Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].C(C(C)=O)C.[F:18][C:19]([F:26])([C:22]([F:25])([F:24])[F:23])[CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(=O)(N(C)C)N(C)C>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:21][CH2:20][C:19]([F:26])([F:18])[C:22]([F:25])([F:24])[F:23])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reactant: OCC(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCC(C)=O
Product: Cc1c(OCC(F)(F)C(F)(F)F)cc[n+]([O-])c1C

Procedure:
A mixture of 2,3-dimethyl-4-nitropyridine-1-oxide (2.0 g), methyl ethyl ketone (30 ml), 2,2,3,3,3-pentafluoropropanol (3.05 ml), anhydrous potassium carbonate (3.29 g) and hexamethyl phosphoric acid triamide (2.07 g) was heated at 70°-80° C. for 4.5 days under stirring, then insolubles were filtered off. The filtrate was concentrated, to which was added water. The mixture was subjected to extraction with ethyl acetate. The extract solution was dried on magnesium sulfate, followed by removing the solvent by evaporation. The residue was chromatographed on a column of silica gel (50 g), eluted with chloroform-methanol (10:1), and recrystallized from ethyl acetate-hexane to yield 2.4 g of 2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine-1-oxide as colorless needles, m.p. 148°-149° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]CC)=[O:8])[CH2:3][CH2:2]1.CI.[C:14](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:14][N:1]1[CH2:2][CH2:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][CH2:6]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CN1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
A mixture of ethyl piperidine-4-carboxylate (4.72 g), methyl iodide (2.24 mL), potassium carbonate (8.29 g) and acetonitrile (50 mL) was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure and water (150 mL) was added. The mixture was extracted with ethyl acetate (150 mL). The ethyl acetate layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A 1N aqueous sodium hydroxide solution (20 mL) was added to the residue (2.64 g), and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized by adding 1N hydrochloric acid (20 mL) and the mixture was concentrated under reduced pressure. Ethanol was added to the residue, and the precipitate was filtered off. The filtrate was concentrated under reduced pressure. This step was repeated and ethanol and ethyl acetate were added to the residue for crystallization to give 1-methylpiperidine-4-carboxylic acid (1.79 g) as a colorless solid.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:26])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][SH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1.[C:29]([O:33][C:34]([NH:36][C@H:37]([C:42](O)=[O:43])[CH2:38][CH2:39][S:40][CH3:41])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([NH:36][CH:37]([CH2:38][CH2:39][S:40][CH3:41])[C:42](=[O:43])[S:18][CH2:17][C:16](=[O:19])[C@:15]1([OH:25])[C@:20]2([CH3:24])[C@H:12]([C@H:11]3[C@:2]([F:1])([C@@H:22]([OH:23])[CH2:21]2)[C@:3]2([CH3:28])[C:8](=[CH:7][C:6](=[O:27])[CH:5]=[CH:4]2)[CH2:9][CH2:10]3)[CH2:13][C@@H:14]1[CH3:26])=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CS
Product: CSCCC(NC(=O)OC(C)(C)C)C(=O)SCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Yield: 79.8 %

Procedure:
The title compound (1.50 gm) was prepared from 1.20 gm of 9-fluoro-11β,17-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione-21-thiol and 2.20 gm of N-(t-butoxycarbonyl)-L-methionine in the same manner as in Synthetic Example 1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]3[C:20]4[CH:19]=[C:18]([O:22][CH:23]([C:35]5[S:36]C=C[CH:39]=5)CNC(=O)OCC[Si](C)(C)C)[C:17]([O:40][CH3:41])=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:11]([CH3:42])[C:10]2=[O:43])=[C:5]([F:44])[CH:4]=1)#[N:2].FC1C=C(C=CC=1N1C2C3C=C(O)C(OC)=CC=3N=CC=2N(C)C1=O)[C:49]#[N:50].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.S1C(CO)=CN=C1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:44][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[N:9]1[C:21]2[C:20]3[CH:19]=[C:18]([O:22][CH2:23][C:35]4[S:36][CH:49]=[N:50][CH:39]=4)[C:17]([O:40][CH3:41])=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]([CH3:42])[C:10]1=[O:43])[C:1]#[N:2]
Reactant: COc1cc2ncc3c(c2cc1OC(CNC(=O)OCC[Si](C)(C)C)c1cccs1)n(-c1ccc(C#N)cc1F)c(=O)n3C
Reactant: COc1cc2ncc3c(c2cc1O)n(-c1ccc(C#N)cc1F)c(=O)n3C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: OCc1cncs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc2ncc3c(c2cc1OCc1cncs1)n(-c1ccc(C#N)cc1F)c(=O)n3C

Procedure:
For the preparation, see also synthesis of 2-trimethylsilanylethyl {2-[1-(4-cyano-2-fluorophenyl)-7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yloxy]-2-thiophen-2-ylethyl}carbamate under Example 3b: 3-fluoro-4-(8-hydroxy-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl)benzonitrile (63 mg, 173 μmol), triphenylphosphine (polymer-bound) (294 mg, 1.12 mmol), thiazol-5-ylmethanol (62 mg, 540 μmol), diisopropyl azodicarboxylate (166 μl, 845 μmol) in tetrahydrofuran (7 ml) were reacted, giving 3-fluoro-4-[7-methoxy-3-methyl-2-oxo-8-(thiazol-5-ylmethoxy)-2,3-dihydroimidazo-[4,5-c]quinolin-1-yl]benzonitrile (15 mg, 32.5 μmol) as solid. MS: 462.0 (M+H+), TLC (HPTLC): Rf=0.44 (ethyl acetate/ethanol 2:1, parts by volume).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COCCOC.[Na].[O:15]([C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=1)[O:25][C:26](F)=[C:27]([F:32])[C:28]([F:31])([F:30])[F:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[O:15]([C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=1)[O:25][C:26]([S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[C:27]([F:32])[C:28]([F:29])([F:30])[F:31])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Sc1ccccc1
Reactant: FC(Oc1cccc(Oc2ccccc2)c1)=C(F)C(F)(F)F
Agent: [Na]
Solvent: O
Solvent: COCCOC
Product: FC(=C(Oc1cccc(Oc2ccccc2)c1)Sc1ccccc1)C(F)(F)F
Temperature: 75 °C
Reaction time: 6 h
Yield: 38 %

Procedure:
Eleven g (0.1 mole) of thiophenol and 150 ml 1,2-dimethoxy ethane are placed into a flask and stirred under nitrogen while 2.3 g of metal sodium are added in portions. When this reaction is complete, 32 g of 1-(3-phenoxyphenoxy)perfluoropropene are added dropwise causing a slight exotherm. The mixture is stirred at 75° C. for six hours following this addition. After cooling, 150 ml of dilute base water solution is added and the mixture is stirred. The product layer is separated and washed with 150 ml water, separated, dried over sodium sulfate, filtered and distilled to produce the title compound as an oil in a yield of 38 percent. The oil has a pour point of -26° C. and a boiling range of 150° to 190° C. at 0.5 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[C:16]1([C:22]2([C:28]#[N:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:25]2[CH2:24][CH2:23][C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:28]#[N:29])[CH2:27][CH2:26]2)=[O:14])=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(C#N)(c3ccccc3)CC2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.045 mmol) in dichloromethane (1 mL) was added 4-phenylpiperidine-4-carbonitrile (10 mg, 0.054 mmol, 1.2 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C23H21N3O2: 371.1634, found 371.1635.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[H-].[Na+].[CH2:9]([CH:11]1[O:13][CH2:12]1)Br>C1COCC1>[CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][O:5][CH2:9][CH:11]1[O:13][CH2:12]1
Reactant: CC(C)=CCO
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCOCC1CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of dimethylallyl alcohol (17.3 g, 20.5 mL, 0.2 mol) in dry THF (200 mL), sodium hydride (4.8 g, 0.2 mol) was added in portions and the mixture was stirred at room temperature for 1 hour. Epibromohydrin (27.4 g, 17.12 mL, 0.2 mol) was added to this reaction mixture dropwise and the mixture was stirred at room temperature for 24 hours. THF was removed on a rotary evaporator and the residue was taken up in ether and filtered. The ether solution was concentrated on a rotary evaporator and the brown oil obtained was distilled under vacuum to yield the title product. bp. 93-94° C./10 mm. Yield: 17.2 g (60.5%). 1H NMR (CDCl3) δ1.68 and 1.75 (s, 6H, CH3), 2.61 and 2.88 (dd,2H, oxirane CH2), 3.17 (m, 1H, oxirane CH), 3.38 and 3.7 (m, 2H, CH2OCH2CH), 4.05 (m, 2H, CH2OCH2CH), 5.35 .(m, 1H, >C═CH).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[C:23]1[CH:28]=[C:27]([F:29])[C:26]([NH2:30])=[CH:25][C:24]=1[F:31])=[O:19])[CH3:16].[O:32]([C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH:42]=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(OCC)(=O)C>ClC(Cl)C>[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[C:23]1[CH:28]=[C:27]([F:29])[C:26]([NH:30][CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[C:39]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:40]=2)=[CH:25][C:24]=1[F:31])=[O:19])[CH3:16]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1cc(F)c(N)cc1F
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1cc(F)c(NCc2cccc(Oc3ccccc3)c2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
Sodium triacetoxyborohydride (0.244 g, 1.15 mmol) was added to a solution of enantiomerically enriched-(trans)-ethyl-2-(4-amino-2,5-difluorophenyl)cyclopropanecarboxylate (III-1e) (0.110 g, 0.46 mmol) and 3-phenoxybenzaldehyde (0.091 g, 0.46 mmol) in 5 mL of dichloroethane. The mixture was stirred at room temperature for one hour. The reaction mixture was partitioned between chlroroform and water. The organic phase was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and the solvent evaporated. The residue was purified by chromatography on silica gel with hexane:ethyl acetate to give 0.127 g (65% yield) of the title compound as a colorless oil. 1HNMR (400 MHz, CDCl3) δ 7.32 (t, J=8.61Hz, 2H), 7.29 (t, J=7.69 Hz, 2H), 7.10 (t, J=7.14 Hz, 1H), 7.06 (d, J=7.69 Hz, 1H), 6.99 (d, J=7.51 Hz, 2H), 6.90 (dd, J=3.11, 8.06 Hz, 1H), 6.55 (dd, J=6.78, 12.09 Hz, 1H), 6.28 (dd, J=7.51, 11.72 Hz, H), 4.36 (br s, 1H), 4.29 (d, J=5.68 Hz, 2H), 4.15 (q, J=7.14 Hz, 2H), 2.50 (m, 1H), 7.79 (m, 1H), 1.53 (m, 1H), 1.27 (t, J=7.14 Hz, 3H), 1.22 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:13])[C:8](=[CH:11][CH:12]=1)[CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:27])([C:23]([F:26])([F:25])[F:24])[CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:2][C:1]([C:5]1[CH:12]=[CH:11][C:8]2[CH:9]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]([C:15]([F:14])([F:27])[C:23]([F:25])([F:24])[F:26])[O:13][C:7]=2[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CCOC(=O)C=CC(F)(F)C(F)(F)F
Reactant: CC(C)(C)c1ccc(C=O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2ccc(C(C)(C)C)cc2OC1C(F)(F)C(F)(F)F
Yield: 70 %

Procedure:
A mixture of 4-tert-butylsalicylaldehyde Example 8, step 1 (1.15 g, 6.4 mmol) and the ethyl ester from Step 2 (1.59 g, 7.3 mmol) was dissolved in anhydrous DMF (4 mL). With stirring, K2CO3 (1.10 g, 9.0 mmol) was added causing the reaction to become deep red. The reaction was stirred at room temperature for 100 hours, acidified with 3 N HCl, diluted with ethyl acetate and washed with saturated NaHCO3 solution, brine, dried over MgSO4, filtered and concentrated in vacuo yielding a brown oil. This oil was purified by flash chromatography over silica gel, eluting with 10% ethyl acetate/hexanes to afford a yellow oil (1.72 g, 70%): 1H NMR (CDCl3/300 MHz) 7.76 (s, 1H), 7.14 (d, 1H, J=8.1 Hz), 7.04 (dd, 1H, J=8.1 Hz 1.8 Hz), 6.94 (s, 1H), 5.92 (dd, 1H, J=22.4 Hz 3.0 Hz), 4.32 (m, 2H), 1.35 (t, 3H, J=7.2 Hz), 1.30 (s, 9H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.C(N(CC)CC)C.[C:38](O)([CH3:41])([CH3:40])[CH3:39]>C(Cl)(Cl)Cl>[CH3:39][C:38]([O:23][C:22](=[O:24])[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:10])=[CH:20][CH:19]=1)([CH3:41])[CH3:40]
Reactant: O=C(O)Cc1ccc(OCCNC(=O)OCc2ccccc2)cc1
Reactant: CC(C)(C)O
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Cc1ccc(OCCNC(=O)OCc2ccccc2)cc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
A solution of 3 g (9.1 mmol) of 4-[2-[[(phenylmethoxy)carbonyl]amino]-ethoxy]benzeneacetic acid in 60 ml of chloroform is cooled to −30° C. and 1.18 g (10.9 mmol) of ethyl chloroformate and 1.52 ml (10.9 mmol) of triethylamine are added. The mixture is stirred for 1 hour at −30° C. and 1.63 g (22 mmol) of t-butanol and 1.52 ml (10.9 mmol) of triethylamine are then added. The mixture is stirred for 16 hours at room temperature and then concentrated under reduced pressure. The evaporation residue is taken up in 100 ml of ethyl acetate and the organic phase obtained is washed with water and then dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel using a dichloromethane/methylcyclohexane mixture (1/1; v/v) as the eluent to give 930 mg of the expected compound (yield=26%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH2:7]([O:14][CH2:15][CH:16]1[CH:20]([CH2:21]I)[O:19][C:18](=[O:23])[NH:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[CH2:7]([O:14][CH2:15][CH:16]1[CH:20]([CH2:21][N:4]2[CH:3]=[C:2]([Br:1])[CH:6]=[N:5]2)[O:19][C:18](=[O:23])[NH:17]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1NC(COCc2ccccc2)C(CI)O1
Reactant: Brc1cn[nH]c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(COCc2ccccc2)C(Cn2cc(Br)cn2)O1
Temperature: 90 °C

Procedure:
A mixture of 4-bromo-1H-pyrazole (2.33 g, 15.9 mmol), 4-[(benzyloxy)methyl]-5-(iodomethyl)-1,3-oxazolidin-2-one (5.00 g, 14.4 mmol), and potassium phosphate tribasic (9.17 g, 43.3 mmol) in DMF (50 mL) was stirred and heated to 90° C. for 16 hours. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by reverse phase HPLC to afford 4-[(benzyloxy)methyl]-5-[(4-bromo-1H-pyrazol-1-yl)methyl]-1,3-oxazolidin-2-one. MS ESI calc'd. for C15H12BrN3O3 [M+H]+ 366 and 368. found 366 and 368. 1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.88 (s, 1H), 7.60 (s, 1H), 7.38-7.29 (m, 5H), 4.63-4.60 (m, 1H), 4.54 (s, 2H), 4.39 (d, J=5.6 Hz, 2H), 3.80-3.76 (m, 1H), 3.41 (d, J=4.8 Hz, 2H).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[BH4-].[Na+].Cl>CCO.O>[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][CH:2]([C:1]#[N:5])[C:3]#[N:4])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: N#CCC#N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CC(C#N)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of malononitrile (3.15 mL, 50.0 mmol) in 50 mL of 95% EtOH, 4-fluorobenzaldehyde (5.28 mL, 50 mmol) was added and the mixture was stirred at room temperature overnight. The white solid precipitated out and this suspension was diluted with 25 mL of EtOH then treated with sodium borohydride (0.946 g, 25.00 mmol) in one portion. This mixture was stirred at ambient temperature for 2 hours until reaction was complete. Water and 1N HCl solution was added carefully to quench sodium borohydride. The precipitate was then filtered, washed with copious amount of water, air-dried to give 5.92 g of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.43 (m, 2H) 7.06-7.17 (m, 2H) 3.90 (t, J=6.78 Hz, 1H) 3.27 (d, J=6.72 Hz, 2H). MS (ESI) m/z 173.1 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].Cl.[N+:16]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23])([O-:18])=[O:17].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([N+:16]([O-:18])=[O:17])[CH:20]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCc1cccc([N+](=O)[O-])c1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a round bottom flask was added 4-chloro-3-(trifluoromethyl)-phenyl isocyanate (443 mg, 2.0 mmol, 1.0 eq.) and acetonitrile (3.0 mL). The solution was cooled to 0° C. before a mixture of 3-nitrobenzylamine HCl (377 mg, 2.0 mmol, 1.0 eq.), DMP (1.0 mL), and triethyl amine (0.27 mL, 2.0 mmol, 1.0 eq.) was added dropwise. The reaction was then allowed to warm to RT slowly, and then stirred for an additional 2 h. The reaction was then concentrated to remove acetonitrile. EtOAc and water were added, and the mixture was extracted, washed with brine, dried with Na2SO4, and concentrated to give an oil. Upon sitting at RT, the oil crystallized to give urea 26 (728 mg, 97% yield). LC/MSD (HP Series 1100 MSD) MS (ES+) m/z 374.1 (M+H)+1 1H-NMR, Varian 400 MHz (DMSO-d6) δ 9.23 (br. s, 1H), 8.14 (m, 1H), 8.09 (m, 1H), 8.04 (d, 1H), 7.74 (d, 1H), 7.62 (m, 2H), 7.52 (d, 1H), 7.04 (br t, 1H), 4.40 (s, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=3[NH:10][C:9]2=[O:21])[CH:7]=1.[Br:23]Br.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([Br:23])[C:5]([OH:22])=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([F:18])([F:20])[F:19])=[CH:16][C:11]=3[NH:10][C:9]2=[O:21])[CH:7]=1
Reactant: BrBr
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2n1-c1cc(Cl)ccc1O
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n1-c1cc(Cl)cc(Br)c1O
Reaction time: 0.33 h

Procedure:
A solution of 1,3-dihydro-1-(5-chloro-2-hydroxyphenyl)-5-trifluoromethyl-2H-benzimidazol-2-one (0.2 g, 0.6 mmol) in glacial acetic acid (5 ml) at room temperature was added bromine (45 μl, 0.9 mmol) and, after stirring for 20 minutes, the mixture was poured into water (25 ml). The crude product was collected by filtration, taken up in hot ethanol and precipitated by addition of water yielding the title compound as white crystals, M.p. 254°-255° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([O:21][CH2:22][C:23](O)=[O:24])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[O:12][C:11](=[O:26])[CH:10]=1.[Si]([O:32][NH2:33])(C)(C)C>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([O:21][CH2:22][C:23]([NH:33][OH:32])=[O:24])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[O:12][C:11](=[O:26])[CH:10]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCC(=O)O
Reactant: C[Si](C)(C)ON
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCC(=O)NO

Procedure:
The title compound was prepared from 2-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)acetic acid (Example 49) following the procedure outlined in Example 84 (except TMSONH2 in place of NH2OH•HCl). 1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 9.54 (s, 1H), 8.82 (s, 2H), 7.97 (d, 1H), 7.23 (d, 1H), 4.65 (s, 1H), 4.43 (s, 2H), 3.93 (s, 3H); MS (ESI): 425.8.
Reaction SMILES: Cl.[CH:2]1[C:7]2[S:8][C:9]3[NH:10][C:11]4[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=4[N:13]=[C:14]([NH2:16])[C:15]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][CH2:23][CH2:24][C@H:25]1[CH2:30]N[CH2:28][CH2:27][NH:26]1>>[CH3:21][O:22][CH2:23][CH2:24][C@@H:25]1[NH:26][CH2:27][CH2:28][N:16]([C:14]2[C:15]3[C:6]4[CH:5]=[CH:4][CH:3]=[CH:2][C:7]=4[S:8][C:9]=3[NH:10][C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[N:13]=2)[CH2:30]1
Reactant: COCC[C@H]1CNCCN1
Reactant: NC1=Nc2ccccc2Nc2sc3ccccc3c21
Agent: Cl
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc4ccccc4c32)CCN1
Temperature: 115 °C
Reaction time: 24 h
Yield: 14.7 %

Procedure:
Following the method of Example 380, using 11H-12-thia-6,11-diaza-dibenzo[a,f]azulen-5-ylamine hydrochloride (0.40 g, 1.3 mmol) and (S)-2-(2-methoxy-ethyl)-piperazine (0.38 g, 2.7 mmol), stirring at 115° C. for 24 hours, wash the separated organic layer with 0.1 N NaOH (2×), and extract the combined aqueous layers with ethyl acetate. Combine the organics and wash them with a saturated solution of sodium chloride (3×), and then dry (sodium sulfate), filter, and concentrate under reduced pressure to a residue. Purify the residue by flash chromatography, eluting with a gradient of a solution of 5% 2M ammonia in methanol, in dichloromethane (in dichloromethane) to give the title compound (0.075 g). Mass spectrum (APCI+, m/e): 393 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](O)([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:16])([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: Nc1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C(C)(C)Nc3ccccn3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Yield: 1.7 %

Procedure:
To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in Example 14, step (d), 120 mg, 0.317 mmol) and 2-aminopyridine (448 mg, 4.76 mmol) in 5 mL of DCM at 0° C. was added 244 μL (3.17 mmol) of TFA. The mixture was allowed to warm to room temperature, at which time it was cooled in an ice bath and filtered. The filtrate was concentrated in vacuo with MeOH (10 mL) and purified by preparative thin layer chromatography ((2×) with 10% MeOH—CHCl3) to afford 2.5 mg (2%) of the title compound as a white solid. 1H-NMR (CDCl3-CD3OD; 400 MHz): δ 8.16 (d, 1H, J=8.6 Hz), 7.88 (m, 1H), 7.64 (s, 1H), 7.29 (m, 1H), 7.18 (d, 1H, J=2.0 Hz), 7.16-7.11 (m, 1H), 7.47-7.44 (m, 1H), 5.81 (d, 1H, J=8.6 Hz), 5.66 (m, 1H), 2.16-2.13 (m, 2H), 1.99 (m, 2H), 1.59 (s, 6H), 1.52-1.44 (m, 2H), 0.99 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C27H30N6O 455.2 (M+H). found 455.1.