Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][C:3]=1[CH3:21].[F:22][C:23]1[C:28]([C:29](O)=[O:30])=[C:27]([F:32])[CH:26]=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:29](=[O:30])[C:28]3[C:27]([F:32])=[CH:26][CH:25]=[N:24][C:23]=3[F:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:4][C:3]=1[CH3:21]
Reactant: O=C(O)c1c(F)ccnc1F
Reactant: Cc1cc(-c2cc(N)cnc2OCC(F)(F)F)ccc1Cl
Product: Cc1cc(-c2cc(NC(=O)c3c(F)ccnc3F)cnc2OCC(F)(F)F)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-3-methyl-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example 57 a) and 2,4-difluoro-3-pyridinecarboxylic acid (CAN 849937-90-2) as starting materials; MS (EI) 458.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[Cl:41][C:42]1[CH:57]=[CH:56][C:45]([CH2:46][N:47]2[CH:52]=[C:51]([CH2:53][OH:54])[CH:50]=[CH:49][C:48]2=[O:55])=[CH:44][CH:43]=1>C1COCC1>[Cl:41][C:42]1[CH:43]=[CH:44][C:45]([CH2:46][N:47]2[CH:52]=[C:51]([CH2:53][O:54][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:50]=[CH:49][C:48]2=[O:55])=[CH:56][CH:57]=1
Reactant: COc1ccc(O)cc1
Reactant: O=c1ccc(CO)cn1Cc1ccc(Cl)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(OCc2ccc(=O)n(Cc3ccc(Cl)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
According to Scheme 16 Method B: 4-Methoxyphenol (1.5 eq, 0.68 mmol, 84.3 mg), PPh3 (2.0 eq, 0.91 mmol, 0.30 g) and DEAD (2 eq, 0.91 mmol, 0.16 g) were added to a solution of 1-(4-chlorobenzyl)-5-(hydroxymethyl)pyridin-2(1H)-one (1 eq, 0.45 mmol, 0.11 g) in THF (5 mL). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent, the reaction mixture was diluted with water. The organic layer washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel chromatography (AIT Flashsmart prepacked column 25 g SiO2) using cyclohexane/AcOEt 80/20 to afford 1-(4-chlorobenzyl)-5-((4-methoxyphenoxy)methyl)pyridin-2(1H)-one (0.19 mmol, 0.07 g, 42%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][NH2:10]>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CN
Solvent: ClCCl
Product: CNc1ccnc(Cl)n1
Temperature: 5 °C
Reaction time: 12 h
Yield: 88.6 %

Procedure:
To a solution of 17.0 g (0.11 mole) of 2,4-dichloropyrimidine in 150 ml of dichloromethane was added methylamine (0.25 mole, 20 ml of 40 % methanol solution) at such a rate that the temperature of the solution was maintained at 5 ° C. After the addition, the solution was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and extracted with dichloromethane. The dichloromethane layer was dried over an anhydrous sodium sulfate, and concentrated under reduced pressure to give 14.0 g (purity 80 %) of 2-chloro-4-methylaminopyrimidine.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]([CH3:12])([CH2:9][C:10]#[CH:11])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO.O>[CH3:12][C:4]([CH2:9][C:10]#[CH:11])([C:3]([OH:13])=[O:2])[C:5]([OH:7])=[O:6]
Reactant: C#CCC(C)(C(=O)OC)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#CCC(C)(C(=O)O)C(=O)O
Temperature: 50 °C

Procedure:
23.7 g [53] (127 mmol) were dissolved in 200 ml methanol and a solution of 28.3 g (708 mmol) of NaOH in 50 ml water was slowly added dropwise. The mixture was heated to 50° C. in a water bath for two hours, the solvent was removed in a rotary evaporator and the residue was dissolved in water. The mixture was acidified with semi-concentrated hydrochloric acid and the free carboxcylic acid was exacted with chloroform, washed and dried.
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:10]([CH2:12][N:13]1[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:16][CH:15]([NH:31][C:32]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][OH:42])[CH:36]=3)=[O:33])[C:14]1=[O:43])=[O:11])[CH2:2]2>CC(C)=O>[CH:1]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[CH2:4][N:3]([C:10]([CH2:12][N:13]1[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:16][CH:15]([NH:31][C:32]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([CH:41]=[O:42])[CH:36]=3)=[O:33])[C:14]1=[O:43])=[O:11])[CH2:2]2
Reactant: O=C(Nc1cccc(CO)c1)NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O
Solvent: CC(C)=O
Product: O=Cc1cccc(NC(=O)NC2N=C(c3ccccc3F)c3ccccc3N(CC(=O)N3CC4CCC(CC4)C3)C2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-hydroxymethylphenyl)urea and mangan dioxide in acetone was stirred at room temperature for 3 hours. The mangan dioxide was removed by filtration, and the filtrate was evaporated to dryness, and washed with isopropyl ether to afford N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-formylphenyl)urea.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[F:9][C:10]1[CH:11]=[C:12]([C:19](=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17]>C1(C)C=CC=CC=1>[F:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:19]([C:20](=[CH:3][N:4]([CH3:5])[CH3:6])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:26]
Reactant: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 50 °C
Yield: 99.7 %

Procedure:
N,N-Dimethylformamide dimethyl acetal (100 g, 810 mmol) was added dropwise (10 min) to a cooled (0° C.) solution of ethyl 3-(3-fluoro-4-nitrophenyl)-3-oxopropanoate (138 g, 540 mmol) in toluene (540 mL). The reaction was warmed (50° C.) for 2.5 h and then the volatiles were evaporated under reduced pressure to afford the desired product (167 g, 100%), which was sufficiently pure (>95% by NMR) to proceed without further purification. 1H NMR (300 MHz, DMSO-d6) δ 8.24-8.29 (m, 1H), 7.92 (s, 1H), 7.60-7.74 (m, 1H), 7.58-7.62 (m, 1H), 3.97 (q, J=7.0 Hz, 2H), 3.44 (s, 3H), 2.81 (s, 3H), 0.99 (t, J=7.0 Hz, 3H); ES-MS m/z 310.9 (MH)+; HPLC RT (Method B) 2.87 min.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[O:21]1[C:25]2([CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][NH2:33])[CH2:27][CH2:26]2)[O:24][CH2:23][CH2:22]1>>[O:21]1[C:25]2([CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][NH:33][C:2]3[N:3]=[C:4]([NH2:20])[C:5]4[N:6]=[CH:7][N:8]([C:18]=4[N:19]=3)[C@@H:9]3[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]3[OH:11])[CH2:27][CH2:26]2)[O:24][CH2:23][CH2:22]1
Reactant: NCCC1CCC2(CC1)OCCO2
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Nc1nc(NCCC2CCC3(CC2)OCCO3)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 4 h

Procedure:
A mixture of 2-chloroadenosine (0.3 g) and 1,4-dioxaspiro[4.5]decane-8-ethanamine (1.0 g) is heated under nitrogen at 140° for 6 hours. It is evaporated to dryness at reduced pressure, the residue is dissolved in ethanol, the solution is treated with propylene oxide (2 ml) and stirred 4 hours. The precipitate is collected, washed with ethanol and dried in vacuo to give 2-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethylamino]adenosine, [alpha]D25 =-27.3° (MeOH), m.p. 133°-137°.
Reaction SMILES: [CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1.[Cl:6][SiH2:7][Cl:8]>>[CH:1]1([Si:7]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)([Cl:8])[Cl:6])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1=CCCC1
Reactant: Cl[SiH2]Cl
Product: Cl[Si](Cl)(C1CCCC1)C1CCCC1

Procedure:
Cyclopentene in an amount of 136 g (2.00 moles) was made to react with dichlorosilane under various conditions set forth in Table 1, and then the solvent was distilled away. Thus, in analogy with Example 1, dicyclopentyldichlorosilane having a boiling point of 104° C./5 mmHg was obtained in various yields. The yield attained under each reaction condition is shown in Table 1.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:25])(=[N:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:18])[CH:12]=2)=[CH:5][C:4]=1[N:26]=[CH:27][N:28](C)[CH3:29])#N.[NH2:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1.ClCCl.CO>CO>[CH2:23]([O:22][C:20]([N:19]=[S:17]([CH3:25])([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][NH:9][C:6]2[CH:5]=[C:4]3[C:3]([C:29]([NH:31][C:32]4[S:33][CH:34]=[CH:35][N:36]=4)=[N:28][CH:27]=[N:26]3)=[CH:8][CH:7]=2)[CH:12]=1)=[O:18])=[O:21])[CH3:24]
Reactant: Nc1nccs1
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(CNc2ccc(C#N)c(N=CN(C)C)c2)c1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)N=S(C)(=O)c1cccc(CNc2ccc3c(Nc4nccs4)ncnc3c2)c1
Yield: 43 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzylamino}phenyl)-N,N-dimethylformimidamide (90 mg, 0.21 mmol) with 2-aminothiazole (26 mg, 0.25 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 43% yield (43 mg).
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:14]1[CH2:20][CH:19](Cl)[C:17](=O)[CH2:16][CH2:15]1>C(Cl)Cl>[C:1]([N:5]=[N:6][C:14]1[CH2:20][CH2:19][CH2:17][CH2:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCCCC1Cl
Reactant: CC(C)(C)NN
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)N=NC1=CCCCC1
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 11 g. (.125 m.) tert.-butylhydrazine in 80 ml. of methylene chloride containing 2 g. anhydrous sodium sulfate, was added 6.8 g. (0.052 m.) alpha-chlorocyclohexanone. The addition was carried out dropwise and the reaction temperature was maintained at 20° C. ±5° by an ice bath. The solution immediately turned yellow, but the reaction was stirred for an additional 1 hour after the addition was complete before filtering it. The filtered methylene chloride solution was washed with 100 ml. water, dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated off. A viscous, gelatinous liquid remained. The material was cooled in the freezer and then filtered. A white solid, 0.1 g., remained on the filter. The filtrate weighed 8.4 g. (97% yield) and its infra-red spectrum was consistent with the proposed structure. It showed the absence of N-H and carbonyl bands and the presence of a carbon-carbon double bond (1650 cm-1) and a conjugated azo bond (1510 cm-1). The product evolves nitrogen at 60 ° C. 1(-tert.-butylazo)eyeclohexane gelled the unsaturated polyester-styrene resin of Example III at room temperature.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][CH2:8][C:9]1[O:13][C:12]([N:14]2[CH:18]=[CH:17][N:16]=[C:15]2[CH3:19])=[N:11][C:10]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=O)=O.O[C:28]1[CH:42]=[CH:41][C:31]([CH2:32][P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:10]2[N:11]=[C:12]([N:14]3[CH:18]=[CH:17][N:16]=[C:15]3[CH3:19])[O:13][C:9]=2[CH2:8][CH2:7][CH2:6][O:5][C:28]2[CH:42]=[CH:41][C:31]([CH2:32][P:33](=[O:40])([O:34][CH2:35][CH3:36])[O:37][CH2:38][CH3:39])=[CH:30][CH:29]=2)=[CH:21][CH:22]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOS(C)(=O)=O)o1
Reactant: CCOP(=O)(Cc1ccc(O)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(OCCCc2oc(-n3ccnc3C)nc2-c2ccc(Cl)cc2)cc1)OCC

Procedure:
3-[4-(4-Chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyl methanesulfonate (400 mg), diethyl 4-hydroxybenzylphosphonate (365 mg), potassium carbonate (276 mg) and N,N-dimethylformamide (10 ml) was stirred at 100° C. for 4 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml×2). The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, and diethyl 4-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyloxy]benzylphosphonate was obtained as a yellow oil (526 mg, 97%) from an ethyl acetate-eluted fraction.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][OH:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl-].[CH3:14][NH2+]C.C=O>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10](=[CH2:14])[CH:11]=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: C[NH2+]C
Reactant: CC(=O)N1CCC(CCO)CC1
Agent: C=O
Agent: [Cl-]
Product: C=C(C=O)C1CCN(C(C)=O)CC1

Procedure:
3.95 g (23.3 mmol) of 2-(1-acetylpiperidin-4-yl)ethanol, 2.12 g (26.3 mmol) of dimethylammonium chloride and 3 ml (40 mmol) of 37% formaldehyde solution are heated at 110° C. for 2 hours with stirring. The mixture is allowed to cool and is extracted several times with diethyl ether. The organic phases are combined, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness by evaporation. 2-(1-acetylpiperidin-4-yl)propenal is obtained in the form of a yellowish oil which can be further reacted without further purification.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:22]2[C:17](=[C:18]([CH3:25])[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>>[Cl:12][C:13]1[C:22]2[C:17](=[C:18]([CH3:25])[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[N+:16]([O-:9])=[CH:15][CH:14]=1
Reactant: COc1ccc2c(Cl)ccnc2c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COc1ccc2c(Cl)cc[n+]([O-])c2c1C
Yield: 18.3 %

Procedure:
Metachloroperbenzoic acid (90.2 g, 366.0 mmol) was added portion wise over 3 h to a solution of 4-chloro-7-methoxy-8-methylquinoline (60, 15.2 g, 73.2 mmol) in CHCl2 (1 L). Then, the solution was partitioned between ice-cooled NaOH 1N and CH2Cl2 (8 successive extractions). The organic layers were combined, dried (Na2SO4) and evaporated. The residue was purified by column chromatography (gradient of AcOEt/CH2Cl2, 1:2 to 1:0) to give 3.0 g (18.3%) of the title product 61 as a pale yellow powder: m/z=224 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:21]=[CH:20][C:11]3[NH:12][C:13]([NH:15][C:16](=[O:19])[O:17][CH3:18])=[N:14][C:10]=3[CH:9]=2)=O)=[CH:4][CH:3]=1.Cl.[O:25]([NH2:27])[CH3:26].CO.[NH4+].[OH-]>O>[F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6](=[N:27][O:25][CH3:26])[C:8]2[CH:21]=[CH:20][C:11]3[NH:12][C:13]([NH:15][C:16](=[O:19])[O:17][CH3:18])=[N:14][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CON
Reactant: COC(=O)Nc1nc2cc(C(=O)c3ccc(F)cc3)ccc2[nH]1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CON=C(c1ccc(F)cc1)c1ccc2[nH]c(NC(=O)OC)nc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Methyl [5-(4-fluorobenzoyl)-1H-benzimidazol-2-yl]carbamate (Janssen Pharmaceutica, U.S. Pat. No. 3,657,267, Apr. 18, 1972) (31.61 g, 0.11 mole) and methoxylamine hydrochloride (0.35 mole) were added to abs. methanol. After heating under reflux for 48 hrs a clear solution was obtained. After 72 hrs this mixture was filtered hot through Celite then allowed to cool to room temperature. Removal of solvent under reduced pressure gave a solid residue. This material was suspended in H2O and adjusted to pH 12 with conc NH4OH. After stirring for 10 min the precipitate was isolated by filtration, washed repeatedly with H2O, then dried at 50° C. under reduced pressure to give the title product as a white solid. Yield: 33.08 g (96%). Mp: 290°-295° C., TLC: Rf=0.66,0.77 (CHCl3 --MeOH,10:1,SiO2) syn and anti isomers. IR (KBr): 3350, 2939, 1735 cm-1. 1H NMR (DMSO-d6): δ 3.73-3.75 (D, 3H, CH3); 3.85-3.87 (d, 3H, CH3); 6.95-7.46 (m, 7H, Ar); 11.74 (brd, s, 2 H, NH).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][N:25]1[C:29]2=[N:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=[C:28]2[N:27]=[CH:26]1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:33]=[C:28]6[N:27]=[CH:26][N:25]([CH3:24])[C:29]6=[N:30][CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cn1cnc2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5c(c4)ncn5C)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine (Stage 74.1.1) to give the title compound as a white solid. (HPLC: tR 2.26 min (Method A); M+H=425 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.52-8.46 (m, 2H), 8.20-8.08 (m, 3H), 8.05-7.98 (m, 1H), 7.60-7.55 (m, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20]([C:22]3[C:23](=[O:36])[N:24]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH:25]=[CH:26][C:27]=3I)=[O:21])=[C:14]([F:37])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[CH2:38]([NH2:40])[CH3:39]>>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20]([C:22]3[C:23](=[O:36])[N:24]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH:25]=[CH:26][C:27]=3[NH:40][CH2:38][CH3:39])=[O:21])=[C:14]([F:37])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(Oc2cc(F)c(NC(=O)c3c(I)ccn(-c4ccc(F)cc4)c3=O)cc2F)ccn1
Reactant: CCN
Product: CCNc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(NC(C)=O)c2)cc1F
Yield: 76.9 %

Procedure:
Using the procedure of Example 7, 1-(4-fluoro-phenyl)-4-iodo-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [4-(2-acetylamino-pyridin-4-yloxy)-2,5-difluoro-phenyl]-amide (90 mg, 0.145 mmol) and a methanolic solution of ethylamine (10 mL) were combined to afford N-(4-((2-acetamidopyridin-4-yl)oxy)-2,5-difluorophenyl)-4-(ethylamino)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (60 mg, 76.9% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.23 (s, 1H), 10.58 (s, 1H), 10.49 (m, 1H), 8.47 (dd, J=12.9, 7.2 Hz, 1H), 8.18 (d, J=5.8 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.65 (m, 1H), 7.52 (dd, J=11.2, 7.4 Hz, 1H), 7.47 (m, 2H), 7.34 (m, 2H), 6.70 (dd, J=5.8, 2.5 Hz, 1H), 6.28 (d, J=7.9 Hz, 1H), 3.42 (m, 2H), 2.03 (s, 3H), 1.24 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 538.0 (M+H+).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[F:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][NH2:14]>C(O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][NH:14][CH2:3][CH2:2][C:1]#[N:4]
Reactant: NNc1cc(F)ccc1F
Reactant: C=CC#N
Solvent: CCO
Product: N#CCCNNc1cc(F)ccc1F
Yield: 73 %

Procedure:
A solution of acrylonitrile (10 mL), ethanol (20 mL) and 2,5-difluorophenylhydrazine (790 mg) was heated to reflux for 2 days. The reaction was concentrated under vacuum and the product purified by flash chromatography on silica gel with methylene chloride to give 790 mg (73%) 3-(2-(2,5-difluorophenyl)hydrazinyl)propanenitrile. LCMS (ESI) m+H=198.2; 1H NMR (400 MHz, CDCl3) δ 6.99 (ddd, 1H), 6.89 (ddd, 1H), 6.38 (tt, 1H), 5.45 (s, 1H), 3.91 (s, 1H), 3.19 (td, 2H), 2.61 (t, 2H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:21][C:22]([CH3:38])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:23])[C:5](=[O:20])[N:6]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([F:19])[C:17]=2[CH3:18])[C:11](OC)=[O:12])[CH:7]=1.[CH:39]1([NH2:42])[CH2:41][CH2:40]1.C([Mg]Cl)(C)C>C1COCC1.[Cl-].[NH4+]>[Br:1][C:2]1[N:3]=[C:4]([NH:21][C:22]([CH3:38])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:23])[C:5](=[O:20])[N:6]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([F:19])[C:17]=2[CH3:18])[C:11]([NH:42][CH:39]2[CH2:41][CH2:40]2)=[O:12])[CH:7]=1
Reactant: NC1CC1
Reactant: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC(C)(C)c3ccccc3OCc3ccccc3)c2=O)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1cc(Br)nc(NC(C)(C)c2ccccc2OCc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-[5-bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methyl-benzoic acid, methyl ester (Example 252h, 10.50 g) dissolved in THF (100 mL) was treated with cyclopropylamine (7.61 mL). Isopropylmagnesium chloride (45.2 mL of a 2.0M solution in THF) was added dropwise over 10 min under nitrogen. The resulting solution was stirred at 25° C. for 1 h. The reaction mixture was diluted with saturated ammonium chloride solution (300 mL) and extracted with ethyl acetate (×3). The organic was dried (MgSO4), filtered and evaporated. The crude product was triturated with diethyl ether and filtered to afford the subtitle compound (9.86 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=O)[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=1)#[N:2].C([OH:26])C>OO.[OH-].[Na+]>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([C:10]2[N:2]=[C:1]([OH:26])[C:3]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:9]=2)[CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20]
Reactant: COc1cc(C(=O)Nc2ccccc2C#N)cc(OC)c1OC
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(-c2nc(O)c3ccccc3n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Into a 1-L 3-necked round-bottom flask, was placed a solution of N-(2-cyanophenyl)-3,4,5-trimethoxybenzamide (22 g, 70.44 mmol, 1.00 equiv) in ethanol (200 mL), H2O2 (200 mL) and sodium hydroxide (200 mL, 20%). The resulting solution was stirred for 16 h at room temperature. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 500 mL of water. The solids were collected by filtration. This resulted in 12 g (55%) of 2-(3,4,5-trimethoxyphenyl)quinazolin-4-ol as a white solid. MS (ESI) m/z 313 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]([Cl:4])=[CH2:3].[CH2:5]([C:7]1(Cl)[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:6].Cl>[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)Cl>[Cl:1][C:2]([Cl:4])=[CH:3][C:7]1([CH2:5][CH3:6])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCC1(Cl)CCCC1
Reactant: C=C(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC1(C=C(Cl)Cl)CCCC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
10 g of anhydrous aluminum chloride were added to 291 g (3 mol) of 1,1-dichloroethene at -20° C., and thereafter 133 g (1 mol) of 1-ethyl-cyclopentyl chloride (Chem. Abstr. 42, 6,328 (1948)) were added dropwise at 0° to 10° C. The reaction solution was allowed to warm up to 20° C., a further 5 g of aluminum chloride were added, and stirring was continued for a further 2 hours at 20° C. The mixture was poured onto ice, and was worked up with methylene chloride and dilute hydrochloric acid. 158 g (82% of theory) of 1-(2,2-dichlorovinyl)-1-ethylcyclopentane of boiling point 45° to 50° C./0.1 mm Hg were obtained by fractional distillation of the organic phase after it had been dried over sodium sulphate. ##STR16##