C@@H](N)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](NCC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1)c1ccccc1
Reaction time: 15 h

Procedure:
1-(1-(4-fluorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carbaldehyde (91 mg, 0.250 mmol) was dissolved in THF (4 mL) and (R)-α-methylbenzylamine (0.048 mL, 0.375 mmol) was added. The solution was stirred at rt for 10 h, at which time the THF was removed in vacuo and the residue dissolved in EtOH (5 mL), and sodium cyanoborohydride (47 mg, 0.749 mmol) and a catalytic drop of glacial acetic acid were added. Stirring was permitted for 15 h, at which time the solvent was removed in vacuo, the residue was taken up in EtOAc. The organic phase was washed with 10% aq. sodium carbonate, dried over magnesium sulfate, and concentrated. Purification was accomplished via silica gel flash chromatography (30 g silica gel, 5:95 7M methanolic ammonia:ethyl acetate.) The title compound was obtained as a yellow oil. (Yield: 52 mg, 0.111 mmol, 44%) 1H NMR (400 MHz, CDCl3) 7.62, 7.39-7.22, 7.14, 7.07-6.99, 6.89-6.80, 6.57, 5.41, 4.56, 4.02, 3.76, 2.73, 2.36-2.18, 1.60, 1.39, 0.97, 0.52
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17]CC3C=CC=CC=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)C.[H][H]>[Pd].O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: COc1ccc(-c2ccc(CCOCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc(-c2ccc(CCO)cc2)cc1
Yield: 92 %

Procedure:
2,59 g (7.85 mol) of 2-{4-(4-methoxyphenyl) phenyl}ethylbenzylether, 0.4 g of 5% palladium activated carbon, 70 ml of ethanol and 6 ml of dioxane were injected and stirred at room temperature for 7 hours under presence of hydrogen. After the reactions had been completed, the catalyst was removed by tuck filtration and the solvent was removed by filtration so that 1.64 g of 2-{4-(4-methoxyphenyl) phenyl}ethanol was obtained (yield 92%).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:8]1[C:16]2[C:11](=[C:12]([CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=4)[CH2:20][CH2:19]3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1>>[CH3:34][CH:32]([CH3:33])[C:31]([NH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:11]=3[CH:10]=[CH:9][N:8]4[C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[CH2:19][CH2:20]2)[CH:25]=1)=[O:35]
Reactant: Ic1cccnc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3cccnc3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 3-iodopyridine and N-(3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 453.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([NH:14][C:15]3[C:16]4[CH:17]=[N:18][NH:19][C:20]=4[CH:21]=[CH:22][CH:23]=3)=[N:10][CH:11]=[CH:12][N:13]=2)[CH:5]=[C:4](S(C)=O)[N:3]=1.[NH3:27]>>[NH2:27][C:4]1[N:3]=[C:2]([CH3:1])[N:7]=[C:6]([C:8]2[C:9]([NH:14][C:15]3[C:16]4[CH:17]=[N:18][NH:19][C:20]=4[CH:21]=[CH:22][CH:23]=3)=[N:10][CH:11]=[CH:12][N:13]=2)[CH:5]=1
Reactant: Cc1nc(-c2nccnc2Nc2cccc3[nH]ncc23)cc(S(C)=O)n1
Reactant: N
Product: Cc1nc(N)cc(-c2nccnc2Nc2cccc3[nH]ncc23)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
The mixture from Step 3 was treated with ammonia (30% in water) in a sealed tube. The mixture was stirred at 100° C. overnight. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 50% THF/CH2Cl2 to give N-(3-(6-amino-2-methylpyrimidin-4-yl)pyrazin-2-yl)-1H-indazol-4-amine (7 mg, 39% yield) as a yellow solid. 1H NMR (300 MHz, d6-DMSO) δ 13.17 (s, 1H); 12.95 (s, 1H); 8.37 (d, J=2.05 Hz, 1H); 8.25 (s, 1H); 8.18 (d, J=2.05 Hz, 1H); 8.10 (d, J=7.75 Hz, 1H); 7.45 (s, 1H); 7.33 (t, J=8.11 Hz, 1H); 7.19 (d, J=7.31 Hz, 1H); 2.65 (s, 3H). m/z (ESI, +ve ion) 319 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH:5]=[C:6]([CH3:8])[CH3:7])[CH3:3].[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12]>>[C:9]([C:10]1[C:6]([CH3:8])([CH3:7])[CH:5]([CH:4]=[C:2]([CH3:3])[CH3:1])[O:12][C:11]=1[CH3:13])([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CC(C)=CC=C(C)C
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)C1=C(C)OC(C=C(C)C)C1(C)C

Procedure:
2,5-Dimethyl-2,4-hexadiene and ethyl acetoacetate were reacted utilizing the oxidative addition procedure to obtain 4-carbethoxy-2-(2-methyl-1-propenyl)-3,3,5-trimethyl-2,3-dihydrofuran. Manganese (III) acetate obtained by the reaction potassium permanganate (19.75 grams) and manganese (II) acetate (122.5 grams) in 250 mls acetic acid was employed for the oxidation. The 2,5-dimethyl-2,4-hexadiene (27.5 gram) and ethyl acetoacetate (32.5 grams) were reacted in the presence of 0.5 grams cupric acetate catalyst. 4Carbethoxy-2-(2-methyl-1-propenyl)-3,3,5-trimethyl-2,3-dihydrofuran was recovered (61% yield) and hydrogenated in ethanol using a supported palladium catalyst (5% Pd on carbon) to obtain 4-carbethoxy-2-(2-methylpropyl)-3,3,5-trimethyl-2,3-dihydrofuran. Essentially pure (97+%) 4-carbethoxy-2-(2-methylpropyl)-3,3,5-trimethyl-2,3-dihydrofuran (B.P. 136° C. @9.2 mm Hg; nD23° 1.4642) was obtained upon distillation of the crude product. The product had a green vegetable odor. The structure of the product ##STR23## was confirmed by infrared and nuclear magnetic resonance.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:14]=3)[CH:10]=[C:9]([C:29]([F:32])([F:31])[F:30])[N:8]=2)[CH:6]=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:35]=1>>[F:28][C:25]([F:26])([F:27])[CH2:24][O:23][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([C:29]([F:31])([F:30])[F:32])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:37]4[CH:38]=[CH:39][C:34]([NH2:33])=[N:35][CH:36]=4)[N:3]=[CH:4]3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[C:19]([F:22])([F:21])[F:20]
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)ccc1C(F)(F)F
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-[3-(2,2,2-trifluoroethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example E.54) (0.268 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure VI. Obtained as a yellow solid (0.056 g, 20%). MS (ISP) 549.2 [(M+H)+]; mp 285° C.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:7][CH:8]=[CH2:9].[CH2:17]([Si:20](Cl)([CH3:22])[CH3:21])[CH:18]=[CH2:19]>C1COCC1>[CH2:17]([Si:20]([CH3:22])([CH3:21])[C:9]#[C:8][CH2:7][CH2:6][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:18]=[CH2:19]
Reactant: C=CC[Si](C)(C)Cl
Reactant: C=CCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC[Si](C)(C)C#CCCOC1CCCCO1
Temperature: -78 °C

Procedure:
A solution of n-butyllithium (12.0 ml, 30 mmol, 2.5 mol dm−3 in hexanes) was added dropwise to a stirred, cooled (−78° C.) solution of compound 2 (4.62 g, 30 mmol) in THF (60 ml) under an atmosphere of dry nitrogen. The reaction mixture was maintained at −78° C. for 1.5 h and a solution of allylchlorodimethylsilane (4.04 g, 30 mmol) in THF (20 ml) added dropwise. The reaction mixture was allowed to warm to room temperature, washed with water and the organic layer extracted into ethyl acetate/hexane (3 times). The combined extracts were washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield a clear oil. The crude product was purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (4:1), Rf: 0.48]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=O)[CH:9]([CH2:13][CH:14]=O)[CH2:8][CH2:7]2.[C:16]([NH:19][CH2:20][CH2:21][NH2:22])(=[O:18])[CH3:17]>C(O)(=O)C>[Cl:1][C:2]1[C:11]2[C:10]3[N:22]([CH2:21][CH2:20][NH:19][C:16](=[O:18])[CH3:17])[CH:14]=[CH:13][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)NCCN
Reactant: O=CCC1CCc2cccc(Cl)c2C1=O
Solvent: CC(=O)O
Product: CC(=O)NCCn1ccc2c1-c1c(Cl)cccc1CC2
Yield: 45.1 %

Procedure:
325 mg of 8-chloro-2-(2-oxoethyl)-1-tetralone and 290 mg of N-acetylethylenediamine were heated to reflux in 14ml of acetic acid under argon for 1 hour. The solvent was removed in a vacuum and the residue was taken up in 10 ml of water and extracted several times with ethyl acetate. Chromatography on 20 g of silica gel with hexane/ethyl acetate 1:1 and then with ethyl acetate gave 190 mg (45%) of N-[2-(9-chloro-4,5-dihydro-1H-benz[g]indol-1-yl)ethyl]-acetamide as yellowish crystals with m.p. 146°-147°.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[NH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][NH:24][CH2:25]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][N:24]([C:10]1[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=1[F:15])[CH2:25]2
Reactant: Nc1cccc2c1CNC2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3Cc4cccc(N)c4C3)c(F)c21
Yield: 41.4 %

Procedure:
136 mg of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 100 mg of 4-aminoisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 80 mg of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[C:7]([C:10]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)=[O:11])=[CH:8][O:9][C:5]=2[C:4]=1[N+:26]([O-])=O.C([O-])=O.[NH4+].COCCOC>[Pd].CO>[NH2:26][C:4]1[C:5]2[O:9][CH:8]=[C:7]([C:10]([C:12]3[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=3)=[O:11])[C:6]=2[CH:24]=[CH:25][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(=O)c2coc3c([N+](=O)[O-])c(OC)ccc23)cc(OC)c1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: COCCOC
Product: COc1cc(C(=O)c2coc3c(N)c(OC)ccc23)cc(OC)c1OC
Temperature: 25 °C
Yield: 54 %

Procedure:
A mixture of 0.022 g (0.057 mmol) of (6-methoxy-7-nitrobenzofuran-3-yl)(3,4,5-trimethoxyphenyl)methanone, 0.1 g of ammonium formate and 0.1 g of 10% palladium on carbon in 5 ml of a mixture of 1,2-dimethoxyethane and methanol (4:1) was refluxed for 30 minutes (TLC controlled reaction). After cooling to room temperature the mixture was filtered through a pad of Celite and washed with methylene chloride. The filtrates were evaporated to dryness under reduced pressure and the residue was purified by flash column chromatography to give 0.011 g (55% yield) of pure title compound as a colorless solid; 1H NMR (CDCl3) δ 3.89 (s, 6H, OMe); 3.92 (s, 6H, OMe); 4.01 (broad s, 2H, NH2); 6.95 (d, 1H, CH aromatic, J=8.54 Hz); 7.14 (s, 2H, CH aromatic); 7.46 (d, 1H, CH aromatic, J=8.54 Hz); 8.0 (s, 1H, CH furan).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH3:19])=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:20][S:21]([O:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH3:19])=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:3]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1[C@@H]2C[C@@H](O)[C@@H](C2)N1C(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1[C@H]2C[C@H]([C@H](OS(C)(=O)=O)C2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a solution of 2-tert-butyl 3-methyl (1R,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (185 mg) in pyridine (2 mL), was added methanesulfonyl chloride (117 mg). The mixture was stirred at room temperature for 2 hrs. The resulting mixture was evaporated in vacuo. To the residue, water was added. The mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane and ethyl acetate (1:1) to give the target compound (237 mg).
Reaction SMILES: [OH-].[Li+].[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[N:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6].O>O1CCCC1>[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[N:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2cnc(CCC(=O)OC)nc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCNC(=O)N(C)c1cccc(-c2cnc(CCC(=O)O)nc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
1.44 ml (1.45 mmol, 5 eq) of lithium hydroxide are added to a solution of 111 mg (0.29 mmol, 1 eq) of methyl 3-{5-[3-(1-methyl-3-pentylureido)phenyl]pyrimidin-2-yl}propanoate in 3 mL of tetrahydrofuran. The reaction mixture is stirred for four hours at room temperature. The reaction is stopped by adding 10 ml of water, washed with ether and then acidified with 1 N hydrochloric acid solution, and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then crystallized from ether. 66.7 mg of 3-{5-[3-(1-methyl-3-pentylureido)phenyl]pyrimidin-2-yl}propanoic acid are obtained in the form of white crystals. Yield=48%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[N+:21]([O-])=O)[CH:10]([CH2:24][C:25]([O:27]C)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Fe]>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[NH:21][C:25](=[O:27])[CH2:24][CH:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC1CN(Cc2ccccc2)CCN1c1ccc(C)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)NC(=O)CC1CN(Cc3ccccc3)CCN21
Temperature: 80 °C

Procedure:
To a solution of Example 49A (150 mg, 0.392 mmol) in acetic acid (5 mL) was added iron powder (65.5 mg, 1.17 mmol), and the reaction was heated to 80° C. for 14 hours. The solution was then concentrated onto silica gel and purified via flash chromatography (0-30% methanol/dichloromethane). The pure fractions were partitioned between dichloromethane and 1 M NaOH. The organic layer was collected and dried with MgSO4 to afford title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.41 (s, 1 H), 7.20-7.41 (m, 5 H), 6.86-7.01 (m, 2 H), 6.73 (s, 1 H), 3.53 (s, 2 H), 3.02-3.27 (m, 2 H), 2.67-3.00 (m, 3 H), 2.42-2.48 (m, 1 H) 2.04-2.30 (m, 5 H), 1.84 (d, J=13.22 Hz, 1 H); MS (APCI+) m/z 322 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1.N1C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>ClCCl>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:4]2[CH2:3][C:2]([CH3:20])([CH3:1])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[NH:5]2)[CH:14]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(NS(=O)(=O)c3ccccc3F)c1)N2
Yield: 47.1 %

Procedure:
To a stirred mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (135 mg, 0.5 mmol) in dichloromethane (3 mL) was added pyridine (60 mg, 0.75 mmol) in dichloromethane (2 mL) and 2-fluoro-benzenesulfonyl chloride (108 mg, 0.56 mmol) under nitrogen. The resultant mixture was stirred for 4 h. The reaction mixture was diluted with dichloromethane, washed with water (twice), saturated brine, and dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and after evaporation, the residue was purified on chromatography column (silica gel, petroleum ether:ethyl acetate=15:1) to afford 100 mg of 2-fluoro-N-[3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide yellow solid (Yield: 47%). MS (ESI+APCI) M+1=425.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[NH2:12][OH:13].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:12][OH:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.1 %

Procedure:
To a solution of 4-methoxybenzaldehyde (5.0 g, 36.8 mmol) in methanol (300 mL) was added hydroxylamine hydrochloride (7.6 g, 110.4 mmol) and 2N NaOH (37 mL, 73.6 mmol). The mixture was stirred at room temperature for 6 hours. The mixture was neutralized to pH 4 by using 1N HCl. Excess methanol was removed in vacuo to precipitate out the oxime. The precipitations were filtered and washed with water. The product was dried under vacuum and yield a white solid (4.9 g, 88%): 1H NMR (270 MHz, acetone-d6) δ 8.07 (s, 1H), 7.55 (d, J=8.2 Hz, 2H), 6.95 (d, J=8.2 Hz, 2H), 3.82 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=2[F:17])=[C:4]([Cl:18])[N:3]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:18][C:4]1[C:5]([C:9]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=2[F:17])=[C:6]([Cl:8])[N:7]=[C:2]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[N:3]=1
Reactant: c1c[nH]cn1
Reactant: Fc1cc(F)c(-c2c(Cl)nc(Cl)nc2Cl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1cc(F)c(-c2c(Cl)nc(-n3ccnc3)nc2Cl)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
A mixture of the above 2,4,6-trichloro-5-(2,4,6-trifluorophenyl)pyrimidine (104 mg), imidazole (23 mg, 0.33 mmol), and potassium carbonate (92 mg, 0.66 mmol) in 2 mL of N,N-dimethylformamide is stirred at room temperature for 3 h. The mixture is partitioned between ethyl acetate and saturated sodium chloride. The organic layer is washed with saturated sodium chloride (×4), dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of hexanes to 50% ethyl acetate in hexanes. Concentration provides 4,6-dichloro-2-(1H-imidazol-1-yl)-5-(2,4,6-trifluorophenyl)pyrimidine as a tan solid (71 mg, mp 72-74° C.). MS: m/z 345.2 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][OH:11])=[CH:7][CH:6]=1)[CH3:3].[CH2:12]1[NH:14][CH2:13]1.CS(O)(=O)=O>O1CCCC1>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][O:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CO)o1
Reactant: C1CN1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(COCCN)o1
Reaction time: 18 h
Yield: 2.5 %

Procedure:
To a solution of 5-(dimethylamino)methyl-2-furanmethanol (6.2 g) and ethylene imine (2.82 g) in dry tetrahydrofuran was added a solution of methanesulphonic acid (11.6 g) in tetrahydrofuran (40 ml). The solution was evaporated and the oily residue heated at 98°-100° for 10 mins. After 18 hr, 5N sodium hydroxide (60 ml) was added and the solution evaporated to dryness. Anhydrous sodium sulphate and ethyl acetate (150 ml) were added and after 2 hr the suspension was filtered, treated with decolourising charcoal and evaporated. The resulting oil was chromatographed on silica, firstly with methanol-ammonia 0.88 79:1, and the eluate discarded, and secondly with methanol-ammonia 0.88 19:1. This eluate was evaporated to give an oil from which the bisoxalate salt of 2-[[5-(dimethylamino)methyl-2-furanyl]methoxy]ethanamine (from ethanol) 0.2 g, m.p. 125°-128°, was obtained. Route (ii)