Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20]2[S:33][CH:32]=[CH:31][C:21]=2[N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]1([Mg]Br)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]([OH:18])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20]2[S:33][CH:32]=[CH:31][C:21]=2[N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:23]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(C(O)c4ccccc4)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-formyl-indole-1-carboxylic acid tert-butyl ester [100 mg, 0.214 mmol, Intermediate (11)] in anhydrous tetrahydrofuran (5 mL) is added phenylmagnesium bromide (1M in tetrahydrofuran, 1 mL) at −78° C. The resulting reaction mixture is stirred at the same temperature for 1 h then quenched it by the addition of water at 0° C. (4 mL). The reaction mixture is extracted three times with ethyl acetate (30 mL). Combined ethyl acetate phases are washed with brine, dried over sodium sulfate and filtered. Evaporation of the solvent in vacuo yielded 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-(hydroxy-phenyl-methyl)-indole-1-carboxylic acid tert-butyl ester [99 mg, 85%, Intermediate (12)] as a white foam; LC/MS: (M+H, 546).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:3]=1.C1C(=O)N([Br:20])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.BrC(C1OC=C(CBr)N=1)(C)C(OC)=O>C(Cl)(Cl)(Cl)Cl>[Br:20][C:7]([C:5]1[O:6][C:2]([CH3:1])=[CH:3][N:4]=1)([CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(C)c1ncc(C)o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: COC(=O)C(C)(Br)c1nc(CBr)co1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)(Br)c1ncc(C)o1
Temperature: 25 °C

Procedure:
A mixture of the intermediate from Step B (0.322 g, 1.903 mmol), NBS (0.373 g, 2.09 mmol), and AIBN (0.016 g, 0.095 mmol) in 15 mL of CCl4 was refluxed for 1 hour. The mixture was cooled to room temperature, filtered, and concentrated. The residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give a 7:1 mixture of the indicated product and methyl 2-bromo-2-[4-(bromomethyl)-1,3-oxazol-2-yl]propanoate (pale yellow oil). The mixture was used in the next step without further purification.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:47]1([CH2:53][CH2:54][CH:55]=[CH2:56])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[N+:22]([C:11]1[CH:10]=[C:9]([CH:56]=[CH:55][CH2:54][CH2:53][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:21]=[CH:20][C:12]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([O-:24])=[O:23]
Reactant: C=CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(C=CCCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
19 mg of palladium acetate (II) was added to 5 mL of toluene solution containing 0.50 g of tert-butyl 4-bromo-2-nitrobenzoate, 50 mg of tri(o-tolyl)phosphine, 0.50 mL of 4-phenyl-1-butene and 0.46 mL of triethylamine, and the resulting mixture was heated to reflux under nitrogen atmosphere for 4 hours and 30 minutes. After the reaction mixture was cooled to room temperature, 20 mg of palladium acetate (II) was added and the resulting mixture was heated to reflux for 5 hours and 30 minutes. After cooled to room temperature, the reaction mixture was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=30:1] to obtain 0.35 g of tert-butyl 2-nitro-4-(4-phenyl-1-butenyl)benzoate.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:14])[CH2:4][N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.N1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[O:25][CH2:26][C:27](OCC)=[O:28])C=CC=1>CCO>[OH:14][C@H:3]([CH2:4][N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][NH:1][C:27](=[O:28])[CH2:26][O:25][C:23]1[CH:24]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)COc1cccc2cccnc12
Reactant: NC[C@H](O)CN1Cc2ccccc2C1
Solvent: CCO
Product: O=C(COc1ccccc1)NC[C@H](O)CN1Cc2ccccc2C1
Yield: 31 %

Procedure:
A solution of (S)-1-amino-3-(isoindolin-2-yl)propan-2-ol (100 mg, 0.52 mmol), ethyl 2-(quinolin-8-yloxy)acetate (120 mg, 0.52 mmol) in EtOH (1 mL) was heated under microwave conditions at 120° C. for 0.5 h. The reaction mixture was concentrated and purified by preparative HPLC purification. (60 mg, yield 31%) MS (ESI+) e/z: 378.1 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 8.93-8.88 (m, 1H), 8.44-8.38 (m, 1H), 7.66-7.57 (m, 3H), 7.34-7.29 (m, 1H), 7.24-7.14 (m, 4H), 4.82-4.79 (m, 2H), 4.08-4.03 (m, 1H), 3.99 (s, 4H), 3.60-3.55 (m, 1H), 3.46-3.40 (m, 1H), 2.91-2.85 (m, 1H), 2.8-2.78 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[N:29]1([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[NH2:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH:38][CH2:37][CH2:36][CH2:35][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:6])=[C:2]([F:1])[CH:10]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: NCCCN1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O=C(Cl)c1ccccc1
Product: Nc1ccc(C(=O)NCCCN2CCOCC2)c(F)c1

Procedure:
Anilines with other sidechains will be readily prepared by a person having ordinary skill in the art having regard to that skill and this disclosure, and will be usable in the syntheses of Reaction Scheme 4. For example, diethyl (4-nitrobenzyl)phosphonate was reacted in a Wittig reaction with pyridin-3-carboxaldehyde and the resulting 3-(4-nitrostyryl)pyridine hydrogenated to give 4-[2-(pyridin-3-yl)ethyl]benzenamine, used to synthesize compound 99A, and the anilines used to synthesize compounds 97A and 98A were similarly prepared; 4-nitrobenzaldehyde was reacted with glyoxal and ammonia to give 2-(4-nitrophenyl)-1H-imidazole, which was N-methylated with methyl iodide and then reduced with stannous chloride to give 4-(1-methyl-1H-imidazol-2-yl)benzenamine, used to synthesize compound 106A; 2-fluoro-4-nitrobenzoic acid was converted to the corresponding benzoyl chloride with oxalyl chloride, then reacted with 3-(morpholin-4-yl)propan-1-amine and reduced to give 4-amino-2-fluoro-N-[3-(morpholin-4-yl)propyl]benzamide, used to synthesize compound 50A; and 4-nitrobenzenesulfonyl chloride was reacted with 2-(morpholin-4-yl)ethan-1-amine and then reduced with stannous chloride to give 4-amino-N[2-(morpholin-4-yl)ethyl]benzenesulfonamide, used to synthesize compound 128A.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27](C=O)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][CH:8]([C:27]2[CH:30]=[CH:31][C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:25][CH:26]=2)[O:7][C:1](=[O:6])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C(O)CC(c2ccc(OCc3ccccc3)cc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 5.0 mL of methyl acetoacetate, 2.0 g of NaH 60% dispersion in oil, 25 mL of 2.0M n-butyl lithium in hexane, 12.0 g of 4-benzyloxybenzaldehyde and 150 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 165°-166° C). 1H NMR (CDCl3) δ 2.91 (dd, 2 H), 3.56 (dd, 2 H), 5.09 (s, 2 H), 5.65 (dd, 1 H), 6.98-7.04 (m, 2 H), 7.30-7.44 (m, 7 H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-].[Li+].Cl>CO>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:16]([CH:15]=[N:14][C:11]2[NH:10][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=2)[CH2:17][CH2:18]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)c1cccc2[nH]c(NCC3CCN(C(=O)OC(C)(C)C)CC3)nc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(C=Nc2nc3c(C(=O)O)cccc3[nH]2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
After dissolving 2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylic acid methyl ester (5.47 g, 14.1 mmol) in methanol (60 ml), an aqueous lithium hydroxide solution (4 mol/L, 20 ml, 80 mmol) was added and the mixture was stirred at 50° C. overnight. The reaction mixture was cooled in an ice bath, and 6N hydrochloric acid (5 ml) was added dropwise. Stirring was continued for 1 hour in an ice bath while gradually adding 1N hydrochloric acid to adjust the pH to approximately 7.5. The precipitate was filtered out and washed with ethyl acetate and water. It was then dried under reduced pressure to obtain 2-[(1-tert-butoxycarbonyl-piperidin-4-ylmethlyl)-amino]-1H-benzimidazole-4-carboxylic acid. The compound was identified by LC-MS.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:17])[CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][C:4]=1[NH2:18].[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[C:19]([NH:27][C:28]([NH:18][C:4]1[CH:5]=[C:6]([N:9]([CH3:17])[CH2:10][CH:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1ccc(N(C)CC2CCOCC2)cc1N
Solvent: CC(C)=O
Product: COc1ccc(N(C)CC2CCOCC2)cc1NC(=S)NC(=O)c1ccccc1
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a stirred solution of 1.70 g (6.8 mmol) 4-methoxy-N1-methyl-N1-(tetrahydro-pyran-4-ylmethyl)-benzene-1,3-diamine in 30 ml acetone was added dropwise 1.0 ml (7.50 mmol) benzoyl isothiocyanate and stirring continued for 1 h at room temperature. The mixture was then concentrated in vacuo and the residue subjected to column chromatography (1/1 hexane/ethyl acetate) to afford 2.0 g (71%) 1-benzoyl-3-{2-methoxy-5-[methyl-(tetrahydro-pyran-4-ylmethyl)-amino]-phenyl}-thiourea as a yellow oil. ES-MS m/e (%): 436 (M+Na+, 13), 414 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15](Br)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([CH:29]=[O:30])[CH:21]=1>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.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].C(Cl)Cl.COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][C:22]=2[CH:29]=[O:30])=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(Br)[nH]1
Reactant: O=Cc1cc(Cl)ccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Cl)cc2C=O)[nH]1
Temperature: 85 °C
Reaction time: 4 h
Yield: 77.9 %

Procedure:
2-(5-Bromo-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.00 g, 6.32 mmol), 4-Chloro-2-formyl-phenylboronic acid (1.17 g, 6.32 mmol), Pd(PPh3)4 (365 mg, 0.316 mmol), Pd(dppf)Cl2-DCM (258 mg, 0.316 mmol) K2CO3 (2 M, 6.3 mL, 12.6 mmol) and DME (30 mL) were combined in a round bottom flask. The stirred suspension was degassed for 10 minutes with bubbling N2 then heated to 85° C. After 4 h, the reaction mixture was poured into saturated aqueous NaHCO3. The aqueous phase was extracted 3× with EtOAc and the combined organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (25% to 75% EtOAc/Hexane) to afford the title compound 2-[5-(4-Chloro-2-formyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.85 g, 78%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[C:12]([F:19])=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[F:27][C:28]([F:43])([F:42])[C:29]([N:31]1[CH2:36][C:35]2([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[O:34][CH2:33][CH2:32]1)=[O:30].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.O>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[C:12]([F:19])=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][N:39]1[CH2:40][CH2:41][C:35]2([O:34][CH2:33][CH2:32][N:31]([C:29](=[O:30])[C:28]([F:27])([F:42])[F:43])[CH2:36]2)[CH2:37][CH2:38]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(C=O)c1F
Reactant: O=C(N1CCOC2(CCNCC2)C1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(CN2CCC3(CC2)CN(C(=O)C(F)(F)F)CCO3)c1F
Reaction time: 0.08 h

Procedure:
3-(2-(tert-Butyldimethylsilyloxy)ethyl)-2-fluorobenzaldehyde (example 78, step b) (2.159 g) was added to stirred solution of 2,2,2-trifluoro-1-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)ethanone trifluoroacetate (example 12, step d) (2.80 g) and acetic acid (0.438 mL) in NMP (25 mL). After 5 minutes, sodium triacetoxyborohydride (3.24 g) was added. After 16 h, water was added and the mixture partitioned between water (250 mL) and ethyl acetate (250 mL). The ethyl acetate solution was washed with water (3×250 mL) and brine, then evaporated to dryness. Purification by silica gel chromatography eluting with 20:1:1, isohexane:ethyl acetate:triethylamine gave the subtitled compound as a gum. Yield 2.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]2[O:8][C:9]3[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=3[C:11]=2[S:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:4][CH:3]=1.[CH2:28]([N:30]([CH2:35][CH3:36])[CH2:31][CH2:32][CH2:33]Cl)[CH3:29]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]2[O:8][C:9]3[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=3[C:11]=2[S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:33][CH2:32][CH2:31][N:30]([CH2:35][CH3:36])[CH2:28][CH3:29])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(O)cc1)c1c(Cc2ccc(Cl)cc2)oc2ccccc12
Reactant: CCN(CC)CCCCl
Product: CCN(CC)CCCOc1ccc(S(=O)(=O)c2c(Cc3ccc(Cl)cc3)oc3ccccc23)cc1

Procedure:
Reaction of 2-(4-chlorobenzyl)-3-(4-hydroxyphenylsulfonyl)benzofuran with 3-diethylaminopropyl chloride by procedures described hereinabove gives the title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[N:19]=[C:18]([CH:27]([CH3:29])[CH3:28])[CH:17]=2)=[CH:12][CH:11]=1.O>CN(C=O)C>[Br:1][C:17]1[C:18]([CH:27]([CH3:29])[CH3:28])=[N:19][N:20]([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1cc(-c2ccc(F)cc2)n(-c2ncccn2)n1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nn(-c2ncccn2)c(-c2ccc(F)cc2)c1Br
Temperature: 25 °C
Yield: 82.6 %

Procedure:
N-Bromosuccinimide (9.97 g, 0.056 mol) was added to a solution of 2-[5-(4-fluorophenyl)-3-(l-methylethyl)-1H-pyrazol-1-yl]pyrimidine (15.8 g, 0.056 mol) in DMF at 0° C. The resulting mixture was allowed to warm to room temperature over 24 hours. This was then poured into 500 mL water. The white solid which precipitated was collected by filtration and dried to yield 16.7 g of 2-[4-bromo-5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]pyrimidine (3), mp 130°-133° C.
Reaction SMILES: [Na+:1].[Na+].[Na+].[NH2:4][C:5]1[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]2[C:14]=1[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:10]2.[OH-].[Na+].[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].Cl>O.C(OCC)C>[Na+:1].[Na+:1].[Na+:1].[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH:4][C:5]2[CH:6]=[C:7]([S:23]([O-:26])(=[O:25])=[O:24])[CH:8]=[C:9]3[C:14]=2[C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:12][C:11]([S:19]([O-:22])(=[O:20])=[O:21])=[CH:10]3)=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(Nc1cc(S(=O)(=O)[O-])cc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c12)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h
Yield: 238.6 %

Procedure:
To a solution of 27.0 g of 8-amino-1,3,6-naphthalenetrisulfonic acid trisodium salt in 100 ml of water and 60 ml of N sodium hydroxide is added 22.5 g of p-nitrobenzoyl chloride and 30 ml of diethyl ether. The reaction mixture is shaken in a separatory funnel for about 15 minutes, and another 60 ml portion of base is added. After shaking for 15 minutes the procedure is repeated with two additional 60 ml portions of base. The reaction mixture is acidified with 7.5 ml of concentrated hydrochloric acid and diluted with 250 ml of water, then extracted 9 times with 300 ml portions of ether. The aqueous phase is neutralized with 5 N sodium hydroxide and allowed to stand overnight at room temperature, then is filtered through diatomaceous earth. The filtrate is concentrated to a low volume in vacuo at 55°-60° C. The crystalline solid formed is collected by filtration, washed and slurried with absolute ethyl alcohol to yield 28.6 g of 8-(p-nitrobenzamido)-1,3,6-naphthalenetrisulfonic acid trisodium salt.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[C:3]1=[N:35]NC1C=CC=CC=1>C(O)(=O)C.[Zn]>[NH2:35][CH:3]1[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:4]1=[O:34]
Reactant: COc1ccc(N(C(=O)Cn2c(=O)c(=NNc3ccccc3)c(=O)n(-c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(N(C(=O)CN2C(=O)C(N)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a stirred solution of 2-[2,4-dioxo-5-phenyl-3-(phenyl-hydrazono)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepine-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (4.28 g) in acetic acid (50 mL) at ambient temperature, was added zinc dust (4.11 g) and stirred three hours. The zinc was filtered off, the filtrate concentrated in vacuo, and the resultant oil partitioned between water (60 mL) and ethyl acetate (100 mL). The pH was adjusted to 8 with 6N sodium hydroxide and the phases separated. The aqueous phase was extracted with ethyl acetate (2×75 mL) and the organics combined, dried with magnesium sulfate, filtered and concentrated in vacuo to give a yellow foam. The crude product was purified via flash chromatography on silica gel (80 g) eluted successively with ethyl acetate (260 mL) (to remove impurity) and methylene chloride/methanol (19:1, 200 ml) (to elute product). Appropriate fractions were combined and concentrated to give the title compound (2.58 g) as a yellow foam.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH:5]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:6][CH:7]([CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[CH:16]=[C:15]2[CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH:8]([CH3:10])[CH3:9])[OH:4].C(=O)([O-])[O-].[Na+].[Na+].[C:41](Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43].O>C(OCC)(=O)C>[CH3:43][C:42]([CH3:45])([CH3:44])[C:41]([NH:1][CH2:2][CH:3]([CH:5]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:6][CH:7]([CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[CH:16]=[C:15]2[CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH:8]([CH3:9])[CH3:10])[OH:4])=[O:46]
Reactant: COCCCc1cn(C)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CN)C(C)C)cc12
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COCCCc1cn(C)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CNC(=O)C(C)(C)C)C(C)C)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The stirred solution of 0.035 g of tert-butyl {1-(2-amino-1-hydroxyethyl)-3-[3-(3-methoxypropyl)-1-methyl-1H-indol-5-ylmethyl]-4-methylpentyl}carbamate in 0.60 ml of ethyl acetate is admixed successively with 0.60 ml of 2M sodium carbonate solution and 0.012 ml of pivaloyl chloride and stirred at room temperature over a further 1 hour. The reaction solution is admixed with water and extracted with ethyl acetate (2×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([C:18]([OH:20])=O)=[C:8]2[N:3]1[CH:4]=[CH:5][C:6]1[CH:23]=[CH:22][S:21][C:7]=12.S(Cl)(Cl)=O.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[Cl-].[Na+]>O1CCOCC1.O>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:18]([C:9]2[CH:10]=[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:2](=[O:1])[N:3]3[C:8]=2[C:7]2[S:21][CH:22]=[CH:23][C:6]=2[CH:5]=[CH:4]3)=[O:20])[CH2:31][CH2:30]1
Reactant: O=C(O)c1cc(-c2ccccc2)c(=O)n2ccc3ccsc3c12
Reactant: CN1CCNCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CN1CCN(C(=O)c2cc(-c3ccccc3)c(=O)n3ccc4ccsc4c23)CC1
Temperature: 25 °C

Procedure:
1.93 g of 7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylic acid were converted into the acid chloride with 2.65 ml of thionyl chloride as described. This acid chloride was taken up in 80 ml of dioxane, treated with 2.7 ml of N-methylpiperazine, and the mixture was then stirred at room temperature until the reaction was completed and poured into 200 ml of water. The aqueous phase was saturated with sodium chloride and extracted several times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. By recrystallization from toluene there was obtained 1-methyl-4-[(7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizin-10-yl)carbonyl]piperazine as yellow crystals of m.p. 233°-234° (dec.).