Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1N.Cl.N([O-])=O.[Na+].[Cl-].ClC1C=CC(Cl)=CC=1[N+]#N.NC(N)=[S:28].[OH-].[Na+]>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[SH:28]
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: NC(N)=S
Agent: [Cu+2]
Agent: Cl
Agent: N#[N+]c1cc(Cl)ccc1Cl
Solvent: O
Product: Sc1cc(Cl)ccc1Cl
Reaction time: 1 h

Procedure:
162 g of 2,5-dichloroaniline are introduced into a mixture of 500 ml of water and 350 ml of 10 N hydrochloric acid and diazotized in the conventional manner at 0° to 5° C. with a solution of 76 g of sodium nitrite in 150 ml of water. The resulting solution of 2,5-dichlorophenyl-diazonium chloride is then run at a temperature of 10° to 15° C. into a well stirred mixture of 91.2 g of thiourea, 5 g of copper(II) sulphate pentahydrate and 5 g of Corlite® in 500 ml of water. The mixture is stirred for approximately 1 further hour, the pH value is raised to 8.5 by means of 330 ml of 10 N sodium hydroxide solution and the mixture is hydrolysed for 1 hour at 90° C. The pH value is then adjusted to 3 by means of 10 N hydrochloric acid and the resulting 2,5-dichlorothiophenol is isolated by steam distillation. (Corlite® is a registered trademark of Corneco-Chemie GmbH., Dortmund) Yield: 154 g of 2,5-dichlorothiophenol (86% of theory), Boiling point: 126° to 129° C./10 mbar.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH:4]3[C:11](Cl)=[O:12])[CH2:2]1)[CH2:8]2.[NH2:14][C@H:15]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16]1>>[C:22]1([CH2:21][CH2:20][N:17]2[CH2:18][CH2:19][CH:15]([NH:14][C:11]([CH:4]3[CH:5]4[CH2:10][N:1]5[CH2:8][CH:7]([CH2:9][C@@H:3]3[CH2:2]5)[CH2:6]4)=[O:12])[CH2:16]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(Cl)C1C2CC3CC1CN(C3)C2
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Product: O=C(NC1CCN(CCc2ccccc2)C1)C1C2CC3C[C@@H]1CN(C3)C2

Procedure:
1-Azaadamantane-4-carbonyl chloride and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-1-azaadamantane-4-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:64]=[CH:63][C:53]2[NH:54][C:55]([C@@H:57]([NH2:62])[CH2:58][O:59][CH2:60][CH3:61])=[N:56][C:52]=2[CH:51]=1.BrCl>O1CCCC1.ClCCl.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([NH:62][C@H:57]([C:55]1[NH:54][C:53]2[CH:63]=[CH:64][C:50]([Cl:49])=[CH:51][C:52]=2[N:56]=1)[CH2:58][O:59][CH2:60][CH3:61])=[O:7]
Reactant: O=C(O)c1ccc(C(=O)N2CC=CC2)c(Br)c1
Reactant: CCOC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClBr
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)c(Br)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 32 %

Procedure:
Prepared analogously to Example 1g from 3-bromo-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-ethoxyethylamine in tetrahydrofuran. Yield: 32%; Rf value: 0.5 (silica gel: dichloromethane/ethanol=9:1); C23H22BrClN4O3 (517.809); mass spectrum: (M+H)+=517/519/521 (bromo-chlorine isotope).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[N+:9]=1[O-:10])=[N+]=[N-]>C(O)(C)C>[C:4]([C:5]1[N:9]([OH:10])[C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)#[N:1]
Reactant: COC(=O)c1cccc(N=[N+]=[N-])[n+]1[O-]
Solvent: CC(C)O
Product: COC(=O)c1ccc(C#N)n1O

Procedure:
A solution of methyl 6-azidopyridine-2-carboxylate 1-oxide (Intermediate 127, 2.6 g, 13 mmol) in isopropanol was bubbled with nitrogen for 20 minutes followed heating to reflux for 16 hours. The solution was concentrated to a red oil (2.55 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: ClCCN1CCOCC1
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Agent: Cl
Product: Cc1cc(N2CCCC2)c2ccc(OCCN3CCOCC3)cc2n1

Procedure:
In analogy to example 6 there was prepared: on reaction of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 4-(2-chloroethyl)-morpholine hydrochloride, whereby the product was isolated as free base, 2-methyl-7-(2-morpholin-4-yl-ethoxy)-4-pyrrolidin-1-yl-quinoline as a brown solid. ISP mass spectrum, m/e: 342.3 (M+1 calculated for C20H27N3O2: 342).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:6][CH:5]=1.[OH-].[K+].Cl>O1CCOCC1>[CH3:20][CH:13]([CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:12][CH2:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:21])=[O:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(OCCC(C)CCCC(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)CCCC(C)CCOc1ccc(C(=O)O)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 92.9 %

Procedure:
Methyl[4-(3,7-dimethyl-1-octyloxy)]benzoate (16.1 g, 54.9 mmol) was dissolved in 1,4-dioxane (300 ml), 50% aqueous potassium hydroxide solution (25 ml) was added and the mixture was stirred at 100° C. for 6 hr. To acidify the reaction mixture, concentrated hydrochloric acid was added dropwise, and the mixture was extracted with ethyl acetate (200 ml), and washed with 10% aqueous sodium hydroxide solution (100 ml) and saturated brine (100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (14.2 g, 92.8%) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[N:8]([CH2:15][C:16]([OH:20])([CH3:19])[CH2:17][OH:18])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[N:11]=1.Cl>N1C=CC=CC=1>[Cl:6][C:7]1[N:8]([CH2:15][C:16]([OH:20])([CH3:19])[CH2:17][O:18][S:2]([CH3:1])(=[O:4])=[O:3])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[N:11]=1
Reactant: CC(O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(O)(COS(C)(=O)=O)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Methanesulfonyl chloride (2.01 ml, 25.72 mmol) was added to a solution of 2-chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 3 (5.05 g, 21.43 mmol) in pyridine (10 ml) with cooling on ice-bath and the resulting mixture was stirred at room temperature for 1.5 hours. 6N hydrochloric acid was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, and then concentrated under reduced pressure to afford 2-chloro-1-(2-hydroxy-3-methanesulfonyloxy-2-methylpropyl)-4-nitroimidazole (6.72 g, quantitative) as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:16])=[C:8](C(O)=O)[CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:16])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(O)c(C(=O)O)cnc2c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1ccc2c(O)ccnc2c1
Temperature: 25 °C

Procedure:
7-Ethyl-4-hydroxyquinoline-3-carboxylic acid (200.8 g.) was added portionwise during 70 minutes to boiling diphenyl ether (1.64 liters). The stirring mixture was cooled to room temperature and an equal volume of petroleum ether (b.p. 60°-80°) added. The brown solid was collected and crystallised from water to give the novel 7-ethyl-4-hydroxyquinoline m.p. 148°-152°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)=[CH:27][CH:26]=[CH:25][C:24]=2[O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[N:3]=1.CC[O:46][C:47]([CH:49](P(OCC)(OCC)=O)[F:50])=O.[Cl-].[Li+].N12CCCN=C1CCCCC2>C(#N)C>[CH:41]1([CH2:40][O:39][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C:23]=2[C:4]2[CH:5]=[C:6]([CH:10]3[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:11]3)[C:7]3[CH:8]=[C:49]([F:50])[C:47](=[O:46])[NH:1][C:2]=3[N:3]=2)[CH2:43][CH2:42]1
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c(C=O)c(N)n2)cc1
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(C3CCCN(C(=O)OC(C)(C)C)C3)c3cc(F)c(=O)[nH]c3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of tert-butyl 3-(2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-3-formyl-4-pyridinyl)-1-piperidinecarboxylate (0.500 g, 0.851 mmol), triethyl-2-fluoro-2-phosphonoacetate (0.350 mL, 1.701 mmol) and anhydrous lithium chloride (0.072 g, 1.701 mmol) in acetonitrile (20 mL) was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.250 mL, 1.701 mmol). The mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue (liquid) was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1-1/1) to give tert-butyl 3-(2-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-6-fluoro-7-oxo-7,8-dihydro-1,8-naphthyridin-4-yl)-1-piperidinecarboxylate as a form (0.261 g, 49%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4](Cl)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([Cl:13])=[C:8]([Cl:14])[CH:7]=2.[CH3:16][S:17]([OH:19])=[O:18].[Na]>CN(C=O)C>[Cl:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[Cl:14])[N:5]=[C:4]([S:17]([CH3:16])(=[O:19])=[O:18])[C:3]([CH2:2][S:17]([CH3:16])(=[O:19])=[O:18])=[N:12]2
Reactant: CS(=O)O
Reactant: ClCc1nc2cc(Cl)c(Cl)cc2nc1Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1nc2cc(Cl)c(Cl)cc2nc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-chloromethyl-2,6,7-trichloroquinoxaline (150 mg, 0.53 mmol) in DMF (3 ml) was added methanesulfinic acid, sodium salt (120 mg, 1.06 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified by column chromatography (ethyl acetate:hexane 1:2) to afford the title compounds as a white solid.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:44]2([CH3:45])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:46])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:24]/[CH:25]=[CH:26]\[C:27]([CH2:38][CH3:39])([O:30][Si](CC)(CC)CC)[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([O:47][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:44]2([CH3:45])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:46])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:24]/[CH:25]=[CH:26]\[C:27]([CH2:38][CH3:39])([OH:30])[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([OH:47])[CH2:10]1
Reactant: CCC(/C=C\CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(/C=C\CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C)CC
Yield: 98 %

Procedure:
By the same procedure as in Example 9, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{(Z)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)}pregna-5,7,16-triene (82.0 mg, 0.103 mmol), tetrahydrofuran (3 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted (heating under reflux for 5.5 hours) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to give the title compound as a white solid (46.1 mg, 98%).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:14][C:15]1[CH:19]=[CH:18][O:17][C:16]=1[C:20](OC)=[O:21].Cl>C1COCC1>[CH3:14][C:15]1[CH:19]=[CH:18][O:17][C:16]=1[C:20](=[O:21])[CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: COC(=O)c1occc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)CC#N
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
Following the method of Turner and Jacks (J. Org. Chem. 1989, 54, 4229), to a stirred solution of 9.4 ml (179 mmol) acetonitrile in 250 ml dry THF under argon at −78° C. was added dropwise 78.9 ml (78.9 mmol) lithium bis(trimethylsilyl)amide solution (1M in THF) and stirring continued for 30 minutes, after which a solution of 5.0 g (35.7 mmol) methyl 3-methyl-2-furoate in 20 ml THF was added dropwise and stirring continued while the reaction mixture was allowed to warm slowly to −20° C. The reaction mixture was then cannulated into a rapidly stirred solution of 1M hydrochloric acid at 0° C. The mixtured was extracted twice with ether and the combined organic phases dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/4) afforded 4.43 g (83%) 3-(3-methyl-furan-2-yl)-3-oxo-propionitrile as a yellow crystalline solid. EI-MS m/e (%): 149 (M+, 20), 109 ([M—CH2CN]+, 100).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][C:10]2[C:11](=[O:17])[NH:12][C:13](=[S:16])[NH:14][CH:15]=2)[CH:6]=[CH:5][N:4]=1.Cl>C(O)(=O)C>[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][C:10]2[C:11](=[O:17])[NH:12][C:13](=[S:16])[NH:14][CH:15]=2)[CH:6]=[CH:5][NH:4]1
Reactant: COc1cc(Cc2c[nH]c(=S)[nH]c2=O)ccn1
Agent: Cl
Solvent: CC(=O)O
Product: O=c1cc(Cc2c[nH]c(=S)[nH]c2=O)cc[nH]1
Temperature: 150 °C
Yield: 75.9 %

Procedure:
5-(2-Methoxy-pyridin-4-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (900 mg, 3.61 mmol, 1 eq) was refluxed in an acetic acid, glacial (12 ml)/HCl conc. (12 ml) mixture for 7 hours. (150° C. on display of heating device). Solvent from the mixture was evaporated as much as possible. In the mixture was added 20 ml of water. pH of the mixture was adjusted to 4-5. The resulting precipitate was collected and was dried. It was obtained 5-(2-Oxo-1,2-dihydro-pyridin-4-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (645 mg, yield=72.1%, purity=95%) in form of white powder. MS: [M+H]+=236.15 1H NMR (300 MHz; DMSO-d6) δ/ppm 3.36 (s, 2H), 6.06 (dd, J=6.81 Hz, J=1.60 Hz, 1H), 6.11 (s, 1H), 7.24 (d, J=6.81 Hz, 1H), 7.43 (d, J=5.66 Hz, 1H), 11.36 (br.s, 1H), 12.30 (d, J=4.89 Hz, 1H), 12.52 (br.s, 1H)
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17]([O:19][CH3:20])=[O:18])=[CH:5][CH:4]=1.[H-].[Na+].S(OCC)(O[CH2:29][CH3:30])(=O)=O>CN(C=O)C.O>[CH2:29]([N:12]1[C:13](=[O:15])[CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:8][CH:7]=2)[C:10]([C:17]([O:19][CH3:20])=[O:18])=[C:11]1[CH3:16])[CH3:30]
Reactant: CCOS(=O)(=O)OCC
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)CC(c2ccc(C(F)(F)F)cc2)C(C(=O)OC)=C1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.8 %

Procedure:
The product from Example 5, Step 1 (0.627 g, 2.00 mmol, 1.00 equiv) was dissolved in DMF (9 mL) and sodium hydride (60% dispersion in mineral oil, 0.112 g, 1.40 equiv) was added. After the reaction had stirred for 20 minutes at room temperature, diethyl sulfate (0.314 mL, 2.40 mmol, 1.20 equiv) was added and the reaction was heated to 100° C. for 4 hours. The reaction was diluted with H2O and extracted with EtOAc. The organic phase was washed four times with H2O and once with satd. NaCl, dried over MgSO4 and concentrated en vacuo to provide 0.627 g (92%) of the title compound as an oil. MS (ES+) m/e 342 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH:9]=[N:10][CH2:11][C:12]2[C:13]([NH2:19])=[N:14][C:15]([CH3:18])=[N:16][CH:17]=2)=[CH:4][N:3]=1.CC1N=C(N)C(CO)=CN=1.CC1N=C(N)C(C=NO)=CN=1>>[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][NH:10][CH2:11][C:12]2[C:13]([NH2:19])=[N:14][C:15]([CH3:18])=[N:16][CH:17]=2)=[CH:4][N:3]=1
Reactant: Cc1ncc(C=NCc2cnc(C)nc2N)c(N)n1
Agent: Cc1ncc(C=NO)c(N)n1
Agent: Cc1ncc(CO)c(N)n1
Product: Cc1ncc(CNCc2cnc(C)nc2N)c(N)n1

Procedure:
And, neither 2-methyl-4-amino-5-pyrimidylmethylidene-(2-methyl-4-amino-5-pyrimidylmethyl)amine nor 2-methyl-4-amino-5-hydroxylmethylpyrimidine was detected. And, 2-methyl-4-amino-5-pyrimidine aldoxime was contained in an amount of 6%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]([OH:30])[C:17]#[C:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[C:21]([OH:29])[CH:20]=2)[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].Cl>C1COCC1.CO>[C:1]([C:5]1[CH:6]=[C:7]([CH:16]([OH:30])[C:17]#[C:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[C:21]([OH:29])[CH:20]=2)[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN(CC)c1ccc(C(O)C#Cc2ccc(C(=O)OC)c(O)c2)cc1C(C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(C(O)C#Cc2ccc(C(=O)O)c(O)c2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
1.7 g (4.3 mmol) of methyl 4-[3-(3-tert-butyl-4-diethylaminophenyl)-3-hydroxyprop-1-ynyl]-2-hydroxybenzoate are dissolved in 50 ml of THF with 1 ml of methanol and 2 ml of 1N aqueous NaCH. The solution is stirred at ambient temperature for 2 hours and then 2 days at reflux. The reaction medium is poured into a saturated solution of ammonium chloride, and the aqueous phase is brought to acidic pH with 1N HCl and then extracted twice with ethyl acetate. The organic phase is dried over magnesium sulphate and then concentrated to dryness. The residue is purified by chromatography (heptane/ethyl acetate: 50/50). 760 mg of 4-[3-(3-tert-butyl-4-diethylaminophenyl)-3-hydroxy-prop-1-ynyl]-2-hydroxybenzoic acid are obtained in the form of a whitish solid (Mp=245° C., yield=45%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2].[CH2:19]([NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH3:20]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:21]([CH2:19][CH3:20])[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCNC1CCCCC1
Product: CCN(c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-])C1CCCCC1

Procedure:
13 g. of 3-nitro-4-chloro-benzophenone are reacted with 15 ml. of N-ethyl-N-cyclohexylamine as described in Example 2. The crude product is recrystallized from n-hexane to yield 15.3 g of pure, crystalline 3-nitro-4-(N-ethyl-N-cyclohexylamino)-benzophenone; m.p. 91.5°-92° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].C([Li])CCC.CCCCCC.C([O:26][B:27](OC(C)C)[O:28]C(C)C)(C)C>C1COCC1.O>[B:27]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11])([OH:28])[OH:26]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1cc(C(=O)O)ccc1B(O)O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 73.1 %

Procedure:
A stirred solution of 4-bromo-3-methylbenzoic acid (5.0 g, 0.020 mole) in dry THF (250 ml) at -78° C. under argon was treated with 1.6M n-butyllithium in hexane (36 ml, 0.057 mole). After 15 minutes, the reaction mixture was treated with triisopropylborate (13.4 ml, 0.050 mole), then stirred at -78° C. for 1 h, followed by room temp. for 19 h. The mixture was treated with water (25 ml), then concentrated in vacuo and the residue chromatographed on silica gel eluting with 10% methanol/dichloromethane to afford the title compound as a white solid (2.63 g, 67%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:20][C:21]([CH3:25])=[CH:22][CH2:23]Br.[H-].[Na+]>C1COCC1>[CH3:20][C:21]([CH3:25])=[CH:22][CH2:23][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COc1cccc2nc(-c3c(F)cccc3F)[nH]c12
Reactant: CC(C)=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2c1nc(-c1c(F)cccc1F)n2CC=C(C)C
Reaction time: 4 h
Yield: 350 %

Procedure:
To 2-(2,6-difluorophenyl)-4-methoxylbenzimidazole (5005, Example 46) (0.28 g, 1.08 mmol) and 3,3-dimethylallyl bromide (0.20 mL, 0.26 mmol, 160 M%) dissolved in THF (3 mL) was added NaH (60% dispersion in mineral oil) (0.15 g, 3.75 mmol, 350 M%). After 4 h, the reaction was quenched with MeOH and concentrated. The residue was redissolved in dichloromethane, washed with water and NaCl (sat. aq.), dried (Na2SO4), filtered and concentrated. The product was purified by flash chromatography eluting with 2% MeOH/CH2Cl2 and recrystallized from hexane to give white powders of 1-(3,3-dimethylallyl)-2-(2,6-difluorophenyl)-4-methoxylbenzimidazole (0.30 g, 0.91 mmol, 84% yield). M.p. 101-103 ° C. 1H-NMR (200 MHz, CD2Cl2): 7.52 (m, 1H, H4″), 7.24 (dd, J=7.9, 8.2 Hz, 1H, H6), 7.08 (m, 2H, H3″,5″), 7.02 (dd, J=0.9, 8.2 Hz, 1H, H5), 6.73 (dd, J=0.9, 7.9 Hz, 1H, H7), 5.19 (t, J=7.0 Hz, 1H, H2′), 4.02 (s, 3H, OCH3), 4.62 (d, J=7.0 Hz, 2H, H1′), 1.64 (s, 3H, CH3), 1.58 (s, 3H, CH3).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([NH:29][C:30]([C:32]4[O:33][CH:34]=[CH:35][C:36]=4[CH3:37])=[O:31])[CH:23]=3)[CH:18]=[CH:17][N:16]=2)[NH:12][CH:11]=1)=[O:9])C.Cl.O.[OH-].[Na+]>O1CCCC1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:13]3[NH:12][CH:11]=[C:10]([C:8]([NH:7][CH2:6][CH2:5][CH:4]=[O:3])=[O:9])[CH:14]=3)[CH:20]=2)=[CH:23][C:24]=1[NH:29][C:30]([C:32]1[O:33][CH:34]=[CH:35][C:36]=1[CH3:37])=[O:31]
Reactant: CCOC(CCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(F)c(NC(=O)c4occc4C)c3)ccn2)c1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccoc1C(=O)Nc1cc(Oc2ccnc(-c3cc(C(=O)NCCC=O)c[nH]3)c2)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-(3,3-diethoxypropyl)-5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxamide (380 mg, 0.69 mmol) in 15 ml of tetrahydrofuran was added 1 ml of 2M HCl (2.0 mmol). The mixture was stirred at room temperature for 90 minutes and poured into 100 ml of water. 1M NaOH solution was added slowly until pH=7˜8. The precipitates were filtered, washed with water and dried in vacuo to give 5-(4-{4-fluoro-3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-N-(3-oxopropyl)-1H-pyrrole-3-carboxamide as white solid. Yield: 270 mg, 82%.