Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH2:21][NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[O:20][C:1](=[O:2])[N:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][C:16]=2[CH:15]=1
Reactant: Oc1ccc(Br)cc1CNc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C1Oc2ccc(Br)cc2CN1c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 99.6 %

Procedure:
Step 2 Carbonyldiimidazole (0.874 g, 5.39 mmol) and DMAP (0.088 g, 0.719 mmol) were added to a solution of 4-bromo-2-((phenylamino)methyl)phenol (1.00 g, 3.60 mmol) in DCM (100 mL) and the resulting mixture was stirred at rt for 60 h. The mixture was diluted with hexanes (100 mL), washed with NaHCO3 (aq) (2×25 mL), 1 M hydrochloric acid (25 mL) and brine (25 mL), dried and filtered through a pad of silica gel. The solids were rinsed with 1:1 EtOAc-hexane and the filtrate was concentrated to give 6-bromo-3-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one as a white solid (1.09 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 7.41-7.56 (3 H, m), 7.30-7.41 (3 H, m), 7.21-7.29 (1 H, m), 7.01 (1 H, d, J=8.80 Hz), 4.80 (2 H, s). Mass spectrum m/z 304, 306 (M+H)+.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1[OH:17].[OH-].[K+]>C(O)C>[C:11]1([C:9]2[CH:8]=[CH:7][C:6]3[O:17][C:1](=[S:3])[NH:4][C:5]=3[CH:10]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: S=C=S
Reactant: Nc1cc(-c2ccccc2)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: S=c1[nH]c2cc(-c3ccccc3)ccc2o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Carbon disulfide (7.7 mL) was added to a mixture of 2-amino-4-phenylphenol (1.0 g, 5.4 mmol), potassium hydroxide (0.36 g, 6.5 mmol) and ethanol (11.7 mL). The flask was fitted with a reflux condenser and the resulting mixture was placed in an oil bath at 60° C. for 16 h. After cooling to RT, the mixture was concentrated and ethyl acetate (20 mL) and 1 M hydrochloric acid (10 mL) were added to the residue. The layers were partitioned and the organic layer was washed successively with 1 M HCl, water and brine. The organic layer was dried (Na2SO4), filtered and concentrated to afford 1.20 g (98%) which was used without further purification: 1H NMR (d6-DMSO, 400 MHz) δ 13.98 (s, 1H), 7.64-7.62 (m, 2H), 7.58-7.49 (m, 2H), 7.46-7.42 (m, 2H), 7.39-7.33 (m, 2H); 13C (d6-DMSO, 400 MHz) δ 181.2, 148.2, 140.1, 138.5, 132.7, 129.7, 128.3, 127.7, 123.4, 111.0, 109.1; MS (Cl) m/z 228.1 (M+1); HPLC retention time=3.09 min.
Reaction SMILES: COC1C=CC(C[O:8][C@H:9]([C@H:63]([O:78]CC2C=CC(OC)=CC=2)[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77])[C@@H:10]([N:52]2[CH:56]=[C:55]([CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[N:54]=[N:53]2)[CH2:11][O:12][C@@H:13]2[C@H:18]([O:19]CC3C=CC=CC=3)[C@@H:17]([O:27]CC3C=CC=CC=3)[C@@H:16]([O:35]CC3C=CC=CC=3)[CH:15]([CH2:43][O:44]CC3C=CC=CC=3)[O:14]2)=CC=1.[H][H]>C(O)C.C(Cl)Cl.[OH-].[OH-].[Pd+2]>[CH2:57]([C:55]1[N:54]=[N:53][N:52]([C@H:10]([C@H:9]([OH:8])[C@H:63]([OH:78])[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH3:77])[CH2:11][O:12][C@@H:13]2[C@H:18]([OH:19])[C@@H:17]([OH:27])[C@@H:16]([OH:35])[CH:15]([CH2:43][OH:44])[O:14]2)[CH:56]=1)[CH2:58][CH2:59][CH2:60][CH2:61][CH3:62]
Reactant: CCCCCCCCCCCCCC[C@@H](OCc1ccc(OC)cc1)[C@@H](OCc1ccc(OC)cc1)[C@H](CO[C@H]1OC(COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)n1cc(CCCCCC)nn1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@H](CO[C@H]1OC(CO)[C@H](O)[C@H](O)[C@H]1O)n1cc(CCCCCC)nn1
Reaction time: 0.17 h
Yield: 80 %

Procedure:
The compound (1.0 eq.) obtained in Step 1 was dissolved in a mixed solvent of ethylalcohol/methylene chloride (3:1, 0.01˜0.1 M) to which Pd(OH)2 (500 massa) was then added. The resulting reaction mixture was stirred for 5˜8 hrs at room temperature under 1 atm of hydrogen gas. After the filtration of the metal catalyst through a Celite pad, the reaction mixture was washed with a solution of ethylalcohol/methylene:chloride (3:1). After two rounds of centrifugation at 1000 rpm for 10 min, the supernatant was concentrated and dried in a vacuum. The concentrate was precipitated in a mixed solvent of hexane/ethyl acetate (1:1) to afford the object compound as a white wax solid (24 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:20]4[CH:24]=[CH:23][O:22][CH:21]=4)=[O:19])[CH:16]=3)[NH:11][C:10](=[O:25])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:29].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:20]4[CH:24]=[CH:23][O:22][CH:21]=4)=[O:19])[CH:16]=3)[N:11]([CH3:29])[C:10](=[O:25])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccoc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccoc3)ccc21
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 9.6 %

Procedure:
A mixture of (intermediate 26) (0.04 mol) in DMF (200 ml) was cooled to 5° C. under N2 flow. NaH 80% in oil (0.048 mol) was added portionwise. The mixture was stirred at 5° C. for 30 min. Then iodomethane (0.048 mol) was added dropwise. The mixture was stirred at 5° C. for 30 min, hydrolized and poured out into water. The precipitate was filtered off, washed with water and taken up in CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (15.5 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/EtOAc 85/15; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue (13.3 g, 91.7%) was crystallized from CH3CN and DIPE. The precipitate was filtered off and dried, yielding 1.5 g (9.6%) of 4-(3-chlorophenyl)-6-(3-furanylcarbonyl)-1-methyl-2(1H)-quinolinone (intermediate 27), melting point 192° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=2[F:27])[CH:14]=[CH:13][N:12]=1)=[O:9])[CH3:2].O1CCCC1>CO.[C].[Pd]>[CH2:28]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=2[F:27])[CH:14]=[CH:13][N:12]=1)=[O:9])[CH3:29]
Reactant: CCN(CC)CCCNC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CC)CCCNC(=O)Nc1cc(Oc2ccc(N)cc2F)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.3 %

Procedure:
To a solution of 1-(3-diethylaminopropyl)-3-[4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]urea (547 mg, 1.35 mmol) in methanol (40 ml)-tetrahydrofuran (20 ml) was added 10% palladium carbon (200 mg), followed by stirring under a hydrogen atmosphere at room temperature for 12 hrs. The catalyst was filtered and washed with methanol. The filtrate was concentrated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=10:1) to provide the titled compound (316 mg, 62.3%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].C([Li])CCC.[O:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1.O>C1COCC1>[Cl:1][C:2]1[C:3]([NH:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14])=[C:4]([C:25]2([OH:28])[CH2:26][CH2:27][O:22][CH2:23][CH2:24]2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: O=C1CCOCC1
Reactant: COc1ccc(Cl)c(NC(=O)C(C)(C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cl)c(NC(=O)C(C)(C)C)c1C1(O)CCOCC1
Temperature: -10 °C
Reaction time: 4 h
Yield: 18 %

Procedure:
To a stirred solution of intermediate 12 (1 g, 4.13 mmol) in THF (25 mL) under nitrogen at −20° C. was added dropwise n-butyllithium (2.5M in hexane, 4.13 mL, 10.34 mmol). The reaction mixture was stirred at −10° C. for 4 h and n-butyllithium (2.5M in hexane, 4.13 mL, 10.34 mmol) was added dropwise at −10° C. The mixture was further stirred for 7 h and tetrahydropyran-4-one was added dropwise at 0° C. The mixture was stirred overnight at room temperature, poured into water and extracted with EtOAc. The organic extracts were washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated. The crude material was purified by precipitation in EtOAc to afford intermediate 13 as a white powder (0.25 g, 18%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].[CH3:41][NH:42][CH2:43][CH3:44]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:39]([S:36]([N:33]1[CH2:34][CH2:35][CH:30]([C:21]2[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=[C:18]([C:15]4[CH:14]=[C:13]([CH2:12][N:10]([CH3:11])[CH2:8][CH2:9][C:43]5[CH:44]=[CH:3][CH:2]=[CH:41][N:42]=5)[S:17][CH:16]=4)[CH:19]=3)[NH:23][CH:22]=2)[CH2:31][CH2:32]1)(=[O:37])=[O:38])[CH3:40]
Reactant: CCNC
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CCc5ccccn5)c4)cc23)CC1
Yield: 7.36 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting methyl[2-(2-pyridinyl)ethyl]amine (75 mg, 1.0 mmol) for N-methylethanamine to afford 5.0 mg of the title compound (7.36%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH:11]1([S:14]([C:17]([C:20]2[CH:25]=[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]3[CH3:32])[N:23]=[C:22]([C:33]3[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=3)[N:21]=2)([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH:11]1([S:14]([C:17]([C:20]2[CH:25]=[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]3[CH3:32])[N:23]=[C:22]([C:33]3[CH:39]=[CH:38][C:36]([NH:37][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:35][CH:34]=3)[N:21]=2)([CH3:18])[CH3:19])(=[O:15])=[O:16])[CH2:13][CH2:12]1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C2CC2)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)C2CC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.1 %

Procedure:
Phenyl chloroformate (0.215 mL, 1.71 mmol) was added dropwise to 4-[4-(2-cyclopropylsulfonylpropan-2-yl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (712 mg, 1.71 mmol) and sodium bicarbonate (215 mg, 2.56 mmol) in dioxane (15 mL) under nitrogen. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was evaporated to dryness and redissolved in ethyl acetate (100 mL) and washed with water (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to give the desired material (983 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19]3[C:25]([C:26]([O:28]C)=O)=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH3:31]>CO>[C:26]([C:25]1[C:19]2[O:18][C:17]([CH:14]3[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:16][CH2:15]3)=[N:21][C:20]=2[CH:22]=[CH:23][CH:24]=1)(=[O:28])[NH2:31]
Reactant: N
Reactant: COC(=O)c1cccc2nc(C3CCN(C(=O)OCc4ccccc4)CC3)oc12
Solvent: CO
Solvent: O
Product: NC(=O)c1cccc2nc(C3CCN(C(=O)OCc4ccccc4)CC3)oc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-(1-(benzyloxycarbonyl)piperidin-4-yl)benzo[d]oxazole-7-carboxylate (102 mg, 0.26 mmol) was added to a mixture of methanol (5 mL) and ammonia water (10 mL) and the mixture was stirred at room temperature for overnight. Then the solid was filtered. 98 mg of solid of benzyl 4-(7-carbamoylbenzo[d]oxazol-2-yl)piperidine-1-carboxylate was obtained. LC-MS (ESI) m/z: 380 (M+1)+.
Reaction SMILES: [N:1]([C:4]1[N:5]=[C:6]([CH:17]2[CH2:19][CH2:18]2)[C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[N:9]([CH2:11][CH3:12])[CH:10]=1)=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[N:5]=[C:6]([CH:17]2[CH2:19][CH2:18]2)[C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[N:9]([CH2:11][CH3:12])[CH:10]=1
Reactant: [H][H]
Reactant: CCN1C=C(N=[N+]=[N-])N=C(C2CC2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CCN1C=C(N)N=C(C2CC2)c2ccccc21

Procedure:
To a stirred solution of 3-azido-5-cyclopropyl-1-ethyl-1H-benzo[e][1,4]diazepine (5.8 g, 21.5 mmol) in ethanol (500 mL) under argon was added 10% palladium on charcoal (1.0 gm). The argon was displaced with hydrogen and the mixture was vigorously stirred for 45 min (1 atm hydrogen). The reaction was filtered and the filtrate concentrated in vacuo to an oil (5.3 gm, 100%) which solidified upon standing. MP 93-95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([CH2:14]Cl)=[C:5]2[O:16][CH3:17].[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[C:6]([CH2:14][N:22]1[C:18](=[O:28])[C:19]3[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:21]1=[O:23])=[C:5]2[O:16][CH3:17]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1c(CCl)n(C)c(=O)c2ccc(Cl)cc12
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(CN2C(=O)c3ccccc3C2=O)n(C)c(=O)c2ccc(Cl)cc12
Yield: 51.4 %

Procedure:
A solution of 6-chloro-3-chloromethyl-4-methoxy-2-methyl-1(2H)-isoquinolinone (0.81 g, 3 mmol) and potassium phthalimide (0.83 g, 4.5 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 4 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-{(6-chloro-4methoxy-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione (0.59 g, 51.8%) as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:7]=[CH:8][C:9]=1[NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:27][C:28]#[N:29]>CN(C)C=O>[C:28]([CH2:27][N:13]1[CH2:14][CH2:15][C@@H:11]([NH:10][C:9]2[CH:8]=[CH:7][C:6]([S:16]([NH2:19])(=[O:17])=[O:18])=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:12]1)#[N:29]
Reactant: NS(=O)(=O)c1ccc(N[C@@H]2CCNC2)c([N+](=O)[O-])c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCN1CC[C@@H](Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])C1
Temperature: 60 °C

Procedure:
To a solution of EXAMPLE 428C (440 mg) in anhydrous N,N-dimethylformamide (10 mL) was added sodium carbonate (132 mg). To the resulting suspension was added 2-bromoacetonitrile (0.077 mL) and the mixture was heated at 60° C. for 18 hours. The crude material was isolated by concentration and was purified on silica gel, and was eluted with a 0.5, 2.5, and 5% methanol in methylene chloride step gradient to provide the title compound.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O.O>CCOCC.C([O-])(=O)C>[Br:14][C:3]1[CH:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: O
Product: Brc1ccc2[nH]c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76989.7 %

Procedure:
32 g (0.19 mmol) of 9H-carbazole was put into a 2 L Erlenmeyer flask, and then ether acetate (1.2 L) was added thereto so that the 9H-carbazole was dissolved in the ether acetate. To this solution was added 34 g (0.19 mol) of N-bromosuccinimide (NBS), and the mixture was stirred for about 15 hours in the air at room temperature. After the stirring, water was added to the mixture so that the precipitate was dissolved in the mixture. The organic layer of this mixture was washed with water three times and then with a saturated saline solution once. Magnesium sulfate was added so that the organic layer was dried. After the drying, the mixture was subjected to gravity filtration. The obtained filtrate was condensed to give a white solid. The obtained solid was recrystallized with ether acetate/hexane to give 36 g of a white powdered solid, which was the object of the synthesis, at a yield of 67%. A synthesis scheme of Step 1 is shown in (c-1) given below.
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[C:26](O)(=[O:30])[C:27]([CH3:29])=[CH2:28].C(N(CC)CC)C.C1(C)C(S(Cl)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[C:26]([O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13])(=[O:30])[C:27]([CH3:29])=[CH2:28]
Reactant: C=C(C)C(=O)O
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)Oc1c(Cc2cc(C)cc(C(C)(C)C)c2O)cc(C)cc1C(C)(C)C
Reaction time: 1 h
Yield: 94 %

Procedure:
To the same flask as used in Example 1 were added 340.51 g (1.0 mole) of 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 86.41 g (1.0 mole) of 98.5% methacrylic acid, 500 g of toluene and 242.86 g (2.4 moles) of triethylamine. After replacing the air in the container with nitrogen, 229.14 g (1.2 moles) of o-toluenesulfonyl chloride was added dropwise with stirring. After completion of the dropwise addition, the reaction solution was kept at 90° C. for 1 hour. Thereafter, the organic layer was washed with water until it became neutral, and toluene was removed under reduced pressure. The residue was recrystallized from n-hexane to obtain 384.1 g of a white crystalline 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monomethacrylate having a melting point of 144° to 146° C. Yield, 94%.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(OC(=O)C)(=O)C>>[C:23]([CH:15]1[CH2:16][C@@:17]2([CH3:18])[C@@H:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C@@H:3]2[O:2][CH3:1])[CH2:13][C:14]1=[O:22])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccccc1
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C(OC(=O)c1ccccc1)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)C(C(=O)c5ccccc5)C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Following the general procedure of U.S. Pat. No. 3,135,743, Example 12, but starting with 17β-methoxy-5α-androstan-3-one and using benzoic acid and benzoic acid anhydride in place of acetic acid and acetic anhydride, 2-benzoyl-17β-methoxy-5α-androstan-3-one is obtained.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][CH:9]([OH:12])[CH2:10][OH:11]>>[C:4]([NH:7][CH2:8][CH:9]([OH:12])[CH2:10][OH:11])(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: NCC(O)CO
Product: CC(=O)CC(=O)NCC(O)CO

Procedure:
Diketene is reacted at a temperature of about 25 to 35° C. with 1-amino-2,3-propane diol in an aqueous solution to produce 1-acetoacetamido-2,3-propane diol, as illustrated below: ##STR1##
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][C:4]([CH3:7])([NH2:6])[CH3:5].[C:9](ON1C(=O)CCC1=O)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>C(O)(C)C.O>[CH3:1][N:2]([CH3:8])[CH2:3][C:4]([NH:6][C:9](=[O:10])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:7])[CH3:5]
Reactant: CN(C)CC(C)(C)N
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CC(C)O
Solvent: O
Product: CN(C)CC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.3 %

Procedure:
N1,N1,2-Trimethylpropane-1,2-diamine (5.68 g, 48.8 mmol) was dissolved into isopropanol/water (1:1, 150 mL). To this solution was added CbzOSu (12.2 g, 1 equiv, 48.8 mmol) in one portion. The reaction was left to stir at room temperature overnight for 17 h. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (300 mL) and water (100 mL). The layers were separated and the organic layer extracted with water (2×100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to an oil. The crude oil was purified on an ISCO purification system with gradient elution from 2% methanol in DCM to 30% methanol in DCM. The desired fraction was collected and concentrated to give a colorless oil (8.95 g, yield: 73.2%). 1H NMR (CDCl3, 400 MHz): δ 1.41 (s, 6H), 2.51 (s, 2H), 2.98 (s, 2 H). LRMS (ESI+) for C14H22N2O2 (250.2); Found: 251 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:44](COCC[Si](C)(C)C)[CH:43]=[N:42][C:5]=2[C:6]([CH2:33][C:34]2[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:41])=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[C:12]([F:30])[C:11]=1[O:31][CH3:32])#[N:2].C(=O)(O)[O-:54].[Na+]>S(=O)(=O)(O)O.O>[Cl:40][C:39]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:41])[C:34]=1[CH2:33][C:6]1[C:5]2[N:42]=[CH:43][NH:44][C:4]=2[C:3]([C:1]([NH2:2])=[O:54])=[C:8]([NH:9][C:10]2[CH:15]=[C:14]([F:16])[C:13]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[C:12]([F:30])[C:11]=2[O:31][CH3:32])[N:7]=1
Reactant: O=C([O-])O
Reactant: COc1c(Nc2nc(Cc3c(Cl)cccc3Cl)c3ncn(COCC[Si](C)(C)C)c3c2C#N)cc(F)c(N2CCN(C(=O)OC(C)(C)C)CC2)c1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1c(Nc2nc(Cc3c(Cl)cccc3Cl)c3nc[nH]c3c2C(N)=O)cc(F)c(N2CCNCC2)c1F
Temperature: 95 °C

Procedure:
To a solution of the product of Example 52D (130 mg, 0.17 mmol) in concentrated sulfuric acid (5 mL) at 0° C. was added water (1 mL) and the mixture was heated at 95° C. for 20 minutes. After cooling to ambient temperature, the mixture was diluted with water (3 mL), adjusted to pH 8-9 with saturated sodium bicarbonate solution and extracted with dichloromethane (3×20 mL). The combined organic phase was concentrated and the residue was purified by preparative HPLC using a gradient of 10/90 to 80/20 acetonitrile/water (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 12.35 (s, 1 H), 9.61 (s, 1 H), 8.97 (s, 2 H), 8.66 (s, 1 H), 7.91 (s, 1 H), 7.74-7.66 (m 1 H), 7.56-7.53 (m, 2 H), 7.43-7.37 (m, 1 H), 4.77 (s, 2 H), 3.82 (s, 3 H), 3.21 (m, 8 H). MS: 562 (M+H+).