Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7](Cl)=[N:6][N:5]2[CH:11]=1.O1C[CH2:15][CH2:14][CH2:13]1.C([Mg]Cl)CC>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:13][CH2:14][CH3:15])=[N:6][N:5]2[CH:11]=1
Reactant: C1CCOC1
Reactant: Clc1cn2nc(Cl)ccc2n1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: CCC[Mg]Cl
Solvent: O
Product: CCCc1ccc2nc(Cl)cn2n1

Procedure:
2,6-Dichloroimidazo[1,2-b]pyridazine (1.6 g, 8.5 mmol), [1,3-bis(diphenylphosphino)propane]nickel (II) dichloride (catalytic amount) and dehydrated tetrahydrofuran (20 ml) were introduced into a 100-ml three-necked flask under a nitrogen stream and stirred under ice-cooling, and a solution of propylmagnesium chloride in tetrahydrofuran (2 M, 6.4 ml, 12.8 mmol) was added dropwise thereto at 10° C. or less. After dropping, the mixture was stirred for 1 hour at the same temperature, for 1 hour at room temperature and for 2 hours at 50 to 60° C. After the reaction was completed, the reaction solution was left and cooled, and water (50 ml) was added thereto, and the mixture was stirred and extracted with ethyl acetate (20 ml×2). The organic layers were combined, washed with water, dried over magnesium sulfate and concentrated, and the residues were purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the title compound as orange crystals (containing a small amount of impurities). The yield was 0.8 g (48.2%).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[C:22]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:21][CH:20]=[C:19]([F:28])[N:18]=1.[Si:29]([O:36][C:37]1([CH2:41]/[CH:42]=[N:43]/[S@@:44]([C:46]([CH3:49])([CH3:48])[CH3:47])=[O:45])[CH2:40][CH2:39][CH2:38]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].N#N>C1COCC1>[Si:29]([O:36][C:37]1([CH2:41][C@H:42]([NH:43][S:44]([C:46]([CH3:49])([CH3:48])[CH3:47])=[O:45])[C:20]2[C:19]([F:28])=[N:18][C:17]([F:16])=[C:22]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH:21]=2)[CH2:40][CH2:39][CH2:38]1)([C:32]([CH3:34])([CH3:35])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)Cc1ccc(F)nc1F
Reactant: CC(C)(C)[S@@](=O)/N=C/CC1(O[Si](C)(C)C(C)(C)C)CCC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)Cc1cc([C@H](CC2(O[Si](C)(C)C(C)(C)C)CCC2)NS(=O)C(C)(C)C)c(F)nc1F
Temperature: -78 °C
Yield: 13.5 %

Procedure:
To a three-necked RBF was added 2,2,6,6-tetramethylpiperidine (0.34 ml, 2 mmol), THF (10 mL), and an ethanol/N2 bath. After cooling to −78° C., butyllithium (0.70 ml, 2 mmol) was added dropwise. After stirring for several minutes, the solution was cooled to −100° C. of 2,6-difluoro-3-neopentylpyridine (0.230 g, 1 mmol) in THF (2 mL) was added dropwise. The solution was then treated with (R,E)-N-(2-(1-(tert-butyldimethylsilyloxy)cyclobutyl)ethylidene)-2-methylpropane-2-sulfinamide (0.71 g, 2 mmol) in THF (3 mL). After the addition was complete the reaction was allowed to warm to 0° C. as the liquid N2 boiled off. The reaction was then quenched with water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 1% to 20% EtOAc in hexane, to provide N-((S)-2-(1-(tert-butyldimethylsilyloxy)cyclobutyl)-1-(2,6-difluoro-5-neopentylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (0.07 g, 11% yield). This material was used without further purification in the next step. MS m/z: 517 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)(OC)O[CH2:12][CH:13]=[CH2:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Pd]>[CH2:14]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH:13]=[CH2:12]
Reactant: O=Cc1ccc(O)cc1
Reactant: C=CCOC(=O)OC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CCOc1ccc(C=O)cc1

Procedure:
A mixture of p-hydroxybenzaldehyde (4.0 g, 33 mmoles), allyl methyl carbonate (16.0 g, 138 mmoles), 5 percent palladium on charcoal (1.3 g, 0.6 mmole palladium) and triphenyl phosphine (0.086 g, 0.32 mmole) is refluxed overnight. After removal of the catalyst and distillation (90° C., 0.6 mm Hg), 4.54 g, 85 percent of substantially pure p-allyloxybenzaldehyde is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:25])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
A suspension of 7-benzyloxy-3-nitroquinolin-4-ol (75.0 g, 253 mmol), which was made in a separate run, in 500 mL of N,N-dimethylformamide was placed under an atmosphere of nitrogen. The suspension was treated with phosphorous oxychloride (27.8 mL, 304 mmol) dropwise over 1.5 h. After 18 h, the reaction mixture was cooled to 0° C. and then poured into 1 L of ice water. The mixture was stirred until the ice had melted. A tan/yellow precipitate was collected by vacuum filtration. The solid was dissolved in dichloromethane (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield 71.7 g of 7-benzyloxy-4-chloro-3-nitro-quinoline as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1.[ClH:14]>[Pd].CO>[Cl-:14].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH3+:7])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(F)ccc1C#N
Reactant: Cl
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1cc(F)ccc1C[NH3+]
Product: [Cl-]
Reaction time: 8 h

Procedure:
4-fluoro-2-(methylsulfonyl)benzonitrile (5.6 g, 28.11 mmol) was added to a dry Parr bottle. Methanol (50 mL) and conc HCl (10 mL) were added and the reaction solution put under an Argon atmosphere. 10% Pd/C (1 gram) was added and the reaction vessel placed on a Parr hydrogenation apparatus. The reaction was placed under an atmosphere of H2 (50 psi) and shaken overnight. After overnight the ratio of starting material to product was 50:50. The reaction was filtered through celite and concentrated slightly. Conc. HCl (10 mL) and 10% Pd/C (1 gram) were added and the reaction was again put under H2 (50 psi). The reaction was again shaken overnight. The crude reaction was filtered through celite and concentrated to afford the desired material as a white solid.
Reaction SMILES: [C:1]([O:5]O)([CH3:4])(C)C.[C:7]([O:30][CH:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][C:33]([CH3:40])([CH3:39])[CH2:32]1)(=[O:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH:19]1[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]1)=[O:17]>[Mo](=O)(=O)=O.CCCCCCCC>[C:7]([O:30][CH:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[N:34]([O:5][CH2:1][CH2:4][CH2:27][CH2:21][CH2:20][CH2:19][CH2:24][CH3:23])[C:33]([CH3:40])([CH3:39])[CH2:32]1)(=[O:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH:19]1[CH2:24][C:23]([CH3:25])([CH3:26])[N:22]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9])[C:21]([CH3:27])([CH3:28])[CH2:20]1)=[O:17]
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: CC(C)(C)OO
Agent: O=[Mo](=O)=O
Solvent: CCCCCCCC
Product: CCCCCCCCON1C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C
Temperature: 115 °C
Reaction time: 0.5 h
Yield: 160.5 %

Procedure:
70% Aqueous t-butyl hydroperoxide (140 g, 1.09 mol) is added over a 6 hour period to a mixture of 75.4 g (0.157 mol) of bis(2,2,6,6-tetramethylpiperidin-4-yl) sebacate, 1.25 g (8.7 mmol) of molybdenum trioxide, and 570 ml of n-octane that has been heated to 115° C. under a nitrogen atmosphere. During the addition, the reaction is maintained at reflux. Water is collected in a Dean-Stark trap. Upon completion of the addition, the red reaction mixture is heated at reflux (95-97° C.) for seven hours to discharge the red color. The molybdenum trioxide is removed by filtration. The yellow filtrate is stirred at ambient temperature for 30 minutes with 15 g of activated charcoal (DARCO) to remove some of the yellow color, and then concentrated at reduced pressure. The crude product is purified by flash chromatography on silica gel (100:3 heptane: ethyl acetate) to afford 92.9 g (80% yield) of di(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl) sebacate, a colorless oil. The column is then eluted with 10:1 heptane:ethyl acetate to obtain the title compound as a mixture of octandiyl isomers. The title compound is a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH:18][S:34]([C:31]3[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:33][CH:32]=3)(=[O:36])=[O:35])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN)OC2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCC2Cc3c(sc(N)c3C(=O)OC(C)(C)C)CO2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
To a solution of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (101 mg, 0.35 mmol) in dichloromethane (1 ml) was added pyridine (32 μl, 0.39 mmol) and 4-methoxybenzenesulfonyl chloride (82 mg, 0.39 mmol). The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with dichloromethane (2 ml) and subjected to preparative TLC (1:1 hexanes/ethyl acetate) affording 10 mg, (10% ) of 2-amino-5-((4-methoxy-benzenesulfonylamino)-methyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:32]([CH3:33])=[CH:31][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:41][C:42]([CH3:44])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:32]([CH3:33])=[CH:31][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:26][CH2:27][N:28]([CH:42]([CH3:44])[CH3:41])[CH2:29][CH2:30]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)=O
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCNCC4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(C)C)CC4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of crude (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(piperazin-1-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate (0.144 mmol) in ethanol (2.0 mL) was added acetone (0.21 mL) and acetic acid (12 μL, 0.21 mmol) at 0° C. Reaction mixture was stirred for 15 minutes, then sodium cyanoborohydride (10 mg, 0.158 mmol) was added and reaction mixture was warmed to room temperature over 2 h. Reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate/brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 10% MeOH/CH2Cl2) to give product. LCMS-ESI+: calc'd for C34H42ClN4O3S: 622.2 (M+H+); Found: 621.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(COc2cccc(Br)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(COc2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of methyl 4-((3-bromophenoxy)methyl)benzoate (1 g, 3.1 mmol) in tetrahydrofuran (30 mL) and methanol (10 mL) was added lithium hydroxide monohydrate (1.3 g, 31 mmol) in water (10 mL). The mixture was stirred at room temperature for 2 hours. The suspension was concentrated in vacuo and acidified with concentrated hydrochloride acid (12 N, 15 mL). Then the mixture was extracted with ethyl acetate (20 mL). The organic phase was separated and concentrated to give the product 4-((3-bromophenoxy)methyl)benzoic acid as a white solid (0.6 g, 63%). LRMS (M+H+) m/z: calcd 305.99. found 305. 1H NMR (300 MHz, d6-DMSO): δ 12.95 (s, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 7.27-7.22 (m, 2H), 7.15-7.12 (m, 1H), 7.05-7.01 (m, 1H), 5.21 (s, 2H).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:28]([O:30]C)=O)=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:20]3[C:25]([CH3:26])=[N:24][C:23]([CH3:27])=[CH:22][N:21]=3)[CH2:17][CH2:18][CH2:19][N:12]21.O1[CH2:36][CH2:35][CH2:34]C1>>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:25]([CH3:26])=[N:24][C:23]([CH3:27])=[CH:22][N:21]=4)[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([C:28]([CH:34]2[CH2:35][CH2:36]2)([CH:1]2[CH2:3][CH2:2]2)[OH:30])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ncc(C)nc1C
Reactant: C1CCOC1
Reactant: Br[Mg]C1CC1
Product: Cc1cnc(N2CCCn3c2nc2c(Cl)ccc(C(O)(C4CC4)C4CC4)c23)c(C)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
Cyclopropylmagnesium bromide (1.0 M solution in tetrahydrofuran, 1.59 mL, 1.59 mmol) was added to a stirred solution of methyl 9-chloro-1-(3,5-dimethylpyrazin-2-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (148 mg, 0.398 mmol) in tetrahydrofuran (2.0 mL), and the mixture was stirred at 60° C. for 3 hr. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 70-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate to give the title compound as a colorless crystal (59.7 mg, 0.141 mmol, 35%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][CH2:45][NH2:46]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:46][CH2:45][CH2:44][CH:40]3[CH2:41][CH2:42][CH2:43][N:39]3[CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CN1CCCC1CCN
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CN1CCCC1CCNc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-(1-methyl-pyrrolidin-2-yl)ethylamine according to conditions described in general procedure C. Mp: 112-114° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.30-1.61 (m, 10 H), 1.37-2.10 (m, 5 H), 2.84 (bs, 2 H), 3.11-3.36 (m, 7 H), 6.15-6.30 (m, 1 H), 6.96 (d, J=12.4 Hz, 1 H), 7.08-7.20 (m, 2 H), 7.37 (d, J=8.0 Hz, 1 H), 7.43 (s, 1 H), 7.52-7.59 (m, 3 H), 7.79 (d, J=8.4 Hz, 1 H), 7.96 (d, J=7.7 Hz, 1 H), 8.21 (s, 1 H), 10.40 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([N:11]([CH2:15][C:16]1[N:20]([CH2:21][CH2:22][CH3:23])[C:19]2[CH:24]=[CH:25][C:26]([CH2:28]O)=[CH:27][C:18]=2[N:17]=1)[CH2:12][CH2:13][CH3:14])=[O:10].S(Cl)([Cl:32])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([N:11]([CH2:15][C:16]1[N:20]([CH2:21][CH2:22][CH3:23])[C:19]2[CH:24]=[CH:25][C:26]([CH2:28][Cl:32])=[CH:27][C:18]=2[N:17]=1)[CH2:12][CH2:13][CH3:14])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: CCCN(Cc1nc2cc(CO)ccc2n1CCC)C(=O)c1cc(F)ccc1F
Product: CCCN(Cc1nc2cc(CCl)ccc2n1CCC)C(=O)c1cc(F)ccc1F
Yield: 93 %

Procedure:
(2,5-difluorophenyl)-N-{[5-(hydroxymethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide 0.96 g (2.3 mmole) is treated with 30 mL of thionyl chloride for 15 min a room temperature. The resulting mixture is concentrated in vacuo and partitioned between 100 mL sat NaHCO3 and 100 mL of ethyl acetate. The ethyl acetate layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting oil is chroamtoagraphed 50% ethyl acetate/hexanes to afford 0.9 g (93%) of (2,5-difluorophenyl)-N-{[5-(chloromethyl)-1-propylbenzimidazol-2-yl]methyl}-N-propylcarboxamide.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH3:20][CH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][C:28](O)=[O:29])[CH2:23][CH2:22]1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:20][CH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][C:28]([N:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]2)=[O:29])[CH2:23][CH2:22]1
Reactant: CC1CCC(CC(=O)O)CC1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCC(CC(=O)N2CC3CC[C@](C)(C2)C3(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine 0.84 ml was added in a methylene chloride 20 ml solution of (IS)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.95 g, and stirred at 0° C. for 30 min. 4-methylcyclohexyl acetic acid 0.94 g and WSC 1.35 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 24 hours. The reaction mixture was washed with saturated sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-(4-methylcyclohexylacetyl)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 30 ml solution of lithium aluminum hydride 0.39 g and refluxed for 1 hour. The reaction mixture was cooled, then added water, and filtered the insoluble material. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform:acetone=10:1) to obtain the product.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[Cl:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C.Cl>CN(C)C=O>[Cl:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[N:8]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[CH2:7]3)=[O:31])[CH:26]=[CH:27][CH:28]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4cccc(Cl)c4)ccc3C2=O)C(=O)N1
Reaction time: 2 h
Yield: 87 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.40 mmol) and 3-chlorophenylisocyanate (0.16 mL, 1.40 mmol) in N,N-dimethylformamide (10 mL), was added triethylamine (0.38 mL, 2.7 mmol) at room temperature under nitrogen. After 2 h, 1 N aq. HCl (40 mL) was added and the solids were isolated by filtration and washed with water (20 mL). The crude product was triturated in EtOAc (50 mL) for 0.5 h. The product was isolated by filtration and dried in vacuo to give 1-(3-chloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as an off-white solid (0.52 g, 90% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 9.26 min (96.05%); mp: 215-217° C.; 1H NMR (DMSO-d6) δ 1.88-2.12 (m, 1H, CHH), 2.27-2.47 (m, 1H, CHH), 2.60 (d, J=17.2 Hz, 1H, CHH), 2.77-3.03 (m, 1H, CHH), 4.31 (d, J=17.4 Hz, 1H, CHH), 4.37-4.54 (m, 3H, CHH, CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 6.85 (t, J=5.9 Hz, 1H, NH), 6.90-7.07 (m, 1H, Ar), 7.10-7.34 (m, 2H, Ar), 7.45 (d, J=7.9 Hz, 1H, Ar), 7.52 (s, 1H, Ar), 7.61-7.78 (m, 2H, Ar), 8.88 (s, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.50, 31.21, 42.80, 47.13, 51.59, 116.12, 117.10, 120.73, 121.91, 122.94, 126.91, 130.22, 130.33, 133.09, 141.95, 142.39, 144.64, 155.00, 167.93, 171.00, 172.85; LCMS: MH=427/429; Anal Calcd for C21H19N4O4Cl: C, 59.09; H, 4.49; N, 13.13; Cl, 8.31. Found: C, 58.82; H, 4.22; N, 13.03; Cl, 8.32.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]([O:20][Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])([C:16]([F:19])([F:18])[F:17])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C(O)(=O)C.O>C(O)C.[Zn]>[OH:1][CH:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]([O:20][Si:21]([CH2:24][CH3:25])([CH2:26][CH3:27])[CH2:22][CH3:23])([C:16]([F:18])([F:19])[F:17])[C:10]2[C:15]1=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CC[Si](CC)(CC)OC1(C(F)(F)F)c2ccccc2C(=O)c2ccccc21
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC[Si](CC)(CC)OC1(C(F)(F)F)c2ccccc2C(O)c2ccccc21
Temperature: 110 °C
Yield: 58 %

Procedure:
A solution of 50 mg (0.13 mmol) of 9,10-dihydro-9-oxo-10-triethylsiloxy-10-trifluoromethylanthracene in 0.5 mL of absolute ethanol was treated successively with 42 mg (0.65 mmol) of zinc dust and 0.5 mL of a solution of 90% acetic acid - 20% water. The mixture was heated to reflux in a 110° C. oil bath for 2 hours, allowed to cool to room temperature, and poured into 10 mL of water. The resulting aqueous mixture was extracted with three 5 mL portions of diethyl ether. Combination, drying, and concentration of the ether layers gave a residue which was purified by PTLC (one 1 mm silica gel plate eluted with 50% dichloromethane-50% petroleum ether) to give 34 mg of 87% pure (58% yield) 9,10-dihydro-9-hydroxy-10-triethysiloxy-10-trifluoromethylanthracene as a white solid: mass spectrum (70 eV) m/z (relative intensity) 363 (8, M--C2H5), 211 (100), 183 (21), 77 (25); TMS derivative 466 (M+), 368 (27), 246 (24), 196 (22), 193 (90), 165 (21), 105 (40), 87 (28), 77 (47), 73 (100), 59 (20), 45 (21).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][N:3]=[C:2]1[C:7]1[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C.[CH3:21][C:22]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:23]=1[O:24][CH2:25][CH2:26][CH2:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][N:3]=[C:2]1[C:7]1[CH:8]=[C:9]([NH:13][C:29](=[O:30])[C:28]([CH3:32])([CH3:33])[CH2:27][CH2:26][CH2:25][O:24][C:23]2[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:22]=2[CH3:21])[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Cl)c1
Reactant: Nc1cccc(C2=NCCCO2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Nc2cccc(C3=NCCCO3)c2)c1
Temperature: 0 °C

Procedure:
To an ice cold solution of 3-(5,6-dihydro-4H-1,3-oxazin-2-yl)benzenamine, 8.8 g (0.05 mol), (Journal of the American Chemical Society, Vol. 59, pp. 2259-2261, (1937)) and triethylamine, 10 ml, in dichloromethane, 300 ml, is added 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride, 13.4 g (0.05 mol), (U.S. Pat. No. 4,285,951). The mixture is worked up to give 18.8 g of N-[3-(5,6-dihydro-4H-1,3-oxazin-2-yl)phenyl]-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide after recrystallization from diisopropyl ether; mp 114°-115° C.