Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[C:15]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][NH:24][CH3:25])[CH2:18][CH2:17]2)=[CH:14][CH:13]=[CH:12][N:11]=1.[CH3:26][N:27]1[CH:31]=[C:30]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[N:28]1>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:9][C:10]1[C:15]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:25])[S:32]([C:30]3[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=3)(=[O:34])=[O:33])[CH2:18][CH2:17]2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CNCCN1CCN(c2cccnc2Cl)CC1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCN1CCN(c2cccnc2Cl)CC1)S(=O)(=O)c1cnn(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Add triethylamine (3.403 mL, 24.414 mmol) to a stirring solution of {2-[4-(2-chloro-pyridin-3-yl)-piperazin-1-yl]-ethyl}-methyl-amine hydrochloride salt (2.000 g, 6.103 mmol) in dichloromethane (100 mL). Add 1-methyl-1H-pyrazole-4-sulfonyl chloride (1.102 g, 6.103 mmol) at room temperature. Stir at room temperature for 30 min. Dilute with dichloromethane and saturated aqueous sodium bicarbonate. Separate phases and extract the aqueous phase with dichloromethane. Combine the organic phases, dry over sodium sulfate, filter, and concentrate. Purify the resulting material by silica gel chromatography eluting with hexanes:acetone 1:1 to afford the title preparation (1.600 g, 66% yield). MS ES: m/z=399 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[CH2:25]([O:27][C:28](=[O:32])[CH2:29][CH2:30][NH2:31])[CH3:26].Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:25]([O:27][C:28](=[O:32])[CH2:29][CH2:30][NH:31][CH2:2][C:3](=[O:4])[N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)[CH3:26]
Reactant: CCOC(=O)CCN
Reactant: O=C(CCl)N1CCc2cc(OC3CCC(C(F)(F)F)CC3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCNCC(=O)N1CCc2cc(OC3CCC(C(F)(F)F)CC3)ccc21
Yield: 10 %

Procedure:
A mixture of crude 2-chloro-1-[5-(4-trifluoromethyl-cyclohexyloxy)-2,3-dihydro-indol-1-yl]-ethanone (80 mg, 0.22 mmol), 3-amino-propionic acid ethyl ester as HCl salt (68 mg, 0.44 mmol) and potassium carbonate (98 mg, 0.71 mmol) in acetonitrile (2 mL) was heated to reflux for 4 hrs. The mixture was treated with water and extracted with ether. The organic phase was dried over MgSO4, concentrated, and purified via a silica gel column to give desired product (11 mg, yield 10%). ESI-MS: 443.20 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:21][S:22]([C:25]1[S:29][C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:27][CH:26]=1)(=[O:24])=[O:23]>>[CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:33]2[CH2:34][CH2:35][N:30]([C:28]3[S:29][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:26][N:27]=3)[CH2:31][CH2:32]2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1cnc(N2CCNCC2)s1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Agent: Cl
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3ncc(S(C)(=O)=O)s3)CC2)c1
Yield: 38 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (Example A4) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride (Example 21(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 38%). MS (m/e): 514.3 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[N:26]=C(C)[C:24]2[C:23](=O)CC(C3C=CC(F)=CC=3)C[C:19]=2[N:18]=1.C(OC(=O)CC)(=O)CC>>[NH2:26][C:17]1[N:18]=[C:19]([CH2:24][CH3:23])[C:11]2[C:10](=[O:15])[CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:13][C:12]=2[N:16]=1
Reactant: O=C1CC(=O)CC(c2ccc(F)cc2)C1
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1)C2
Agent: CCC(=O)OC(=O)CC
Product: CCc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1)C2

Procedure:
The title compound was prepared from 5-(4-fluoro-phenyl)-cyclohexane-1,3-dione, following the procedure describing the synthesis of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 3/a stage 1, 2 and 3). Propionic anhydride was used instead of acetic anhydride in stage 1.
Reaction SMILES: [CH2:1]([S:5]([C:8]1[CH:17]=[CH:16][C:11]([NH:12]C(=O)C)=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[N:18]([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>O.Cl.C(O)C>[CH2:1]([S:5]([C:8]1[CH:17]=[CH:16][C:11]([NH:12][NH2:18])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)c1ccc(NC(C)=O)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCS(=O)(=O)c1ccc(NN)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
255 g of p-butylsulphonylacetanilide, in a mixture of 1.5 l of water and 300 ml of concentrated hydrochloric acid, are boiled for 1 hour under reflux. After cooling to 0° C, the product is diazotised with a solution of 70 g of NaNO2 in 175 ml of water. The filtered diazonium salt solution is added, at 5°-10° C, to a mixture of 750 g of 40% strength sodium sulphite solution and 750 ml of water which had been adjusted to pH 7 with concentrated sodium hydroxide solution, the pH being maintained at 6-7 by means of concentrated sodium hydroxide solution. After standing overnight, 300 ml of concentrated hydrochloric acid are added and the mixture is boiled for 1 hour. p-Butylsulphonylphenylhydrazine of melting point 138° C (from ethanol) is obtained, in a yield of approx. 70- 75% of theory, from the cooled solution by careful addition of alkali.
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:9]=1)[C:4](O)=[O:5])#[N:2].C(Cl)(=O)C([Cl:26])=O>ClCCl.CN(C=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH:7]=[C:3]([C:4]([Cl:26])=[O:5])[C:1]#[N:2])=[CH:9]1)[CH3:22]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)Cn1cc(C=C(C#N)C(=O)O)c2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)Cn1cc(C=C(C#N)C(=O)Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a stirred suspension of 2-cyano-3-(1-ethoxycarbonylmethyl-1H-indol-3-yl)-acrylic acid (3.0 g, 10 mmol) in dry dichloromethane (120 ml), in the presence of a few drops of dry DMF, was added oxalyl chloride (1.7 ml, 20 mmol). After stirring at rt overnight, the volatiles were removed under reduced pressure, the residue azeotoped twice with dry toluene and dried in vacuo, affording crude title compound (3.18 g) in quantitative yield. This material was stored under argon and was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[S:10])[NH2:9])[CH2:4][CH2:3]1.Br[CH2:12][C:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19])=O>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:10][CH:12]=[C:13]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=[O:19])[N:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(C(N)=S)CC1
Reactant: O=C(O)c1cccc(C(=O)CBr)c1
Solvent: C1CCOC1
Product: CN1CCN(c2nc(-c3cccc(C(=O)O)c3)cs2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Methyl-piperazine-1-carbothioic acid amide (2.47 mmol) and 3-(2-Bromo-acetyl)-benzoic acid (2.47 mmol) were mixed in THF (12 mL). After stirring at room temperature for 5 minutes the mixture was heated to 80° C. for 2 hours. The mixture was then cooled to room temperature and filtered. The solid was washed with a small amount of diethylether and dried. m/z=304.1 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:17])[C@@H:8]([NH2:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>ClCCl.O>[C:2]([O:6][C:7](=[O:17])[C@@H:8]([NH:16][C:27](=[O:28])[CH2:26][Cl:25])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)CCl
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.4 %

Procedure:
To a mixture of 3.0 g (11.6 mmol) (S)-2-amino-3-phenyl-propionic acid tert-butyl ester hydrochloride (Aldrich) and 3.32 mL (23.9 mmol) triethylamine (Aldrich) in dichloromethane (30 mL), 0.97 mL (12.2 mmol) chloroacetyl chloride (Aldrich) is added dropwise and the resulting mixture is stirred at room temperature for 4 h. The reaction mixture is diluted with water (25 mL), the organic layer is separated, washed with 10% NaHCO3 solution (25 mL), dried (MgSO4) and finally evaporated under reduced pressure to yield the title compound (3.4 g).
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3].[CH3:27][N:28]1[C:32]2=[CH:33][C:34]3[C:39]([CH:40]=[C:31]2[NH:30][S:29]1(=[O:42])=[O:41])=[CH:38][CH:37]=[CH:36][CH:35]=3.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.ClCCl.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[C:14]([CH2:17][N:30]3[C:31]4=[CH:40][C:39]5[C:34]([CH:33]=[C:32]4[N:28]([CH3:27])[S:29]3(=[O:41])=[O:42])=[CH:35][CH:36]=[CH:37][CH:38]=5)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: CN1c2cc3ccccc3cc2NS1(=O)=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3c4cc5ccccc5cc4N(C)S3(=O)=O)[C@H](C)[C@H]12
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
A solution of allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-2-hydroxymethyl-1-methyl-carbapen-2-em-3-carboxylate (60 mg, 0.164 mmol), 1-methyl-1,3-dihydro-2-thia-1,3-diaza-cyclopenta[b]naphthalene 2,2-dioxide (42 mg, 0.180 mmol), and triphenylphosphine (65 mg, 0.246 mmol) in anhydrous tetrahydrofuran (1 mL) was cooled in an ice bath and treated with diisopropyl azodicarboxylate (0.049 mL, 0.246 mmol). The mixture was stirred at 0-5° C. for 30 minutes, then streaked onto two 1 mm ×20 cm×20 cm silica gel GF plates. The plates were developed with 5% ethyl acetate in dichloromethane. The product band was removed and eluted with ethyl acetate to afford allyl (1S,5R,6S)-6-[1(R)-allyloxycarbonyloxy-ethyl]-1-methyl-2-(3-methyl-2,2-dioxo-2,3-dihydro-2-thia-1,3-diaza-cyclopenta[b]naphthalen-1-yl-methyl)-carbapen-2-em-3-carboxylate (52 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([OH:14])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[O:15][CH:16]([C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=1[Cl:26])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:46]1([CH2:52][CH2:53]O)[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.CCOC(/N=N/C(OCC)=O)=O>>[Cl:26][C:19]1[C:20]([F:25])=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=1[CH:16]([O:15][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:53][CH2:52][N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:12][CH:13]=2)[CH:6]=[N:7][C:2]=1[NH2:1])[CH3:17]
Reactant: OCCN1CCOCC1
Reactant: CC(Oc1cc(-c2ccc(O)nc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(Oc1cc(-c2ccc(OCCN3CCOCC3)nc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a mixture of 6′-amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-ol (78 mg, 0.20 mmol), triphenylphosphine (63 mg, 0.24 mmol) and 2-morpholin-4-yl-ethanol (0.026 mL, 0.22 mmol) was added DEAD (0.034 mL, 0.22 mmol). After stirring overnight more PPh3 (63 mg, 0.24 mmol) and more DEAD (0.034 mL, 0.22 mmol) were added. After several hours, more alcohol (0.026 mL, 0.22 mmol) was added. After several more hours, more PPh3 (63 mg, 0.24 mmol) and more DEAD (0.034 mL, 0.22 mmol) were added. After stirring overnight, the mixture was partitioned between dichloromethane and half-saturated brine. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over Na2SO4 and concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of dichloromethane, methanol to afford 5-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-6′-(2-morpholin-4-yl-ethoxy)-[3,3′]bipyridinyl-6-ylamine (53 mg, 53%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](OCC2C=CC=CC=2)=[C:9]([O:21][CH3:22])[CH:8]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:33]([O:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][O:49]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:43][CH:42]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>C(#N)C>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:49][CH2:48][CH2:47][C:44]2[CH:43]=[CH:42][C:41]([NH:40][C:38]([O:37][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:39])=[CH:46][CH:45]=2)=[C:9]([O:21][CH3:22])[CH:8]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(OCc2ccccc2)c(OC)c1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)c(OC)c1)OCC
Yield: 77.2 %

Procedure:
3-(4-Benzyloxy-3-methoxyphenyl)-2-ethoxypropanoic acid ethyl ester (0.5 g; 1.86 mmole) was dissolved in acetonitrile and potassium carbonate (0.53 g; 3.91 mmole) was added. 2-[4-(tert-Butoxycarbonylamino)phenyl]ethyl-4-methylbenzenesulfonate (described in Example 40a) (0.755 g, 1.92 mmole) was added. The resulting mixture was stirred and refluxed over night then filtered and the filtrate was evaporated. The residue was treated with sodium hydroxide (0.5 M) and diethyl ether. The phases were separated and the organic phase was dried with magnesium sulfate. Evaporation gave 0.7 g (77.2% yield) of 3-{4-[2-(4-tert-butoxycarbonylaminophenyl)ethoxy]-3-methoxyphenyl}-2-ethoxypropanoic acid ethyl ester.
Reaction SMILES: BrC1C=CC=C2C=1C(O)(C1C(O)=CC3OCOC=3C=1)C(=O)N2CCCCC.[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([CH2:38][C:39]1[O:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=1)[C:33](=[O:48])[C:32]2(O)[C:49]1[C:57]([OH:58])=[CH:56][C:52]2[O:53][CH2:54][O:55][C:51]=2[CH:50]=1>>[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34]([CH2:38][C:39]1[O:40][C:41]([C:44]([F:47])([F:45])[F:46])=[CH:42][CH:43]=1)[C:33](=[O:48])[CH:32]2[C:49]1[C:57]([OH:58])=[CH:56][C:52]2[O:53][CH2:54][O:55][C:51]=2[CH:50]=1
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccc(F)cc2C1(O)c1cc2c(cc1O)OCO2
Agent: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: O=C1C(c2cc3c(cc2O)OCO3)c2cc(F)ccc2N1Cc1ccc(C(F)(F)F)o1

Procedure:
Following the procedure as described in PREPARATION 1D, and making non-critical variations to replace 4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 5-fluoro-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one, the title compound was obtained (72%) as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 9.31 (s, 1H), 7.13 (dd, 1H), 7.02 (dd, 2H), 6.82 (d, 1H), 6.59 (d, 2H), 6.39 (s, 1H), 5.87 (d, 2H), 5.07-4.96 (m, 2H), 4.84 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 176.1, 160.5, 157.4, 153.9, 150.5, 147.5, 140.2, 139.6, 139.1, 132.3 (d, 2JCF=33.3 Hz), 115.3, 114.5 (m), 114.2, 113.9, 111.9 (d, 1JCF=98.7 Hz), 109.9, 109.7 (d, 2JCF=32.7 Hz), 101.3, 98.3, 48.5, 36.8; MS (ES+) m/z 436.2 (M+1).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@:15]2([CH3:16])[C@@H:13]([O:14]2)[CH2:12][C@H:11]([OH:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.Cl[Si:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:25][CH3:26].O>CN(C)C=O>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][C@@H:9]1[CH2:10][C@@H:11]([O:17][Si:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:12][C@H:13]2[C@:15]1([CH3:16])[O:14]2)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)C[C@@H]2O[C@@]21C
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC[Si](CC)(CC)O[C@H]1C[C@@H]2O[C@]2(C)[C@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
The compound of Example 16D (4.71 g, 18.2 mmol) and imidazole (1.76 g, 25.6 mmol, 1.4 equivalents) were dissolved in 36 mL of dimethylformamide. Then chlorotriethylsilane (3.34 g, 21.9 mmol) was added, and the reaction was stirred at ambient temperature for 2 hours. 125 mL of Water was added to the reaction mixture. Two layers of liquors were obtained and about 6 g of upper layer was separated. Then the lower aqueous layer was extracted three times with 100 mL each of tert-butyl methyl ether. The combined organic layers were washed with 125 mL of 10% aqueous NaCl, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound (6.71 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:4]([C@@H:11]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][C@H:12]2[C:23]([O:25]C)=[O:24])[CH:5]=[C:6]([CH2:8][CH2:9][CH3:10])[CH:7]=1.[OH-].[Li+].Cl>C1COCC1.O>[C:19]([O:18][C:16]([N:14]1[CH2:15][C@@H:11]([C:4]2[CH:5]=[C:6]([CH2:8][CH2:9][CH3:10])[CH:7]=[C:2]([Cl:1])[C:3]=2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C@H:12]([C:23]([OH:25])=[O:24])[CH2:13]1)=[O:17])([CH3:20])([CH3:22])[CH3:21]
Reactant: CCCc1cc(Cl)c(C(=O)OCC)c([C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(Cl)c(C(=O)OCC)c([C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a solution of (±)-trans-1-tert-butyl 3-methyl 4-(3-chloro-2-(ethoxycarbonyl)-5-propylphenyl)pyrrolidine-1,3-dicarboxylate (0.78 g, 1.72 mmol) in 20 mL of THF and 10 mL of water was added lithium hydroxide (0.051 g, 2.15 mmol). The reaction was stirred at ambient temperature for 3 h and then was acidified with 1N HCl. The reaction mixture was extracted with EtOAc and the organics were washed with brine, dried (MgSO4) and concentrated to afford 0.75 g (98%) of the title compound as a white foam. LRMS (ES)+: 340.17/342.16 (M+H—BOC)+.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[C:11]1([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1>[CH:5]([N:29]1[CH2:30][CH2:31][N:26]([C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:18]=2)[CH2:27][CH2:28]1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CN1CCN(c2nn(-c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
To a solution of 3.4 ml of acetic anhydride and 1.5 ml of formic acid heated at 55° C. for 1.5 hours and then cooled to ambient temperature was added, dropwise, a solution of 5.6 g of 1-phenyl-3-(1-piperazinyl)-1H-indazole in 20 ml of tetrahydrofuran. The reaction mixture was stirred at ambient temperature for 2 hours and then concentrated to an oil. Trituration of the oil with refluxing diethyl ether yielded a solid which was recrystallized from isopropanol (3×) to yield 2.6 g (42%) of 4-formyl-1-(1-phenyl-1H-indazol-3-yl)piperazine, m.p. 130°-132°.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH:13]=[CH2:14])[CH2:3]1.[N:26]1([CH2:32][C:33]([OH:35])=[S:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.O>CC(C)=O>[OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH2:13][CH2:14][S:34][C:33](=[O:35])[CH2:32][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:3]1
Reactant: OC(=S)CN1CCCCC1
Reactant: C=CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCSC(=O)CN4CCCCC4)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
A solution of 3α-hydroxy-21-methylene-5α-pregnane-11,20-dione (350 mg) in acetone (15 ml) was refluxed with piperidinothioacetic acid for 1/2 hour, poured into water and the suspension extracted into ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulphate and evaporated to give title compound (400 mg) as a white foam. [α]D + 50° (c = 0.19 ).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[CH2:21][CH:20]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([NH:30][OH:31])=[NH:29])[CH2:24][CH2:23]3)[O:19][C:16]2=[CH:17][N:18]=1.[C:32](Cl)(=O)[CH:33]([CH3:35])[CH3:34]>>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[CH2:21][CH:20]([CH:22]3[CH2:23][CH2:24][N:25]([C:28]4[N:29]=[C:32]([CH:33]([CH3:35])[CH3:34])[O:31][N:30]=4)[CH2:26][CH2:27]3)[O:19][C:16]2=[CH:17][N:18]=1
Reactant: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(C(=N)NO)CC2)C3)c(F)c1
Reactant: CC(C)C(=O)Cl
Product: CC(C)c1nc(N2CCC(C3Cc4cc(-c5ccc(CS(C)(=O)=O)cc5F)ncc4O3)CC2)no1

Procedure:
The title compound is prepared from 4-[5-(2-fluoro-4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-N-hydroxy-piperidine-1-carboxamidine and isobutyryl chloride following a procedure analogous to that described in Example 8. LC (method 6): tR=1.59 min; Mass spectrum (ESI+): m/z=501 [M+H]+.