Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])(=[O:5])=[O:4].C([Li])CCC.CN([CH:27]=[O:28])C>C1COCC1>[CH3:1][N:2]([CH3:18])[S:3]([N:6]1[CH:10]=[C:9]([CH:27]=[O:28])[N:8]=[C:7]1[Si:11]([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:13])[CH3:12])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(C=O)nc1[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h

Procedure:
To a stirred, cooled (−78° C.) solution of 2-(tert-butyl-dimethyl-silanyl)-imidazole-1-sulfonic acid dimethylamide (1.02 g; CAS 129378-52-5) in THF (20 ml) under an argon atmosphere was added dropwise butyl lithium (3.3 ml; 1.6 M solution in hexanes) over a period of 10 minutes. After 30 minutes of stirring, DMF (1.3 ml) was added over a period of 5 minutes and the mixture (clear light yellow solution) was stirred at −78° C. for another 2 hours. The mixture was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated to give 2-(tert-butyl-dimethyl-silanyl)-4-formyl-imidazole-1-sulfonic acid dimethylamide (1.22 g) as viscous orange oil which was used in the next reaction step without further purification. MS (ISP): 318.3 ([M+H]+)
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[C:5]([O:20][CH3:21])[CH:4]=1.[C-:22]#[N:23].[K+].C1OCCOCCOCCOCCOCCOC1.O>CN(C)C=O>[CH3:21][O:20][C:5]1[CH:4]=[C:3]([CH2:2][C:22]#[N:23])[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=1
Reactant: COc1ccc(-c2cc3cc(OC)cc(CBr)c3o2)cc1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3cc(OC)cc(CC#N)c3o2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a solution of benzyl bromide 17 (0.640 g, 1.843 mmole) in 100 mL dimethylformamide was added pulverized potassium cyanide (0.186 g, 2.76 mmole) and 18-crown-6 ether (0.786 g, 2.965 mmole). After stirring at 80° C. for 2 hours, the reaction mixture was cooled and poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 9:1) to afford 0.529 g (98%) of acetonitrile 18 as a white solid: Mp=149–150° C.; 1H NMR (DMSO-d6) δ 7.87 (d, 2 H, J=8.8 Hz), 7.26 (s, 1 H), 7.12 (d, 1 H, J=2,4 Hz), ), 7.10 (d, 2 H, J=8.7 Hz), 6.88 (d, 1 H, J=2.4 Hz), 4.42 (s, 2 H), 3.82 (s, 3 H), 3.81 (s, 3 H); MS 294 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14]CCN1C(=O)C3C(=CC=CC=3)C1=O)[C:7]([CH3:28])=[C:6]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:35]([NH:42][CH2:43]CBr)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH2:14][CH2:43][NH:42][C:35](=[O:36])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:7]([CH3:28])=[C:6]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc2c(=O)n(CCCN3C(=O)c4ccccc4C3=O)c(C)c(-c3ccccc3)c2c1
Reactant: CC(C)(C)OC(=O)NCCBr
Product: COc1ccc2c(=O)n(CCNC(=O)OC(C)(C)C)c(C)c(-c3ccccc3)c2c1

Procedure:
Following the procedure for 2-[3-(6-methoxy-3-methyl-1-oxo-4-phenylisoquinolin-2(1H)-yl)propyl]-1H-isoindole-1,3(2H)-dione, using 2-(Boc-amino) ethyl bromide in place of 3-phthalimido-1-bromopropane, tert-butyl 2-(6-methoxy-3-methyl-1-oxo-4-phenylisoquinolin-2(1H)-yl)ethylcarbamate was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[C:7]([NH:9][CH2:10][C:11]([NH:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:12])=[O:8])([O-])=O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[C:7]([NH:9][CH2:10][C:11]([NH:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:12])=[O:8]
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc([N+](=O)[O-])c1)c1ccccc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(N)c1)c1ccccc1

Procedure:
A solution of ethyl 3-{2-[(3-(nitro)benzoyl)amino]acetamido}-3-phenyl-propanoate from II.3a (2.7 g) in 100 ml of ethanol was treated with Tin(II) chloride (7.6 g) and heated under reflux for 3 h. The reaction mixture was then added to ice, rendered neutral with NaHCO3 solution and filtered through Celite. The filtrate was extracted with methylene chloride, dried (MgSO4) and concentrated. Chromatographic purification (purification (methylene chloride/methanol (5:1)) yielded the product (yield: 2.0 g).
Reaction SMILES: [NH2:1][C:2](=[N:23][OH:24])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]2)[CH:4]=1.[CH3:25][O:26][CH2:27]C(Cl)=O>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:25][O:26][C:27]1[O:24][N:23]=[C:2]([C:3]2[CH:8]=[CH:7][N:6]=[C:5]([N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:16])[CH2:11][CH2:10]3)[CH:4]=2)[N:1]=1
Reactant: COCC(=O)Cl
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(C(N)=NO)ccn2)CC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1nc(-c2ccnc(N3CCN(C(=O)OCC(C)(C)C)CC3)c2)no1

Procedure:
2,2-Dimethylpropyl 4-{4-[amino(hydroxyimino)methyl]pyridin-2-yl}piperazine-1-carboxylate (84 mg) obtained in Example 26-1) was dissolved in pyridine (2 mL), and methoxyacetyl chloride (0.035 mL) was added thereto and heated under reflux for 90 minutes. The reaction liquid was diluted with ethyl acetate, washed with 1 N hydrochloric acid, aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through silica gel column chromatography (hexane/ethyl acetate=7/3) to obtain 54 mg of the entitled compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[OH:30])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O-:26])=[S:25])=[C:15]([CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:32]([O:38][CH2:39]I)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[OH:30])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O:26][CH2:39][O:38][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[S:25])=[C:15]([CH:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: Nc1nc(/C(=N/O)C(=O)NC2C(=O)N3C(C([O-])=S)=C(C4CCOCC4)CS[C@H]23)cs1
Agent: [Na+]
Product: CC(C)(C)C(=O)OCOC(=S)C1=C(C2CCOCC2)CS[C@@H]2C(NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12
Yield: 55.5 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(tetrahydropyran-4-yl)thio-3-cephem-4-carboxylate (85 mg) was reacted with iodomethyl pivalate (61 mg), followed by purifying the reaction product in accordance with the procedure of Example 4, yielding the titled compound (56 mg, 55%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[CH:6][CH2:7][CH3:8])[CH:3]1[C:9](O)=[O:10].S(Cl)([Cl:15])=O>CN(C)C=O.CCCCCC>[CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[CH:6][CH2:7][CH3:8])[CH:3]1[C:9]([Cl:15])=[O:10]
Reactant: CCC=CC1C(C(=O)O)C1(C)C
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCC=CC1C(C(=O)Cl)C1(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
Fifty grams (50 g) of 2,2-dimethyl-3-(1-butenyl)cyclopropanecarboxylic acid, 350 ml of hexane and 0.6 g of N,N-dimethylformamide were mixed together. At 50° C., 39 g of thionyl chloride was eye-dropped thereto over 30 minutes. Subsequently, the reaction mixture was stirred for 1 hour at 50° C. The reaction mixture was then concentrated under reduced pressure to provide 48 g of 2,2-dimethyl-3-(1-butenyl)cyclopropane carboxylic chloride.
Reaction SMILES: C(OC([N:8](CC1C=CC(OC)=CC=1)[C:9]1[C:10]([Cl:29])=[C:11]([C:17]2([F:28])[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]2)[CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)=O)(C)(C)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([C:17]2([F:28])[CH2:18][NH:19][CH2:20]2)[C:10]=1[Cl:29])[C:15]#[N:16]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(C#N)cc(C3(F)CN(C(=O)OC(C)(C)C)C3)c2Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: N#Cc1cc(N)c(Cl)c(C2(F)CNC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-(3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanophenyl)-3-fluoroazetidine-1-carboxylate, (Example 658B) (321 mg) in DCM (15 ml) was added anisole (0.5 mL, 4.52 mmol), followed by TFA (7 ml). The resulting mixture was stirred at room temperature overnight. Solvent was removed. The residue was taken in MeOH and applied onto a cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and the product was eluted with 2 N solution of ammonia in methanol. Removal of the solvents left 3-amino-4-chloro-5-(3-fluoroazetidin-3-yl)benzonitrile (127 mg) as a solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:35])[NH:15][CH:16]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:20]1([CH2:19][CH2:18][CH2:17][CH:16]([NH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:35])[CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
4-[4-Phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (3) (0.77 g; 1.61 mmol) is dissolved in methylene chloride (20 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added in a slow stream, and the solution is stirred for 90 minutes at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is slurried in a mixture of methylene chloride (10 mL) and water (100 mL), then potassium carbonate is added until the slurry is alkaline. The slurry is diluted with water (200 mL) then extracted with methylene chloride (3×100 mL). The organic extracts are dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (0.58 g) as an oil.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[Cl:27][C:28]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:29]=1[NH2:30].C(=O)([O-])[O-].[Na+].[Na+].ClC1C=CC=CC=1Cl>[Cu]I.C1(C)C=CC=CC=1.N1C=CC=CC=1>[Cl:27][C:28]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:29]=1[NH:30][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:18][C:19](=[O:26])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: O=C(Nc1ccc(Cl)c2c1C(=O)c1ccccc1C2=O)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Nc2ccc([N+](=O)[O-])cc2Cl)c2c1C(=O)c1ccccc1C2=O)c1ccccc1
Reaction time: 7 h

Procedure:
36.15 parts of 1-chloro-4-benzoylaminoanthraquinone, 21.6 parts of 2-chloro-4-nitroaniline and 10 parts of sodium carbonate are stirred in 400 parts of o-dichlorobenzene. A solution of 0.4 part of copper-(I) iodide in 5 parts of pyridine, and 25 parts of toluene, are added and the mixture is heated to the boil -- 160° to 165°. The water liberated is distilled off azeotropically and the toluene is recirculated. After a reaction time of 45 minutes, the reaction product begins to precipitate. The mixture is stirred for 7 hours at 160°-165° and is then allowed to cool. The precipitate is filtered off, washed with o-dichlorobenzene, acetone and hot water, and extracted by boiling with dilute hydrochloric acid. 34.4 parts of 1-(2'-chloro-4'-nitroanilino)-4-benzoylaminoanthraquinone are obtained in the form of a dark powder. The colorant bulk-dyes PES in claret-colored shades of good fastness properties.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:22][C:23](=O)[CH2:24][C:25]([O:27]CC)=O)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=2)=[N:6][CH:7]=1.C(O)C.O.[NH2:35][NH2:36]>C1COCC1>[Br:1][C:2]1[C:3]([CH2:22][C:23]2[CH2:24][C:25](=[O:27])[NH:36][N:35]=2)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)Cc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Reactant: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C1CC(Cc2cc(Nc3nc(CCc4ccccc4)cs3)ncc2Br)=NN1
Temperature: 45 °C
Reaction time: 4 h
Yield: 55.6 %

Procedure:
A flask was charged with ethyl 4-(5-bromo-2-(4-phenethylthiazol-2-ylamino)pyridin-4-yl)-3-oxobutanoate (0.0500 g, 0.1024 mmol) and ethanol (2 mL), and hydrazine hydrate (0.007471 mL, 0.1536 mmol) was added. The mixture was stirred at 45° C. for 4 hours. THF (2 mL) was added, and the mixture was stirred for 18 hours at 60° C. The mixture was concentrated and the residue was triturated with 50% ethyl acetate/hexane to afford the desired product (26 mg, 55.65% yield) as a white solid. 1H NMR (d6-DMSO) δ 2.83-2.96 (m, 4H), 3.87 (s, 2H), 5.27 (s, 1H), 6.59 (s, 1H), 6.94 (s, 1H), 7.17-7.29 (m, 5H), 8.38 (s, 1H).
Reaction SMILES: [O:1]([CH2:9][C:10]1[N:14]([CH2:15][C:16]2[CH:35]=[CH:34][C:19]3/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=4[O:23][CH2:24][C:18]=3[CH:17]=2)[C:13]2[CH:36]=[CH:37][CH:38]=[C:39]([OH:40])[C:12]=2[N:11]=1)[Si](C(C)(C)C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:48]([F:53])([F:52])C([O-])=O.[Na+].[Cl-].[NH4+]>CN(C=O)C>[F:52][CH:48]([F:53])[O:40][C:39]1[C:12]2[N:11]=[C:10]([CH2:9][OH:1])[N:14]([CH2:15][C:16]3[CH:35]=[CH:34][C:19]4/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=5[O:23][CH2:24][C:18]=4[CH:17]=3)[C:13]=2[CH:36]=[CH:37][CH:38]=1
Reactant: C/C(C#N)=C1/c2ccc(Cn3c(CO[Si](C)(C)C(C)(C)C)nc4c(O)cccc43)cc2COc2cc(F)ccc21
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C/C(C#N)=C1/c2ccc(Cn3c(CO)nc4c(OC(F)F)cccc43)cc2COc2cc(F)ccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
[step 2] (E)-2-[8-({2-[(tert-butyldimethylsiloxy)methyl]-4-hydroxy-1H-benzo[d]imidazol-1-yl}methyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (200 mg, 0.36 mmol) obtained in step 1 was dissolved in DMF (5.5 mL), cesium carbonate (352 mg, 1.08 mmol) and sodium 2-chloro-2,2-difluoroacetate (165 mg, 1.08 mmol) were added, and the mixture was stirred at 60° C. for 1 hr. To the mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 v/v-20/80 v/v) to give (E)-2-(8-{[4-(difluoromethoxy)-2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl]methyl}-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (55 mg, 31%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Cl-].[Cl-].[Al+3].[CH3:11][O:12][CH2:13][CH2:14][NH:15][C:16]([C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][NH:24]2)=[CH:20][CH:19]=1)=O>O1CCCC1>[CH3:11][O:12][CH2:13][CH2:14][NH:15][CH2:16][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][NH:24]2)=[CH:20][CH:19]=1
Reactant: COCCNC(=O)c1ccc2cc[nH]c2c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COCCNCc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
To a suspension of lithium aluminum hydride (0.93 g, 24.5 mmol) in anhydrous tetrahydrofurane (15 ml), aluminum trichloride (3.5 g, 24.5 mmol) was added portionwise at 0° C. for 30 min and then 6-[N-(2-methoxyethyl)carbamoyl]indole (1 g, 4.5 mmol) was added portionwise at 0° C. for 1 h. After stirring overnight at room temperature, the reaction mixture was quenched with 20% NaOH while cooling in ice water. The precipitate was filtered and washed with dichloromethane and the solvent evaporated after dried over anhydrous sodium sulfate. The residue was chromatographed on silica gel (eluent, dichloromethane:methanol, 9:1) and then the product was precipitated with hexane to give 0.3 g (32%) of 6-[(2-methoxyethyl)aminomethyl]indole.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](C(C)=O)[CH3:8].C(I)C.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1>O>[CH2:7]([O:23][C:19]1[CH:18]=[C:17]([C:16]([F:24])([F:25])[F:15])[CH:22]=[CH:21][CH:20]=1)[CH3:8]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: O
Product: CCOc1cccc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
Potassium carbonate (22.6 g) and then a mixture of methyl ethyl ketone (MEK) (150 mL) and ethyl iodide (47.8 g) were added to a mixture of MEK (310 mL) and 3-trifluoromethylphenol (a) (25.0 g) at room temperature, and the reaction mixture was heated and stirred for 2 hours. After returning the mixture to room temperature, water was added for liquid separation and the aqueous layer was extracted three times with diethyl ether. The organic layers were combined, washed with an 1 M aqueous sodium hydroxide solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 19.3 g of Compound (b).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:20](=O)[C:21]([F:24])([F:23])[F:22])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=[CH:6]2.[CH3:26][C:27]([S:30]([NH2:32])=[O:31])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1.CCOC(C)=O.[Cl-].[Na+].O>[C:27]([S:30]([N:32]=[C:20]([C:4]1[C:3]([O:2][CH3:1])=[CH:11][C:10]([CH3:12])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[C:21]([F:22])([F:24])[F:23])=[O:31])([CH3:29])([CH3:28])[CH3:26]
Reactant: CC(C)(C)S(N)=O
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(=NS(=O)C(C)(C)C)C(F)(F)F
Temperature: 100 °C

Procedure:
To a solution of tert-butyl 5-methoxy-7-methyl-4-(2,2,2-trifluoroacetyl)-1H-indole-1-carboxylate (0.45 g, 1.26 mmol) and 2-methyl-2-propanesulfinamide (0.46 g, 3.78 mmol) in toluene (12.6 mL), Zr(O-t-Bu)4 (2.52 mL, 6.30 mmol) was added at room temperature, and the reaction was heated to 100° C. After 15 minutes the reaction mixture was cooled to room temperature and diluted with EtOAc and sat. aq. brine. The resulting mixture was filtered and the layers separated. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-50% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 461.3 (M+H).
Reaction SMILES: CC(C)(C)C[C:4](=[O:20])[CH2:5][C@H:6]([C:10]1[O:11][CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=1)[CH2:7][CH:8]=[CH2:9].O.[OH-].[Li+].[OH-].[Li+].C(O)(=O)[CH2:29][C:30]([CH2:35]C(O)=O)([C:32](O)=O)[OH:31]>O1CCOCC1.O>[C:30]([O:31][C:4](=[O:20])[CH2:5][C@H:6]([C:10]1[O:11][CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=1)[CH2:7][CH:8]=[CH2:9])([CH3:35])([CH3:32])[CH3:29]
Reactant: C=CC[C@H](CC(=O)CC(C)(C)C)c1nc(C(=O)OCC)co1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=CC[C@H](CC(=O)OC(C)(C)C)c1nc(C(=O)O)co1
Temperature: 0 °C
Reaction time: 4 h
Yield: 228.7 %

Procedure:
Two identical reactions were put on each containing the following: A solution of ethyl 2-[(1R)-1-(4,4-dimethyl-2-oxopentyl)-3-butenyl]-1,3-oxazole-4-carboxylate (Preparation 115) (4.0 g, 12.9 mmol) in 1,4-dioxan (40 ml) and water (20 ml) was cooled to 0° C. and treated with lithium hydroxide monohydrate (0.8 g, 19.0 mmol). The mixture was stirred at 0° C. for 4 hours. Further lithium hydroxide monhydrate (0.8 g, 19.0 mmol) was added and stirred at 0° C. for 10 minutes. The two reactions were combined and partitioned between ethyl acetate and water. The aqueous layer was neutralised with citric acid (16.3 g, 38.0 mmol) and extracted with ethyl acetate (×3). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a colourless oil (8.3 g).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([CH2:23][CH2:24][C:25](O)=[S:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][SH:34])=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:16]([CH2:23][CH2:24][C:25](=[S:26])[S:34][CH2:33][C:32]1[CH:35]=[CH:36][C:29]([F:28])=[CH:30][CH:31]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Fc1ccc(CS)cc1
Reactant: OC(=S)CCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Fc1ccc(CSC(=S)CCCc2ccccc2)cc1
Reaction time: 8 h

Procedure:
6.18 g (30 mmoles) of dicyclohexylcarbodiimide in 20 ml of methylene chloride were added to a solution, which had been cooled to 0° C., of 5.9 g (30 mmoles) of 3-benzylthiopropionic acid and 4.26 g (30 mmoles) of 4-fluorobenzylmercaptan in 25 ml of methylene chloride, and the mixture was kept overnight at room temperature. After filtering off the dicyclohexylurea and stripping off the solvent, the crude product was purified, first by chromatography, on silica gel, from 1:2 methylene chloride/petroleum ether and then by distillation in a bulb tube.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15]>ClCCl>[CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[O:15]
Reactant: CC(C)CCCCCCCCCCCCO
Solvent: ClCCl
Product: CC(C)CCCCCCCCCCCC=O
Reaction time: 1.5 h
Yield: 50.9 %

Procedure:
Chloro-chromic pyridine (161.6 g, 0.75 mole) and 450 ml dichloromethane were added to a flask. With stirring, 150 ml dichloromethane solution of 13-methyl-1-tetradecanol (114 g, 0.50 mole) was slowly added to the flask and stirring continued for 1.5 hours at room temperature. Let the mixture stand and separate into two phases. Decant upper phase and wash the remainder with 100 ml diethyl ether. Combine all liquid and wash sequentially with saturated NaCl, 10% HCl, and saturated NaCl solution with 5% NaHCO3. Desiccate with anhydrous CaCl2 and remove solvent by evaporation to yield 13-methyl-tetradecanaldehyde (57.6 g, yield rate 51%).
Reaction SMILES: C(OCC)(=O)CC(C)=O.Cl.[C:11]([NH:15][NH2:16])([CH3:14])([CH3:13])[CH3:12].[CH:17]1([C:20]2N(C(C)C)N=[CH:22][C:21]=2[CH:28]=[O:29])CC1>>[C:11]([N:15]1[C:20]([CH3:17])=[C:21]([CH:28]=[O:29])[CH:22]=[N:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCOC(=O)CC(C)=O
Product: Cc1c(C=O)cnn1C(C)(C)C

Procedure:
1-tert-Butyl-5-methyl-1H-pyrazole-4-carbaldehyde was prepared with ethyl acetoacetate and tert-butyl hydrazine hydrochloride in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).