Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:22])[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][N:12]2[CH2:15][CH3:16])=[CH:7][C:6]=1[F:23])=O.[C:24]([NH:27][CH2:28][C:29]([NH2:31])=[S:30])(=[O:26])[CH3:25].C(N(CC)CC)C>CN(C)C=O>[C:24]([NH:27][CH2:28][C:29]1[S:30][CH:2]=[C:3]([C:5]2[CH:14]=[C:13]3[C:8]([C:9](=[O:22])[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][N:12]3[CH2:15][CH3:16])=[CH:7][C:6]=2[F:23])[N:31]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)NCC(N)=S
Reactant: CCOC(=O)c1cn(CC)c2cc(C(=O)CBr)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2cc(-c3csc(CNC(C)=O)n3)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 57.6 %

Procedure:
A suspension of 0.59 g (1.54 mmol) ethyl 7-bromoacetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 4 ml N,N-dimethylformamide was treated with 0.22 g (1.67 mmol) acetamidothioacetamide [prepared according to J. Am. Chem. Soc. 51, 1817 (1929)]. After stirring three hours the mixture was treated with 0.22 ml (1.58 mmol) triethylamine, stirred one hour more and poured into 40 ml ice water. The precipitate was filtered, washed with water and dried to afford 0.45 g crude solid. Chromatography on a column of 20 g silica gel with chloroform-methanol (9:1) and crystallization from ethanol gave 0.37 g ethyl 7-[2(acetamidomethyl)-4-thiazolyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, mp 230°-233° C. (dec).
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:20][CH2:19][N:18](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]>C(Cl)Cl>[C:1]([C:3]([C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)N2CC[C@H](C(C#N)(c3ccccc3)c3ccccc3)C2)cc1
Solvent: ClCCl
Product: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCNC1

Procedure:
A similar procedure starting with 3-(R)-(-)-(1-cyano-1,1-diphenylmethyl)-1-tosylpyrrolidine (19.5 g-see Preparation 6(C)), gave 3-(R)-(-)-(1-cyano-1,1-diphenylmethyl)pyrrolidine, yield 9.5 g, [α]D25 -9.8° (c 1.0, CH2Cl2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[N:15]=[CH:16][NH:17][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([I:25])C(=O)C1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2[N:17]=[C:16]([I:25])[NH:15][C:12]=2[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nc[nH]c2CC1
Reactant: O=C1CCC(=O)N1I
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2nc(I)[nH]c2CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
To a solution of 4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepine-6-carboxylic acid tert-butyl ester (Preparation 27, 4.8 g, 20.23 mmol) in THF (60 mL) was added NIS (4.78 g, 21.24 mmol). The reaction was stirred at room temperature for 18 hours and the solvent was then removed in vacuo. The residue was dissolved in EtOAc (200 mL) and the resulting solution was washed with sodium thiosulfate solution (150 mL). The aqueous layer was re-extracted with EtOAc (150 mL) and the combined organic layers were washed with brine (150 mL), dried over MgSO4 and concentrated in vacuo to give the title compound as a tan solid (6.14 g) in an 84% yield.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH2:10][OH:11])[CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3].[CH2:12]([O:15][C:16]1([CH3:45])[CH2:21][CH2:20][N:19]([C:22]2[N:27]3[N:28]=[C:29]([CH2:31]I)[CH:30]=[C:26]3[N:25]=[C:24]([CH3:33])[C:23]=2[C@H:34]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:18][CH2:17]1)[CH:13]=[CH2:14].[H-].[Na+]>CN(C=O)C.O>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][O:11][CH2:31][C:29]1[CH:30]=[C:26]2[N:25]=[C:24]([CH3:33])[C:23]([C@H:34]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:22]([N:19]3[CH2:20][CH2:21][C:16]([O:15][CH2:12][CH:13]=[CH2:14])([CH3:45])[CH2:17][CH2:18]3)[N:27]2[N:28]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CCc1cccc(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4cccc(CC=C)c4)nn23)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
To a mixture of (3-allylphenyl)methanol (33.0 mg, 0.222 mmol) in DMF (3 mL) at 0° C. was added (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (130 mg, 0.222 mmol) and NaH (8.90 mg, 0.222 mmol). The reaction mixture was stirred at 0° C. for 2 h. It was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 25% EtOAc/hexane to obtain (S)-ethyl 2-(2-(((3-allylbenzyl)oxy)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (50 mg, 0.083 mmol, 37.2% yield) as an oil. LCMS (M+1)=605.4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1.I[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:6]([O:11][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(O)c1
Reactant: CCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCOc1ccc(C(=O)OC)cc1OCCCCCCC
Yield: 198.2 %

Procedure:
A mixture of 25 g of product from Example 102, 72.3 g of 1-iodoheptane, 61.65 g of potassium carbonate and 500 ml of 2-butanone is heated at reflux temperature for 44 hours. The cooled reaction mixture is filtered and concentrated in vacuo. The oily residue is purified by chromatography (silica gel: 10% ethyl acetate/hexane) to give 53.7 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:12]([NH:23][C:24]([N:26]2[CH2:35][CH2:34][C:33]3[CH:32]=[N:31][C:30]([NH:36][CH:37]([CH3:39])[CH3:38])=[N:29][C:28]=3[CH2:27]2)=[O:25])[CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:15][CH2:14][CH2:13][C@@H:12]([NH:23][C:24]([N:26]1[CH2:35][CH2:34][C:33]2[CH:32]=[N:31][C:30]([NH:36][CH:37]([CH3:39])[CH3:38])=[N:29][C:28]=2[CH2:27]1)=[O:25])[C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:10])([F:9])[F:11])=[C:2]([F:1])[CH:3]=1
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@H](CCNC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)c(F)c1)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@H](CCN)c1ccc(C(F)(F)F)c(F)c1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution 292 (0.090 g, 0.16 mmol) and DCM (3 mL) at RT was added TFA (1 mL) and the reaction was stirred at RT for 1 h and then concentrated to dryness. The resulting product was next dissolved in minimal DCM (using MeOH to aid solubility) and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to afford 0.060 g (75%) of I-72: MS m/z (APCI-pos) M+1=455.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH:7]=[CH2:8])[CH2:5][OH:6].[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12]Br.[Cl-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12][O:6][CH2:5][CH:4]([CH3:3])[CH:7]=[CH2:8]
Reactant: C=CC(C)CO
Reactant: COC(CBr)OC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CC(C)COCC(OC)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60 wt %, 928 mg) was added to a solution of 2-methyl-3-buten-1-ol (2 g) in DMF (30 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Bromoacetaldehyde dimethyl acetal (5.45 mL) was added dropwise to the reaction solution at the same temperature. The reaction solution was stirred for 16 hours with gradual heating to room temperature. Ethyl acetate and aqueous sodium chloride were added to the reaction solution, and the organic layer was separated. The same operation was performed on the same scale. The combined organic layers were washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (4.92 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][C:10]([F:9])([F:20])[F:21])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)Oc1ccc(CCl)cc1
Reactant: Cc1ccc(S)cc1
Product: Cc1ccc(SCc2ccc(OC(F)(F)F)cc2)cc1
Yield: 80.1 %

Procedure:
The procedure of Example 87 is repeated using 11.8 g of p-thiocresol and 9.6 g of 4-(trifluoromethoxy)benzyl chloride. This affords 10.9 g of the desired product as white crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[C:6]([N:14]=[C:15]=[S:16])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:15]([NH:14][C:6](=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[S:16]
Reactant: COCCN
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: COCCNC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
2-Methoxyethylamine (17.7 mL, 202.2 mmol) was added dropwise over 30 minutes to a stirring solution of benzoylisothiocyanate (30.00 g, 183.8 mmol) in CH2Cl2 (300 mL) at room temperature under argon and the mixture was stirred at room temperature for 16 hours. The mixture was washed sequentially with 10% aqueous citric acid (75 mL), water (75 mL) and brine (75 mL), dried over MgSO4 and concentrated in vacuo. The resulting yellow oil solidified on standing to give the title compound (41.85 g, 96%). The material was used directly in the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][NH2:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(Cl)(Cl)Cl>[O:27]=[C:21]([NH:12][NH:11][C:9](=[O:10])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NNC(=O)CCc1ccccc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=O)NNC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The 3-phenylpropionic acid hydrazide mixture (499 mg) obtained in Production Example 22-1 was dissolved in chloroform (30 mL), and triethylamine (0.86 mL) and ethyl chloroglyoxalate (0.4 mL) were added thereto, and stirred at room temperature for 5 hours. After the reaction, the reaction liquid was entirely concentrated, and the resulting residue was purified through silica gel column chromatography (chloroform/methanol=94/6) to obtain the entitled compound (760 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC>[C:12]([NH:20][C:21]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(N)c(C(N)=O)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCOCC
Product: Cc1ccc(NC(=S)NC(=O)c2ccccc2)c(C(N)=O)c1
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a stirred mixture of 4.5 g of 2-amino-5-methylbenzamide and 200 ml of ether was added dropwise, a solution of 4.9 g benzoyl isothiocyanate in 100 ml of ether over 20 minutes. After stirring overnight, the solid was collected, giving 8.7 g of the desired product as white crystals, mp 198°-201° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:9]([CH3:11])=[N:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=3)=[N:6][C:5]=2[S:4][C:3]=1[C:22]([NH2:24])=[O:23].[O:25]=[C:26](Cl)OC(Cl)(Cl)Cl.O>O1CCOCC1>[CH3:11][C:9]1[C:10]2[C:2]3[NH:1][C:26](=[O:25])[NH:24][C:22](=[O:23])[C:3]=3[S:4][C:5]=2[N:6]=[C:7]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=2)[N:8]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1nc(-c2ccc(OC(C)C)cc2)nc2sc(C(N)=O)c(N)c12
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc(OC(C)C)cc2)nc2sc3c(=O)[nH]c(=O)[nH]c3c12
Temperature: 25 °C
Yield: 72.4 %

Procedure:
1.0 g (3 mmol) 5-amino-4-methyl-2-(4-iso-propoxy-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide was suspended in 200 ml dioxane, and following the addition of 0.73 ml (6 mmol) diphosgene the suspension is refluxed for 2 h. Having cooled down to room temperature, 20 ml water was carefully added and the precipitate was subsequently sucked off. 0.8 g (68%) 9-methyl-7-(4-iso-propoxy-phenyl)-thieno[2,3-d:4,5-d′]-dipyrimidine-2,4(1H,3H)-dione is obtained.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7](Cl)[C:6]([F:10])=[CH:5][N:4]=1.[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([O:18][C:3]1[N:8]=[C:7]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]([F:10])=[CH:5][N:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: OCc1ccccc1
Agent: [Na]
Solvent: Cc1ccccc1
Product: Fc1cnc(OCc2ccccc2)nc1OCc1ccccc1
Yield: 87.1 %

Procedure:
A 5.8 g quantity of metal sodium is dissolved in a mixture of 100 ml of benzyl alcohol and 200 ml of toluene, 16.7 g of 2,4-dichloro-5-fluoropyrimidine is added to the solution, and the mixture is refluxed for 4 hours. The resulting reaction mixture is washed with water, dried and distilled at reduced pressure to give 27.0 g of colorless oily 2,4-di(benzyloxy)-5-fluoropyrimidine in a yield of 87.1%, b.p. 205°-206° C/3-4 mm Hg and m.p. 48.5°-49.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@H:4]([CH:5]=O)[C@H:3]1[C:7]([O:9][CH3:10])=[O:8].[Br-].[O:13]=[C:14]([CH3:35])[CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClC(Cl)C>[CH3:1][C:2]1([CH3:11])[C@H:4](/[CH:5]=[CH:15]/[C:14](=[O:13])[CH3:35])[C@H:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)[C@@H]1[C@@H](C=O)C1(C)C
Reactant: CC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CC(Cl)Cl
Product: COC(=O)[C@@H]1[C@@H](/C=C/C(C)=O)C1(C)C
Yield: 80.3 %

Procedure:
A mixture of 5 g of methyl (1R,trans) 2,2-dimethyl-3-formyl-cyclopropane-1-carboxylate, 11.3 g of 2-oxopropyl-triphenylphosphonium bromide and 50 ml of dichloroethane was refluxed for 2 hours and the temperature was allowed to return to room temperature. The mixture was evaporated to dryness under reduced pressure and the 19 g of oil residue were empasted with ether and filtered. The filtrate was evaporated to dryness and the 5 g of oil residue were chromatographed over silica gel. Elution with a 7-3 cyclohexane-ethyl acetate mixture yielded 4.46 g of methyl (1R,trans) 2,2-dimethyl-3-[(E)-3-oxo-1-butenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+108°±2.5° (c=0.6% in benzene).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].N1C=CN=C1>CN(C=O)C.[NH4+].[Cl-].C(Cl)Cl>[C:10]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([CH2:7][CH2:8][O:9][Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20])[N:5]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)c1cc(N)n(CCO)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(N)n(CCO[Si](C)(C)C(C)(C)C)n1
Reaction time: 6 h
Yield: 70.8 %

Procedure:
A solution of Intermediate 10a (1.00 g, 5.46 mmol), tert-butyl-dimethyl-chlorosilane (823 mg. 5.46 mmol), and imidazole (774 mg, 11.38 mmol) in DMF (9 mL) was stirred at RT under a nitrogen atmosphere for 18 h. Additional tert-butyl-dimethyl-chlorosilane (823 mg. 5.46 mmol) and imidazole (774 mg, 11.38 mmol) were added to the reaction mixture and stirred for 6 h. The reaction mixture was diluted with NH4Cl saturated aqueous solution (10 mL) and DCM (10 mL). The layers were separated and aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and purified by FCC, using 0-50% EtOAc in cyclohexane, to give the title compound (1.15 g, 70%). LCMS (Method 3): Rt 3.06, 3.23 min, m/z 298 [MH+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[C:24]([Cl:25])=[C:23]([CH3:26])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl>[Cl:15][C:16]1[C:24]([Cl:25])=[C:23]([CH3:26])[CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: O=C1CNCCN1
Reactant: Cc1ccc(C(=O)Cl)c(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CCNC(=O)C2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-piperazinone (1 g, 9.99 mmol, commercially available from e.g. Sigma-Aldrich) and triethylamine (2.78 mL, 19.98 mmol) were dissolved in Dichloromethane (DCM) (25 mL) at 0° C. 2,3-dichloro-4-methylbenzoyl chloride (I71) (2.232 g, 9.99 mmol) dissolved in Dichloromethane (DCM) (25 mL) was added dropwise and the solution stirred to room temperature overnight. Solvents were removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate solution (25 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water (2×50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated to a crude solid. A 100 mg sample was purified by MDAP to afford product in 69 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[NH:9][C:10](=[O:12])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:13]([C:6]1[C:7]2[S:11][C:10](=[O:12])[NH:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: COc1cccc2sc(=O)[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(C)=O)c2sc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-methoxy-1,3-benzothiazol-2(3H)-one (DE 3017977 A1) (1.92 g) in dry dichloromethane (50 ml) was cooled to ˜5° C. under nitrogen. Acetyl chloride (1.43 ml) and aluminium chloride (3.43 g) were added in one portion, and stirred for 2 h at RT. The reaction was quenched carefully with water, followed by addition of 2N HCl and dichloromethane. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with brine and dried (Na2SO4) and evaporated in vacuo to give the title compound (1.92 g). LCMS RT=2.50 min
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15](O)=[O:16])[C:9]2=[O:18])=[CH:4][CH:3]=1.[N:26]1([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([N:29]3[CH2:30][CH2:31][N:26]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:27][CH2:28]3)=[O:16])[C:9]2=[O:18])=[CH:4][CH:3]=1
Reactant: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid (0.34 g, 1.0 mmol, Example 23D) in CH2Cl2 (15 mL) was added benzyl piperazine-1-carboxylate (0.22 g, 1.0 mmol) under nitrogen. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.38 g, 2.0 mmol) and 4-(dimethylamino)pyridine (0.012 g, 0.1 mmol) were added to the reaction, and the mixture was stirred overnight at room temperature. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography on silica gel (Analogix Intelliflash 280; CH3OH/CH2Cl2, 2:98 eluant) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.39-7.31 (m, 5H), 7.30-7.21 (m, 4H), 6.97 (dd, J=9.7, 7.7, 4H), 5.15 (s, 2H), 4.19 (s, 2H), 3.70-3.59 (m, 2H), 3.58-3.37 (m, 8H), 2.64-2.52 (m, 2H), 1.90-1.76 (m, 2H); MS (DCI +) m/z 565 (M+MH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-])=O)[C:3]=1[OH:15].[H][H]>[Pd].C(OCC)(=O)C>[NH2:12][C:4]1[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:15]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc(Cl)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(C(F)(F)F)cc(Cl)c1O

Procedure:
A mixture of 5.01 g of a mixture containing 2-chloro-4-(trifluoromethyl)-6-nitrophenol, 15 ml of ethyl acetate and 1.0 g of 5% palladium on carbon was stirred under about one atmosphere of hydrogen at room temperature for 15 hours. The mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2.78 g of 2-amino-6-chloro-4-(trifluoromethyl)phenol.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[CH2:29]1[CH2:34][O:33][CH:32]=[CH:31][CH2:30]1>ClCCl>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH:32]2[CH2:31][CH2:30][CH2:29][CH2:34][O:33]2)[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5]
Reactant: C1=COCCC1
Reactant: O=Cc1c(O)cc(O)cc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1c(O)cc(OC2CCCCO2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a mixture of 2-fluoro-4,6-dihydroxybenzaldehyde (3.12 g, 20.0 mmol) and PPTS (0.51 g, 2.0 mmol) in dichloromethane (100 mL) was added dropwise DHP (3.02 g, 36.0 mmol). The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc/PE=1/15) on silica gel to give the title compounds as a colorless oil (3.99 g, Yield: 83.2%). MS (ESI) m/z=241 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[CH:14][N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[CH2:16]([N:15]1[C:5]2[C:4]3[CH:3]=[C:2]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=[CH:14]1)[CH:17]([CH3:19])[CH3:18]
Reactant: OB(O)c1cccnc1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(Br)cc3c21
Product: CC(C)Cn1cnc2c(N)nc3ccc(-c4cccnc4)cc3c21

Procedure:
8-Bromo-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and pyridine-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Purification by chromatography on silica gel (7%–10% methanol in CH2Cl2 gradient) afforded 1-isobutyl-8-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 244–246° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH3:22]>>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][S:9][C:4]1[N:5]=[C:6]([NH2:22])[CH:7]=[C:2]([Cl:1])[N:3]=1)[CH3:15]
Reactant: N
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)CSc1nc(N)cc(Cl)n1

Procedure:
A mixture of 10.7 g of (4,6-dichloro-2-pyrimidinylthio) acetic acid, ethyl ester and 4.2 g of sodium carbonate in 150 ml. of saturated ethanolic ammonia solution was stirred at room temperature for 1 week. The reaction mixture was filtered and petroleum ether was added to the filtrate until a precipitate was formed. The precipitate was recrystallized from petroleum ether-ethanol to give 1.2 g of product, mp. 113°-116°C.