Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=1)[O:12][C:13]1[CH:20]=[C:19]([CH3:21])[C:16]([CH:17]=[O:18])=[C:15]([O:22]COC)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=1)[O:12][C:13]1[CH:20]=[C:19]([CH3:21])[C:16]([CH:17]=[O:18])=[C:15]([OH:22])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1cc(Oc2cccc(OCc3ccccc3)c2)cc(C)c1C=O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(Oc2cccc(OCc3ccccc3)c2)cc(O)c1C=O
Yield: 85 %

Procedure:
To a solution of 4-(3-benzyloxy-phenoxy)-2-methoxymethoxy-6-methyl-benzaldehyde (3.3 g, 8.8 mmol) in THF (50 mL) was added 6M HCl (6 mL) and the solution refluxed for 2 hours. The volatile organics were removed in vacuo and the aqueous residue extracted with EtOAc (2×25 mL). The organic extracts were dried and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (hex:EtOAc 70:30) to give 4-(3-benzyloxy-phenoxy)-2-hydroxy-6-methyl-benzaldehyde (2.5 g, 85%). 1H NMR (400 MHz, CDCl3): δ 10.13 (s, 1H), 7.43-7.25 (m, 6H), 6.85 (d, J=8.4 Hz, 1H), 6.68 (d, J=13.2 Hz, 2H), 6.34 (s, 1H), 6.24 (s, 1H), 5.04 (s, 2H), 2.52 (s, 3H). MS (ESI) m/z=335 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:6]=1[C:7]([N:9]1[CH2:13][CH2:12][CH:11]([O:14]S(C)(=O)=O)[CH2:10]1)=[O:8])([CH3:3])[CH3:2].[F:27][C:28]([F:41])([F:40])[C:29]1[CH:30]=[C:31](O)[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1>>[F:27][C:28]([F:40])([F:41])[C:29]1[CH:30]=[C:31]([CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=1)[O:14][CH:11]1[CH2:12][CH2:13][N:9]([C:7]([C:6]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])=[O:8])[CH2:10]1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(OS(C)(=O)=O)C1
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Yield: 19 %

Procedure:
Prepared in analogy to Example 3(c) from rac-methanesulfonic acid 1-(2-isopropoxy-5-methanesulfonyl-benzoyl)-pyrrolidin-3-yl ester (Example 14(a)) and 3,5-bis(trifluoromethyl)phenol. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 19%). MS (m/e): 540.3 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[N:16][C:15]([NH2:18])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[N:13]3)[CH:5]=[N:6][CH:7]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=1>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:18][C:15]2[N:16]=[CH:17][C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[C:9]3[C:14]=2[N:13]=[CH:12][CH:11]=[CH:10]3)=[N:21][CH:22]=1
Reactant: Clc1ccc(Br)nc1
Reactant: Nc1ncc(-c2cncc(F)c2)c2cccnc12
Product: Fc1cncc(-c2cnc(Nc3ccc(Cl)cn3)c3ncccc23)c1

Procedure:
The title compound, MS: m/e=352.1 (M+H+), was prepared in accordance with the general method of example 15 step 3 from 5-(5-fluoro-pyridin-3-yl)-[1,7]naphthyridin-8-ylamine and 2-bromo-5-chloropyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:38]([OH:40])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[CH3:37][O:36][C:35]1[C:23]2[N:22]=[C:21]([C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]3[CH2:11][C@@H:10]([C:38]([N:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)=[O:40])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13]3)=[O:20])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]=2[CH:32]=[CH:33][CH:34]=1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2c(OC)cccc21
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCCCC3)CN(C(=O)OC(C)(C)C)C2)nc2c(OC)cccc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-{{{4-methoxy-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-3-carboxylic acid (205 mg), piperidine (69 μl), HOBt (40 mg) and triethylamine (140 μl) were dissolved in DMF (10 ml), WSC.HCl (134 mg) was added, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9)-ethyl acetate was concentrated under reduced pressure to give the object product (65 mg).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][N:17]3[C:22]([OH:23])=[C:21]([C:24]([O:26]CC)=[O:25])[CH:20]=[N:19][C:18]=23)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>O>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[N:16][N:17]3[C:22]([OH:23])=[C:21]([C:24]([OH:26])=[O:25])[CH:20]=[N:19][C:18]=23)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2c(-c3ccc(Cc4ccccc4)cc3)cnn2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc2c(-c3ccc(Cc4ccccc4)cc3)cnn2c1O
Yield: 99.3 %

Procedure:
A mixture of 3-(4-benzylphenyl)-6-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine (1.35 g), sodium hydroxide (1.50 g), ethanol (35 ml) and water (35 ml) was stirred under heating reflux for 2 hours. Then, to the reaction mixture was added water (50 ml), and hydrochloric acid was added at 0° C. to adjust to acid. After stirring for 30 minutes, the precipitate was separated by filtration, washed with water, and dried to give the title compound (1.24 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].N1C=CC=CC=1.[C:19](Cl)(=[O:23])[O:20][CH2:21][CH3:22]>C(OCC)(=O)C>[C:19](=[O:23])([O:20][CH2:21][CH3:22])[O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:12]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)OCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.5 %

Procedure:
To a mixture of tert-butyl 3-hydroxypropylcarbamate (8.00 g) obtained in Reference Example 40 and ethyl acetate (50 mL) were added pyridine (4.06 mL) and ethyl chlorocarbonate (5.95 g) under ice-cooling, and the mixture was stirred at room temperature for 24 hrs. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL), an aqueous copper sulfate solution (30 mL), water (30 mL) and saturated brine (30 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the title compound (9.31 g) as a colorless oil.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[CH:33]=[CH:32][C:17]2[C:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]([CH2:30][CH3:31])[CH2:28]O)[CH2:23][CH2:22]3)=[N:19][O:20][C:16]=2[CH:15]=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[F:13][C:14]1[CH:33]=[CH:32][C:17]2[C:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]([CH3:28])[CH2:30][CH2:31][N:38]4[C:34](=[O:44])[C:35]5=[CH:43][CH:42]=[CH:41][CH:40]=[C:36]5[C:37]4=[O:39])[CH2:23][CH2:22]3)=[N:19][O:20][C:16]=2[CH:15]=1
Reactant: CCC(CO)N1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(CCN1C(=O)c2ccccc2C1=O)N1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of diethyl azodicarboxylate (DEAD, 4.9 g, 28.3 mmol) in THF (50 ml) was added dropwise to a solution of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-butanol (6.9 g, 23.6 mmol), phthalimide (4.16 gm, 1.2 eq), and triphenylphosphine (7.4 g, 28.3 mmol) in THF (200 ml) at room temperature. The solution was stirred at room temperature for 24 hours. After the reaction, the solvent was stripped and the residue was stirred in ether (200 ml). The insolubles were removed by filtration. The oily residue from concentration of the ether solution was purified by two flash chromatography (SiO2, 75 g; eluted with dichloromethane, DCM, and 1-2%CH3OH in DCM) and SiO2, 100 g; eluted with DCM, 1 l; and 1%CH3OH in DCM, 1.2 l). Two close compounds were separated. The lower compound on TLC 3.66 g) was treated with HCl/ether in ethanol, and the solid salt was precipitated with hexane. Recrystallization from ethanol and isopropyl ether yielded white crystals 3.26 g, m.p. 210°-214° C. dec.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[C:16]3[C:23]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[CH:22][S:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:7]=[N:6][CH:5]=1.[OH-].[Li+].Cl>O1CCOCC1.O>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]2[C:16]3[C:15]([O:14][CH2:13][CH2:12][CH2:11][O:10][C:8]4[CH:7]=[N:6][CH:5]=[C:4]([CH:9]=4)[C:3]([OH:31])=[O:2])=[N:20][CH:19]=[N:18][C:17]=3[S:21][CH:22]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)c1cncc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cncc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a solution of 5-{3-[5-(4-fluorophenyl)-thieno[2,3-d]pyrimidin-4-yloxy]-propoxy}-nicotinic acid methyl ester (100 mg) in dioxane (10 mL) was added 0.80 M lithium hydroxide in water (2.0 mL). The reaction was stirred at ambient temperature for 16 hours, then acidified with 1M hydrochloric acid to pH 3, and the solvent removed under reduced pressure. The residue was dissolved in 20% methanol/dichloromethane (40 mL), filtered, and the filtrate was concentrated. The product was purified by column chromatography over silica gel using 10% methanol in dichloromethane as eluant to give 90 mg (93%) of 5-{3-[5-(4-fluorophenyl)-thieno[2,3-d]pyrimidin-4-yloxy]-propoxy}-nicotinic acid as a white solid. MS [M+H] 425.9, 1H NMR (CD3OD) δ (ppm) 8.91 (s, 1H), 8.63 (s, 1H), 8.62 (s, 1H), 8.27 (s, 1H), 7.60-7.45 (m, 3H), 7.10 (t, J=8.7 Hz, 2H), 4.67 (t, J=9.0 Hz, 2H), 3.94 (t, J=9.3 Hz, 2H), 2.22 (t, J=9.0 Hz, 2H).
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[CH:18]=[CH:19][N:20]=[C:14]2[CH2:13]1)=[O:11])=O)C.[ClH:31]>CO>[ClH:31].[ClH:31].[NH2:7][C@H:8]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[CH:18]=[CH:19][N:20]=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1cc(F)ccc1F
Agent: Cl
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1cc(F)ccc1F

Procedure:
The title compound was prepared from 7-[(3R)-3-[(1,1-dimethylethoxycarbonyl)-amino]-4-(2,5-difluorophenyl)butanoyl]-5,6,7,8-tetrahydroimidazo[1,2-c]pyrazine (349.8 mg, 0.72 mol, from Step A) in 1.5 mL of methanol saturated with hydrogen chloride, using a procedure analogous to that described in Example 1, Step D. Evaporation of solvent gave 299 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CD3OD): δ 3.10-3.17 (m, 2H), 2.89-2.99 (m, 2H), 3.94-4.22 (m, 4H), 4.33 (m, 1H), 4.91-5.48 (m, 2H), 7.07-7.23 (m, 3H), 8.05 (m, 1H). ESI-MS 389 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH:11]([CH3:13])[CH3:12])[N:5]=[C:4]([NH:14][CH:15]([CH3:17])[CH3:16])[N:3]=1.[CH3:18][O-:19].[Na+]>CO>[CH:15]([NH:14][C:4]1[N:3]=[C:2]([O:19][CH3:18])[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH:11]([CH3:13])[CH3:12])[N:5]=1)([CH3:17])[CH3:16]
Reactant: C[O-]
Reactant: CC(C)Nc1nc(Cl)c(C#N)c(NC(C)C)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(NC(C)C)nc(NC(C)C)c1C#N
Reaction time: 16 h
Yield: 121.1 %

Procedure:
To a solution of 6.3 grams of 4-chloro-2,6-bis(isopropylamino)-5-pyrimidinecarbonitrile in 100 ml of methanol was added a solution of methanolic sodium methoxide (0.805 grams of sodium in 50 ml of methanol). After complete addition, the reaction mixture was stirred for 16 hours. The reaction mixture was then heated under reflux for 5 hours. The excess methanol was removed under reduced pressure. The residue was extracted with a mixture of diethyl ether and water. The organic layer was separated and dried over magnesium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was recrystallized from cyclohexane, to give 4.5 grams of 2,6-bis(isopropylamino)-4-methoxy-5-pyrimidinecarbonitrile; mp, 131°-133°.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(C1C=C[N:18]=[C:17](CN)C=1)(C)C>>[C:17]([C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH3:1])[N:11]=1)#[N:18]
Reactant: CC(C)c1ccnc(CN)c1
Reactant: COC(=O)c1cccnc1C
Product: COC(=O)c1ccc(C#N)nc1C

Procedure:
methyl 6-cyano-2-methylnicotinate was synthesized from methyl 2-methylnicotinate following the general procedure as described for 4-isopropyl-2-pyridylmethylamine.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH2:12][CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:12][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:7][CH2:6]2)[O:4][CH:3]=[CH:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCOC(=O)C(=CN)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNC1CCC2(CC1)OC=CO2)C(=O)OCC

Procedure:
1,4-Dioxaspiro[4.5]decan-8-one (40 g) and diethyl aminomethylenemalonate (47.94 g) are dissolved in 500 ml of toluene. p-Toluenesulfonic acid monohydrate (2.44 g) and 100 ml of toluene are then added and the mixture is refluxed for 3 days collecting water in a Dean-Stark trap. The resulting mixture is decanted and solvent is removed to leave on oil. This oil is flash chromatographed on 750 g silica gel using 9:1 CH2Cl2, EtOAc as eluant to yield diethyl N-(1,4-dioxaspiro[4.5]decen-8-yl)aminomethylenemalonate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[N:32]1[C:37]2[CH:38]=[CH:39][S:40][C:36]=2[C:35]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[N:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:44]4[CH2:45][CH2:46][N:41]([C:35]5[C:36]6[S:40][CH:39]=[CH:38][C:37]=6[N:32]=[CH:33][N:34]=5)[CH2:42][CH2:43]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: c1nc(N2CCNCC2)c2sccc2n1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2ncnc3ccsc23)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-thieno[3,2-d]pyrimidinyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=649.98 (M+H+); retention time=0.65 minutes.
Reaction SMILES: C([O-])(O)=O.[Na+].[SH:6][C:7]1[CH:8]=[C:9]([CH2:13][OH:14])[CH:10]=[CH:11][CH:12]=1.Br[C:16]1[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[OH:14][CH2:13][C:9]1[CH:8]=[C:7]([S:6][C:16]2[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1ccc(Br)cn1
Reactant: OCc1cccc(S)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Sc2cccc(CO)c2)cn1
Yield: 58.5 %

Procedure:
Add NaHCO3 (12.0 g, 143 mmol) to a solution of (3-mercaptophenyl)methanol (10.0 g, 71.3 mmol) and 5-bromopicolinonitrile (13.0 g, 71.3 mmol) in DMF. Heat the mixture overnight. Dilute with ethyl acetate. Wash the mixture with water. Dry, filter and concentrate to afford the title compound (10.1 g, 59%) (Solidifies after standing). MS (APCI-pos) m/z (rel intensity): 243 (M+H, 100%).
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=[CH:3][C:2]1=O.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cnc2c([nH]1)CCCC2
Product: Clc1cnc2c(n1)CCCC2
Yield: 86 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-2(1H)-quinoxalinone in phosphoryl chloride (200 ml) was stirred and refluxed for 3 hours. The solvent was evaporated. The residue was taken up in ice and CH2Cl2. The mixture was basified with NH4OH. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated, yielding 34 g (86%) of 2-chloro-5,6,7,8-tetrahydroquinoxaline (interm. 3).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:34]=[CH:33][C:30]([CH2:31][OH:32])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:34]=[CH:33][C:30]([CH2:31][OH:32])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: OCc1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: OCc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (2.0 g, 6 mmol) and commercially available 4-bromobenzyl alcohol (1.37 g, 7 mmol) according to general procedure II. Obtained as a light brown solid (575 mg, 22%). MS (ISP) 462.1 [(M+H)+]; mp 200-202° C.
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[O:11]/[N:12]=[C:13](/[C:19](=[O:21])[CH3:20])\[C:14]([O:16][CH2:17][CH3:18])=[O:15].[Br:22]Br>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:20][C:19](=[O:21])/[C:13](=[N:12]/[O:11][CH:2]1[CH2:3][CH2:4][CH:5]2[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:1]1)/[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)/C(=N\OC1CCC2CCCCC2C1)C(C)=O
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C(=N\OC1CCC2CCCCC2C1)C(=O)CBr
Temperature: 25 °C

Procedure:
Ethyl (Z)-2-(decahydronaphth-2-yloxyimino)-3-oxobutyrate (1.7 g) in carbon tetrachloride (10 ml) was treated with bromine (0.29 ml). The mixture was stirred at room temperature for lh, then the solvent was evaporated under reduced pressure. The residue was dissolved in ether, washed with water, dried (MgSO4) and evaporated under reduced pressure. The title compound (0.7 g) was isolated by flash chromatography on silica eluting with chloroform:carbon tetrachloride. δH (CDCl3) 1.33 (3H, t), 1.10-2.00 (16H, m), 6.35 (2H, s), 4.40 (2H, q), and 4.40 (1H, m).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH2:7])[CH2:2]1.[OH-].[Na+].[CH3:10][NH:11][C:12](=[N:15][N+:16]([O-:18])=[O:17])OC.Cl>C(#N)C.O>[CH3:10][NH:11][C:12]([NH:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[N:15][N+:16]([O-:18])=[O:17]
Reactant: CNC(=N[N+](=O)[O-])OC
Reactant: NCC1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CNC(=N[N+](=O)[O-])NCC1CCOC1
Reaction time: 4 h

Procedure:
[(3-tetrahydrofuryl)methyl]amine (38.0 g, 0.38 mole) and 56.99 g of water were mixed, and the resulting mixture was cooled to 5 degree centigrade. Furthermore, 3.05 g (0.07 mole) of 1N NaOH was added to the solution, and then N,O-dimethyl-N′-nitroisourea (49.2 g, 0.37 mole) was introduced to the solution. The suspension was stirred at 5 degree centigrade for 4 hours, and then heated to 10 degree centigrade, and further stirred for 10 hours. 35% hydrochloric acid (6.7 g, 0.07 mole) was added to the suspension so that the pH became not more than 4. Water and acetonitrile were added to the above suspension for complete dissolution. The resulting solution was analyzed by HPLC and as a result, the reaction yield of the titled compound was 86%.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[O:7][C:6]2[C:8]([CH:13]([C:15]3[N:16]=[CH:17][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:19]=3)O)=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=2[CH2:4][O:3]1>CO.[Pd].C(OCC)C>[CH3:1][C:2]1([CH3:39])[O:7][C:6]2[C:8]([CH2:13][C:15]3[N:16]=[CH:17][NH:18][CH:19]=3)=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: Cc1cc2c(c(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c1)OC(C)(C)OC2
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Product: Cc1cc2c(c(Cc3c[nH]cn3)c1)OC(C)(C)OC2

Procedure:
9.45 g (0.0183 mole) of alpha-(2,2,6-trimethyl-4H-1,3-benzodioxin-8-yl)-1-triphenylmethyl-1H-imidazole-4-methanol (prepared in Example 1.C.6.), dissolved in 300 ml of methanol, are subjected to hyrogeolysis in the presence of 0.6 g of 10% palladium on carbon for 4 hours at 80° C., under a hydrogen pressure of 2 hours. The catalyst is then filtered off and the solvent removed. The residue obtained is stirred in diethyl ether to remove the triphenylmethane, then chromatographed on 700 g of silica (10 μm) (eluent: 95:5 v/v dichloromethane-methanol). A 60:40 mixture of 4-[(2,2,6-trimethyl-4H-1,3-benzodioxin-8-yl)(methoxy)methyl]-1H-imidazole and 4-[(2,2,6-trimethyl-4H-1,3-benzodioxin-8-yl)methyl]-1H-imidazole is isolated and identified by NMR by the presence of a peak corresponding to the methoxy radical (DMSO: delta 3.13). The mixture is used as such in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([CH3:37])[C:35]=1O)[C:31]#[N:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:14][O:15][C:35]3[C:34]([CH3:37])=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=3[CH3:27])[C:11]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: OCC(C1CCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: Cc1cc(C#N)cc(C)c1O
Product: Cc1cc(C#N)cc(C)c1OCC(C1CCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclopentyl-ethanol, 3,5-dimethyl-4-hydroxybenzonitrile (commercially available), tri-n-butylposphine and N′N′N′N-tetramethylazodicarboxamide. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 60:40). The product containing fractions were pooled and evaporated. The resulting light yellow foam was dissolved in acetonitrile, upon which crystallisation occurred. The suspension was filtered, washed with a small amount of acetonitrile and dried under high vacuum. White solid (34%). MS (Turbo Spray): m/z=506.182 [M+H].
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([N:28]([CH3:30])[CH3:29])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][C:10]=2[N:25]([CH3:27])[CH3:26])=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:24][C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([N:25]([CH3:27])[CH3:26])[CH:11]=1)[N:8]=[C:7]([N:28]([CH3:29])[CH3:30])[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23]
Reactant: CCOC(=O)c1c(N(C)C)nc2c(N(C)C)cc(Cl)cc2c1Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)c1nc2c(N(C)C)cc(Cl)cc2c(Cc2ccccc2Cl)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 12 step B from a mixture of 6-chloro-4-(2-chloro-benzyl)-2,8-bis-dimethylamino-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 61 step D) and 1N NaOH in ethanol. Light yellow solid. MS (ESI): 418 (M+H)+.