Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[N:11]([CH3:12])[C:10](=[O:13])[O:9][C:8](=O)[C:7]=2[CH:15]=1.Cl.[NH2:19][CH2:20]C(OC)=O.CC(O)=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:20][NH:19][C:8](=[O:9])[C:7]=2[CH:15]=1
Reactant: COC(=O)CN
Reactant: COc1cc2c(=O)oc(=O)n(C)c2cc1OC
Agent: Cl
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)N(C)C(=O)CNC2=O
Temperature: 130 °C
Yield: 71 %

Procedure:
Heat under reflux for 6 hours a mixture of 320 mg (1.35 mmol) of 6,7-dimethoxy-1-methyl-1,2-dihydro-4H-3,1-benzoxazine-2,4-dione (XVI), 452 mg (3.24 mmol) of methyl glycinate hydrochloride in 4 ml of pyridine. Add 3 ml of AcOH and heat at 130° C. for 12 hours. Evaporate to dryness. Add 10 ml of a water-ice mixture. Allow to crystallize at 0° C. for 30 minutes. Filter and wash twice with 2 ml of H2O, twice with 1 ml of EtOH and twice with 5 ml of Et2O. Recrystallize in EtOH. One obtains 240 mg of the abovenamed product in the form of colorless crystals. Yield: 71%. M: 260–263° C. 1H-NMR (CDCl3, 300 MHz): d 3.42 (s, 3H, NCH3), 3.75–3.92 (m, 2H, CH2), 3.98 (s, 6H, 2×OCH3), 6.39 (s, 1H exchangeable, NH), 6.69 (s, 1H Ar), 7.37 (s, 1H Ar).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3C[CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[C:12]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH2:3][CH2:2][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:29])[CH2:30][CH3:31])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cccc(OCCCCl)c1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: CCC(=O)Nc1cccc(C2CCN(CCCOc3cccc(C(C)=O)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-[3-(3-chloropropoxy)phenyl]ethanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 421.2 (M+H)+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:8]=1)=O.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([NH:33]N)=[CH:25][CH:24]=1>>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:33]([C:26]4[C:27]5[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:23]=[CH:24][CH:25]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: NNc1ccnc2ccccc12
Reactant: COc1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Product: COc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccnc4ccccc34)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methoxy-phenyl)-1H-pyridazin-4-one (A-5) and quinolin-4-yl-hydrazine according to the method described for example 91. MS: M=396.0 (M+H)+
Reaction SMILES: [CH:1]([C:3]1[CH:32]=[CH:31][C:6]([C:7]([NH:9][CH2:10][C:11](=[O:30])[N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:29])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH2:14][CH2:13]2)=[O:8])=[CH:5][CH:4]=1)=[O:2].S(=O)(=O)([OH:35])N.Cl([O-])=O.[Na+]>CC(C)=O.O.O>[O:30]=[C:11]([N:12]1[CH2:13][CH2:14][N:15]([C:18](=[O:29])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])[CH2:16][CH2:17]1)[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:31]=[CH:32][C:3]([C:1]([OH:35])=[O:2])=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1
Reactant: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
4-Formyl-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide (40 mg, 0.90 mmol) was dissolved in an acetone-water mixture (1:1, 0.9 mL) and cooled to 0° C. A mixture of sulphamic acid (26 mg, 0.27 mmol) and sodium chlorite (32 mg, 0.36 mmol) dissolved in minimum amount of water was then added. The resulting mixture was allowed to warm to room temperature and stirred for 30 minutes. 5 mL of water was then added, and the product was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulphate and concentrated to afford 25 mg (61% yield) of N-{2-Oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-terephthalamic acid. LCMS Purity: 95.8%, 1H NMR (DMSO-d6): δ 13 (bs, 1H). 8.8 (m, 1H), 8.1-7.9 (m, 4H), 7.9-7.8 (m, 1H), 7.8-7.7 (m, 1H), 7.7 (m, 1H), 7.6-7.5 (m, 1H), 4.3-4.1 (m, 4H), 3.6-3.4 (m, 8H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:22](OC=C)(=[O:24])[CH3:23].C(Cl)(Cl)Cl>COC(C)(C)C>[Si:1]([O:8][CH:9]1[CH2:13][CH:12]([O:14][C:22](=[O:24])[CH3:23])[CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=COC(C)=O
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CC(=O)OC1C=CC(O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 51.1 %

Procedure:
Cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (10.0 g, 46.6 mmol, prepared in example 3a) is dissolved in tert-butyl methyl ether (60 mL, anhydrous). To the solution is added triethylamine (4.5 mL, 32.3 mmol), pancreatin (30 g, available from Sigma Chemical Company), and vinyl acetate (22 mL, 239 mmol). The reaction is allowed to stir for 7 hours at room temperature. The reaction is then filtered through diatomaceous earth and the filtrate is concentrated under vacuum. The products are separated by chromatography on silica gel (5% to 20% ethyl acetate/hexane) to provide (-)-acetic acid 4-tert-butyldimethylsilyloxy-cyclopent-2-enyl ester (B. 6.1 g, 51% yield, 99% ee), [α]D -0.2°, (c=0.52, chloroform) as a yellow oil and (-)-cis-4-tert-butyldimethylsilyloxy-2-cyclopentenol (A, 4.7 g, 47% yield, >99% ee), [α]D -18.6°, (c=1.01, chloroform) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:10]([OH:11])=[C:9]([F:12])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]2=[O:13].CI.[C:20](=O)(O)[O-].[Na+]>CN(C)C=O>[Br:1][C:2]1[C:10]([O:11][CH3:20])=[C:9]([F:12])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]2=[O:13]
Reactant: CCCCC1Cc2c(cc(F)c(O)c2Br)C1=O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCCC1Cc2c(cc(F)c(OC)c2Br)C1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.6 %

Procedure:
A mixture of 4-bromo-2-butyl-6-fluoro-5-hydroxy-1-indanone (2.17 g, 7.23 mmol), N,N-dimethylformamide (14.5 mL), methyl iodide (0.675 mL, 10.84 mmol), and sodium bicarbonate (1.50 g, 18.1 mmol) was stirred at room temperature for 17 hours. The solvent was evaporated under vacuum. The residue in EtOAc (150 mL) was washed with water (5×100 mL) and brine (50 mL), dried over MgSO4, filtered, and evaporated under vacuum to an oil (2.29 g). The crude product was dissolved in CH2CL2 (5 mL) and the solution filtered through a pad of EM silica gel 60 (20 mL) using an additional 60 mL of CH2Cl2 to elute the silica gel. The CH2Cl2 filtrate was evaporated under vacuum to afford 4-bromo-2-butyl-6-fluoro-5-methoxy-1-indanone (1.86 g) as a pink oil.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:3]=1[CH2:4][C:5]1[C:10]2[N:11]=[CH:12][N:13](COCC[Si](C)(C)C)[C:9]=2[C:8]([C:22]#[N:23])=[C:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:27][C:26]=2[O:37][CH3:38])[N:6]=1.C(=O)(O)[O-:45].[Na+]>S(=O)(=O)(O)O.O>[Cl:43][C:39]1[CH:40]=[CH:41][CH:42]=[C:2]([Cl:1])[C:3]=1[CH2:4][C:5]1[C:10]2[N:11]=[CH:12][NH:13][C:9]=2[C:8]([C:22]([NH2:23])=[O:45])=[C:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:27][C:26]=2[O:37][CH3:38])[N:6]=1
Reactant: COc1cc(CN2CCCC2)ccc1Nc1nc(Cc2c(Cl)cccc2Cl)c2ncn(COCC[Si](C)(C)C)c2c1C#N
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cc(CN2CCCC2)ccc1Nc1nc(Cc2c(Cl)cccc2Cl)c2nc[nH]c2c1C(N)=O
Temperature: 95 °C

Procedure:
To a solution of the product of Example 49C (80 mg, 0.13 mmol) in concentrated sulfuric acid (5 mL) at 0° C. was added water (1 mL) and the mixture was heated to 95° C. for 20 minutes. After cooling, 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 via preparative HPLC using a gradient of 10/90 to 75/25 acetonitrile/water (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 12.00 (br, 1 H), 9.68 (br, 1 H), 8.62 (s, 1 H), 7.85 (d, J=8.4 Hz, 1 H), 7.73 (s, 1 H), 7.61-7.58 (m, 2 H), 7.48-7.42 (m, 1 H), 7.08 (d, J=1.2 Hz, 1 H), 6.62-6.58 (dd, J=8.4, 1.2 Hz, 1 H), 4.75 (s, 2 H), 4.23 (d, 2 H), 3.88 (s, 3 H), 3.44-3.41 (m, 8 H). MS: 525 (M+H+).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[CH:7][C:6]=1[F:13]>O.C(O)C>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:1]#[N:2])=[CH:7][C:6]=1[F:13]
Reactant: [C-]#N
Reactant: Fc1cc(CBr)ccc1Br
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1ccc(Br)c(F)c1
Temperature: 25 °C

Procedure:
Powered sodium cyanide (12.0 g, 0.24 mol) was dissolved in a 20 mL of water, and was added a solution of 1-bromo-4-(bromomethyl)-2-fluorobenzene (60 g, 0.22 mol) in 30 mL of ethanol. After heating at reflux for 4 h, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was diluted with CH2Cl2, filtered, and concentrated to afford (4-bromo-3-fluorophenyl)acetonitrile, which was used without further purification.
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.C(OC([N:17]1[CH2:22][CH2:21][CH:20]([N:23]([C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[CH2:19][CH2:18]1)=O)(C)(C)C.ClC1C=CC(N(C2CCNCC2)C(=O)[C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([O:55]C)[CH:50]=2)=CC=1.C12OC1CCCC2>>[OH:55][C@@H:51]1[CH2:52][CH2:53][CH2:54][CH2:49][C@H:50]1[N:17]1[CH2:22][CH2:21][CH:20]([N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:32](=[O:39])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:19][CH2:18]1
Reactant: COc1cccc(N(C(=O)c2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: COc1cccc(C(=O)N(c2ccc(Cl)cc2)C2CCNCC2)c1
Agent: C1CCC2OC2C1
Solvent: O=C(Cl)c1ccccc1
Product: COc1cccc(N(C(=O)c2ccccc2)C2CCN([C@@H]3CCCC[C@H]3O)CC2)c1

Procedure:
The title compound, MS (ISP): m/e=485.4 (M+H+), was prepared as for example 98, steps (A) to (F). Step (A) was performed using 3-methoxy-aniline, and yielded 4-(3-methoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester which was acylated with benzoyl chloride to 4-[benzoyl-(3-methoxy-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (B). This was then deprotected to N-(3-methoxy-phenyl)-N-piperidin-4-yl-benzamide (C), and reacted with cyclohexene oxide to gave (+/−)-N-[trans-1-(2-hydroxy-cyclohexyl)-piperidin-4-yl]-N-(3-methoxy-phenyl)-benzamide [step (D)]. Oxidation to (+/−)-N-(3-methoxy-phenyl)-N-[1-(2-oxo-cyclohexyl)-piperidin-4-yl]-benzamide in step (E) and reaction with phenyl lithium [step (F)] led to the title compound of the example.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)([OH:11])=[O:10]>>[NH2:8][C:5]1[CH:4]=[CH:3][C:2]([C:15]2[CH:16]=[CH:17][C:12]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=2)=[CH:7][N:6]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: Nc1ccc(-c2ccc(C(=O)O)cc2)cn1

Procedure:
In the same manner as in Example 2, a reaction was conducted using 5-bromo-2-aminopyridine and 4-carboxyphenyboronic acid as starting materials, whereby 4-(2-aminopyridin-5-yl)benzoic acid was obtained.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:6]=[N:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Br:22][CH2:23][C:24](Br)=[O:25]>C(Cl)Cl.O>[Br:22][CH2:23][C:24]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:6]=[N:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)=[O:25]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(NC(C)C)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COc1ccc(N(C(=O)CBr)C(C)C)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.3 %

Procedure:
To a solution of isopropyl-(6-methoxy-pyridin-3-yl)-amine (6.73 g, 41.0 mmol) in CH2Cl2 (130 mL) at 0° C. was added diisopropylethylamine (7.15 mL, 41.0 mmol) followed by bromoacetyl bromide (8.28 g, 41.0 mmol) in CH2Cl2 (60 mL) over 0.5 hours. The reaction was stirred at room temperature for 24 hours and was diluted with water. The organic solution was washed with brine (1×), dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with a solvent gradient (1% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2) to provide 2.27 g of 2-bromo-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. 1H NMR (CD3OD) δ 8.08 (d, 1H), 7.62 (dd, 1H), 6.89 (d, 1H), 4.84 (m, 1H), 3.9 (s, 3H), 3.60 (s, 2H), 1.06 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]=[C:13]([C:18]([O:20]CC)=O)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:7][CH:6]=1)[CH3:2]>P(Cl)(Cl)(Cl)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[N:11]=[CH:12][C:13]([S:14]([CH3:17])(=[O:15])=[O:16])=[C:18]2[OH:20])=[O:23])[CH3:2]
Reactant: CCOC(=O)C(=CNc1ccc(C(=O)OCC)cc1)S(C)(=O)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc2ncc(S(C)(=O)=O)c(O)c2c1
Temperature: 25 °C

Procedure:
To the solution of 4-(2-ethoxycarbonyl-2-methanesulfonyl-vinylamino)-benzoic acid ethyl ester (example 61d) in phosphorous oxychloride (700 mL), Polyphosphoric acid (PPA, 445 g) was added. The resulted mixture was heated at 70 degrees for 8 hours under mechanical stirring. After the reaction, the reaction mixture was cooled to room temperature, and then phosphorous oxychloride was evaporated under reduced pressure. To the residue, water was added. The solid was filtered, collected, washed with water thoroughly, and then dried. Column chromatography gave 4-hydroxy-3-methanesulfonyl-quinoline-6-carboxylic acid ethyl ester (25 g, purity 70%). LC-MS m/e 232 (MH+)
Reaction SMILES: N1C=CC=C[CH:2]=1.ClC(OCC)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][S:22][C:23]2[N:24]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:25]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][N:28]=2)=[CH:17][CH:16]=1>ClCCl.CCOCC>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][S:22][C:23]2[N:24]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:25]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=3)[C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:27]([CH3:2])[N:28]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1=CN=C(SCc2ccc(OC)cc2)N(C(=O)OCC)C1c1cccc(Cl)c1
Reactant: c1ccncc1
Agent: CCOC(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)N=C(SCc2ccc(OC)cc2)N(C(=O)OCC)C1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A cold solution of the ethyl ester product from part (a) (2.0 g., 4.6 mmole) and pyridine (0.76 ml., 9.3 mmole) in dichloromethane (15 ml.) is treated dropwise with ethyl chloroformate (0.48 g., 4.4 mmole) and stirred at room temperature for 24 hours. The solution is diluted with ether and washed with water, 1N hydrochloric acid, sodium bicarbonate, and brine. The dried solution is evaporated to give 1.87 g. of 2-[[(4-methoxyphenyl)methyl]thio]-6-(3-chlorophenyl)-1,5(6H)-pyrimidinedicarboxylic acid, diethyl ester as an oil.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([Br:15])[C:12]([O:16][C:17]2[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:26])=[C:19]([CH:27]=[O:28])[CH:18]=2)=[C:11]([Br:29])[C:10]=1[CH3:30])=[O:7])C.[Li+].[OH-].Cl>C1COCC1>[Br:29][C:11]1[C:10]([CH3:30])=[C:9]([NH:8][C:6](=[O:7])[CH2:5][C:4]([OH:31])=[O:3])[CH:14]=[C:13]([Br:15])[C:12]=1[O:16][C:17]1[CH:22]=[C:21]([CH:23]([CH3:24])[CH3:25])[C:20]([OH:26])=[C:19]([CH:27]=[O:28])[CH:18]=1
Reactant: CCOC(=O)CC(=O)Nc1cc(Br)c(Oc2cc(C=O)c(O)c(C(C)C)c2)c(Br)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)CC(=O)O)cc(Br)c(Oc2cc(C=O)c(O)c(C(C)C)c2)c1Br
Reaction time: 1 h
Yield: 42 %

Procedure:
To a stirred solution of compound N-[3,5-dibromo-4-[3-formyl-4-hydroxy-5-isopropylphenoxy]-2-methyl-phenyl]malonamic acid ethyl ester of Part 8F (15 mg, 0.027 mmol) and THF (0.5 mL) was added LiOH (0.25 mL, 1N). After 1 hour of stirring the pH of reaction was adjusted to 1 with 1N HCl and the organic phase removed in vacuo. The residue was extracted with EtOAc (3×3 mL) and the combined organic phases were dried over Na2SO4 before concentration. The residue was purified on column (silica gel, gradient elution: CHCl3/MeOH/AcOH from 1:0:0 to 90:10:1) to yield 6 mg (42%) of N-[3,5-dibromo-4-[3-formyl-4-hydroxy-5-isopropylphenoxy]-2-methylphenyl]malonamic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.FC(F)(F)C(=N[Si](C)(C)C)O[Si](C)(C)C.[Si](S(C(F)(F)F)(=O)=O)(C)(C)C.C(O[C@@H:43]1[O:65][C@H:64]([CH2:66][O:67]C(=O)C2C=CC=CC=2)[C@@H:54]([O:55]C(=O)C2C=CC=CC=2)[C@H:44]1[O:45]C(=O)C1C=CC=CC=1)(=O)C>C(#N)C>[Cl:1][C:2]1[N:3]([C@@H:43]2[O:65][C@H:64]([CH2:66][OH:67])[C@@H:54]([OH:55])[C@H:44]2[OH:45])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Agent: C[Si](C)(C)S(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Temperature: 75 °C
Reaction time: 0.75 h

Procedure:
2,5,6-Trichlorobenzimidazole (700 mg, 0.0032 moles) was dissolved in acetonitrile and BSTFA (1 ml, 0.0038 moles) was added. The mixture was heated at 75° C. for 20 minutes. TMSTf (1 ml, 0.0051 moles) and 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (1.9 g, 0.0038 moles) were added while heating was continued for 45 min. The acetonitrile was removed under reduced pressure and the protected nucleoside was separated on a silica column, eluting with chloroform. The benzoyl protecting groups were removed by overnight treatment at room temperature with methanolic ammonia. The nucleoside was separated on a column using 50% EtOAc/hexane and then 10% MeOH/CHCl3. The isolated compound was recrystallized from methanol. Yield: (74%); MP: 185°-186° C.; TLC (10% MeOH/CHCl3): Rf=0.20; 1H NMR (DMSO-d6) δ3.68 ppm (q, 2H), 4.00 (d, 1H), 4.12 (t, 1H), 4.40 (q, 1H), 5.28 (d, 1H), 5.41 (t, 1H), 5.49 (d, 1H), 5.57 (d, 1H), 7.96 (s, 1H), 8.55 (s, 1H); 13C NMR (DMSO-d6, Broad band decoupling): d 61.08 ppm, 69.80, 71.70, 86.47, 89.16, 114.93, 120.04, 125.77, 125.97, 132.30, 140.96, 142.16; MS (Fast Atom Bombardment): m/e (M+ 6) 359, (M+ 4) 357, (M+ 2) 355, (M+) 353, 319, 285, 263, 221, 187, 177, 133, 115, 103, 97, 85.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[C:10](=[O:13])[CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](C1C(=O)C(=O)N(C2C=CC=CC=2)N1)(C)(C)C.C1(N2C(=O)C(=O)C(C3C=CC=CC=3)N2)C=CC=CC=1.C1(N2C(=O)C(=O)C(C3C=CC(C)=CC=3)N2)C=CC=CC=1.C1(N2C(=O)C(=O)C(C3C=CC(OC)=CC=3)N2)C=CC=CC=1.C1(N2C(=O)C(=O)C(C3C=CC([N+]([O-])=O)=CC=3)N2)C=CC=CC=1.COC1C(=O)C(=O)N(C2C=CC=CC=2)N1.C(OC1C(=O)C(=O)N(C2C=CC=CC=2)N1)C.C(NC1C(=O)C(=O)N(C2C=CC=CC=2)N1)(=O)C.CN(C)C1C(=O)C(=O)N(C2C=CC=CC=2)N1.C(N(CC)C1C(=O)C(=O)N(C2C=CC=CC=2)N1)C.C(C1C(=O)C(=O)N(C2C=CC=CC=2)N1)(O)=O.COC(C1C(=O)C(=O)N(C2C=CC=CC=2)N1)=O.C(OC(C1C(=O)C(=O)N(C2C=CC=CC=2)N1)=O)C>>[CH3:14][CH:9]1[C:10](=[O:13])[C:11](=[O:12])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:8]1
Reactant: CC(C)(C)C1NN(c2ccccc2)C(=O)C1=O
Reactant: O=C1CNN(c2ccccc2)C1=O
Agent: CC(=O)NC1NN(c2ccccc2)C(=O)C1=O
Agent: CCN(CC)C1NN(c2ccccc2)C(=O)C1=O
Agent: CCOC(=O)C1NN(c2ccccc2)C(=O)C1=O
Product: CC1NN(c2ccccc2)C(=O)C1=O

Procedure:
1-phenyl-4,5-pyrazolinedione; 3-tert-butyl-1-phenyl-4,5-pyrazolinedione; 1,3-diphenyl-4,5-pyrazolinedione; 1-phenyl-3-(4′-methylphenyl)-4,5-pyrazolinedione; 1-phenyl-3-(3′-methoxymethyl)-4,5-pyrazolinedione; 1-phenyl-3-(4′-methoxyphenyl)-4,5-pyrazolinedione; 1-phenyl-3-(4′-nitrophenyl)-4,5-pyrazolinedione; 3-methoxy-1-phenyl-4,5-pyrazolinedione; 3-ethoxy-1-phenyl-4,5-pyrazolinedione; 3-acetamido-1-phenyl-4,5-pyrazolinedione; 3-dimethylamino-1-phenyl-4,5-pyrazolinedione; 3-diethylamino-1-phenyl-4,5-pyrazolinedione; 3-carboxy-1-phenyl-4,5-pyrazolinedione; 3-methoxycarbonyl-1-phenyl-4,5-pyrazolinedione; 3-ethoxycarbonyl-1-phenyl-4,5-pyrazolinedione;
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][OH:13])[CH:10]=2)[N:5]=[C:4]([N:14]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17](=[O:26])(=[O:25])[CH2:16][CH2:15]2)[CH:3]=1.[NH2:27][CH2:28][C:29]1([NH2:33])[CH2:32][O:31][CH2:30]1>>[NH2:33][C:29]1([CH2:28][NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][OH:13])[CH:10]=3)[N:5]=[C:4]([N:14]3[CH2:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[S:17](=[O:26])(=[O:25])[CH2:16][CH2:15]3)[CH:3]=2)[CH2:32][O:31][CH2:30]1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(CO)ccc3n2)Cc2ccccc21
Reactant: NCC1(N)COC1
Product: NC1(CNc2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccc(CO)cc23)COC1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-chloro-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-quinoline-6-methanol and 3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 455, 1H NMR (400 MHz, CD3OD) δ ppm 8.33 (s, 1 H), 8.08-8.05 (d, J=11.2 Hz, 2 H), 7.94-7.92 (d, J=7.2 Hz, 1 H), 7.74-7.68 (m, 3 H), 7.57-7.53 (t, J=7.6 Hz, 1 H), 6.26 (s, 1 H), 5.31 (s, 2 H), 4.72 (s, 2 H), 44.57 (s, 4 H), 4.44 (s, 1 H), 3.88 (s, 2 H), 3.77-3.71 (m, 2 H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:24][C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:33])[C:9]([C@@H:10]([CH3:31])[CH2:11]2)=[CH:8][C:7](=[O:32])[CH2:6][CH2:5]1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[C:34]([O:19][CH2:18][C:17](=[O:20])[C@:16]1([O:24][C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:33])[C:9](=[CH:8][C:7](=[O:32])[CH2:6][CH2:5]2)[C@@H:10]([CH3:31])[CH2:11]3)[CH2:14][CH2:15]1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Product: CCCCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
Analogously to Example 9, 1.0 g of 11β,21-dihydroxy-6α-methyl-17-valeryloxy-4-pregnene-3,20-dione is reacted with acetic anhydride, worked up, and purified, thus isolating 980 mg of 21-acetoxy-11β-hydroxy-6α-methyl-17-valeryloxy-4-pregnene-3,20-dione.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]1([O:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:15]2[CH:16]=[CH:17][C:12]([O:18][CH3:19])=[CH:13][CH:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: COc1ccc(S(=O)(=O)c2ccc(Br)cc2)cc1

Procedure:
The subtitle compound was prepared by the method of example 9 step (i) using 4-bromobenzenesulfonyl chloride and anisole.