Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S)C.[Al].C[O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]([CH2:23][CH:24]([CH3:25])[CH3:26])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CCOC(=O)CN(CC(C)C)S(=O)(=O)c1ccc(OC)cc1
Agent: [Al]
Solvent: CCS
Solvent: ClCCl
Product: CCOC(=O)CN(CC(C)C)S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of ethanethiol (15 mL) and methylene chloride (15 mL) is cooled to 0° C. Aluminum trichlofide (9.62 g, 72.2 mmol) is added (the solution turns green), and the reaction is warmed to room temperature. Ethyl 2-[[4-methoxybenzenesulfonyl](isobutyl)-amino]acetate (4.75 g, 14.44 mmol) is added in methylene chloride (5 mL), and the reaction is stirred for 3.5 hours at room temperature. The reaction is then slowly quenched with water, and the crude reaction is partitioned between water and methylene chloride. The aqueous layer is extracted well with methylene chloride, the combined organic layers are dried (Na2SO4), and the solvent is evaporated. The product is purified by silica gel chromatography (25% to 50% ethyl acetate/hexane) to give ethyl 2-[[4-hydroxybenzenesulfonyl](isobutyl)amino]acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[C:20]1([CH2:26][CH2:27][C:28](Cl)=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.C(OCC)(=O)C>[C:20]1([CH2:26][CH2:27][C:28]([NH:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1ccnc(N)c1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccnc(NC(=O)CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of ethyl 2-aminoisonicotinate (4.50 g, 27.08 mmol) and triethylamine (9.0 mL, 64.93 mmol) in tetrahydrofuran (100 mL) was added 3-phenylpropanoyl chloride (8.3 mL, 56.11 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=95/5-0/100) and recrystallized from hexane/ethyl acetate to give the title compound (6.85 g, yield 85%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:12]Br.S([O-])(O)=O.[Na+]>C(O)(=O)C>[Br:12][C:3]1[CH:4]=[CH:5][C:6]2[O:7][CH2:8][CH2:9][O:10][C:11]=2[C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cccc2c1OCCO2
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(Br)ccc2c1OCCO2
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
In 30 ml of acetic acid, was dissolved 10 g of 5-methyl-1,4-benzodioxane and 11.8 g of bromine was added dropwise to the solution. After stirring for 30 minutes, the reaction mixture was poured into a sodium hydrogen sulfite aqueous solution and extracted with diethyl ether. The resulting diethyl ether layer was washed successively with a sodium hydrogen carbonate aqueous solution, water and saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 15.0 g of 6-bromo-5-methyl-1,4-benzodioxane (bp. 126°-135° C. (7 mmHg)).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([OH:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6](O)[CH2:5][C:4]1=[O:57])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([OH:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6]=[CH:5][C:4]1=[O:57])[CH3:2]
Reactant: CCC1C=C(C)C(O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC1C=C(C)C(O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Temperature: 60 °C

Procedure:
To a stirred solution of 17-ethyl-1,14,20-trihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (in benzene) is added p-toluenesulfonic acid and the mixture warmed to 60° C. in an oil bath. The reaction mixture is cooled to room temperature, neutralized by the addition of a saturated aqueous NaHCO3 solution and extracted with ethyl acetate (3 times). The combined organics are washed with saturated NaCl solution, dried over Na2SO4 and purified by flash chromatography on silica gel (20% hexanes in ethyl acetate and 1% MeOH) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([CH:27]2[CH2:29][CH2:28]2)[CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:34]5[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([CH:27]2[CH2:29][CH2:28]2)[CH:3]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C3CC3)c2)S1
Reactant: CN1CCNCC1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C4CC4)c3)S2)CC1

Procedure:
5-[1-(4-Chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-chloro-2-cyclopropyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 1-methyl-piperazine following General Procedure C.
Reaction SMILES: [OH-].[Na+].O.Cl.[F:5][C:6]([F:20])([F:19])[C:7]1[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.Br[CH2:22][CH2:23][CH2:24][Cl:25]>CC(C)=O>[F:20][C:6]([F:5])([F:19])[C:7]1[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][N:16]([CH2:22][CH2:23][CH2:24][Cl:25])[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: ClCCCBr
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: FC(F)(F)c1cccc(N2CCN(CCCCl)CC2)c1
Reaction time: 18 h

Procedure:
To a solution of 7.36 g. (0.184 mole) of sodium hydroxide in 75 ml. of water and 75 ml. of acetone there is added 19.02 g. (0.074 mole) of 1-[3-(trifluoromethyl)phenyl]piperazine hydrochloride and 11.59 g. (0.074 mole) of 1-bromo-3-chloropropane, and the resulting mixture is stirred at 27° for 18 hrs. The organic layer is then separated and concentrated to an oil under reduced pressure. The oil is treated with hot (85°) 6 N HCl until solution is complete, and the resulting solution is filtered and stored at 5° for 18 hrs. The precipitate which forms is collected on a filter to afford 14.73 g. (66%) of the hydrochloride salt of the product, m.p. 190°-192°.
Reaction SMILES: O=[C:2]1[CH2:18][CH2:17][CH2:16][O:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.N(OCCCC)=O.S(=O)(O)[O-].[Na+]>>[C:13]1(=[O:14])[O:15][CH2:16][CH2:17][CH2:18][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=C1CCCCCCCCCCC(=O)OCCC1
Agent: CCCCON=O
Agent: O=S([O-])O
Agent: [Na+]
Product: O=C1CCCCCCCCCCCCCCO1

Procedure:
The process of Russian Inventor's Certificate 521,274 is a variant in which the macrocyclic ring is retained in all the reaction steps: II is converted into 12-oxo-15-pentadecanolide (VI) using butyl nitrite/sodium bisulphite, and the product is reduced by the Clemmensen method to give 15-pentadecanolide: ##STR5## The yield of I in this process is only 36%, as can be seen from the examples. Electrochemical reduction of VI to I in accordance with German Offenlegungsschrift 3,127,242 also proceeds in only moderate yields of about 60%.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: O[C@H]1CCNC1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 8.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 2.3) and (S)-pyrrolidin-3-ol to afford an off-white crystalline powder. HPLC (Condition 4) tR=5.83 min, UPLC-MS (Condition 3) tR=1.06 min, m/z=446.1 [M+H]+.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:3])[CH3:2].Cl.[OH:21][C:22]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[N:16]=[C:15]([C:17]([N:26]2[CH2:25][CH2:24][C:23]3[C:28](=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:22]=3[OH:21])[CH2:27]2)=[O:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1O)CCNC2
Reactant: CC(=O)NCCc1nc(C(=O)O)c2ccccc2n1
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(CCNC(C)=O)nc3ccccc13)C2
Yield: 30 %

Procedure:
Reaction of 2-(2-(acetamido)ethyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 74 (30% yield) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.74 (d, 3H), 2.60 and 2.86 (2t, 2H), 3.16 (t, 2H), 3.44 and 3.98 (2t, 2H), 3.59 (t, 2H), 3.73 and 3.79 (2s, 3H), 4.33 and 4.87 (2s, 2H), 6.32-6.91 (m, 2H), 7.65-7.75 (m, 1H), 7.82-7.92 (m, 2H), 8.01-8.05 (m, 2H), 8.66-8.70 (m, 1H); MS (ESI) m/z 421 ([M+H]+).
Reaction SMILES: Cl.C([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])=[N:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34])C1C=CC=CC=1.CN(C=O)C>[Pd].CO.ClC(Cl)Cl>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:18]2[C:17]3[C:22](=[CH:23][C:14]([O:13][CH2:12][CH2:11][CH2:10][OH:9])=[C:15]([O:33][CH3:34])[CH:16]=3)[N:21]=[CH:20][N:19]=2)=[C:26]([F:32])[CH:27]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCOCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCO
Reaction time: 2 h
Yield: 31.8 %

Procedure:
A mixture of 7-(3-benzyloxypropoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (180 mg, 0.4 mmol) and 5% palladium-on-charcoal catalyst (50 mg) in methanol (5 m), trichloromethane (5 ml) a nd DMF (1 ml) was stirred under hydrogen at 1 atmosphere pressure for 2 hours. The catalyst was removed by filtration through diatomaceous earth and the solvent removed by evaporation. The residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution, the organic layer separated and dried (MgSO4) and the solvent removed by evaporation. The residue was recrystallised from ethyl acetate/hexane to give 4-(4-chloro-2-fluoroanilino)-7-(3-hydroxypropoxy)-6-methoxyquinazoline (48 mg, 33%).
Reaction SMILES: O=C1C2NC(C(OC)=O)=CC=2CC1.ClC1C=C([Mg]Br)C=CC=1.[Cl:23][C:24]1[CH:25]=[C:26]([C:30]2(O)[C:34]3[NH:35][C:36]([C:38]([O:40][CH3:41])=[O:39])=[CH:37][C:33]=3[CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>CO>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]2[C:34]3[NH:35][C:36]([C:38]([O:40][CH3:41])=[O:39])=[CH:37][C:33]=3[CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1cc2c([nH]1)C(O)(c1cccc(Cl)c1)CC2
Agent: COC(=O)c1cc2c([nH]1)C(=O)CC2
Agent: Clc1cccc([Mg]Br)c1
Solvent: CO
Product: COC(=O)c1cc2c([nH]1)C(c1cccc(Cl)c1)CC2
Yield: 29 %

Procedure:
The title compound was synthesized in two steps. First, methyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.508 g, 2.84 mmol) was reacted with 3-chlorophenylmagnesium bromide (0.5 M in THF, 14 mL, 7.0 mmol) according to General Procedure 3 to give the carbinol-containing methyl 6-(3-chlorophenyl)-6-hydroxy-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, followed by hydrogenation according to General Procedure 6 (with Pt2O), and was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-30% EtOAc/heptane affording the title compound: 0.99 g (29% yield). 1H NMR (400 MHz, ACETONE-d6) δ ppm 2.27 (ddt, J=13.17, 8.32, 5.22, 5.22 Hz, 1H), 2.58-2.67 (m, 1H), 2.72-2.79 (m, 1H), 2.90-3.01 (m, 1H), 3.73 (s, 3H), 4.31 (dd, J=8.57, 5.20 Hz, 1H), 6.63-6.65 (m, 1H), 7.06-7.10 (m, 1H), 7.13 (t, J=1.90 Hz, 1H), 7.22 (ddd, J=7.99, 2.16, 1.12 Hz, 1H), 7.30 (t, J=7.79 Hz, 1H), 10.66 (br. s, 1H); LCMS (ESI−) 274.2 (M−H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=3[CH3:24])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].[C:25](Cl)(=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([NH:23][C:25](=[O:34])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=4)[CH:20]=[CH:19][C:18]=3[CH3:24])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cncc2c(COc3cc(N)ccc3C)csc12
Reactant: COc1cccc(C(=O)Cl)c1
Product: CCOC(=O)c1cncc2c(COc3cc(NC(=O)c4cccc(OC)c4)ccc3C)csc12

Procedure:
3-[5-(3-Methoxy-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester was prepared from 3-(5-amino-2-methyl-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 23 supra) and 3-anisoyl chloride (Aldrich) following the procedure described in Example 10 as an off-white solid.
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:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[S:32]1[CH:36]=[CH:35][N:34]=[C:33]1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[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:26]=[CH:25][C:21]([C:22]([N:40]4[CH2:41][CH2:42][N:37]([C:33]5[S:32][CH:36]=[CH:35][N:34]=5)[CH2:38][CH2:39]4)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: c1csc(N2CCNCC2)n1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2nccs2)CC1
Yield: 61 %

Procedure:
4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7-yl}benzoic acid (70 mg) was reacted with 1-thiazol-2-yl-piperazine as in General Procedure 8 to give the title compound as a yellow solid (61% yield). M.p. 243-244, LCMS: m/z=598.92 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.49-3.92 (m, 12H), 4.63 (s, 2H), 5.06 (bs, 1H), 6.57-6.64 (m, 2H), 7.21 (d, J=3.52 Hz, 1H), 7.35-7.43 (m, 5H), 7.51 (s, 1H), 7.65 (d, J=8.4 Hz, 1H) 7.76 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[OH-].[Na+].Cl>CCO.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:23]2[CH2:24][C:25]([CH3:32])([CH3:31])[CH2:26][C:27]([CH3:30])([CH3:29])[CH2:28]2)[C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)c(F)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(/C=C/C(=O)O)cc2)c2ccc(O)c(F)c2)CC(C)(C)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of Ethyl(2E)-3-{4-[(3-fluoro-4-hydroxyphenyl)(3,3,5,5-tetramethyl cyclohexylidene)methyl]phenyl}-2-propenoate (140) (0.235 g, 0.54 mmol) in a mixture of EtOH (6 mL) and THF (6 mL) was added an aqueous solution of 1 N NaOH (7 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 2 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract washed with brine and dried over Na2SO4. Upon concentration and adding hexanes, compound 141 was obtained as pale yellow solid (0.182 g, 83%). mp 193-195° C. 1H NMR (400 MHz, DMSO-d6): δ 0.87 (s, 6H), 0.89 (s, 6H), 1.25 (s, 2H), 1.88 (s, 2H), 1.91 (s, 2H), 6.45 (d, J=15.9 Hz, 1H), 6.76 (dd, J1=8.2 Hz, J2=1.6 Hz, 1H), 6.80-6.92 (m, 2H), 7.17 (d, J=8.0 Hz, 2H), 7.53 (d, J=16.1 Hz, 1H), 7.59 (d, J=8.2 Hz, 2H), 9.72 (s, 1H), 12.32 (s, 1H). LCMS (ES): m/z 407 (M−H)−. Anal. Calcd for C26H29FO3.⅙H2O: C, 75.89; H, 7.19; Found: C, 75.91; H, 7.17.
Reaction SMILES: [C:1]([NH2:6])(=O)[CH:2]([CH3:4])[CH3:3].C1(N)CC1.[CH:11]1([C:14]2[N:18](C)[C:17]([CH:20]=[O:21])=[CH:16]N=2)[CH2:13]C1>>[CH:14]1([N:18]2[C:17]([CH:20]=[O:21])=[CH:16][N:6]=[C:1]2[CH:2]([CH3:4])[CH3:3])[CH2:11][CH2:13]1
Reactant: Cn1c(C=O)cnc1C1CC1
Reactant: CC(C)C(N)=O
Agent: NC1CC1
Product: CC(C)c1ncc(C=O)n1C1CC1

Procedure:
3-Cyclopropyl-2-isopropyl-3H-imidazole-4-carbaldehyde was prepared from isobutyramide and cyclopropylamine in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[OH:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1.[H-].[Na+]>CN(C=O)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][CH:25]=[N:26]4)=[CH:21][CH:20]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Oc1ccc2cccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)ncn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 250-mL, round-bottomed flask containing 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (2.5 g, 9.7 mmol) and 7-hydroxyquinoline (2.0 g, 14 mmol, Acros) in DMF (30 mL), was added NaH (5.4 g, 14 mmol, 60% in mineral oil, Aldrich) at room temperature The solution was then stirred at room temperature for 4 h. After the solvent was removed in vacuum, EtOAc (100 mL) and water (50 mL) were added to the residue. The solid precipitate was filtered and the filtrate was poured into a separatory funnel. The organic layer was separated, combined with the previously isolated solid, concentrated in vacuum, and purified by silica gel chromatography (2:1 hexanes/EtOAc). The purified product was dissolved in acetone (30 mL) and MeOH (10 mL), and to the solution was added water (30 mL) in small portions. The precipitated solid was filtered, washed with water (5 mL), and dried under vacuum at 50° C. for 48 h to furnish the title compound as a white solid. Mp: 178-180° C. MS (ESI, pos. ion) m/z: 368 (M+1). Anal. Calcd for C20H12F3N3O: C, 65.40; H, 3.29; N, 11.44. Found: C, 65.42; H, 3.23; N, 11.43.
Reaction SMILES: C1([Si](OC)(OC)OC)C=CC=CC=1.C(O[Si](OCC)(OCC)OCC)C.C[Si](OCC)(OCC)OCC.[C:38]([O-:45])(=[O:44])/[CH:39]=[CH:40]\[C:41]([O-:43])=[O:42].C(O[Si](CCC[NH+:59]1[CH2:63][CH2:62][N:61]=[CH:60]1)(OCC)OCC)C.C(O[Si](CCC[NH+:77]1[CH2:81][CH2:80][N:79]=[CH:78]1)(OCC)OCC)C.Cl.C(OCC(O)C)C>O.CC(C)=O.CO.C(O)C>[C:38]([O-:45])(=[O:44])/[CH:39]=[CH:40]\[C:41]([O-:43])=[O:42].[NH+:59]1[CH:63]=[CH:62][NH:61][CH:60]=1.[NH+:77]1[CH:81]=[CH:80][NH:79][CH:78]=1
Reactant: CCO[Si](CCC[NH+]1C=NCC1)(OCC)OCC
Agent: CCOCC(C)O
Agent: CCO[Si](C)(OCC)OCC
Agent: CCO[Si](OCC)(OCC)OCC
Solvent: CCO
Solvent: CO
Solvent: O
Product: c1c[nH+]c[nH]1
Temperature: 25 °C

Procedure:
4.92 g of phenyltrimethoxysilane, 72.39 g of tetraethoxysilane, 22.04 g of methyltriethoxysilane, 0.65 g of the 30% ethanol solution of triethoxysilylpropyl-4,5-dihydroimidazolium maleate, and 150 g of acetone were charged into a 500 mL flask to be dissolved and the resultant mixed solution was warmed while stirring the mixed solution with a magnetic stirrer to reflux. Next, 33.10 g of 0.01 M hydrochloric acid was added to the mixed solution. The mixed solution was subjected to the reaction for 240 minutes and then the resultant reaction solution was cooled down to room temperature. Then, 200 g of propylene glycol monoethyl ether was added to the reaction solution, and ethanol and methanol as reaction by-products, acetone, water, and hydrochloric acid were distilled off under reduced pressure to obtain a hydrolysis-condensation product. The polymer thus obtained corresponded to Formula (VII-10):
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][C:17]([O:20][CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])([CH3:19])[CH3:18])[C:14]([CH2:27][O:28][CH2:29][CH3:30])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.B1([C:37]2[CH:42]=[CH:41][CH:40]=[N:39][CH:38]=2)OCCCO1>>[CH2:29]([O:28][CH2:27][C:14]1[N:15]([CH2:16][C:17]([O:20][CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])([CH3:19])[CH3:18])[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:37]4[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH3:30]
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Reactant: c1cncc(B2OCCCO2)c1
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Yield: 58.6 %

Procedure:
7-Bromo-2-ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-1H-imidazo[4,5-c]quinolin-4-amine (1.2 g, 2.4 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (0.47 g, 2.9 mmol) were coupled according to the method described in Part J of Example 1. The work-up procedure used in Part F of Examples 125-135 was followed. The crude product was purified by column chromatography on silica gel (eluting sequentially with 95:5 and 90:10 dichloromethane:methanol) followed by recrystallization from acetonitrile (52 mL/g). The crystals were isolated by filtration, washed with acetonitrile, and dried for four hours under vacuum at 65° C. to provide 0.70 g of 2-ethoxymethyl-1-{2-[2-(methanesulfonyl)ethoxy]-2-methylpropyl}-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as white, crystalline plates, mp 202-204° C.
Reaction SMILES: [C:1](=[S:3])=[S:2].OS(O[CH2:9][C@@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][NH:11]1)(=O)=O>[OH-].[Na+]>[CH2:9]1[C@H:10]2[N:11]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:19]2)[C:1](=[S:3])[S:2]1
Reactant: S=C=S
Reactant: O=S(=O)(O)OC[C@@H]1Cc2ccccc2CN1
Agent: [Na+]
Agent: [OH-]
Product: S=C1SC[C@@H]2Cc3ccccc3CN12
Reaction time: 3 h
Yield: 84.6 %

Procedure:
Carbon disulphide (40 g) is added dropwise, whilst stirring vigorously, to a solution of (S)-3-hydroxysulphonyloxymethyl-1,2,3,4-tetrahydroisoquinoline (100 g) in 0.25 N aqueous sodium hydroxide solution (4000 cc). The reaction is exothermic. A solid precipitates; the stirring is continued for 3 hours. The reaction mixture is then neutralised by the addition of 4 N hydrochloric acid. The resulting crystals are filtered off, washed copiously with water and then recrystallized from ethanol (3000 cc). (S)-1,5,10,10a-Tetrahydrothiazolo[3,4-b]isoquinoline-3-thione (77 g) is thus obtained in the form of fine white needles which melt at 150° C.