Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC[S:53]CC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][S:53][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CSCCN1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCSCC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and thiomorpholine and isolated as light-yellow gum (10.2 mg, 54%). MS(m/e): 403.4 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH:12]=O)=[CH:10][C:5]=2[CH2:4][O:3]1.[F:14][C:15]([F:30])([F:29])[CH:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1.C([BH3-])#N.[Na+]>CO>[O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:21]3[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:17][CH:16]3[C:15]([F:29])([F:14])[F:30])=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: CC(C)(C)OC(=O)N1CCNC(C(F)(F)F)C1
Reactant: O=CCc1ccc2c(c1)COC2=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CCc2ccc3c(c2)COC3=O)C(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (0.495 g, 2.8 mmol) and tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate (0.65 g, 2.6 mmol) in methanol (5 ml) at 0° C. was added sodium cyanoborohydride (0.21 g, 3.3 mmol) and the reaction stirred 12 hours at RT. The reaction mixture was concentrated and diluted with water. The aqueous was extracted with dichloromethane and the combined organics washed with brine, dried (MgSO4), filtered and concentrated. MPLC chromatography (2→20% EtOAc:hexane) provided tert-butyl 4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-3-(trifluoromethyl)piperazine-1-carboxylate. LC-MS (IE, m/z): 415.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:20])=[C:4]([F:23])[CH:3]=1.O[CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:8](=[O:20])[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:15][CH:14]=3)=[CH:12]2)=[C:4]([F:23])[CH:3]=1
Reactant: O=c1ccc(-c2ccc(O)cc2)cn1Cc1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCOc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Yield: 66.7 %

Procedure:
The title compound was prepared from 1-(4-chloro-2-fluorobenzyl)-5-(4-hydroxyphenyl)pyridin-2(1H)-one (1 eq, 0.60 mmol, 0.20 g, Example 20 Step 2) and tert-butyl 2-hydroxyethylcarbamate (1.5 eq, 0.90 mmol, 0.10 g) according to the procedure described for Example 25 Step 2. The crude product was purified by crystallization in pentane/Et2O followed by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2, CH2Cl2/AcOEt 80/20) to afford tert-butyl 2-(4-(1-(4-chloro-2-fluorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenoxy)ethylcarbamate (0.40 mmol, 0.19 g, 66%) as a yellow oil.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1O)([O-:9])=[O:8]>>[CH:1]1([O:6][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N+:7]([O-:9])=[O:8])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: OC1CC=CC1
Product: O=[N+]([O-])c1ccccc1OC1CC=CC1

Procedure:
Cyclopent-3-en-1-ol was reacted with o-nitrophenol to yield 2-cyclopent-3-en-oxynitrobenzene; which was reduced to the corresponding aniline; then reacted with 5-methyl-N-chloromethyl-2-pyrrolidone to form the corresponding 5-methyl-N'-methylene-2-pyrrolidonyl derivative.
Reaction SMILES: [Na+:1].[Na+].[Na+].[NH2:4][C:5]1[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]2[C:14]=1[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:10]2.O.O.O.C([O-])(=O)C.[Na+].[N+](C1C=CC(C([O:44][C:45](=O)[C:46]2[CH:51]=[CH:50][C:49]([N+:52]([O-:54])=[O:53])=[CH:48][C:47]=2[S:55]([OH:58])(=[O:57])=[O:56])=O)=C(S(O)(=O)=O)C=1)([O-])=O>O>[Na+:1].[Na+:1].[Na+:1].[Na+:1].[N+:52]([C:49]1[CH:50]=[CH:51][C:46]([C:45]([NH:4][C:5]2[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]3[C:14]=2[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:20])=[O:21])=[CH:10]3)=[O:44])=[C:47]([S:55]([OH:58])(=[O:56])=[O:57])[CH:48]=1)([O-:54])=[O:53]
Reactant: Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12
Reactant: O=C(OC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Reaction time: 0.17 h

Procedure:
To an ice-bath cooled solution (5° C.) of 8-amino-1,3,6-naphthalenetrisulfonic acid trisodium salt and 6.7 g of sodium acetate trihydrate in 100 ml of water is added 8.8 g of 4-nitro-2-sulfobenzoic acid anhydride. The mixture is stirred vigorously for 10 minutes and is filtered. The filtrate is cooled in an ice bath and diluted with 500 ml of cold ethyl alcohol. The mixture is filtered and the product is washed with ethyl alcohol and ether and then is dried. The product is dissolved in 50 ml of warm water and is stirred for 10 minutes after the addition of one ml of acetone. The mixture is treated with activated charcoal, filtered through diatomaceous earth and is washed with 20 ml of water. The filtrate is cooled in an ice bath and acidified with 1.5 ml of concentrated hydrochloric acid. The solution is diluted with 500 ml of cold ethyl alcohol, and the precipitated material is filtered, washed with ethanol followed by ether and dried. The above purification process is repeated without acidification. The product obtained is dried overnight at 110° C. to give 18.5 g of 8-(4-nitro-2-sulfobenzamido)-1,3,6-naphthalenetrisulfonic acid tetrasodium salt.
Reaction SMILES: [CH2:1]([C@@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].CCN(CC)CC.[C:31](Cl)([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>C(Cl)Cl>[CH2:1]([C@@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H]2CCCNC2)C(=O)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H]2CCCN(C(=O)OCc3ccccc3)C2)C(=O)O1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
To a solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one (112 mg, 0.35 mmol) and Et3N (71 mg, 0.70 mmol) in CH2Cl2 (10 mL) was added CbzCl (71 mg, 0.7 mmol) at 0° C. Then the mixture was stirred at rt till the reaction was over. The reaction was quenched with H2O. The mixture was extracted with EtOAc, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC to afford (S)-benzyl 3-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)piperidine-1-carboxylate (78 mg, 49%). 1H NMR (CDCl3): 1.63 (m, 3H), 2.07-2.26 (m, 2H), 2.54 (m, 3H), 2.21 (m, 2H), 3.09 (m, 1H), 3.68 (m, 1H), 3.99 (m, 1H), 4.93-5.09 (m, 4H), 5.09-5.18 (m, 1H), 6.87-7.03 (m, 2H), 7.14 (m, 1H), 7.31 (m, 6H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9](C1C=CC=CC=1O)([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:10]([F:13])([F:12])[F:11]>>[CH3:8][C:9]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)[C:10]([F:11])([F:12])[F:13]
Reactant: Oc1ccccc1
Reactant: CC(c1ccc(O)cc1)(c1ccccc1O)C(F)(F)F
Product: CC(c1ccc(O)cc1)(c1ccc(O)cc1)C(F)(F)F

Procedure:
Repeating the process of Example 5 using 470 g (5 moles) of phenol in place of the xylenol, yielded a reaction mixture consisting of 66% of 4,4-(1-methyltrifluoroethylidene)bisphenol and 34% of 2,4'-(1-methyltrifluoroethylidene)bisphenol. After the removal of excess phenol by distillation, the mixture of the two isomers was readily separated by elution chromatography over silica, using methylene chloride as eluant. After the emergence of the 2,4'-isomer, the 4,4'-isomer was eluted. The 4,4'-isomer crystallized out readily from the concentrated solution in the form of white crystals which melted at 93°-94.5° C. and had a purity of 98.2%.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[N:12]1([C:18]2[N:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>>[N:19]1[CH:20]=[CH:21][CH:22]=[N:23][C:18]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:14][CH2:13]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc(N2CCN(Cc3nc4cccnc4s3)CC2)nc1

Procedure:
The product from Example 38A (150 mg, 0.81 mmol), 2-(1-piperazinyl)pyrimidine (160 mg, 0.98 mmol), and DIEA (280 μL, 1.6 mmol were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.65 (m, 4H) 3.80 (m, 4H) 4.04 (s, 2H) 6.63 (t, J=4.92 Hz, 1H) 7.56 (dd, J=8.14, 4.75 Hz, 1H) 8.34 (m, 2H) 8.43 (d, J=4.75 Hz, 1H) 8.59 (dd, J=4.75, 1.70 Hz, 1H); (ESI) m/z 313 (M+H)+.
Reaction SMILES: C1(C)C=CC=C(C)C=1.C(C1OC1)Cl.[CH2:14]([O:18][CH2:19][CH:20](CC)[CH2:21][CH2:22]CC)[CH:15]1[O:17][CH2:16]1.C1(CN)C=CC=C(CN)C=1.OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1>>[CH2:14]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:15]1[O:17][CH2:16]1
Reactant: CCCCC(CC)COCC1CO1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: NCc1cccc(CN)c1
Solvent: ClCC1CO1
Solvent: Cc1cccc(C)c1
Product: CCCCOCC1CO1
Temperature: 80 °C
Reaction time: 1 h
Yield: 203.4 %

Procedure:
In the same reaction vessel as in Example 1 was fed 275 g of the modified polyamine synthesized in Production Example 2 (corresponding to the modified polyamine based on 1 mol of metaxylene, 0.125 mol of polyethylene glycol, and 0.28 mol of epichlorohydrin), and then 163 g (0.88 mol) of 2-ethylhexyl glycidyl ether (epoxy equivalent of 186, produced by NOF Corporation, the trademark "Epiol EH") was added dropwise thereto over one hour at 80° C. in an atmosphere of nitrogen under stirring. After the completion of the dropwise addition, the reaction was carried out for one hour at a reaction temperature raised 100° C. Then, the vessel interior was cooled to 80° C., and then 200 g (1.47 mol) of metaxylylenediamine was added thereto. Then, a mixture of 282 g (0.743 mol) of epoxy resin in a liquid form of bisphenol A type (epoxy equivalent 190, produced by Yuka Shell Epoxy Co., Ltd., the trademark "Epicoat 828") with 236 g (1.79 mol) of butyl glycidyl ether (epoxy equivalent of 132, produced by NOF Corporation, the trademark Epiol B") was added dropwise thereto over one hour at 80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])=[C:16]([S:28][CH3:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClN1C(=[O:40])CCC1=O>ClCCCl.O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][CH2:21][C:22]([F:23])([F:25])[F:24])=[O:19])=[C:16]([S:28]([CH3:29])=[O:40])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F
Solvent: ClCCCl
Solvent: O
Product: CS(=O)c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Yield: 43.4 %

Procedure:
In a solution of 0.38 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methylthio-N-(2,2,2-trifluoroethyl)benzoic acid amide (Compound of the present invention No. 5-322) synthesized similarly to Synthetic Example 13 in 6 ml of 1,2-dichloroethane, 0.10 g of N-chlorosuccinic acid imide was added with stirring at room temperature, and stirred at the same temperature for 11 hours. After the completion of the reaction, the reaction mixture was poured in 30 ml of water, and extracted with ethyl acetate (20 ml×3). The organic phase was washed with 30 ml of saturated sodium hydrogen carbonate, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2), and 0.17 g of the aimed product was obtained as colorless oily substance.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28]>CN(C)C=O>[OH:8][C:7]1[CH:9]=[CH:10][C:2]([C:1]([O:12][CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=[CH2:23])=[O:11])=[CH:3][C:4]=1[O:5][CH3:6]
Reactant: C=CCCCCBr
Reactant: COc1cc(C(=O)O)ccc1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCOC(=O)c1ccc(O)c(OC)c1
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of vanillic acid (0.6 g, 3.56 mmol) in N,N-dimethylformamide (7 ml), diisopropylethylamine (0.93 ml, 5.35 mmol) and 6-bromohex-1-ene (0.71 ml, 5.35 mmol) were added. The reaction was stirred at 50° for 8 hours. The solvent was evaporated under vacuum. The residue was purified by flash chromatography (Biotage System, column FLASH 40+M™ KP-Sil, eluent: gradient n-hexane/ethyl acetate 95/5 (200 ml), to n-hexane/ethyl acetate 7/3 during 2000 ml, n-hexane/ethyl acetate 3/7 (400 ml)). The product (0.59 g) was obtained.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](Cl)(=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>O1CCCC1>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:24])=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccc3oc4c(c3c2)CCCC4)cc1
Yield: 62.2 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), anisoyl chloride (0.91 g, 5.3 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (25 mL) provided 4-methoxy-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-benzamide (1.0 g). Mp 197.0-197.5° C.; Anal. Calcd. for C20H19NO3: C, 74.75; H, 5.96; N, 4.36; Found: C, 74.67; H, 5.87; N, 4.46.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:10][C:9]2[N:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([NH:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:12]=3)[N:7]=[C:6]([CH:26]([F:28])[F:27])[C:5]=2[C:4](=[O:29])[CH2:3]1.C([OH:33])C.CS(C)=O.[OH-].[Na+].OO>O>[CH3:1][C:2]1([CH3:30])[CH2:10][C:9]2[N:8]([C:11]3[CH:18]=[CH:17][C:14]([C:15]([NH2:16])=[O:33])=[C:13]([NH:19][CH:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[CH:12]=3)[N:7]=[C:6]([CH:26]([F:27])[F:28])[C:5]=2[C:4](=[O:29])[CH2:3]1
Reactant: CC1(C)CC(=O)c2c(C(F)F)nn(-c3ccc(C#N)c(NC4CCOCC4)c3)c2C1
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)CC(=O)c2c(C(F)F)nn(-c3ccc(C(N)=O)c(NC4CCOCC4)c3)c2C1
Yield: 93 %

Procedure:
To a solution/suspension of 4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzonitrile (897 mg, 2.16 mmol, 1.0 eq) in 10.8 mL of 4:1 mixture of ethanol-dimethyl sulfoxide was added 1 mL of 1 M aqueous sodium hydroxide and 1 mL of 30% hydrogen peroxide. After 30 minutes the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound, 4-(6,6-dimethyl-4-oxo-3-difluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, (869 mg, 93%) as a tan solid: LC/MS (m/z): [M+H]+ 433.3.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[CH:8][C:7]2[N:10]=[C:11]([CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[C:15]3[C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[NH:12][C:6]=2[CH:5]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:31][CH3:32]>CN(C=O)C.O>[CH2:31]([N:10]1[C:7]2[CH:8]=[N:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=2[N:12]=[C:11]1[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[CH3:32]
Reactant: CCI
Reactant: CC(C)c1cc2[nH]c(Cn3ccnc3-c3nccs3)nc2cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(Cn2ccnc2-c2nccs2)nc2cc(C(C)C)ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-isopropyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-1H-imidazo[4,5-c]pyridine (160 mg, 0.493 mmol) in DMF (1.0 mL) at room temperature under N2 is added Cs2CO3 (168 mg, 0.518 mmol) followed by iodoethane (0.047 mL, 0.592 mmol). The mixture is stirred at room temperature for 1 h and then diluted with water and extracted twice with CH2Cl2. The combined extracts are dried over K2CO3 and concentrated. The residue is purified by preparative TLC, developing with 15:1 CHCl3-MeOH (+0.5% Et3N). The less polar (top) band affords 3-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-3H-imidazo[4,5-c]pyridine. 1H NMR (CDCl3, 300 MHz) δ 8.70 (d, J=1.2 Hz, 1H), 7.83 (d, J=3.0 Hz, 1H), 7.53 (d, J=0.9 Hz, 1H), 7.39 (d, J=3.0 Hz, 1H), 7.18 (d, J=0.9 Hz, 1H), 7.14 (d, J=0.9 Hz, 1H), 6.32 (s, 2H), 4.32 (q, J=7.2 Hz, 2H), 3.18 (sept, J=6.9 Hz, 1H), 1.34 (d, J=6.9 Hz, 6H), 1.17 (t, J=7.2 Hz, 3H) ppm. The more polar (bottom) band affords 74 mg (43%) of 1-ethyl-6-isopropyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-1H-imidazo[4,5-c]pyridine. 1H NMR (CDCl3, 300 MHz) δ 9.01 (s, 1H), 7.83 (d, J=3.2 Hz, 1H), 7.38 (d, J=3.2 Hz, 1H), 7.15 (8, 1H), 7.12 (s, 1H), 7.09 (s, 1H), 6.32 (s, 2H), 4.21 (q, J=7.2 Hz, 2H), 3.17 (sept, J=6.8 Hz, 1H), 1.34 (d, J=6.8 Hz, 6H), 1.10 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)=[O:2].CC[N:21]([CH:25]([CH3:27])C)[CH:22]([CH3:24])C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1CCCC1>CN(C=O)C>[N:21]1([C:11]([C:10]2[CH:9]=[C:8]([CH:16]=[CH:15][CH:14]=2)[O:7][C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:18][CH:17]=2)=[O:13])[CH2:22][CH2:24][CH2:27][CH2:25]1
Reactant: O=Cc1ccc(Oc2cccc(C(=O)O)c2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: O=Cc1ccc(Oc2cccc(C(=O)N3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1 g (4.1 mmol) of 3-(4-formyl-phenoxy)-benzoic acid were dissolved in 25 ml DMF and combined with 0.86 ml (4.95 mmol) of DIPEA and 1.32 g (4.1 mmol) of TBTU, stirred for 5 min at ambient temperature and then 0.29 g (4.1 mmol) of pyrrolidine were added. The mixture was stirred at ambient temperature, filtered through basic Alox, concentrated by rotary evaporation and purified by chromatography (silica gel column, dichloromethane with gradient of 0-10% methanol).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:8](N1C=CN=C1)([N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)(=[O:10])=[O:9].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[N:11]1([S:8]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:10])=[O:9])[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccccc1
Reactant: O=S(=O)(n1ccnc1)n1ccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=S(=O)(Oc1ccccc1)n1ccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.2 %

Procedure:
To a solution of phenol (400 mg, 4.3 mmol) in THF (25 mL) was added 1,1′-sulfonyldiimidazole (1.0 g, 5.1 mmol) and Cs2CO3 (2.8 g, 8.5 mmol). The mixture was stirred at ambient temperature for 16 h. The solvent was removed and the residue was purified by silica gel chromatography to yield the title compound (580 mg, 60%).
Reaction SMILES: [CH:1]1([N:6]2[C:14]([NH:15][C:16]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=3[F:24])=[N:13][C:12]3[C:7]2=[N:8][C:9]([NH:25][C:26]2[CH:27]=[N:28][C:29]([O:32]C)=[CH:30][CH:31]=2)=[N:10][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1>Br.C(O)(=O)C>[CH:1]1([N:6]2[C:14]([NH:15][C:16]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=3[F:24])=[N:13][C:12]3[C:7]2=[N:8][C:9]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[N:28][CH:27]=2)=[N:10][CH:11]=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(Nc2ncc3nc(Nc4c(F)cc(F)cc4F)n(C4CCCC4)c3n2)cn1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(Nc2ncc3nc(Nc4c(F)cc(F)cc4F)n(C4CCCC4)c3n2)cn1
Temperature: 80 °C
Yield: 62.5 %

Procedure:
9-Cyclopentyl-N2-(6-methoxypyridin-3-yl)-N8-(2,4,6-trifluorophenyl)-9H-purine-2,8-diamine (0.350 g, 0.769 mmol) was dissolved in 30% HBr/acetic acid in a sealed tube and heated to 80° C. for 16 hours. Product confirmed by LC-MS. The solution was partitioned between 1.75 M potassium carbonate and ethyl acetate (3×). The organics were combined, dried over magnesium sulfate, filtered and solvent removed under reduced pressure. The resultant solid was purified via preparative HPLC (5-55% acetonitrile/water, 20 mL/min.) to afford the title compound (0.212 g, 34%). ES-MS (m/z) 442 [M+1]+. Melting point 257-260° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH:15]1([C:13]([C:6]2[C:7]([CH3:12])=[N:8][C:9]3[C:4]([C:5]=2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:3][C:2]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:11][CH:10]=3)=[O:14])[CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C1CC1
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccccc2)c1C(=O)C1CC1
Yield: 67 %

Procedure:
The title compound was prepared from [(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-cyclopropyl-methanone [example 55] and morpholine according to the procedure of example 51. Yield: 67%; MS: m/z=373 (M+H).
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[S-:11][C:12]#[N:13].[K+].[I-].[Na+].O>CN(C)C=O>[CH:1]([CH:3]([N:13]=[C:12]=[S:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: N#C[S-]
Reactant: C=CC(Cl)c1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(N=C=S)c1ccccc1
Temperature: 150 °C

Procedure:
Vinylbenzyl isothiocyanate was prepared in the following manner. 76 g (0.5 moles) of vinylbenzyl chloride were dissolved in 300 ml of dimethylformamide (DMF). To this solution were added 56 g (0.575 moles) of potassium thiocyanate and 28 g (0.187 moles) of sodium iodide. The mixture was heated for 30 minutes at 150°C and then the major portion of DMF was flashed off with a water aspirator vacuum. The solid flask residue was extracted with 750 ml of diethyl ether. The filtered diethyl ether phase yielded 80 g of yellowish liquid. Vacuum distillation gave 30 g (35% yield) of pale yellow vinylbenzyl isothiocyanate liquid, ##SPC9##