Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([C:4]([O:8][N:9]1N=NC2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1([F:35])[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.Cl.CONC>CN(C=O)C>[CH3:4][O:8][N:9]([CH3:10])[C:32]([CH:29]1[CH2:30][CH2:31][C:26]([F:35])([F:25])[CH2:27][CH2:28]1)=[O:33]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C1CCC(F)(F)CC1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CCC(F)(F)CC1
Temperature: 25 °C

Procedure:
2.78 g HATU were added to a solution of 1 g 4,4-difluoro-cyclohexanecarboxylic acid and 1.3 ml diisopropylethlyamine in 10 ml anhydrous DMF at 0° C. The reaction was stirred at 0° C. for 0.5 hours when 0.891 g O,N-Dimethyl-hydroxylamine hydrochloride were added. The reaction was allowed to warm to rt overnight. The solution was concentrated in vacuo by co-evaporation with toluene (3×) and filtered. The filtrate was concentrated in vacuo. Purification was achieved by silica gel column chromatography (solvent: 5:1→3:1 petroleum ether/EtOAc).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][C:8]=1[OH:9].[OH-].[Na+].Cl.CN([CH:21]=[O:22])C>O>[OH:9][C:8]1[C:7]([CH3:6])=[C:13]([OH:14])[CH:12]=[CH:11][C:10]=1[CH:21]=[O:22]
Reactant: Cc1c(O)cccc1O
Reactant: CN(C)C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(O)ccc(C=O)c1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To an ice-cooled solution of POCl3 (4.9 g, 32.2 mmol) in dry DMF (10.0 mL, 64.4 mmol) was slowly added a solution of 2-methylresorcinol (2.0 g, 16.1 mmol) in dry DMF (5.0 mL). After stirring at room temperature for 12 h, the mixture was cooled to 0° C. and then carefully treated with iced water (15 mL). 2 M sodium hydroxide was added to adjust pH to 10. The resulting mixture was heated to reflux for 10 min. Then, the mixture was acidified by 3 M HCl (pH=3). The resulting solid was collected by filtration, and the precipitate was washed with water (10 mL×3). The obtained orange solid (4.0 g, 46%) was dried in vacuo and used for the next reaction without further purification. 1H-NMR (DMSO-d6, 400 MHz): δ9.71 (1H, s), 7.43 (1H, d, J=8.5 Hz), 6.55 (1H, d, J=8.5 Hz), 1.97 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.I.[C:20](SC)(=[NH:22])[CH3:21]>CO>[C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1)(=[NH:22])[CH3:21]
Reactant: CSC(C)=N
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Agent: I
Solvent: CO
Product: CC(=N)Nc1ccc(CCc2csc(NC(C)=O)n2)cc1
Temperature: 25 °C
Yield: 142.6 %

Procedure:
N-(4-(2-(4-Aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (100 mg) prepared in a similar manner according to Step 6 of Production Example 1, methyl ethanimidothioate hydriodide (166 mg) and methanol (3 ml) were combined, and refluxed for 1.5 hours. After cooled to room temperature, the mixture was concentrated in vacuo. The residue was purified by flash column chromatography over NH silica gel with chloroform/methanol (20:1→10:1) as an eluent to give N-(4-{2-[4-(ethanimidoylamino)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (165 mg) as a pale yellow amorphous substance.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([N:23]4[CH2:28][CH2:27][CH:26]([CH2:29][NH2:30])[CH2:25][CH2:24]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C-:34]#[N:35].[K+].[OH2:37]>CC#N>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([N:23]4[CH2:24][CH2:25][CH:26]([CH2:29][NH:30][C:34]([NH2:35])=[O:37])[CH2:27][CH2:28]4)[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(N4CCC(CN)CC4)n3)cc2)CC1
Reactant: O
Reactant: [C-]#N
Agent: [K+]
Solvent: CC#N
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(C(N)=O)c(N4CCC(CNC(N)=O)CC4)n3)cc2)CC1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To a suspension of 2-(4-(4-acetylpiperazin-1-yl)phenylamino)-4-(4-(aminomethyl)piperidin-1-yl)pyrimidine-5-carboxamide (8 mg, 0.018 mmol) in CH3CN (1 mL), a solution of KCN (18 mg, 0.22 mmol) in H2O (1 mL) was added. The mixture was stirred at 70° C. for 20 h. It was then purified by HPLC to give the titled compound (6 mg). MS 496.5 (M+H); UV 200.8, 271.8 nm.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24]C3N=CC(C=O)=CN=3)[C:16]=2[C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[Cl-].[NH4+:43].[CH2:44]([OH:46])[CH3:45]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][C:16]3[CH:17]=[N:43][C:45]([CH2:44][OH:46])=[N:14][CH:15]=3)[C:16]=2[C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCO
Reactant: [NH4+]
Reactant: Cc1ccc(-c2c(OCCOc3ncc(C=O)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Product: Cc1ccc(-c2c(OCCOc3cnc(CO)nc3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 1 h

Procedure:
To 4-(tert-butyl)-N-[3-{2-[(5-formyl-2-pyrimidinyl)oxy]ethoxy}-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide (Example 38) (25 mg) in ethanol (0.5 ml) at room temperature was added sodium borohydride (2 mg) the mixture was stirred for 1 hr. The reaction was treated with ammonium chloride (aq. sat. 5 ml) and extracted with diethyl ether (1×5 ml, 1×2 ml). The organic fraction was dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the title compound as a white solid (20 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[S:14][CH2:13][C:12]1([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH3:23].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].O>ClCCl>[CH3:39][S:40]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[S:14][CH2:13][C:12]1([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH3:23])(=[O:42])=[O:41]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 91 %

Procedure:
4-(9-Hydroxynonyl)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (131 mg, 0.30 mmol) obtained in Example 30 was dissolved in dichloromethane (12 ml) and then triethylamine (0.2 ml, 1.48 mmol) and methanesulfonyl chloride (0.11 ml, 1.48 mmol) were added thereto. The reaction mixture was stirred for 40 minutes at room temperature. When the reaction is completed, water was added to the reaction solution which was then extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The residue was purified with column chromatography (n-hexane:ethyl acetate=7:3) to obtain 141 mg (yield: 91%, 3RS,4RS/3RS,4SR=8.5/1) of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[N:12]([O-])=O.[Na+].[O:16]=[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH2:27][C:28](=[O:32])[CH2:29][C:30]#[N:31]>S(=O)(=O)(O)O.C(O)(=O)C.O.CN(C=O)C>[O:16]=[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH2:27][C:28](=[O:32])[C:29](=[N:12][NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2)[C:30]#[N:31]
Reactant: O=N[O-]
Reactant: N#CCC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: Nc1cccc2cnccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: N#CC(=NNc1cccc2cnccc12)C(=O)CN1C(=O)c2ccccc2C1=O
Yield: 83.3 %

Procedure:
5-Aminoisoquinoline (175 mg, 1.2 mmole) was mixed in 1.5 mL 4 M sulfuric acid in an ice bath. To this mixture was added slowly a 0.3 mL of aqueous solution of NaNO2 (80 mg, 1.16 mmole). The red diazonium solution was then added to the mixture of 4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-3-oxobutyronitrile (200 mg, 0.88 mmole) and NaOAc trihydrate (1.7 g, 12.5 mmole) dissolved in a mixture of 3 mL of acetic acid, 1.5 mL of water and 6 mL of DMF. The resulting brown precipitate was isolated by filtration to give 281 mg of 4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-2-(isoquinolin-5-ylhydrazono)-3-oxobutyronitrile, in the form of a salt. The solid was then suspended with NaOAc trihydrate (108 mg, 0.8 mmole) in 24 mL of ethanol and heated to reflux. Excess hydrazine hydrate was added to the mixture in 4 portions (4×36 mg, 2.8 mmole) at intervals of one hour. The suspension became a clear red solution. The solvent was removed in vacuo. The residue was purified by column chromatography (CH2Cl2:MeOH=10:1) to afford a yellow solid. This material was further purified by preparative TLC (CH2Cl2:MeOH:NH3.H2O=200:40:2) to yield 18 mg of the title compound as an orange powder. MS (m/z, ES+): 268 (M+1, 90%).
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])C(C)C.C[C:21]([CH3:24])([O-:23])[CH3:22].[Li+].CN(C)C=[O:29]>>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH2:9][CH2:8][N:7]1[CH2:22][C@H:21]([CH2:24][OH:29])[O:23][C:6]1=[O:5]
Reactant: CC(C)(C)[O-]
Reactant: CN(C)C=O
Reactant: COc1ccccc1OCCNC(=O)OCC(C)C
Agent: [Li+]
Product: COc1ccccc1OCCN1C[C@H](CO)OC1=O

Procedure:
Using N,N-dimethylformamide solution of isobutyl-2-(2-methoxyphenoxy)ethylcarbamate 53.46 g (0.2 mol), lithium-t-butoxide 3.20 g (0.04 mol) and (R)-2-oxyranylmethoxy-tetrahydropyran 34.76 g (0.22 mol), the procedures as described in Example 1 were carried out to obtain the targeted product.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].C(OCC)(=O)C.O>CS(C)=O>[C:1]([CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])#[N:2]
Reactant: [C-]#N
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
0.924 g of sodium cyanide was dissolved in 15 mL of dimethylsulfoxide, to which a solution of 4.00 g of methyl 3-(bromomethyl)benzoate in 5 mL of dimethylsulfoxide was added in an ice bath, and this solution was stirred for 2 hours at room temperature. The reaction mixture was added to a mixture of ethyl acetate and water, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield 3.00 g of methyl 3-(cyanomethyl)benzoate as orange oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[NH2:9][NH2:10]>>[NH:9]([C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1)[NH2:10]
Reactant: Clc1cc(I)ccn1
Reactant: NN
Product: NNc1cc(I)ccn1
Temperature: 70 °C

Procedure:
A mixture of 2-chloro-4-iodopyridine (5000 mg, 20.88 mmol) (commercially available from Frontier Scientific, Inc., Logan Utah) and anhydrous hydrazine (32.8 mL, 1045 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) was heated at 70° C. for 30 minutes. LC-MS indicated complete conversion to desired product. The reaction mixture was concentrated under vacuum, and the solid was washed with water (3×15 mL) and air dried. The gray colored solid was used directly without further purification. m/z (ESI) 236.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][F:20])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:21][OH:22].C[O-].[Na+].O>O1CCCC1>[CH3:21][O:22][C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][F:20])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: FCCOc1ccc2cc(-c3ccnc(Cl)n3)sc2c1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1nccc(-c2cc3ccc(OCCF)cc3s2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
2-(2-Chloropyrimidine-4-yl)-6-(2-fluoroethoxy)benzothiophene (105b, 80 mg, 0.26 mmol) obtained in Preparation Example 20 was dissolved in anhydrous tetrahydrofuran (4 mL). A 0.5 M sodium methoxide methanol solution (NaOMe in MeOH, 1.0 mL, 0.5 mmol) was added to the reaction mixture and stirred at room temperature for 18 hours. To the reaction mixture was added water, and organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Column chromatography was performed to give the target compound 2-(2-methoxypyrimidine-4-yl)-6-(2-fluoroethoxy)benzothiophene (1-34, 60 mg, 70%) as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:48])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[C:38]([CH2:39][O:40]C3CCCCO3)=[CH:37][N:36]=[N:35]2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:17]1([CH2:16][N:14]([CH3:15])[C:12]2[C:11]([C:20]([F:21])([F:23])[F:22])=[CH:10][C:9]3[NH:24][C:25](=[O:48])[CH2:26][C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([N:34]5[C:38]([CH2:39][OH:40])=[CH:37][N:36]=[N:35]5)[CH:29]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:18][CH2:19]1
Reactant: CN(CC1CC1)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CC1CC1)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-(cyclopropylmethyl-methyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M67) (939 mg, 1.37 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (544 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[NH2:17]>CC(O)C>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[F:12])[N:5]=[CH:4][N:3]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: Fc1cccc2ncnc(Cl)c12
Solvent: CC(C)O
Product: Fc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: 25 °C
Yield: 47.9 %

Procedure:
4-Chloro-5-fluoroquinazoline (6.75 g) was added to a stirred solution of 3-chloro-4-(2-pyridylmethoxy)aniline (9.27 g, obtained as described in Example 15-21 (note u) of WO 96/15118) in IPA (200 ml), and the solution was stirred and heated at reflux for 8 hours. The solution was allowed to cool to ambient temperature overnight and the precipitated solid was filtered off, washed with acetone and dried. The solid was added to 50% aqueous methanol (400 ml) and the mixture was heated on a steam bath until the entire solid had dissolved. The solution was basified by careful addition of aqueous ammonia (0.880), and the mixture was concentrated to remove methanol. Water (300 ml) was added and the mixture was extracted with DCM (600 ml). The extract washed with water, and brine, and dried. The solvent was removed by evaporation to give a solid, which was re-precipitated from a mixture of ethyl acetate, tetrahydrofuran and isohexane to give N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine as a beige solid (6.75 g, 48%); NMR spectrum (DMSO-d6) 5.3 (s, 2H), 7.2-7.3 (d, 1H), 7.35-7.5 (m, 2H), 7.5-7.65 (m, 3H), 7.8-7.95 (m, 3H), 8.55 (s, 1H), 8.55-8.6 (d, 1H), 9.1-9.2 (bs, 1H); Mass spectrum MH+ 381.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](C=C[CH:30]=1)[CH:7]=[CH:8][C:9]([CH2:11][C:12]([O:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=1)=[O:13])=O)([O-:3])=[O:2].[NH2:31]/[C:32](/[CH3:38])=[CH:33]\[C:34]([O:36][CH3:37])=[O:35].[CH2:39](O)[CH3:40]>>[CH3:39][C:40]1[NH:31][C:32]([CH3:38])=[C:33]([C:34]([O:36][CH3:37])=[O:35])[CH:9]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:30]=2)[C:11]=1[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=1)=[O:13]
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)Nc1ccc(OCCOC(=O)CC(=O)C=Cc2cccc([N+](=O)[O-])c2)cc1
Reactant: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOc2ccc(NC(C)=O)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 7 °C
Yield: 68 %

Procedure:
15 g (0.04 moles) of 2-(4-acetylaminophenoxy)-ethyl 2-(3-nitrobenzilidene)acetylacetate and 4.19 g (0.04 moles) of methyl 3-aminocrotonate are heated for 4 hours under reflux in 40 ml of ethanol. The solution is cooled to 7° C. to obtain 2-(4-acetylaminophenoxy)ethyl 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate as yellow crystals melting--after recrystallisation in isopropanol--at 202°-204° C. The yield was 68% of the theoretical yield.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[ClH:10].[CH2:11]=O>>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:11][Cl:10]
Reactant: O=Cc1ccc(O)cc1
Reactant: Cl
Reactant: C=O
Product: O=Cc1ccc(O)c(CCl)c1
Reaction time: 1.5 h

Procedure:
Through a well-stirred suspension of 0.1 mole 4-hydroxybenzaldehyde, 88ml concentrated HCl and 8.8ml 37% aqueous formaldehyde was bubbled HCl gas for approximately 4 hours. A product had fallen out of solution. The reaction mixture was refrigerated for 1.5 hours and then the product was isolated on a scintered-glass funnel and washed with a total of 1 liter cold water. mp 123°-124° C.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.[CH:28]([S:30]([CH:33]=C)(=[O:32])=[O:31])=[CH2:29]>>[CH:23]([N:19]1[C:18]([C:12]2[N:11]=[C:10]3[C:9]4[CH:26]=[CH:27][C:6]([CH:4]5[CH2:3][N:2]([CH2:29][CH2:28][S:30]([CH3:33])(=[O:32])=[O:31])[CH2:5]5)=[CH:7][C:8]=4[O:17][CH2:16][CH2:15][N:14]3[CH:13]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: C=CS(=O)(=O)C=C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Agent: Cl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(CCS(C)(=O)=O)C3)cc1OCC2

Procedure:
Following the procedure for 152, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (Example 65) was reacted with vinyl sulfone to give 191 as a white solid. 1H NMR δ (ppm) (CDCl3): 8.44 (1 H, d, J=8.28 Hz), 7.84 (1 H, s), 7.60 (1 H, s), 7.05 (1 H, dd, J=8.32, 1.83 Hz), 6.94 (1 H, d, J=1.78 Hz), 5.99-5.89 (1 H, m), 4.48-4.39 (4 H, m), 3.78-3.70 (2 H, m), 3.71-3.62 (1 H, m), 3.25-3.18 (2 H, m), 3.04 (3 H, s), 3.02-2.95 (4 H, m), 1.56 (6 H, d, J=6.64 Hz). LCMS: RT=5.58 min, M+H+=457
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:22])[N:4]([CH2:20][CH3:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[CH3:23][O:24][CH2:25][CH2:26][C:27](O)=[O:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:20]([N:4]1[C:3](=[O:22])[C:2]([NH:1][C:27](=[O:28])[CH2:26][CH2:25][O:24][CH3:23])=[C:7]([CH3:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=2)[C:5]1=[O:19])[CH3:21]
Reactant: COCCC(=O)O
Reactant: CCn1c(=O)c(N)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c(NC(=O)CCOC)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
A solution of 5-amino-3-ethyl-6-methyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 239) (200 mg), 3-methoxypropionic acid (0.15 ml), HATU (487 mg), HOAT (174 mg) and diisopropylethyl amine (0.21 ml) in DMF (5.0 ml) was stirred at room temperature for two hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford the above-mentioned N-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-3-methoxypropaneamide (222 mg). UPLC/MS 400 (M+H)/0.754 min. (measurement condition 9)
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:7][CH2:6][CH:5]([Br:8])[C:4]1=[O:9].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[Br-:8].[CH3:1][O:2][N:3]1[CH2:7][CH2:6][CH:5]([P+:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:4]1=[O:9]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CON1CCC(Br)C1=O
Solvent: C1CCOC1
Product: CON1CCC([P+](c2ccccc2)(c2ccccc2)c2ccccc2)C1=O
Product: [Br-]
Yield: 30.6 %

Procedure:
A mixture of 75 g of N-methoxy-3-bromo-2-pyrrolidone, 105 g of triphenylphosphine and 700 ml of tetrahydrofuran was heated and refluxed for 24 hours. After cooled, the resulting precipitates were taken with filtration and washed with tetrahydrofuran. Dried, 54 g of the title compound 5 was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-])=O.C(O)C>[Pt]=S.C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[NH2:13]
Reactant: O=C(O)C=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: S=[Pt]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(CCC(=O)O)ccc1Cl
Temperature: 50 °C
Yield: 99.8 %

Procedure:
A slurry of 4-chloro-3-nitrocinnamic acid (12.2 g, 53.2 mmol), ethyl alcohol (50 mL) and ethyl acetate (20 mL) was treated with 5% Platinum sulfide on carbon (0.6 g) and was placed in a Parr autoclave. The autoclave was placed under a hydrogen atmosphere and heated overnight at 50° C. After cooling to room temperature, the reaction mixture was filtered through celite, and was concentrated in vacuo to yield 10.6 g of 3-(4-chloro-3-aminophenyl)propionic acid.
Reaction SMILES: C[Al](C)C.C1(C)C=CC=CC=1.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH2:16].C([O:20][C:21]([C:23]1[N:24]=[C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:35]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=4)=[N:34][N:33]4[CH2:43][CH2:44][CH2:45][C:32]=34)=[CH:27][N:26]2[CH:46]=1)=O)C>ClCCl>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][NH:16][C:21]([C:23]1[N:24]=[C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:35]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=4)=[N:34][N:33]4[CH2:43][CH2:44][CH2:45][C:32]=34)=[CH:27][N:26]2[CH:46]=1)=[O:20]
Reactant: CN(C)CCN
Reactant: CCOC(=O)c1cn2cc(-c3c(-c4cccc(C)n4)nn4c3CCC4)ccc2n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cccc(-c2nn3c(c2-c2ccc4nc(C(=O)NCCN(C)C)cn4c2)CCC3)n1
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
Add 2M trimethylaluminum in toluene (0.38 mL, 0.38 mmol) to a solution of N,N-dimethylethylenediamine (0.034 g, 0.38 mmol) in dichloromethane (20 mL). Stir for 20 min and transfer via cannula to a solution of 6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (0.1 g, 0.26 mmol) in dichloromethane (20 mL). Heat at 45° C. and stir for 1.5 h. Add saturated aqueous sodium bicarbonate and extract into dichloromethane. Reversed phase chromatography gives the titled compound (0.067 g, 60%) as a white solid. MS ES+ m/e 430.0 (M+1).