Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[C:22]([Si:26]([CH3:43])([CH3:42])[O:27][CH:28]1[CH2:33][CH2:32][C:31](OS(C(F)(F)F)(=O)=O)=[CH:30][CH2:29]1)([CH3:25])([CH3:24])[CH3:23].ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:31]2[CH2:32][CH2:33][CH:28]([O:27][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:42])[CH3:43])[CH2:29][CH:30]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:7])[CH3:8])=[O:5]
Reactant: CC(C)(C)[Si](C)(C)OC1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CN(C)C(=O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)c1cc(C2=CCC(O[Si](C)(C)C(C)(C)C)CC2)ccc1N

Procedure:
A solution of 2-amino-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Compound 173D: 0.500 g, 1.72 mmol) and trifluoro-methanesulfonic acid 4-(tert-butyl-dimethyl-silanyloxy)-cyclohex-1-enyl ester (WO 2005092863, 0.745 g, 2.07 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) was charged with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.063 g, 0.086 mmol) and potassium carbonate (0.71 g, 5.2 mmol) in a microwave vial. The reaction mixture was evacuated and purged with nitrogen (3×) and irradiated in the microwave for 30 min at 100° C. The reaction mixture was partitioned between EtOAc and water and separated. The aqueous was extracted with EtOAc (3×) and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated. The compound was purified on an Isco Combiflash eluting with 50 to 100% EtOAc in heptane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.17 (dd, J=2.27, 8.59 Hz, 1H), 7.00 (d, J=2.27 Hz, 1H), 6.64 (d, J=8.59 Hz, 1H), 5.83 (d, J=2.02 Hz, 1H), 5.16 (s, 2H), 3.89-3.98 (m, 1H), 2.91 (br. s., 6H), 2.32-2.44 (m, 2H), 2.00-2.09 (m, 1H), 1.85 (d, J=10.86 Hz, 1H), 1.55-1.67 (m, 1H), 0.87 (s, 12H), 0.06 (d, J=2.27 Hz, 6H); MS (ES+): m/z: 375.2372 [MH+]. HPLC: tR=1.96 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:24]([CH2:25][OH:26])=[CH:23][N:22]=[C:21]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:37])=[C:9]([CH2:11][O:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][O:18][C:19]3[C:24]([CH:25]=[O:26])=[CH:23][N:22]=[C:21]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:20]=3)=[CH:15][C:14]=2[O:35][CH3:36])[N:10]=1
Reactant: COc1cc(COc2nc(-c3ccccc3)ncc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1cc(COc2nc(-c3ccccc3)ncc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of {4-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-2-phenylpyrimidin-5-yl}methanol (2.10 g), activated manganese dioxide (8.40 g) and tetrahydrofuran (80 mL) was stirred at room temperature for 3 hrs. Manganese dioxide was removed by filtration, and the filtrate was concentrated. Recrystallization of the obtained crystal from ethyl acetate-hexane gave 4-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-2-phenylpyrimidine-5-carbaldehyde as colorless prism crystals (1.50 g, yield 72%). melting point: 143-144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]1[NH:13][CH2:14][NH:15][CH:16]=1.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:30])=CC=1>C1COCC1.O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]1[NH:13][C:14](=[S:30])[NH:15][CH:16]=1
Reactant: Clc1cccc2c1ccn2CC1=CNCN1
Reactant: S=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: S=c1[nH]cc(Cn2ccc3c(Cl)cccc32)[nH]1
Reaction time: 4 h
Yield: 50 %

Procedure:
4-(4-Chloro-indol-1-ylmethyl)-1,3-dihydro-imidazole (Intermediate A4) (0.5 mmol) in THF (3 mL) and water (3 mL) was treated with NaHCO3 (5 mmol) at rt for 20 m. Phenyl chlorothionoformate (1.3 mmol) was added and stirring was continued for 4 h. The mixture was diluted with water (15 mL) and extracted with ether (3×25 mL). The organic portions were combined, dried over MgSO4, filtered and the solvent was removed under vacuum. The residue was dissolved in MeOH (4 mL) and treated with NEt3 (0.35 mL) for 18 h at rt. The solvent was evaporated and the product was washed on a glass frit with 50% CH2Cl2:hexanes to give a solid 4-(4-chloro-indol-1-ylmethyl)-1,3-dihydro-imidazole-2-thione (Compound 1) (˜50%)
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18]C)[CH:16]=2)[C:11](=[O:20])[C:10]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.[OH-].[Na+]>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[C:11](=[O:20])[C:10]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(=O)c(N3CCN(c4ccncc4)CC3)cn(Cc3ccccc3)c2c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=c1c(N2CCN(c3ccncc3)CC2)cn(Cc2ccccc2)c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 336 h
Yield: 9.5 %

Procedure:
To a solution of the product of step (vi) (815 mg) in dry dichloromethane (10 ml) under argon was added a 1M solution of boron tribromide in dichloromethane (10 ml). The reaction was stirred at room temperature for 14 days, extra aliquots of BBr3 solution being added after 3 and 7 days. After 2 weeks, excess 1M aqueous sodium hydroxide solution was added, dropwise at first, and the mixture stirred at room temperature for 3 hours. The precipitated material was filtered off and the aqueous layer of the filtrate separated. The pH of the aqueous layer was adjusted to 8 by addition of 2N HCl (aq.) and 1M NaHClO3 (aq.) before being extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4) and evaporated to dryness to yield 1-benzyl-3-(4-(4-pyridyl)piperazin-1-yl)-4-quinolon-7-ol (75 mg) as an off-white solid: m.p. 141°-6° C.; NMR (d6DMSO) δ 3.10 (4H, m), 3.50 (4H, m), 5.40 (2H, s), 6.67 (1H, d), 6.72 (1H, dd), 6.90 (2H, m), 7.30 (5H, m), 7.76 (1H, s), 8.07 (1H, d), 8.15 (2H, s), 10.15 (1H, br, s); m/Z 413 (H+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccccc1N1CCN(C(=O)c2cnc3c(C(=O)O)cnn3c2NCc2ccccc2)CC1
Product: Cc1ccccc1N1CCN(C(=O)c2cnc3c(C(=O)NS(C)(=O)=O)cnn3c2NCc2ccccc2)CC1
Yield: 41.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(2-methylphenyl)piperazine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.149 g, 0.317 mmol) obtained in step 2 and methanesulfonamide (0.175 g, 1.82 mmol), the title compound (0.072 g, 41%) was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][CH:8]=1)=O.[CH3:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1>>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[C:19]3[N:18]([C:17]([CH3:16])=[N:21][CH:20]=3)[CH2:2][CH2:3][CH:4]=2)=[CH:8][CH:9]=1)[CH3:15]
Reactant: CCOc1ccc(C(=O)CCCCl)cc1
Reactant: Cc1ncc[nH]1
Product: CCOc1ccc(C2=CCCn3c2cnc3C)cc1

Procedure:
Combine 150 g (0.66 mol) of 4-chloro-4'-ethoxybutyrophenone with 300 g (3.65 mol) of 2-methylimidazole and heat to 175° C. for 18 hr. Crystallization from ethyl acetate provides the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[C:14]([Cl:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([NH:18][CH2:19][C:20]([OH:22])=O)[CH:10]=1.CCN(CC)CC.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.[C:53]([N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH:58]1[C:63]([NH2:65])=[O:64])(=[O:56])[CH:54]=[CH2:55]>CN(C=O)C>[C:53]([N:57]1[CH2:62][CH2:61][N:60]([C:20](=[O:22])[CH2:19][NH:18][C:11]2[CH:10]=[C:9]([C:3]3[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]([Cl:15])=[CH:13][C:12]=2[O:16][CH3:17])[CH2:59][CH:58]1[C:63]([NH2:65])=[O:64])(=[O:56])[CH:54]=[CH2:55]
Reactant: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1NCC(=O)O
Reactant: C=CC(=O)N1CCNCC1C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCN(C(=O)CNc2cc(-c3cc(Cl)ccc3Cl)c(Cl)cc2OC)CC1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 3 %

Procedure:
2-((2′,5′,6-Trichloro-4-methoxy-[1,1′-biphenyl]-3-yl)amino)acetic acid (231 mg, 0.641 mmol) and Et3N (592 mg, 2.564 mmol) in DMF (3 mL) at 0° C., EDCI.HCl (184 mg, 0.961 mmol) and HOBt (134 mg, 0.961 mmol) were added and the resulting mixture was stirred at 0° C. for 30 min. To this mixture, the above 1-acryloylpiperazine-2-carboxamide hydrochloride (160 mg) was added and stirred at room temperature for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM/MeOH=30:1) to afford the desired product (10 mg, 2.97% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ: 7.60-7.38 (m, 3H), 6.70-6.99 (m, 1H), 6.86-6.78 (m, 1H), 6.54-6.49 (m, 1H), 6.16-6.10 (m, 1H), 5.76-5.69 (m, 1H), 5.32-5.31 (m, 1H), 4.93-4.84 (m, 1H), 4.93-4.84 (m, 1H), 4.70-4.62 (m, 1H), 4.35-4.32 (m, 1H), 4.04-3.96 (m, 2H), 3.89-3.63 (m, 1H), 2.90-2.86 (m, 1H). ESI-MS m/z: 525.2[M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][O:11][CH2:12][CH2:13][CH2:14][C:15](O)=[O:16].Cl.C(N=C=NCCCN(C)C)C>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:7][NH:8][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][O:11][CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: COCCCC(=O)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 64 h

Procedure:
Carbazic acid tert-butyl ester (9.21 g) was dissolved in pyridine (120 ml), followed by addition of 4-methoxybutyric acid (9.06 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt (20.0 g), and stirred at ambient temperature for 64 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, which was then washed with aqueous 1 mol/liter hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, N′-(4-methoxybutyryl)hydrazine carboxylic acid tert-butyl ester was obtained in yellow oil (9.30 g, 57%). The physico-chemical values are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17]CC)=[O:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([OH:17])=[O:16])=[CH:13][CH:14]=2)=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OC)c(-c3cccc([N+](=O)[O-])c3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 90 °C

Procedure:
A stirred mixture of 4′-methoxy-3′-(3-nitrophenyl)-[1,1′-biphenyl]-4-carboxylic acid, ethyl ester (1.88 g. 5 mmol) and aqueous sodium hydroxide (20 mL of 2 M) in ethanol (30 mL) is heated at 90° C. for 3 h. The cooled mixture was then acidified with hydrochloric acid (100 mL of 1.0 M) and the resulting precipitate is filtered off and dried to give 4′-methoxy-3′-(3-nitrophenyl) -[1,1′-biphenyl]-4-carboxylic acid as a colourless crystalline solid, m.p. 270-274° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]2)[C:3]1=[O:23].CCN(C(C)C)C(C)C.CN(C(ON1N=[N:48][C:43]2C=[CH:45][CH:46]=[N:47][C:42]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N1CCNCC1)(OC(C)(C)C)=O.OS(O)(=O)=O>CN(C=O)C.C(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([N:47]3[CH2:42][CH2:43][NH:48][CH2:45][CH2:46]3)=[O:22])[CH2:16][CH2:15]2)[C:3]1=[O:23]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cn1c(=O)n(C[C@H]2CC[C@H](C(=O)O)CC2)c(=O)c2ccccc21
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)n(C[C@H]2CC[C@H](C(=O)N3CCNCC3)CC2)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
trans-4-(1-Methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-cyclohexanecarboxylic acid (1.0 g, 3.2 mmol), DIPEA (560 μL, 3.2 mmol), HATU (1.2 g, 0.32 mmol) were dissolved in 20 ml of DMF. The mixture was stirred at room temperature for 2 hours and then 14 ml of the solution were transferred in a different flask. To this solution Boc-piperazine (411 mg, 2.2 mmol) was added and the mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue dissolved in DCM and washed with 0.4 M solution of Na2CO3. The organic phase was separated and the solvent removed under reduced pressure to give 900 mg of crude boc protected intermediate. The compound was dissolved in 10 ml of DCM, 255 μL of H2SO4 were added and the mixture was left stirring at room temperature for 18 hours. The solution was washed with a solution of NaOH (10% W/W), the organic phase was separated and concentrated under reduced pressure to give 570 mg (yield 80%) of the titled compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1COCC1>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: c1ccc2cc(CN3CCNCC3)ccc2c1

Procedure:
Synthesized according to General Procedure A: 2-(bromomethyl)naphthalene (4{25}, 5 g, 22.6 mmol, 1 equiv.), piperazine (11.7 g, 135.7 mmol, 6 equiv.), THF (49.4 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{25} (4.67 g, 91%) as a beige solid. 1H-NMR (500 MHz, CDCl3): δ 7.82-7.79 (m, 3H), 7.74 (s, 1H) 7.50 (dd, 1H, J=1.5, 8.5 Hz), 7.48-7.42 (m, 2H), 3.64 (s, 2H), 2.88 (t, 4H, J=5.0 Hz), 2.45 (br s, 4H), 1.52 (br s, 1H). 13C-NMR (125 MHz, CDCl3): δ 135.6, 133.2, 132.6, 127.7, 127.5, 127.5, 127.5, 127.4, 125.8, 125.4, 63.7, 54.5, 46.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[Cl:11].[CH2:12]([O:14][C:15](=[O:24])[CH:16]=[CH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:13].C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=CN2)C1C=CC=CC=1)C>>[CH2:12]([O:14][C:15](=[O:24])[CH:16]=[C:17]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[Cl:11])[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH3:13]
Reactant: CCOC(=O)C=Cc1cccnc1
Reactant: Clc1n[nH]c2ccc(Br)cc12
Agent: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1cccnc1)c1ccc2[nH]nc(Cl)c2c1

Procedure:
3-(3-Chloro-1H-indazol-5-yl)-3-pyridin-3-yl-acrylic acid ethyl ester CCXXIII was prepared from 5-bromo-3-chloro-1H-indazole and 3-pyridin-3-yl-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: C([N:4]([CH2:8][C:9]1[S:13][C:12]([S:14]([NH:17][CH:18]([CH2:22][CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][N:26]=2)[C:19]([NH2:21])=[O:20])(=[O:16])=[O:15])=[CH:11][CH:10]=1)CC=C)C=C.CN1C(=O)CC(=O)N(C)C1=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:4][CH2:8][C:9]1[S:13][C:12]([S:14]([NH:17][CH:18]([CH2:22][CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][N:26]=2)[C:19]([NH2:21])=[O:20])(=[O:16])=[O:15])=[CH:11][CH:10]=1
Reactant: C=CCN(CC=C)Cc1ccc(S(=O)(=O)NC(CCNc2ccc([N+](=O)[O-])cn2)C(N)=O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Product: NCc1ccc(S(=O)(=O)NC(CCNc2ccc([N+](=O)[O-])cn2)C(N)=O)s1

Procedure:
A solution of the bisallylamine 2c (7.25 mmol), N,N′-dimethylbarbituric acid (NDMBA 2.8 g, 18.1 mmol), and Pd(PPh3)4 (148.8 mg, 0.13 mmol) in CH3Cl2 is degassed by bubbling argon for 10 min. The reaction mixture for 3 h at r.t. whereupon the desired amine 2d precipitates as its NDMBA salt. The mixture is diluted with EtOAc (200 ml) and hexane (200 ml) and washed with water (3×50 ml). The crude compound 2D is pure enough to be used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](OCC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].Cl.O>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH2:16][OH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2c(Cl)cccc2-n2cnc(CO)c2[C@@H]2CCCN12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 81.2 g (234.8 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate in 450 ml of dry tetrahydrofuran is heated to about 50° and a suspension of 6.1 g (279 mmol) of lithium borohydride in 60 ml of tetrahydrofuran is added dropwise to the solution obtained. The suspension is subsequently heated to boiling under reflux for 3 hour. The mixture is cooled to room temperature and there are added dropwise thereto firstly 40 ml of 3N hydrochloric acid and then 260 ml of a solution consisting of 130 ml of conc. hydrochloric acid and 130 ml of water. The solution obtained is stirred at 40° for 15 minutes, the tetrahydrofuran is distilled off in vacuo and the aqueous residue is made alkaline with 25 percent ammonia. The precipitated material is then filtered off under suction, washed with water and dried at 80° in high vacuum. There is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-1-(hydroxymethy)-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 303°-305° .
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH:13]([CH3:15])[CH3:14])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].[N:16]1([C:22]2[S:23][C:24]([C:27]#[N:28])=[CH:25][N:26]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH:13]([CH3:15])[CH3:14])=[C:7]([CH:11]=1)[C:8]([N:19]1[CH2:20][CH2:21][N:16]([C:22]2[S:23][C:24]([C:27]#[N:28])=[CH:25][N:26]=2)[CH2:17][CH2:18]1)=[O:10])#[N:2]
Reactant: CC(C)Oc1ccc(C#N)cc1C(=O)O
Reactant: N#Cc1cnc(N2CCNCC2)s1
Product: CC(C)Oc1ccc(C#N)cc1C(=O)N1CCN(c2ncc(C#N)s2)CC1
Yield: 70 %

Procedure:
Prepared in analogy to example 1 (b) from 5-cyano-2-isopropoxy-benzoic acid (Example A28) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a white solid (yield 70%). MS (m/e): 382.3 (M+H+, 100%).
Reaction SMILES: [C:1]([C:3]1[C:4]([F:20])=[C:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1)#N.CC(C[AlH]CC(C)C)C.C(Cl)Cl.C1C[O:36]CC1>>[F:20][C:4]1[C:3]([CH:1]=[O:36])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1CCOC1
Reactant: N#Cc1cccc(NC(=O)OCc2ccccc2)c1F
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=Cc1cccc(NC(=O)OCc2ccccc2)c1F
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a slightly tan, homogeneous solution of benzyl 3-cyano-2-fluorophenylcarbamate (4.45 g, 16.47 mmol) in THF (211 mL) in a −78° C. bath under nitrogen was syringed DIBAL-H (65.9 mL, 65.9 mmol)/CH2Cl2 dropwise over 75 min. The reaction was stirred for 30 min. The cold bath was removed, and the reaction was stirred to room temperature. After 4 hr, the solution was added to ice-cold water (300 mL) over 50 minutes; heavy emulsion ensued. After stirring for another 30 min, the organic layer was separated, and the aqueous layer/emulsion was filtered, and the insoluble materials were rinsed with CH2Cl2 (200 mL). The organic layers were combined and concentrated in vacuo. The residue was dissolved in CH2Cl2 (300 mL) and washed with brine (75 mL), dried over MgSO4, and concentrated in vacuo to give the desired product (4.0253 g, 11.78 mmol, 71.6% yield) as a tan solid.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.C1C=C[NH+]=CC=1.[Br:43][Br-]Br.C(OCC)(=O)C.O>C1COCC1>[Br:43][C:2]1[N:1]=[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][C:6]3[N:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]2[C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:26][CH2:27][CH2:28]2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3cnc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
tert-Butyl {1-[4-(9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (9.8 g, 20.4 mmol) was dissolved in THF (350 mL). A solution of pyridinium bromide perbromide (6.5 g, 20.4 mmol) in THF (50 mL) was added to the mixture at −78° C. After three hours stirring at r.t., pyridinium bromide perbromide (2.6 g, 8.2 mmol) in THF was added to the mixture and the mixture was stirred at rt overnight. The mixture was poured into ethyl acetate (1.5 L) and mixed with water and separated. The combined organic phase was washed with saturated sodium bicarbonate solution in water, then dried with anhydrous sodium sulfate and evaporated. The residue was purified with silica gel column chromatography (dichloromethane/ethyl acetate, 20:1) to give the titled compound as a white solid (6.8 g, 59%). 1HNMR (CDCl3) 400 MHz δ: 8.04 (d, J=8.0 Hz, 2H), 7.40 (d, J=7.4 Hz, 2H), 7.31 (t, J=7.4 Hz, 1H), 7.23 (d, J=6.9 Hz, 2H), 7.12 (t, J=7.7 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 6.88-6.80 (m, 1H), 6.66-6.62 (m, 1H), 6.29 (s, 1H), 5.10 (s, 1H), 2.58-2.37 (m, 4H), 2.18-2.08 (m, 1H), 1.94-1.84 (m, 1H), 1.39 (br s, 9H); LC/MS [M+H]: 558