Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[O:20]1[CH2:22][CH:21]1[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>CN(C=O)C>[CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:22][CH:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[OH:20])[C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Reactant: c1cncc(C2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2cccnc2)CCN2CCCC12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19.6 %

Procedure:
9-Methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene (200 mg, 0.88 mmol) was dissolved in DMF (3 ml), sodium hydride (106 mg, 2.65 mmol) was added and the mixture was stirred at RT for 15 min. 3-Oxiranyl-pyridine (214 mg, 1.76 mmol) was added dropwise into the reaction mixture and the mixture was stirred at RT for 3 h. The reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was quenched with ice cold water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was washed with water (2×60 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 60 mg of 2-(9-Methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-1-pyridin-3-yl-ethanol as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.7 (d, 1H), 8.53 (s, 1H), 8.4 (d, 1H), 7.85 (t, 1H), 7.25 (s, 1H), 7.08 (t, 1H),6.9 (d, 1H), 5.28 (t, 1H), 5.03 (t, 1H), 4.42 (s, 2H), 3.76 (m, 1H), 3.6 (m, 2H), 3.4 (m, 1H), 3.2 (m, 2H),2.7 (m, 1H), 2.38 (s, 3H), 2.2 (m, 3H). Separation by chiral HPLC provides diastereomers II-131a-d.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[CH2:4][CH2:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C1C=CC([As](C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C[Sn](C)(C)[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][N:40]=1>CN1C(=O)CCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:45][C:42]1[CH:43]=[CH:44][C:39]([C:2]2[C:3](=[O:17])[CH2:4][CH2:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[N:40][CH:41]=1
Reactant: C[Sn](C)(C)c1ccc(Cl)cn1
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)CC2)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(Cl)cn3)C(=O)CC2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 18.7 %

Procedure:
To a degassed r.t. solution of 2-bromo-3-(4-(methylsulfonyl)-phenyl)-2-cyclopenten-1-one (0.630 g, 2.0 mmol), Pd2 (dba)3 (0.036 g, 0.04 mmol), and AsPh3 (0.098 g, 0.32 mmol) in NMP (5 mL) was added a degassed NMP solution (8 mL) of 2-trimethylstannanyl-5-chloropyridine (~4.0 mmol). The resulting mixture was heated to 60° C. for 16 h, then to 100° C. for a further 2 h. The mixture was then cooled to r.t., diluted with EtOAc, washed 2 times with 10% NH4OH and brine, dried over MgSO4, and concentrated to dryness. The residue was purified by flash chromatography (70% EtOAc/hexanes) followed by a CH2Cl2 /Et2O swish to provide 130 mg of the title compound.
Reaction SMILES: [CH2:1](S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(S[CH2:17][CH:18]([CH2:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1)=[O:24])[C:19]([OH:21])=[O:20])C1C=CC=CC=1.O[O:33][S:34]([O-:36])=O.[K+]>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[CH3:31][N:28]1[CH2:27][CH2:26][N:25]([C:23](=[O:24])[CH2:22][CH:18]([CH2:17][S:34]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:36])=[O:33])[C:19]([OH:21])=[O:20])[CH2:30][CH2:29]1
Reactant: SCc1ccccc1
Reactant: O=S([O-])OO
Reactant: CN1CCN(C(=O)CC(CSCc2ccccc2)C(=O)O)CC1
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)CC(CS(=O)(=O)Cc2ccccc2)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring mixture of itacconic anhydride 1.1209 g, 10 mmol) in 10 ml of methylene chloride at 0° C. was added drop wise methyl piperizine (1.0 g, 10 mmol). The reaction was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure to give compound 2-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-acrylic acid. The residue was dissolved in 10 ml of DMF, then benzyl mercaptan (1.17 g, 10.0 mmol) and DMAP (122 mg, 1 mmol) were added and heated to 50–60° C. until reaction turned clear then the reaction was stirred at room temperature for overnight. Another 0.59 ml of benzyl mercapton (5 mmol) was added and the reaction was stirred overnight at room temperature. The mixture containing compound 2-benzylsulfanylmethyl-4-(4-methyl-piperazin-1-yl)-4-oxo-butyric acid was cooled to 0° C. and oxone® (6.1378 g, 10 mmol) in 20 ml of water was added and stirred for overnight at room temperature. More oxone® was added and the reaction was stirred at room temperature for 2 hours. The reaction was filtered and the product was in the aqueous phase and was purified on HPLC to give 0.2477 gram of pure 4-(4-methyl-piperazin-1-yl)-4-oxo-2-benzylsulfonylmethyl-butyric acid; LCMS retention time: 1.72 minutes; M+1 (369.3).
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[OH-].[Na+].O.Cl.[CH3:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1.[CH3:21]N(C=O)C>>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:21][C:19]2[N:20]=[C:16]([CH3:15])[S:17][CH:18]=2)[NH:6][C:7](=[O:9])[CH:8]=1
Reactant: Cc1nccs1
Reactant: Nc1cc(O)nc(S)n1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(CSc2nc(N)cc(=O)[nH]2)cs1
Reaction time: 3 h

Procedure:
4-Amino-6-hydroxy-2-mercaptopyrimidine monohydrate (0,161 g) and sodium hydroxide (0.08 g) were stirred in dry DMF (4 ml) for 20 mins. 4-Chloromethyl, 2-methylthiazole hydrochloride hydrate (0.2 g) was added and the mixture stirred for 3 hr then poured onto water (150 ml) to give a solution. The subtitled product crystallised and was collected, washed with water and dried (0.2 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([NH:1][CH2:2][CH2:3][CH2:4][CH:5]1[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: NCCCC1c2ccccc2C=Cc2ccccc21
Solvent: c1ccncc1
Product: CC(=O)NCCCC1c2ccccc2C=Cc2ccccc21

Procedure:
A solution of 5-(3-aminopropyl)-5H-dibenzo[a,d]cycloheptene (0.75 g., 0.003 mole) in 5 ml. of dry pyridine is treated with 1 ml. of acetic anhydride and then heated to refluxing for 30 minutes. The cooled solution is poured into 100 ml. of water and the oil extracted into benzene. The benzene extract is washed with water, 3N hydrochloric acid, water, and evaporated to dryness under reduced pressure. The 5-(3-acetamidopropyl)-5H-dibenzo[a,d]cycloheptene is obtained as a yellow oily residue weighing 0.87 g.
Reaction SMILES: O.[H-].[Na+].[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH2:12][C:13]#[N:14].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]Br)=[CH:18][CH:17]=1>CS(C)=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH:12]([C:6]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=2[Cl:4])[C:13]#[N:14])=[CH:18][CH:17]=1
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: BrCCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC(CCOc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Reaction time: 0.5 h

Procedure:
To a stirred and cooled (water-bath) suspension of 7 parts of a sodium hydride dispersion 78% and 75 parts of dimethylsulfoxide is added dropwise, during a 30 minutes-period, a solution of 37 parts of 2,4-dichlorobenzeneacetonitrile in 100 parts of dimethylsulfoxide. The whole is stirred for 30 minutes while cooling in a water-bath. Then there is added dropwise, during a 30 minutes-period, a solution of 56 parts of 1-bromo-4-(2-bromoethoxy)benzene in 125 parts of dimethylsulfoxide and stirring is continued for another 30 minutes. The reaction mixture is poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed twice with water, dried, filtered and evaporated. The residue is triturated in petroleumether. The product is filtered off and crystallized from ethanol, yielding 38 parts of α-[2-(4-bromophenoxy)ethyl]-2,4-dichlorobenzeneacetonitrile; mp. 73.9° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([NH2:19])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[NH:19][S:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:37])=[O:36])[N:10]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccc(CNc2ccc3c(N)cccc3n2)o1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(CNc2ccc3c(NS(=O)(=O)c4ccccc4)cccc3n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N2-(5-Methyl-furan-2-ylmethyl)-quinoline-2,5-diamine (example 26, step A+B, 200 mg, 0.791 mmol) was dissolved in 2 mL N,N-dimethylformamide. N,N-Diisopropyl ethyl amine (104 mg; 0.806 mmol) and benzenesulfonyl chloride (155 mg, 0.876 mmol) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 50 mL water and extracted three times with ethyl acetate (50 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The residue purified by flash chromatography on silica gel (cyclohexane/ethyl acetate/methanol 100:0:0->0:90:10 gradient). The title compound was obtained as a yellow solid (130 mg, 42%), MS: m/e=394.1 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20]C(=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.CS(O[CH:31]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[C:32]([F:35])([F:34])[F:33])(=O)=O>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH:31]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[C:32]([F:33])([F:34])[F:35]
Reactant: CS(=O)(=O)OC(c1ccccn1)C(F)(F)F
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: Cl
Product: FC(F)(F)C(Sc1c(Cl)ccc2c1CCNCC2)c1ccccn1

Procedure:
Use a method similar to the Preparation 177 to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine with (±)-2-[1-methanesulfonyloxy-(2,2,2-trifluoroethyl)]-pyridine. Use a method similar to the General Procedure 1-5, basic workup, and a method similar to the General Procedure 2-2 to give the title compound as a white solid. MS (APCI+) m/z: 373 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[C:15]([Cl:27])[C:14]=1[OH:28].O>CN(C)C=O>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:16]=[C:15]([Cl:27])[C:14]=1[O:28][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(OCc2ccccc2)cc(Cl)c1OCCCBr
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
A reaction vessel was charged with 5.10 g of 1,3-dibromopropane, 2.40 g of potassium carbonate and 50 ml of N,N-dimethylformamide, to which a solution of 4.24 g of 2,6-dichloro-4-(benzyloxy)phenol dissolved in 10 ml of N,N-dimethylformamide was slowly added dropwise. After stirring at room temperature for 24 hours, the reaction mixture was poured into water, and extracted twice with 150 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 4.24 g of 3,5-dichloro-4-(3-bromopropyloxy)-1-(benzyloxy)benzene (68% yield).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([CH2:9][C:10]([OH:12])=O)[CH2:2]2.[CH:13]([C:16]1[CH:17]=[C:18]([C:22]([NH2:25])([CH3:24])[CH3:23])[CH:19]=[CH:20][CH:21]=1)([CH3:15])[CH3:14]>>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([CH2:9][C:10]([NH:25][C:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:13]([CH3:15])[CH3:14])[CH:17]=1)([CH3:24])[CH3:23])=[O:12])[CH2:2]2
Reactant: CC(C)c1cccc(C(C)(C)N)c1
Reactant: O=C(O)CC1CN2CCC1CC2
Product: CC(C)c1cccc(C(C)(C)NC(=O)CC2CN3CCC2CC3)c1
Yield: 10 %

Procedure:
Using general procedure I, (1-aza-bicyclo[2.2.2]oct-3-yl)-acetic acid (200 mg, 1.20 mmol) and 1-(3-isopropyl-phenyl)-1-methyl-ethylamine gave the title compound as a white solid (42 mg, 10%). 1H NMR (400 MHz, DMSO-d6) δ 7.15-1.20 (m, 3H), 7.05 (d, J=8.4 Hz, 1H), 3.41-3.45 (m, 1H), 3.26 (s, 2H), 3.15-3.22 (m, 2H), 2.71-2.82 (m, 2H), 2.41-2.47 (m, 3H), 2.05-2.12 (m, 1H), 1.79-1.90 (m, 4H), 1.61 (d, J=8.0 Hz, 6H), 1.21 (d, J=6.4 Hz, 6H) ppm. 13C NMR (400 MHz, DMSO-d6) δ 171.1, 148.7, 147.3, 128.1, 123.9, 122.8, 122.2, 55.6, 52.1, 46.5, 45.9, 38.8, 34.5, 30.7, 28.9, 28.5, 23.8, 23.4, 18.0 ppm. Purity: 96.8% HPLCMS (210 nm); retention time 1.93 min; (M+1) 329.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH2:12])=[N:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])C.Br[C:15]1[CH:16]=[N:17][CH:18]=[N:19][CH:20]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[ClH:21].[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:4]([C:6]2[C:11]([NH:12][C:15]3[CH:16]=[N:17][CH:18]=[N:19][CH:20]=3)=[N:10][CH:9]=[C:8]([CH3:13])[N:7]=2)=[O:5])[CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1nc(C)cnc1N
Reactant: Nc1cccc(Cl)c1
Reactant: Brc1cncnc1
Product: Cc1cnc(Nc2cncnc2)c(C(=O)Nc2cccc(Cl)c2)n1
Product: Cl

Procedure:
The title compound, MS: m/e=341.2 (M+H+), was prepared in accordance with the general method of example 10 from 3-amino-6-methyl-pyrazine-2-carboxylic acid ethyl ester (Example C), 5-bromopyrimidine and 3-chloroaniline.
Reaction SMILES: [ClH:1].[CH3:2][NH:3][C:4]12[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH:9]1[CH2:8][CH:7]=[CH:6][CH2:5]2.[H][H]>CO.[Pd]>[ClH:1].[CH3:2][NH:3][C:4]12[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5]2
Reactant: [H][H]
Reactant: CNC12CC=CCC1Cc1ccccc12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC12CCCCC1Cc1ccccc12

Procedure:
General procedure: A solution of 5 g of N-methyl- 1,4,9,9a-tetrahydro-4aH-fluoren-4a-amine hydrochloride in 100 ml of methanol is hydrogenated by shaking it with 0.5 g of 20% palladium on charcoal catalyst in contact with a hydrogen atmosphere. When the theoretical amount of hydrogen corresponding to hydrogenation of one double bond has been absorbed, the catalyst is removed by filtration and the solvent distilled under reduced pressure to yield N-methyl1,2,3,4,9,9a-hexahydro-4aH-fluoren-4a-amine hydrochloride; mp 202° to 203° C. following recrystallization from methanol-ether. The free base is obtained by treating an aqueous solution of the hydrochloride with sodium hydroxide and extracting with ether. The hydrobromide is obtained by adding a slight excess of hydrogen bromide to a solution of the free base in ether.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26](=[O:34])[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:14]([C:12]1[CH:11]=[CH:10][N:9]=[C:8]([C:3]2[N:4]=[CH:5][N:6]([CH3:7])[C:2]=2[C:20]2[CH:21]=[CH:22][C:17]([F:16])=[C:18]([CH:19]=2)[C:26]([NH:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:34])[CH:13]=1)#[N:15]
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: O=C(Nc1ccccc1)c1cc(B(O)O)ccc1F
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(F)c(C(=O)Nc2ccccc2)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 2) and 4-fluoro-3-(phenyl carbamoyl)phenyl boronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C23H16FN5O, 398. Found, 398.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3[C:14](=[O:27])[NH:15][CH:16]=[CH:17][C:18]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.O1CCCC1.[Pt]=O>[NH2:1][C:4]1[C:12]2[N:11]=[C:10]([C:13]3[C:14](=[O:27])[NH:15][CH:16]=[CH:17][C:18]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=c1[nH]ccc(NCc2ccccn2)c1-c1nc2c([N+](=O)[O-])cccc2[nH]1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc2[nH]c(-c3c(NCc4ccccn4)cc[nH]c3=O)nc12
Temperature: 25 °C
Yield: 113 %

Procedure:
Platinum oxide (0.146 g, 0.65 mmol) was added to a stirred solution of 3-(4-nitro-1H-benzoimidazol-2-yl)-4-[(pyridin-2-ylmethyl)-amino]-1H-pyridin-2-one in methanol (12 ml) and tetrahydrofuran (12 ml). The reaction was purged with nitrogen three times and the atmosphere replaced with hydrogen and the reaction stirred at room temperature. After 72 hours the reaction was recharged with platinum oxide (0.146 g, 0.65 mmol) and hydrogen and stirred for a further 24 hours. The reaction was filtered through Celite and the filter cake washed with tetrahydrofuran and methanol. The solvent was concentrated under reduced pressure to give the desired crude aniline (0.610 g, 113%), which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([NH:19][NH2:20])=[O:18])=[C:4]2[CH2:3]1.[N:21]([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)(=O)C>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([N:19]=[N+:20]=[N-:21])=[O:18])=[C:4]2[CH2:3]1
Reactant: CN1Cc2c(C(=O)NN)ncn2-c2ccccc2C1=O
Reactant: O=N[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN1Cc2c(C(=O)N=[N+]=[N-])ncn2-c2ccccc2C1=O
Reaction time: 1 h

Procedure:
A solution of 19 g (70 mmol) of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid hydrazide in 60 ml of water and 150 ml of glacial acetic acid is treated dropwise at 0° to 5° with a solution of 16.5 g of sodium nitrite in 30 ml of water. The white suspension is subsequently stirred in an ice-bath for 1 hour and cautiously poured into 150 g of sodium carbonate in 400 ml of water. The precipitated material is filtered off under suction, washed with water and dried. There is obtained 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid azide which decomposes at 160°.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([C@H:11]2[C@H:16]([N:17]([CH3:34])[C:18](=[O:33])[C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)[CH2:15][CH2:14][N:13]([C:35](=[O:44])[CH2:36][NH:37][CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10].[C:45](O)(=[O:47])[CH3:46]>>[ClH:3].[C:45]([N:41]1[CH2:40][CH2:39][CH:38]([NH:37][CH2:36][C:35]([N:13]2[CH2:14][CH2:15][C@@H:16]([N:17]([CH3:34])[C:18](=[O:33])[C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)[C@H:11]([C:6]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=3)[CH2:12]2)=[O:44])[CH2:43][CH2:42]1)(=[O:47])[CH3:46]
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CCN(C(=O)CNC2CCNCC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)O
Agent: Cl
Product: CC(=O)N1CCC(NCC(=O)N2CC[C@@H](N(C)C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1

Procedure:
Using the compound obtained in step 2 and acetic acid, and by the reaction and purification in the same manner as in Example 3, the title compound was obtained.
Reaction SMILES: Br.[F:2][C:3]1[CH:4]=[C:5]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.O.C(=O)([O-])[O-:20].[Na+].[Na+]>CS(C)=O>[F:2][C:3]1[CH:4]=[C:5]([C:9](=[O:17])[C:10]([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)=[O:20])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cc1ccncc1)c1cccc(F)c1
Reactant: O=C([O-])[O-]
Agent: Br
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(C(=O)c1cccc(F)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
Hydrobromic acid (7.9 mL, 48% in H2O, 69.7 mmol) was added with caution to a stirred solution of 1-(3-fluorophenyl)-2-pyridin-4-ylethanone (5.0 g, 23.2 mmol) in DMSO (40 mL) at 55° C. The reaction was stirred for 2 h and then allowed to cool to room temperature. Water was added and the aqueous phase was neutralized with solid sodium carbonate and extracted twice with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4) and evaporated under reduced pressure to provide the title compound as a yellow solid (2.85 g, 67%).
Reaction SMILES: [NH2:1][C:2]1[C:3](I)=[CH:4][C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[C:10]([CH:30]=3)[C@@H:11]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:12][CH2:13][CH2:14][C@@H:15]([CH3:21])[C:16](=[O:20])[NH:17][C:18]=2[CH:19]=1.[C:32]([O:36][CH3:37])(=[O:35])[CH:33]=[CH2:34].C(N(CCCC)CCCC)CCC>CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[C:3](/[CH:34]=[CH:33]/[C:32]([O:36][CH3:37])=[O:35])=[CH:4][C:5]2[C:6]3[CH:7]=[CH:8][N:9]=[C:10]([CH:30]=3)[C@@H:11]([NH:22][C:23]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:29])[CH2:12][CH2:13][CH2:14][C@@H:15]([CH3:21])[C:16](=[O:20])[NH:17][C:18]=2[CH:19]=1
Reactant: C=CC(=O)OC
Reactant: C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)c2cc(ccn2)-c2cc(I)c(N)cc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)/C=C/c1cc2c(cc1N)NC(=O)[C@H](C)CCC[C@H](NC(=O)OC(C)(C)C)c1cc-2ccn1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a solution of 86B (0.15 g, 0.280 mmol) in DMF (2.80 ml) was added methyl acrylate (0.048 g, 0.559 mmol), Pd(OAc)2 (2.51 mg, 0.011 mmol), and tributylamine (0.067 ml, 0.280 mmol). The reaction was microwaved at 150° C. for 10 min and the reaction was cooled to rt. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated. Purification by normal phase chromatography afforded 86C (0.124 g, 90% yield) as a yellow solid. MS (ESI) m/z: 495.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:12])[NH:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH:20]([CH3:31])[C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[CH3:30])=[O:22].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:12][CH:20]([CH3:31])[C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])=[O:22])=[N:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: Cc1ccc(C(=O)C(C)Br)c(C)c1
Reactant: CCOC(=O)c1c(C)[nH][nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OC(C)C(=O)c2ccc(C)cc2C)n[nH]c1C

Procedure:
To a well stirred mixture of 5-methyl-3-oxo-2,3-dihydro-1H-pyrazole4-carboxylic acid ethyl ester (200 mg, 1.18 mmol, 1 eq.) and K2CO3 (179 mg, 1.29 mmol, 1.1 eq.) in DMF (5 ml) is added dropwise a solution of 2-bromo-1-(2,4-dimethyl-phenyl)-propan-1-one (Intermediate BA) (298 mg, 1.23 mmol, 1.05 eq.) in DMF (2.5 ml) at 50° C. After the addition, the reaction mixture is further stirred at 50° C. for 1 h then poured into water (50 ml) and extracted with EtOAc (2×25 ml). The combined organic fractions are dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The resulting crude residue is purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [iso-hexane/DCM 1:1]/TBME 95:5→7:3) to yield the title compound as a white solid. TLC: RF=0.74 (iso-hexane/DCM/TBME 1:1:2); HPLC: AtRet=2.30; MS: m/z 331.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 1.24 (t, J 7.1, 3H), 1.43 (d, J 6.8, 3H), 2.31 (s, 6H), 2.33 (s, 3H), 4.15 (m, 2H), 5.75 (q, J 6.8, 1H), 7.13 (m, 2H), 7.83 (m, 1H), 12.24 (br. s., 1H).