Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:31])[N:7]([CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:26][CH:25]=2)=[CH:21][CH:22]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Oc2ccc(N)cc2)cc1)Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCc1ccc(Oc2ccc(NC(=O)c3ccccc3)cc2)cc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
Add a solution of {2-[4-(4-amino-phenoxy)-phenyl]-ethyl}-benzyl-carbamic acid tert-butyl ester (100 mg, 0.24 mmol) in dichloromethane (5 mL) dropwise to a solution of benzoyl chloride (40 mg, 0.29 mmol) in dichloromethane (5 mL) at room temperature. Upon complete addition of the amine, add triethylamine (48 mg, 0.48 mmol) and a crystal of DMAP to the reaction and stirred at room temperature for 18 hours. Concentrate on a rotary evaporator then purify by flash column chromatography on silica gel eluting with ethyl acetate and hexanes to yield {2-[4-(4-benzoylamino-phenoxy)-phenyl]-ethyl}-benzyl-carbamic acid tert-butyl ester (120 mg). Add trifluoroacetic acid (0.23 mL) dropwise to a solution of [4-(4-benzoylamino-phenoxy)-phenyl]-ethyl}-benzyl-carbamic acid tert-butyl ester (120 mg, 0.23 mmol) in dichloromethane (5 mL) at room temperature and stir overnight. Concentrate on a rotary evaporator, dilute with saturated aqueous sodium bicarbonate then extract with dichloromethane (3×50 mL). Dry the dichloromethane extracts over sodium chloride/magnesium sulfate, filter, then concentrate on a rotary evaporator to yield N-{4-[4-(2-benzylamino-ethyl)-phenoxy]-phenyl}-benzamide, (27 mg): 1H NMR (CDCl3, 300.00 MHz): 7.96-6.93 (m, 18H), 3.85 (s, 2H), 2.99-2.80 (m, 4H), 1.56 (s, 2H); m/z=423.4(M+1); HPLC=99% (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[O:18])[C:12]1=[O:26].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:26]=[C:12]1[C:13]([C:17]([NH:19][C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)=[O:18])=[CH:14][CH:15]=[CH:16][N:11]1[CH:6]1[C:2]2[C:3](=[C:7]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:4][CH2:5]1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Nc1ccncc1)c1cccn(C2CCc3c(Cl)cccc32)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(Nc1ccncc1)c1cccn(C2CCc3c(-c4ccccc4)cccc32)c1=O
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a mixture of 1-(4-chloro-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (200 mg, 1.0 eq) in DME (4 mL) was added phenylboronic acid (3.5 eq), Pd(PPh3)2Cl2 (0.2 eq) and aqueous Na2CO3 (2M, 2 mL). The mixture was stirred at 120° C. for 30 mins by microwave. At the end of reaction 50 mL of H2O was added and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over MgSO4, evaporated the filtrate to give the crude product, which was purified by HPLC to afford 2-oxo-1-(4-phenyl-2,3-dihydro-1H-inden-1-yl)-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (21 mg, 10%). MS (ESI) 408.0 (M+H); 1H NMR (300 MHz, DMSO-d6) δ12.93 (s, 1H), 8.71 (br, 2H), 8.53 (d, J=3.9 Hz, 1H), 8.15 (d, J=3.3 Hz, 2H), 7.84 (d, J=3.9 Hz, 1H), 7.57 (d, J=4.5 Hz, 2H), 7.50 (t, J=4.5 Hz, 2H), 7.37-7.43 (m, 3H), 7.17 (d, J=4.5 Hz, 1H), 6.61-6.69 (m, 2H), 3.15-3.25 (m, 1H), 3.05-3.15 (m, 1H), 2.60-2.75 (m, 1H), 2.50 (s, 6H), 2.10-2.15 (m, 1H).
Reaction SMILES: [C:1]([Mg]Cl)#[CH:2].[S:5](Cl)(Cl)(=[O:7])=[O:6].[C:10]([OH:14])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C1COCC1>[C:1]([S:5]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:7])=[O:6])#[CH:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)(C)O
Reactant: C#C[Mg]Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CS(=O)(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of ethynylmagnesium chloride in THF (0.5M, 10 mmol) is added to a solution of sulfuryl chloride (20 mmol) in 100 mL of THF cooled to −78° C. After 1 hour, a solution of tert-butanol (60 mmol) and triethylamine (60 mmol) in 50 mL of THF is added dropwise. The solution is allowed to warm to room temperature, the volatile components are evaporated in vacuo, the residue is partitioned between ether (150 mL) and 0.05M HCl (50 mL), the organic phase is washed with brine (50 mL) and dried over MgSO4, and the volatile components are evaporated in vacuo. The residue is purified by flash chromatography to give the product as a colorless oil.
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:41])[C@@H:10]([NH:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[C:33]([Cl:39])[C:32]=1[CH3:40])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][Si](C(C)(C)C)(C)C)[CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[Cl:39][C:33]1[C:32]([CH3:40])=[C:31]([NH:30][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)=[N:14][N:15]=2)[C@@H:9]([OH:8])[CH3:41])[CH:38]=[CH:37][C:34]=1[C:35]#[N:36]
Reactant: Cc1c(N[C@@H](c2nnc(-c3cccc(O[Si](C)(C)C(C)(C)C)c3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3cccc(O)c3)o2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
To a 25 mL round bottom flask equipped with a magnetic stirrer and a septum was added 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(3-(tert-butyldimethyl-silyloxy)phenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (intermediate 7c) (62 mg, 0.1 mmol), which was then dissolved in anhydrous THF (3 mL) under an atmosphere of nitrogen. To this was added the tetrabutylammonium fluoride as a 1M solution in THF (0.4 mL, 0.4 mmol) producing an instant color change to yellow. This was allowed to stir at room temperature for a period of 4 h. The solvent was then removed under reduced pressure to yield a black residue. This residue was taken up in EtOAc (20 mL) and washed with water (2×10 mL), brine (1×10 mL) and dried over Na2SO4. The solution was then filtered and concentrated under reduced pressure using rotary evaporation to reveal a yellow solid. This was purified via silica gel chromatography eluted with 70% EtOAc/hexanes to provide the title compound as a white solid (31 mg, 81%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 8.88 (br s, 1H), 7.48 (m, 3H), 7.38 (m, 1H), 7.06 (m, 1H), 6.86 (d, J=8.8 Hz, 1H), 5.68 (d, J=8.5 Hz, 1H), 5.10 (dd, J=3.6, 8.5 Hz, 1H), 4.83 (br s, 1H), 4.62 (m, 1H), 2.40 (s, 3H), 1.41 (d, J=6.3 Hz, 3H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[C:28]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH2:42])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C=O)C>[C:31]([O:30][C:28](=[O:29])[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:18](=[O:20])/[CH:17]=[CH:16]/[C:13]1[CH:14]=[CH:15][N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[CH:12]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(I)cc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(I)cc2)c1
Reaction time: 0.5 h

Procedure:
A mixture of 2.5 g (E)-3-[1-(4-Iodo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid is dissolved in 140 ml DMF. To this mixture are added 0.949 g HOBtxH2O, and 6.27 g Et3N. After 30 min 3.57 g EDCxHCl are added and the resulting mixture is stirred for 30 min. Now 1.29 g of N-boc-o-phenylenediamine are added and the reaction mixture is stirred overnight. The solvent is evaporated and the residue is partitioned between ethyl acetate and water. The organic phase is dried and evaporated and the crude product is purified by silica gel flash chromatography.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH3:23].C([OH:26])C>C(O)(=O)C.Cl>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[NH:5][CH:4]=[C:3]([CH3:23])[C:2]2=[O:26])=[O:22]
Reactant: CCO
Reactant: Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Cl
Agent: Cl
Solvent: CC(=O)O
Product: Cc1c[nH]c2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1=O
Temperature: 25 °C

Procedure:
A solution of 4-chloro-8-(2,6-dichlorobenzoylamino)-3-methylquinoline (500 mg) in acetic acid (16 ml) and 6N hydrochloric acid (20 ml) was heated at 130° C. for 5 days. The mixture was concentrated in vacuo and the precipitate was collected and washed with water. The residue was purified by a silica gel column chromatography (methanol:methylene chloride=1:20, V/V) to give a yellow crystal. The solid was treated with hot ethanol (5 ml), allowed to cool to ambient temperature, filtered and washed with water to give 8-(2,6-dichlorobenzoylamino)-1,4-dihydro-3-methyl-4-oxoquinoline (280 mg) as yellow crystal.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9]C)=O.[NH2:11][C:12](N)=[O:13]>>[S:5]1[C:6]2[C:7](=[O:9])[NH:11][C:12](=[O:13])[NH:1][C:2]=2[N:3]=[CH:4]1
Reactant: NC(N)=O
Reactant: COC(=O)c1scnc1N
Product: O=c1[nH]c(=O)c2scnc2[nH]1
Temperature: 190 °C

Procedure:
A mixture of methyl 4-aminothiazole-5-carboxylate 40 (WO 2006/096338; WO 2005/049613) and urea is heated at 190° C. for 2 hours. The hot reaction mixture is poured onto sodium hydroxide solution and any insoluble material is removed by filtration. The mixture is acidified (HCl, 2N) to yield thiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione 41 (Baker et al (1970) Jour. of the Chem. Soc. 18:2478-84; U.S. Pat. No. 3,277,093; Childress and McKee (1951) J. Am. Chem. Soc. 73:3862-64; Erlenmeyer and Furger (1943) Helv. Chem. Acta 26:366-68) as a white precipitate, which was collected by filtration and air dried.
Reaction SMILES: [C:1]([OH:22])(=O)[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:35][CH:36]([CH2:39][OH:40])[CH2:37][NH2:38]>CN(C=O)C.C(Cl)Cl>[OH:35][CH:36]([CH2:39][OH:40])[CH2:37][NH:38][C:1](=[O:22])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCC#CCC#CCC#CCCCC(=O)O
Reactant: NCC(O)CO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCC#CCC#CCC#CCCCC(=O)NCC(O)CO

Procedure:
In the same manner as in the above example, 8 g of 5,8,11-eicosatriynoic acid in 40 cm3 of anhydrous DMF are treated initially with 5.62 g of carbonyldiimidazole. 4.1 cm3 of 2,3-dihydroxypropylamine are then added at 0° C. At the end of the reaction, the reaction mixture is poured into ice-cold water. The precipitated product is drained and dissolved in 300 cm3 of methylene chloride. The solution is dried over sodium sulphate and then concentrated under reduced pressure. The solid obtained is directly recrystallized in acetonitrile. 9 g of N-(2,3-dihydroxypropyl)-5,8,11-eicosatriynamide are thereby obtained in the form of very pate beige crystals of melting point 87° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:28]1([O:33][CH2:32][CH2:31][O:30]1)[CH3:29])[C:5]([NH:7][CH:8]1[C:26](=[O:27])[N:10]2[C:11]([C:23]([OH:25])=[O:24])=[C:12]([CH2:15]SC3SC(C)=NN=3)[CH2:13][S:14][C@H:9]12)=[O:6]>O1CCCC1.O.C(O)(=O)C.[Zn]>[CH3:1][O:2][N:3]=[C:4]([C:28]1([O:33][CH2:32][CH2:31][O:30]1)[CH3:29])[C:5]([NH:7][CH:8]1[C:26](=[O:27])[N:10]2[CH:11]([C:23]([OH:25])=[O:24])[C:12](=[CH2:15])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)C1(C)OCCO1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: C=C1CS[C@@H]2C(NC(=O)C(=NOC)C3(C)OCCO3)C(=O)N2C1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
Zinc powder (500 mg.) and copper sulfate 5-hydrate (50 mg.) were added to a solution of 7-(2-methoxyimino-3,3-ethylenedioxybutyramido)-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 500 mg.) in tetrahydrofuran (6 ml.), water (2 ml.) and acetic acid (1 ml.), and stirred at room temperature for 2 hours. The resultant mixture was filtered and washed with tetrahydrofuran (5 ml.). The filtrate and the washings were combined and treated in a similar manner to that of Example 10-(3) to give a mixture (160 mg.) of 7-(2-methoxyimino-3,3-ethylenedioxybutyramido)-3-methylenecepham-4-carboxylic acid (syn isomer) and 7-(2-methoxyimino-3,3-ethylenedioxybutyramido)-3-methyl-3-cephem-4-carboxylic acid (syn isomer).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:6]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:7]=2[S:8][CH:9]=1)=O.[NH:15]1[CH2:19][CH2:18][NH:17][C:16]1=[S:20].C(O)C>C(O)(=O)C>[BrH:1].[Cl:14][C:12]1[CH:11]=[CH:10][C:7]2[S:8][CH:9]=[C:5]([C:3]3[N:17]4[CH2:18][CH2:19][N:15]=[C:16]4[S:20][CH:2]=3)[C:6]=2[CH:13]=1
Reactant: S=C1NCCN1
Reactant: O=C(CBr)c1csc2ccc(Cl)cc12
Solvent: CC(=O)O
Solvent: CCO
Product: Br
Product: Clc1ccc2scc(C3=CSC4=NCCN34)c2c1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
A mixture of the crude 3-(2-bromoacetyl)-5-chlorobenzo[b]thiophen (4.2 g), 2-imidazolidinethione (1 g), ethanol (15 ml) and acetic acid (10 ml) was heated under reflux under nitrogen for 18 hours, then allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with ethanol (15 ml), and dried in vacuo to give 3-(5-chlorobenzo[b]thiophen-3-yl)-5,6-dihydroimidazo[2,1-b]thiazole monohydrobromide as a white solid (2.1 g), m.p. 286°-288° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)=[N:10][C:9]=2[C:18]2[C:19]([F:36])=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1.[NH3:37]>>[NH2:37][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:17][CH2:16][O:15][CH2:14]3)=[N:10][C:9]=2[C:18]2[C:19]([F:36])=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Product: Nc1nccc(-c2sc(C3CCOC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 51, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-3-furanyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.100 g, 0.181 mmol) and ammonia (7 N solution in MeOH, 3.88 mL, 27.1 mmol) the title compound was obtained as a light yellow solid (53 mg, 0.099 mmol, 55% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.90 (s, 1H), 7.99 (d, J=5.1 Hz, 1H), 7.62-7.79 (m, 1H), 7.40-7.49 (m, 1H), 7.36 (t, J=6.1 Hz, 1H), 7.17-7.33 (m, 3H), 6.78 (br. s., 2H), 5.84 (d, J=5.1 Hz, 1H), 3.96-4.09 (m, 1H), 3.73-3.95 (m, 4H), 2.34-2.47 (m, 1H), 2.05-2.22 (m, 1H). MS (ESI) 534.10 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][CH:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14](OC)=[CH:13][CH:12]=2)[C:5](=[O:19])[CH:4]=1.[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23]N.C(Cl)(Cl)Cl.CO>CO>[C:11]1([CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:9][C:6]2[C:5](=[O:19])[CH:4]=[C:3]([CH2:2][OH:1])[N:8]([CH2:23][CH:22]([O:25][CH3:26])[O:21][CH3:20])[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(CN)OC
Reactant: COc1ccc(COC2C=NC(CO)=CC2=O)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(Cn1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1CO)OC
Reaction time: 72 h

Procedure:
To a suspension of 3.33 g of 6-hydroxymethyl-3-(p-methoxybenzyl)oxy-4-pyridone in 20 ml of methanol is added 11.35 g of 2,2-dimethoxyethylamine at room temperature, and the mixture is stirred for 3 days. The reaction mixture is condensed under reduced pressure, and subjected to flash column chromatography on 100 g of Wako-Gel C-300 (manufactured by Wako Pure Chemical Industries, Ltd.) with an eluent of chloroform-methanol (20:1) to perform separation and purification. The title compound is obtained as colorless foam in a yield of 2.062 g.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[CH2:29]([N:31]1[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=2)[C:32]1=[O:49])[CH3:30].ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[F:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:36]3[CH:37]=[C:38]4[C:33](=[CH:34][CH:35]=3)[C:32](=[O:49])[N:31]([CH2:29][CH3:30])[CH2:39]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CCN1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCN1Cc2cc(-c3n[nH]c4cc(-c5c(F)c(OC)cc(OC)c5F)ncc34)ccc2C1=O
Temperature: 110 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
A mixture of 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (9 mg, 0.02 mmol), 2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (7.7 mg, 0.027 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (1 mg, 0.001 mmol), and sodium carbonate (5.7 mg, 0.054 mmol) in 1,4-dioxane (0.2 mL) and water (0.03 mL) was degassed and recharged with nitrogen three times. The mixture was stirred at 110° C. for 3 h. After cooling the solid was filtered off. The filtrate was concentrated. The residue was dissolved in methanol (0.5 mL). At r.t. to the solution was added HCl solution prepared previously from acetyl chloride (0.30 mL) and methanol (0.30 mL). The mixture was stirred at r.t. for 2 h, and purified by RP-HPLC (pH=10) to afford the desired product (5.6 mg). LCMS (M+H)+=451.1.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18](/[CH:24]=[CH:25]/[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH:17]=1
Reactant: OCc1ccc(F)cc1/C=C/c1ccc(F)cc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(F)cc2/C=C/c2ccc(F)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-fluoro-2-[(E)-2-(4-fluorophenyl)ethenyl]phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.31 (2H, s), 5.82 (1H, d, J=1.6 Hz), 6.96-7.04 (4H, m), 7.22-7.23 (1H, m), 7.34-7.41 (5H, m), 7.59 (1H, d, J=1.6 Hz), 7.90 (1H, s), 8.51 (1H, d, J=4.8 Hz). [M+H] Calc'd for C24H16F2N4O, 415. Found, 415.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[C:11](=[O:22])[C:10]([C:23]#[N:24])=[C:9]([C:25]([F:28])([F:27])[F:26])[CH:8]=2)[S:5][CH:6]=1.[CH3:29][O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=1.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>COCCOC.O>[CH3:29][O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[CH:3]=[C:4]([C:7]3[N:12]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=4[F:21])[C:11](=[O:22])[C:10]([C:23]#[N:24])=[C:9]([C:25]([F:27])([F:26])[F:28])[CH:8]=3)[S:5][CH:6]=2)[CH:38]=1
Reactant: COC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: N#Cc1c(C(F)(F)F)cc(-c2cc(Br)cs2)n(Cc2ccc(F)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1cccc(-c2csc(-c3cc(C(F)(F)F)c(C#N)c(=O)n3Cc3ccc(F)cc3F)c2)c1
Temperature: 85 °C
Reaction time: 5 h
Yield: 51.6 %

Procedure:
6-(4-Bromo-thiophen-2-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile 620 mg, 1.3 mmoles), [3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester (520 mg, 1.95 mmoles), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with DCM (1:1) (32 mg, 0.39 mmoles), and K2CO3 (540 mg, 3.91 mmoles) were combined in 6 ml of DME/H2O (9:1, degassed), and were stirred at 85° C. for 5 hours. After this period the reaction mix was evaporated and purified using flash silica chromatography (0-30% EtOAc/Hexane) to yield (3-{5-[5-cyano-1-(2,4-difluoro-benzyl)-6-oxo-4-trifluoromethyl-1,6-dihydro-pyridin-2-yl]-thiophen-3-yl}-phenyl)-acetic acid methyl ester (365 mg, 52%) as a yellow solid. 1H-NMR (CDCl3): δ 7.64 (br d, J=1.3 Hz, 1H), 7.39-7.35 (m, 2H), 7.33 (br d, J=1.3 Hz, 1H), 7.14-7.07 (m, 1H), 6.92-6.85 (m, 1H), 6.84-6.77 (m, 1H), 6.65 (s, 1H), 5.44 (s, 2H), 3.72 (s, 3H), 3.67 (s, 2H). MS (ES+): 545.3 (M+H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](O)=O)=[CH:12][N:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)=[CH:12][N:11]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2nc3ccccc3[nH]2)cn1

Procedure:
11.9 g. of o-phenylenediamine, 13.7 g. of 2-methylpyridine-5-carboxylic acid and 100 g. of polyphosphoric acid were stirred under nitrogen gas current at 180° C. to 200° C. for 4 hours. To the reaction mixture were added 800 ml. of water and then a concentrated aqueous solution of sodium carbonate to neutrality. The resulting crystals were filtered off, dried and recrystallized from acetonitrile to give 15.7 g. of colorless needles of the product (75% of theory), M.P. 265.5°-266.0° C.