Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[N:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[C:6]=1[C:25]1[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=1)=[O:4].[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][C:41]=1[Cl:42]>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][C:39]3[CH:38]=[CH:37][C:36]([Cl:35])=[C:41]([Cl:42])[CH:40]=3)[CH:12]=2)[N:7]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=2)[C:6]=1[C:25]1[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:30]=1)=[O:4]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(-c2c(C(=O)OC)c3cc(O)ccc3n2-c2ccc(OC(C)C)cc2)cc1
Product: COC(=O)c1ccc(-c2c(C(=O)OC)c3cc(Oc4ccc(Cl)c(Cl)c4)ccc3n2-c2ccc(OC(C)C)cc2)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 5-hydroxy-1-(4-isopropoxyphenyl)-2-(4-methoxycarbonylphenyl)indole-3-carboxylic acid methyl ester (150 mg, 0.32 mmol, see step (b) Example 43) and 3,4-dichlorophenylboronic acid (120 mg, 0.64 mmol). Yield 60 mg (32%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[CH:14][C:15]([OH:17])=[O:16])[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.CO.[N+](=[CH2:29])=[N-]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[CH:14][C:15]([O:17][CH3:29])=[O:16])[CH2:9][N:8]=[C:7]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:6]=2[CH:24]=1
Reactant: O=C(O)C=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
To a stirred suspension of 6.29 g. (0.017 mole) 7-chloro-2-[[1-carboxymethylene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine, methanol solvate, in 300 ml. of methylene chloride is slowly added an ethereal solution of diazomethane (9.27 ml., 0.22 mole) under nitrogen, at ambient temperature. After an hour, the solvent is removed in vacuo and the residue is recrystallized from ethyl acetate to give 3.20 g. of 7-chloro-2-[[1-(methoxycarbonyl)methylene]hydrazino]-5-phenyl-3H-1,4benzodizepine. The analytical sample is recrystallized from ethyl acetate-hexane.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[N:21]=[C:20]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:27]=[CH:26]4)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:4].C1COCC1.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C=O)C>[O:47]1[CH2:48][CH2:49][N:44]([CH2:2][C:3]([NH:5][C:6]2[CH:7]=[C:8]([C:12]3[N:21]=[C:20]([NH:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:27]=[CH:26]5)[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH:9]=[CH:10][CH:11]=2)=[O:4])[CH2:45][CH2:46]1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)CCl)c4)nc4ccccc34)ccc21
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)CN5CCOCC5)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-(2-chloroacetamido)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate (1.0 g, 1.89 mmol) in DMF:THF (3 mL:4 mL) was added morpholine (1.8 mL, 20.6 mmol). The reaction mixture was stirred at RT for 2.5 h. The reaction mixture was concentrated in vacuo to remove volatiles. The residue was poured into ice-water and the resulting white solid was filtered and dried for several hours under high vacuum. The crude product re-crystallized using absolute EtOH to afford tert-butyl 5-(2-(3-(2-morpholinoacetamido)-phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (830 mg, 75%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[CH2:20](Cl)Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([N:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[C:10](=[O:12])[CH3:20])=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)N1CCCC1
Solvent: CO
Product: CC(=O)C(Cc1ccc(Cl)cc1)N1CCCC1

Procedure:
The title compound was prepared according to the procedure of Reference Example 10, Step C except that ethyl 3-(4-chlorophenyl)-2-(1-pyrrolidinyl)-propanoate (from Step A) was the ester used (two steps). TLC Rf=0.7 (95:5 CH2Cl2: MeOH). LC/MS m/e=252 (M+1). 500 MHz 1H NMR (CDCl3) δ 1.86(br s, 4H), 2.03 (s, 3H), 2.66 (m, 2H), 2.78 (m, 2H), 2.98 (dd, J=2.9, 10.3 Hz, 1H), 3.08 (m, 1H), 3.43 (m, 1H), 7.12 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H)
Reaction SMILES: C([Li])CCC.[CH3:6]CCCCC.[F:12][C:13]1[CH:25]=[C:24]([F:26])[C:23]2[C:22]3[C:17](=[CH:18][C:19]([F:28])=[CH:20][C:21]=3[F:27])[CH2:16][C:15]=2[CH:14]=1.[C:29](=[O:31])=[O:30]>[Au].CCOCC.C1COCC1>[F:12][C:13]1[CH:25]=[C:24]([F:26])[C:23]2[C:22]3[C:17](=[CH:18][C:19]([F:28])=[CH:20][C:21]=3[F:27])[CH:16]([C:29]([O:31][CH3:6])=[O:30])[C:15]=2[CH:14]=1
Reactant: Fc1cc(F)c2c(c1)Cc1cc(F)cc(F)c1-2
Reactant: CCCCCC
Reactant: O=C=O
Agent: [Au]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C1c2cc(F)cc(F)c2-c2c(F)cc(F)cc21
Reaction time: 0.33 h
Yield: 57 %

Procedure:
Under nitrogen, n-butyllithium (5.6 mL of a 2.5M hexane solution) was added dropwise, to a -78° C. solution of the 2,4,5,7-tetrafluorofluorene in gold label THF (80 mL) over 2 min. After 20 min, the mixture was poured onto a slurry of dry-ice (10 g) in anhydrous ether. The solvents were evaporated and the residue was dissolved in methanol (200 mL) and acidified with acetyl chloride (5 mL). After stirring for 18 h, the reaction was concentrated and the residue was diluted with saturated aqueous sodium bicarbonate (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organics were washed with brine (3×100 mL), dried (MgSO4), and evaporated. The residue was chromatographed on silica gel using petroleum ether to provide 2.1 g (57%) of product: 1H NMR (DMSO-d6, 200 MHz) δ 7.44 (dd, 2 H, J=2.2 and 8.3 Hz), 7.40-7.25 (m, 2 H), 5.37 (s, 1 H), 3.76 (s, 3 H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:21]2[C:16]([C:17]([NH2:22])=[N:18][CH:19]=[N:20]2)=[CH:15][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:23]N1C(C)(C)C(=O)N(Br)C1=O>O1CCCC1>[Br:23][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[N:21]2[C:16]=1[C:17]([NH2:22])=[N:18][CH:19]=[N:20]2
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1ccc2c(N)ncnn12
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCc1cc(Br)c2c(N)ncnn12
Temperature: -20 °C
Reaction time: 2 h
Yield: 180.2 %

Procedure:
To a cooled (−20° C.) solution of 7-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (5.60 g, 17.5 mmol) in tetrahydrofuran (85 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (2.50 g, 8.74 mmol) in four portions over 15 min. The mixture was allowed to stir (−20° C.) for 2 h. The reaction was quenched with the addition saturated aqueous Na2SO3 solution and was allowed to warm to rt. The mixture was extracted with ethyl acetate (3×75 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated to dryness. The crude material was purified by MPLC chromatography using a gradient of 50% to 75% ethyl acetate in hexanes to afford 6.29 g (90%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.80 (s, 1H), 6.58 (s, 1H), 3.56 (t, 2H), 2.81 (t, 2H), 1.72-1.61 (m, 2H), 1.51-1.42 (m, 2H), 0.83 (s, 9H), 0.00 (s, 6H); ES-MS m/z 399.2 [M+H]+, HPLC RT (min) 3.72.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][NH:10][CH:11]([C:14]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](=[O:31])[C:21]2[C:16](=[CH:17][C:18]([Cl:32])=[CH:19][CH:20]=2)[N:15]=1)[CH2:12][CH3:13])(C)(C)C.C(N1[C:50](=[O:51])[C:49]2C(=CC(Cl)=CC=2)N=C1C(Br)CC)C1C=CC=CC=1.C(OC(=O)NCCN)(C)(C)C.C(=O)(O)[O-].[Na+]>CCO>[CH2:24]([N:23]1[C:22](=[O:31])[C:21]2[C:16](=[CH:17][C:18]([Cl:32])=[CH:19][CH:20]=2)[N:15]=[C:14]1[CH:11]([N:10]1[C:50](=[O:51])[CH2:49][CH2:6][NH:7][CH2:8][CH2:9]1)[CH2:12][CH3:13])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCC(Br)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: CCC(NCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCC(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCCC1=O

Procedure:
Preparation of {2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-propylamino]-ethyl}-carbamic acid tert-butyl ester: A mixture of 3-benzyl-2-(1-bromo-propyl)-7-chloro-3H-quinazolin-4-one (3.9 g, 10 mmol) (WO 0130768), (2-amino-ethyl)-carbamic acid tert-butyl ester (2.40 g, 15 mmol) and sodium bicarbonate (1.26 g, 15 mmol) in EtOH (50 mL) was refluxed overnight. The salts were removed by filtration and the filtrate was concentrated to dryness. The residue which remained was purified by flash chromatography on silica gel (10–15% EtOH in hexane) to give the title compound (2.90 g) as a white solid: MS (ES) m/e 471.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].C([O:10][C:11](=[O:23])[C:12]1[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:13]=1[NH2:22])C>N1C=CC=CC=1.[OH-].[Na+]>[OH2:7].[CH2:1]([N:5]1[C:11](=[O:10])[C:12]2[C:13](=[CH:14][CH:15]=[C:16]([O:20][CH3:21])[C:17]=2[O:18][CH3:19])[NH:22][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:1]([N:5]1[C:11](=[O:23])[C:12]2[C:13](=[CH:14][CH:15]=[C:16]([O:20][CH3:21])[C:17]=2[O:18][CH3:19])[NH:22][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)c1c(N)ccc(OC)c1OC
Reactant: CCCCN=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCCCn1c(=O)[nH]c2ccc(OC)c(OC)c2c1=O
Product: O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To n-butyl isocyanate (2.06 g, 2.34 ml, 20.8 mM) in pyridine (9.2 ml) at 0° C. was added a cold solution of 2-amino-5,6-dimethoxybenzoic acid ethyl ester (3.0 g, 13.3 mM) in pyridine (16.7 ml). The solution was stirred at 0° C. for thirty minutes, then kept at room temperature for one hour. The mixture was concentrated to dryness to give an off-white solid. This was dissolved in 69.9 ml of 1N NaOH (4:1 MeOH-H2O) and heated at reflux for 2 hours. The solvent was removed in vacuo and the residue dissolved in H2O (150 ml). The mixture was taken to pH 6 with acetic acid and the resulting white solid filtered, washed with H2O (50 ml) and dried to afford the title compound as a white solid; 2.38 g (64.3%); mp 159°-161° C.; CDCl3 (TMS) 7.21 (d, 1H, J7,8 =9.0 Hz, 7-H), 6.82 (d, 1H, J8,7 =9.0 Hz, 8-H), 4.10 (t, 2H, J9,10 =7.0 Hz, 9-H), 3.95 (s, 3H, 5 or 6-OCH3), 3.85 (s, 3H, 5 or 6-OCH3), 0.80-2.10 (m, 7H, 10-H, 11-H, 12-H), M+ 278.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[N:21]=[C:20]([N:22]3[CH2:27][C@@H:26]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][C@@H:24]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:23]3)[N:19]=[C:18]([N:44]3[CH2:49][C@@H:48]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][C@@H:46]([NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:45]3)[N:17]=2)[CH:12]=[CH:11][C:10]=1[NH2:66])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:67][C:68]1[CH:79]=[CH:78][C:71]2[C:72](=O)[O:73]C(=O)[O:75][C:70]=2[CH:69]=1>CN1C(=O)CCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[N:21]=[C:20]([N:22]3[CH2:27][C@@H:26]([NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:25][C@@H:24]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:23]3)[N:19]=[C:18]([N:44]3[CH2:45][C@@H:46]([NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:47][C@@H:48]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49]3)[N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:66][C:72](=[O:73])[C:71]1[CH:78]=[CH:79][C:68]([Cl:67])=[CH:69][C:70]=1[OH:75])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc(Nc3ccc(N)c(OCc4ccccc4)c3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)C1
Reactant: O=c1oc(=O)c2ccc(Cl)cc2o1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc(Nc3ccc(NC(=O)c4ccc(Cl)cc4O)c(OCc4ccccc4)c3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)C1
Temperature: 80 °C
Yield: 60 %

Procedure:
2-Benzyloxy-N4-(4,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl)-[1,3,5]triazin-2-yl)-benzene-1,4-diamine (83) (0.16 g, 0.174 mmol) and 7-chloro-benzo[1,3]dioxine-2,4-dione (91) (0.2 g, 1.0 mmol) were combined and dissolved in NMP (8 mL). The mixture was heated to 80° C. for 16 h. LC-MS indicated complete reaction at this point. The mixture was diluted with EtOAc (30 mL), washed with water (2×15 mL), saturated aqueous NaHCO3 (2×15 mL) and brine (2×15 mL) via extraction, dried over MgSO4 and concentrated to give a brown oil. Purification by flash chromatography on silica gel using a gradient of hexane and EtOAc (15–100% EtOAc in hexane) gave the desired product (92) as a yellow powder upon concentration (0.111 g, 0.103 mmol, 60% yield). LC-MS (ESI): (exact mass: 1073.51) m/e=1074.6 [M+1]+ (100%).
Reaction SMILES: CC(O)=O.[NH2:5][C@H:6]([CH3:9])[CH2:7][OH:8].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH3-]C#N.[Na+]>CO>[CH2:10]([NH:5][C@H:6]([CH3:9])[CH2:7][OH:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[C@@H](N)CO
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@H](CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.1 %

Procedure:
Glacial HOAc (1.5 mL) was added dropwise at room temperature to a well stirred solution of (R)-(+)-2-amino-1-propanol (10.0 g, 133 mmol) and benzaldehyde (13.5 mL, 133 mmol) in CH3OH (260 mL). The reaction mixture was stirred at room temperature for 1.5 h followed by addition of NaCNBH3 (12.6 g, 200 mmol) and the reaction stirred at room temperature overnight. The reaction was concentrated under reduced pressure and the recovered solids dissolved in EtOAc (500 mL) and then washed with saturated bicarbonate (2×250 mL), H2O (250 mL) and saturated brine (250 mL). The organic phase was then dried over Na2SO4, filtered and concentrated to yield (R)-2-(benzylamino)propan-1-ol (19.8 g, 94%) as a colorless oil: MS consistent.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[O:28]=[C:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH2:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1>>[O:28]=[C:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH2:34][C:35]1[CH:41]=[CH:40][C:38]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:37][CH:36]=1
Reactant: Nc1ccc(CN2CCCC2=O)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCC2=O)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(2-oxo-pyrrolidin-1-yl-methyl)-aniline Rf value: 0.3 (silica gel, methylene chloride/methanol=20:1) C28H25N3O4
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:29]C(=O)C)[NH:11][C:12]=2[C:13]2[CH:28]=[CH:27][C:16]3[N:17]([CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[C:18](=[O:21])[N:19]([CH3:20])[C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O>CO.O>[ClH:1].[NH2:29][C:10]1[NH:11][C:12]([C:13]2[CH:28]=[CH:27][C:16]3[N:17]([CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[C:18](=[O:21])[N:19]([CH3:20])[C:15]=3[CH:14]=2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:9]=1
Reactant: CC(=O)Nc1nc(-c2cccc(Cl)c2)c(-c2ccc3c(c2)n(C)c(=O)n3C2CCCC2)[nH]1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: Cl
Product: Cn1c(=O)n(C2CCCC2)c2ccc(-c3[nH]c(N)nc3-c3cccc(Cl)c3)cc21
Temperature: 25 °C
Yield: 139 %

Procedure:
To a stirred solution of N-[4-(3-chloro-phenyl)-5-(1-cyclopentyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-1H-imidazol-2-yl]-acetamide (prepared as described above, 102 mg) in methanol:water (1:1, 10 mL) was added concentrated sulfuric acid (ca. 0.5 mL). The mixture was heated to reflux for 4 hours, after which the reaction was cooled to room temperature and the concentrated in vacuo. The resulting aqueous solution was diluted with water and the pH was adjusted to 10 with aqueous ammonium hydroxide. The mixture was filtered and the resulting white powder was taken up in 1M HCl in ether and concentrated in vacuo to afford 70 mg of the title compound as the HCl salt. MS (M+1)=408.1 (free base).
Reaction SMILES: [Li+].[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:9]=[C:10]([C:12]([O-])=[O:13])[S:11][C:4]=12.S(Cl)(Cl)=O.[BH4-].[Na+]>CN(C=O)C.C(Cl)(Cl)Cl>[OH:13][CH2:12][C:10]1[S:11][C:4]2[C:5](=[N:6][CH:7]=[CH:8][C:3]=2[Cl:2])[CH:9]=1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: OCc1cc2nccc(Cl)c2s1
Reaction time: 2 h
Yield: 38.5 %

Procedure:
7-Chloro-thieno[3,2-b]pyridine-2-carboxylic acid lithium salt (2.0 g, 9.1 mmole) was dissolved in a solution of DMF (10 mL) and chloroform (50 mL). The carboxylate was treated with thionyl chloride (2.0 mL, 27.3 mmole) and refluxed for one hour. The resultant acid chloride was cooled to room temperature and added dropwise to a solution of sodium borohydride (0.7 g, 18.2 mmole) in DMF (10 mL) at 0° C. The temperature was allowed to reach room temperature over 2 hours and the reaction was quenched with concentrated HCl. The reaction mixture was neutralized with NaOH and the workup was performed with MTBE, brine and MgSO4. The crude product was triturated with MTBE, which provided the title compound as a beige solid (0.7 g, 40%): 1H-NMR (DMSO-d6, 400 MHz) δ 8.58 (1H, d, J=5.1 Hz), 7.51 (1H, d, J=5.1 Hz), 7.47 (1H, s), 5.94 (1H, t, J=5.8 Hz), 4.84–4.82 (2H, m); MS m/z 200 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH2:10][C@H:9]4[CH2:15][C@@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[N:2]1>C(Cl)Cl.O=[Mn]=O>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[CH:13][C:12]3[NH:11][CH:10]=[C:9]4[CH2:15][C@@H:16]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:17][C:7]=2[C:8]=34)=[N:2]1
Reactant: CCCN(CCC)[C@H]1Cc2c(-c3ccon3)ccc3c2[C@@H](CN3)C1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCCN(CCC)[C@@H]1Cc2c[nH]c3ccc(-c4ccon4)c(c23)C1
Yield: 30.9 %

Procedure:
A mixture of (+)(2aS,4R)-6-(3-isoxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (180 mg, 0.5 mmol) and 1 g of MnO2 in 40 mL of CH2Cl2 was sonicated at 50-55 KHz for 2 hr. The reaction mixture warmed to reflux during the time period. The reaction mixture was filtered through a celite pad and the filtrate was concentrated to dryness in vacuo. The residue was chromatographed (flash column, silica gel, ethyl acetate) to provide 50 mg of the isoxazole indole product as an oil. MS (FD) 323
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH2:29]CC#N)[CH2:25][CH2:24]3)=[O:22])[C:11]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:34]=3[O:43][CH2:44][CH3:45])=[N:10]2)=[CH:5][CH:4]=1.C(Cl)(Cl)=[O:47].[NH:50]1[CH2:55][CH2:54][NH:53][CH2:52][C:51]1=[O:56].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29]([N:53]4[CH2:54][CH2:55][NH:50][C:51](=[O:56])[CH2:52]4)=[O:47])[CH2:25][CH2:24]3)=[O:22])[C:11]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][C:34]=3[O:43][CH2:44][CH3:45])=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C1CNCCN1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCC#N)CC1
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)N2CCNC(=O)C2)CC1
Reaction time: 0.5 h

Procedure:
[4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone (50 mg, 0.085 mmol, example 8A) was dissolved in methylene chloride (1 mL) and cooled in an ice bath. Phosgene (250 uL, 20% solution in toluene)) was added, and the mixture was stirred for 30 min. The solvent was evaporated and the residue was taken in methylene chloride. One third of this solution (0.028 mmol) was treated with 2-piperazinone (8.5 mg) and diisopropylethylamine (15 ul). The mixture was sonicated to aid in dissolving the amine and allowed to stand at ambient temperature overnight. It was diluted with methylene chloride and washed with water. The organic portion was separated and evaporated to give the crude urea. Purification of the crude urea by flash chromatography (silica gel) using ethyl acetate and hexanes gave 4-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazine-1-carbonyl}-piperazin-2-one (9.0 mg). LR-MS: 718.4 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH:7]([OH:29])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[O:28])[CH2:17][CH2:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2)([CH3:4])[CH3:3].[Cl:30]N1C(=O)CCC1=O.C(O)(=O)C.[OH-].[Na+]>O>[Cl:30][C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[CH:27][C:19]=2[CH2:18][CH2:17][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH:7]([OH:29])[CH2:6][NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:28])[NH:23][CH:22]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)NCC(O)COc1ccccc1C(=O)CCc1cccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)NCC(O)COc1ccccc1C(=O)CCc1cccc2[nH]cc(Cl)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
A mixture of 8.6 g of 1-[2-[3-(1,1-dimethylethylamino)-2-hydroxypropoxy]-phenyl]-3-(1H-indol-4-yl)-1-propanone, 3 g of N-chlorosuccinimide and 170 ml of acetic acid was stirred at room temperature for 2 hours and was then diluted with water. The mixture was made alkaline by addition of sodium hydroxide and was extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica and eluted with a 6-3-1 chloroform-acetone-triethylamine mixture to obtain 6.37 g of 3-(3-chloro-1H-indol-4-yl)-1-[2-[3-(1,1-dimethylethylamino)-2-hydroxypropoxy]-phenyl]-1-propanone.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]1[C:10](/[CH:11]=[C:12]2\[CH2:13][N:14](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:15][CH2:16][CH:17]\2O)=[N:9][N:8]=[N:7]1)=[O:4].[C:38]([OH:41])(=[S:40])[CH3:39].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61]>ClCCl>[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61].[C:38]([S:40][CH:17]1[CH2:16][CH2:15][NH:14][CH2:13]/[C:12]/1=[CH:11]\[C:10]1[N:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[N:7]=[N:8][N:9]=1)(=[O:41])[CH3:39]
Reactant: COC(=O)Cn1nnnc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Reactant: CC(O)=S
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Cn1nnnc1/C=C1\CNCCC1SC(C)=O
Yield: 27 %

Procedure:
Following a procedure similar to that described in Example 150-(e), (E)-3-{[1-(methoxycarbonylmethyl)-1H-tetrazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (1.5 g) was subjected to the reaction with thioacetic acid and N,N-dimethylformamide dineopentyl acetal. The product was purified by silica gel chromatography to afford (E)-4-(acetylsulfanyl)-3-{([1-(methoxycarbonylmethyl)-1H-tetrazol-5-yl]methylidene}-1-(triphenylmethyl)piperidine (980 mg). This product was similarly treated with trifluoroacetic acid in dichloromethane, and the resulting product was purified by silica gel chromatography using dichloromethane and methanol (20:1) as an eluent to afford the title compound (342 mg, overall yield: 27%) as a yellow amorphous solid.