Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[Cl:26][CH2:27][C:28](Cl)=[O:29]>ClCCl>[Cl:26][CH2:27][C:28]([N:8]1[CH2:9][CH2:10][CH:5]([O:4][C:3]2[C:11]([F:18])=[C:12]([F:17])[C:13]([F:16])=[C:14]([F:15])[C:2]=2[F:1])[CH2:6][CH2:7]1)=[O:29]
Reactant: O=C(Cl)CCl
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1

Procedure:
A chilled (ice bath temperature) solution of 10.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine and 5.72 ml of triethylamine in 100 ml of dichloromethane was treated, dropwise, with a solution of 3.26 ml of chloroacetyl chloride in 40 ml of dichloromethane, and then stirred at room temperature for four hours. The reaction mixture was then washed with water followed by a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to afford 13.35 g of 1-(2-chloroacetyl)-4-(2,3,4,5,6-pentafluorophenoxy)piperidine as an oil.
Reaction SMILES: [CH:1]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]=1)=[CH:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.[Cl:20][B:21](Cl)[N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24]>C(OCC)C>[Cl:20][B:21]([N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH:1]=[CH:2][CH2:3][CH2:4][CH3:5])=[CH:7]1
Reactant: CCCC=CC1=CCc2ccccc21
Reactant: CC(C)N(B(Cl)Cl)C(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC=CC1=CC(B(Cl)N(C(C)C)C(C)C)c2ccccc21
Temperature: -74 °C
Reaction time: 3 h

Procedure:
Metallocenes MET 1, MET 3, and MET 4 were produced using suitable procedures. MET 2 was synthesized by first reacting lithiated indene with 5-bromo-1-pentene. Pure 3-(1-pentenyl) indene was obtained via vacuum distillation as a pale yellow oil. One mole of 3-(1-pentenyl) indene was added to diethyl ether and cooled to −74° C., and one mole of n-butyllithium was added. The reaction mixture was stirred at 21° C. for 3 hr, then cooled again to −74° C., followed by the addition of a diethyl ether solution of dichloro(diisopropylamino) boron, and then stirred for 12 hr while warming to 21° C. The resulting yellow slurry was centrifuged, and the bright yellow solution was poured off and solvent removed under reduced pressure. Monochloro(diisopropylamino)-3-(1-pentenyl)indenylboron was obtained as a yellow oil. One mole of monochloro(diisopropylamino)-3-(1-pentenyl)indenylboron was added to tetrahydrofuran and cooled to 0° C., followed by the addition of one mole of sodium cyclopentadiaenide, producing a yellow slurry, which was stirred at 21° C. for 12 hr. The reaction solution was centrifuged and then decanted off. Concentration under reduced atmosphere yielded the ligand shown below as a yellow oil:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[NH2:24])=[O:20]>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:24][C:23]2[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=[C:21]([C:19]([O:18][CH3:17])=[O:20])[CH:22]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1cc(N)cc(C(F)(F)F)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: COC(=O)c1cc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)cc(C(F)(F)F)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3-methoxycarbonyl-5-trifluoromethylaniline gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-(3-methoxycarbonyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.98 (s, 1H), 9.52 (s, 1H), 8.53 (s, 1H), 8.38 (s, 1H), 8.20 (d, 1H, J=4.2 Hz), 7.69 (s, 1H), 7.27 (d, 1H, J=8.1 Hz), 7.14 (s, 1H), 7.05 (t, 1H, 7.8 Hz), 6.49 (dd, 1H, J=1.8 and 8.4 Hz), 3.80 (s, 3H); LCMS: purity: 82%; MS (m/e): 423 (MH+).
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[C:13](=O)[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:22]=[C:13]1[CH:12]2[CH2:15][CH2:16][N:9]([CH2:10][CH2:11]2)[C:8]1=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C(=Cc2ccccc2)N2CCC1CC2
Reactant: COc1ccccc1CN
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: COc1ccccc1CN=C1C(=Cc2ccccc2)N2CCC1CC2
Temperature: 116 °C

Procedure:
To a 12 L three neck round bottom flask (3 nrbf) fitted with mechanical stirrer, thermometer, condenser, and Dean Stark trap, was charged 5.9 L toluene, 79I.8 g (3.7 moles) of 2-phenylmethylene-1-azabicyclo[2.2.2]octan-3-one, 764 g (5.6 moles, 1.5 equivalents) 2-methoxybenzylamine, and 8.8 g (0.039 moles) (+)camphor sulfonic acid. The solution was heated to reflux (116° C.) and refluxed for 42 hours. A total of 75 ml water was collected in the Dean Stark trap showing that the reaction was proceeding. The solution containing the title product was cooled to room temperature.
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=1.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:27]3[C:28]([CH3:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[O:26])[CH:23]=2)[N:18]=[C:17]([O:35][CH3:36])[C:16]=1[CH2:37][C:38]1[CH:39]=[N:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=1>C1COCC1>[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:7]3[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=3)([C:27]3[C:28]([CH3:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[OH:26])[CH:23]=2)[N:18]=[C:17]([O:35][CH3:36])[C:16]=1[CH2:37][C:38]1[CH:39]=[N:40][C:41]([C:44]([F:46])([F:45])[F:47])=[CH:42][CH:43]=1
Reactant: COc1nc2ccc(C(=O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Reactant: Cc1ncc(Br)n1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 1.2 mL, 3.0 mmol) was added dropwise by syringe to a solution of 5-bromo-1,2-dimethyl-1H-imidazole (570.8 mg, 3.261 mmol) in dry THF (6 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of (4-chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanone (0.790 g, 1.626 mmol, Intermediate 47: step b) in dry THF (2 mL) was added dropwise. The reaction was stirred for 5 minutes, then was moved into an ice bath and allowed to warm to ambient temperature. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-5% MeOH-DCM) followed by reverse-phase HPLC (acetonitrile/H2O+0.05% TFA). The product fractions were basified with saturated aqueous sodium bicarbonate and extracted with DCM, before being dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J=2.0 Hz, 1H), 8.13 (d, J=2.2 Hz, 1H), 7.79-7.73 (m, 2H), 7.57 (dd, J=8.1, 0.9 Hz, 1H), 7.41 (dd, J=8.7, 2.2 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 6.04 (s, 1H), 4.35 (s, 2H), 4.08 (s, 3H), 3.39 (s, 3H), 2.53 (s, 3H), 2.41 (s, 3H), 2.37 (s, 3H); MS m/e 582.2 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@@H:2]4[NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[N:15]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4N)no2)cc1C#N
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4NS(C)(=O)=O)no2)cc1C#N
Reaction time: 1 h
Yield: 44.7 %

Procedure:
Prepared using General Procedure 8A: To a stirred solution of (S)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 50 (18 mg, 0.05 mmol) in DCM (1 mL) was added TEA (13.9 μL, 0.1 mmol) and methanesulfonyl chloride (19 mg, 0.1 mmol). After 1 h, additional TEA (13.9 μL, 0.1 mmol) and methanesulfonyl chloride (19 mg, 0.1 mmol) were added. After an additional 1 h of stirring the solvent was evaporated and purified by preparative HPLC to afford 9.8 mg (45%) of (S)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)methane sulfonamide 69. LCMS-ESI (m/z) calculated for C22H22N4O4S: 438.1; found 439.1 [M+H]+, tR=3.70 min. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.2 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 8.12 (d, J=7.7 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 5.07 (dd, J=16.5, 7.8 Hz, 1H), 4.78 (hept, J=6.1 Hz, 1H), 4.48 (d, J=9.3 Hz, 1H), 3.51 (ddd, J=17.5, 8.8, 3.4 Hz, 1H), 3.29-3.12 (m, 1H), 3.09 (s, 3H), 2.74 (dtd, J=12.9, 8.0, 3.5 Hz, 1H), 2.07-1.92 (m, 1H), 1.46 (d, J=6.1 Hz, 6H).
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[C:13]([OH:15])=[O:14])[CH:2]=[CH2:3].C(=O)([O-])[O-].[Na+].[Na+]>CC#N.CC#N.Cl[Pd]Cl.C1COCC1>[CH3:3][C:2]1[O:14][C:13](=[O:15])[C:5]2[C:4]([CH:1]=1)=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=2
Reactant: C=CCc1ccc(C(=O)O)cc1C(=O)O
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1cc2ccc(C(=O)O)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.6 %

Procedure:
Under oxygen atmosphere, a mixture of 4-allyl isophthalic acid (500 mg), bis(acetonitrile)dichloropalladium (629 mg), sodium carbonate (514 mg), and THF (30 mL) was stirred at room temperature for 4 hours. The insoluble material of the reaction mixture was separated by filtration, and the filtrate was concentrated under reduced pressure. A mixture of the resulting residue and DMF (5 mL) was diluted with 1M hydrochloric acid, and the precipitate was collected by filtration to obtain 3-methyl-1-oxo-1H-isochromene-7-carboxylic acid (112 mg).
Reaction SMILES: [CH:1]([N:4]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:5]1=2)([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:39][CH3:40])[C:23]([Cl:41])=[CH:22][N:21]=1>>[Cl:41][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:28]=2[O:39][CH3:40])=[N:25][C:20]([NH:16][C:13]2[CH:14]=[CH:15][C:5]3[N:4]([CH:1]([CH3:3])[CH3:2])[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]=3[CH:12]=2)=[N:21][CH:22]=1
Reactant: CC(C)N1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C(C)C)ncc1Cl
Yield: 52 %

Procedure:
In an analogous procedure to Example 651, part c, 1-isopropyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one was combined with (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine to yield 7-[5-Chloro-4-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-2-ylamino]-1-isopropyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (50.70 mg, 52% yield) as a beige powder. 1H-NMR (CDCl3) δ 8.15 (d, J=8.8 Hz, 1H), 8.03 (s, 1H), 7.53 (s, 1H), 7.48 (s, 1H), 7.37 (d, J=8.5 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.98 (s, 1H), 6.54 (s, 1H), 6.47 (d, J=8.9 Hz, 1H), 4.83 (m, 1H), 3.90 (m, 8H), 3.13 (m, 5H), 2.75 (m, 1H), 2.53 (m, 1H), 2.23 (m, 3H), 1.86 (m, 1H), 1.42 (d, J=6.7 Hz, 3H), 1.05 (d, J=6.9 Hz, 3H). LC/MS (ESI+)=537 (M+H). MP=153-154° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:10]1[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[N:14][CH:15]=1)=O.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41](=[O:43])[CH3:42])=[CH:37][CH:36]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[OH-].[K+]>CCO>[C:21]([O:25][C:26]([N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41](=[O:43])/[CH:42]=[CH:8]/[C:10]3[CH:15]=[N:14][C:13](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:12][CH:11]=3)=[CH:37][CH:36]=2)[CH2:32][CH2:33]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=Cc1ccc(/C=C/C(=O)O)nc1
Reactant: CC(=O)c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)nc3)cc2)CC1
Temperature: 4 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
A mixture of (E)-3-(5-formyl-pyridin-2-yl)-acrylic acid trifluoroacetate (described in Example 45 STEP A, 206 mg, 0.71 mmol), 4-(4-acetyl-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (described in Preparation 12, 368 mg, 1.16 mmol) and 1.7 M KOH (2 ml) in EtOH (12 ml) was stirred at 4° C. overnight. The resulting precipitate was filtered and washed with AcOEt to give 250 mg of 4-(4-{(E)-3-[6-((E)-2-carboxy-vinyl)-pyridin-3-yl]-acryloyl}-benzyl)-piperazine-1-carboxylic acid tert-butyl ester as its potassium salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][CH:10]=[C:11]2[C:16](=[O:17])OC(C)(C)OC2=O)=[CH:5][CH:4]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][CH:10]=[CH:11][C:16]2=[O:17]
Reactant: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cn1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: COc1ccc2[nH]ccc(=O)c2n1
Temperature: 250 °C

Procedure:
A suspension of 5-((6-methoxypyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (51.3 g, 0.185 mol) in diphenylether (1275 mL) was heated to 250° C. under nitrogen atmosphere for 20 min. The reaction mixture was cooled to RT and diluted with hexane. The gummy solid was then triturated with hexane to obtain 6-methoxy-1,5-naphthyridin-4(1H)-one as a pale brown color solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13](Cl)(=[O:15])=[O:14])=[O:11])[N:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:15])=[O:14])=[O:11])[N:3]=1
Reactant: Cc1cc(C)nc(NC(=O)NS(=O)(=O)Cl)n1
Reactant: C1CCNC1
Solvent: ClCCl
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)N2CCCC2)n1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a methylene chloride solution of [(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]sulfamoyl chloride, prepared as in Example 1, was added dropwise 2.9 g of pyrrolidine while maintaining the temperature at 20° C. The mixture was stirred for 16 hours and added to 50 ml of ice-water. Enough methylene chloride was added to dissolve the solids present and the methylene chloride solution was washed twice with equal volumes of water, dried over magnesium sulfate, filtered and evaporated in-vacuo. The residue, m.p. 180°-181° C., showed absorption peaks by infrared spectroscopy at 1690, 1605 and 1550 cm-1 and Nuclear Resonance Spectroscopy (60 MC) at 2.02 δ (mult.) and 3.64 δ (mult.) for the pyrrolidine hydrogens, 2.6 δ (singlet) for CH3 and 6.85 δpyrimidine H with integration ratios of 4:4:6:1, consistent for the desired structure.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH:18]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][CH:21]1[CH2:26][NH:25][CH2:24][CH2:23][N:22]1[C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH2:18][N:25]2[CH2:24][CH2:23][N:22]([C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)[CH:21]([CH3:20])[CH2:26]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(N2CCNCC2C)c1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccccc4)n(C(C)(C)C)n3)CC2C)c1

Procedure:
64 mg (44%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.312 mmol), 2-methyl-1-m-tolylpiperazine (59 mg, 0.312 mmol), DIPEA (82 mL, 0.468 mmol) and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [CH:1]([C:4]1[C:5]([Cl:12])=[N:6][C:7]([Cl:11])=[N:8][C:9]=1Cl)([CH3:3])[CH3:2].[CH3:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([CH3:20])[CH:19]=1.[H-].[Na+]>CN(C=O)C.CCOCC>[Cl:11][C:7]1[N:6]=[C:5]([Cl:12])[C:4]([CH:1]([CH3:3])[CH3:2])=[C:9]([O:21][C:16]2[CH:17]=[C:18]([CH3:20])[CH:19]=[C:14]([CH3:13])[CH:15]=2)[N:8]=1
Reactant: Cc1cc(C)cc(O)c1
Reactant: CC(C)c1c(Cl)nc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cc(C)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: -40 °C
Yield: 90.1 %

Procedure:
To a stirred mixture of 5-isopropyl-2,4,6-trichloropyrimidine (23.68 g, 0.105M), 3,5-dimethylphenol (12.2 g, 0.2M) in anhydrous DMF (200 ml) cooled in a dry ice-acetone bath (−40° C.) under nitrogen atmosphere, was portionwise added 60% sodium hydride (4.2 g, 0.105M). The reaction temperature was then slowly raised to room temperature during 3 hr. The reaction mixture was then diluted with ether, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product as a pale yellow solid. The crude product was purified by silica gel column chromatography (eluent, ether:hexanes (1:9)) to afford 28 g (90%) of a white solid. m.p. 107-108° C.; 1H NMR (200 MHz, CDCl3) δ 1.40 (6H, d, J=7.0 Hz), 2.35 (6H, s), 3.58 (1H, m), 6.72 (2H, s), 6.91 (1H, s).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1.Cl[CH2:21][C:22]1[N:26]([CH3:27])[N:25]=[CH:24][N:23]=1.O>CN(C)C=O>[CH3:27][N:26]1[C:22]([CH2:21][N:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:5][C:4]2=[O:3])=[N:23][CH:24]=[N:25]1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: Cn1ncnc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1CN1CCN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 281 mg, 7.0 mmol) was added to a solution of phenylmethyl 3-oxo-1-piperazinecarboxylate (1.5 g, 6.4 mmol) in dry dimethyl formamide (5 mL) and the mixture was stirred at room temperature for 30 minutes. 5-(Chloromethyl)-1-methyl-1H-1,2,4-triazole (WO0023449, 920 mg, 7.0 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was poured into water (150 mL) and extracted with diethyl ether (2×100 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a pale oil (2 g, 94%). m/z (ES+) 330 (M+1).
Reaction SMILES: O.S(=O)(=O)(O)O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[Br:17]Br>S([O-])([O-])(=O)=O.[Ag+2].ClCCl>[Br:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[F:7]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: BrBr
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)c(Br)c1
Temperature: 10 °C
Yield: 70 %

Procedure:
In a 20 L 4-necked RB flask, fitted with a mechanical stirrer, reflux condenser, add DM water (550 ml), conc. Sulphuric acid (6.2 L, 113 M), 4-fluronitrobenzene(1.0 kg, 7.09 M) at 25-35° C. under stirring. The reaction mixture was cooled to 10° C. and bromine (1.13 kg, 7.06 M) was added to reaction mixture under stirring. The reaction mixture was brought to temp. 25-35° C., silver sulfate (1.1 kg, ˜3.53 M) was added in one portion to the reaction mixture at 25-35° C. and maintained for 30-32 h under stirring. Monitor the progress of the reaction by GC and after ascertaining completion, the reaction mixture was poured slowly into ice cold water (12 L) and dichloromethane (12 L) mixture. Filter the insoluble and wash the inorganic with dichloromethane (2 L). Combine the organic layer, wash with 10% sodium bicarbonate (3 L), water (5 L). The dichloromethane layer was distilled below 40° C. under vacuum and add n-Hexane (4.5 L) to the residue. The resulting mass was stirred at 25-35° C. for 4-5 hr, filter the product and dried in vacuum oven below 35° C. till LOD reaches <1%. The dried product appears as white lustrous crystalline solid, weighs about 1.1-1.2 kg, yield 70-77%, purity 97-98% by HPLC, m.p. 56-58° C. The structure assigned to the product is in agreement with spectral data.
Reaction SMILES: [Na].[CH2:2]([N:9]1[CH2:15][CH2:14][CH2:13][NH:12]/[C:11](=[C:16]2/[C:17]([CH2:29][C:30]([O:32]C)=O)=[N:18][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:20]/2=[O:21])/[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>CO.O>[CH2:2]([N:9]1[CH2:15][CH2:14][CH2:13][N:12]2[C:30](=[O:32])[CH:29]=[C:17]3[NH:18][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[C:20](=[O:21])[C:16]3=[C:11]2[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CC1=NN(c2ccccc2Cl)C(=O)/C1=C1/CN(Cc2ccccc2)CCCN1
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: O=c1c2c3n(c(=O)cc2[nH]n1-c1ccccc1Cl)CCCN(Cc1ccccc1)C3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
An isopropanolic solution of MeONa, obtained by dissolving of sodium (0.055 g, 2.4 mmol, 2 eq.) in MeOH (3 ml) under nitrogen, was treated with methyl [(4Z)-4-(4-benzyl-1,4-diazepan-2-ylidene)-1-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of Formula (II) (530 mg, 1.2 mmol, 1 eq.). The reaction mixture was stirred at room temperature for 0.5 h, then cooled, diluted with water (8 mL) and neutralized to pH 6 by addition 1M HCl solution. The precipitate was filtered off and dried under vacuo. The crude was purified by flash chromatography to yield 129 mg of pure product 10-benzyl-2-(2-chlorophenyl)-2,3,8,9,10,11-hexahydro-1H-pyrazolo[4′,3′:3,4]pyrido [1,2-a][1,4]diazepine-1,5(7H)-dione. Yield 26%. 1HNMR (500 MHz, DMSO-d6): 1.62-1.68 (m, 2H); 2.83 (t, 2H, J=7.5 Hz); 3.62-3.66 (m, 2H); 4.40-4.76 (m, 2H); 5.73 (s, 1H); 7.21-7.32 (m, 5H); 7.44-7.50 (m, 2H); 7.55-7.60 (m, 1H); 7.61-7.67 (m, 1H); 10.75-10.68 (bs, 1H). MS (ESI+): 421.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12]>CO.O.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C=CC(=O)c1ccccc1N
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC(=O)CCC(=O)c1ccccc1N
Yield: 76.2 %

Procedure:
A solution of 4.87 g (23.73 mM) of methyl 4-(2-aminophenyl)-4-oxo-2-butenoate in 120 ml of methanol and 6 ml of water is hydrogenated in the presence of 974 mg of 10% Pd-C at room temperature under atmospheric pressure. After removal of the catalyst, the mixture is concentrated to give a residue, which is chromatographed on a column of silica gel (274 g), eluting with toluene-ethyl acetate (30:1-19:1 v/v) to give 3.746 g of methyl 4-(2-aminophenyl)-4-oxobutyrate as orange crystals. This is recrystallized from Et2O-n-hexane to give 3.162 g (Yield: 64.3%) melting at 50.0°-51.0° C. as yellow crystals.