Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[N:26]=[C:27]([CH3:35])[N:28]2[C:33]=1[C:32](=O)[NH:31][CH:30]=[N:29]2>C(#N)C>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[N:26]=[C:27]([CH3:35])[N:28]2[C:33]=1[C:32]([N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)=[N:31][CH:30]=[N:29]2
Reactant: c1nc[nH]n1
Reactant: Cc1nc(-c2ccccc2F)c2c(=O)[nH]cnn12
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(-c2ccccc2F)c2c(-n3cncn3)ncnn12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1H-1,2,4-Triazole (15.1 g, 219 mmol) in acetonitrile (220 mL) was cooled to 0° C. and treated slowly with phosphorus oxychloride (5.99 mL, 65.4 mmol). After 10 minutes, triethylamine (36.5 mL, 262 mmol) was slowly added; the reaction was stirred for an additional 10 minutes at 0° C., then slowly warmed to room temperature over 15 minutes. C5 (5.33 g, 21.8 mmol) was added to the reaction mixture and stirring was continued at room temperature for 2 hours. After concentration in vacuo, the residue was diluted with ethyl acetate (˜250 mL) and poured into ice-cold stirring aqueous potassium phosphate solution (25%, 250 mL). After stirring for 10 minutes, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification via silica gel chromatography (small plug of silica gel employed; Eluent: 2:1 heptane/ethyl acetate) provided the product as a bright yellow solid. Yield: 6.50 g, 21.8 mmol, 100%. LCMS m/z 296.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.06 (s, 1H), 8.35 (s, 1H), 7.77 (s, 1H), 7.74 (ddd, J=7.6, 7.4, 1.8 Hz, 1H), 7.35-7.40 (m, 1H), 7.26 (ddd, J=7.6, 7.5, 1.2 Hz, 1H), 6.88 (ddd, J=10.2, 8.3, 1.1 Hz, 1H), 2.87 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:11]([N:18]1[C:24](=O)[CH:23]([OH:26])[CH:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[O:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[CH2:11]([N:18]1[CH2:24][CH:23]([OH:26])[CH:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[O:21][CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1C(O)C(c2ccc(Cl)c(Cl)c2)OCCN1Cc1ccccc1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: OC1CN(Cc2ccccc2)CCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.7 %

Procedure:
To a solution of lithium aluminum hydride (11.2 g) in THF (120 ml) was added, in an argon stream, aluminum(III) chloride (10.5 g) at room temperature, and the mixture was stirred at room temperature for 40 min. The reaction mixture was cooled to 0° C., a solution of (6RS,7RS)-4-benzyl-7-(3,4-dichlorophenyl)-6-hydroxy-1,4-oxazepan-5-one (28.9 g) in THF (100 mL) was added dropwise, and the mixture was stirred for 3 hr. To the reaction mixture was added 10% aqueous Rochelle salt solution (90 mL) at 0° C., and the mixture was stirred at room temperature for 30 min, and filtered through celite. The filtrate was washed with brine, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (27.7 g).
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].C1CCN2C(=NCCC2)CC1.[OH:20][CH:21]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[CH:22]1[CH2:24][CH2:23]1>C1COCC1>[O:20]([CH:21]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[CH:22]1[CH2:24][CH2:23]1)[Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC(c1nccs1)C1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC(c1nccs1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
TBDMSCl (3.5 g, 23.2 mmol) and DBU (3.5 mL, 23.2 mmol) were added to a solution of 2-(1-hydroxy-1-cyclopropylmethyl)thiazole (3.0 g, 19.4 mmol) in dry THF (40 mL). The mixture was stirred at rt for 16 h, then quenched with water and the layers separated. The aqueous portion was extracted with EtOAc, the combined extracts dried (MgSO4) and concentrated. The material was purified by flash chromatography using 5% EtOAc/hexane to give 4.97 g (95%) of 2-(1-t-butyldimethylsiloxy-1-cyclopropylmethyl)thiazole as a colorless oil.
Reaction SMILES: COP(=O)OC.O1C=CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].COC1C=CC(C=O)=CC=1[N+]([O-])=O.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([CH:44]=[C:45]([C:53]2[CH:58]=[C:57]([O:59][CH3:60])[C:56]([O:61][CH3:62])=[C:55]([O:63][CH3:64])[CH:54]=2)[O:46]C2CCCCO2)=[CH:40][C:39]=1[N+:65]([O-:67])=[O:66]>C1COCC1.CCOC(C)=O.C1(C)C=CC=CC=1>[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45]([C:53]2[CH:54]=[C:55]([O:63][CH3:64])[C:56]([O:61][CH3:62])=[C:57]([O:59][CH3:60])[CH:58]=2)=[O:46])=[CH:40][C:39]=1[N+:65]([O-:67])=[O:66]
Reactant: COc1ccc(C=C(OC2CCCCO2)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: C1=COCCC1
Agent: CO[PH](=O)OC
Agent: COc1ccc(C=O)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 1.5 h

Procedure:
A round-bottom flask equipped with thermometer, condenser and gas inlet was purged and maintained under nitrogen and charged with hydroxy-(3,4,5-trimethoxy-phenyl)-methyl]-phosphonic acid dimethyl ester (10 g, 32.6 mmol), 3,4-dihydro-2H-pyran (3.57 g, 42.4 mmol), toluene (100 mL) and p-toluenesolfonic acid hydrate (62.1 mg, 0.01 eq). Resulted solution was stirred at 55° C. for 1.5 hours. TLC (EtOAc) showed full conversion of starting material into a less polar compound. Reaction mixture was cooled to −10° C. and a solution of sodium bis(trimethylsilyl)amide in THF (1M, 33.3 mL) was added drop-wise, followed by a solution of 4-methoxy-3-nitrobenzaldehyde (5.91 g, 32.6 mmol) in THF (20 mL). Reaction mixture was stirred at 0° C. for 1 hour before allowed to warm to room temperature. TLC (Hx:EtOAc, 2:1) showed formation of Z/E isomers of 2-[2-(4-methoxy-3-nitro-phenyl)-1-(3,4,5-trimethoxy-phenyl)-vinyloxy]-tetrahydro-pyran and traces of starting materials remaining. Reaction was quenched with water (140 mL), diluted with EtOAc (60 mL) and transferred into separatory funnel. Organic layer was separated, washed with water (2×50 mL), brine, and concentrated. A residue was dissolved in methanol (100 mL) with energetic mechanical stirring, and 1M aqueous solution of HCl (10 mL) was added. Precipitation of product started soon, and a resulted suspension was stirred for 1 hour. Solid was filtered out, washed with methanol (50 mL), then with water (3×30 mL) and dried on filter followed by vacuum-drying at 60° C. until constant weight. Crude deoxybenzoin 2, 6.81 g (58%) showed LC purity of ≧97% and was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1
Agent: Cl[Ru]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1ccc(C(C)C)cc1
Product: CC(O)c1ccc(F)cc1
Temperature: 105 °C
Reaction time: 1 h

Procedure:
Dichloro(p-cymene)ruthenium(II) dimer (1.2 mg, 2 μmol, 0.5 mol %) and a chiral ligand (M=Ru, R=i-Pr, Ar=C6H5—, 2.6 μmol, 0.65 mol %) were dissolved in 1,4-dioxane (3 mL) under nitrogen atmosphere, and then heated and stirred for 1 h at 105° C. After the mixture was cooled to room temperature, p-fluoroacetophenone (0.4 mmol), 1,4-dioxane (2 mL) and a solution of sodium carbonate in 1,4-dioxane (0.8 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 24 h under H2 (5 atm) at 10° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent: ethyl acetate/petroleum ether=1/5). Accordingly, pure 1-(p-fluorophenyl)ethanol was obtained and the ee value (ee=98%) was measured by GC analysis.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17]C(=O)C.O.S(=O)(=O)(O)O>CO.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[C:7]([C:13]([F:14])([F:16])[F:15])=[CH:6][C:5]=1[NH2:17]
Reactant: COC(=O)c1cc(C(C)=O)c(C(F)(F)F)cc1NC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(C(C)=O)c(C(F)(F)F)cc1N
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 5-acetyl-2-acetylamino-4-trifluoromethyl-benzoic acid methyl ester (11.5 g, 37.8 mmol) in MeOH (120 mL)/water (24 mL) was cooled to 0° C. and concentrated sulfuric acid (15.0 mL, 271 mmol) was added dropwise. Upon completion of the addition, the mixture was heated to reflux for 45 min under nitrogen, and then allowed to cool to r.t. The mixture was diluted with EtOAc and washed once with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo providing 5-acetyl-2-amino-4-trifluoromethyl-benzoic acid methyl ester (9.87 g, 37.8 mmol, quantitative) as a white solid, m.p. 118-121° C., ESI-MS: m/z 262 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>ClCCl>[C:7]([C:9]1[CH:14]=[N:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:17][CH2:16]2)=[N:11][CH:10]=1)(=[O:8])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(c1ccccc1)c1cnc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cnc(N2CCN(C(=O)OCc3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a solution of phenyl(2-(piperazin-1-yl)pyrimidin-5-yl)methanone (crude, 2.6 mmol assumed) and triethylamine (780 mg, 7.8 mmol) in dichloromethane (10 mL) was added benzyl chloroformate (663 mg, 3.9 mmol). The reaction mixture was stirred at room temperature for 2 hours, and diluted with dichloromethane (100 mL). The organic phase was washed with water (100 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (etroleum ether/ethyl acetate=4:1˜2:1) to give benzyl 4-(5-benzoylpyrimidin-2-yl)piperazine-1-carboxylate (600 mg, 57%) as a yellow solid. MS (ES+) C23H22N4O3 requires: 402, found: 403 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7](=[O:15])[NH:8][CH:9]=[N:10]2.[C:16]([O:22][CH2:23]Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:16]([O:22][CH2:23][N:8]1[C:7](=[O:15])[C:6]2[C:11](=[CH:12][CH:13]=[CH:14][C:5]=2[O:4][CH3:3])[N:10]=[CH:9]1)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1cccc2nc[nH]c(=O)c12
Reactant: CC(C)(C)C(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2ncn(COC(=O)C(C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Sodium hydride (1.24 g, 60% in oil, 31 mmol) was added portion-wise to a solution of 5-methoxyquinazolin-4(3H)-one (5 g, 28.4 mmol; obtained as described in WO-96/09294) in anhydrous DMF (50 ml) while maintaining the temperature at 25° C. The mixture was stirred at room temperature for 30 minutes. Chloromethyl pivalate (4.45 ml, 31 mmol) was added at room temperature for 3 hours. Additional sodium hydride (0.12 g, 3 mmol) and chloromethyl pivalate (0.67 ml, 4.5 mmol) were added and the mixture was stirred another hour. After evaporation of the solvents under high vacuum, the mixture was diluted with water and extracted with DCM. After drying with magnesium sulfate and evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: ethyl acetate-petroleum ether, 6:4 to 8:2) to give (5-methoxy-4-oxoquinazolin-3(4H)-yl)methyl pivalate as a white solid (7.4 g, 90%); HPLC tR: 2.69 min; Mass spectrum MH+ 291.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][C:4]([C:7]#[N:8])=[CH:3]1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C@@H:2]3[CH2:6][CH2:5][C:4]([C:7]#[N:8])=[CH:3]3)[CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: N#CC1=CC(Br)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CC1=C[C@H](N2CCN(c3ccc(F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.1 %

Procedure:
To a stirred solution of 3-bromocyclopent-1-enecarbonitrile (3 g, 17.44 mmol) in N,N-dimethylformamide (25 ml) was added 1-(4-fluorophenyl)piperazine (3.14 g, 17.44 mmol) followed by the addition of triethylamine (7.29 ml, 52.3 mmol) in a dropwise manner at 0° C. The reaction mixture was stirred at 25° C. for 3 h. The progress of reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue was then diluted with ethyl acetate (100 ml) and washed with water (4×30 ml). The organic layer was dried over sodium sulphate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column over silica gel (100-200 mesh) using 20% ethyl acetate in hexane as eluent to obtain the title compound (2.7 g, 57.1%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[N:14][CH:13]=3)[CH2:9][C:8](=[O:18])[NH:7][C:6]=2[CH:19]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[N:14][CH:13]=3)[CH2:9][C:8](=[O:18])[NH:7][C:6]=2[CH:19]=1
Reactant: O=C1CC(c2ccnnc2)=Nc2ccc(Br)cc2N1
Reactant: OB(O)c1ccccc1F
Product: O=C1CC(c2ccnnc2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
The title compound was prepared from 8-bromo-4-(pyridazin-4-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one (Example 1; 1 mmol) and commercial available 2-fluorophenylboronic acid (CAS-No: 1993-03-9; 1.5 mmol) according to the general procedure G. Obtained as a yellow solid (67%), MS (EI) 333 [(M+1)+].
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([NH:34][CH:31]5[CH2:33][CH2:32]5)=[O:26])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: NC1CC1
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Agent: Cl
Product: O=C(NC1CC1)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1

Procedure:
50 mg (0.11 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzothien-7-yl)benzoic acid hydrochloride (Example 75) and 12.9 mg (0.23 mmol) of cyclopropylamine are reacted together by general method E. 17.6 mg (31.1% of theory) of the title compound are obtained.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:25])[C@H:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH3:16])C1C=CC=CC=1.[O-:26]O.[Li+].O[Li].O.OO>C1COCC1.O.C(OCC)(=O)C>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C@H:15]([CH3:16])[C:14]([OH:25])=[O:26])=[CH:22][CH:21]=1
Reactant: COc1ccc([C@H](C)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Reactant: [O-]O
Agent: OO
Agent: [Li+]
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([C@H](C)C(=O)O)cc1
Yield: 100 %

Procedure:
To a mechanically stirred solution of the above amide (27) (56.2 g) in THF (750 mL) and H2O (250 mL) at 0° C. was added a solution of lithium hydroperoxide prepared by adding a solution of LiOH.H2O (10.4 g) in H2O (250 mL) to 30% H2O2 (84 mL). After stirring for 1 h at 0° C. the excess peroxide was destroyed by the slow addition of a solution of Na2SO3 (103 g) in H2O (500 mL) (exothermic!). After removing most of the THF by evaporation the remaining solution was washed with CH2Cl2 twice to remove recoverable (S)-4-benzyl-2-oxazolidinone, acidified to pH ~2 with 3N HCl and extracted twice with ethyl acetate to isolate the product. The ethyl acetate phases were combined, washed with saturated NaCl, dried over MgSO4 and evaporated to give TLC pure product, (28) (29.87 g, 100%). TLC Rf 0.49 (95:4:1 CHCl3 :MeOH:HOAc) Rf 0.33 streaks (98:2 CHCl3 :MeOH); 1H NMR (CDCl3)δ1.5(3H, d, J=7 HZ), 2.25 (2H, br s), 2.78 (3H, s), 4.08 (1H, q), 7.15 (4H, q).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:40])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH3:39])[C:36](O)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[NH4+].O[N:43]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN(C)C=O>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[C:17](=[O:40])[N:18]([C@H:28]3[CH2:29][CH2:30][C@H:31]([O:34][CH:35]([CH3:39])[C:36]([NH2:43])=[O:37])[CH2:32][CH2:33]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:13][CH:14]=1)#[N:2]
Reactant: On1nnc2ccccc21
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(=O)O)CC2)c2ncnn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(N)=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]propanoic acid (1.1 g), 1-hydroxybenzotriazole ammonium salt (0.42 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.47 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.8 g, 73%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[C:13]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=4)=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:26][NH2:27]>C1COCC1.CC(O)C>[Cl:25][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([C:9]3[CH:10]=[C:11]4[C:6](=[CH:7][CH:8]=3)[N:5]=[CH:4][N:3]=[C:2]4[NH:27][CH3:26])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: CN
Reactant: Fc1ccc(-c2ncccc2-c2ccc3ncnc(Cl)c3c2)cc1Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CNc1ncnc2ccc(-c3cccnc3-c3ccc(F)c(Cl)c3)cc12

Procedure:
4-Chloro-6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)quinazoline (75 mg), 2M MeNH2 in THF (2 mL) and i-PrOH (3 mL) were heated and stirred in a screw capped vial for 12 h at 65° C. The heterogeneous reaction mixture was cooled and filtered. The solid on the funnel was washed with water and dried to obtain 6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)-N-methylquinazolin-4-amine (53 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 8.72 (dd, J=4.7, 1.7 Hz, 1H), 8.47 (s, 1H), 8.31 (q, J=4.7 Hz, 1H), 8.25 (d, J=1.9 Hz, 1H), 7.95 (dd, J=7.8, 1.7 Hz, 1H), 7.61-7.50 (m, 3H), 7.36 (dd, J=8.6, 1.9 Hz, 1H), 7.24 (t, J=8.9 Hz, 1H), 7.13 (ddd, J=8.6, 4.8, 2.2 Hz, 1H), 2.98 (d, J=4.4 Hz, 3H). 19F NMR (282 MHz, DMSO-d6): δ −117.17 (td, J=8.6, 5.1 Hz). LCMS: rt 4.68 min (A), purity 99%, MS (m/e) 365 MH+.
Reaction SMILES: [C:1]([C:4]1[C:5](I)=[N:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2].[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:1]([C:4]1[C:5]([C:24]2[CH:25]=[CH:26][C:27]([F:28])=[C:22]([Cl:21])[CH:23]=2)=[N:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCn2nc(I)c(C(N)=O)c2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCn2nc(-c3ccc(F)c(Cl)c3)c(C(N)=O)c2C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 83.8 %

Procedure:
To a stirred solution of Intermediate 156C (5 g, 12.7 mmol), (3-chloro-4-fluorophenyl)boronic acid (3.33 g, 19.12 mmol) in 1,4-dioxane (75 mL) and water (7.5 mL) was added and K3PO4 (8.12 g, 38.2 mmol) and the reaction mixture was purged with nitrogen for 5 min PdCl2(dppf)-CH2Cl2 (0.521 g, 0.637 mmol) was added and the reaction mixture was stirred at 80° C. for 12 h. The reaction mixture was diluted with water (75 mL) and extracted with EtOAc (3×75 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude reaction mixture was purified by silica gel chromatography (24 g REDISEP® column, eluting with 2% MeOH in CHCl3). Fractions were collected and concentrated to afford Intermediate 185A (4.2 g, 78%) as white solid. MS(ES): m/z=395 [M+H]+; 1H NMR 1H NMR (300 MHz, DMSO-d6) δ ppm 7.81-7.87 (m, 1H), 7.63-7.72 (m, 1H), 7.47 (s, 1H), 7.15-7.37 (m, 2H), 4.74 (s, 2H), 4.16 (s, 2H), 3.80-3.88 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: O([C:8]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])C1C=CC=CC=1.[CH2:28]([NH2:34])[C:29]1[O:33][CH:32]=[CH:31][CH:30]=1.Cl>C(O)(=O)C>[O:33]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:28][NH:34][C:8]1[C:9](=[CH:13][C:14]([S:24](=[O:26])(=[O:27])[NH2:25])=[C:15]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=1)[C:10]([OH:12])=[O:11]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(Oc2ccccc2)cc1Oc1ccccc1
Reactant: NCc1ccco1
Agent: Cl
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Oc1ccccc1
Temperature: 80 °C

Procedure:
43 g (1.0 mol) of the 2,4-diphenoxy-5-sulfamoyl-benzoic acid prepared according to (d) were stirred for 4 hours under nitrogen at 135° C with 90 ml of freshly distilled furfurylamine. The faintly yellow reaction solution, which had been cooled to about 80° C, was then introduced while stirring into 1 l of 10 % acetic acid, and the pH of the mixture was then adjusted to 3 by means of 5N HCl. After standing for a short time at room temperature, the N-(2-furylmethyl)-4-phenoxy-5-sulfamoyl-anthranilic acid which had precipitated in crystals was suction-filtered, washed with water and ethanol and dried on a steam bath.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26](C)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([NH2:30])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Reactant: N
Product: CC(C)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(4-fluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 376) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.024 g, 6%). mp 132–136° C. 1H NMR (300 MHz, DMSO d6) δ 0.79 (d, J=6 Hz, 6H), 1.83 (m, 1H), 4.19 (d, J=6 Hz, 2H), 7.36 (m, 2H), 7.50 (m, 2H), 7.66 (m, 2H), 7.84 (m, 2H), 7.95 (m, 2H), 8.18 (s, 1H). MS (DCI/NH3) m/z 418 (M+H)+, 435 (M+NH)+. Anal. calc. for C20H20FN3O4S: C, 57.54; H, 4.83; N, 10.07. Found C, 57.26; H, 5.00; N, 9.78.