Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8](OCC)=[O:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>C1COCC1>[Cl:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[CH2:8][OH:9]
Reactant: CCOC(=O)c1c(C)nsc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nsc(Cl)c1CO
Reaction time: 1 h
Yield: 91.7 %

Procedure:
A solution of 2.06 g (10.0 mmoles) of ethyl 5-chloro-3-methyl-isothiazole-4-carboxylate dissolved in 10 ml of THF was dropwise added, at −30° C., to a solution of 0.42 g (11.0 mmoles) of lithium aluminum hydride dissolved in 10 ml of THF. The mixture was stirred at the same temperature for 1 hour to give rise to a reaction. After confirmation of the completion of the reaction, ethyl acetate was added to the reaction mixture. The resulting mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 1.50 g (yield: 91.5%) of (5-chloro-3-methyl-isothiazol-4-yl)-methanol.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C@@:5]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH3:27])[CH:21]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:47][S:48]([NH2:51])(=[O:50])=[O:49].C([O-])([O-])=O.[K+].[K+]>>[CH3:27][N:22]1[C:23](=[O:26])[CH:24]=[CH:25][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C@@H:12]([N:8]3[CH2:7][CH2:6][C@:5]([CH2:4][CH2:3][CH2:2][NH:51][S:48]([CH3:47])(=[O:50])=[O:49])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:10][C:9]3=[O:11])[CH3:13])=[CH:15][CH:16]=2)=[CH:21]1
Reactant: CS(N)(=O)=O
Reactant: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Agent: O=[Cr](=O)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one by treatment with (i) MeSO2C1 and (ii) MeSO2NH2, K2CO3. LC-MS Method 2 tR=1.095 min, m/z=524.1; 1H NMR (CDCl3) 1.30-1.41 (m, 1H), 1.52 (d, 3H), 1.71 (m, 1H), 1.87-2.07 (m, 3H), 2.09-2.20 (m, 3H), 2.22-2.32 (m, 2H), 2.88 (s, 3H), 3.06 (m, 2H), 3.60 (s, 3H), 4.32 (s, 1H), 5.65 (m, 1H), 6.67 (d, 1H), 6.94 (m, 2H), 7.11 (d, 2H), 7.25 (m, 1H), 7.27-7.40 (m, 4H), 7.53 (dd, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17](I)=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][N:32](C(OC(C)(C)C)=O)[CH:33]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(C([O-])=O)(C)C>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17]([C:29]3[CH:30]=[N:31][NH:32][CH:33]=3)=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(I)ccc1OCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)C(=O)[O-]
Solvent: COCCOC
Product: COC(=O)c1cc(-c2cn[nH]c2)ccc1OCc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-{[(4-fluorophenyl)methyl]oxy}-5-iodobenzoate (may be prepared as described in Description 112; 1.4 g, 3.63 mmol) in 1,2-dimethoxyethane (40 ml) was added 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (3.20 g, 10.88 mmol), tripotassium phosphate (1.54 g, 7.25 mmol), PdCl2(dppf) (0.16 g, 0.22 mmol) and the mixture was heated to 80° C. for 6 hours. The temperature was raised to 90° C. for 2 hours. Further catalyst was added and the mixture was divided into two. One 20 ml portion was subjected to 120° C. for 30 min under microwave conditions. The second portion of 20 ml was heated to reflux for 12 hrs. The 1,1-dimethylethyl carboxylate protected products were deprotected. The products were then combined and evaporated under reduced pressure on a buchi. The mixture was taken up into dichloromethane (20 ml), treated with trifluoroacetic acid (10 ml) and stirred at room temperature for 1 hour. The mixture was evaporated and purified using the Flashmaster eluting with 0-25% methanol/dichloromethane to yield the title compound. 1.15 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:43][C:44]1([CH3:51])[O:48][CH:47]([CH2:49]O)[CH2:46][O:45]1.[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH2:49][CH:47]3[CH2:46][O:45][C:44]([CH3:51])([CH3:43])[O:48]3)=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OCC(CO)O1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)OCC2COC(C)(C)O2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 27746624 %

Procedure:
In a manner similar to the method described in Example 7, chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (100.8 mg, 0.164 mmol) was reacted with N,N′-carbonyldiimidazole (Aldrich, 67.8 mg, 0.406 mmol) and then a mixture of (2,2-Dimethyl-[1,3]dioxolan-4-yl)-methanol (Aldrich, 69.3 mg, 0.514 nmol) and sodium hydride (11.2 mg, 0.443 mmol) in tetrahydrofuran to give (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white lyophilized solid (104.2 mg, 87% yield). MS (ES+) m/z calcd. for C37H40Cl2F2N3O6 [(M+H)+]: 730. found: 730.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]([C:7]([O:9]C)=[O:8])[CH2:4][O:3]1.[OH-].[K+:13]>CO.CCOCC>[K+:13].[CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]([C:7]([O-:9])=[O:8])[CH2:4][O:3]1
Reactant: COC(=O)[C@H]1COC(C)(C)O1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: CC1(C)OC[C@H](C(=O)[O-])O1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.9 %

Procedure:
To a solution of methyl (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylate (0.16 mL, 1.0 mmol) in MeOH (2 mL), 2 N KOH (0.5 mL, 1 mmol) was added. The resulting solution was stirred at RT for 20 min and concentrated in vacuo. The residue obtained was suspended in ether (10 mL) and sonicated for 5 min. The ether was then removed and the resulting residue was dried in vacuo for 4 h to obtain (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid potassium salt (173 mg, 94%) which was directly used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:31][C:32]([NH:34][C:35](=[O:43])[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[S:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19](COCC[Si](C)(C)C)[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12>Cl.O1CCOCC1>[NH:19]1[CH:20]=[CH:21][N:22]=[C:18]1[C:16]1[S:17][C:10]2[C:11](=[N:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]2[CH:6]=[CH:5][C:4]([NH:31][C:32]([NH:34][C:35](=[O:43])[CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[S:33])=[CH:3][C:2]=2[F:1])[CH:15]=1
Reactant: C[Si](C)(C)CCOCn1ccnc1-c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ncc[nH]4)sc23)c(F)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
A solution of 112 (21 mg, 0.033 mmol) in 4N HCl in dioxane (3.5 mL) was allowed to stir at 55° C. for 1 h. The mixture was then cooled and solvent was removed under reduced pressure. The resultant gum was triturated with ether several times to form a solid material that was dried under high vacuum to afford the product 113 as a beige solid (5 mg, 28% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.50 (1H, s), 11.84 (1H, s), 8.66 (1H, d, J=5.67 Hz), 8.39 (1H, s), 8.06 (1H, d, J=12.72 Hz), 7.68 (2H, s), 7.59-7.58 (2H, m), 7.36-7.30 (5H, m), 6.86 (1H, d, J=5.48 Hz), 3.83 (2H, s). MS (m/z) 504.1 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.[CH2:15]([O:17][C:18]([C:20]1[C:21](=[O:40])[C:22]2[CH:27]=[N:26][C:25](S(C)(=O)=O)=[N:24][C:23]=2[N:32]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH:33]=1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[C:21](=[O:40])[C:22]2[CH:27]=[N:26][C:25]([NH:14][C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)[CH:9]=3)=[N:24][C:23]=2[N:32]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH:33]=1)=[O:19])[CH3:16]
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(Nc3cccc(N4CCN(C)CC4)c3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1 (g) the title compound was prepared from 3-(4-methyl-piperazin-1-yl)-phenylamine (from Example 37(A), 55 mg, 0.29 mmol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 17(e), 100 mg, 0.26 mmol). The title compound was obtained as a yellow solid (72 mg, 56%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.27 (s, 1H), 8.46 (s, 1H), 7.75 (br, 1H), 7.29 (m, 1H), 7.22 (d, J=8.5 Hz, 1H), 6.86 (m, 1H), 6.66 (d, J=8.5 Hz, 1H), 5.05 (m, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.17 (t, J=4.9 Hz, 4H), 2.51 (t, J=4.9 Hz, 4H), 2.28 (s, 3H), 1.94 (m, 4H), 1.76-1.19 (m, 6H), 1.34 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=CC=1)([O-])=O.[F:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[C:16]1=[N:17][CH:18]=[CH:19][CH:20]=[C:15]1[CH2:14]2>C1(C)C(C)=CC=CC=1.[Pd]>[F:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[C:16]1=[N:17][CH:18]=[CH:19][CH:20]=[C:15]1[CH2:14]2.[CH2:4]1[NH:1][CH2:7][CH2:8][CH2:9]1
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Pd]
Agent: Fc1ccc2c(c1)Cc1cccnc1-2
Solvent: Cc1ccccc1C
Product: C1CCNC1

Procedure:
The process typically involves the addition of 1.1 molar equivalents of the enamine to 1 molar equivalent of bromopropylamine hydrobromide in dimethylformamide at elevated temperature until the exothermic reaction is initiated wherein the temperature is kept at 90°-120° C. for several hours. The product is isolated by a combination of acidification and ether washing followed by basification and ether extractions. Evaporation yields the tetrahydroimine product such as: ##STR72## The tetrahydroimine product is aromatized in xylene and nitrobenzene and 10% palladium on charcoal according to Parcell and Hauch, ibid. The resulting product, e.g., 7-fluoro-5H-indeno[1,2-b]pyridine (which may be further derivatized according to Method V) is derivatized according to Methods II to IV to yield the corresponding spiro-derivatives such as spiro-(7-fluoro-5H-indeno[1,2-b]pyridin-5,5-thiazolidine)-2',4'-dione;spiro-(7-fluoro-5H-inden[1,2-b]pyridin-5,5'-(oxazolidine)-2',4'-dione and spiro-(7-fluoro-5H-indeno[1,2-b]pyridin-5,3'-suiccinimide. Oxidation (Method VII) of 5H-indeno[1,2-b]pyridine or its derivatives according to the method of Sprinzak, J. Amer. Chem. Soc., 80, 5449 (1958) yields the corresponding 5-one or ketone derivative, which may be further derivatized according to Method V. When reacted in accordance with Method I, the ketone will yield a spiro-hydantoin derivative such as spiro-(7-fluoro-5H-indeno[1,2-b]pyridin-5,4'-imidazolidine)-2',5'-dione. Any of the aforementioned spiro derivatives may be further derivatized, e.g., nitrated, in accordance with Method VI. See Examples XVIII, XI and XII.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:34])=[O:3])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)=[CH:38][CH:37]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(Cl)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-chlorophenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.87 (dd, J=6.60, 3.18 Hz, 6H), 1.41-1.51 (m, 1H), 1.65 (ddd, J=13.69, 7.21, 6.97 Hz, 1H), 1.95 (ddd, J=13.57, 7.70, 7.58 Hz, 1H), 3.74 (t, J=7.83 Hz, 1H), 7.33-7.40 (m, 2H), 7.50-7.59 (m, 4H), 7.65 (s, 1H), 7.67 (d, J=1.47 Hz, 2H), 7.75 (d, J=8.31 Hz, 2H); Calcd for C25H22ClF3O2 (M+H) 447.13, Found 447.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]3[CH2:16][C@H:17]4[C:22](=[O:23])[N:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:20](=[O:29])[N:18]4[CH2:19][C:8]2=3)=[CH:4][CH:3]=1.[OH-].[Na+:33]>O1CCCC1>[Na+:33].[F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]3[CH2:16][C@H:17]4[C:22](=[O:23])[N:21]([CH2:24][CH2:25][C:26]([O-:28])=[O:27])[C:20](=[O:29])[N:18]4[CH2:19][C:8]2=3)=[CH:4][CH:3]=1
Reactant: O=C(O)CCN1C(=O)[C@@H]2Cc3c(n(Cc4ccc(F)cc4)c4ccccc34)CN2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])CCN1C(=O)[C@@H]2Cc3c(n(Cc4ccc(F)cc4)c4ccccc34)CN2C1=O
Yield: 110.9 %

Procedure:
(S)-3-(6-(4-fluorobenzyl)-1,3-dioxo-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H)-yl)propanoic acid (A) (40.35 g, 95.7 mmol) dissolved in tetrahydrofuran (960 mL) in 2 L round bottom flask equipped with addition funnel was degassed and cooled in ice water bath. 1M NaOH (86.2 mL, 86.2 mmol) was added dropwise over 3 hr at 0° C. The solvent removed under reduce pressure to afford (S)-3-(6-(4-fluorobenzyl)-1,3-dioxo-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indol-2(3H)-yl)propanoic acid sodium salt (Compound A sodium salt; 42.4 g, 100%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 7.53 (d, 1H), 7.47 (d, 1H), 7.16-7.02 (m, 6H), 5.40 (q, 2H), 4.89 (d, 1H), 4.36-4.28 (m, 2H), 3.56-3.49 (m, 2H), 3.27-3.20 (m, 1H), 2.76-2.67 (m, 1H), 2.17-2.11 (m, 2H); LC-MS [M+H+ 422].
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.[C:11]([O:14][CH2:15][CH:16]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH2:17][CH2:18]I)(=[O:13])[CH3:12]>>[C:11]([O:14][CH2:15][CH:16]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH2:17][CH2:18][P:1](=[O:2])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])(=[O:13])[CH3:12]
Reactant: CCOP(OCC)OCC
Reactant: CC(=O)OCC(CCI)COC(C)=O
Product: CCOP(=O)(CCC(COC(C)=O)COC(C)=O)OCC

Procedure:
Triethyl phosphite (6.58 g, 6.8 ml, 39.67 mmol) and 4-acetoxy-3-(acetoxymethyl)butyl iodide (5 g, 15.87 mmol) were stirred at 130° C. for 9 hours. The reaction mixture was then allowed to cool and the excess of triethyl phosphite was evaporated under reduced pressure. The product distilled at 235° C./0.3 mm Hg, yield 4.6 g, 75%. 1HNMR: δH (CDCl3) 1.33 (6H, t, J=7Hz, (OCH2CH3)2, 1.74 (5H, m, CHCH2CH2P), 2.06 (6H, s, 2xCOCH3), 4.12 (8H, m, (OCH2CH3)2, 2xCH2OAc). Found: C,47.29; H,7.83%. C13H25O7P 0.25 H2O requires C,47.48; H,7.81%.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:30]2([CH3:31])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:32])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([OH:25])([CH2:23][CH3:24])[CH3:22])[CH2:12][C@@H:11]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br/[CH:42]=[CH:43]\[CH2:44][C:45]([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])([CH3:47])[CH3:46].[H-].[Na+].C1OCCOCCOCCOCCOC1>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:30]2([CH3:31])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:29]2[CH2:28][CH2:27][C@@:26]2([CH3:32])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:25]/[CH:42]=[CH:43]\[CH2:44][C:45]([O:48][Si:49]([CH2:50][CH3:51])([CH2:52][CH3:53])[CH2:54][CH3:55])([CH3:46])[CH3:47])([CH2:23][CH3:24])[CH3:22])[CH2:12][C@@H:11]([O:33][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:35])[CH3:36])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[Si](CC)(CC)OC(C)(C)C/C=C\Br
Reactant: CCC(C)(O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(O/C=C\CC(C)(C)O[Si](CC)(CC)CC)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 98 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-ethylpregna-5,7,16-triene (103 mg, 0.180 mmol), 1-bromo-4-triethylsilyloxy-4-methyl-(2Z)-pentene (211 mg, 0.719 mol), sodium hydride (60% in oil, 43 mg, 1.08 mmol), 15-crown-5 (40 mg, 0.182 mmol) and tetrahydrofuran (3 ml) were subjected to reaction using a procedure similar to that of Example 5(1) (reflux under heating for 1 hour), worked up and purified by column chromatography (hexane:toluene=1:1) to give the titled compound (141 mg, 100%) as a colorless solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:8][CH:7]=2.[N:31]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(#N)C>[N:31]1([CH:37]2[CH2:42][CH2:41][N:40]([CH2:2][C:3]3[C:4]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)=[N:5][C:6]4[C:11]([C:12]=3[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:8][CH:7]=4)[CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CC#N
Product: COC(=O)c1c(CN2CCC(N3CCCCC3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Reaction time: 3 h
Yield: 145.4 %

Procedure:
A suspension of methyl 3-(bromomethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.45 g, 2.88 mmol) and 1,4′-bipiperidine (0.630 g, 3.74 mmol) in acetonitrile (10 mL) was stirred for 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in DMSO and was purified via HPLC (Biotage, 0-50% MeCN/H2O with 0.1% TFA). Fractions containing the product were neutralized with saturated aqueous NaHCO3 and extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford methyl 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.47 g, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J=1.76 Hz, 1H), 8.37 (d, J=8.78 Hz, 1H), 8.27-8.33 (m, 1H), 8.00 (s, 1H), 7.89-7.96 (m, 2H), 7.76-7.82 (m, 1H), 4.04 (s, 3H), 3.66 (s, 2H), 3.39 (s, 3H), 2.54-2.71 (m, 3H), 2.31-2.47 (m, 4H), 1.82 (br. s., 2H), 1.53 (d, J=10.04 Hz, 2H), 1.45 (br. s., 4H), 1.21-1.40 (m, 4H); MS (m/z) 590.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][NH:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:2].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1>CN(C=O)C>[C:11]([O:10][C:8]([NH:7][N:6]([C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C1CCC(=O)O1
Reactant: CCOC(=O)CNNC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CN(NC(=O)OC(C)(C)C)C(=O)CCC(=O)O
Temperature: 75 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
Into a solution of (N′-tert-Butoxycarbonyl-hydrazino)-acetic acid ethyl ester 4 (1.85 g, 18.5 mmol) in DMF (30 mL) was added succinic anhydride (4.84 g, 22.2 mmol) and the mixture was stirred at 75° C. for 18 h. DMF was evaporated and the crude mixture was purified by flash column chromatography using hexane:ethylacetate (1% acetic acid) as an eluent (yield 50%). 1H NMR (500 MHz, CDCl3) 1.28 (3H, CH2—CH3, t), 1.48 (9H, C—CH3, s), 2.55-3.00 (6H, NH—CH2—CO, N—CH2—CH2—CO, m), 4.20 (2H, CH2CH3, q); MS Anal. Mol. Wt. 318.25 (M−1).
Reaction SMILES: [S:1]1[C:5]([NH:6][C:7]2[CH:12]=[C:11](Cl)[N:10]=[C:9]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:26][CH2:25]4)=[O:23])=[CH:17][CH:16]=3)[N:8]=2)=[N:4][CH:3]=[N:2]1.Cl.[CH:28]1([C:31]2([F:35])[CH2:34][NH:33][CH2:32]2)[CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>O1CCOCC1>[S:1]1[C:5]([NH:6][C:7]2[CH:12]=[C:11]([N:33]3[CH2:34][C:31]([CH:28]4[CH2:30][CH2:29]4)([F:35])[CH2:32]3)[N:10]=[C:9]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:26][CH2:25]4)=[O:23])=[CH:17][CH:16]=3)[N:8]=2)=[N:4][CH:3]=[N:2]1
Reactant: O=C(Nc1ccc(Sc2nc(Cl)cc(Nc3ncns3)n2)cc1)C1CC1
Reactant: FC1(C2CC2)CNC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Sc2nc(Nc3ncns3)cc(N3CC(F)(C4CC4)C3)n2)cc1)C1CC1
Temperature: 130 °C
Yield: 3.6 %

Procedure:
A mixture of crude N-(4-(4-(1,2,4-Thiadiazol-5-ylamino)-6-chloropyrimidin-2-ylthio)phenyl)cyclopropanecarboxamide (780 mg, 1.93 mmol), 3-cyclopropyl -3-fluoroazetidine hydrochloride (818 mg, 5.4 mmol), DiPEA (0.7 mL, 4.6 mmol) in 1,4-dioxane (20 mL) was heated in the microwave to 130° C. for 20 minutes. The mixture was concentrated and purified by preparative HPLC to yield 34 mg of N-(4-(4-(1,2,4-Thiadiazol-5-ylamino)-6-(3-cyclopropyl-3-fluoroazetidin-1-yl)pyrimidin-2-ylthio)phenyl)cyclopropanecarboxamide with a purity of 95+% (HPLC method A, Rf=8.573 minutes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)=[C:10]2[C:27]([O:29]CC)=[O:28])[CH:6]=[CH:7][CH:8]=1.OC1(C2C=CC=C(OC)C=2)C2C(=CC=CC=2)C(C2C=CC3OCOC=3C=2)=C1C(OCC)=O.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([OH:29])=[O:28])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1cccc(OC)c1
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1cccc(OC)c1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)c1
Reaction time: 0.5 h
Yield: 31 %

Procedure:
Ethyl (1RS )-1-(3-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate. To a solution of ethyl (1RS)-1-hydroxy-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-indene-2-carboxylate (150 mg, 0.35 mmol) in CH2Cl2 was added triethylsilane (67 μl, 0.42 mmol), followed by boron trifluoride etherate (213 μl, 1.73 mmol). The reaction mixture was allowed to stir for 30 min, at which time was added slowly 5% aqueous HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 10% EtOAc/ hexanes to provide the title compound (45 mg, 31%) as a mixture of Δ1 and Δ2 double bond isomers.