Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:21][C:22]2[CH:23]=[C:24]([NH:28]C(=O)OC(C)(C)C)[CH:25]=[CH:26][CH:27]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:11]([OH:20])[CH:10]=2)=[N:6][CH:7]=1.C(OCC)(=O)C.CCCCCC>C(Cl)Cl>[NH2:28][C:24]1[CH:23]=[C:22]([NH:21][C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:11]([OH:20])[CH:10]=3)[N:4]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)OC(C)(C)C)c3)n2)cc1O
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)cc1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
To a solution of tert-butyl (3-((5-fluoro-2-((3-hydroxy-4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)carbamate (0.240 g) in DCM (5.0 mL) TFA (2.0 mL) was added at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes followed by stirring at room temperature for 30 minutes. The reaction was monitored by TLC using ethyl acetate:hexane (7:3) as mobile phase. After completion of the reaction, the mixture was quenched in water and basified with saturated sodium bicarbonate solution. Product was extracted into DCM. The organic layer was washed with brine and dried over sodium sulfate and concentrated completely under reduce pressure at 40° C. The obtained solid was purified by trituration with ether to give 0.175 g of 5-((4-((3-aminophenyl)amino)-5-fluoropyrimidin-2-yl)amino)-2-(2-methoxyethoxy)phenol. 1H NMR: DMSO-d6 (400 MHz): 3.282 (s, 3H), 3.617-3.640 (t, 2H, J=4.4), 4.004-4.040 (t, 2H, J=4.4), 4.992 (s, 2H), 6.306-6.316 (d, 1H, J=3.2), 6.772-6.793 (d, 1H, J=8.4), 6.952-7.042 (m, 3H), 7.095 (s, 1H), 7.187 (s, 1H), 8.004-8.013 (d, 1H, J=3.6), 8.811 (s, 1H), 8.861 (s, 1H), 9.001 (s, 1H).
Reaction SMILES: NCCC1C=CC=CN=1.[CH3:10][C:11]([C:14]1[CH:15]=[C:16]([S:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[S:31][CH2:32][C:33]([N:35](C)[CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[O:34])[CH:17]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:19]=1)([CH3:13])[CH3:12]>>[CH3:13][C:11]([C:14]1[CH:15]=[C:16]([S:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[S:31][CH2:32][C:33]([NH:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[O:34])[CH:17]=[C:18]([C:20]([CH3:21])([CH3:22])[CH3:23])[CH:19]=1)([CH3:10])[CH3:12]
Reactant: CN(CCc1ccccn1)C(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Agent: NCCc1ccccn1
Product: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2SCC(=O)NCCc2ccccn2)cc(C(C)(C)C)c1

Procedure:
Substituting 2-(2-aminoethyl)pyridine for the 2-(2-methylaminoethyl)pyridine of Example 16, and following the procedure described therein, gives trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexyl]thio]-N-(2-pyridinylethyl)acetamide.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][C:6]([C:12]([O:14]C)=[O:13])=[CH:7][CH:8]=2)[N:3]1C(OCC)=O.[OH-].[K+]>C(O)C>[CH3:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][C:6]([C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[NH:3]1
Reactant: CCOC(=O)n1c2cc(C(=O)OC)ccc2c(=O)n1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cn1[nH]c2cc(C(=O)O)ccc2c1=O
Temperature: 65 °C
Yield: 55.1 %

Procedure:
To a suspension of 1-ethyl 6-methyl 2-methyl-3-oxo-2,3-dihydro-1H-indazole-1,6-dicarboxylate (formed in Step 3 of Intermediate 28) (514 mg, 1.85 mmol) in ethanol (6 mL) was added 1 N aqueous potassium hydroxide (18.5 mL, 18.5 mmol). The reaction was heated to 65° C. for 1.5 hours. The reaction was cooled to room temperature and concentrated to dryness. The residue was taken up in water and acidified with 1 N aqueous hydrochloric acid until a precipitate formed. The solid was collected by filtration and dried under vacuum to give the title compound (196 mg, 55%) as a brown solid. 1H NMR (400 MHz, DMSO-d6, δ): 13.12 (br. s., 1H), 10.61 (br. s., 1H), 7.76 (s, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.60 (dd, J=8.2, 1.2 Hz, 1H), 3.38 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:17]([OH:19])=[O:18])[CH2:15][OH:16])[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:6]=2[CH:27]=1.[N+](=[CH2:30])=[N-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:17]([O:19][CH3:30])=[O:18])[CH2:15][OH:16])[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:6]=2[CH:27]=1
Reactant: O=C(O)C(CO)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Reactant: C=[N+]=[N-]
Product: COC(=O)C(CO)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 10, a solution of 7-chloro-2-[(1-carboxy-2-hydroxyethylidene)hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-chloro-2-[[1-(methoxycarbonyl)-2-hydroxyethylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: CO[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][N:12]=2)[CH2:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH3:3])[CH2:6][CH2:7]3)=[N:12][NH:13]2)=[CH:18][CH:17]=1
Reactant: COC(=O)N1CCC(c2n[nH]c3cc(Cl)ccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(c2n[nH]c3cc(Cl)ccc23)CC1
Yield: 68.8 %

Procedure:
To a stirred solution, under nitrogen, of 13.0 g of 4-(6-chloro-1H-indazol-3-yl)piperidine-1-carboxylic acid methyl ester in 150 ml of tetrahydrofuran was added, dropwise, 48 ml of a 1M solution of lithium aluminum hydride (0.048 mole) in tetrahydrofuran. The solution was stirred under reflux for 1 hr. The reaction mixture was cooled in an ice-salt bath and water was added slowly. The reaction mixture was filtered, the filter cake washed with tetrahydrofuran and methanol, and the filtrate was concentrated. Recrystallization of the residue from ethanol-water yielded 7.6 g (69%) of product, mp 211°-213° C.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:14]([Br:15])=[CH:13][C:12]([Br:16])=[C:11]([C:17](=[O:19])[NH2:18])[C:10]=1[Br:20])C.[OH-].[Na+]>O>[C:17]([C:11]1[C:10]([Br:20])=[C:9]([C:14]([Br:15])=[CH:13][C:12]=1[Br:16])[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:21])=[O:3])(=[O:19])[NH2:18]
Reactant: CCOC(=O)CCCOc1c(Br)cc(Br)c(C(N)=O)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1c(Br)cc(Br)c(OCCCC(=O)O)c1Br
Reaction time: 3 h

Procedure:
18 g (36.9 mmol) of 4-(3-carbamoyl-2,4,6-tribromophenoxy)butyric acid ethyl ester is suspended in 180 ml of water and, after adding 10 ml of concentrated sodium hydroxide solution, saponified at 60° C. within three hours. The solution is filtered over active carbon and brought to pH 1 by the dropwise addition of concentrated hydrochloric acid. After several hours of agitation in an ice bath, the resultant precipitate is vacuum-filtered, washed with water, and dried at 60° C. Yield: 15 g (88% of theory) of 4-(3-carbamoyl-2,4,6-tribromophenoxy)butyric acid as a white powder, mp 193°-194° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:25][C:24]4[CH:27]=[CH:28][CH:29]=[C:22]([C:21]([F:20])([F:30])[F:31])[CH:23]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-(trifluoromethyl)benzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[4-[[3-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[SH:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH2:19]([S:12][C:8]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:11]=[CH:10][N:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Sc1nccn1-c1ccccn1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(CSc2nccn2-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.3 %

Procedure:
A mixture consisting of 5.1 g of 1-(2-pyridyl)imidazole-2-thiol, 5.2 g of anhydrous potassium carbonate, 3.7 g of benzyl chloride and 50 ml of acetonitrile was stirred at room temperature for 4 hours. After completion of the reaction, solids were filtered off and the filtrate was concentrated under reduced pressure. Crystals precipitated were collected by filtration to give 7.1 g of 2-benzylthio-1-(2-pyridyl)imidazole (m.p.: 76° to 77° C.). To a mixture consisting of 7.1 g of the thus obtained crystals, 50 ml of methylene chloride, 50 ml of water and 22 g of conc. hydrochloric acid was added dropwise 80 g of 6% sodium hypochlorite solution under vigorous stirring at -10° to 0° C. over 1 hour. After completion of the dropwise addition, the resulting mixture was stirred at the same temperature for 30 minutes. Then, the organic layer was separated and the aqueous layer was extracted with methylene chloride. After the organic layers were combined and washed with water, to the organic layer was added dropwise 10 ml of a 28% aqueous ammonia under ice-cooling while vigorous stirring. After completion of the dropwise addition, the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to dryness and the thus obtained concentrated residue was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to give 3.0 g of a crude product of the desired compound. Crystals precipitated from the resulting crude product were collected by filtration to give 0.8 g of the desired compound. m.p.: 187° to 188° C.
Reaction SMILES: [CH3:1][S:2]([C:5]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([NH2:22])[C:6]1[CH:7]=[C:8]([C:12]2[N:13]([CH3:21])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=[N:10][CH:11]=1)(=[O:4])=[O:3].ClS([N:34]=[C:35]=O)(=O)=O.CN(C=O)C>ClCCl>[CH3:1][S:2]([C:5]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([NH2:22])[C:6]1[CH:7]=[C:8]([C:12]2[N:13]([CH3:21])[C:14]3[C:19]([C:20]=2[C:35]#[N:34])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=[N:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Cn1c(-c2cncc(C(N)(C(=O)OC(C)(C)C)S(C)(=O)=O)c2)cc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1c(-c2cncc(C(N)(C(=O)OC(C)(C)C)S(C)(=O)=O)c2)c(C#N)c2ccccc21
Reaction time: 1 h

Procedure:
To a solution of 2-[5-(methanesulfonyl-(tert-butoxycarbonyl)-amino-methyl)-pyridin-3-yl]-1-methyl-indole (350 mg, 0.842 mmol) in dichloromethane (10 mL) is added chlorosulfonyl isocyanate (0.358 g, 2.53 mmol). The mixture is stirred at ambient temperature for 20 min, whereupon anhydrous DMF (2 mL) is added. After 1 h, the mixture is concentrated to a volume of 3 mL, and filtered. Purification by RP HPLC affords 2-[5-(methanesulfonyl-(tert-butoxycarbonyl)-amino-methyl)-pyridin-3-yl]-1-methyl-3-cyano-indole. MS (ESI) m/z 441.1 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]([F:19])([F:18])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH:12]([CH2:16][NH2:17])[CH2:11]2)=[CH:6][CH:5]=1.[CH2:20]([N:22]([CH2:33][C:34](O)=[O:35])[S:23]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH3:21].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:20]([N:22]([S:23]([C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)(=[O:25])=[O:24])[CH2:33][C:34]([NH:17][CH2:16][CH:12]1[O:13][CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:18])[F:19])=[CH:9][CH:8]=2)[CH2:11]1)=[O:35])[CH3:21]
Reactant: NCC1CN(c2ccc(C(F)(F)F)cc2)CCO1
Reactant: CCN(CC(=O)O)S(=O)(=O)c1ccc(F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCN(CC(=O)NCC1CN(c2ccc(C(F)(F)F)cc2)CCO1)S(=O)(=O)c1ccc(F)cc1
Reaction time: 8 h
Yield: 73 %

Procedure:
(4-(4-(Trifluoromethyl)phenyl)morpholin-2-yl)methylamine hydrochloride (99 mg, 0.34 mmol), [ethyl-(4-fluoro-benzenesulfonyl)-amino]-acetic acid (87.2 mg, 0.34 mmol), BOP reagent (148 mg, 0.34 mmol) and TEA (0.2 mL) were combined in 5 mL of dichloromethane. The mixture was stirred overnight and solvents were evaporated. The residue was extracted with ethyl acetate and water. The organic layer was washed with sodium bicarbonate solution and dried. Solvents were evaporated and the residue was purified by ISCO flash column chromatography (11 g silica gel, ethyl acetate in hexanes 0% to 60%) to give the desired compound as a white solid (125 mg, 74%). [MH]+=504.0.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:11]2[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([OH:26])=O)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28].O>C(Cl)(Cl)Cl>[CH2:27]([N:29]([CH2:30][CH3:31])[C:24](=[O:26])[CH2:23][CH2:22][CH2:21][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:20]=1)[CH3:28]
Reactant: CCNCC
Reactant: O=C(O)CCCc1cc(-c2ccccc2)nc2ccccc12
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)CCCc1cc(-c2ccccc2)nc2ccccc12
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (1.02 cc) is added to a solution of 2-phenyl-4-quinolinebutanoic acid (3.7 g) in chloroform (60 cc), and the mixture is heated under reflux for 15 minutes. The solvents are evaporated off under reduced pressure. The residue obtained is dissolved in chloroform (40 cc). Diethylamine (6 cc) is added slowly to this solution in the course of 20 minutes. The mixture is stirred for 3 hours at room temperature (approximately 20° C.) and taken up with water (40 cc). The organic phase is decanted, washed with water (40 cc), dried over magnesium sulphate and evaporated under reduced pressure. The residue is chromatographed on silica gel, using a cyclohexane/ethyl acetate (50:50 by volume) mixture as eluant. N,N-Diethyl-2-phenyl-4-quinolinebutanamide (3.3 g) is thereby obtained, and this is converted to the monohydrochloride in acetone. The hydrochloride melts at 130° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4](I)[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.[Cu]I.O>[Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([N:19]2[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]2)[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1I
Reactant: OC1CCNCC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Solvent: O
Product: COc1c(C(C)=O)cc(Cl)c(C)c1N1CCC(O)CC1
Temperature: 80 °C
Yield: 11 %

Procedure:
To a mixture of 1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone (150 mg, 0.46 mmol) and 4-hydroxypiperidine (56 mg, 0.56 mmol) in isopropyl alcohol (1 mL) was added 1,2-ethanediol (0.052 mL, 0.92 mmol), potassium phosphate (200 mg, 0.93 mmol), and copper(I) iodide (5 mg, 0.02 mmol). The reaction was heated at 80° C. overnight and then cooled to room temperature. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with brine and dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexanes, to give the desired product (15 mg, 11%). LCMS calculated for C15H21ClNO3 (M+H)+: m/z=298.1. found: 298.0.
Reaction SMILES: [CH3:1][CH:2]([SH:5])[CH2:3][CH3:4].[C:6](#[N:9])[CH:7]=[CH2:8].C[O-].[Na+]>>[CH3:1][CH:2]([S:5][CH2:8][CH2:7][C:6]#[N:9])[CH2:3][CH3:4]
Reactant: C=CC#N
Reactant: CCC(C)S
Agent: C[O-]
Agent: [Na+]
Product: CCC(C)SCCC#N

Procedure:
β-(1-Methyl-1-propylmercapto)propionitrile was prepared according to the procedure of Example 1 using 1-methyl-1-propanethiol (25.0 g; 0.28 moles), acrylonitrile (14.9 g; 0.28 moles) and sodium methoxide (0.5 g).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[N:10]([CH2:16][C:17]2([C:20](O)=[O:21])[CH2:19][CH2:18]2)[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[BH4-].[Na+].Cl>O.[Cl-].[Na+].O.C1COCC1>[CH2:1]([N:8]1[CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[N:10]([CH2:16][C:17]2([CH2:20][OH:21])[CH2:18][CH2:19]2)[C:9]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn(Cc2ccccc2)c(=O)n(CC2(C(=O)O)CC2)c1=O
Agent: COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn(Cc2ccccc2)c(=O)n(CC2(CO)CC2)c1=O
Temperature: 0 °C
Yield: 90.6 %

Procedure:
A mixture of 1-(1-benzyl-5-methyl-2,4-dioxo-(1H,3H)-pyrimidin-3-ylmethyl)-1-cyclopropanecarboxylic acid (11 g, 35 mmol), triethylamine (6.46 mL, 45.6 mmol) and THF (138 mL) was cooled to 0° C. under argon and a mixture of methyl chloroformate (3.23 mL, 42 mmol) and THF (20 mL) was added at a rate such that the temperature of the reaction mixture remained at 0° C. The mixture was cooled 30 minutes with stirring at 0° to 2° C. and then filtered (washing through with THF (3×50 mL)). The combined filtrate was cooled to 0° C. under argon and added to a mixture of sodium borohydride (3.29 g, 87 mmol) and water (23.3 mL) at <10° C. The mixture was stirred 2 hours, diluted with water (20 mL), treated with 10% hydrochloric acid, diluted with brine (40 mL) and extracted with ethyl acetate (4×100 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated to dryness. The residue was purified by flash chromatography on silica gel eluting with hexane/ethyl acetate (7:3) to give 1-(1-benzyl-5-methyl-2,4-dioxo-(1H,3H)-pyrimidin-3-ylmethyl)cycloprop-1-ylmethanol (9.52 g, 31.7 mmol), m.p. 81.5° C.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=[O:35])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[O:22])=[CH:16][CH:15]=1.CC(O)=O.C(Cl)Cl>CCCCCCC.CCOC(C)=O.[Zn]>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:23][C:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([S:13][CH2:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5]([OH:35])=[O:4])=[CH:19][CH:18]=2)=[O:22])=[CH:26][CH:27]=1
Reactant: O=C(Cc1ccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)cc1)OCc1ccc(C(F)(F)F)cc1
Agent: [Zn]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(SCc2ccccc2C(=O)O)cc1)OCc1ccc(C(F)(F)F)cc1
Yield: 62.5 %

Procedure:
The titled compound was prepared according to the method described for example 1 above from 2-[4-(4-trifluoromethyl-benzyloxycarbonylmethyl)phenylsulfanylmethyl]-benzoic acid 2,2,2-trichloro-ethyl ester (74 mg, 0.125 mmol), zinc (164 mg, 2.50 mmol), HOAc, 97% (0.72 mL, 12.5 mmol) and DCM (5 mL). The crude was submitted to flash chromatography using heptane and EtOAc (70/30-60/40) as eluent to give the titled compound (36 mg, 63%) as a solid; 1H NMR (400 MHz, CDCl3): δ 3.64 (s, 2H), 4.54 (s, 2H), 5.18 (s, 2H), 7.16 (d, 2H), 7.23-7.29 (m, 3H), 7.29-7.35 (m, 3H), 7.37-7.43 (m, 3H), 7.60 (d, 2H), 8.03 (d, 1H); Mass spectrum: M−H+ 459.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10](O)[N:11]=2)[N:8]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:10]1[N:11]=[C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[N:8][N:7]2[CH:9]=1
Reactant: Oc1cn2nc(Cl)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na]
Product: Clc1cn2nc(Cl)ccc2n1

Procedure:
Sodium salt of 6-chloro-2-hydroxyimidazo [1,2-b]pyridazine (16.0 g) is gradually added to 100 ml of phosphorus oxychloride and heated under reflux for 5 hours. The mixture is distilled under reduced pressure to remove about two-thirds amount of phosphorus oxychloride used, and the residue is poured into ice water, neutralized with aqueous ammonia and extracted with chloroform. The extract is dried over anydrous sodium sulfate and distilled to remove chloroform. The residue then is purified by silica gel chromatography (eluent: dichloromethane) to give 1.5 g of the title compound as crystals.
Reaction SMILES: [CH3:1]OC(=O)C1C=C([N+]([O-])=O)C(OC)=C([N+]([O-])=O)C=1.[OH:19][C:20]1[C:28]([I:29])=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=1[I:30]>>[OH:19][C:20]1[C:21]([I:30])=[CH:22][C:23]([C:24]([O:26][CH3:1])=[O:25])=[CH:27][C:28]=1[I:29]
Reactant: O=C(O)c1cc(I)c(O)c(I)c1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(OC)c([N+](=O)[O-])c1
Product: COC(=O)c1cc(I)c(O)c(I)c1

Procedure:
Methyl 4-hydroxy-3,5-diiodobenzoate (D254) was prepared in an analogous manner to Description 25 (D25) from commercially available 4-hydroxy-3,5-diiodobenzoic acid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:22])[C:12]=2[N:11]=[CH:10]1)(=O)C.N>CO>[OH:4][CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:22])[C:12]=2[N:11]=[CH:10]1
Reactant: CC(=O)OCCOCn1cnc2c(N)nc3ccccc3c21
Agent: N
Solvent: CO
Product: Nc1nc2ccccc2c2c1ncn2COCCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 2.1 g portion of 1-[(2-acetoxyethoxy)-methyl]-1H-imidazo[4,5-c]quinolin-4-amine was combined with 25 mL of 15% ammonia in methanol and stirred at room temperature for about 16 hours. The resulting precipitate was collected, rinsed with ether and dried to provide 1.1 g of a solid. This solid was recrystallized from 50 mL of ethanol to provide 0.8 g of 1-[(2-hydroxyethoxy)]methyl-1H-imidazo[4,5c]quinolin-4-amine as a yellow crystalline solid, m.p. 210°-212° C. Analysis: Calculated for C13H14N4O2 : % C, 60.4; % H, 5.5; % N, 21.7; Found: % C, 60.3; % H, 5.5; % N, 21.5.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH3:27])[C:15]=3[N:14]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[CH2:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=1)=[O:31].C([O-])(=O)C>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[N:17]([CH2:29][C:30](=[O:31])[NH:32][C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=3)[C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][CH2:24][O:25][CH2:26][CH3:27])[C:15]=3[N:14]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCOCCOc1cccc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)nc12
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Agent: CC(=O)[O-]
Product: CCOCCOc1cccc2c1nc(C(=O)NC1CCN(C(C)C)CC1)n2CC(=O)Nc1ccc(Cl)cn1

Procedure:
1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(2-ethoxy-ethoxy)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 108 (v) starting from 540.0 mg (1.44 mmol) 4-(2-Ethoxy-ethoxy)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide and 359.8 mg (1.44 mmol) 2-bromo-N-(5-chloro-pyridin-2-yl)-acetamide. The title compound was transformed into its acetate affording a colorless amorphous material.