Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH:15]2[CH:17]([CH2:18][CH2:19][CH2:20][CH3:21])[O:16]2)[CH:12]=[CH:11][C:10]=1[N:22]1[S:26](=[O:28])(=[O:27])[NH:25][C:24](=[O:29])[CH2:23]1)C1C=CC=CC=1>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH:17]([OH:16])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[N:22]1[S:26](=[O:28])(=[O:27])[NH:25][C:24](=[O:29])[CH2:23]1
Reactant: CCCCC1OC1c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCCC(O)Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1
Reaction time: 48 h

Procedure:
A mixture of 5-[2-benzyloxy-4-(3-butyloxiranyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (110 mg) and Pd(OH)2 (11 mg) in EtOAc (5 mL) is hydrogenated at 1 atm for 48 h. The catalyst is filtered and the filtrate evaporated. The residue is purified by preparative HPLC to give the title compound: (M−1)−=327; HPLC retention time=0.93 min (method A).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].C([Mg]Cl)(C)C.[Si:16]([O:23][C@H:24]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26](=[O:36])[CH2:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].[BH4-].[Na+].[NH4+].[Cl-]>C1COCC1.C(OCC)C.CO>[Si:16]([O:23][C@H:24]([CH2:25][CH:26]([C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)[OH:36])[CH2:28][NH:27][C:29](=[O:30])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC1=O
Agent: CC(C)[Mg]Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@@H](CC(O)c1cc(F)cc(C#N)c1)O[Si](C)(C)C(C)(C)C
Temperature: -30 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-5-fluorobenzonitrile (5.2 g, 0.26 mmol) in THF (26 mL) at −78° C. was slowly added isopropylmagnesium chloride (13.6 mL of a 2.0 M solution in diethyl ether, 0.27 mmol). The mixture was warmed and stirred at −30° C. for 1 hour then cooled to −78° C. The resulting aryl Grignard was added to a solution of (R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-oxopyrrolidine-1-carboxylate (I-1) (7.8 g, 25 mmol) in THF (25 mL) at −78° C. The reaction mixture was stirred at 0° C. for 30 minutes. Methanol (20 mL) was added to the reaction mixture followed by NaBH4 (1.4 g, 37 mmol). The mixture was stirred to room temperature for 12 hours then poured into 10% aqueous NH4Cl. The mixture was extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel with EtOAc/hexanes gradient as eluant to yield tert-butyl ((2R)-2-((tert-butyldimethylsilyl)oxy)-4-(3-cyano-5-fluorophenyl)-4-hydroxybutyl)carbamate (I-10). 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1 H), 7.38-7.33 (m, 1 H), 7.25-7.20 (m, 1 H), 4.95 (d, J=9.2 Hz, 1 H), 4.81 (bs, 1 H), 4.12-4.05 (m, 1 H), 3.76 (bs, 1 H), 3.45-3.35 (m, 1 H), 3.23-3.12 (m, 1 H), 1.87-1.71 (m, 2 H), 1.45 (s, 9 H), 0.91 (s, 9 H), 0.12 (s, 6 H). MS m/z 461.2 (M+23)+.
Reaction SMILES: C(O[C:6](=[O:23])[CH2:7][CH:8]([NH:16][C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH:9]([O:13]CC)[O:10][CH2:11][CH3:12])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:20]([O:19][C:17](=[O:18])[NH:16][CH:8]1[CH2:7][C:6](=[O:23])[O:13][CH:9]1[O:10][CH2:11][CH3:12])[CH:21]=[CH2:22]
Reactant: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(OCC)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCOC(=O)NC1CC(=O)OC1OCC
Yield: 85 %

Procedure:
A solution of the crude 3-Allyloxycarbonylamino-4,4-diethoxy-butyric acid tert-butyl ester, 103, obtained in the procedure above, in CH2Cl2(50 mL) is treated with triflouroacetic acid (50 mL). After the consumption of starting material, the organics are reduced under vacuum. The residual triflouroacetic acid is removed with ethyl acetate by azeotroping conditions. The final residue is purified over silica (hexanes/ethyl acetate 80:20) to afford 10.1 g (85% yield) of the desired product as a slightly yellow oil. 1H-NMR, (300 MHz, CDCl3): δ 1.23 (m, 3H), 2.41–2.54 (m, 1H), 2.82–3.06 (m, 2H), 3.61–3.73 (m, 1H), 3.82–3.98 (m, 1H), 4.06–4.25 (m, 1H), 4.61 (br s, 2H), 5.24–5.53 (m, 3H), 5.86–6.01 (m, 1H); MS (ESI): m/e=230.03 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=1.[S:26]1[CH:30]=[CH:29][N:28]=[C:27]1[S:31](Cl)(=[O:33])=[O:32]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:19][CH:20]=2)[S:31]([C:27]2[S:26][CH:30]=[CH:29][N:28]=2)(=[O:33])=[O:32])[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(C(C)(C)C)cc2)c1
Reactant: O=S(=O)(Cl)c1nccs1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(C(C)(C)C)cc2)S(=O)(=O)c2nccs2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 1 from 3-{3-[(4-tert-butyl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 12s, and thiazole-2-sulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, 1H), 7.56 (d, 1H), 7.23 (d, 2H), 7.14 (m, 1H), 7.04 (m, 3H), 6.98 (m, 2H), 4.47 (s, 2H), 4.41 (s, 2H), 3.67 (s, 3H), 2.84 (t, 2H), 2.54 (t, 2H), 1.27 (s, 9H); MS 487 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:25])=[C:4]([C:8]([I:24])=[C:9]([NH:12][C:13](=[O:23])[CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:10]=1[I:11])[C:5]([OH:7])=[O:6].S(OC)(O[CH3:30])(=O)=O>>[NH2:1][C:2]1[C:3]([I:25])=[C:4]([C:8]([I:24])=[C:9]([N:12]([CH3:30])[C:13](=[O:23])[CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:10]=1[I:11])[C:5]([OH:7])=[O:6]
Reactant: COS(=O)(=O)OC
Reactant: COCCOCCOCC(=O)Nc1c(I)c(N)c(I)c(C(=O)O)c1I
Product: COCCOCCOCC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)O)c1I

Procedure:
3-Amino-2,4,6-triiodo-5-(N-methyl-3,6,9-trioxadecanamido)benzoic Acid [C; Ro is H(CH2OCH2)3CON(CH3), Q is H, Z is OH] was prepared by methylation of 3-amino-2,4,6-triiodo-5-(3,6,9-trioxadecanamido)benzoic acid with dimethyl sulfate according to the procedure of Example 41, and was obtained as an amorphous pink solid, m.p. 100°-109° C. when recrystallized from methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][CH:5]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.II.Cl>C(O)(=O)C>[CH2:5]([C:4]1[CH:3]=[C:2]([Br:1])[CH:10]=[CH:9][C:8]=1[C:7]([OH:11])=[O:6])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1OC(c2ccccc2)c2cc(Br)ccc21
Agent: Cl
Agent: II
Solvent: CC(=O)O
Product: O=C(O)c1ccc(Br)cc1Cc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
The mixture of 5-bromo-3-phenyl-3H-isobenzofuran-1-one (D3) (14.4 g, 50 mmol), iodine (9 g, 70 mmol), amorphous red phosphorous (7.8 g, 250 mmol), acetic acid (125 mL) and distilled water (15 mL) are taken in this order in a 3-neck flask with a mechanical stirrer and condenser. After stirring overnight at 50° C. (90% product and 10% starting material), the reaction is quenched by adding into water (500 mL), added ether (200 mL) and filtered off phosphorous. The aqueous layer is extracted with ether (3×100 mL) and the combined organic layers are washed with sodium bisulfite solution (100 mL) and water (2×100 mL). The organic phase is extracted using 1N NaOH aqueous solution (4×100 mL), washed again with water (4×100 mL), dried over Na2SO4 and evaporated to get the neutral fraction (2 g, mp 180° C.). The basic phase is acidified with 5N HCl (150 mL) and extracted with DCM (4×100 mL). The combined extracts are washed with water (3×100 mL), dried over Na2SO4 and evaporated to get product (12 g, mp 137° C.). This is further recrystallized from boiling ACN (50 mL) to afford 2-benzyl-4-bromo-benzoic acid (239) (10 g, 83%, mp 145° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH:12]=[CH2:13])[CH:3]=1.Br[CH2:15][C:16]1[C:17](Cl)=[N:18][C:19]([Cl:23])=[C:20]([F:22])[CH:21]=1.C(N1C2C=CC=CC=2C=CC2N=C(Cl)C(F)=CC=2C1)(=O)C>>[C:9]([N:8]1[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH:12]=[CH:13][C:17]2[N:18]=[C:19]([Cl:23])[C:20]([F:22])=[CH:21][C:16]=2[CH2:15]1)(=[O:11])[CH3:10]
Reactant: Fc1cc(CBr)c(Cl)nc1Cl
Reactant: C=Cc1cc(Cl)ccc1NC(C)=O
Agent: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Product: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2cc(Cl)ccc21

Procedure:
Compound 9C was prepared from 9B and 1B by a route analogous to that used for the preparation of 1D. HPLC Rt=3.146 min; LCMS Found: (M+H)+=337.
Reaction SMILES: Br[C:2]1[S:6][CH2:5][N:4]([CH3:7])[CH:3]=1.C([Li])CCC.[CH3:13][Sn:14](Cl)([CH3:16])[CH3:15]>CCOCC>[CH3:7][N:4]1[CH:3]=[C:2]([Sn:14]([CH3:16])([CH3:15])[CH3:13])[S:6][CH2:5]1
Reactant: CN1C=C(Br)SC1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN1C=C([Sn](C)(C)C)SC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.2 %

Procedure:
A solution of 4.45 g 5-bromo-3-methylthiazole in 50 ml dry ether was cooled to -° C. and treated dropwise over 10 min. with butyllithium (10.5 ml, 26.25 mmol). The mixture was stirred at -° C. for 15 min., and a solution of 5.20 g trimethyltin chloride in 20 ml ether was added dropwise over 10 min. The reaction mixture was allowed to warm to room temperature, stirred overnight, and then washed with water. The ether layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 6.60 g 3-methyl-5-trimethylstannylthiazole as a light-brown liquid used directly in the next reaction.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH:6]=1)C>C(O)C.[OH-].[Na+]>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[CH2:15][CH2:14][O:13][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[O:11][CH3:12])[C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)c1ccc(OC)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)O)cc1OCCc1ccc(Cl)cc1Cl
Yield: 73 %

Procedure:
A solution of 3.6 g (9.8 mmol) of 3-[2-(2,4-dichlorophenyl)ethoxy]-4-methoxybenzoic acid ethyl ester in 30 ml of ethanol and 5.4 ml of 2N sodium hydroxide solution was stirred at room temperature for 12 h. The precipitate was filtered off. The resulting solid was stirred with 5 ml of 2N HCl and filtered to give 2.44 g (73%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=1.[P:26](Cl)([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:25][P:26](=[O:27])([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)(=[O:23])=[O:24])=[CH:20][CH:21]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=1
Reactant: COc1ccc(-c2c(Cl)ncn2-c2ccc(S(N)(=O)=O)cc2)cc1F
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Product: COc1ccc(-c2c(Cl)ncn2-c2ccc(S(=O)(=O)NP(=O)(Oc3ccccc3)Oc3ccccc3)cc2)cc1F
Yield: 10 %

Procedure:
Following a similar procedure to that described in sections a and b of example 12, but using 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (obtained as described in WO 00/23426) instead of 4-[4-chloro-5-(4-ethoxyphenyl)imidazol-1-yl]benzenesulfonamide and diphenyl chlorophosphate instead of diethyl chlorophosphate, the title compound of the example was obtained in 10% yield.
Reaction SMILES: [C:1]1([CH:7]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][NH:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([CH:31]=[C:32]([C:34]([CH3:41])([CH3:40])[C:35]([O:37]CC)=[O:36])[N:33]=4)[N:30]=3)[CH2:17][CH2:16]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([CH:7]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][NH:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([CH:31]=[C:32]([C:34]([CH3:41])([CH3:40])[C:35]([OH:37])=[O:36])[N:33]=4)[N:30]=3)[CH2:17][CH2:16]2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(NC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)O)c1cn2nc(NCCCN3CCC(NC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Yield: 86.6 %

Procedure:
612 mg of ethyl 2-[6-[3-[4-(diphenylmethylamino) piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate was dissolved in 5 ml of ethanol; 2.2 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by thermal refluxing for 6 hours. After cooling, the mixture was concentrated under reduced pressure; the residue was diluted with water, washed with ethyl acetate and ajusted to pH 5 by the addition of 1 N hydrochloric acid. The mixture was saturated with sodium chloride and extracted with tetrahydrofuran; the extract was dried with magnesium sulfate. The dry product was concentrated under reduced pressure, powdered by the addition of ethyl ether, collected by filtration and dried to yield 503 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4=[CH:19][NH:20][CH:21]=[C:15]4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.[NH:23]1[CH:27]=[N:26][N:25]=[N:24]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4=[C:19]([C:27]5[NH:26][N:25]=[N:24][N:23]=5)[NH:20][CH:21]=[C:15]4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: c1nnn[nH]1
Reactant: CC1c2c[nH]cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Product: CC1c2c[nH]c(-c3nnn[nH]3)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 52, (6-chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-methyl-2,4,6,7-tetrahydro-pyrrolo[3,4-c]pyridin-5-yl)-methanone is reacted with 1H tetrazole to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])[CH:4]=1.[CH3:23]OC(=O)C(OC)=O.C[O-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][C:11](=[CH2:23])[C:12]2=[O:22])[CH:4]=1
Reactant: COC1=CC2=CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C=C1C[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@]2(C)C1=O

Procedure:
3-Methoxyandrosta-3,5-dien-17-one (I, 50.0 g) was dissolved in THF containing TEA (1 ml). Dimethyloxalate (55.5 ml) was added and the mixture cooled to 2°. Sodium methoxide (25%) in methanol (45.7 ml) was added slowly over 10 minutes. The ice bath was removed and the reaction warmed to 24° over five minutes with stirring. The mixture was stirred at 20°-25° for 55 minutes, then cooled to 5° over 10 minutes. Acetic acid (2.4 ml) was added, immediately followed by TEA (17.4 ml), then paraformaldehyde (7.49 g), followed by methanol (63 ml). The ice bath was removed and the mixture warmed to 20°-25° over 5 minutes. The mixture was stirred at 28° for 5 hrs and stored in a freezer (-20°) overnight. The mixture was then warmed to 20°-25° and stirred at 25° for 4 hrs for a total time of approximately 9.0 hrs at 20°-28°. Water (300 ml) and ethyl acetate (300 ml) were added, the mixture stirred and the layers separated. The organic layer was washed with saline (2×100 ml). The aqueous portion is backextracted with ethyl acetate (2×100 ml, washing each with 50 ml of saline). The organic phases are combined, concentrated under reduced pressure to an oil, taken up in methylene chloride (450 ml) and ethyl acetate (200 ml). This mixture was dried over sodium sulfate, filtered and concentrated under reduced pressure to a solid. Trituration of the solid with boiling methanol (100 ml) containing 1% TEA gives the title compound in crystalline form.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30]>CC#N>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:30][CH2:29][C:28]([F:32])([F:31])[F:27])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCC(F)(F)F
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=S)NCC(F)(F)F)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.56 g, 1.44 mmol) in CH3CN, was added neat 2,2,2-trifluoroethylamine (0.236 g, 1.74 mmol), dropwise. The reaction was stirred at room temperature until complete by TLC (3 h). The reaction was quenched with saturated aqueous NaHCO3 (15 mL). The aqueous layer was then extracted three times with DCM, and the organic layers were combined, dried with MgSO4, filtered and concentrated. The concentrated mixture was purified via flash column chromatography in a solvent system of 1:1 EtOAc and hexanes, providing (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-(2,2,2-trifluoroethyl)thioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.576 g, 81% yield). 1H NMR (500 MHz, CDCl3) δ 2.00 (6H, s), 2.04 (s, 3H), 3.87-3.90 (m, 1H), 4.03-4.11 (m, 1H), 4.20-4.26 (m, 2H), 4.36 (s, 1H), 5.07 (t, 1H, J=9.6 Hz), 5.27 (t, 1H, J=9.8 Hz), 5.73 (d, 1H, J=8.5 Hz), 6.75 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:15]1[C@H:23]([C:24]([O:26]CC)=[O:25])[CH2:22][C:17]2([S:21][CH2:20][CH2:19][S:18]2)[CH2:16]1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:15]1[C@H:23]([C:24]([OH:26])=[O:25])[CH2:22][C:17]2([S:18][CH2:19][CH2:20][S:21]2)[CH2:16]1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CN1C(=O)CNC(=O)OCc1ccccc1)SCCS2
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCC(=O)N1CC2(C[C@H]1C(=O)O)SCCS2)OCc1ccccc1

Procedure:
Hydrolyze 1.43 g of 7-(N-benzyloxycarbonylglycyl)-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, ethyl ester (prepared as described in paragraph B next above) with sodium hydroxide as described in Example 1D to obtain 7-(N-benzyloxycarbonylglycyl)-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, a colorless oil, [α]D26 -7.9° (ethanol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])=[CH:8][C:7]=1[Cl:19].[Br:20][C:21]1[O:25][C:24]([C:26](O)=[O:27])=[CH:23][CH:22]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(OCC)(=O)C.C(Cl)(Cl)Cl>[Cl:19][C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:11]([Cl:12])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:26]([C:24]1[O:25][C:21]([Br:20])=[CH:22][CH:23]=1)=[O:27]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(Br)o1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a mixture of 0.35 g of 4-(3-aminopropyloxy)-3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)benzene, 0.19 g of 5-bromo-2-furancarboxylic acid, 0.18 ml of triethylamine and 10 ml of chloroform was added 0.23 g of WSC hydrochloride, while stirring at room temperature. After stirring at room temperature for 6 hours, the reaction mixture was concentrated to give a residue. The residue was dissolved in 50 ml of ethyl acetate, and the ethyl acetate layer was successively washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.35 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(5-bromo-2-furancarboxamido)propyloxy)-benzene (64% yield), nD24.0 1.5918.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=3)[CH2:18][CH:17]([NH2:29])[CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1.[C:30](O)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH:8]1([C:13]([N:15]2[CH2:20][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH3:28])=[CH:25][CH:26]=3)[CH2:18][CH:17]([NH:29][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:16]2)=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=C(O)c1ccccc1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)C3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)c3ccccc3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
170 mg (0.41 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-amine trifluoroacetate (Example 8A) and 50 mg (0.41 mmol, 1.0 eq.) of benzoic acid were reacted according to General Method 1. Yield: 58 mg (35% of theory)
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Si:13]([O:20][C@@H:21]1[CH2:26][C@H:25]2[C@H:27]3[C@H:36]([CH2:37][CH2:38][C@:23]2([CH3:24])[C@H:22]1[OH:40])[C:35]1[CH:34]=[CH:33][C:32]([OH:39])=[CH:31][C:30]=1[CH2:29][CH2:28]3)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>>[Si:13]([O:20][C@@H:21]1[CH2:26][C@H:25]2[C@H:27]3[C@H:36]([CH2:37][CH2:38][C@:23]2([CH3:24])[C@H:22]1[O:40][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:35]1[CH:34]=[CH:33][C:32]([O:39][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:31][C:30]=1[CH2:29][CH2:28]3)([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:15])[CH3:14]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]2(C)[C@H]1O
Product: CCCCCCCCCC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]2OC(=O)CCCCCCCCC

Procedure:
With decanoyl chloride, under the conditions described in Example 3(a), 750 mg of 16α-(tert-butyldimethylsilyloxy)-1,3,5(10)-estratriene-3,17β-diol yields 1.10 g of 16α-(tert-butyldimethylsilyloxy)-3,17β-didecanoyloxy-1,3,5(10)-estratriene.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[CH:13]=[C:12]([OH:16])[CH:11]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O)(=O)C.[BH4-].[Na+].O>C(#N)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[CH2:13][C@H:12]([OH:16])[C@@H:11]2[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(N2C(=O)C=C(O)C2Cc2ccc(F)cc2)cc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: N#Cc1ccc(N2C(=O)C[C@H](O)[C@@H]2Cc2ccc(F)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a mixture of 2-chloro-4-[2-(4-fluorobenzyl)-3-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl]benzonitrile (1.00 g) and acetic acid (1.84 mL) in acetonitrile (10 mL) was added sodium borohydride (276 mg) at 0° C. in small portions. The mixture was warmed to room temperature and stirred for 1 hr. Water and saturated brine were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=4:1→ethyl acetate), and recrystallized from tetrahydrofuran-hexane to give the title compound as colorless crystals (yield: 717 mg, 71%).