Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:33])[N:12](COCC[Si](C)(C)C)[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(S)(S)C.O>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:33])[NH:12][N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cc(C(=O)NCc3ccc(Cl)cc3)c(=O)n(COCC[Si](C)(C)C)n2)ccc1O
Agent: CC(S)S
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(-c2cc(C(=O)NCc3ccc(Cl)cc3)c(=O)[nH]n2)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
70.7 mg of 6-(4-hydroxy-3-methoxy-phenyl)-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3-dihydro-pyridazine-4-carboxylic acid 4-chloro-benzyl amide and 60 μl ethandithiol and 60 μl water were dissolved in 750 μl TFA and stirred at room temperature for 3 h. Afterwards, the solvent was distilled off and the raw product purified by HPLC (column 125×25, PurospherStar RP18 endcapped, 5 μm; solvent: A: water (0.05% HCOOH), B: acetonitrile (0.05% HCOOH)).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].CN1CCCC1=O.C(N(CC)C(C)C)(C)C.[Cl:25][C:26]1[N:31]=[C:30](Cl)[C:29]([Cl:33])=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:28]1[C:29]([Cl:33])=[CH:30][N:31]=[C:26]([Cl:25])[N:27]=1
Reactant: Nc1ccccc1Cl
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Clc1ncc(Cl)c(Nc2ccccc2Cl)n1
Temperature: 100 °C
Yield: 83.6 %

Procedure:
Into a round bottom flask was added o-chloroaniline (6.46 mL, 39.2 mmol) and N-methylpyrrolidinone (37.8 mL, 392 mmol). N,N-Diisopropylethylamine (8.19 mL, 47.0 mmol) was added followed by 2,4,5-trichloro-pyrimidine (5.39 mL, 47.0 mmol) and the mixture was heated at 100° C. for 24 hours. The reaction mixture was then concentrated under reduced pressure and the residue was taken up in DCM (150 mL) and washed with water (150 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-12% EtOAc/hex as the eluting solvent to obtain (2-chloro-phenyl)-(2,5-dichloro-pyrimidin-4-yl)-amine as a yellow solid (9.0 g, 84%). LCMS (m/e) 274 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.54 (d, 1H, J=8.3 Hz), 8.28 (s, 1H), 8.00 (bs, 1H), 7.47 (d, 1H, J=8.0 Hz), 7.44-7.37 (m, 1H), 7.17-7.11 (m, 1H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].O.[OH-].[Li+].CO>O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)(C)C)C[C@H](C)N3C(C)=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 50 °C
Reaction time: 0.83 h
Yield: 97.6 %

Procedure:
To a stirring solution of crude methyl 6-((2S,4R)-1-acetyl-4-((tert-butoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinate (Intermediate 62) (2.2 g, 5.01 mmol) in MeOHl (12 mL), was added lithium hydroxide monohydrate (0.144 g, 6.01 mmol) in water (12 mL) and the mixture warmed to 50° C. for 70 mins. MeOH (10 mL) was added and the mixture stirred at 50° C. for a further 50 mins. The mixture was allowed to cool to room temperature before being partitioned between saturated aqueous sodium bicarbonate (150 mL) and DCM (3×150 mL). The aqueous layer was then treated with 2M HCl until acidic (˜pH 3) before being extracted with DCM (3×150 ml). The organics were combined, dried by passing through a hydrophobic frit and concentrated in vacuo to give 6-((2S,4R)-1-acetyl-4-((tert-butoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinic acid (2.08 g, 4.89 mmol). LCMS: (Formate, 2 min), Rt=0.86 mins, MH+426.
Reaction SMILES: [Cl:1]Cl.[CH3:3][CH:4]1[C:8]2[CH:9]=[CH:10][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:12][C:7]=2[O:6][C:5]1=[O:19]>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:10]1[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:12][C:7]2[O:6][C:5](=[O:19])[CH:4]([CH3:3])[C:8]=2[CH:9]=1
Reactant: ClCl
Reactant: CC1C(=O)Oc2cc(N3CCOCC3)ccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1C(=O)Oc2cc(N3CCOCC3)c(Cl)cc21

Procedure:
A cold solution of chlorine in chloroform is added dropwise at from 0° to 5° C., while stirring, to a mixture of 14.7 g (0.063 mole) of 3-methyl-6-morpholinobenzofuran-2(3H)-one in 100 ml of chloroform until no more educt is visible in the thin layer chromatograph. The reaction mixture is diluted with methylene chloride and washed in succession with 10% strength sodium thiosulphate solution, dilute sodium bicarbonate solution and water. The crude product remaining after drying and concentrating by evaporation the organic phase is chromatographed over silica gel with petroleum ether/ether. Recrystallisation of the pure fractions from ether/petroleum ether yields 5-chloro-3-methyl-6-morpholinobenzofuran-2(3H)-one having a melting point of 103°-105° C.
Reaction SMILES: [C:1](=[N:14][C:15]1[C:20]([F:21])=[C:19]([CH2:22][O:23][Si](C(C)(C)C)(C)C)[CH:18]=[CH:17][N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1>[C:1](=[N:14][C:15]1[C:20]([F:21])=[C:19]([CH2:22][OH:23])[CH:18]=[CH:17][N:16]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(N=C(c2ccccc2)c2ccccc2)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1ccnc(N=C(c2ccccc2)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of benzhydrylidene-[4-(tert-butyldimethylsilyloxymethyl)-3-fluoropyridin-2-yl]-amine (14 mg, 32 μmol) and tetrabutylammonium fluoride (1 mol/L in THF) (65 μL, 65 μmol) in THF (0.5 mL) was stirred at room temperature for 30 minutes. Ethyl acetate was then added to the reaction solution, and the solution was washed with sodium hydrogen carbonate solution and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The resultant residue was purified by silica gel column chromatography to yield the title compound.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=4)=[CH:15][C:14]=3[Cl:27])[C:8]2=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:34]([O:33][C:31](=[O:32])[C:30]([O:26][C:23]1[CH:24]=[CH:25][C:20]([C:16]2[CH:15]=[C:14]([Cl:27])[C:13]([CH2:12][CH:9]3[CH2:10][CH2:11][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[C:8]3=[O:28])=[C:18]([Cl:19])[CH:17]=2)=[CH:21][CH:22]=1)([CH3:37])[CH3:36])[CH3:35]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=C1C(Cc2c(Cl)cc(-c3ccc(O)cc3)cc2Cl)CCN1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Yield: 104.3 %

Procedure:
Combine 1-Cyclohexyl-3-(3,5-dichloro-4′-hydroxy-biphenyl-4-ylmethyl)-pyrrolidin-2-one (prep 55) (0.15 g, 0.36 mmol), ethyl 2-bromoisobutyrate (0.28 g, 1.43 mmol) and Cs2CO3 (0.35 g, 1.07 mmol) in DMF (7 mL) and heat to 60° C. for 16 hours. Cool the reaction, extract with diethyl ether and water, dry (Na2SO4) and then purify by normal phase chromatography (30 to 80% gradient of ethyl acetate in hexanes) to afford 200 mg (100%) of the title compound: LC-MS (ES +) m/z=exact mass calcd for C29H35Cl2NO4 531, found 532 and 534 (M+1 and M+3, 100%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].CO.S(OC)(O[CH3:22])(=O)=O>O>[CH3:22][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
A mixture of 38 g of 4-phenylphenol, 9 g of sodium hydroxide, 200 ml of methanol and 20 ml of water was heated. 28 g of dimethyl sulfate was dropped in the mixture with stirring at 50° C. After one hour, 20 ml of 10N-sodium hydroxide was dropped in the solution and continued stirring for 2 hours. The crystals were obtained after the solution was cooled to room temperature. After washing with water and methanol for several times, 30 g of 4-methoxybiphenyl (O) was obtained. 154 g of (O) was dissolved with mixed solution of 200 ml of chloroform and 75 ml of carbon tetrachloride, and then 11 g of aluminum chloride powder was added to the solution. 14 g of octanic acid chloride was added to the solution with stirring after changing colour of the solution to greenish blue. 150 ml of ice-water and 5 ml of conc. hydrochloric acid was added, after refluxing 5 hours. The water layer was removed, then the organic layer was washed with 0.1N hydrochloric acid and dehydrated with magnesium sulfate anhydride, and then evaporated after filtration to obtain crude crystals of 4'-nonylcarbonyloxy-4-methoxybiphenyl (P). 13 g of (P), 1 g of 10% palladium-carbon, 130 ml of acetic acid were put into an autoclave and then gave the pressure to 25 kg/cm2 by using hydrogen. (P) was reduced by heating for 3 hours at 80° C. After substituting nitrogen for hydrogen, palladium-carbon was separated by filtrating the reacted solution. 4'-decyl-4-methoxybiphenyl (Q) was obtained after cooling and drying. 8 g of (Q), 90 ml of acetic acid 30 ml of hydrogen bromide water solution were mixed and refluxed for 5 hours to obtain crude crystals. After cooling, the crude crystals were washed with methanol to crystallize 5.5 g of 4-(4'-octylphenyl)phenol.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].O=C1CCC(=O)N1[O:41][C:42](=O)[NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1>C(#N)C>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:42]([NH:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)=[O:41])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Nc1ccccn1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)Nc4ccccn4)c3C2=O)C(=O)N1
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.4 g, 2.4 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) in acetonitrile (50 mL). After stirring for 30 minutes, pyridin-2-yl-carbamic acid 2,5-dioxo-pyrrolidin-1-yl ester (0.7 g, 3.0 mmol) was added, and the mixture was stirred at room temperature overnight. The solid was collected and slurried with hot acetone (20 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-pyridin-2-yl-urea (0.5 g, 64%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.49-2.65 (m, 2H), 2.84-2.79 (m, 1H), 4.83 (d, J=6.1 Hz, 2H), 5.14-5.21 (dd, J=5.5 and 12.7 Hz, 1H), 6.91-6.96 (m, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.64-7.88 (m, 4H), 8.17-8.20 (dd, J=1.3 and 5.0 Hz, 1H), 8.90 (t, J=5.7 Hz, 1H), 9.44 (s, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) δ 21.96, 30.92, 38.67, 48.85, 93.31, 111.57, 116.91, 121.90, 127.20, 131.67, 133.43, 134.80, 138.23, 139.82, 146.69, 153.27, 154.93, 166.97, 167.49, 169.81, 172.75; Anal. calcd. for C20H17N5O5: C, 58.97; H, 4.21; N, 17.19. Found: C, 58.69; H, 4.10; N, 17.05.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.O=[C:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.O>C(OCC)C>[F:1][C:2]1[N:3]=[CH:4][C:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Fc1ccc(C2CCNCC2)cn1
Temperature: -35 °C
Reaction time: 0.25 h
Yield: 52.7 %

Procedure:
A solution of 2-fluoro-5-bromopyridine (7.69 g) in diethyl ether (160 ml) was cooled to −78° C., and into which n-butyl lithium (1,56M-hexane solution, 30 ml) was added dropwise at a temperature not higher than −70° C. After 15 minutes' stirring, tert-butyl 4-oxo-1-piperidinecarboxylate (8.7 g) was added. Temperature of the reaction liquid was raised to −35° C. and water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was condensed under reduced pressure and isopropyl ether was added to the resulting residue. Whereupon precipitated crystals were recovered by filtration to provide the title compound (4.15 g). The filtrate was purified on column chromatography (hexane/ethyl acetate=3/1-2/1) to provide tert-butyl 4-(6-fluoro-3-pyridinyl)-4-hydroxy-tetrahydro-1(2H)-pyridinecarboxylate (1.25 g).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:15][O:16]/[CH:17]=[CH:18]/[C:19](Cl)=[O:20]>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:19](=[O:20])/[CH:18]=[CH:17]/[O:16][CH3:15])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CO/C=C/C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CO/C=C/C(=O)Nc1ccc(Br)cc1
Yield: 95.6 %

Procedure:
Combined 4-bromoaniline (285 mg, 1.659 mmol), CH2Cl2 (2.0 ml) and pyridine (0.25 ml, 3.09 mmol) and slowly added (E)-3-methoxyacryloyl chloride (200 mg, 1.659 mmol) and stirred at room temperature for 2 h. The resulting yellow solid was filtered off and washed with water. The solid was dried under vacuum to give the title compound (406 mg, 96%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[N:26]2[CH:27]=[CH:28][N:29]=[C:25]2[CH:24]=[CH:23][CH:22]=1)[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:30][C:31]([Cl:36])([Cl:35])[C:32](Cl)=[O:33]>CN(C1C=CN=CC=1)C.C1COCC1>[Cl:30][C:31]([Cl:36])([Cl:35])[C:32]([C:27]1[N:26]2[C:21]([CH2:20][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:22][CH:23]=[CH:24][C:25]2=[N:29][CH:28]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)N(CCCCNC(=O)C(F)(F)F)Cc1cccc2nccn12
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCCCNC(=O)C(F)(F)F)Cc1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Temperature: 0 °C
Yield: 47.9 %

Procedure:
To a solution of 7.69 g (18.56 mmol) of 5-[N-tert-butoxycarbonyl-N-(4-trifluoroacetamidobutan-1-yl)amino methyl]imidazo[1,2-a]pyridine and 10.20 g (83.52 mmol) of 4-(N,N-dimethylamino)pyridine in 100 ml of THF was added 6.21 ml (55.67 mmol) of trichloroacetyl chloride. The reaction mixture was heated for 16 hours under reflux. The reaction mixture was poured into ice-water, and extracted with 100 ml of ethyl acetate. The organic layer was washed with 150 ml of a saturated aqueous saline solution, dried over magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform) to afford 4.98 g of the desired compound (48.0%, a pale yellow amorphous).
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[Al].[C:21]([O:33][CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38])(=[O:32])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]C=C.ClC(Cl)C(OC)=O>C1(C)C=CC=CC=1>[C:21]1(=[O:32])[O:33][CH2:34][CH2:35][CH2:36][CH:37]=[CH:38][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C=CCCCCCCCCC(=O)OCCCC=C
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: COC(=O)C(Cl)Cl
Agent: [Al]
Solvent: Cc1ccccc1
Product: O=C1CCCCCCCCC=CCCCO1
Temperature: 80 °C
Reaction time: 16 h
Yield: 40.1 %

Procedure:
0.05 g of tricyclohexylphosphine, 0.06 g (0.1 mmol) of di-μ-chlorobis ((p-cymene)chlororuthenium), 10 ml of toluene, 0.05 g (1.85 mmol) of an aluminum powder, 0.252 g (1 mmol) of 4-pentenyl 10-undecenoate and 0.021 ml (0.2 mmol) of methyl dichloroacetate were blended and the mixture was stirred at 80° C. for 16 hours in a nitrogen stream. A solvent was distilled and the residue was refined by silica gel column chromatography (toluene/ethyl acetate=10/1) to obtain 0.09 g of an object material (yield: 40%). The result of 1H-NMR of the above reaction solution is as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5][OH:6].CC1C=C(C=CC=1C)C=[O:16].C1(C(=CC(=CC=1)C)C)C>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]([OH:16])=[O:6]
Reactant: Cc1ccc(CO)cc1C
Reactant: Cc1ccc(C=O)cc1C
Agent: Cc1ccc(C)c(C)c1
Product: Cc1ccc(C(=O)O)cc1C

Procedure:
FIG. 9 demonstrates the formation of 3,4-dimethylbenzyl alcohol commenced immediately. The formation of 3,4-dimethylbenzaldehyde commenced after 2 hours. 11 hours after starting the fed-batch culture, another 1% (v/v) of pseudocumene was added. However, only some of this substrate was now converted. The end concentration of 3,4-dimethylbenzylaldehyde was 113 mM. When the biotransformation was stopped, the pseudocumene and 3,4-dimethylbenzyl alcohol concentrations were 65 mM. Virtually no 3,4-dimethylbenzoic acid was produced.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][C@H:3]1[NH2:13].[C:14](=S)=[S:15].O>C(O)C>[F:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C@H:2]1[NH:1][C:14](=[S:15])[NH:13][C@@H:3]1[CH2:4][CH2:5]2
Reactant: S=C=S
Reactant: N[C@@H]1CCc2cc(F)ccc2[C@H]1N
Solvent: CCO
Solvent: O
Product: Fc1ccc2c(c1)CC[C@H]1NC(=S)N[C@H]21
Yield: 82 %

Procedure:
Trans-1,2-diamino-6-fluoro-1,2,3,4-tetrahydronaphthalene (3.84 g, 21.3 m mol) was dissolved in ethanol (40 ml) and carbon disulfide (1.4 ml, 23.4 m mol) was added to the solution. After the resulting white suspension was stirred for a while, water (20 ml) was added to the suspension and they were heated under reflux for 30 minutes. The reaction mixture was cooled with ice and the precipitate was filtered. The solid was washed in turn with water (three portions of 20 ml, totaling 60 ml), ethyl ether (20 ml) and n-hexane (50 ml) and dried under vacuum to give trans-7-fluoro-3a,4,5,9b-tetrahydronaphth[1,2-d]imidazoline-2-thione as a yellowish grey solid (3.88 g, 17.4 m mol) in 82% yield. The product was recrystallized from acetone-acetonitrile to give light-yellow needles melting at 256.5° to 257.5° C. (decomposition). The data on spectroscopy were as follows:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:15][C:14]=3[CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:26]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][C:16]([CH:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:15][C:14]=3[CH:24]=2)=[CH:4][CH:3]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CC(=O)NC(C)c1cc2cc(CCc3ccc(O)cc3)ccc2o1
Reactant: CCCCBr
Product: CCCCOc1ccc(CCc2ccc3oc(C(C)NC(C)=O)cc3c2)cc1
Yield: 66 %

Procedure:
Using N-(1-{5-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (124 mg, 0.348 mmol) obtained in Example 157 and bromobutane (263 mg, 1.92 mmol) and in the same manner as in Example 158, the title compound was obtained (96.3 mg, yield 66%) as colorless crystals.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][N:14]([CH2:25][C@H:26]([OH:28])[CH3:27])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])(=O)=O)=CC=1.[H-].[Na+].O>C1COCC1>[CH3:27][C@H:26]1[O:28][CH2:12][CH2:13][N:14]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)OCCN(C[C@@H](C)O)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCO[C@H](C)C2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2-{[(2R)-2-hydroxypropyl][(4-methylphenyl)sulfonyl]amino}ethyl 4-methylbenzenesulfonate (340 g, 0.80 mol) in dry THF (3 L) at 0° C. was added NaH (60%, 120 g, 3.00 mol) portion wise. The reaction mixture was warmed to room temperature and stirred for 14 h. The reaction was then cooled to 0° C., and water (100 mL) was added to quench the reaction. The mixture was completely quenched by pouring into water (1 L) and the phases were separated. The aqueous phase was extracted with EtOAc (3×500 mL) and the combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (8:1 petroleum ether:EtOAc) to yield the title compound as an oil.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH2:5]([O:7][CH2:8][CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=[C:11]1[CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH3:6].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH2:5]([O:7][CH2:8][CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[N:12]=[C:11]1[CH2:19][N:20]1[CH2:21][CH2:22][N:23]([CH2:2][C:3]#[N:4])[CH2:24][CH2:25]1)[CH3:6]
Reactant: N#CCCl
Reactant: CCOCCn1c(CN2CCNCC2)nc2cccnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCn1c(CN2CCN(CC#N)CC2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
A mixture of 5.3 parts of chloroacetonitrile, 14.4 parts of 3-(2-ethoxyethyl)-2-(1-piperazinylmethyl)-3H-imidazo[4,5-b]pyridine, 7.4 parts of sodium carbonate and 288 parts of N,N-dimethylformamide was stirred overnight at room temperature. The reaction mixture was stirred into water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding 13 parts (79.2%) of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperazineacetonitrile; mp. 80.7° C. (compound 75).
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25](=[O:33])[C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)[CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[O:7])=[CH:34][CH:35]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2ccc(N)cc2)cc1C
Product: CC(=O)Nc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccc(C)c(C)c2)cc1
Yield: 99.7 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3,4-dimethylphenyl)benzamide (333.1 mg, 0.70 mmol) and acetic anhydride (0.080 ml, 0.85 mmol), the procedure of Inventive Example 94 was repeated to obtain 359.9 mg (99.7%) of the title compound in a light brown amorphous form.