Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([OH:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:12]2)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:11]1([OH:22])[CH2:12][CH:13]2[NH:8][CH:9]([CH2:15][CH2:14]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ccccn1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2ccccn2)CC2CCC(C1)N2
Reaction time: 1 h

Procedure:
3-Hydroxy-3-pyridin-2-yl-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.8 g, 2.6 mmol) was dissolved in TFA (3 mL) and DCM (10 mL). The mixture was stirred for 1 hour and the solvent removed by evaporation under vacuum and the residues were passed through an SCX cartridge, eluting with 2 M ammonia in methanol to give the title compound. LCMS m/z 205.2 [M+H]+. R.T.=0.38 min (Analytical Method 3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.[NH:15]1[C:23]2[C:18](=[CH:19][C:20](B(O)O)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1.C(O)(C(F)(F)F)=O>O.CC#N>[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([C:2]3[CH:7]=[CH:6][N:5]4[C:8]5[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=5[N:10]=[C:4]4[N:3]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: Brc1ccn2c(n1)nc1ccccc12
Reactant: OB(O)c1ccc2[nH]ccc2c1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: c1ccc2c(c1)nc1nc(-c3ccc4[nH]ccc4c3)ccn12
Yield: 50 %

Procedure:
The title compound was prepared using General Experimental Procedure A (Suzuki coupling reaction) from 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine and (1H-indol-5-yl)boronic acid on a 0.12 mmol scale. The crude product was subjected to reversed phase HPLC (TFA buffered water/MeCN) to afford 2-(1H-indol-5-yl)benzo[4,5]imidazo[1,2-a]pyrimidine (T759) as a orange solid (20 mg, 50%). 1H NMR (400 MHz, DMSO-d6): 9.85 (d, J=7.2 Hz, 1H), 8.80 (s, 1H), 8.52 (d, J=8.0 Hz, 1H), 8.46 (d, J=7.2 Hz, 1H), 8.26 (dd, J=8.8, 1.2 Hz, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.77 (t, J=7.2 Hz, 1H), 7.68-7.64 (m, 2H), 7.55 (t, J=2.4 Hz, 1H), 6.70 (m, 1H); MS (ESI) m/z [M+H]+285.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC.C([Li])CCC.[CH:35]1([NH:41][C:42]2[CH:51]=[C:50]3[C:45]([C:46](=[O:59])[C:47]([CH:57]=O)=[CH:48][N:49]3[CH:52]3[CH2:56][CH2:55][CH2:54][CH2:53]3)=[CH:44][C:43]=2[F:60])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.[BH4-].[Na+]>C1COCC1.C(O)C.O>[CH:35]1([NH:41][C:42]2[CH:51]=[C:50]3[C:45]([C:46](=[O:59])[C:47]([CH2:57][CH2:2][OH:3])=[CH:48][N:49]3[CH:52]3[CH2:53][CH2:54][CH2:55][CH2:56]3)=[CH:44][C:43]=2[F:60])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCO
Solvent: CCCCCC
Solvent: O
Product: O=c1c(CCO)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 9.7 %

Procedure:
428 mg of (methoxymethyl)triphenylphosphonium chloride was dissolved in 5 ml of THF, and 1.2 ml of 1.6 M n-butyl lithium hexane solution was added under ice-cooling in an atmosphere of argon, followed by stirring at the same temperature for 30 minute. A 5 ml THF solution of 178 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde was added under ice-cooling thereto, followed by stirring at the same temperature for 15 minutes and then stirring at room temperature for 3 hours. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate, drying over anhydrous sodium sulfate and then concentration under a reduced pressure. The resulting residue was dissolved in 10 ml of dioxane, and 5 ml of a 4 M hydrogen chloride dioxane solution was added, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into an ice-cooled aqueous saturated sodium hydrogen carbonate, followed by extraction with ethyl acetate, drying over anhydrous sodium sulfate and then concentration under a reduced pressure. By purifying the resulting residue by silica gel column chromatography, 239 mg of crude product of [7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl)acetaldehyde was obtained. The resulting crude product was dissolved in 10 ml of ethanol, and 75 mg of sodium borohydride was added, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate, drying over anhydrous sodium sulfate and then concentration under a reduced pressure. The resulting residue was purified by silica gel column chromatography and crystallized from ethyl acetate to obtain 18 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(2-hydroxyethyl)quinolin-4(1H)-one.
Reaction SMILES: [S:1]([C:5]1[CH:23]=[CH:22][C:8]([N:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C[Si]([C:28]#[N:29])(C)C.O>C1COCC1.[Cl-].[Zn+2].[Cl-]>[S:1]([C:5]1[CH:23]=[CH:22][C:8]([NH:9][CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)[C:28]#[N:29])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: C[Si](C)(C)C#N
Reactant: NS(=O)(=O)c1ccc(N=Cc2ccc(-c3ccco3)cc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(Nc1ccc(S(N)(=O)=O)cc1)c1ccc(-c2ccco2)cc1
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a suspension of 4-sulfamoyl-N-[4-(2-furyl)benzylidene]aniline (0.37 g, 1.13 mmol) in anhydrous THF (5 mL) at 0° C. was added trimethylsilyl cyanide (0.135 g, 1.36 mmol),zinc chloride (1.36 mL, 1.0 M solution in ether, 1.36 mmol). The temperature of the reaction mixture was then allowed to return to room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water and the whole was extracted with ethyl acetate (20 mL×2). The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the subtitle compound (0.288 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[CH:14][C:15]([OH:18])=[N:16][CH:17]=1.CS(O[CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[CH:14][C:15]([O:18][CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[N:16][CH:17]=1
Reactant: CC(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)cn2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(COc2cnc(-c3ccc(S(C)(=O)=O)cc3F)cn2)CC1

Procedure:
The title compound (80 mg, 49%) was prepared as a white solid from 5-[2-fluoro-4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 161, Step 2, 98 mg, 0.37 mmol), 1-methylethyl 4-{[(methylsulfonyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 131, Step 4, 0.138 g, 0.49 mmol) and K2CO3 (0.102 g, 0.73 mmol) in DMF (4 mL) in a manner similar to Example 152, Step 3. The crude product was purified by chromatography on an ISCO silica gel column using 0 to 50% EtOAc/hexanes to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.66 (s, 1H), 8.33 (d, 1H, J=1.3 Hz), 8.23 (t, 1H, J=7.8 Hz), 7.85-7.70 (m, 2H), 4.91 (septet, 1H, J=6.2 Hz), 4.30-4.15 (m, 4H), 3.09 (s, 3H), 2.85-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.85-1.75 (m, 2H), 1.35-1.20 (m, 8H); LRMS (ESI), m/z 452 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][CH2:3]1>[Pd].C(O)C>[CH3:1][N:2]1[C:8]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCOc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: CN1CCCOc2ccc(N)cc21
Yield: 81.4 %

Procedure:
9-Methyl-2-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (0.296 g, 1.42 mmol) and 10% Palladium on Carbon (50% Wet) (0.097 g) in Ethanol (20 mL) was shaken under an atmosphere of Hydrogen (30 psi) overnight. The mixture was filtered, washing with 20 mL ethanol. The filtrate was concentrated to give 9-Methyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-ylamine as a white solid (206 mg, 81%). 1H-NMR (CDCl3): 6.77 (d, 1H, J=8.2 Hz), 6.21 (s, 1H), 6.14 (d, 1H, J=8.2 Hz), 3.96 (t, 2H, J=5.5 Hz), 3.35 (br s, 2H), 3.09 (t, 2H, J=5.6 Hz), 2.86 (s, 3H), 1.99 (tt, 2H, J=5.5, 5.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c[nH]nc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c[nH]nc1-c1ccc(F)cc1
Yield: 103.4 %

Procedure:
To a solution of the compound (25.0 g, 107 mmol) obtained in step 2 in ethanol (90 mL) was added 2N aqueous sodium hydroxide solution (117 mL, 235 mmol) at room temperature, and the mixture was heated under reflux for 24 hr. The organic solvent was evaporated, and ethyl acetate was added to the residue. The aqueous layer was separated, and 2N hydrochloric acid was added until the aqueous layer became pH2. The precipitate was collected by filtration to give 3-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid (22.8 g, 100%) as a yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:10][C:9](=[O:11])[C:8]=2[CH:12]=1)([O-])=O.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[CH2:10][C:9](=[O:11])[C:8]=2[CH:12]=1
Reactant: O=C1Cc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Nc1ccc2c(c1)C(=O)C2
Temperature: 25 °C

Procedure:
In a 100 mL two-neck round-bottomed flask fitted with a reflux condenser, were placed 5-nitrobenzocyclobutenone (2.50 g, 15.34 mmol), iron powder (2.50 g) and aqueous ethanol (50%, 25 mL). The mixture was heated to gentle boiling. With a good stirring, concentrated hydrochloric acid (36%, 0.15 mL) in aqueous ethanol (50%, 5 mL) was added slowly. Stirring and reflux stopped until TLC showed no more starting compound. It usually took 5-60 min. After cooling to room temperature, the reaction solution was treated with sodium carbonate powders to pH 8-9. The insoluble solids were removed by filtration and further washed with methanol. The filtrate and washing solution were combined and concentrated by distillation at 50° C. under vacuum. Upon cooling, the pure product crystallized out and then collected by suction filtration: 1.88 g (92.4%); mp 92°-93° C.; IR (KBr) 1620, 1744, 3362, 3466 cm-1 ; 1H NMR (200 MHz, CDCl3) 3.85 (s, 2H), 3.86 (s, 2H), 6.64 (s, 1H), 6.88 (d, 1H), 7.33 (d, 1H); MS (EI, m/e, relative intensity %) 133 (M+., 31.2), 105 (M+. -CO, 100) .
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[C:28]([O:34][CH3:35])[CH:27]=1>CC(O)C>[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[N:8][NH:7][C:5](=[O:6])[C:4]2[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([NH2:1])[CH:3]=2)=[C:28]([O:34][CH3:35])[CH:27]=1
Reactant: COc1cc(OCCN2CCc3ccccc3C2)ccc1C=O
Reactant: NNC(=O)c1ccc(O)c(N)c1
Solvent: CC(C)O
Product: COc1cc(OCCN2CCc3ccccc3C2)ccc1C=NNC(=O)c1ccc(O)c(N)c1
Yield: 47.8 %

Procedure:
The above 3-amino-4-hydroxybenzoic acid hydrazide (50 mg, 0.3 mmol) and the above 4-[2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethoxy]-2-methoxybenzaldehyde (93 mg, 0.3 mmol) were dissolved in 2-propanol (4 ml) and the mixture was heated at reflux temperature for 16 hours. The cooled mixture was filtered and the precipitate was washed with 2-propanol (2×4 ml) and dried by suction to afford 66 mg (48%) of the title compound as a solid. M.p.: 162-164° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:8]=1[CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[N:20]=[N:21][C:22]([C:26]([CH3:32])([CH3:31])[C:27]([O:29]C)=O)=[C:23](O)[N:24]=2)=[N:11]1.[NH3:38]>C(#N)C>[F:6][C:7]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:8]=1[CH2:9][N:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[N:20]=[N:21][C:22]3[C:26]([CH3:32])([CH3:31])[C:27](=[O:29])[NH:38][C:23]=3[N:24]=2)=[N:11]1
Reactant: N
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccc(F)cc3F)c3ncccc23)nc1O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccc(F)cc4F)c4ncccc34)nnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
29 ml of phosphoryl chloride were added to 2.74 g (6.221 mmol) of the compound from Example 77A, and the mixture was stirred at RT overnight. The reaction mixture was then taken up in 430 ml of acetonitrile and, with ice cooling, stirred into 260 ml of concentrated ammonia solution (33% in water). The mixture was stirred at room temperature overnight and then concentrated on a rotary evaporator. The residue was stirred with water and ethyl acetate and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulphate, filtered and concentrated on a rotary evaporator. The residue was stirred with ethyl acetate and diethyl ether. A solid was filtered off with suction and then washed with diethyl ether and ethyl acetate. Drying under high vacuum gave 2.13 g of the title compound in a purity of 94% (79% of theory).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10](=[O:23])[CH2:11][C:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH:21]=O)=[CH:20][C:15]=2[S:14][CH:13]=1)[CH3:8].[Cl-:24].[CH3:25][C:26]1[C:31]([CH2:32][P+:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:30][CH:29]=[C:28]([CH3:52])[N:27]=1>CN(C=O)C>[CH2:7]([O:9][C:10](=[O:23])[CH2:11][C:12]1[C:16]2[CH:17]=[CH:18][C:19](/[CH:21]=[CH:32]/[C:31]3[C:26]([CH3:25])=[N:27][C:28]([CH3:52])=[CH:29][CH:30]=3)=[CH:20][C:15]=2[S:14][CH:13]=1)[CH3:8].[Cl-:24].[CH3:25][C:26]1[C:31]([CH2:32][P+:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:30][CH:29]=[C:28]([CH3:52])[N:27]=1
Reactant: CCOC(=O)Cc1csc2cc(C=O)ccc12
Agent: Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1csc2cc(/C=C/c3ccc(C)nc3C)ccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of K2CO3 (134 mg), ethyl(6-formyl-1-benzothiophen-3-yl)acetate (160 mg), ((2,6-dimethylpyridin-3-yl)methyl) (triphenyl)phosphonium chloride (323 mg) and DMF (5 mL) was stirred at room temperature for 3 d. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give ethyl(6-((E)-2-(2,6-dimethylpyridin-3-yl)vinyl)-1-benzothiophen-3-yl)acetate (example 179, 60 mg) and ethyl(6-((Z)-2-(2,6-dimethylpyridin-3-yl)vinyl)-1-benzothiophen-3-yl)acetate (example 180, 110 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>>[Cl:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: O=C1NCCCn2c1cc1cc(O)ccc12
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1NCCCn2c1cc1cc(OCCCCl)ccc12
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 2, intermediate, from 9-hydroxy-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (example 15, intermediate a)), potassium carbonate and 1-bromo-3-chloropropane, to give the desired compound as a light yellow solid (35%).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=2[O:29][CH2:30][CH2:31]OS(C)(=O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[N:9]3[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=2[O:29][CH2:30][CH2:31]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc([N+](=O)[O-])c3OCCOS(C)(=O)=O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c-3cccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 97.1 %

Procedure:
To a solution of methyl 3-cyclohexyl-2-[2-(2-methanesulfonyloxyethoxy)-3-nitrophenyl]-1H-indole-6-carboxylate (12.60 g, 24.4 mmol) in N,N-dimethylformamide (190 ml) was added potassium carbonate (5.06 g, 36.6 mmol), and the mixture was stirred at 90° C. for 1.5 hr. The reaction mixture was allowed to iv cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was concentrated under reduced pressure to give methyl 12-cyclohexyl-4-nitro-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (9.96 g, yield 97%).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([NH:10][CH2:11][CH2:12][OH:13])[CH2:6][N+:7]([O-])=O.C(=O)=O>[Ni].CO>[ClH:2].[ClH:1].[NH2:7][CH2:6][CH:5]([NH:10][CH2:11][CH2:12][OH:13])[C:4]1[CH:14]=[CH:15][CH:16]=[CH:17][C:3]=1[Cl:2]
Reactant: O=[N+]([O-])CC(NCCO)c1ccccc1Cl
Agent: [Ni]
Agent: Cl
Agent: O=C=O
Solvent: CO
Product: NCC(NCCO)c1ccccc1Cl
Reaction time: 2 h

Procedure:
To a mixture of 26 parts of 2-{N-[o-chloro-α-(nitromethyl)benzyl]amino}ethanol hydrochloride and 2 parts of Raney-Nickel catalyst is added 120 parts of methanol (cooled in a mixture of methaol/carbon dioxide), followed by the addition of 20 parts of carbon dioxide. The whole is hydrogenated at 50 lbs./sq. inch pressure over 2 hours. The catalyst is filtered off and the filtrate is acidified with an excess of 2-propanol previously saturated with gaseous hydrogen chloride. The precipitated salt is filtered off, washed with methanol and dried, yielding 2-{N-[α-(aminomethyl)-o-chlorobenzyl]amino}ethanol dihydrochloride.
Reaction SMILES: [CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9](=O)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(O)CCC>[CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=c1nc(C2CCCCC2)c2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCO
Product: O=C(O)c1ccc(Nc2nc(C3CCCCC3)c3ccccc3n2)cc1
Temperature: 140 °C
Yield: 48.4 %

Procedure:
A mixture of 4-cyclohexylquinazolin-2(1H)-one (500 mg, 2.2 mmol) and phosphorous oxychloride (10 mL, 111 mmol) was heated to reflux for 1 h. The volatiles were removed under reduced pressure, and then the residue was treated with ice water and extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium chloride and dried over sodium sulfate. The solvent was removed on a rotary evaporator, and to this residue was added 4-aminobenzoic acid (300 mg, 2.2 mmol), triethylamine (435 μL, 3.0 mmol) and n-butanol (5 mL). This mixture was heated to 140° C. for 25 min. The mixture was cooled to rt and triturated with ether. The residual solid was collected via vacuum filtration, washed with ether and dried to afford 4-(4-cyclohexylquinazolin-2-ylamino)benzoic acid (370 mg, 48%) as an off white solid.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:13]=[C:12]2[I:25])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[N:13]=[C:12]2[I:25]
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(I)c2cc(O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of tert-butyl 5-(tert-butyldimethylsilyloxy)-3-iodo-1H-indazole-1-carboxylate (1 g, 2.11 mmol) in THF (10 mL), was added TBAF (5.6 g, 21.1 mmol) in THF (5 mL). The mixture was stirred at room temperature for 0.5 hour. The solvent was removed under reduced pressure. The residue was diluted with water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the crude product was used in the next step without purification. LCMS: 361 [M+H]+.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=3)[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: COc1ccc(N2CCNCC2)cc1
Product: CCc1cc(NC(=O)N2CCN(c3ccc(OC)cc3)CC2)c(OC)nc1C
Yield: 78 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: N1C2C(=CC=CC=2)C(CC2C3N(C(C4C=CC=CC=4)=NN=3)C3C=CC=CC=3N([CH2:31][C:32]([N:34]([CH:43]([CH3:45])[CH3:44])[C:35]3[CH:36]=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=3)=[O:33])C2=O)=C1>CCOC(C)=O>[CH:43]([N:34]([C:35]1[CH:36]=[N:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)[C:32](=[O:33])[CH3:31])([CH3:44])[CH3:45]
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3c[nH]c4ccccc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Solvent: CCOC(C)=O
Product: COc1ccc(N(C(C)=O)C(C)C)cn1

Procedure:
The racemic product of Step B, 2-[4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide (217 mg, 0.355 mmol), was separated into its enantiomers by high pressure chromatography using a Chiralpak AD column (5 cm×50 cm), eluting with heptane in EtOH (75:12), using a flow rate of 85 mL/minute to give enantiomer 1 having a retention time of 7.04 minutes. The enantiomer was dissolved in EtOAc and the organic layer was washed with water (1×) and brine (1×). The organic extract was dried (MgSO4), filtered and concentrated to provide 85 mg of 2-[4-1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide (enantiomer 1). 1H NMR (CD3OD) δ 8.08 (d, 1H), 7.61 (m, 3H), 7.39-7.53 (m, 6H), 7.25 (d, 1H), 7.14 (m, 2H), 7.00 (t, 1H), 6.90 (m, 3H), 4.78 (m, 1H), 4.54 (m, 1H), 4.11 (m, 1H), 3.95 (s, 3H), 3.89 (t, 1H), 3.68-3.82 (m, 2H), 1.01 (m, 6H); MS 612.9 (M+1), 610.5 (M−1); [α]D21 −79.6 (c 0.325, ethanol).