Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[N:10][C:11]3[C:12]=2[NH:13][C:14]([C:17]([O:19]C)=[O:18])=[CH:15][CH:16]=3)[CH2:4][CH2:3]1.[ClH:21]>>[ClH:21].[ClH:21].[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[CH:9]=[N:10][C:11]3[C:12]=2[NH:13][C:14]([C:17]([OH:19])=[O:18])=[CH:15][CH:16]=3)[CH2:6][CH2:7]1
Reactant: COC(=O)c1ccc2ncc(C3CCN(C)CC3)c-2[nH]1
Agent: Cl
Product: CN1CCC(c2cnc3ccc(C(=O)O)[nH]c2-3)CC1
Yield: 87 %

Procedure:
A solution of 0.125 gm (0.46 mMol) methyl 3-(1-methyl-piperidin-4-yl)pyrrolo[3,2-b]pyridine-5-carboxylate in 30 mL 1N hydrochloric acid was heated at reflux for 18 hours. The reaction mixture was concentrated under reduced pressure to provide 0.10 gm (87%) title compound.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[C:22]([O:26][C:27]([N:29]1[CH:34]([CH3:35])[CH2:33][N:32]([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[CH:40][CH:41]=2)[CH2:31][CH:30]1[CH3:43])=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[C:22]([O:26][C:27]([N:29]1[CH:30]([CH3:43])[CH2:31][N:32]([C:36]2[CH:37]=[N:38][C:39]([NH:42][C:7]3[N:8]=[CH:9][C:4]4[C:3]([CH3:21])=[C:2]([Br:1])[C:14](=[O:15])[N:13]([CH:16]5[CH2:20][CH2:19][CH2:18][CH2:17]5)[C:5]=4[N:6]=3)=[CH:40][CH:41]=2)[CH2:33][CH:34]1[CH3:35])=[O:28])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC1CN(c2ccc(N)nc2)CC(C)N1C(=O)OC(C)(C)C
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Solvent: Cc1ccccc1
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CC(C)N(C(=O)OC(C)(C)C)C(C)C4)cn3)ncc12
Temperature: 25 °C
Yield: 37.5 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.70 mmol) and 4-(6-amino-pyridin-3-yl)-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (1.14 g, 3.73 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was collected by filtration and washed on the funnel with toluene (3×10 mL) to give 4-[6-(6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester as a dark brown-gray solid (0.620 g, 37.6%). 1H NMR δ(400 MHz, CDCl3) 8.79 (s, 1H), 8.23 (d, J=8.8 Hz, 1H), 7.99 (d, J=2.7 Hz, 1H), 7.36 (dd, J=2.7, 8.8 Hz, 1H), 5.99 (m,1H), 4.28 (m, 2H), 3.30 (m, 2H), 2.93 (dd, J=4.4, 11.7 Hz 2H), 2.61 (s, 3H), 2.30 (m, 2H), 2.11 (m, 2H), 1.89 (m, 2H), 1.68 (m, 2H), 1.49 (s, 9H), 1.38 (d, J=6.8 Hz, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH:22]4[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]4)[CH2:18]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[N:19]12[CH2:20][CH2:21][CH:22]([CH2:23][CH2:24]1)[CH:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)=[CH:15][CH:14]=1)[CH2:18]2
Reactant: O=[N+]([O-])c1ccc(-c2ccc(OC3CN4CCC3CC4)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2ccc(OC3CN4CCC3CC4)cc2)cc1
Yield: 65.7 %

Procedure:
The product of Example 5A (150 mg, 0.46 mmol) in methanol (5 mL) was treated with Pd/C (Aldrich, wt. 10%, 20 mg) at ambient temperature for 30 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide the title compound (89 mg, yield, 65%). 1H NMR (MeOH-d4, 300 MHz) δ 1.44-1.58 (m, 1H), 1.63-1.89 (m, 2H), 1.99-2.13 (m, 1H), 2.15-2.23 (m, 1H), 2.72-3.04 (m, 5H), 3.29-3.39 (m, 1H), 4.50-4.58 (m, 1H), 6.77 (dt, J=8.8, 2.5 Hz, 2H), 6.91 (dt, J=8.8, 2.4 Hz, 2H), 7.32 (dt, J=8.5, 2.5 Hz, 2H), 7.43 (dt,J=9.2, 2.8 Hz, 2H) ppm. MS (DCl/NH3) m/z 295 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.CO[C:14](OC)(N(C)C)[CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][C:14]([CH3:15])=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: COC(C)(OC)N(C)C
Reactant: NNC(=O)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(Br)cc2)o1
Temperature: 60 °C

Procedure:
4-Bromo-benzoic acid hydrazide (12.90 g, 60 mmol) and N,N-dimethylacetamide dimethyl acetal (12 mL, 82.0 mmol) were dissolved in N,N-dimethylformamide (100 mL) and the solution heated to 60° C. for 2 hours. The solution was concentrated in vacuo and the residue taken up in toluene (80 mL) and treated with para-toluenesulfonic acid monohydrate (200 mg, 1.50 mmol). The mixture was heated to reflux for 2 hours, allowed to cool, and the product crystallised from the solution and was collected by filtration. The crude product was washed with ether and dried in vacuo to yield a white solid. The filtrate was concentrated in vacuo and the residue combined with the white solid, dissolved in toluene (50 mL) and treated with para-toluenesulfonic acid monohydrate (100 mg, 0.75 mmol). The mixture was heated to reflux for 3 hours, allowed to cool and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with pentane:ethyl acetate 80:20 to 40:60 to yield the title product, 12.00 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][C:7]=1[O:8]C>Br>[NH2:12][CH2:11][CH2:10][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=1
Reactant: COc1ccc(CCN)cc1F
Agent: Br
Product: NCCc1ccc(O)c(F)c1

Procedure:
Intermediate 82 was dissolved in 200 mL of 48% aqueous HBr and the mixture heated to reflux for 2 hours. The Solvent was removed by rotary evaporation. The residue was taken up in 100 mL of ethanol and the solvent again removed. This was repeated twice more to remove residual water. LC-MS showed the product was >90% pure had the expected M+H+ of 156.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:33])([CH3:32])[C:13](=[O:31])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[OH:30])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:41][C:42]([NH2:44])=[O:43]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:33])([CH3:32])[C:13](=[O:31])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:41][C:42]([NH2:44])=[O:43])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4O)CC3)C(=O)C2(C)C)cc1OC
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4OCC(N)=O)CC3)C(=O)C2(C)C)cc1OC

Procedure:
1.0 g of 5-(3,4-dimethoxyphenyl)-2-{1-[(2-hydroxyphenyl)carbonyl]piperidin-4-yl}-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 94) and 1.0 g potassium carbonate are suspended in 20 ml of acetonitrile. 0.3 g of 2-chloroacetamide are added and the reaction mixture is heated to reflux for 5 h until the reaction is completed according to TLC analysis. The solvent is evaporated under reduced pressure, and the remaining residue is taken up in DCM. The organic phase is washed with water, dried over MgSO4, and the solvent is removed under reduced pressure. Purification of the resulting crude product by crystallization from EA yields the title compound.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15]/[C:16](=[C:23]2\[C:24](=[O:32])[NH:25][C:26]3[C:31]\2=[CH:30][CH:29]=[CH:28][CH:27]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.C(OCC)(=O)C.Cl>ClCCl.CCOCC>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15]/[C:16](=[C:23]2\[C:24](=[O:32])[NH:25][C:26]3[C:31]\2=[CH:30][CH:29]=[CH:28][CH:27]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1.7 g (4 mmol) of (Z)-3-[1-(4-tert.butoxycarbonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone are suspended in 15 ml of dichloromethane and after the addition of 35 ml of ethyl acetate/hydrogen chloride for 18 hours at ambient temperature and stirred for 2 hours at 40° C. After cooling the mixture is diluted with ether and the precipitate is suction filtered. The residue is divided between sodium chloride solution and methylene chloride, the organic extracts are dried and concentrated by evaporation.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=4[F:50])[CH:34]=3)[O:32][C@@:10]1([CH2:51][OH:52])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:54].[Na+].[Br-].[K+].Cl[O-].[Na+].Cl>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=4[F:50])[CH:34]=3)[O:32][C@@:10]1([C:51]([OH:54])=[O:52])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: COc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc([C@]34OC[C@](C(=O)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 210 (0.38 g, 0.49 mmol, obtained from the synthetic method described in step 13 example 21) in tetrahydrofuran (10 mL) were added aqueous sodium bicarbonate (0.46 g, 5.43 mmol), potassium bromide (11.75 mg, 0.10 mmol) and 2,2,6,6-tetramethylpiperidinooxy (7.7 mg, 0.05 mmol) in turn at 0° C., and then sodium hypochlorite (6.8 mL, 8.5 mmol, available chlorine ≧3.5%) was added dropwise. The mixture was stirred at 0° C. for 3 hours and acidified with aqueous HCl (3 N) till pH becomes 6. The resulting mixture was extracted with ethyl acetate (40 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 22a (0.37 g, 100%) as yellow oil. This material was not further purified.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13](SC)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][C:5]([NH:22][C:23]([NH:25][C:26]2[O:30][N:29]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:27]=2)=[O:24])=[C:4]([F:35])[CH:3]=1.[CH3:36][NH2:37]>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13]([NH:37][CH3:36])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][C:5]([NH:22][C:23]([NH:25][C:26]2[O:30][N:29]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:27]=2)=[O:24])=[C:4]([F:35])[CH:3]=1
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(F)(F)F)no4)c(F)cc3Cl)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(F)(F)F)no4)c(F)cc3Cl)c(=O)n(C)c2n1
Yield: 21 %

Procedure:
Using a procedure analogous to Example A1, 1-(4-chloro-2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea (75 mg, 0.140 mmol) and 2.0 N methylamine in THF (0.71 mL) were combined to afford 1-(4-chloro-2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea (15 mg, 21% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.89 (s, 3H), 3.51-3.58 (m, 3H), 6.48 (s, 1H), 7.61 (d, J=11 Hz, 1H), 7.77 (s, 1H), 7.88-7.90 (m, 1H), 8.04 (d, J=9.5 Hz, 1H), 8.61-8.69 (m, 1H), 9.01 (s, 1H), 11.0 (s, 1H); MS (ESI) m/z: 512.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17](=[CH:18][C:19](=[O:29])[CH:20]=[CH:21]3)[CH2:16][C@H:15]4O)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(OCC)(=O)C.CCCCCC>C1C=CC=CC=1>[CH3:31][C:2]1([CH3:1])[CH2:3][O:4][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17](=[CH:18][C:19](=[O:29])[CH:20]=[CH:21]3)[CH:16]=[CH:15]4)[CH2:12][CH2:11]2)[CH3:9])[O:6][CH2:7]1
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 3.00 g (6.98 mmoles) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-7α-hydroxypregna-1,4-dien-3-one in 200 ml of benzene was added 50 mg of p-toluenesulfonic acid and the mixture was refluxed for 5 hours, with the byproduct water being constantly removed from the reaction system by means of a Dean-Stark trap. The reaction mixture thus obtained was cooled to room temperature and washed with aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with ether and the extract was combined with the organic layer. This mixture was washed with aqueous sodium chloride solution and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Finally the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane =1:10, v/v) to recover 2.58 g of 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregna-1,4,6-trien-3-one (yield: 90%). The 1H-NMR spectrum of this product was in agreement with that of the 20-(5,5-dimethyl-1,3-dioxan-2-yl)pregna-1,4,6-trien-3-one obtained in Example 3.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]1[CH2:11][O:10]1)[CH:2]=[CH2:3].[NH2:16][C@@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])[CH2:19][CH2:18]1.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>C(O)(C)C>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33].[CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:10])[CH2:11][NH:16][C@@H:17]1[CH2:18][CH2:19][C@H:20]([N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])[CH2:21][CH2:22]1)[CH:2]=[CH2:3].[CH2:1]([O:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]([OH:10])[CH2:11][NH:16][C@@H:17]1[CH2:18][CH2:19][C@H:20]([N:23]2[CH2:27][CH2:26][NH:25][C:24]2=[O:28])[CH2:21][CH2:22]1)[CH:2]=[CH2:3]
Reactant: N[C@H]1CC[C@@H](N2CCNC2=O)CC1
Reactant: C=CCOc1ccccc1OCC1CO1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Product: C=CCOc1ccccc1OCC(O)CN[C@H]1CC[C@@H](N2CCNC2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 657.6 g of 92% pure o-(allyloxy)phenoxymethyloxirane (U.S. Pat. No. 3,483,221) and 512 g of cis-1-(4-aminocyclohexyl)-2-imidazolidinone is stirred and refluxed for 6 hours in 6,000 ml of isopropanol. To the above reaction mixture, while still hot, is added 162.1 g of fumaric acid. The resulting mixture is allowed to stir at room temperature overnight. The crude product is filtered and washed with 1000 ml of isopropyl alcohol. The thus obtained wet solid is first recrystallized from 5000 ml of isopropyl alcohol and then dried in a vacuum oven at 65° to constant weight to give a white crystalline product, m.p. 154°-155°. Recrystallization of 1781 g of the resulting salt from 9700 ml of anhydrous ethanol yields cis-1-{4-[3-(o-allyloxyphenoxy)-2-hydroxypropylamino]-cyclohexyl}-2-imidazolidinone hemifumarate salt, m.p. 156°-7°, being the cis compound of formula III wherein R3 represents hydrogen and R7 represents allyloxy, as the hemifumarate salt.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])C(OC)=O>O.CN1C(=O)CCC1>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17]
Reactant: COC(=O)C(C(=O)OC)c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)Cc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 102.6 %

Procedure:
A solution of 2-(4-Chloro-2-nitro-phenyl)-malonic acid dimethyl ester (195 g, 679.4 mmol) in water (100 mL) and NMP (1000 mL) was heated to reflux for 3.5 hours. The solvent was removed by rotary evaporation to an oil. The oil was dissolved in EtOAc, and then washed with water (5×300 mL). The aqueous layer was then extracted with EtOAc (4×300 mL). The organic was washed with water. The organic layers were combined and dried over MgSO4. After removing the solids by filtration, the solvent was evaporated to yield the desired product as a orange/brown solid (160.0 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:4]1[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]1
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)c1c[nH]nc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: COC(=O)c1cn(-c2ccccc2OC)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (7.3 g) synthesized in Example 1(3) was dissolved in N,N-dimethylacetamide (150 mL), 2-methoxyphenylboronic acid (15.9 g), copper acetate (18.2 g) and pyridine (16.2 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (100 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (10.3 g, 80%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]([OH:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][OH:15])=[CH:5][CH:4]=1.C(O)(=O)C.[Se](=O)=O>CC(O)C>[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=[O:15])(=[O:16])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=1
Reactant: COc1ccc(C(O)c2ccccc2CO)cc1
Agent: O=[Se]=O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COc1ccc(C(=O)c2ccccc2C=O)cc1

Procedure:
A solution of 26 g. of 4'-methoxy-2-hydroxymethylbenzhydrol in 140 ml. of acetic acid and 14.5 g. selenium dioxide was refluxed for 2 hours. The mixture was filtered and the filtrate was made basic. An oil separated which crystallized on standing and was collected. Recrystallization from a mixture of methylene chloride and petroleum ether gave off-white platelets melting at 90°-91°. Ultraviolet maxima (2-propanol) at 221 μ (ε = 21,600), 258 μ ε = 12,400) and 292 μ (ε = 17,000); infrared absorption (CHCl3) at 1660 cm-1 and at 1700 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[N:15]([NH:20][C:21](=[O:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:16](=S)[S:17][CH:18]=1.IC>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[N:15]2[N:20]=[C:21]([OH:28])[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]2[S:17][CH:18]=1
Reactant: CCOC(=O)CC(=O)Nn1c(-c2c(OC)cc(COC)cc2OC)csc1=S
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)c1c(O)nn2c(-c3c(OC)cc(COC)cc3OC)csc12
Reaction time: 23 h
Yield: 58 %

Procedure:
Acetone (235 mL) was added to ethyl 3-{[4-(2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-thioxo-1,3-thiazole-3(2H)-yl]-amino}-3-oxopropanoate (11.7 g, 27.6 mmol), and then iodomethane (17.1 mL, 276 mmol) was added dropwise at room temperature and the mixture was stirred for 23 hours. The solvent in the filtrate was distilled off under reduced pressure. To the obtained residue were added tert-butanol (235 mL) and potassium tert-butoxide in that order, and the mixture was stirred at room temperature for 3.5 hours. Water was added to the mixture while cooling on ice, and then aqueous 2N hydrochloric acid was added until the pH of the mixture reached approximately 4. The precipitated solid was collected by filtration, and the resulting residue was washed with water and dried under reduced pressure to obtain the title compound (6.3 g, 16 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.BrC1C=CC(OC)=CC=1.[Mg].Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:5][CH:4]=1
Reactant: Brc1ccccn1
Reactant: COc1ccc([Mg]Br)cc1
Agent: COc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccn2)cc1

Procedure:
That is, as shown in the Reaction Scheme below, (4-methoxyphenyl)magnesium bromide was synthesized from 22.4 g (120 mmol) of 4-bromoanisole by a conventional method by using 3.4 g of magnesium (Mg) in dry tetrahydrofuran (THF) under argon stream and added slowly into a solution of 15.8 g (100 mmol) of 2-bromopyridine and 1.8 g of (1,2-bis(diphenylphosphino)-ethane)dichloronickel (II) (Ni(dppe)Cl2) in dry THF and the mixture was refluxed for 1 hour. After adding 250 ml of an aqueous solution of 5% hydrochloric acid to the reaction mixture, the reaction mixture was washed with chloroform. The water layer was neutralized with an aqueous solution of sodium hydrogen carbonate and the objective compound was extracted with chloroform and the organic layer was distilled off under reduced pressure. The distillate immediately solidified at room temperature to obtain 15.1 g (81.5 mmol) of 2-(4-methoxy-phenyl)pyridine (4-MeO-PPy) as white solid. Identification was performed by elementary analysis of C, H and N and 1H-NMR.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Na+].[I-]>C(O)C>[CH2:9]([O:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH2:7][CH2:8][CH2:1][CH2:3][CH2:4][CH3:5])=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCBr
Reactant: Oc1ccc(O)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCOc1ccc(OCCCCCC)cc1

Procedure:
Under argon atmosphere, 6.90 g (300 mmol) of Na is reacted with 200 ml of absolute ethanol. Then, 16.5 g (150 mmol) of hydroquinone 5 is added, followed by 42.2 ml (300 mmol) of hexylbromide and 200 mg of anhydrous NaI. The mixture is refluxed overnight. Ethanol is evaporated under reduced pressure and water (150 ml) is added. The product is extracted with dichloromethane and dried over MgSO4. After filtration, the solvents are removed and the crude compound is recrystallized from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](N(OC)C)=[O:12])=[CH:5]2.[Li][CH2:18][CH2:19][CH2:20][CH3:21]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:12])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:5]2
Reactant: [Li]CCCC
Reactant: CON(C)C(=O)c1cc2cc(Cl)ccc2[nH]1
Solvent: C1CCOC1
Product: CCCCC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1.5 h

Procedure:
To a cooled (−78° C.) solution of the title compound of Example 1 Step A (2.40 g, 10.1 mmol) in THF (30 mL) was added n-BuLi (15.7 mL, 1.6 M in hexanes, 25.1 mmol), and the mixture was stirred for 1.5 h, whereupon it was transferred to a 0° C. bath. After 45 min, the reaction mixture was quenched by addition of 2 N aq. HCl. The aqueous phase was extracted with EtOAc, and the organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 25%, then 25 to 100% EtOAc in hexanes) provided the title compound: LCMS A, tr=3.74 min, m/z 236.1 [M+H]+; 1H NMR (500 MHz, CDCl3) □9.34 (br s, 1H), 7.68 (d, J=2.0 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 7.29 (dd, J=8.5, 1.5 Hz, 1H), 7.13 (d, J=1.5 Hz, 1 H), 2.95 (t, J=7.5 Hz, 2H), 1.80-1.74 (m, 2H), 1.47-1.40 (m, 2H), 0.97 (t, J=7.5 Hz, 3H).