Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28]>>[F:21][C:22]1[CH:23]=[C:24]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:1])[CH3:20])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC1(C)CC(=O)c2ccc(-c3ccc(F)c(F)c3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3,4-difluorophenyl boronic acid according to the procedure described in example 21. MS m/z 273; HRMS: calcd for C17H14F2O+H+, 273.10855; found (ESI, [M+H]+), 273.1078.
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.I[C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9].CN(C)C=O.O>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([C:4]#[C:5][NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:7]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccccc1I
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: C(#CC1CC1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.26 g of copper(I) iodide, 0.30 g of bis(triphenylphosphine)palladium(II) dichloride and then 0.78 ml of cyclopropylacetylene are successively added to a solution of 1.0 g of 2-iodoaniline in 5 ml of triethylamine under argon. The reaction mixture is stirred at ambient temperature for 30 minutes, and then 1 ml of N,N-dimethylformamide is added. The reaction mixture is stirred at ambient temperature for 30 minutes, then 1 ml of N,N-dimethylformamide is again added. The reaction mixture is stirred at ambient temperature for 15 hours, and is then poured into 100 ml of water. After the addition of 50 ml of ethyl acetate, the mixture is filtered through Celite®, and then separated by settling out. The organic phase is separated and the aqueous phase is extracted with 3×40 ml of ethyl acetate. The organic phases are combined, washed with 2×40 ml of water, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified on a 50 g column of 20-45 μm silica, elution being carried out with an 80/20 v/v dichloromethane/cyclohexane mixture. 0.42 g of 2-cyclopropylethynylphenylamine is thus obtained in the form of a brown oil which is used directly in the next step.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH:14]([CH3:16])[CH3:15])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:13]([CH:14]([CH3:15])[CH3:16])[CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:19][CH:20]=1
Reactant: CC(C)N(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(Cc1ccc(Cl)cc1)C1CCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-[(4-chloro-benzyl)-isopropyl-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester in dichloromethane cooled at 0° C. was treated with trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate. The product was used without any further purification. ESI-MS m/z: 253 (M+1, UV retention time: 0.59 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:6]=[CH:5]2.[Br-].[Li+].[CH3:22][Mg]Br>O1CCCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[CH:8]=2)[CH:3]=1
Reactant: C[Mg]Br
Reactant: O=S(=O)(Oc1ccc2cc(Br)ccc2c1)C(F)(F)F
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2cc(Br)ccc2c1
Temperature: 80 °C
Yield: 47 %

Procedure:
Under an atmospheric argon gas flow, trifluoromethane sulfonic acid-6-bromo-2-naphthyl ester in an amount of 32 g (90 mmol), dichloro(diphenylphosphinoferrocene)palladium in an amount of 3.6 g (5% by mol), lithium bromide in an amount of 7.8 g (90 mmol) and desiccated tetrahydrofuran in an amount of 100 milliliter were placed into a three neck flask with cooling pipe and having a capacity of 500 milliliter, and then, the resultant solution was cooled down to −20° C. After slowly dripping methylmagnesiumbromide in an amount of 90 milliliter (90 mmol, 1 mol/liter (tetrahydrofuran)) into the flask, the resultant solution was stirred under heating at the temperature of 80° C. for 4 hours. After the reaction terminated, adding dilute hydrochloric acid in an amount of 100 milliliter into the reacted solution, an organic layer was separated and washed with the use of sodium bicarbonate solution and sodium chloride solution, followed by drying with the use of magnesium sulfate. After removing the solvent by distillation by means of a rotary evaporator, the resultant crude product was refined by means of column chromatography (silicagel, hexane/dichloromethane=90/10), and as a result, 9.4 g of aimed compound (white crystal) was obtained (yield: 47%).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10](Cl)(=[O:13])[CH2:11][CH3:12].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:35][C:34]3[CH:33]=[N:32][N:31]([CH3:36])[C:30]=3[NH:29][C:28]3[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:27]2=3)=[O:25])=[CH:20][C:19]=1[F:42].C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+]>ClCCl>[Cl:41][C:38]1[CH:39]=[CH:40][C:27]2[N:26]([C:24]([C:21]3[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:10](=[O:13])[CH2:11][CH3:12])=[C:19]([F:42])[CH:20]=3)=[O:25])[CH2:35][C:34]3[CH:33]=[N:32][N:31]([CH3:36])[C:30]=3[NH:29][C:28]=2[CH:37]=1
Reactant: CCC(=O)Cl
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CN)c(F)c1)C2
Agent: Cl
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)NCc1ccc(C(=O)N2Cc3cnn(C)c3Nc3cc(Cl)ccc32)cc1F
Reaction time: 2 h
Yield: 56 %

Procedure:
DIEA (0.27 ml, 1.56 mmol) and propionyl chloride (0.048 ml, 0.55 mmol) were added to a solution of (4-aminomethyl-3-fluoro-phenyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E102.2 (220 mg, 0.52 mmol) in dichloromethane (6 ml) at room temperature. The mixture was stirred for 2 h, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (129 mg, 56%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8]Br.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Sc1ccccc1
Reactant: COC(=O)C=CC=CCBr
Solvent: CCN(CC)CC
Product: COC(=O)C=CC=CCSc1ccccc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 141.8 %

Procedure:
To a solution of 6-bromohexa-2,4-dienoic acid methyl ester (0.57 g, 2.8 mmol) and thiophenol (0.28 mL, 2.8 mmol) was added triethylamine (0.43 mL, 3.1 mmol), dropwise, under an atmosphere of nitrogen. The mixture was stirred at 20° C. for one hour. The slurry was then filtered and the filtrate was washed with aqueous sodium hydroxide (1 M) then with brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to column chromatography (9:1 60-80° C. petroleum ether:diethyl ether) to give the title compound (0.93 g, 88%) as a clear oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[C:8]([OH:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20](S(C)(=O)=O)[N:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[C:8]([O:15][C:20]2[N:21]=[C:22]([O:24][CH3:25])[CH:23]=[C:18]([O:17][CH3:16])[N:19]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=O)c1nc(NC(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(NC(C)=O)ccc1Oc1nc(OC)cc(OC)n1
Yield: 70 %

Procedure:
0.78 g (3.7 mmol) of the obtained methyl 6-acetylamino-3-hydroxypicolinate, 0.81 g (3.7 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.51 g (3.7 mmol) of potassium carbonate were added to 50 ml of DMF, and the mixture was reacted at 80° C. for two hours. After completion of the reaction, the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water, dried and concentrated. The oily product thereby obtained was purified by column chromatography to obtain methyl 6-acetylamino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:16])([CH3:15])[C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[Br:17]Br>C(Cl)(Cl)(Cl)Cl>[Br:17][CH:5]([O:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[C:4](=[O:14])[C:3]([CH3:16])([CH3:15])[CH2:2][Cl:1]
Reactant: CC(C)(CCl)C(=O)COc1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(CCl)C(=O)C(Br)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7890.2 %

Procedure:
210 g (0.81 mol) of 4-chloro-1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one were dissolved in 1,000 ml of carbon tetrachloride. 41 ml (0.01 mol) of bromine were added dropwise at room temperature at a rate such that it was continuously consumed. The mixture was then stirred at room temperature for 30 minutes. After distilling off the solvent in vacuo, 268.3 g (98% of theory) of crude 1-bromo-4-chloro-1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one were obtained and were further reacted directly. ##STR13##
Reaction SMILES: N1C=CC=CC=1[C:7]1[C@@H:11]2[CH2:12][N:13]([C:15]3[C:24]([O:25][CH3:26])=[C:23]4[C:18]([C:19](=[O:33])[C:20]([C:30]([OH:32])=[O:31])=[CH:21][N:22]4[CH:27]4[CH2:29][CH2:28]4)=[CH:17][C:16]=3[F:34])[CH2:14][C@@H:10]2[O:9][N:8]=1.ON=C(Cl)[C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>>[N:40]1[CH:41]=[CH:42][CH:43]=[C:38]([C:7]2[C@@H:11]3[CH2:12][N:13]([C:15]4[C:24]([O:25][CH3:26])=[C:23]5[C:18]([C:19](=[O:33])[C:20]([C:30]([OH:32])=[O:31])=[CH:21][N:22]5[CH:27]5[CH2:29][CH2:28]5)=[CH:17][C:16]=4[F:34])[CH2:14][C@@H:10]3[O:9][N:8]=2)[CH:39]=1
Reactant: COc1c(N2C[C@@H]3ON=C(c4ccccn4)[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: ON=C(Cl)c1cccnc1
Product: COc1c(N2C[C@@H]3ON=C(c4cccnc4)[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
The title compound was prepared in an analogous manner to acid 122, but using chloro oxime 2f. Acid 123 was isolated.
Reaction SMILES: [CH3:1][C:2]([NH:16]C(=O)OCC1C=CC=CC=1)([CH2:4][CH2:5][S:6]([CH:9]([CH:12]([OH:15])[CH2:13][OH:14])[CH2:10][OH:11])(=[O:8])=[O:7])[CH3:3]>CO.[Pd]>[NH2:16][C:2]([CH3:3])([CH3:1])[CH2:4][CH2:5][S:6]([CH:9]([CH2:10][OH:11])[CH:12]([OH:15])[CH2:13][OH:14])(=[O:8])=[O:7]
Reactant: CC(C)(CCS(=O)(=O)C(CO)C(O)CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(N)CCS(=O)(=O)C(CO)C(O)CO
Reaction time: 12 h

Procedure:
To a solution of benzyl 2-methyl-4-(1,3,4-trihydroxybutan-2-ylsulfonyl)butan-2-ylcarbamate (6.69 g, 17.2 mmol) in MeOH (100 ml) was added 10% palladium on carbon (490 mg). The suspension was put under an atmosphere of H2 (1.3 atmospheres) and stirred for 12 hours, filtered through Celite, and concentrated in vacuo. The residue was used without further purification. LRMS (ESI/APCI): 256 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([O:16][CH3:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([O:16][CH3:17])[CH:3]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: COc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: COc1cc(-c2ccc(F)c(F)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (66 mg, 80%), MS (ISP) m/z=329.4 [(M+H)+], mp 216° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-methoxy-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 18) (73.8 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.Cl.[NH:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([OH:19])[CH2:14]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:13]3[CH2:18][CH2:17][CH2:16][C@H:15]([OH:19])[CH2:14]3)[S:8][C:4]=2[CH:3]=1
Reactant: O[C@H]1CCCNC1
Reactant: Clc1nc2ccc(Br)cc2s1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@H]1CCCN(c2nc3ccc(Br)cc3s2)C1
Temperature: 150 °C

Procedure:
A mixture of 6-bromo-2-chlorobenzo[d]thiazole (1.0 g, 4.0 mmol) and (S)-piperidin-3-ol hydrochloride (0.609 g, 4.43 mmol), and N,N-diisopropylethylamine (3.51 mL, 0.02012 mole) in N,N-dimethylformamide (2.0 mL) was heated to 150° C. under microwave irradiation for 15 minutes. The reaction mixture was transferred to a 100 mL round bottom flask (methanol rinse) and volatiles were removed under reduced pressure. The residue was partitioned between CHCl3 and saturated aqueous sodium carbonate. The organic layer was dried over MgSO4. Drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography on an Analogix IntelliFlash-280 (Analogix SF15-12 g, 100% CHCl3 to 60:40 CHCl3/ethyl acetate). Fractions containing product were combined and concentrated under reduced pressure to provide (S)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-ol.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][C:20]([CH3:49])([CH2:33][S:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][Si](C(C)(C)C)(C)C)=[CH:37][CH:36]=1)[C:21]([O:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:22].[Cl-].[NH4+]>C1COCC1>[CH3:19][C:20]([CH3:49])([CH2:33][S:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[C:21]([O:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:22]
Reactant: CC(C)(CSc1ccc(O[Si](C)(C)C(C)(C)C)cc1)C(=O)OCOCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(CSc1ccc(O)cc1)C(=O)OCOCc1ccccc1

Procedure:
A 1.0M solution of tetra-n-butylammonium fluoride in THF (3.6 mL, 1.1 equiv) was added to the tert-butyldimethylsilylether (XXVII) (1.50 g, 3.3 mmol) in 25 mL of THF at -10° C. After 1 hour the reaction was acidified with saturated ammonium chloride (25 mL) and extracted with ether. The ether layer was washed with H2O, saturated NaCl, dried over anhydrous MgSO4 and concentrated. The residue was chromatographed on silica gel to give 0.92 g (82%) of V. 1H NMR (CDCl3) δ1.27 (s, 6H), 3.10 (s, 2H), 4.67 (s, 2H), 5.10 (br s, 1H), 5.28 (s, 2H), 6.74 (d, 2H, J=8.4 Hz), 7.2-7.4 (m, 7H); 13C NMR (CDCl3) δ25.10, 44.82, 47.19, 72.41, 89.38, 116.72, 128.07, 128.68, 128.76, 129.24, 134.49, 137.74, 155.91, 176.91.
Reaction SMILES: B(Br)(Br)Br.ClCCl.[CH2:8]([N:10]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[C:14](=[O:20])[N:13]([CH3:21])[C:12]2[CH:22]=[C:23]([O:26]C)[CH:24]=[CH:25][C:11]1=2)[CH3:9].O>CO.ClCCl>[CH2:8]([N:10]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[C:14](=[O:20])[N:13]([CH3:21])[C:12]2[CH:22]=[C:23]([OH:26])[CH:24]=[CH:25][C:11]1=2)[CH3:9]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OC)ccc21
Agent: BrB(Br)Br
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
A 1.0 M boron tribromide/dichloromethane solution (1.22 ml) was added to a dichloromethane solution (3 ml) of 1-ethyl-7-methoxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (169 mg, 1.0 mmol) at 0° C., and stirred at room temperature overnight. Water and methanol were added to the reaction mixture and extraction with the mixture solvent (dichloromethane:methanol=10:1) was performed. The organic layer was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to thereby obtain 156.4 mg (yield: 98%) of 1-ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([NH2:24])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:25])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[Cl:25][C:12]1[N:11]=[CH:10][C:9]2[O:8][C:5]3[C:4]([C:15]4([C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:17]([NH2:24])=[N:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:26]1[C:28]([F:31])=[N:11][CH:10]=[CH:9][CH:14]=1)=[CH:7][CH:6]=3
Reactant: NC1=NC2(c3cc(Br)ccc3Oc3cnc(Cl)cc32)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3cnc(Cl)cc32)c2ccccc21

Procedure:
The title compound was synthesized by procedures and steps analogous to those described in Example 5 above, but using 7-bromo-3-chlorospiro[chromeno[2,3-c]pyridine-5,1′-isoindol]-3′-amine in step 3. MS m/z=429.0 [M+H]+. Calculated for C24H14ClFN4OC2HF3O2: 542.87 (TFA salt).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[N:11]=[C:10]([CH3:12])[C:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:7]2[CH:30]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C1COCC1.O>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[C:8]1[N:7]2[CH:30]=[C:4]([CH:1]([OH:3])[CH3:2])[N:5]=[C:6]2[N:11]=[C:10]([CH3:12])[C:9]=1[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CNC(=O)OC(C)(C)C)c(C)nc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2nc(C(C)O)cn2c(-c2ccc(Cl)cc2Cl)c1CNC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 110.8 %

Procedure:
To a stirred solution of tert-butyl (2-acetyl-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidin-6-yl)methylcarbamate (intermediate for Example 150, 5 mg, 0.01 mmol) in THF (2 mL) and H2O (0.3 mL) at room temperature was added NaBH4 (2 mg, 0.05 mmol). After 30 min, the reaction was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with satd aq NH4Cl and brine prior to drying over MgSO4. Filtration, concentration under reduced pressure and purification by silica gel chromatography afforded crude tert-butyl (5-(2,4-dichlorophenyl)-2-(1-hydroxyethyl)-7-methylimidazo[1,2-a]pyrimidin-6-yl)methylcarbamate (5 mg, 100% crude yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.C([Li])(C)(C)C.CN(C)[CH:17]=[O:18].C(=O)=O>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:8][CH3:9])[C:5]([CH:17]=[O:18])=[CH:6][CH:7]=1
Reactant: COc1cccc(Cl)n1
Reactant: CN(C)C=O
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1nc(Cl)ccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To 2-Chloro-6-methoxypyridine (25, 0.511 g, 3.56 mmol) in tetrahydrofuran (10 mL) cooled in a −78° C. acetone/dry ice bath was added tert-butyllithium (1.7 M in pentane, 5.0 mL, 7.66 mmol). The reaction was allowed to stir for 1 hour. Dimethylformamide (0.673 mL, 17.4 mmol) was added and the reaction was allowed to continue for an additional 30 minutes at −78° C., then stirred for 30 minutes outside of the dry-ice bath. The reaction was placed back in the dry-ice bath and quenched with 6 N HCl (1.5 mL) followed by water and allowed to warm to room temperature. The reaction was extracted with diethyl ether and aqueous (1 M) sodium bicarbonate. The organic layer was separated, dried with anhydrous magnesium sulfate, filtered and volatiles removed by rotary evaporation, and the resulting yellow solid was dried under vacuum to provide 561 mg of compound 26 (3.27 mmol, 92% yield). MS(ESI) [M+H+]+=172.0.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[C:12]1([CH2:18][C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:19](=[O:20])[CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nc1ccccc1C(F)(F)F
Yield: 42.8 %

Procedure:
Using the procedure of Step A of Example 6, 40.28 g of o-trifluoromethyl aniline and 42.5 g of phenylacetyl chloride were reacted in the presence of 27.83 g of triethylamine in 400 ml of benzene to obtain 29.85 g of N-(2-trifluoromethylphenyl)-benzeneacetamide melting at 104° C after crystallization from hexane which was used as is for the next step.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][C:11]2[C:15]([C:16]#[N:17])=[C:14]([N:18]=[CH:19][N:20](C)C)[NH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)N>CO>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]2[C:15]3[C:14](=[N:18][CH:19]=[N:20][C:16]=3[NH:17][C:32]3[CH:31]=[CH:29][CH:28]=[C:27]([Cl:26])[CH:33]=3)[NH:13][N:12]=2)=[CH:23][CH:24]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(CNc2n[nH]c(N=CN(C)C)c2C#N)cc1
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: CO
Product: CC(=O)Nc1ccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 20 °C

Procedure:
A mixture of 0.34 g (1.04 mmol) of 3-(4-acetylamino-benzylamino)-4-cyano-5-(dimethylamino-methyleneamino)-pyrazole, 0.189 g (1.15 mmol) of 3-chloro-aniline hydrochloride and 4 ml of methanol is heated under reflux for 20 hours. Cooling to approx. 20° C., filtering and washing the filter residue with diethyl ether yields the title compound; m.p. >260° C.; TLC-Rf =0.34 (toluene/isopropanol/conc. ammonia [70:29:1]).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]Cl)=[CH:7][CH:6]=1)=[O:4].[C:13]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=[O:26])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:20]2([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(SCl)cc1
Reactant: CC(C)(C)OC(=O)C1CCCCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(SC2(C(=O)OC(C)(C)C)CCCCC2=O)cc1
Reaction time: 0.25 h
Yield: 56.7 %

Procedure:
A solution 10.8 g (53.2 mmol) of 4-methoxycarbonylphenylsulphenic acid chloride in 20 ml of methylene chloride (analytically pure) is added dropwise to a solution of 11.4 g (57 mmol) of 2-tert.butoxycarbonylcyclohexanone and 7.5 g (75 mmol) of triethylamine in 150 ml of methylene chloride. When the dropwise addition has ended the mixture is subsequently stirred for 15 mins. and is then diluted with methylene chloride and the organic phase is washed with 2N sulphuric acid and a saturated bicarbonate solution, dried with sodium sulphate and concentrated by evaporation. 20.5 g of a crude product are thus obtained, which is chromatographed on 2 kg of silica gel (Merck Si 60, 0.04-0.063 nm) using petroleum ether/ether 8:20 as the mobile solvent. A fraction is thus obtained which, after being concentrated by evaporation, yields 11 g of a solid product.