Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:31]=[CH:30][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:23])=[C:15]([CH:20]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].[N+:32]([O-])([O-:34])=[O:33].[K+]>FC(F)(F)C(O)=O>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:12]=[C:13]([N+:32]([O-:34])=[O:33])[C:14]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[O:23])=[C:15]([CH:20]=2)[C:16]([O:18][CH3:19])=[O:17])=[CH:30][CH:31]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(Oc2ccc(NC(=O)c3ccccn3)c(C(=O)OC)c2)cc1
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)c1ccc(Oc2cc(C(=O)OC)c(NC(=O)c3ccccn3)c([N+](=O)[O-])c2)cc1
Temperature: 80 °C
Yield: 88.8 %

Procedure:
1.9 g of methyl 5-[4-(ethylsulfonyl)phenoxy]-2-[(2-pyridinylcarbonyl)amino]benzoate was dissolved in 20 ml of trifluoroacetic acid, and 2.2 g of potassium nitrate was added to it and stirred under heat at 80° C. for 2 hours. The reaction liquid was restored to room temperature, trifluoroacetic acid was evaporated away under reduced pressure, the residue was dissolved in chloroform, and aqueous saturated sodium hydrogencarbonate solution was added to it. This was extracted with chloroform, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=2/1 to 1/1) to obtain 1.86 g of the entitled compound as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[CH:2].[C:13](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:22]1[CH:29]=[CH:28][C:25]([O:26][CH3:27])=[CH:24][CH:23]=1)[C:14]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:27][O:26][C:25]1[CH:24]=[CH:23][C:22]([C:13]([C:14]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[CH:20][CH:21]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:12][S:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[CH:2])=[CH:8][CH:7]=2)(=[O:10])=[O:11])=[CH:29][CH:28]=1
Reactant: C#Cc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: C#Cc1ccc(S(=O)(=O)NC(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a stirring slurry of 4-ethynylbenzenesulfonamide (1.81 g, 10.0 mmol) and DMTr-Cl (4.07 g, 12.0 mmol) in DCM (100 mL) was added TEA (2.8 mL). The resulting solution was allowed to stir at room temperature for overnight. Silica gel (3 g) was added to the solution followed by rotary evaporation of solvent in vacuo. The sample was absorbed onto silica gel was then loaded onto a pre-equilibrated column (with 10% TEA in hexane). Flash chromatography using 0-30% EtOAc in hexane as the gradient eluents gave the product 5 as a yellow solid (4.8 g, 99%).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[NH2:12][C@@H:13]1[C:49]([CH3:51])([CH3:50])[C@H:48]2[C@@:16]3([O:44][C:20]4[C:21]5[CH2:22][N:23]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:24](=[O:36])[C:25]=5[CH:26]=[C:27]([O:28][CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:19]=4[CH2:18][C@:17]3([CH3:53])[C@@H:45]([CH3:52])[CH2:46][CH2:47]2)[CH2:15][CH2:14]1>ClCCl>[C:8]([NH:12][C@@H:13]1[C:49]([CH3:51])([CH3:50])[C@H:48]2[C@@:16]3([O:44][C:20]4[C:21]5[CH2:22][N:23]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:24](=[O:36])[C:25]=5[CH:26]=[C:27]([O:28][CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:19]=4[CH2:18][C@:17]3([CH3:53])[C@@H:45]([CH3:52])[CH2:46][CH2:47]2)[CH2:15][CH2:14]1)(=[O:10])[CH3:9]
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](N)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1CC[C@@]23Oc4c(c(OCc5ccccc5)cc5c4CN(C(=O)OC(C)(C)C)C5=O)C[C@]2(C)[C@@H](C)CC[C@H]3C1(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 82 %

Procedure:
Under nitrogen, 25 μl (0.18 mmol) of triethylamine and 8 μl (0.11 mmol) of acetyl chloride was added to a solution of Compound (45a) (50 mg, 0.087 mmol) in 2.0 ml of dry dichloromethane under ice-cooling, and the mixture stirred for 40 min at the same temperature. After addition of ice-water, the reaction was extracted with ethyl acetate. The extract was washed with aqueous saturated sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a preparative thin layer chromatography (Merck, Kieselgel 60 F254, 0.5 mm; chloroform:methanol=30:1) to give 44 mg (82%) of Compound (45b).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH:18]=O)[CH2:13]1>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:18]([CH:14]1[CH2:15][CH2:16][CH2:17][O:12][CH2:13]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=CC1CCCOC1
Solvent: CCO
Solvent: O
Product: O=C1CC(C2CCCOC2)Oc2ccc(Br)cc21
Yield: 17.7 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxyphenyl)ethanone (39 g, 181.8 mmol), tetrahydro-2H-pyran-3-carbaldehyde (20 g, 181.8 mmol) and borax (69.3 g, 181.8 mmol) in ethanol (240 mL) and H2O (400 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 6-bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-one (10 g, 20%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]=O)=[CH:11][N:10]=[C:9]2[S:15]([CH2:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=2[F:26])=[O:16])=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH:32]=[C:31]([CH2:33][NH:34][CH3:35])[C:30]([CH3:36])=[N:29]1.C([BH3-])#N.[Na+]>CN(C=O)C.C(O)(=O)C>[CH3:27][N:28]1[CH:32]=[C:31]([CH2:33][N:34]([CH2:13][C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:9]([S:15]([CH2:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=3[F:26])=[O:16])=[N:10][CH:11]=2)[CH3:35])[C:30]([CH3:36])=[N:29]1
Reactant: O=Cc1cnc(S(=O)Cc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reactant: CNCc1cn(C)nc1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1nn(C)cc1CN(C)Cc1cnc(S(=O)Cc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
A solution of 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)sulfinyl)-1H-imidazole-5-carbaldehyde (33) (39 mg, 0.10 mmol), 1-(1,3-dimethyl-1H-pyrazol-4-yl)-N-methylmethanamine (15 mg, 0.11 mmol), sodium cyanoborohydride (30 mg, 0.11 mmol) and DMF/acetic acid (10/1, 1 mL) was stirred at room temperature overnight. The reaction mixture was directly loaded on to reverse phase preparative HPLC column and purified to yield 1-(1,3-dimethyl-1H-pyrazol-4-yl)-N-((1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)sulfinyl)-1H-imidazol-5-yl)methyl)-N-methylmethanamine (501). 1H NMR (400 MHz, CDCl3) δ: 7.63 (s, 1H), 7.52 (s, 1H), 7.45-7.36 (m, 1H), 7.24-7.09 (m, 4H), 6.90-6.85 (m, 1H), 4.87 (d, J=13.0, 1H), 4.58 (d, J=13.0, 1H), 4.27 (d, J=14.5, 1H), 4.11 (s, 1H), 3.99 (d, J=13.2, 1H), 3.90-3.79 (m, 4H), 2.57 (s, 3H), 2.18 (s, 3H). LC-MS ESI m/z; found 506.2 [M+H]+.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[C:3]([O:5]C)=[O:4].C(=O)([O-])[O-:18].[Na+].[Na+].Cl.[Cl-].[Na+]>O>[OH:18][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)CCCCCCC(Br)C(=O)OC
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCCCCC(O)C(=O)O

Procedure:
A stirred mixture of 295 g. of dimethyl 2-bromononanedioate, [Acta. Chim. Acad. Sci. Hung., 46, 85 (1965)], 371 g. of anhydrous sodium carbonate, and 3 liters of water is heated at reflux for 22 hours. The solution which forms is cooled and acidified with 600 ml. of 12 N hydrochloric acid. The mixture is saturated with sodium chloride and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give 184 g. of white solid, m.p. 86°-92° C.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][C:7](=[O:9])[CH:6]([C:10](=[O:13])[CH2:11][CH3:12])[C:5](=[O:14])[CH2:4]1)=O.[NH2:15]OS(O)(=O)=O>O>[O:14]=[C:5]1[CH:6]([C:10](=[O:13])[CH2:11][CH3:12])[C:7](=[O:9])[CH2:8][CH:3]([C:1]#[N:15])[CH2:4]1
Reactant: CCC(=O)C1C(=O)CC(C=O)CC1=O
Reactant: NOS(=O)(=O)O
Solvent: O
Product: CCC(=O)C1C(=O)CC(C#N)CC1=O
Reaction time: 8 h
Yield: 77 %

Procedure:
30.7 g (0.16 mol) of 5-formyl-2-propionylcyclohexane-1,3-dione in 150 ml of distilled water were initially taken, and 21.0 g (0.19 mol) of hydroxylamine-O-sulfonic acid were added at room temperature. Stirring was then carried out overnight at room temperature. The precipitate was filtered off under suction, washed with water and dried. 23.8 g (71% of theory) of 3,5-dioxo-4-propionylcyclohexanenitrile of melting point 70-74° C. were obtained.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][C:9]1=[CH2:10].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:7][C:1]1[CH:6]=[CH:5][C:4]([C:12]([CH2:11][C:9](=[CH2:10])[C:8]([OH:15])=[O:14])=[O:13])=[CH:3][CH:2]=1
Reactant: C=C1CC(=O)OC1=O
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=C(CC(=O)c1ccc(C)cc1)C(=O)O
Yield: 52.9 %

Procedure:
In 150 ml of methylene chloride were dissolved 35.0 g of toluene and 22.4 g of itaconic anhydride. To this was added gradually 50.0 g of anhydrous aluminum chloride under ice-cooling with stirring, and then the mixture was stirred at room temperature for 5 hours for proceeding the reaction. After completion of the reaction, the reaction solution was concentrated under reduced pressure, poured into a mixture of 40 ml of conc. hydrochloric acid and 500 g of ice, and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solvent was evaporated and the residue was recrystallized from a mixture of hexane and ethyl acetate to give 21.6 g of 3-(4-methylbenzoyl)-2-methylenepropionic acid (a compound of formula II wherein X is CH3 and Y is H) (yield: 53%)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:30]=[CH:29][C:8]([O:9][CH:10]([CH3:28])[C:11](=[O:27])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:16][CH:15]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:38][S:39]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:28])[C:11](=[O:27])[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])=[CH:18][CH:19]=2)=[CH:29][CH:30]=1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: CC(Oc1ccc(CCCO)cc1)C(=O)COc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(CCCOS(C)(=O)=O)cc1)C(=O)COc1ccc(C(=O)OC(C)(C)C)cc1
Reaction time: 0.75 h
Yield: 83.1 %

Procedure:
A solution of (3R and 3S)-3-[4-(3-hydroxypropyl)phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone (0.092 g, 0.22 mmol) in dry dichloromethane (5 ml) was cooled to 0° C. and treated with triethylamine (0.07 ml, 0.5 mmol) followed by methanesulfonyl chloride (0.03 ml, 0.39 mmol). After 45 minutes at 0° C., the reaction mixture was quenched by addition of ethyl acetate (100 ml) and water. The organic phase was washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation and chromatography of the residue on silica gel (elution toluene and ethyl acetate, 9:1) gave 0.090 g (82%) of the title material as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([C:24]1[CH:50]=[CH:49][C:27]([C:28]([NH:30][C:31]2[CH:47]=[C:46]([NH2:48])[CH:45]=[CH:44][C:32]=2[C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[O:34])=[O:29])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].C1(N=C=NC2CCCCC2)CCCCC1.C1C=NC2N(O)N=NC=2C=1>CN(C)C=O>[C:20]([C:24]1[CH:50]=[CH:49][C:27]([C:28]([NH:30][C:31]2[CH:47]=[C:46]([NH:48][C:17](=[O:19])[C@H:9]([CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:45]=[CH:44][C:32]=2[C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[O:34])=[O:29])=[CH:26][CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COc1ccc(NC(=O)c2ccc(N)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2ccc(NC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-L-phenylalanine (130 mg, 0.49 mmol) in N,N-dimethylformamide (5 mL) cooled to 0° C. was added 2-(4-tert-butylbenzoylamino)-4-amino-N-(4-methoxyphenyl)benzamide (240 mg, 0.49 mmol), dicyclohexylcarbodiimide (112 mg, 0.54 mmol), and 7-aza-1-hydroxybenzotriazole (71 mg, 0.52 mmol). After stirring for 1 h, the reaction mixture was allowed to warm to room temperature. After 12 h, the mixture was filtered and the filtrate diluted with ethyl acetate. The solution was washed with 1 N aqueous sodium carbonate solution, 1.5 N aqueous citric acid solution, and water. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, 10% ethyl acetate/90% methylene chloride) to give 195 mg (60%) of the title compound.
Reaction SMILES: C(N1CCOCC1)C.ClC1C=C(Cl)C(Cl)=CC=1O[C:19](=[O:26])[C@@H:20]1[CH2:24][CH2:23][C:22](=[O:25])[NH:21]1.Cl.[C:28]([O:32][C:33](=[O:38])[CH2:34][CH2:35][CH2:36][NH2:37])([CH3:31])([CH3:30])[CH3:29]>CN(C)C=O>[C:28]([O:32][C:33](=[O:38])[CH:34]([C:19](=[O:26])[C@@H:20]1[CH2:24][CH2:23][C:22](=[O:25])[NH:21]1)[CH2:35][CH2:36][NH2:37])([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C1CC[C@@H](C(=O)Oc2cc(Cl)c(Cl)cc2Cl)N1
Reactant: CC(C)(C)OC(=O)CCCN
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(CCN)C(=O)[C@@H]1CCC(=O)N1
Reaction time: 8 h

Procedure:
1.3 ml of N-ethylmorpholine and 3.08 g of L-pyroglutamic acid 2,4,5-trichlorophenyl ester were added to a solution of 1.95 g (10 mmols) of 4-aminobutyric acid tert. butyl ester hydrochloride in 20 ml of dimethylformamide. The solution was left overnight at room temperature. It was concentrated, the residue was dissolved in a mixture of ethyle acetate and water, and the ethyl acetate solution was shaken with sodium bicarbonate solution, KHSO4 -solution and NaCl-solution, dried with Na2SO4 and concentrated. The residue was triturated with petroleum ether.
Reaction SMILES: [C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:8]2)=[CH:3][CH:2]=1.[CH2:28]([N:30]([CH2:34][CH3:35])[CH2:31][C:32]#[CH:33])[CH3:29]>CCCCCCC.CCOC(C)=O>[CH2:28]([N:30]([CH2:34][CH3:35])[CH2:31][C:32]#[C:33][C:9]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:27])=[CH:6][CH:5]=2)[N:8]=1)[CH3:29]
Reactant: Cc1ccc(-n2nc(OS(=O)(=O)c3ccc(C)cc3)c3cccnc32)cc1
Reactant: C#CCN(CC)CC
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCN(CC)CC#Cc1nn(-c2ccc(C)cc2)c2ncccc12

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-p-tolyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester and diethyl-prop-2-ynyl-amine following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 4:6; yield (64 mg, 40%); 1H NMR δ (CDCl3): 8.64 (m, 1H), 8.19 (m, 1H), 8.11 (d, J=8.52 Hz, 2H), 7.33 (d, J=8.49 Hz, 2H), 7.21-7.28 (m, 1H), 3.86 (s, 2H), 2.73 (q, J=7.17 Hz, 4H), 2.40 (s, 3H), 1.20 (t, J=7.16 Hz, 6H); LCMS m/z: 318.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19](=[O:28])[C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:27])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH:46]1([C:49](Cl)=[O:50])[CH2:48][CH2:47]1>C(Cl)Cl>[C:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:49]([CH:46]2[CH2:48][CH2:47]2)=[O:50])=[CH:3][CH:4]=1)[CH:9]1[CH2:10][CH2:11][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19](=[O:28])[C:20]2[C:21]([CH3:27])=[CH:22][CH:23]=[CH:24][C:25]=2[CH3:26])[CH2:13][CH2:14]1)#[N:38]
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(N)cc2)CC1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(NC(=O)C3CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.5 %

Procedure:
To a solution of COMPOUND 142 (61 mg, 0.12 mmol) in CH2Cl2 (1 mL) and Et3N (33 μL, 0.24 mmol) was added cyclopropanecarbonyl chloride (17 μL, 0.18 mmol) and the solution was stirred at room temperature for 4 hours to afford COMPOUND 153 as a white solid (69 mg, 100%) following work-up and purification. 1H NMR (CDCl3) δ 0.75-0.83 (m, 2H), 1.01 (m, 6H), 1.01-1.16 (m, 1H), 1.42-1.61 (m, 2H), 1.61-1.77 (m, 3H), 2.15 (t, 1H, J=11.1 Hz), 2.30 (s, 6H), 2.55 (t, 1H, J=10.8 Hz), 2.74-2.86 (m, 3H), 3.28 (t, 1H, J=11.1 Hz), 3.54 (m, 1H), 3.76 (s, 2H), 3.85 (m, 1H), 6.50 (d, 2H, J=6.49 (d, 2H, J=8.4 Hz), 6.91-6.99 (m, 3H), 7.24 (d, 2H, J=9.3 Hz), 7.36-7.44 (m, 4H), 7.50 (br s, 1H), 8.40 (br s, 1H). 13C NMR (CDCl3) δ 7.98, 8.39, 13.77, 15.72, 19.54, 29.29, 30.57, 31.31, 40.14, 44.03, 48.66, 52.46, 57.39, 60.82, 112.78, 114.85, 119.40, 122.01, 127.67, 128.79, 129.56, 129.66, 130.50, 130.82, 131.47, 134.45, 138.91, 142.66, 145.31, 170.35, 172.09. ES-MS m/z 578 (M+H). Anal. Calcd. for C36H43N5O2.0.3CH2Cl2: C, 72.28; H, 7.28; N, 11.61. Found. C, 72.57; H, 7.38; N, 11.30.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][C:19]([NH:21][CH2:22][CH2:23][CH3:24])=[O:20])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:48]>>[NH2:48][C:8]1[C:7]2[N:16]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:17][CH2:18][C:19]([NH:21][CH2:22][CH2:23][CH3:24])=[O:20])[C:6]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: [NH4+]
Reactant: CCCNC(=O)CCn1c(CCC)nc2cnc3ccccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCNC(=O)CCn1c(CCC)nc2c(N)nc3ccccc3c21

Procedure:
3-(2-Propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-propylpropanamide (3.5 g, 11 mmol) was treated with mCPBA (5.85 g, 32.4 mmol) followed by ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (2.76 g, 14.6 mmol) according to a modification of the method described in Part D of Example 8. When the reaction was complete, the organic layer was separated, washed with 10% aqueous sodium bicarbonate, and concentrated under reduced pressure. The crude product was purified as described in Part D of Example 8 to provide 1.026 g of 3-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-propylpropanamide as beige needles, mp 157-158° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>CC(C)=O.O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([N:26]2[CH2:31][CH2:30][S:29][CH2:28][CH2:27]2)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:4]=1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(NC2CCCCC2)n1
Reactant: C1CSCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CSc1nc(NC2CCCCC2)c([N+](=O)[O-])c(N2CCSCC2)n1
Temperature: 25 °C

Procedure:
3.0 gm of 2-methylmercapto-4-chloro-5-nitro-6-cyclohexylamino-pyrimidine were dissolved in 30 ml of acetone, a solution of 1.38 gm of potassium carbonate in 1.5 ml of water was added, and the mixture was admixed with a solution of 1.2 gm of thiomorpholine in 10 ml of acetone. The resulting mixture was stirred at room temperature, whereby after a short time a voluminous, crystalline precipitate was formed which was further increased by addition of water. The mixture was suction-filtered and the filter cake, 2-methylmercapto-4-thiomorpholino-5-nitro-6-cyclohexylamino-pyrimidine, was recrystallized from isopropanol. Yield: 2.3 gm (62% of theory), m.p. 145°-146°C.
Reaction SMILES: [Cl:1][SiH2:2][Cl:3].[CH2:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>Cl[Ni]Cl>[CH2:15]([SiH:2]([Cl:3])[Cl:1])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: C=CCCCCCCCCCC
Reactant: Cl[SiH2]Cl
Agent: Cl[Ni]Cl
Product: CCCCCCCCCCCC[SiH](Cl)Cl
Reaction time: 30 h

Procedure:
Dichlorosilane in an amount of 75.8 g (0.75 mol), 228.5 g of 1-dodecene (1.36 mol) and 0.05 mol % of a catalyst NiCl2 --(PPh3)2 (relative to dichlorosilane) were charged in a 500 ml pressure-proof stainless steel reactor and sealed. A reaction was carried out at 100° C. for 30 hours and the reacted liquid was distilled to obtain n-dodecyldichlorosilane (n--C12H25SiHCl2).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[N:23]=[C:22]([NH:24][CH3:25])[C:21]([N+:26]([O-])=O)=[CH:20][C:6]=1[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]1)=[O:8].CO>[Ni].C1COCC1>[NH2:26][C:21]1[C:22]([NH:24][CH3:25])=[N:23][C:5]([O:4][CH2:3][CH2:2][F:1])=[C:6]([CH:20]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([F:18])([F:17])[F:19])[CH2:12][CH2:11]1)=[O:8]
Reactant: CNc1nc(OCCF)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1nc(OCCF)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 2-(2-fluoro-ethoxy)-6-methylamino-5-nitro-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (105 mg, 0.26 mmol), Ra—Ni (25 mg), MeOH (5 mL) and THF (10 mL) is stirred at rt for 2.5 h under a hydrogen atmosphere (3.0 bar). The catalyst is removed by filtration and the filtrate is concentrated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].CC([O-])(C)C.[K+].Cl[C:17]1[CH:26]=[CH:25][C:24]2[C:23](=[O:27])[NH:22][CH2:21][CH2:20][C:19]=2[N:18]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][C:17]1[CH:26]=[CH:25][C:24]2[C:23](=[O:27])[NH:22][CH2:21][CH2:20][C:19]=2[N:18]=1
Reactant: O=C1NCCc2nc(Cl)ccc21
Reactant: OCc1cccc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NCCc2nc(OCc3cccc(F)c3)ccc21
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
3-Fluorobenzyl alcohol (1.66 g, 13.14 mmol) was dissolved into DMF (25 mL) and treated with KOtBu (3.2 g, 26.29 mmol) and stirred for 30 min. The mixture was treated with 2-chloro-7,8-dihydro-1,6-naphthyridin-5(6H)-one and heated to 100° C. overnight. The mixture was adsorbed onto silica and purified (0 to 80% EtOAc/Hexanes) to give a semi-pure solid. This material was further purified on RP-HPLC (eluting with 40-90% MeCN/H2O with 0.1% TFA modifier) to give 840 mg of the compound, 2-((3-fluorobenzyl)oxy)-7,8-dihydro-1,6-naphthyridin-5(6H)-one. 1H NMR (400 MHz, CDCl3) δ 8.44 (1H, d, J=7.6), 7.38 (1H, dd, J=14.6, 7.6), 7.24 (1H, d, 7.5), 7.22 (1H, d, J=9.6), 7.04 (1H, t, J=8), 6.79 (1H, d, J=8.4), 5.79 (1H, br s), 5.45 (2H, s), 3.64 (2H, t, J=6.4), 3.10 (2H, t, J=6.4); LC-MS (M+H)=273.2.