Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][S:4]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])=[CH:15][C:14]=2[F:30])[CH2:9][CH2:8]1)(=[O:6])=[O:5])#[N:2].C1C=C([O:37]O)C(C(O)=O)=C(C(O)=O)C=1>CO>[C:1]([CH2:3][S:4]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@@H:22]([CH2:24][NH+:25]([O-:37])[C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])=[CH:15][C:14]=2[F:30])[CH2:9][CH2:8]1)(=[O:6])=[O:5])#[N:2]
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(S(=O)(=O)CC#N)CC3)c(F)c2)C(=O)O1
Solvent: CO
Product: CC(=O)[NH+]([O-])C[C@@H]1CN(c2ccc(N3CCN(S(=O)(=O)CC#N)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(S)-N-[[3-[4-[4-[(cyanomethyl)sulfonyl]-1-piperazinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (VIII-G, R1=COCH3, R9=NCCH2, X1=F, X2=H) (0.550 g) is dissolved in 15 mL of methanol. Monoperoxyphthalic acid, magnesium salt hexahydrate (80% pure, 0.616 g) is added and the reaction is stirred at room temperature for 4 hours. The reaction is then filtered and the filtrate is concentrated to afford an oil. This oil is chromatographed on silica gel using 10% methanol (saturated with ammonia) in chloroform as eluent to afford 0.42 g of the N-oxide.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:12]2[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)=[CH:21][CH:20]=1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Fc1ccc(CBr)cc1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc(F)cc1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 4-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:55]=[C:54]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH:53]=[C:52]3[C:48]=2[CH:49]=[N:50][NH:51]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:47]4[CH:55]=[C:54]([NH:56][S:57]([CH3:60])(=[O:58])=[O:59])[CH:53]=[C:52]5[C:48]=4[CH:49]=[N:50][NH:51]5)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:38])[CH3:36])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(NS(C)(=O)=O)cc3[nH]ncc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)cc5[nH]ncc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 44.8 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (25 mg, 0.04 mmol) was treated with N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-6-yl)methanesulfonamide (35 mg, 0.10 mmol), sodium carbonate (11 mg, 0.10 mmol), 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (10 mg, 0.01 mmol) and 2 ml 1,2-dimethoxyethane and 1 ml water as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (hexane-ethyl acetate) to obtain 13 mg (42% yield) of the title compound. Purity 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([CH3:10])[CH:3]=1.CC(C[AlH]CC(C)C)C.CC[O:22]CC>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:22])=[C:4]([CH3:10])[CH:3]=1
Reactant: CCOCC
Reactant: Cc1cc(Cl)ccc1C#N
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1C=O
Reaction time: 1 h

Procedure:
To a stirred −78° C. solution of 4-chloro-2-methylbenzonitrile (5.00 g, 32.98 mmol) in Et2O (190 mL) was added 1 M DIBAL in THF (66.0 mL) over 10 min. After 5 h additional 1M DIBAL in THF (3.30 mL) was added dropwise and the solution was stirred for 1 hour. The reaction was quenched with water followed by concentrated H2SO4 and stirred at ambient temperature for 16 h. The solution was extracted into Et2O, dried (Na2SO4) and reduced in vacuo. 4-Chloro-2-methylbenzaldehyde was isolated as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 2.59 (s, 3H), 7.19 (s, 1H), 7.26 (d, J=8.2 Hz, 1H), 7.66 (d, J=8.2 Hz, 1H), 10.15 (s, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[C:16]1[N:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1.O>CS(C)=O>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:16]2[CH:17]=[CH:18][C:19]([C:22](=[O:24])[CH3:23])=[CH:20][N:21]=2)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To 4-hydroxy-boc-piperidine (1.55 g, 7.71 mmol) in DMSO (12 mL) was added 1M KtOBu (8.36 mL), followed by 1-(6-chloropyridin-3-yl)ethanone (1.00 g, 6.43 mmol). After overnight stirring at 100° C., the reaction was poured into water, extracted with dichloromethane, washed with brine, dried over sodium sulfate, and concentrated. The product was purified using a Single Step column (7:3 hexanes:ethyl acetate) to obtain 0.5 g (25%); MS m/z 321 (M+H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10]([Cl:15])=[N:9][C:8]=2[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1)[C:2]#[C:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[C:36]([C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[CH2:40]Br)#[N:37]>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:40][C:39]3[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=3[C:36]#[N:37])[C:10]([Cl:15])=[N:9][C:8]=2[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2nc(Cl)[nH]c(=O)c21
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2nc(Cl)n(Cc3ccccc3C#N)c(=O)c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.1 %

Procedure:
A mixture consisting of 100 mg of t-butyl [1-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl]piperidin-3-yl]carbamate, 66 mg of anhydrous potassium carbonate, 70 mg of 2-cyanobenzyl bromide and 1 ml of N,N-dimethylformamide was stirred at room temperature for five hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and then with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography using 50% ethyl acetate/hexane to give 44.7 mg of the title compound.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]1[C:26](=[O:27])[N:6]2[C:7]([C:23]([OH:25])=[O:24])=[C:8]([CH2:11][S:12][C:13]3[N:17]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[N:16]=[N:15][N:14]=3)[CH2:9][S:10][C@H:5]12.C([O-])(=O)C.[K+].[CH3:33][CH:34]([CH3:44])[CH2:35][C:36]([O:38][CH:39](I)[CH:40]([CH3:42])[CH3:41])=[O:37].Cl>C(Cl)Cl.CN(C)C=O>[ClH:1].[ClH:1].[NH2:3][C@@H:4]1[C:26](=[O:27])[N:6]2[C:7]([C:23]([O:25][CH:39]([O:38][C:36](=[O:37])[CH2:35][CH:34]([CH3:44])[CH3:33])[CH:40]([CH3:42])[CH3:41])=[O:24])=[C:8]([CH2:11][S:12][C:13]3[N:17]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[N:16]=[N:15][N:14]=3)[CH2:9][S:10][C@H:5]12
Reactant: CN(C)CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)CC(=O)OC(I)C(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)CC(=O)OC(OC(=O)C1=C(CSc2nnnn2CCN(C)C)CS[C@@H]2[C@H](N)C(=O)N12)C(C)C
Temperature: 0 °C
Yield: 106 %

Procedure:
To 60 ml of dimethylformamide solution containing 4.22 g of 7β-amino-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]methyl]ceph-3-em-4-carboxylic acid dihydrochloride is added 1.67 g of potassium acetate. The mixture is cooled to 0° C. With stirring, 5.0 g of 1-iodo-2-methylpropyl 3-methylbutyrate is added dropwise to the solution, followed by stirring at 0° C. for 5 minutes. The reaction mixture is poured into a mixture of 60 ml of methylene chloride and 60 ml of 0.1N-HCl and the aqueous layer is separated. The aqueous solution is adjusted to pH 6.0 with a saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. To the methylene chloride solution is added water and the mixture is adjusted to pH 2.0 with 4N-HCl. The aqueous layer is separated and lyophilized to obtain 3.0 g of the title compound.
Reaction SMILES: Cl.[N:2]1([CH2:8][C:9]([OH:11])=O)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][O:32][CH2:31][C@H:13]([NH:12][C:9](=[O:11])[CH2:8][N:2]2[CH2:3][CH2:4][O:5][CH2:6][CH2:7]2)[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)=[O:15])=[CH:35][CH:36]=1
Reactant: O=C(O)CN1CCOCC1
Reactant: N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCOCC1)N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 55 %

Procedure:
Proceeding as in Example 1, but substituting 2-morpholin-4-ylacetic acid hydrochloride and (S)-2-amino-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 210, (S)-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-morpholinoacetamido)propanamide (60 mg, 55%). 1H-NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 8.00 (s, 1H), 7.37-7.25 (m, 5H), 7.10-6.90 (m, 7H), 4.79-4.73 (m, 1H), 4.63 (m, 2H), 4.00-3.80 (m, 6H), 3.20-3.10 (s, 2H), 2.60-2.45 (m, 4H). MS (EI) for C28H29F2N3O5 found 526 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9](C#N)[CH2:10][CH2:11][C:12]([CH3:20])([CH3:19])[CH2:13][C:14]([O:16]CC)=O.Cl.C(O)(=[O:26])C.O>C(OCC)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10](=[O:26])[CH2:11][C:12]([CH3:19])([CH3:20])[CH2:13][C:14]1=[O:16]
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(C)(C)CCC(C#N)c1ccc(C)cc1C
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(C2C(=O)CC(C)(C)CC2=O)c(C)c1
Reaction time: 12 h
Yield: 32 %

Procedure:
A one-neck round bottom flask was charged with 52.50 g (0.17 mol) of ethyl 6-(2',4'-dimethylphenyl)-6-cyano-3,3-dimethylhexanoate, 250 ml of concentrated hydrochloric acid, 250 ml of glacial acetic acid, and 100 ml of water. The reaction mixture was stirred and refluxed for 48 hours. After 12 hours and 24 hrs. of refluxing, an additional 100 ml of conc. HCl and 100 ml glacial HOAC were added. After 48 hours, the mixture was stripped to dryness under reduced pressure. To the residue were added 150 ml of water and 150 ml of ethyl ether, and the mixture shaken vigorously. A white, crystalline precipitate formed, and this was removed by suction filtration to give 13.20 g (32%) of 2-(2',4'-Dimethylphenyl)-5,5-dimethyl-1,3-cyclohexanedione as a white, crystalline solid, m.p. 167°-168.5° C.
Reaction SMILES: [CH2:1]([C:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])([C:10]#[N:11])[C:8]#[N:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[H][H]>C(OCC)C>[CH2:12]([C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])([CH2:8][NH2:9])[CH2:10][NH2:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: [H][H]
Reactant: CCCCCCC(C#N)(C#N)CCCCCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCCCCCC(CN)(CN)CCCCCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.1 %

Procedure:
2,2-Dihexylpropanedinitrile (22.0 g, 94 mmol) dissolved in dry diethyl ether (100 ml) was added slowly to a suspension of lithium aluminium hydride (8.7 g, 0.23 mol) in dry diethyl ether (250 ml) under nitrogen. Upon complete addition, the mixture was heated under reflux using a water bath for 1 h and then stirred at room temperature for 24 h. Water was carefully added to the reaction mixture with cooling of the flask in an ice bath, until no more hydrogen was evolved. The reaction mixture separated into two layers and the ether layer was decanted from the aqueous layer, washed with water, and dried with anhydrous magnesium sulphate. The ether was evaporated to yield a viscous oil that was distilled under reduced pressure to yield 2,2-dihexylpropane-1,3-diamine as a colorless liquid (11.2 g, 49%) b.p. 138°-142° C./0.7 mm.
Reaction SMILES: [OH:1][C:2]1([C:8]2[N:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl.CO>C1COCC1>[OH:1][C:2]1([C:8]2[N:13]=[C:12]([CH2:14][NH2:15])[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: N#Cc1cccc(C2(O)CCOCC2)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NCc1cccc(C2(O)CCOCC2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 63.8 %

Procedure:
6-(4-Hydroxytetrahydropyran-4-yl)pyridine-2-carbonitrile (ca. 18.9 mmol) was dissolved in anhydrous THF (80 mL) and a 1 M solution of BH3 in THF (95 mL, 95 mmol) added. The solution was stirred at ambient temperature for 2.5 hours, then quenched with methanol. The solution was adjusted to pH 1 by addition of 2 N hydrochloric acid solution and then neutralised to pH 5 with a 5 N solution of sodium hydroxide. Extraction with dichloromethane was followed by addition of further 2 N sodium hydroxide to the aqueous phase until the pH reached 14. This phase was twice extracted with dichloromethane and these combined extracts were evaporated to give a yellow gum. The aqueous extracts were acidified with 2 N hydrochloric acid and concentrated to dryness to yield a white residue. Three trituration of this residue with methanol and concentration of the methanolic liquors yielded a second crop of yellow gum. Drying in vacuo gave the title compound (2.51 g, 64%) as a foamy yellow solid; NMR δH (400 MHz, DMSO) 8.53 (1H, br s), 7.85 (1H, t, J 7.8 Hz), 7.62 (1H, d, J 7.8 Hz), 7.34 (1H, d, J 7.5 Hz), 5.75 (1H, s), 3.72 (4H, m), 3.16 (2H, s), 2.29 (2H, m), 1.42 (1H, d, J 12.3 Hz); LC-MS Retention time 0.43 min, (M+H)+ 209.
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[CH:7][O:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C1C=CC=CC=1>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([Br:11])[O:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1c(C)coc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)c1c(C)oc(Br)c1C
Yield: 88 %

Procedure:
A mixture of 3-acetyl-2,4-dimethylfuran (commercially available from Aldrich Chemical Co., Inc., 1 g, 7.24 mmol), N-bromosuccinimide (NBS; 1.3 g, 7.3 mmol), and 2,2′-azobisisobutyronitrile (AIBN; 3 mg) in benzene (10 mL) was heated at reflux temperature for one hour. After cooling, water (50 mL) was added to the mixture. The whole was extracted with benzene (50 mL), the organic layer washed with water, brine, dried over MgSO4, and concentrated in vacuo. Chromatographic purification of the residue eluting with ethyl acetate-hexane (1:10) provided the subtitle compound (1.38 g, 88% yield) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:28][C:27]([CH3:29])=[N:26][C:25]=2[C:30](O)=[O:31])=[CH:20][CH:19]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([NH:16][C:30]([C:25]2[N:26]=[C:27]([CH3:29])[O:28][C:24]=2[C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[O:31])[CH:13]=[N:12]1
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(Cl)cc2)o1
Product: CC(=O)CCCCn1cc(NC(=O)c2nc(C)oc2-c2ccc(Cl)cc2)cn1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and 5-(4-chloro-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 01: tR=0.99 min; [M+H]+=401.13.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[CH3:15][CH:16]([CH3:20])[CH2:17][CH2:18]Br>>[CH3:15][CH:16]([CH3:20])[CH2:17][CH2:18][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14]
Reactant: CC(C)CCBr
Reactant: OCCCCCCCCCCCCBr
Product: CC(C)CCCCCCCCCCCCCCO

Procedure:
15-methylhexadecan-1-ol was prepared from 12-bromo-1-dodecanol and 3-methylbutylbromide. The 1H NMR was identical to that reported by Masuda et al. ((2002) Biosci. Biotech. Biochem. 66:1531-1537).
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: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CN1CCCC1CCN
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, 3H), 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: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.[C:13]1(O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(Cl)(Cl)(Cl)=O>CCOCC>[C:1]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Reactant: Oc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C(Oc1ccccc1)c1cc(O)c(O)c(O)c1

Procedure:
A reaction mixture was prepared containing 15 g. of anhydrous gallic acid, 8 g. of phenol, 4 ml. of phosphorous oxychloride and 200 ml. of anhydrous ether in a round-bottom flask. The mixture was heated to refluxing temperature for about 18 hours. The ether solvent was removed by evaporation. Water was added to the resulting residue and the pH of the aqueous layer adjusted to about 5 by the addition of dilute aqueous sodium hydroxide. Phenyl gallate, being insoluble at pH=5, separated and was extracted with ether. The ether extracts were separated and dried and the ether removed therefrom by evaporation. Recrystallization of the residue yielded phenyl gallate melting at about 190°-191° C.
Reaction SMILES: [C:1]1([C:7]([NH:20][CH2:21][CH2:22][OH:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:26][CH:27](Cl)[C:28]1[C:29]([CH3:34])=[CH:30][CH:31]=[CH:32][CH:33]=1.O>C1COCC1>[Cl:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][O:23][CH2:22][CH2:21][NH:20][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1C(Cl)Cl
Reactant: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: ClCc1ccccc1COCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 2-(triphenylmethylamino)ethanol (5.00 g, 16.5 mmol) in THF (20 ml) was added dropwise to a suspension of NaH (60% in oil, 0.79 g, 19.8 mmol) in THF (30 ml) at room temperature and the mixture was stirred for 0.5 hour. α,α-Dichloro-o-xylene (1.56 g, 66.0 mmol) was added and the mixture was stirred for 24 h at reflux temperature. The mixture was poured into water (50 ml) and the whole was extracted with ether (50 ml×2). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=15/1 as eluent) to afford the titled compound as a colorless oil. (1.00 g, 14%)
Reaction SMILES: Br[C:2]1[C:3]([F:31])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[N:22]([CH3:23])[N:21]=[C:20]([C:24]5[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=5)[N:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:30]=1.[CH3:32][C:33]([OH:37])([C:35]#[CH:36])[CH3:34]>>[F:31][C:3]1[C:2]([C:36]#[C:35][C:33]([OH:37])([CH3:34])[CH3:32])=[CH:30][C:6]2[C:7]3[N:8]([C:12]([C:18]4[N:22]([CH3:23])[N:21]=[C:20]([C:24]5[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=5)[N:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(C)O
Reactant: Cn1nc(-c2ccncc2)nc1-c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Product: Cn1nc(-c2ccncc2)nc1-c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#CC(C)(C)O)cc1-2
Yield: 35.3 %

Procedure:
The title compound was prepared similarly according to Procedure E. 10-bromo-9-fluoro-3-(1-methyl-3-(pyridin-4-yl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-methyl-3-butyn-2-ol to afford 35.3% yield of the titled product. 1H NMR (400 MHz, DMSO) δ 8.73-8.67 (m, 3H), 7.99 (br s, 1H), 7.97-7.93 (m, 2H), 7.47 (br s, 1H), 7.06 (d, J=10.5 Hz, 1H), 5.53 (s, 1H), 4.58-4.52 (m, 2H), 4.38-4.28 (m, 2H), 3.83 (s, 3H), 1.51 (s, 6H). M+H=488.2
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:16]=[C:17]([Cl:28])[C:18]([S:20][C:21]4[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)=[CH:19][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.C1COCC1.O[Li].O>O>[Cl:28][C:17]1[C:18]([S:20][C:21]2[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=2)=[CH:19][C:13]2[N:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)[NH:15][C:14]=2[CH:16]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Sc4cccc(C)c4)c(Cl)cc3[nH]2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(Sc2cc3nc(-n4cc(C(=O)O)cn4)[nH]c3cc2Cl)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
To a mixture of 1-(6-chloro-5-m-tolylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.100 g, 0.242 mmol), THF (1 mL), and water (0.3 mL) was added LiOH.H2O (40.7 mg, 0.969 mmol). The mixture was stirred for 18 h at 23° C. The solvent was evaporated, water (3 mL) was added and the mixture acidified with 1M HCl. The resulting white precipitate was filtered and dried to yield the titled compound (85.0 mg, 89%). MS (ESI/CI): mass calcd. for C18H13ClN4O2S, 384.0; m/z found, 385.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 8.82 (s, 1H), 8.22 (s, 1H), 7.73 (s, 1H), 7.43 (s, 1H), 7.27 (t, J=7.9 Hz, 1H), 7.15-7.10 (m, 2H), 7.04 (d, J=7.9 Hz, 1H), 2.27 (s, 3H).