Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[N:8]([C:9]2[N:17]=[C:16]3[C:12]([N:13]=[C:14]([CH:19]=O)[N:15]3[CH3:18])=[C:11]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:10]=2)[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]=1.[O:31]1[CH2:34][CH:33]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:43])C.[Na+]>ClCCCl>[CH3:18][N:15]1[C:14]([CH2:19][N:38]2[CH2:39][CH2:40][CH:35]([CH:33]3[CH2:34][O:31][CH2:32]3)[CH2:36][CH2:37]2)=[N:13][C:12]2[C:16]1=[N:17][C:9]([N:8]1[C:7]3[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=3[N:5]=[C:4]1[CH:3]([OH:43])[CH3:2])=[N:10][C:11]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(-n3c(CCO)nc4ccccc43)nc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C1CC(C2COC2)CCN1
Agent: [Na+]
Solvent: ClCCCl
Product: CC(O)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C4COC4)CC3)n(C)c2n1
Reaction time: 18 h
Yield: 19.5 %

Procedure:
A solution of 2-[2-(2-hydroxyethyl)benzoimidazol-1-yl]-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (200 mg, 0.49 mmol), 4-oxetan-3-ylpiperidine (83 mg, 0.59 mmol) and molecular sieves (4 Å, powdered, 1 g) in DCE (5 mL) was stirred at ambient temperature for 5 h. Sodium triacetoxyborohydride (156 mg, 0.74 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0 to 99:1 to 98:2 to 97:3 to 95:5) to afford 512 as a white solid (51 mg, 20%). LCMS (Method I): RT=2.39 min, M+H+=533. 1H NMR (CDCl3, 400 MHz) δ 8.04 (m, 1 H); 7.75 (m, 1 H); 7.33 (m, 2 H); 4.76 (dd, J=7.8, 6.0 Hz, 2 H); 4.45 (t, J=6.0 Hz, 2 H); 4.35 (m, 4 H); 4.19 (t, J=5.5 Hz, 2 H); 3.94-3.80 (m, 9 H); 3.54 (t, J=5.5 Hz, 2 H); 3.02 (m, 2 H); 2.81-2.72 (m, 1H); 2.29 (m, 2 H); 1.71 (m, 5 H) and 1.28 (m, 1 H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.[C:30](Cl)(Cl)=[S:31].[CH:34]([N:37]([CH:41]([CH3:43])[CH3:42])[CH2:38][CH2:39][NH2:40])([CH3:36])[CH3:35]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30]([NH:40][CH2:39][CH2:38][N:37]([CH:41]([CH3:43])[CH3:42])[CH:34]([CH3:36])[CH3:35])=[S:31])=[CH:18][CH:17]=1
Reactant: S=C(Cl)Cl
Reactant: CC(C)N(CCN)C(C)C
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NCCN(C(C)C)C(C)C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (50 mg) was then added to the solution, and the mixture was stirred at room temperature for 6 hr. Next, N,N-diisopropylethylenediamine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 15 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (47 mg, yield 58%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:8]([O:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([Cl:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[Cl-:32].[C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:8]([O:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:15])[CH3:16])=[O:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CN(C)CCCOC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CC#N
Product: CC(C)(C)c1cc(C(=O)OCCC[N+](C)(C)Cc2ccccc2)cc(C(C)(C)C)c1O
Product: [Cl-]
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A solution of 33.55 g (100 mmol) of 3-dimethylaminopropyl 3,5-di-tert-butyl-4-hydroxybenzoate prepared as described above and 12.66 g (100 mmol) of benzyl chloride in 140 ml of acetonitrile was heated at reflux for 1 hour and 15 minutes and then concentrated under vacuum to a clear, thick oil. The resultant oil was allowed to stand overnight and crystallized. The solid was washed with ether, collected and dried giving 45.2 g (97.8% of theory) of N-[3-(3,5-di-tert-butyl-4-hydroxybenzoyloxy)propyl]-N,N-dimethylbenzylammonium chloride.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].CCN(C(C)C)C(C)C.[Cl:14][S:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[F:27])[C:21](Cl)=[O:22])(=[O:17])=[O:16]>C(Cl)Cl>[F:27][C:26]1[CH:25]=[CH:24][C:20]([C:21](=[O:22])[NH:4][CH2:1][C:2]#[CH:3])=[CH:19][C:18]=1[S:15]([Cl:14])(=[O:17])=[O:16]
Reactant: O=C(Cl)c1ccc(F)c(S(=O)(=O)Cl)c1
Reactant: C#CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C#CCNC(=O)c1ccc(F)c(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
Propargylamine (0.67 mL, 10.5 mmol) and DIEA (1.83 mL, 10.5 mmol) in DCM (10 mL) were added dropwise to 3-(chlorosulfonyl)-4-fluorobenzoyl chloride (2) in DCM (10 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 15 minutes. The reaction was washed with 2N HCl and brine, dried (MgSO4) and evaporated. The residue was purified by Biotage flash column chromatography (30% EtOAc/Hep) to give product as an oil (2.52 g, 87%).
Reaction SMILES: [N:1]1([C:19]([O:21]C(C)(C)C)=O)[C@H:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:4][C@@H:3]2[CH2:16][CH2:17][CH2:18][C@H:2]12.[CH3:26][O:27][C:28]([NH:30][C@@H:31]([C@@H:35]([CH3:38])[CH2:36][CH3:37])C(O)=O)=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:26][O:27][C:28]([NH:30][C@@H:31]([C@@H:35]([CH3:38])[CH2:36][CH3:37])[C:19]([N:1]1[C@H:5]([C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:4][C@@H:3]2[CH2:16][CH2:17][CH2:18][C@H:2]12)=[O:21])=[O:29]
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCC[C@@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCC[C@@H]21
Reaction time: 8 h
Yield: 132.1 %

Procedure:
To a solution of commercially available (2S,3aS,6aS)-2-benzyl 1-tert-butyl hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate (10.0 g, 35.489 mmol) in methylene chloride (100 mL) was added (2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid (10.072 g, 53.23 mmol), HATU (21.59 g, 56.78 mmol), and DIPEA (18.59 mL, 106.46 mmol). The reaction was stirred overnight, at which time it was concentrated in vacuo, diluted in ethyl acetate and washed with HCl (1N). The aqueous layer was backextracted with ethyl acetate, and the combined organics were dried over sodium sulphate, filtered and concentrated. The resulting oil was diluted in a small amount of chloroform and filtered to remove tetramethyl urea precipitate. The resulting oil was purified by normal phase chromatography (50% ethyl acetate in hexanes) to give (2S,3aS,6aS)-benzyl 1-((2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoyl)octahydrocyclopenta[b]pyrrole-2-carboxylate (19.53 g, >99% yield) which was used without further purification. LCMS-ESI+ calc'd for C23H33N2O5: 417.23. Found: 417.37.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34](Cl)=[O:35])=[CH:28][CH:27]=1>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:34](=[O:35])[CH2:33][CH2:32][C:29]4[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=4)[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(Cl)CCc1ccc(Cl)cc1
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCC(OC(=O)CCc2ccc(Cl)cc2)N(c2nnc(C3CC3)s2)C1=O

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. β-(4-Chlorophenyl)propionyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-[β-(4-chlorophenyl)propionyloxy]-2(1H)-pyrimidinone as the residue.
Reaction SMILES: C([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O)C.[C:10]([O-:14])(=O)[CH:11]=[O:12].[Cl:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:17]=1[NH2:18]>CO>[Cl:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:17]=1[N:18]1[C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=2[C:10](=[O:14])[C:11]1=[O:12]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: O=CC(=O)[O-]
Reactant: CCC1CCCCC1=O
Solvent: CO
Product: O=C1C(=O)N(c2c(Cl)cccc2Cl)C2=C1CCCC2

Procedure:
A solution of 65 g (0.33 mols) of ethyl 2-cyclohexanone-glyoxylate and 135 g (0.83 mols) of 2,6-dichloroaniline in 150 ml of methanol is refluxed for 30 hours. After this period, there is introduced steam into the reaction vessel, thus removing the excess 2,6-dichloroaniline. The residue of the steam distillation is removed by filtration and recrystallized from methanol.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16](=[O:24])[NH:17][C:18]([CH3:23])([CH3:22])[CH2:19][CH2:20][OH:21])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([NH:17][C:18]([CH3:23])([CH3:22])[CH2:19][CH:20]=[O:21])=[O:24])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(CCO)NC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CC=O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
DMSO (1.22 mL, 17.2 mmol) was added to a solution of oxalyl chloride (1.1 mL, 12.9 mmol) at -78° C. in dichloromethane (15 mL). The mixture was stirred for 15 min at -78° C. A solution of 3-hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester (1.75 g, 8.6 mmol) in dichloromethane (10 mL) was added dropwise over a period of 15 min. The solution was stirred at -78° C. for another 15 min. Triethylamine (6.0 mL, 43 mmol) was added. The solution was stirred at -78° C. for 5 min and then warmed to room temperature. The solution was diluted with dichloromethane (100 mL) and extracted with 1 N hydrochloric acid (100 mL). The aqueous phase was extracted with dichloromethane (50 mL). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 mL) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by column chromatography on silica (140 g) with ethyl acetate/heptane (1:3) to give 1.10 g of 3-(tert-butoxycarbonylamino)-3-methylbutanal.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C@@H:5]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH2:6][NH:7][C:8](=[O:30])[CH2:9][CH2:10][NH:11][C:12](=[O:29])[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[NH:28])[NH:20]C(OC(C)(C)C)=O)=[CH:15][CH:14]=1)[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:41])[C@@H:5]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:33])=[O:34])[CH2:6][NH:7][C:8](=[O:30])[CH2:9][CH2:10][NH:11][C:12](=[O:29])[C:13]1[CH:14]=[CH:15][C:16]([C:19](=[NH:20])[NH2:28])=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](CNC(=O)CCNC(=O)c1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)NS(=O)(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](CNC(=O)CCNC(=O)c1ccc(C(=N)N)cc1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2S)-2-Benzenesulfonylamino-3-(3-(4-(N-t-butoxycarbonylamidino)benzoylamino)propanoylamino)propanoic acid ethyl ester (1.489) obtained in the same manner as in the synthesis of the compound of Example 1-(8) is dissolved in TFA (50 ml) under ice-cooling, and the mixture is stirred at room temperature for one hour. The reaction mixture is concentrated under reduced pressure, and the residue is washed with ether, and purified by HPLC to give the title compound (448 mg) as a colorless powder.
Reaction SMILES: [ClH:1].Cl[C:3]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]2[C:4]=1[C:5]([OH:26])=[C:6](SC1C=CC(NC(=N)C)=CC=1)[C:7](=[O:14])[NH:8]2.ClC[C:29](Cl)=[O:30].C(N(CC)CC)C>CO>[CH3:29][O:30][C:5](=[O:26])[C:4]1[CH:3]=[CH:12][C:11]([Cl:13])=[CH:10][C:9]=1[NH:8][C:7](=[O:14])[CH2:6][Cl:1]
Reactant: CC(=N)Nc1ccc(Sc2c(O)c3c(Cl)cc(Cl)cc3[nH]c2=O)cc1
Reactant: Cl
Reactant: O=C(Cl)CCl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)cc1NC(=O)CCl

Procedure:
The intermediate 7 was prepared by the same procedure for the intermediate 6, using a intermediate 5 (2.7 g, 14.6 mmol), chloroacetyl chloride (2.37 mL, 30.0 mmol) and triethylamine. After normal workup, the pure title compound was obtained by recrystallization from MeOH as a white solid (3.44 g, 90%):
Reaction SMILES: [O:1]([CH:19]([CH3:24])[CH2:20][CH2:21][CH2:22][OH:23])[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[S:31](Cl)([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:33])=[O:32]>C(Cl)Cl>[O:1]([CH:19]([CH3:24])[CH2:20][CH2:21][CH2:22][O:23][S:31]([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[Si:2]([C:15]([CH3:16])([CH3:17])[CH3:18])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(CCCO)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCC(C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Reaction time: 8 h
Yield: 85 %

Procedure:
4-(t-Butyldiphenylsiloxy)-pentanol (15 g, 0.04 mol) was dissolved in methylene chloride (100 mL) containing pyridine (7 g). Tosyl chloride (15.3 g, 0.08 mol) was added slowly and the mixture stirred overnight. The mixture was washed with saturated NaHCO3 (2×100 mL) and the aqueous then backwashed with methylene chloride (100 mL). The organic phases were combined and washed with 2M HCl (100 mL) and water. The solution was dried over Na2SO4, evaporated and purified by column chromatography (light petroleum: ethyl acetate, 3:1) to give the title compound as a thick oil (yield 85%). δC (CDCl3, 62.9 MHz): 19.2, 21.7, 21.8, 26.9, 28.6, 31.8, 63.5, 70.6, 127.7, 127.9, 129.6, 129.9, 133.2, 133.9, 135.6 and 144.7
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C>C1COCC1.CCCCCC>[CH:9]([O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:20]=[O:21])([CH3:11])[CH3:10]
Reactant: CN(C)C=O
Reactant: CC(C)Oc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)Oc1cccc(C=O)c1
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
A solution of 1-bromo-3-iso-propyloxybenzene (2.16 g, 10 mmol) in dry THF (30 mL) was cooled to −78° C. and n-BuLi (4.8 mL of a 2.5 m solution in hexane, 12 mmol) was added. The resulting solution was stirred 0.5 hours and DMF (7.3 g, 10 mmol) was added at −78° C. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under vacuum. Purification on silica gel with 25% ethyl acetate/hexane afforded the title compound (1.64 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:9]([CH:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[OH:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:32](=O)[CH3:33].[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:36].[Na+]>CO.C(O)(=O)C.C(=O)([O-])O.[Na+].[OH-].[Na+]>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH:11]([OH:12])[C:9]1[N:8]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[C:7]2[C:2]([N:1]([CH2:32][CH3:33])[CH2:35][CH3:36])=[CH:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)NCCCn1c(C(O)c2ccc(Cl)cc2Cl)nc2cccc(N)c21
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCCNC(=O)OC(C)(C)C)c12
Yield: 90.4 %

Procedure:
To a solution of tert-butyl (3-{7-amino-2-[(2,4-dichlorophenyl)(hydroxy)methyl]-1H-benzimidazol-1-yl}propyl)carbamate (3.00 g, 6.45 mmol) in methanol (65 mL) and acetic acid (3.3 mL) was added acetoaldehyde (2.41 mL, 38.7 mmol) at 0° C. The resultant mixture was stirred at 0° C. for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (8.20 g, 38.7 mmol) at 0° C. After the resultant mixture was stirred at 0° C. for 3 h, the mixture was diluted with aqueous sodium hydrogen carbonate and 1N aqueous sodium hydroxide, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a ethyl acetate to give a crude solid, which was washed with diisopropyl ether to give the title compound as a colorless solid (3.04 g, 5.83 mmol, 90%).
Reaction SMILES: Br[CH:2]1[C:10]2[N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:8]=[C:7]([CH3:17])[C:6]=2[C:5](=[O:18])[CH2:4][C:3]1([CH3:20])[CH3:19].[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]([O-])=O.[Na+].[CH3:30]N(C)C=O>[Cl-].[Na+].O>[C:22]1([S:26][CH:2]2[C:10]3[N:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)[N:8]=[C:7]([CH3:17])[C:6]=3[C:5](=[O:18])[CH2:4][C:3]2([CH3:20])[CH3:19])[CH:30]=[CH:21][CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)C=O
Reactant: O=C([O-])c1cccs1
Reactant: Cc1nn(-c2ccccn2)c2c1C(=O)CC(C)(C)C2Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1nn(-c2ccccn2)c2c1C(=O)CC(C)(C)C2Sc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
The solution of 7-bromo-1-(2-pyridyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazole (0.6 g, 1.8 mmol), prepared as described in example 4, and sodium thiophenate (0.3 g, 2.24 mmol) in dry N,N-dimethylformamide (10 ml) was stirred at room temperature for about 5 hours and then poured into brine and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate end evaporated. The residue was chromatographed on silica gel (cyclohexane:ethyl acetate=90:10) to give 0.3 g (45% yield) of the title compound as a colourless solid which crystallized on standing.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:29][C:30]1[CH:31]=[C:32]([CH:35]=O)[S:33][CH:34]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:32]3[S:33][CH:34]=[C:30]([Br:29])[CH:31]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cc(Br)cs4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 4-bromo-2-formylthiophene according to the procedure of step 1, Example 66. MS (ESI) m/z 553.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.Cl.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23].NC1C=CC=CC=1C(F)(F)F.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:23])([F:24])[F:25])=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1ccccc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1cc2ncnc(Nc3ccccc3C(F)(F)F)c2cn1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 40.7 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (300 mg, 1.56 mmol), 2-aminobenzotrifluoride hydrochloride (1.00 g, 5.06 mmol) and 2-aminobenzotrifluoride (2.00 g, 12.4 mmol) is stirred at 160° C. for 10 min. The resulting product is neutralized with excess NaHCO3, dissolved in MeOH/CHCl3, dried onto silica gel and chromatographed over silica gel (6-7% MeOH/CH2Cl2) to give 7-amino-4-(2-trifluoromethylanilino)pyrido(4,3-d]pyrimidine (194 mg, 41%) as a cream solid, mp (MeOH/CHCl3/light petroleum) 126-130° C. (dec.). 1H NMR (DMSO) δ 10.60 (1H, brs), 9.17 (1H, brs), 8.13 (1H, brs), 7.76, 7.69 (1H, 1H, m, m), 7.45 (2H, m), 6.66 (2H, brs), 6.36 (1H, s).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:16][OH:17].[CH2:18]([OH:20])C>>[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16]([O:20][CH2:18][CH:4]([CH2:3][CH3:2])[CH2:5][CH2:6][CH2:1][CH3:7])(=[O:17])[C:9]([CH3:10])=[CH2:8].[C:2]([O:20][CH3:18])(=[O:17])[C:1]([CH3:7])=[CH2:6]
Reactant: Cc1ccccc1
Reactant: CO
Reactant: CCO
Solvent: C=Cc1ccccc1
Product: C=C(C)C(=O)OC
Product: C=C(C)C(=O)OCC(CC)CCCC

Procedure:
First, 100 parts of a 20 wt. % toluene solution of the above styrene copolymer and 20 parts of a 1.0 wt. % methanol solution of a quaternary ammonium salt in which the quaternary ammonium salt as shown in "Exemplary compound 6" was dissolved (solubility: not less than 1.0 g/100 g.ethanol) were stirred using a stirrer until they were thoroughly blended. A coating resin material solution was thus prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12](Cl)=[O:13])[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH2:22]([O:24][C:25](=[O:49])[CH2:26][C:27]1[CH:28]=[C:29]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:36]=2[CH2:45][NH:46][CH2:47][CH3:48])[C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)[CH3:23].O>C(Cl)Cl>[CH2:22]([O:24][C:25](=[O:49])[CH2:26][C:27]1[CH:28]=[C:29]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][C:36]=2[CH2:45][N:46]([C:12]([C:9]2([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH2:11][CH2:10]2)=[O:13])[CH2:47][CH3:48])[C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)[CH3:23]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)C1(c2ccc(Cl)cc2Cl)CC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2(c3ccc(Cl)cc3Cl)CC2)c1
Reaction time: 0.17 h

Procedure:
To a solution of 1-(2,4-dichloro-phenyl)-cyclopropanecarbonyl chloride (0.37 mmol) in CH2Cl2 was added triethylamine (0.16 mL, 1.12 mmol), and the mixture was stirred for 10 minutes. (2′-Ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.146 g, 0.37 mmol) in CH2Cl2 was then added, and the reaction was stirred for 30 minutes at room temperature. Additional triethylamine (0.1 mL, 0.72 mmol) was added, and the reaction was stirred for another 30 minutes. Analytical LCMS indicated that starting material was still present, so another portion of triethylamine (0.1 mL, 0.72 mmol) was added, and the reaction was stirred for 1 hour and then worked-up with CH2Cl2 and H2O. The combined organic layers were dried and concentrated, and the residue was purified by silica gel chromatography (10-40% EtOAc in hexanes) to give the title compound.