Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[C:3]([C:12]([OH:14])=O)=[CH:2]1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:22][O:23][C:24](=[O:42])[C@H:25]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:30][CH:29]=1)[NH2:26].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:22][O:23][C:24](=[O:42])[C@@H:25]([NH:26][C:12]([C:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1][CH:2]=1)=[O:14])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:30][CH:29]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)c1coc2ccccc2c1=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)c1coc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.1 %

Procedure:
To a stirring solution of 360 mg (2 mmol) of chromone-3-carboxylic acid in 25 mL of CH2Cl2 at 0° C. were added several drops of DMF followed by 1 mL of 2M solution of oxalyl chloride in CH2Cl2. The resulting solution was stirred 3 h at rt and 643 mg (2 mmol) of O-benzyl-L-tyrosine methyl ester hydrochloride and 0.2 g (2.0 mmol) of triethylamine in 15 mL of CH2Cl2 were added and stirring continued overnight. Solvent was removed under reduced pressure. Product was purified by LCC on SiO2 (Hexane: EtOAc 13:7) providing 83 mg of title compound as a white solid: low resolution MS (ES+ (M+H), 458; RP-HPLC (Dynamax C-8 25 cm×4.1 mm; 50-90% CH3CN in H2O with 0.1% TFA buffer; 15 minutes; 2 mL/min): tr=10.44 min.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=O)[CH2:12][CH:13]=O)=[CH:7][CH:6]=1.OO>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][N:3]=[N:2][C:15]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)C(CC=O)c2ccc(Cl)cc2)cc1
Reactant: NN
Agent: OO
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2nnccc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Hydrazine hydrate (0.8 mP, 16.5 mmol) was added to a solution of 3-(4-chlorophenyl)-4-[4-(methylsulfonyl)phenyl]-4-oxo-butyraldehyde (4.5 g, 12.8 mmol) in ethanol (100 ml), followed by stirring at room temperature for 1 hour. Hydrogen peroxide solution 31% (6 ml) was added to the reaction mixture, and the resulting mixture was stirred at 60° C. for 18 hours. The mixture was concentrated under reduced pressure and the residue was separated and purified by chromatography on a silica gel column [silica gel 70 g, chloroform/methanol (50/1)], whereby the title compound was obtained as a pale yellow amorphous solid (2.60 g, 58.8%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][N:3]=1.[OH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.CC(C)([O-])C.[K+]>O1CCCC1.O>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][N:3]=1
Reactant: OCc1ccccn1
Reactant: CCOC(=O)c1cnc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(OCc2ccccn2)nc1NCc1ccc(OC)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (prepared in Example 95) 356 mg and 2-hydroxymethylpyridine 109 mg in anhydrous tetrahydrofuran 4.5 ml is added potassium tert-butoxide 112 mg under ice cooling, and the mixture is stirred for 30 minutes. The reaction mixture is diluted with water, extracted twice with ethyl acetate. The combined organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel chromatography (silica gel 10 g, solvent; chloroform:ethyl acetate=5:1→2:1) and concentrated in vacuo to give 2-(2-pyridylmethoxy)-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (the compound prepared in Example 67-(3)) as a colorless caramel, 338 mg, which is crystallized on standing at room temperature overnight. mp 90-92° C.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:36][O:37][CH3:38])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=1>>[CH2:34]([O:33][C:31]([C:30]([C:28]1[N:29]=[C:25]([NH:24][C:1]([C:4]23[CH2:5][CH2:6][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]2)[CH2:10][CH2:11]3)=[O:2])[S:26][CH:27]=1)=[N:36][O:37][CH3:38])=[O:32])[CH3:35]
Reactant: CCOC(=O)C(=NOC)c1csc(N)n1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CCOC(=O)C(=NOC)c1csc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)n1
Yield: 52.5 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and ethyl 2-amino-α-methoxyiminothiazole-4-acetate (78.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-[(1-ethoxycarbonyl-1-methoxyiminomethyl)thiazol-2-yl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (43.4 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F-:11].[K+]>CS(C)=O.[Cl-].[Na+].O.C(OCC)(=O)C>[F:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(F)nc1
Temperature: 70 °C
Yield: 84.8 %

Procedure:
To 100 g of 2-chloro-5-nitropyridine (Aldrich) in 600 mL of dimethyl sulfoxide under an inert atmosphere was added 100 g of anhydrous KF. The reaction was heated at 70° C. for 18 hours before cooling and diluting with 500 mL each of brine, ethyl acetate, and hexanes. This mixture was filtered through a pad of celite, the organic phase was separated, and the aqueous phase was extracted three times with equal volumes of ethyl acetate and hexanes. The pooled organic phases were washed with brine, dried with anhydrous sodium sulfate, and stripped of the solvents. This crude product was passed through a plug of silica gel with a gradient of 10-30% ethyl acetate/hexanes and stripped to constant weight on a rotary evaporator to give 76 g (84%) of 2-fluoro-5-nitropyridine as an oil, which was used in the following procedure.
Reaction SMILES: [NH2:1][C:2](=[O:20])[C@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH3:21][S:22]([O-:24])=[O:23].[Na+].CNCCNC.O>CS(C)=O.CCOC(C)=O>[NH2:1][C:2](=[O:20])[C@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(I)cc1)C(N)=O
Reactant: CS(=O)[O-]
Agent: CNCCNC
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(S(C)(=O)=O)cc1)C(N)=O
Reaction time: 3 h
Yield: 87.8 %

Procedure:
A mixture of (R)-tert-butyl 1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamate (200 mg, 0.512 mmol), sodium methanesulfinate (200 mg, 85%, 1.66 mmol), CuOTf hemi-toluene complex (120 mg, 0.464 mmol) and N,N′-dimethylethylenediamine (0.030 mL, 0.279 mmol) in DMSO (5 mL) was stirred at 115 C for 3 h. Water and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (R)-tert-butyl 1-amino-3-(4-(methylsulfonyl)phenyl)-1-oxopropan-2-ylcarbamate (154 mg).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[OH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][C:18]2=[O:23].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[O:23]=[C:18]1[C:19]2[C:15](=[C:14]([O:13][C:2]3[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:17]1
Reactant: O=C1CCc2c(O)cccc21
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(Oc2cccc3c2CCC3=O)nc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
1.86 g of ethyl 6-chloronicotinate and 1.48 g of 4-hydroxy-1-indanone were dissolved in 15 ml of DMF. To the resulting solution, 0.97 g of potassium carbonate was added and the mixture was stirred at 120° C. After 1 hour, ethyl acetate and water were added to the reaction solution, thereby partitioning between an organic layer and an aqueous layer. The organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. The residual oily substance was purified by column chromatography (eluent: ethyl acetate/n-hexane (1:4)) to obtain the titled compound (2.52 g) as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[SH:17][CH2:18][C:19]([OH:21])=[O:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[S:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=C(O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)CSC(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
A solution of 4,4'-dichlorobenzhydrol (Aldrich) (500 mg, 1.97 mmol), mercaptoacetic acid (181 mg, 1.97 mmol) and ρ-toluenesulfonic acid monohydrate (93 mg, 0.49 mmol) in 7 mL of toluene is stirred at room temperature for 2 hours followed by heating at 50°-60° C. for 1 hour. Upon cooling, the mixture is diluted with ethyl acetate, washed with water, brine, and dried over magnesium sulfate. The product is concentrated in vacuo to give [[bis-(4-chlorophenyl)methyl]thio]acetic acid as a pale yellow oil.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:40](=[O:41])[N:6]2[C:7]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)=[O:28])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[CH2:42]([Br:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(#N)C>[Br-:49].[CH2:42]([N+:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]([C:16]2[N:17]=[CH:18][N:13]3[CH:12]=[C:11]([C:8]4[C@H:9]([CH3:10])[C@@H:5]5[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:40](=[O:41])[N:6]5[C:7]=4[C:27]([O:29][CH2:30][C:31]4[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=4)=[O:28])[S:15][C:14]=23)=[O:20])[CH:22]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cccnc5)c4s3)[C@H](C)[C@H]12
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5ccc[n+](Cc6ccccc6)c5)c4s3)[C@H](C)[C@H]12
Product: [Br-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (78.1 mg) was suspended in 1.5 ml of acetonitrile to prepare a suspension. Benzyl bromide (0.032 ml) was added to the suspension, and the mixture was stirred at room temperature for 10 hr. The reaction solution was concentrated under the reduced pressure to give 4-nitrobenzyl (1S,5R,6S)-2-[7-(1-benzylpyridinium-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate bromide.
Reaction SMILES: C(O)(C)(C)C.[C:6]1([C:14]([CH2:16][C:17]2[CH:24]=[CH:23][C:20]([O:21][CH3:22])=[CH:19][CH:18]=2)=[O:15])[CH:13]=[CH:12][C:9]([O:10][CH3:11])=[CH:8][CH:7]=1.CC(C)([O-])C.[K+].CO[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[O:36]>CCCCCC>[CH3:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([C:16]([C:14]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[CH:12][CH:13]=2)=[O:15])=[CH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:24][CH:23]=1
Reactant: COC=CC(=O)OC
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)(C)O
Product: COC(=O)CC=C(C(=O)c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To 430 ml of tert-butanol were added 128 g of deoxyanisoin, 67.3 g of potassium tert-butoxide and 116 g of methyl 3-methoxyacrylate, and the mixture was stirred at 70° C. for 3 hours. After the completion of reaction, the reaction mixture was allowed to stand at room temperature with addition of n-hexane. The product separating out was filtered off and dissolved with 1000 ml of ethyl acetate and 300 ml of 3N sulfuric acid. The organic layer was collected, washed with 3N sulfuric acid and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The organic layer was concentrated at a reduced pressure, giving 153 g (yield 90%) of the above-identified compound as an oily product.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([O:14]C)=[O:13])[C:7](=[O:23])[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([OH:14])=[O:13])[C:7](=[O:23])[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(C(Cc2ccccc2)C(=O)OC)C(=O)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCN1CCN(C(Cc2ccccc2)C(=O)O)C(=O)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-(4-butyl-2,3-dioxopiperazin-1-yl)-3-phenylpropanoate from Step A (130 mg, 0.39 mmol) in 10 mL THF and 3.9 mL water was added lithium hydroxide monohydrate (50 mg, 1.2 mmol). The reaction was stirred at rt for 2 h and HCl (1M, 1.2 mL) was added. Solvent evaporation gave 2-(4-butyl-2,3-dioxopiperazin-1-yl)-3-phenylpropanoic acid. 1H NMR (CD3OD) δ 7.26 (m, 5H), 5.18 (X of ABX, 1H, J=11.6 Hz, J=5 Hz), 3.55-3.17 (m, 8H), 1.50 (m, 2H), 1.27 (m, 2H), 0.92 (t, 3H, J=7.3 Hz).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH2:12][CH2:13][CH2:14][CH:15]2[O:19][CH2:18][CH2:17][O:16]2)=[O:10])[CH2:5][CH2:4]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1>[S:26]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH2:12][CH2:13][CH2:14][CH:15]2[O:16][CH2:17][CH2:18][O:19]2)=[O:10])[CH2:5][CH2:4]1)([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: O=C(OCCCC1OCCO1)[C@H]1CC[C@H](CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](C(=O)OCCCC3OCCO3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of trans-3-(1,3-dioxolan-2-yl)propyl 4-(hydroxymethyl)cyclohexanecarboxylate (0.306 g, 1.13 mmol) in pyridine (0.9 mL) was added para-toluenesulfonyl chloride (0.236 g, 1.24 mmol). The reaction mixture was stirred at this temperature for 1 hour and the coolant removed. The reaction mixture was stirred at RT for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water, brine, dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was used directly without purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH:10]2[NH:14][C:13](=[O:15])[N:12]([CH3:16])[C:11]2=[O:17])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>CN(C)C=O.O.C(OCC)(=O)C>[Cl:8][C:6]1[N:7]=[C:2]([NH:30][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([CH3:24])=[CH:26][CH:27]=2)[N:3]=[C:4]([NH:9][CH:10]2[NH:14][C:13](=[O:15])[N:12]([CH3:16])[C:11]2=[O:17])[N:5]=1
Reactant: CN1C(=O)NC(Nc2nc(Cl)nc(Cl)n2)C1=O
Reactant: Cc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(CNc2nc(Cl)nc(NC3NC(=O)N(C)C3=O)n2)cc1
Reaction time: 24 h

Procedure:
To a stirred suspension of 5-(4,6-dichloro-[1,3,5]triazin-2-ylamino)-3-methyl-imidazolidine-2,4-dione (Example 1.3, Part D) (200 mg, 0.72 mmol) and potassium carbonate (219 mg, 1.59 mmol) in dimethylformamide (5 mL) at room temperature was added 4-methyl-benzylamine (0.1 mL, 0.79 mmol). The reaction mixture was stirred at 35° for 24 h and then diluted with water and ethyl acetate. The ethyl acetate layer was separated, dried and evaporated to give the crude product which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:36]=[C:37]([CH2:41][N:42]([CH2:49][CH2:50][N:51]([CH3:53])[CH3:52])C(=O)C(F)(F)F)[CH:38]=[CH:39][CH:40]=1>CC(O)C.Cl.C(Cl)Cl.CO>[CH3:52][N:51]([CH3:53])[CH2:50][CH2:49][NH:42][CH2:41][C:37]1[CH:36]=[C:35]([NH:34][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]5[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=5[F:32])[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: CN(C)CCN(Cc1cccc(N)c1)C(=O)C(F)(F)F
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCNCc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)c1
Temperature: 180 °C
Yield: 24.2 %

Procedure:
To a suspension of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (75 mg, 0.16 mmol) (prepared according to a procedure similar to that described in Example 27, Step C) and N-[(3-aminophenyl)methyl]-N-[2-(dimethylamino)ethyl]-2,2,2-trifluoroacetamide (58 mg, 0.20 mmol) in 2-propanol (3 mL) was added 2 drops of concentrated HCl. The mixture was heated to 180° C. in a microwave for 25 min. The reaction mixture was diluted with 20 mL DCM and 5 mL MeOH, and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM, and the combined organic layers were dried over Na2SO4, filtered, and purified by flash chromatography to give the title compound (24 mg, 24% yield). 1H NMR (400 MHz, d6-DMSO): δ 10.94 (s, 1H), 9.52 (s, 1H), 8.85 (d, J=7.0 Hz, 1H), 8.51 (d, J=9.2 Hz, 1H), 8.27 (d, J=5.1 Hz, 1H), 8.02 (s, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.74 (s, 1H), 7.46-7.60 (m, 4H), 7.36 (d, J=7.9 Hz, 1H), 7.26 (t, J=8.1 Hz, 2H), 7.12-7.21 (m, 2H), 6.92 (d, J=7.7 Hz, 1H), 6.53 (d, J=5.2 Hz, 1H), 3.66 (s, 2H), 2.54-2.57 (m, 2H), 2.27-2.33 (m, 2H), 2.08 (s, 6H). MS (ESI) m/z=620 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:13](O)=[O:14])[C:9](=[O:11])[CH:10]=1.[CH3:30][C:31]1([CH3:43])[O:35][C@H:34]([CH2:36][N:37]2[CH:41]=[CH:40][C:39]([NH2:42])=[N:38]2)[CH2:33][O:32]1>>[F:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:2]([F:1])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][C:17]2[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=2[F:23])[C:13]([NH:42][C:39]2[CH:40]=[CH:41][N:37]([CH2:36][C@@H:34]3[CH2:33][O:32][C:31]([CH3:43])([CH3:30])[O:35]3)[N:38]=2)=[O:14])[C:9](=[O:11])[CH:10]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: O=C(O)C(Cc1c(F)cccc1F)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(Cc3c(F)cccc3F)n3ncc(Oc4c(F)cccc4F)cc3=O)n2)O1

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(2,6-difluoro-phenyl)-propionic acid (Intermediate 34) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(2,6-difluoro-phenyl)-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide as an off-white solid as a mixture of diastereomers (367.9 mg, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([OH:23])=O)[CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[Cl:24]CCl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([Cl:24])=[O:23])[CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(NS(=O)(=O)c2cccc(C=CC(=O)O)c2)c1
Reactant: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(NS(=O)(=O)c2cccc(C=CC(=O)Cl)c2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a suspension of 3-[3-(3-methoxyphenyl-sulfamoyl)-phenyl]-acrylic acid (5i) (0.38 g, 1.14 mmol) in dichloromethane (4 ml) oxalyl chloride (0.3 ml, 3.43 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.40 g, 100%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.CN(C)[CH:16]=[O:17]>>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:16]=[O:17])[CH:11]=[CH:10]2
Reactant: CN(C)C=O
Reactant: COc1ccc2cc(Br)ccc2c1
Product: COc1ccc2cc(C=O)ccc2c1

Procedure:
Another embodiment of this invention comprises preparing 2-bromo-6-methoxynaphthalene as described herein, converting the 2-bromo-6-methoxynaphthalene into a Grignard reagent, and reacting the Grignard reagent with N,N-dimethylformamide (DMF) which yields after workup, 6-methoxy-2-naphthaldehyde. The Grignard reagent is formed by adding finely divided magnesium and, optionally a crystal of iodine, to a solution of 2-bromo-6-methoxynaphthalene in a suitable ether, such as diethyl ether or tetrahydrofuran in a dry, inert environment, and stirring the mixture at a temperature in the range of about 25° to about 80° C. The reaction of the resultant Grignard reagent with DMF is preferably conducted by adding the DMF portionwise to the Grignard reagent while stirring the mixture at a temperature in the range of about 25° to about 100° C., followed by acid hydrolysis. The following Example 57 is based in part on the procedure of A. Horeau, J. Jacques and R. Emiliozzi, Bull. Soc. Chim. Fr. 1959, at page 1857.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[C:13]([CH:15]=[C:16]([O-])[C:17]([F:20])([F:19])[F:18])#[N:14].[Na+].[NH2:23][C:24]1[CH:29]=[CH:28][NH:27][C:26](=[O:30])[CH:25]=1.C(O)(=O)C>C(O)(C)C>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]2[C:25]3[C:26](=[O:30])[NH:27][CH:28]=[CH:29][C:24]=3[NH:23][C:16]([C:17]([F:20])([F:19])[F:18])=[C:15]2[C:13]#[N:14])=[C:4]([O:11][CH3:12])[CH:5]=1)#[N:8]
Reactant: N#CC=C([O-])C(F)(F)F
Reactant: Nc1cc[nH]c(=O)c1
Reactant: COc1cc(C#N)ccc1C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COc1cc(C#N)ccc1C1C(C#N)=C(C(F)(F)F)Nc2cc[nH]c(=O)c21

Procedure:
500 mg (3.1 mmol) of 4-formyl-3-methoxybenzonitrile are dissolved with 493 mg (3.1 mmol) of sodium 1-cyano-3,3,3-trifluoroprop-1-en-2-olate, 341 mg (3.1 mmol) of 4-aminopyridin-2(1H)-one [Searls, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)] and 266 μl (4.65 mmol) of acetic acid in 40 ml of isopropanol and heated under reflux under argon for 12 h. After cooling, the solution is concentrated, and the residue is again stirred in 45 ml of acetic acid under reflux overnight. The solution is cooled and then concentrated, and the residue is purified by preparative HPLC. 392 mg (34% of theory) of the title compound are obtained as a white solid.