Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:15])=[CH2:14])[CH:8]=1)([CH3:6])[CH3:5])=C=O.[OH-].[K+]>CC(O)(C)C>[C:13]([C:9]1[CH:8]=[C:7]([C:4]([NH2:1])([CH3:6])[CH3:5])[CH:12]=[CH:11][CH:10]=1)([CH3:15])=[CH2:14]
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: C=C(C)c1cccc(C(C)(C)N)c1
Yield: 37.7 %

Procedure:
To a solution of 1-(1-isocyanato-1-methyl-ethyl)-3-isopropenyl-benzene (10 g, 50 mmol) in t-BuOH (1000 mL) was added KOH (40.0 g, 71.6 mmol). The mixture was stirred at reflux for 3 h. The resultant mixture was cooled down to room temperature, concentrated and dissolved in CH2Cl2. Solid residue was filtered off and the organic layer was adjusted to pH<7 using conc. HCl. The ammonium salt was extracted with water. The aqueous layer was made basic using an aqueous NaOH solution[5% w/w, 200 ml] and free based amine was then extracted with CH2Cl2. The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-(3-isopropenyl-phenyl)-1-methyl-ethylamine (3.3 g, 63%).
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]2[CH:29]=[CH:28][C:20]3[O:21][C:22]([CH3:27])([CH3:26])[O:23][C:24](=[O:25])[C:19]=3[CH:18]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][C:38](Cl)=[O:39]>>[C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][N:16]([C:17]2[CH:29]=[CH:28][C:20]3[O:21][C:22]([CH3:26])([CH3:27])[O:23][C:24](=[O:25])[C:19]=3[CH:18]=2)[C:38](=[O:39])[CH2:37][C:33]2[S:32][CH:36]=[CH:35][CH:34]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCCCCCCCC#Cc1ccc(CNc2ccc3c(c2)C(=O)OC(C)(C)O3)cc1
Product: CCCCCCCCC#Cc1ccc(CN(C(=O)Cc2cccs2)c2ccc3c(c2)C(=O)OC(C)(C)O3)cc1

Procedure:
The title compound was prepared following the procedure E using 6-[(4-dec-1-ynylbenzyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one and thien-2-ylacetyl chloride. HPLC, Rt: 6.1 min (purity: 82.6%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:10]([F:12])[F:11])=[CH:5][CH:4]=1.[CH2:13]([NH:20][C:21]([C:23]1[S:24][C:25]([N:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]2=[O:36])=[CH:26][C:27]=1[CH3:28])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:21]([C:23]1[S:24][C:25]([N:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([O:9][CH:10]([F:12])[F:11])=[CH:5][CH:4]=3)=[CH:31][C:30]2=[O:36])=[CH:26][C:27]=1[CH3:28])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: FC(F)Oc1ccc(CBr)cc1
Product: Cc1cc(-n2ccc(OCc3ccc(OC(F)F)cc3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 35 %

Procedure:
Following the procedure as described in Example 9, making variations only as required to use 1-(bromomethyl)-4-(difluoromethoxy)benzene in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-benzyl-5-(4-hydroxy-2-oxopyridin-1(2H)-yl)-3-methylthiophene-2-carboxamide, the title compound was obtained as a pinkish solid in 35% yield: mp 178-180° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.55 (t, J=6.0 Hz, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.53 (d, J=8.5 Hz, 2H) 7.38-7.20 (m, 9H), 6.28 (dd, J=7.9, 2.7 Hz, 1H), 6.14 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.41 (d, J=6.0 Hz, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.1, 162.4, 160.9, 150.8, 139.6, 138.8, 137.2, 135.1, 132.4, 129.9, 128.2, 127.3, 127.4, 127.1, 126.6, 120.6, 118.7, 116.2, 102.5, 97.3, 69.2, 42.5, 15.5; MS (ES+) m/z 497.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:22][CH2:23][OH:24])[CH:10]=[C:11]([C:13]3[N:14]([CH:19]([CH3:21])[CH3:20])[N:15]=[C:16]([CH3:18])[N:17]=3)[N:12]=2)=[C:4](F)[CH:3]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[N:9]([CH2:22][CH2:23][O:24][C:4]=2[CH:3]=1)[CH:10]=[C:11]([C:13]1[N:14]([CH:19]([CH3:21])[CH3:20])[N:15]=[C:16]([CH3:18])[N:17]=1)[N:12]=3
Reactant: Cc1nc(-c2cn(CCO)c(-c3ccc(Br)cc3F)n2)n(C(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A suspension of 2-[2-(4-bromo-2-fluoro-phenyl)-4-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol (2.3 g, 5.6 mmol) in DMF (50 mL) was treated with sodium hydride (60% dispersion, 247 mg, 6.2 mmol) portionwise over 5 min and the mixture stirred at RT for 1 h. The reaction was quenched by the slow addition of water (200 mL). The precipitate formed was filtered off, washed with water to give 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene as a white solid (1.64 g, 53%). LCMS: RT=3.43 min, [M+H]+=388/390. 1H NMR 400 MHz (CDCl3) δ: 8.37 (1H, d, J=8.61 Hz), 7.70 (1H, s), 7.26-7.25 (2H, m), 5.87-5.86 (1H, m), 4.50-4.48 (2H, m), 4.46-4.42 (2H, m), 2.42 (3H, s), 1.57 (6H, d, J=6.64 Hz)
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([CH:14]4[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:22])[C:6]([C:23]([O:25]CC)=[O:24])=[CH:5]2)[CH2:3][CH2:2]1.[ClH:28]>>[ClH:28].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:21])=[C:11]([CH:14]4[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(C3CCN(C)CC3)c(F)cc2c1=O
Agent: Cl
Product: CN1CCC(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1

Procedure:
A solution of 3.71 g (10 mmoles) of ethyl 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(1-methyl-4-piperidinyl)-4-oxo-3-quinolinecarboxylate in 50 ml 6 N HCl was refluxed 1 hour and evaporated to dryness to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:11]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:47][N:48]([CH3:53])[S:49](Cl)(=[O:51])=[O:50]>N1C=CC=CC=1>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([NH:1][S:49]([N:48]([CH3:53])[CH3:47])(=[O:51])=[O:50])[CH:3]=[C:4]([C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:11]=2)[CH:5]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1cc(N)cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Solvent: c1ccncc1
Product: COc1cc(NS(=O)(=O)N(C)C)cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Temperature: 45 °C
Reaction time: 48 h
Yield: 44 %

Procedure:
(S)-2-(1-((5-(3-Amino-5-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with dimethylsulfamoyl chloride (25 μL, 0.23 mmol) and 200 μL pyridine according to the method described in Preparation 15b but stirring at 45° C. during 48 h. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 30 mg (44% yield, 85% purity) of the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([OH:12])=O.CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:43]1[CH2:48][CH2:47][CH:46]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:45][CH2:44]1>C(Cl)Cl.O.C(OCC)(=O)C>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]([N:43]1[CH2:48][CH2:47][CH:46]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:45][CH2:44]1)=[O:12]
Reactant: O=C(O)c1nc2ccccc2[nH]1
Reactant: CCOC(=O)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1CCN(C(=O)c2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1H-benzo[d]imidazole-2-carboxylic acid, H2O (500 mg, 2.78 mmol), EDCI (1170 mg, 6.11 mmol), and 1-HYDROXYBENZOTRIAZOLE (825 mg, 6.11 mmol) were dissolved in DCM. The reaction was allowed to stir for 10 minutes before Hunig's Base (1.066 mL, 6.11 mmol) and ethyl piperidine-4-carboxylate (0.941 mL, 6.11 mmol) were added. The reaction was allowed to stir overnight at room temperature. The reaction was diluted with water and ethyl acetate. The organic phase was washed with 1N HCl, saturated sodium bicarbonate, and saturated sodium chloride solution. The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated. The resulting crude material was triturated with ethyl acetate to obtain white solid as a product. (Yield: 113 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 13.09, 7.74, 7.53, 7.36-7.20, 5.31, 4.42, 4.09, 3.48, 3.05, 2.77-2.66, 1.97, 1.69-1.50, 1.20
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1.C([O-])(=O)C.[Na+].S(=O)(=O)(O)O>C(O)(=O)C.O>[Br:1][C:9]1[CH:10]=[C:5]([O:4][CH3:3])[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[C:8]=1[OH:11]
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Br)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bromine (16.0 g, 100 mmol) in acetic acid (20 mL) was added into a mixture of 4-methoxy-2-nitrophenol (16.9 g, 100 mmol, sodium acetate (16.4 g, 200 mmol) and acetic acid (100 mL). The mixture was stirred for 30 min at room temperature, and then at 70° C. for 2 h and poured into water (1.5 l) containing concentrated sulfuric acid (10 mL). The precipitated solid filtered and crystallized from (chloroform/hexane) to give a brownish solid, m.p. 116–118° C.; MS m/e 246 (M−H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[N:14][N:4]2[N:3]=1.[CH3:15][NH2:16]>CO>[CH3:15][NH:16][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][N:13]=[N:14][N:4]2[N:3]=1
Reactant: Clc1nn2nnnc2c2c1CCCC2
Reactant: CN
Solvent: CO
Product: CNc1nn2nnnc2c2c1CCCC2

Procedure:
A mixture of 6.0 g of 6-chloro-7,8,9,10-tetrahydrotetrazolo[5,1-a]phthalazine and 125 ml of 40% aqueous methylamine in 15 ml of methanol was heated under reflux for 3 hours. The reaction mixture was then cooled and the crystalline solid present was separated by filtration. It was recrystallized from a mixture of dimethylsulfoxide and water to give 6-methylamino-7,8,9,10-tetrahydrotetrazolo[5,1-a]phthalazine melting at about 318° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:37])[C@@H:3]([C:27]1[CH:36]=[CH:35][C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[N:9]=[CH:8]2.[F:38][C:39]([F:44])([CH3:43])[C:40](O)=[O:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:38][C:39]([F:44])([CH3:43])[C:40]([NH:1][C@@H:2]([CH3:37])[C@@H:3]([C:27]1[CH:36]=[CH:35][C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([O:19][CH2:20][CH:21]([CH3:22])[CH3:23])=[O:18])[N:9]=[CH:8]2)=[O:41]
Reactant: CC(F)(F)C(=O)O
Reactant: CC(C)COC(=O)c1cccc(-n2ncc3cc(O[C@H](c4ccc5c(c4)OCCO5)[C@H](C)N)ccc32)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)COC(=O)c1cccc(-n2ncc3cc(O[C@H](c4ccc5c(c4)OCCO5)[C@H](C)NC(=O)C(C)(F)F)ccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isobutyl 3-(5-((1R,2S)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-1H-indazol-1-yl)benzoate (I4b) (0.5 g, 1.00 mmol), 2,2-difluoropropanoic acid (0.16 g, 1.45 mmol) and HBTU (0.567 g, 1.50 mmol) in DCM (4 mL) was treated with DIEA (0.696 mL, 3.99 mmol), the mixture was stirred at ambient temperature for 1 hour. The reaction was quenched by addition 10% NaHSO4 (aq), brine was added to help phase separation. The lower red DCM phase was separated, the waterphase was extracted with one portion of EtOAc, the combined organic solutions were dried over MgSO4 and filtered, solvents was removed by evaporation. Obtained a crude product as red oil. The crude material was further purified by flashchromatography using an 70 g prepacked silica column, an gradient of 0% to 50% EtOAc in Heptane was applied. Fractions with product was combined and solvents was removed by evaporation. An slightly yellow sticky oil was obtained after final evaporation from DCM. Yield 540 mg (91%).
Reaction SMILES: [CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([Cl:14])[C:8]=1Cl)[CH2:2][CH2:3][CH3:4].[CH2:16]([Mg]Br)[CH3:17]>[Cl-].[Mn+2].[Cl-]>[CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([Cl:14])[C:8]=1[CH2:16][CH3:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC/N=C/c1c(F)ccc(Cl)c1Cl
Reactant: CC[Mg]Br
Agent: [Mn+2]
Agent: [Cl-]
Product: CCCC/N=C/c1c(F)ccc(Cl)c1CC

Procedure:
Butyl-[1-(3-chloro-2-ethyl-6-fluoro-phenyl)-meth-(E)-ylidene]-amine was prepared from butyl-[1-(2,3-dichloro-6-fluoro-phenyl)-meth-(E)-ylidene]-amine, ethylmagnesium bromide and manganese(II) chloride in analogy to Example 194a): yellow oil; 1H-NMR (CDCl3): 0.97 (3H, t, CH3), 1.15 (3H, t, CH3), 1.43 (2H, sextet, CH2), 1.70 (2H, quintet, CH2), 3.06 (2H, q, CH2), 3.66 (2H, t, CH2), 6.88 (1H, dd, ArH), 7.34 (1H, dd, ArH), 8.51 (1H, s, CH═N).
Reaction SMILES: [C:1]([CH:5]1[CH2:12][CH2:11][CH2:10][C:9](=[CH:13][C:14](OCC)=[O:15])[CH:8]([O:19][SiH:20]([CH3:22])[CH3:21])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Li+].CC(C[AlH]CC(C)C)C.[Cl-].[NH4+].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[C:1]([CH:5]1[CH2:12][CH2:11][CH2:10][C:9](=[CH:13][CH2:14][OH:15])[CH:8]([O:19][SiH:20]([CH3:22])[CH3:21])[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C=C1CCCC(C(C)(C)C)CCC1O[SiH](C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: C[SiH](C)OC1CCC(C(C)(C)C)CCCC1=CCO
Temperature: -50 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
5.7 g of the above product (a) was dissolved in 150 ml of toluene, and the solution was cooled to −50° C. To the solution was added 20 ml of a solution (1.0M) of diisobutyl alminum lithium hydride (DIBAL) in toluene. The solution was stirred at −50° C. for one hour. To the reaction solution was added 26 ml of DIBAL solution, followed by stirring for further twenty minutes. Then, to the reaction solution was added 50 ml of a saturated ammonium chloride solution, followed by stirring at room temperature for ten minutes. To the reaction solution was added 10 g of Rochelle salt, followed by stirring for further thirty minutes and filtering through Celite. The filtrate was washed with a saturated Rochelle salt solution and a saturated saline solution, and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by column chromatography on silica gel, and the eluate with ethyl acetate-hexane (1:8) was collected, to afford 3.9 g of the titled compound (b) as a colorless oily matter.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:30]=[CH:29][C:7]([C:8]([C:10]2[CH:11]=[CH:12][C:13]3[NH:19][C:18](=[O:20])[CH2:17][N:16]=[C:15]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[C:14]=3[CH:28]=2)=[O:9])=[CH:6][CH:5]=1.I[CH3:32]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([CH3:32])[C:18](=[O:20])[CH2:17][N:16]=[C:15]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[C:14]=3[CH:28]=2)=[O:9])=[CH:29][CH:30]=1
Reactant: O=C1CN=C(c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CN=C(c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
NaH 80% in oil (0.0366 mol) was added at 10° C. under N2 flow to a mixture of intermediate (6) (0.0244 mol) in N,N-dimethylformamide (100 ml). The mixture was brought to room temperature and then stirred for 30 min. and iodomethane (0.0293 mol) was added. The mixture was stirred for 3 hours, hydrolyzed, filtered, washed with water and taken up in DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (9.1 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 4.5 g (43%) of 7-(4-chlorobenzoyl)-5-(3-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (intermediate 7), mp. 176° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH3:1][C:2]1([CH3:8])[CH2:7][N:6]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH2:5][CH2:4][N:3]1[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1
Reactant: CC1(C)CNCCN1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1(C)CN(CCc2ccc([N+](=O)[O-])cc2)CCN1CCc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C

Procedure:
A mixture of 2,2-dimethylpiperazine (35 mg, 0.31 mmol), 1-(2-bromoethyl)-4-nitrobenzene (280 mg, 1.2 mmol), tetrabutylammonium iodide (11 mg, 0.031 mmol), and K2CO3 (169 mg, 1.2 mmol) in DMF (2 mL) was heated to 60° C. for 16 hours. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 413 [M+1]+. (0.21 μm)
Reaction SMILES: [OH:1][C:2]1C=C[C:5]([CH:6]=O)=[CH:4][C:3]=1OC.C(O)(=O)CC(O)=O.Br[CH:20]([CH3:32])[CH2:21][C:22]1[CH:27]=[C:26](OC)[C:25](OC)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:32]=1[CH:20]=[CH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: COc1ccc(CC(C)Br)cc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: Oc1ccccc1C=Cc1ccccc1
Yield: 25 %

Procedure:
A mixture of 4-hydroxy-3-methoxybenzaldehyde (3.47 mmol), malonic acid (13.8 mmol), 2-bromo-4,5-dimethoxypropylbenzene (1.93 mmol), palladium acetate (0.09 mmol), triphenylphosphine (0.14 mmol), piperidine (15.8 mmol) and DMF (20 ml) were taken in a 100 ml round bottom flask fitted with a condenser. The flask was shaken well and placed inside the monomode microwave oven and irradiated (250 W, 160° C.) for 30 minutes in parts. After completion the reaction was worked up as in example I and provided a white crystalline solid; 25% yield (m.p. 74-78° C.); 1H NMR (300 MHz, CDCl3) δ 7.11-6.93 (4H, m), 6.86 (1H, d), 6.78 (1H, d), 6.61 (1H, s), 5.62 (1H, s), 3.88 (3H, s), 3.86 (3H, s), 3.78 (3H, s), 2.61 (2H, t), 1.55 (2H, m), 0.91 (31-1, t): δC (75.4 MHz, CDCl3) δC 148.4, 147.3, 146.7, 145.3, 133.2, 130.7, 128.3, 127.9, 124.2, 119.8, 114.6, 112.8, 108.6, 108.5, 56.0, 35.1, 24.7 and 14.0. The above obtained hydroxystilbene derivative was alkylated or acetylated/benzoylated in the same pot with addition of alkyl halide or acetyl chloride or benzoyl chloride etc.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]=[O:12])=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1.[CH3:16]I>CN(C)C=O>[CH3:16][N:10]([C:7]1[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][C:6]=1[N+:13]([O-:15])=[O:14])[CH:11]=[O:12]
Reactant: Cc1ccc(NC=O)c([N+](=O)[O-])c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(N(C)C=O)c([N+](=O)[O-])c1
Temperature: 50 °C
Yield: 83.7 %

Procedure:
In an argon flow, 8.1 g (202 mmols) of sodium hydride (60% in oil) was added to 400 ml of dry dimethylformamide and the mixture was cooled to 5° to 10° C. To the mixture was dropwise added 34.7 g (192 mmols) of N-(4-methyl -2nitrophenyl)formamide (a solution in 150 ml of dry dimethylformamide). The mixture was stirred at 50° C. for an hour. After cooling again to 5° to 10° C., 18 ml (289 mmols) of methyl iodide (a solution in 30 ml of dry dimethylformamide) was dropwise added to the mixture. The system was stirred at room temperature for 16 hours. After the solvent was distilled off under reduced pressure, 200 ml of water was added to the residue followed by extraction with ethyl acetate. After the ethyl acetate layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting crystals were washed with n-hexane to give 31.2 g (83.4%) of N-methyl-N-(4-methyl2-nitrophenyl)formamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[OH:10].[CH:11]1(Br)[CH2:15][CH2:14][CH2:13][CH2:12]1.[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[O:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(Br)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Br)cc1OC1CCCC1

Procedure:
20 g (0.1 mol) 1-Methoxy-2-hydroxy-4-bromo-benzene (Preparation 1) was dissolved in 40 ml ethanol. Then 21 g (0.14 mol) cyclopentylbromide and a solution of 5.5 g NaOH in 6.6 ml water was added and the mixture refluxed for 13 hours. Thereafter, the solvent was removed in vacuo and the residue taken up with methylene chloride and washed (4×) with 1N NaOH. After drying over Na2SO4, the organic solvent was removed in vacuo to give the title compound as an oily product, yield: 182 g (67%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[O:27][C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]1[O:7]C(=O)C1C=CC=CC=1)(=[O:3])C.Br.O>C(Cl)Cl>[C:1]([O:4][C@@H:5]1[O:27][C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]1[OH:7])(=[O:3])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)O[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: Br
Solvent: O
Solvent: ClCCl
Product: O=C(OC[C@@H]1O[C@@H](OC(=O)c2ccccc2)[C@@H](O)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
Compound 10 (9 g, 17.84 mmol) was stirred in 100 ml of CH2Cl2 at 0° C. while 70 ml of CH2Cl2 containing HBr (3.2 g, 30.5 mmol) was added in one portion. The mixture was stirred at 0° C. for 3.5 hrs, water (55 ml) was added and the mixture stirred at r.t. for 18 hrs. The organic layer was separated, washed with sat. NaHCO3, dried (MgSO4). After evaporation of the solvent, a foam was obtained, which upon recrystallization from CH2Cl2 and n-hexane, gave 11 as a white solid. (6.2 g, 75.5%). m.p. 137°-138° C., lit. 140°-141° C., [α]D =-81.960 (c 0.55, CHCl3 ; D form: [α]D =+83.71.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:13][C:12]([C:27]([C:33]([F:36])([F:35])[F:34])([C:29]([F:32])([F:31])[F:30])[OH:28])=[N:11]1.[CH3:37][N:38]([CH3:43])[S:39](Cl)(=[O:41])=[O:40]>>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:22][CH2:23][N:24]([S:39](=[O:41])(=[O:40])[N:38]([CH3:43])[CH3:37])[CH2:25][CH2:26]3)=[CH:19][CH:20]=2)[CH2:13][C:12]([C:27]([C:29]([F:30])([F:32])[F:31])([C:33]([F:34])([F:35])[F:36])[OH:28])=[N:11]1
Reactant: OC(C1=NN(c2ccc(F)cc2F)C(c2ccc(N3CCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Product: CN(C)S(=O)(=O)N1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)CC1

Procedure:
The titled compound was prepared in accordance with the same procedures as in Example 406, except for using 1-(2,4-difluoro-phenyl)-5-[4-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride prepared in Example 405; and using dimethylsulfamoyl chloride instead of methanesulfonyl chloride.