Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.Cl.[N:43]1([C:50]2[CH:55]=[CH:54][N:53]=[CH:52][CH:51]=2)[CH2:48][CH2:47][CH:46]([NH2:49])[CH2:45][CH2:44]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:49][CH:46]5[CH2:45][CH2:44][N:43]([C:50]6[CH:51]=[CH:52][N:53]=[CH:54][CH:55]=6)[CH2:48][CH2:47]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCN(c2ccncc2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(c3ccncc3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a mixture of 0.10 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.2 mL (1.1 mmole) of ethyldiisopropyl amine and 0.062 mL (0.25 mmole) of 3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylamine hydrochloride salt in 2.0 mL of dimethylformamide was added 0.11 g (0.25 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-70:30) gave 0.089 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-benzamide (I-62) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[C:11]=1[C:12]([NH:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=[O:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:34])([F:35])[F:36])[C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)c1ccc(NC(=O)c2c(F)cc(C(F)(F)F)cc2C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)c2c(Oc3ccc(F)cc3)cc(C(F)(F)F)cc2C(F)(F)F)cc1
Temperature: 90 °C

Procedure:
4-Fluorophenol (12.05 mg, 0.1075 mmol), methyl 4-[[2-fluoro-4,6-bis(trifluoromethyl)benzoyl]amino]benzoate (40 mg, 0.09774 mmol), and K2CO3 (40.52 mg, 0.29 mmol) were combined in DMF (0.5 mL) and heated at 90° C. for 10 min resulting in complete conversion to methyl 4-[[2-(4-fluorophenoxy)-4,6-bis(trifluoromethyl)benzoyl]amino]benzoate. NaOH (97.73 μL of 3 M, 0.29 mmol) was added and the reaction heated at 90° C. for 2 hours, then at 50° C. for overnight. Additional NaOH was added [2×NaOH (97.73 μL of 3 M, 0.29 mmol), 6 eq] and the reaction heated at 90° C. for 5 hours. HPLC purification using a gradient of acetonitrile in water (10-99%) with 5 mM HCl as a modifier provided 4-(2-(4-fluorophenoxy)-4,6-bis(trifluoromethyl)benzamido)benzoic acid (11) as a white solid. ESI-MS m/z calc. 487.06, found 488.3 (M+1)+; Retention time: 1.84 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 11.14 (s, 1H), 7.99 (s, 1H), 7.94 (d, J=8.7 Hz, 2H), 7.73 (d, J=8.7 Hz, 2H), 7.48 (s, 1H), 7.36-7.22 (m, 4H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][C:15]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=2[F:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Oc1ccc(F)cc1F
Reactant: COC(=O)c1cc(Cl)ccc1F
Product: COC(=O)c1cc(Cl)ccc1Oc1ccc(F)cc1F

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 5-chloro-2-fluorobenzoate and 2,4-difluorophenol: 1H-NMR (CDCl3) δ 7.90 (1H, d, J=2.8 Hz), 7.39 (1H, dd, J=8.8, 2.8 Hz), 7.05–6.91 (2H, m), 6.89–6.80 (1H, m), 6.80 (1H, d, J=8.8 Hz), 3.85 (3H, s).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=2[OH:11])[CH2:3][CH2:2]1.ClC1C=CC=CC=1Cl.[OH-].[Cs+].[OH:22][C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[N:25][C:24]=1Cl>C(O)(C)(C)C>[Cl:29][C:27]1[N:26]=[N:25][C:24]([O:11][C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:23]([OH:22])[CH:28]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: [Cs+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: Clc1ccccc1Cl
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a mixture of 12.8 g (86.4 mmol) of 2-cyclopropyl-6-methylphenol and 1,2-dichlorobenzene (78.3 mL) was added 15.3 g (86.4 mmol) of 95% cesium hydroxide at room temperature. The resultant mixture was heated to 180° C. and subjected to azeotropic dehydration under reflux while stirring for 30 minutes. To the resultant solution was added dropwise the preliminarily prepared solution of 5.00 g (purity: 95.0%; 28.8 mmol) of 4-hydroxy-3,6-dichloropyridazine in t-butanol (95.0 g) at 180° C. over 2 hours. (The t-butanol was distilled off simultaneously with the dropwise addition of the solution.) After stirring at 180° C. for another 2 hours, the reaction mixture was cooled to room temperature, and 100 g of pure water was added to the cooled mixture and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. 50.0 g of toluene was added to the resultant aqueous phase and stirred at room temperature for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol was separated. This operation was repeated twice. Then, the resultant aqueous phase containing a cesium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was added dropwise to a 4% aqueous hydrochloric acid solution at 0° C. to deposit solids, followed by filtration. The resultant solids were washed with pure water and dried under a reduced pressure, and dissolved in an organic solvent and quantitatively determined by an HPLC internal standard analysis method, which showed that 7.92 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (purity: 76.1%; yield: 76%) and 166 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 2.1%) were obtained.
Reaction SMILES: [OH-].[Na+].[C:3]([O:18]CC)(=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14][CH2:15][CH3:16].O.Cl>CO>[C:3]([OH:18])(=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14][CH2:15][CH3:16]
Reactant: CCOC(=O)CCCCSCCCCCSCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCSCCCCCSCCCCC(=O)O
Reaction time: 4 h
Yield: 93.9 %

Procedure:
Sodium hydroxide (1M, 6.2 mL, 6.2 mmol) was added to a solution of ethyl 6,12-dithiatetradecanoate (0.9 g, 3.1 mmol) in MeOH (15 mL). After stirring for 4 hours, water (20 mL) was added and the reaction mixture was acidified (pH 1, HCl) extracted with EtOAc (2×100 mL), and the organic phase was washed with water (20 mL ), brine (20 mL ), and then dried (Na2SO4). The product crystallized from n-hexane to yield the title compound as a white solid (0.77 g, 95%, mp 49.5°-50.0° C). IR: 3000, 1720 cm-1 ; 1H NMR, 1.23 (t, 3H), 1.49 (quintet, 2H), 1.56-1.68 (m, 6H), 1.74 (quintet, 2H:), 2.38 (t, 2H), 2.51 (t, 2H), 2.53 (t, 4H), 2.54 (q, 2H), and 10.45 (b, 1H). Anal. Calcd for C12H24S2O2 : C, 54.50; H, 9.15%. Found: C, 54.59; H, 9.21%.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1.[CH2:21](Br)[C:22]#[CH:23]>>[CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH2:23][C:22]#[CH:21])[C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Reactant: C#CCBr
Product: C#CCn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2

Procedure:
5-(4,4-Dimethyl-2-oxo-1,4,dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-2-carbonitrile (0.74 g, 2.8 mmol) and propargylbromide (0.5 g, 4.2 mmol) were reacted, according to General Method A, to afford the title compound, m.p. 222-224° C. (0.13 g, 15%). 1H-NMR (DMSO-d6) δ 1.65 (s, 6H), 3.64 (t, J=2.3 Hz, 1H), 4.85 (d, J=2.3 Hz, 2H), 6.37 (d, J=4 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 7.11 (d, J=4 Hz, 1H), 7.43 (m, 2H), 10.45 (s, 1H), MS (APCI (−)) m/z 304 (M−H)−
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9]Cl)=[O:7].[C:11]([NH:14][C:15]1[C:16]([I:31])=[C:17]([N:26]([C:28](=[O:30])[CH3:29])[CH3:27])[C:18]([I:25])=[C:19]([C:22]([O-:24])=[O:23])[C:20]=1[I:21])(=[O:13])[CH3:12].[Cs+].[I-].[Na+]>CN(C=O)C>[C:11]([NH:14][C:15]1[C:16]([I:31])=[C:17]([N:26]([C:28](=[O:30])[CH3:29])[CH3:27])[C:18]([I:25])=[C:19]([C:22]([O:24][CH2:9][O:8][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])=[O:23])[C:20]=1[I:21])(=[O:13])[CH3:12]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: O=C(OCCl)c1cccs1
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OCOC(=O)c2cccs2)c(I)c(N(C)C(C)=O)c1I
Reaction time: 4 h

Procedure:
Chloromethyl 2-thiopbenecarboxylate (0.63 g, 3.6 mmol) (Intermediate 6) in dry DMF (70 ml) is added dropwise at 50° C. to a solution of cesium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (3.00 g, 3.9 mmol) and sodium iodide (28 mg, 0.19 mmol) in dry DMF (45 ml). The precipitate is removed by filtration after stirring for 4 hours and the solvent is removed at reduced pressure. The residue is dissolved in chloroform (50 ml) and washed four times with a saturated sodium hydrogen carbonate solution. After drying with magnesium sulfate the solvent is removed at reduced pressure to give the title compound:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[O:21][CH3:22]>CN(C=O)C>[CH3:22][O:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:8][CH2:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][N:2]1[CH3:1]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: CN1CCC[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1OC[C@@H]1CCCN1C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A mixture of [(2S)-1-methylpyrrolidin-2-yl]methanol (11.5 g, 0.10 mol), DMF (150 mL) and NaH (4.0 g, 60% in mineral oil, 0.1 mol) was agitated for 30 minutes under an atmosphere of nitrogen. A DMF (100 mL) solution of 1-chloro-2-methoxy-4-nitrobenzene (18.7 g, 0.10 mol) was added and the mixture agitated overnight at RT. The mixture was concentrated, diluted with ethyl acetate, extracted three times with water, dried, filtered, then concentrated to give the product as a tan oil (16.78 g, 63%). LCMS m/z 267 (MH+). 1H NMR (300 MHz, DMSO-d6) δ 7.88 (d, 1H), 7.73 (s, 1H), 7.19 (d, 1H), 4.06 (m, 2H), 3.88 (s, 3H), 2.80 (m, 1H), 2.60 (m, 1H), 2.36 (s, 3H), 2.20 (m, 1H). 1.90 (m, 1H), 1.67 (m, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:3]=1.[Cl:26][C:27]1[CH:32]=[C:31](I)[CH:30]=[CH:29][N:28]=1>C([Mg]Cl)(C)C.[Cl-].[Cl-].[Zn+2]>[Cl:26][C:27]1[CH:32]=[C:31]([C:6]2[CH:5]=[C:4]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=3)[CH:3]=[C:2]([CH3:1])[N:7]=2)[CH:30]=[CH:29][N:28]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(OS(=O)(=O)C(F)(F)F)n1
Reactant: Clc1cc(I)ccn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)c2)n1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl ester (example A.32) (3.0 g, 7.8 mmol), commercially available 2-chloro-4-iodo-pyridine [CAS No. 153034-86-7] (1.92 g, 8.0 mmol) and i-PrMgCl/ZnCl2 according to the general procedure IVc protocol a. Obtained as a white solid (1.50 g, 55%). MS (ISP) 349.2 [(M+H)+] and 351 [(M+2+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:12]([O:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH:28][NH:27][C:25](=[O:26])[C:24]1[CH:29]=[CH:30][C:21]([O:20][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:22][CH:23]=1)=[O:5]
Reactant: CCCCCCCCOc1ccc(C(=O)NN)cc1
Reactant: O=C(Cl)c1cc(Br)ccc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCOc1ccc(C(=O)NNC(=O)c2cc(Br)ccc2Br)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 126.5 %

Procedure:
Under a blanket of nitrogen, 2,5-dibromobenzoyl chloride (57.43 g, 0.11925 mol) was added to a solution of 4-octyloxybenzoic acid hydrazide (50.88 g, 0.1925 mol) and triethylamine (27 mL, 19.48 g, 0.1925 mol) in 800 mL of methylene chloride. The reaction mixture was stirred for 5 hours at room temperature. The precipitated solid was filtered off and re-crystallized from hot DMF/water gave 79.38 g (78% yield) 2,5-dibromo-N′-[4-(octyloxy)benzoyl]benzohydrazide.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.C([CH2:14][C:15]([OH:17])=[O:16])#N.C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([C:3]=1[CH2:14][C:15]([OH:17])=[O:16])=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: N#CCC(=O)O
Reactant: CC1Cc2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC1=C(CC(=O)O)c2ccccc2C1
Reaction time: 21 h

Procedure:
2-Methylindanone (0.112 mole), cyanacetic acid (10.5 g., 0.123 mole), acetic acid (6.6 g.), and ammonium acetate (1.7 g.) in dry toluene (15.5 ml.) was refluxed with stirring for 21 hrs., as the liberated water was collected in a Dean Stark trap. The toluene was concentrated and the residue dissolved in 60 ml. of hot ethanol and 14 ml. of 2.2 N aqueous potassium hydroxide solution. 22 g. Of 85% KOH in 150 ml. of water was added and the mixture refluxed for 13 hr. under N2. The ethanol was removed under vacuum, 500 ml. water added, the aqueous solution washed well with ether and then boiled with charcoal. The aqueous filtrate was acidified to pH 2 with 50% hydrochloric acid, cooled and the precipitate of 2-methylinden-3-acetic acid was collected.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[O:18][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[I:1]
Reactant: BrCc1ccccc1I
Reactant: Oc1cc(F)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Br)c(OCc2ccccc2I)c1
Yield: 102.5 %

Procedure:
Stir a mixture of 2-iodobenzyl bromide (0.29 mol, 90 g), 2-bromo-5-fluorophenol (0.29 mol, 57.9 g), and potassium carbonate (0.46 mol, 63 g) in N,N-dimethylformamide (750 mL) at room temperature for 16 h. Add water (1 L), stir the resulting mixture for one hour, filter off solids, rinse with water and dry in a vacuum oven (20 mm Hg/60° C.) to obtain the title compound (121 g, >100%). 1H NMR (400 MHz, DMSO-d6) δ 5.11 (s, 2H), 6.81 (t, 1H), 7.13 (t, 1H), 7.19 (dd, 1H), 7.46 (t, 1H), 7.59 (d, 1H), 7.62 (t, 1H), 7.93 (d, 1H).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=O)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH2:23])[C:19]([CH3:22])([CH3:21])[CH3:20].P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>CC1C=CC(C)=CC=1>[CH2:18]([NH:23][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][N:9]=1)[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)CN
Reactant: O=c1[nH]nc(-c2ccccc2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccc(C)cc1
Product: CC(C)(C)CNc1nnc(-c2ccccc2)c2ccccc12

Procedure:
To a suspension of 100 g of 4-phenyl-1(2H)-phthalazinone and 96.2 g of neopentylamine in 300 ml of p-xylene were added dropwise 83.7 g of phosphorus oxychloride with stirring and the resulting mixture was stirred under reflux for 4 hours. After allowing to be cooled, a saturated aqueous solution of NaHCO3 was added to the reaction mixture. Then, the mixture was extracted with chloroform and the organic layer was separated, dried and then concentrated. The residue was recrystallized from ethanol to afford the title compound as a pale yellow crystal. 100.8 g (Yield, 77%) Melting point: 215.5°-216.5° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]1>>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]1)[CH:11]=[CH:10]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: O[C@H]1CCNC1
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@H](O)C3)ccc12
Yield: 78.3 %

Procedure:
Prepared according to the method of example 27, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (0.533 g) and (3S)-3-pyrrolidinol (0.365 g) to afford the title compound (0.48 g).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([CH3:13])[C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CNC
Product: CN(C)C(=O)Cc1ccccc1

Procedure:
Phenylacetyl chloride (25 ml) was added dropwise to a 50% aqueous solution of dimethylamine with ice-cooling. After the solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3 solution, dried over MgSO4, and concentrated under reduced pressure to provide the title compound as colorless oil. Yield 28.90 g (95%) 1H-NMR (CDCl3) δ: 2.95(3H,s), 2.98(3H,s), 3.71(2H,s), 7.26-7.30(5H,m).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH3:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3]>>[CH3:14][N:5]1[CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:2][C:3]1=[O:4]
Reactant: CN(CCc1ccccc1)C(=O)CCl
Agent: [Al+3]
Agent: [Cl-]
Product: CN1CCc2ccccc2CC1=O
Temperature: 25 °C
Yield: 110.5 %

Procedure:
At 140° C., 2-chloro-N-methyl-N-phenethyl-acetamide (20 g, 94 mmol) and aluminum trichloride (18.9 g, 142 mmol, 1.5 eq.) were heated for 8 hours. The mixture was allowed to cool to ambient temperature and poured over ice. The mixture was extracted with dichlomethane (3×200 mL) and dried with sodium sulfate. The solvent was evaporated to give 3-methyl-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (18.2 g, 100%): 1H NMR (300 MHz, CDCl3) δ 7.1 (m, 4H), 3.92 (s, 2H), 3.71 (t, 2H), 3.15 (t, 2H), 3.03 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>O1CCOCC1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:30]([NH:29][CH2:27][CH3:28])=[O:31])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: CCN=C=O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.04 g, 0.11 mmol) was dissolved in 1,4-dioxan (0.5 mL) and ethyl isocyanate (0.013 mL, 0.16 mmol) was added. The solution was stirred at room temperature for 18 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using a gradient of EtOAc/petroleum ether (40-60) 30:70→100:0 as the eluent. This afforded the title compound as an amorphous compound. 13C NMR (DMSO-d6) δ 195.6, 159.0 (dd), 156.0 (dd), 155.3, 149.2, 139.3, 138.3, 133.7, 133.5, 131.5, 129.2, 127.5, 126.4 (dd), 124.5 (dd), 120.2, 118.4, 115.1, 112.1 (dd), 112.0, 105.1 (dd), 34.0, 19.1, 15.4
Reaction SMILES: [F:1][CH:2]([F:11])[N:3]1[N:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[N:4]1>[Pd]>[F:1][CH:2]([F:11])[N:3]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4]1
Reactant: O=[N+]([O-])c1cnn(C(F)F)n1
Agent: [Pd]
Product: Nc1cnn(C(F)F)n1
Yield: 81.5 %

Procedure:
Following the procedure of Example 151e, and starting with 159a (300 mg, 1.83 mmol) and 10% palladium on carbon (50% wet, 60 mg) afforded 159b as a yellow liquid (200 mg, 81%). 1H NMR (500 MHz, CDCl3) δ 7.24 (s, 1H), 7.14 (t, J=58.5 Hz, 1H), 4.08 (brs, 2H).
Reaction SMILES: [N:1]1([C:6]2[CH:19]=[CH:18][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]3=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.Cl[S:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])(=[O:32])=[O:31]>ClCCl>[N:1]1([C:6]2[CH:19]=[CH:18][C:9]([CH2:10][N:11]3[CH2:16][CH2:15][N:14]([S:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])(=[O:32])=[O:31])[CH2:13][C:12]3=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CNCCN1Cc1ccc(-n2ccnc2)cc1
Reactant: COC(=O)CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CS(=O)(=O)N1CCN(Cc2ccc(-n3ccnc3)cc2)C(=O)C1
Yield: 19.7 %

Procedure:
To a solution of 1-[4-(1-imidazolyl)benzyl]piperazin-2-one (586 mg) and diisopropylethylamine (388 mg) in dichloromethane (10 ml) was added dropwise, under ice-cooling, a solution of methyl chlorosulfonylacetate (380 mg) in dichloromethane (10 ml), and the mixture was stirred at room temperature overnight. The reaction solution was washed with 0.5N hydrochloric acid and saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (eluent: methanol/dichloromethane=1/10) to give colorless oil of 1-[4-(1-imidazolyl)benzyl]-4-methoxycarbonylmethylsulfonyl-2-oxopiperazine (0.170 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])=[CH:20][CH:19]=1>CN1C(=O)CCC1>[Cl:16][C:12]1[CH:11]=[C:10]([C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])=[CH:22][CH:23]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCc1cc(Cl)nc(-c2cccc(Cl)c2)n1
Reactant: CC(C)(CO)c1ccc(N)cc1
Solvent: CN1CCCC1=O
Product: CCc1cc(Nc2ccc(C(C)(C)CO)cc2)nc(-c2cccc(Cl)c2)n1
Yield: 59.6 %

Procedure:
Following General Procedure A1, 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.075 g, 0.29 mmol) in NMP (3 mL) was reacted with 2-(4-aminophenyl)-2-methylpropan-1-ol (0.054 g, 0.33 mmol) to afford the title compound (0.066 g, 88%) as a light yellow solid. MW=381.91. 1H NMR (DMSO-d6, 500 MHz) δ 9.54 (s, 1H), 8.35-8.28 (m, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.58-7.55 (m, 2H), 7.42-7.32 (m, 2H), 6.59 (s, 1H), 4.64 (t, J=5.4 Hz, 1H), 3.42 (d, J=5.4 Hz, 2H), 2.66 (q, J=7.6 Hz, 2H), 1.32-1.18 (m, 9H); APCI MS m/z 382 [M+H]+.