Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(CC)C.[C:41](OCC)(=[O:47])[C:42]([O:44][CH2:45][CH3:46])=[O:43]>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:41](=[O:47])[C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 80.8 %

Procedure:
(2R,6S)-4-[6-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3, 0.5 g, 1.01 mmol) was dissolved in 10 ml of THF and cooled to −78° C. Sec-butyl lithium (1.358 ml, 1.77 mmol) was added drop wise over 5 minutes. The reaction stirred at −78° C. for 1.5 hours. The reaction mixture was cannulated into a −78° C. cooled flask containing diethyl oxalate (1.370 ml, 10.09 mmol) in 10 ml of THF. The reaction was allowed to stir at −78° C. for 30 minutes; quenched cold with 1 ml sat NH4Cl and allowed to warm to room temp. The reaction was diluted with water and extracted twice with ethyl acetate. The organic layers were combined and washed twice with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography using a gradient of hexanes to ethyl acetate to give the title compound (486 mg, 81% yield) contaminated with diethyl oxalate. This material was taken to the next step without further purification.
Reaction SMILES: C[C:2]([C:15]1[CH:20]=[CH:19][C:18](OCC2OC2)=[CH:17][CH:16]=1)([C:4]1[CH:9]=[CH:8][C:7]([O:10]CC2OC2)=[CH:6]C=1)C.CCC.C(OCC1OC1)C1[O:32]C1>>[CH:17]1[CH:16]=[C:15]([C:2]2[CH:4]=[CH:9][CH:8]=[C:7]([OH:10])[CH:6]=2)[C:20]([OH:32])=[CH:19][CH:18]=1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Reactant: C(OCC1CO1)C1CO1
Solvent: CCC
Product: Oc1cccc(-c2ccccc2O)c1
Temperature: 110 °C

Procedure:
To a suitable reactor were added 885 parts of the diglycidyl ether of Bisphenol A having an epoxide equivalent weight of 186 and 615 parts of 2,2'-bis(3,5-dibromo, 4-hydroxyphenyl) propane. Heat and agitation were applied raising the temperature to 230° F. When solution of the diphenol in the glycidyl ether was obtained, heating was discontinued and 30 parts of a nonionic surfactant, made by polymerizing ethylene oxide with a condensate of propylene oxide with propylene glycol (plutonic F98, obtained from Wyandotte Chemicals Corp.) were added. Deionized water, 1530 parts, was slowly added dropping the temperature to 120° F. Triphenyl phosphine, 4.15 parts, was added and heat was applied raising the temperature to 200° F. The temperature was held at 200° F., while the resinous reactants went from a taffy slurry to finely divided beads. After heating for 2 hours and 30 minutes at 200° F., the acid value of the reactants was reduced tp 0, indicating no free phenolic groups. Heating was discontinued and 2000 parts of cold water were added. The water was drawn off and the resin was washed with an additional 2000 parts of water. The resin produce was then placed on foil sheets and dried at 212° F. for 2 days. The produce had an epoxide equivalent weight of 606, a Durran's melting point of 86° C., and at 40% solids in diethylene glycol monobutyl ether, a Gardner color of 1-2 and a Gardner-Holdt viscosity at 25° C. of B-C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:27]=[C:26]([OH:28])[C:25]([CH3:29])=[CH:24][C:22]=1[NH2:23]>>[CH3:20][C:21]1[CH:27]=[C:26]([OH:28])[C:25]([CH3:29])=[CH:24][C:22]=1[NH:23][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1
Reactant: Cc1cc(O)c(C)cc1N
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Cc1cc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c(C)cc1O

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine with 2,5-dimethyl-4-hydroxyaniline gave N2-(2,5-dimethyl-4-hydroxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.69 (d, 1H, J=3.9 Hz), 7.16 (d, 1H, J=2.4 Hz), 7.05 (d, 1H, J=2.4 Hz), 7.02 (d, 1H, J=1.2 Hz), 6.66 (s, 1H), 6.63 (s, 1H), 6.62 (s, 1H), 4.19 (s, 4H), 2.12 (s, 3H), 2.10 (s, 3H); LCMS: ret. time: 19.80 min.; purity: 90%; MS (m/e): 383 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[C:14]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[C:14]([O:22][CH2:23][CH3:24])=[O:21])[CH3:20]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
2,5-Dibromonitrobenzene (41.5 g, 148 mmol) was dissolved in anhydrous DMF (500 ml) and sodium hydride (17.7 g of a 60% suspension in mineral oil, 443 mmol) was added under argon. Diethyl malonate (49.6 g, 295 mmol) was added dropwise over 10 minutes giving a strong exotherm (mixture rose to 60° C.). The reaction mixture was maintained at 60° C. for 6 hours then left to cool to ambient temperature and stirred for 18 hours. The resulting dark red solution was poured slowly into 2M hydrochloric acid (1500 ml) and extracted with ether (500 ml×4). The organic phases were combined, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The crude oil was purified by flash chromatography eluting with isohexanes/ethyl acetate (100/0, then 95/5 and finally 80/20) to give diethyl(4-bromo-2-nitrophenyl)malonate (51 g, 96%).
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C>[NH:12]=[C:13]1[NH:15][C:3](=[O:4])[CH:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[S:14]1
Reactant: NC(N)=S
Reactant: O=C(O)C(Br)c1ccccc1
Solvent: CCO
Product: N=C1NC(=O)C(c2ccccc2)S1
Yield: 157.2 %

Procedure:
A mixture of 100 g (0.47 mole) of α-bromophenylacetic acid (Aldrich) and 41.0 g (0.54 mole) of thiourea (Baker) in 600 mL of ethanol was stirred and heated on a steam bath for 4 hr. The solvent was evaporated under reduced pressure to give 142.0 g crude title compound as a white solid. An analytical sample of title compound, mp 249°-252° C., was prepared from 95% ethanol as white flakes.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10]>C1(C)C=CC=CC=1.C(NC(C)C)(C)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].[Cu]I>[CH3:8][Si:9]([C:12]#[C:13][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)([CH3:11])[CH3:10]
Reactant: Brc1cncnc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cncnc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
Tetrakis(triphenylphosphine)palladium(O) (727 mg, 0.6 mmol) was added to a stirred, degassed suspension of 5-bromopyrimidine (5.0 g, 31.4 mmol) and copper(I)iodide (120 mg, 0.6 mmol) in toluene and diisopropylamine (1:1, 200 ml) under nitrogen. The reaction mixture was heated to 60° C., trimethylsilylacetylene (4.89 ml, 34.6 mmol) was added and the reaction mixture was stirred for 3 hours at 60° C. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (200 ml) and washed with saturated aqueous ammonium chloride solution (3×100 ml). The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (5% ethyl acetate/heptane) to give 5-trimethylsilanylethynyl-pyrimidine as a pale brown solid, 4.71 g (85% yield). LC at 215 nm; Rt 2.07: 88%, m/z (ES+): 177 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:2]1.[N:20]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:21]=[O:22].CCN(C(C)C)C(C)C>C1COCC1>[CH2:23]([NH:20][C:21]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[CH:19][C:9]=23)[CH2:2]1)=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=NCc1ccccc1
Reactant: NC(=O)c1cnc2[nH]ccc2c1NC1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)c1cnc2[nH]ccc2c1NC1CCCN(C(=O)NCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.4 %

Procedure:
To a solution of 4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (62 mg, 0.24 mmol, 1.0 eq) and (isocyanatomethyl)benzene (35 mg, 0.26 mmol, 1.1 eq) in THF (2 mL) were added DIPEA (93 mg, 0.72 mmol, 3.0 eq). The mixture was stirred at rt for 3 h and the solvent was removed in vacuo to afford a residue which was purified by prep-HPLC (MeOH/H2O with 0.05% NH3.H2O) to give the title compound as a light brown solid (23 mg, yield: 11%). 1H NMR (400 MHz, CD3OD) δ: 8.32 (s, 1H), 7.15-7.09 (m, 6H), 6.91 (d, J=3.6 Hz, 1H), 4.23-4.20 (m, 3H), 3.87-3.83 (m, 1H), 3.46-3.34 (m, 3H), 2.09-2.05 (m, 1H), 1.81-1.80 (m, 2H), 1.62-1.59 (m, 1H). ESI-MS (M+H)+: 393.20.
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13][CH:7]2[CH2:6][CH:5]=[CH:4][CH2:3]1.C(=O)(O)[O-].[Na+].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCOCC>O.C1COCC1>[C:22]([NH:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@H:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13][C@H:7]2[CH2:6][CH:5]=[CH:4][CH2:3]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC1CC=CCC2CCC(C(=O)O)N2C1=O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@H]1CC=CC[C@@H]2CC[C@@H](C(=O)O)N2C1=O)c1ccccc1
Reaction time: 18 h

Procedure:
A solution of 6-amino-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid, 9, (5.6 g, 25 mmol) in 70 mL of H2O/THF solution is then treated with sodium bicarbonate (2.3 g, 27.4 mmol) and benzoyl chloride (3 ml, 25.84 mmol). The reaction is stirred for 18 hours and then ether (100 mL) is added. The organics are washed two times with 1 N HCl, once with water, and dried over MgSO4, filtered, and concentrated in vacuo to a residue which is purified over silica to afford the desired compound which is used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([N:25]3C(=O)C4C(=CC=CC=4)C3=O)[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.O.NN>C1COCC1>[CH3:1][N:2]([CH3:36])[C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)c1cccc(C(=NOCc2cccc(N3C(=O)c4ccccc4C3=O)n2)c2nnnn2C)c1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1cccc(C(=NOCc2cccc(N)n2)c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
To a stirred solution of 2-(6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-yl)-1H-isoindole-1,3(2H)-dione (5.22 g, 11 mmol) in dry THF (130 mL) was added hydrazine hydrate (2.63 mL, 54 mmol). The reaction mixture was stirred at room temperature for 6 h, then insolubles were removed by filtration and washed with ethyl acetate. The filtrates were combined and concentrated in vacuo. The residue was dissolved in ethyl acetate (250 mL), washed with water (2×100 mL), and the organic layer was dried over MgSO4 and concentrated in vacuo to afford 6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-amine as an orange solid [3.56 g, yield 89%; HPLC/MS: m/z=353 (M+H); logP(HCOOH)=1.19].
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][C:7](=[O:24])[NH:8][C:9]3[CH:16]=[C:15]([Cl:17])[C:14]([C:18]#[C:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:13][C:10]=3[C:11]=2[N:12]=1>O.C1COCC1.[Ni]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][C:7](=[O:24])[NH:8][C:9]3[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][CH2:19][CH2:20][N:21]([CH3:22])[CH3:23])=[CH:13][C:10]=3[C:11]=2[N:12]=1
Reactant: CN(C)CC#Cc1cc2c(cc1Cl)NC(=O)Cc1cnc(N)nc1-2
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCCc1cc2c(cc1Cl)NC(=O)Cc1cnc(N)nc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
A slurry of Raney Ni (3.0 mL) in water was added to 2-amino-9-chloro-10-[3-(dimethylamino)prop-1-yn-1-yl]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.30 g, 0.88 mmol) in THF (6 mL). The reaction mixture was allowed to stir under an atmosphere of H2 at rt overnight. The reaction mixture was filtered over Celite and the filter cake was washed with THF. The filtrate was concentrated and the resulting solid was triturated with MeOH, diethyl ether, and hexanes. The solid was collected via suction filtration to give 2-amino-9-chloro-10-[3-(dimethylamino)propyl]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.158 g, 52%) as a light yellow solid. LCMS (FA): m/z=346 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][NH:11][CH3:12])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][NH:31][CH:32]=2)O1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)=[CH:3][CH:4]=2)[CH2:9][CH2:10][NH:11][CH3:12])=[CH:14][CH:15]=1
Reactant: CNCCC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CNCCC(c1ccc(Cl)cc1)c1ccc(-c2cn[nH]c2)cc1

Procedure:
[3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propyl]-methyl-amine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-B3) Rt 2.63 [M+H]+ 326.00. 1H NMR (Me-d3-OD) δ 2.37-2.47 (2H, m), 2.66 (3H, s), 2.91 (2H, t), 4.05 (1H, t), 7.25-7.34 (6H, m), 7.54 (2H, d), 7.92 (2H, s), 8.51 (1H, br s—due to formic acid).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:23](Br)[CH2:24][CH2:25][CH3:26].[H-].[Na+]>CN(C=O)C>[CH2:23]([N:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[C:11]([CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)=[O:12])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCBr
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN(C(=O)C1CCCc2ccccc21)c1ccc(C(C)C)cc1
Reaction time: 0.5 h

Procedure:
N-(4-Isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) and butyl bromide (0.22 mL) were dissolved in DMF (3 mL), and sodium hydride (0.08 g) was added under ice-cooling. The mixture was stirred at the same temperature for 30 min and then at room temperature for 3 hr. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give N-butyl-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.53 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH2:10]1.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:21][CH2:22][N:23]([S:39]([CH:36]4[CH2:38][CH2:37]4)(=[O:41])=[O:40])[CH2:24][CH2:25]3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:28]([F:31])([F:30])[F:29])([C:32]([F:33])([F:35])[F:34])[OH:27])[CH2:10]1
Reactant: OC(C1=NN(c2cccc(N3CCNCC3)c2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C1CC1)N1CCN(c2cccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.6 %

Procedure:
The 5-(2-chloro-phenyl)-1-[3-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.055 mmol) in the form of a yellow liquid, cyclopropanesulfonyl chloride (9.3 mg, 0.066 mmol), and triethylamine (31.0 uL, 0.221 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[CH:23])=[N:20][CH:21]=2)=[CH:12][CH:11]=1.BrCl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:23]#[C:22][C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=3)=[CH:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Agent: ClBr
Product: Clc1ccc(-c2ccc(C#Cc3ccc(Br)cc3)nc2)cc1

Procedure:
The product was obtained analogously to Example 7.1e starting from 4-bromoiodobenzene and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 7.10 g (90% of theoretical); C19H11BrClN (M=368.654); calc.: molpeak (M+H)+: 368/370/372 (BrCl); found: molpeak (M+H)+: 368/370/372 (BrCl); HPLC-MS: 7.60 minutes (method A).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[C:51]([C:59]2[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=2)[CH:50]=1>CN(C=O)C>[N:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[C:51]([C:59]2[CH:60]=[C:61]([NH:65][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:62]=[CH:63][CH:64]=2)[CH:50]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2cnc3ccccc3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cnc3ccccc3c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 46.8 %

Procedure:
DIEA (0.013 mL, 0.075 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.014 g, 0.068 mmol) and HATU (0.028 g, 0.075 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-quinolin-3-yl-phenylamine (0.015 g, 0.068 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.013 g of product in 48% yield: LCMS (ESI) m/z 409 (MH+).
Reaction SMILES: C1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:10](=[O:22])[CH:9]([NH:23][C:24]([O:26]C3C=CC([N+]([O-])=O)=CC=3)=O)[N:8]=2)CCCCC1.C(N([CH2:41][CH3:42])CC)C.CN(C)C=O.[CH3:48][S:49]([NH:52][C:53]([C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([NH2:61])[CH:56]=1)=[O:54])(=[O:51])=[O:50]>CO>[CH2:42]1[CH2:41][CH:7]([C:9]2([NH:23][C:24]([NH:61][C:57]3[CH:58]=[CH:59][CH:60]=[C:55]([C:53]([NH:52][S:49]([CH3:48])(=[O:51])=[O:50])=[O:54])[CH:56]=3)=[O:26])[N:8]=[CH:7][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:10]2=[O:22])[CH2:13][CH2:12][CH2:17]1
Reactant: CC(C)CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCC2)c2ccccc21
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)NC(=O)c1cccc(N)c1
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)CN1C(=O)C(NC(=O)Nc2cccc(C(=O)NS(C)(=O)=O)c2)(C2CCCCC2)N=Cc2ccccc21

Procedure:
The title compound was prepared from 5-cyclohexyl-1,3-dihydro-l-(2-methylpropyl)-3(R,S)-[(4-nitrophenyloxycarbonyl)amino]-2H- 1,4-benzodiazepin-2-one (0.3 g, 0.63 mmol), triethylamine (87 μl, 0.63 mmol), dimethylformamide (6 ml) and 1-(methylsulphonylaminocarbonyl)-3-aminobenzene (0.15 g, 0.69 mmol) [Example 16, Step 2] using the procedure described in Example 11, Step 4. The product (0.17 g, 49%) was afforded as a pale cream solid after trituration with methanol. mp 250°-252° C. 1H NMR (360 MHz, D6 -DMSO) δ 0.64 (3H, d, J=6.6 Hz), 0.76 (3H, d, J=6.7 Hz), 0.92-1.70 (9H, m), 1.74-1.82 (1H, m), 1.98 (1H, m), 2.90-3.30 (1H, m), 3.33 (3H, m), 3.62 (1H, dd, J=14.0 and 4.7 Hz), 4.14 (1H, dd, J=13.9 and. 9.4 Hz), 5.04 (1H, m), 7.37 (3H, m), 7.47 (1H, m), 7.60 (3H, m) , 7.78 (1H, m), 7.90 (1H, s), 9.18 (1H, s), 12.06 (1H, brs).
Reaction SMILES: Cl.Cl[C:3]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]1[N:14]=[N:15][N:16]=[C:9]1[N:8]=[C:7]2[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1.[NH3:37].CC([OH:41])C>C1COCC1>[OH2:41].[Cl:23][C:19]1[CH:18]=[C:17]([C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([C:3]([C:31]4[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=4)([C:24]4[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=4)[NH2:37])[CH:5]=3)[N:10]3[N:14]=[N:15][N:16]=[C:9]3[N:8]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)O
Reactant: N
Reactant: Cc1ccc(C(Cl)(c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)c2cncn2C)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(N)(c2ccc3c(c2)c(-c2cccc(Cl)c2)nc2nnnn23)c2cncn2C)cc1
Product: O
Temperature: 5 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A mixture of intermediate 26 (0.0083 mol) in THF (80 ml) was cooled to 5° C. under N2 flow. NH3/iPrOH (80 ml) was added dropwise. The mixture was stirred at 5° C. for 1 hours, then brought to room temperature. The mixture was stirred at room temperature overnight, poured out into ice water and extracted with DCM. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (15-40 μm) (eluent: DCM/MeOH/NH4OH 96/4/0.2). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 1.37 g (33%) of 5-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-α-(4-methylphenyl)-tetrazolo[1,5-a]quinazoline-7-methanamine hydrate (1:1) (intermediate 27), mp. 150° C.