Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:16])[CH2:10][O:11][S:12]([CH3:15])(=[O:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([C@@](N)(C)CO)(OC(C)(C)C)=O>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:16])[CH2:10][O:11][S:12]([CH3:15])(=[O:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)[C@](C)(N)CO
Product: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Yield: 97 %

Procedure:
In the same manner was prepared methanesulfonic acid (R)-2-tert-butoxycarbonylamino-propyl ester (white solid) using the 2-(R)-boc-2-amino-propanol as starting material (yield=14.09 g, 97% yield); 1H NMR (400 MHz, CDCl3) δ ppm 4.55-4.67 (1 H, m), 4.17-4.27 (1 H, m), 4.11-4.17 (1 H, m), 3.90-4.02 (1 H, m), 3.02 (3 H, s), 1.43 (9 H, s), 1.22 (3 H, d, J=6.85 Hz).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=S(=O)(Nc1ccc(I)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.0 g of 4-iodoaniline (9.13 mmol) in 40 ml of acetonitrile there are added 1.48 ml of pyridine (18.26 mmol) and then, dropwise, a solution of 1.28 ml of benzenesulphonyl chloride (10 mmol) in 20 ml of acetonitrile. The reaction mixture is stirred overnight at ambient temperature and the acetonitrile is evaporated off under reduced pressure. The residue is taken up in 1N HCl and extracted with ethyl acetate. The organic phase is washed with brine, dried (MgSO4) and evaporated under reduced pressure. The oily residue obtained is triturated in isopropyl ether until the title product crystallises.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](=[O:25])[C@H:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH2:17].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[CH3:13][O:14][C:15](=[O:25])[CH:16]([NH:17][C:10](=[O:11])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccccc1)NC(=O)CCc1ccc(O)cc1
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
3-(4-hydroxyphenyl)propionic acid (1.0 g, 6.0 mmol), phenylalanine methyl ester (1.2 g, 6.7 mmol) and 1-hydroxybenzotriazole hydrate (1.0 g, 7.4 mmol) were dissolved in dimethylformamide (25 mL). The resulting solution was then placed in a water bath at 0° C. and treated with triethylamine (3.5 mL), followed by stirring for 10 minutes. To the resulting mixture, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.4 g, 7.4 mmol) was added. After removing the water bath, the mixture was stirred for 18 hours at room temperature. The reaction was diluted in water (60 mL), extracted with ethylacetate (EtOAc) (200 mL), dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (column size: 25 mm×150 mm, silica gel 70-230 mesh, eluent: hexane/EtOAc (1/1)) to obtain 1.8 g of the title compound. The yield was 91%. The results of analyses of the compound are as follows:
Reaction SMILES: Br.C1(C)C=C(C)C=C(C)C=1S([N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21](S(C1C(C)=CC(C)=CC=1C)(=O)=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27](S(C1C(C)=CC(C)=CC=1C)(=O)=O)[CH2:28][CH3:29])[CH2:14][CH3:15])(=O)=O.C1(O)C=CC=CC=1.C(Cl)(Cl)[Cl:63]>>[ClH:63].[ClH:63].[ClH:63].[CH3:29][CH2:28][NH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:13][CH2:14][CH3:15]
Reactant: ClC(Cl)Cl
Reactant: CCN(CCCCCN(CCCCCN(CC)S(=O)(=O)c1c(C)cc(C)cc1C)S(=O)(=O)c1c(C)cc(C)cc1C)S(=O)(=O)c1c(C)cc(C)cc1C
Agent: Br
Solvent: Oc1ccccc1
Product: CCNCCCCCNCCCCCNCC
Product: Cl
Yield: 77 %

Procedure:
HBr (30% in HOAc, 20 mL), 56 (2.9 g, 3.67 mmol), and phenol (3.25 g, 34.5 mmol) in CHCl3 (27 mL) were reacted, and product was isolated by the method of 2 to give 1.0 g (77%) of 26 as white crystals: NMR (D2O) δ 1.28 (t, 6 H, J=7), 1.45 (m, 4 H), 1.73 (m, 8 H), 3.08 (m, 12 H). Anal. (C14H36Cl3N3) C, H, N.
Reaction SMILES: [Na].[S:2](=[C:5]([CH2:13][CH3:14])[CH2:6][C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)(=[O:4])=[O:3].[CH3:15]I>>[CH3:15][N:11]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:6][C:5](=[S:2](=[O:4])=[O:3])[CH2:13][CH3:14])[CH2:12]1
Reactant: CCC(Cc1cnccn1)=S(=O)=O
Reactant: CI
Agent: [Na]
Product: CCC(CC1=NC=CN(C)C1)=S(=O)=O

Procedure:
3.2 g of 2-(2-sulfonylbutyl)pyrazine (900) was added to a solution of 10 ml methyl iodide/25 ml methanol and the mixture refluxed for 4 days. It was then concentrated and purified by gel permeation chromatography (Biogel P-2/water). Freeze-drying gave 2.9 g of an amorphous solid (1000) which was crystallized from ethyl acetate/propanol, m.p. 224°-5° (dec.). UV H2O max: 283 (3.88).
Reaction SMILES: [C:1]1([C@H:13]2[C@@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:27])[NH:15][C:14]2=[O:28])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.N1C2C(=CC=CC=2)CCC1.N1C2C(=CC=CC=2)C(CC(N)=O)=C1.COC(=O)C=O>>[C:1]1([C:13]2[C:14](=[O:28])[NH:15][C:16](=[O:27])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@H]1c1c[nH]c2ccccc12
Agent: COC(=O)C=O
Agent: NC(=O)Cc1c[nH]c2ccccc12
Agent: c1ccc2c(c1)CCCN2
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccccc12

Procedure:
Preferred embodiments of the invention include mixtures of compounds of formula IVa and IVb, including racemic mixtures. In another preferred embodiment, the compounds of formula IVa and IVb are the separate enantiomers of (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione. In this embodiment the preparation of (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione is prepared as a mixture beginning with the starting materials 1,2,3,4-tetrahydroquinoline and indole-3-acetamide. The 1,2,3,4-tetrahydroquinoline is converted into 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester as described in Example 1, steps 1-5. The 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester is reacted with indole-3-acetamide as described in Example 1, step 6, to yield 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrole-2,5-dione. The mixture of (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione is then prepared by catalytic hydrogenation as described in Example 2 using Procedure B.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:13]([CH2:29][CH2:30][N:31]=3)[C:14]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)=[N:15][C:16]=2[C:17]=1[O:18][CH3:19].C(N(CC)C(C)C)(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>CN(C)C=O>[CH3:19][O:18][C:17]1[C:16]2[N:15]=[C:14]([NH:20][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=3)[N:13]3[CH2:29][CH2:30][N:31]=[C:12]3[C:11]=2[CH:10]=[CH:9][C:8]=1[O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:42]([CH3:41])(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(OCCOCCN)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(OCCOCCNS(C)(=O)=O)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.4 %

Procedure:
N-{8-[2-(2-Aminoethoxy)-ethoxy]-7-methoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl}-nicotinamide (Step 4, 75 mg, 0.18 mmol) was dissolved in dimethylformamide (2 mL). N,N-diisopropylethylamine (0.03 mL) was added, followed by methanesulfonyl chloride (0.01 mL, 0.14 mmol). The mixture was stirred at rt for 3 h, then was quenched by the addition of water. Saturated aqueous sodium bicarbonate was added, and the mixture was extracted several times with dichloromethane. The combined organic extracts were dried and concentrated to afford a residue, which was purified by preparative HPLC (gradient elution of 10-70% acetonitrile in water, 0.1% TFA). The product fractions were free based with saturated aqueous sodium bicarbonate, and the desired was isolated by extraction with dichloromethane. The organic layer was dried over sodium sulfate, and concentrated to give the title compound (8.7 mg, 12%). HPLC MS RT=1.79 min, MH+=503.2. 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.89 (3H, s), 3.11 (2H, t), 3.56 (2H, t), 3.85 (2H, m), 4.03 (3H, s), 4.26 (2H, m), 4.43 (2H, m), 4.57 (2H, m), 7.50 (1H, d), 7.86 (1H, m), 8.02 (1H, d), 8.83 (1H, m), 8.94 (1H, m), 9.47 (1H, m).
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH:67]1([CH2:73][NH2:74])[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]1>ClCCl>[CH:67]1([CH2:73][NH:74][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([N:13]3[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH:7]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:15][CH2:14]3)[CH:17]=2)[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]1
Reactant: O=C(O)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Reactant: NCC1CCCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCC1CCCCC1)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
The compound (0.12 g) prepared in step (c) of Example 1 was dissolved in dichloromethane (5 ml), and a BOP reagent (0.16 g) and diisopropylethylamine (0.078 ml) were added to the solution. The mixture was stirred at room temperature for 30 min. Cyclohexanemethylamine (0.057 ml) was then added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by preparative TLC (hexane:ethyl acetate=1:1) to give 0.13 g (91.6%) of N-cyclohexylmethyl-3-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]benzamide.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:54])([F:53])[C:10]1[CH:11]=[C:12]([C@H:20]2[O:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[C:32]([C:33]4[C:34]([O:46][CH3:47])=[N:35][CH:36]=[C:37]([C:39]([OH:45])([CH3:44])[C:40]([F:43])([F:42])[F:41])[CH:38]=4)=[CH:31][N:30]=[C:29](S(C)(=O)=O)[N:28]=3)[C@H:21]2[CH3:52])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.Cl.[F:56][CH:57]1[CH2:60][NH:59][CH2:58]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.C1COCC1>[F:8][C:9]([F:54])([F:53])[C:10]1[CH:11]=[C:12]([C@H:20]2[O:24][C:23](=[O:25])[N:22]([CH2:26][C:27]3[C:32]([C:33]4[C:34]([O:46][CH3:47])=[N:35][CH:36]=[C:37]([C:39]([OH:45])([CH3:44])[C:40]([F:43])([F:42])[F:41])[CH:38]=4)=[CH:31][N:30]=[C:29]([N:59]4[CH2:60][CH:57]([F:56])[CH2:58]4)[N:28]=3)[C@H:21]2[CH3:52])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1
Reactant: COc1ncc(C(C)(O)C(F)(F)F)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: FC1CNC1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ncc(C(C)(O)C(F)(F)F)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 60 °C

Procedure:
Triethylamine (0.218 mL, 1.566 mmol) was added to a mixture of THF (2 mL), (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-{2-methoxy-5-[(2RS)-1,1,1-trifluoro-2-hydroxypropan-2-yl]pyridin-3-yl}-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Step B, 220 mg, 0.313 mmol) and 3-fluoroazetidine hydrochloride (105 mg, 0.939 mmol). The reaction was placed under nitrogen and heated to 60° C. for 45 minutes; LCMS showed complete conversion to product. The reaction was diluted with 20 mL ethyl acetate and poured into 20 mL 10% citric acid, The organic layer was washed with 30 mL brine, then dried over sodium sulfate and concentrated. Purification on an X-Bridge 21.2×150 mm RP column with sample loaded using 7:3:1 CH3CN/water/DMSO (3 mL) employed a 10-100% acetonitrile/water (0.1% NH4OH) linear gradient at 15 mL/minutes over 20 minutes. The product of interest eluted in 70% portion of the above gradient. Rich cut of pure product peak was lyophilized to give product as a white solid. LCMS (M+H)+: 698.5. 1H NMR (500 MHz, CDCl3): 1:1 diasteromeric mixture: δ 8.38 (m, 1H), 8.26 (s, 0.5H), 8.24 (s, 0.5H), 7.91 (bs, 1H), 7.82 (m, 0.5H), 7.79 (d, J=2.2 Hz, 0.5H), 7.74 (s, 1H), 7.71 (s, 1H), 5.62 (d, J=8.4 Hz, 0.5H), 5.55 (m, 0.5H), 5.44 (m, 0.5H), 4.86 (m, 0.5H), 4.72 (d, J=16.5 Hz, 0.5H), 4.52 (m, 2.5H), 4.33 (m, 3H), 4.00 (s, 1.5H), 3.42 (bs, 0.5H), 3.28 (s, 0.5H), 3.99 (s, 1.5H), 1.85 (s, 3H), 0.77 (d, J=6.6 Hz, 1.5H), 0.73 (d, J=6.6 Hz, 1.5H). RTA IC50: 14 Nm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:20](B(O)O)=[CH:21][S:22][CH:23]=1>>[CH2:12]([NH:11][C:9](=[O:10])[C:8]([CH3:17])([C:5]1[CH:6]=[CH:7][C:2]([C:20]2[C:19]([CH3:18])=[CH:23][S:22][CH:21]=2)=[CH:3][CH:4]=1)[CH3:16])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Reactant: Cc1cscc1B(O)O
Product: Cc1cscc1-c1ccc(C(C)(C)C(=O)NCC(C)C)cc1
Yield: 67 %

Procedure:
Prepared in a similar manner to Example 1 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and 4-methylthiophen-3-ylboronic acid. Yield: 67%. 1H NMR (400 MHz, dDMSO): δ 0.73-0.79 (d, 6H), 1.48 (s, 6H), 1.67-1.74 (m, 1H), 2.23 (s, 3H), 2.84-2.87 (m, 2H), 7.26-7.27 (m, 1H), 7.34-7.40 (m, 5H), 7.43-7.44 (d, 1H). MS(M+H, 316).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:5](=O)[CH3:6].[Cl-].[OH:13][NH3+:14]>CO.O.N1C=CC=CC=1>[CH3:1][O:2][N:3]=[C:4]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:5](=[N:14][OH:13])[CH3:6]
Reactant: C=C(C)CC(=NOC)C(C)=O
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: c1ccncc1
Product: C=C(C)CC(=NOC)C(C)=NO
Temperature: 23 °C
Reaction time: 3 h

Procedure:
283.4 g of 5-methylhex-5-ene-2,3-dione 3-(O-methyloxime) in 800 ml of methanol were added dropwise to the solution of 140.6 g of hydroxylammonium chloride in 400 ml of water and 216.7 g of pyridine, and the mixture was stirred at 23° C. for 3 hours. The solvent was then removed under reduced pressure and the residue was poured into ice-water. The pH was subsequently adjusted to 1 using 20% strength sulfuric acid, and the precipitated product was filtered off with suction, taken up in methyl tert-butyl ether and washed with water. The organic phase was then dried over sodium sulfate and the solvent was removed under reduced pressure. This gave 266 g of the title compound as a colorless solid.
Reaction SMILES: BrC1C=CC=C2C=1C=CN2.[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:23])[C:16](=[O:22])[NH:17]2.BrCCCCC.Br[CH2:31][C:32]1[O:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=1>>[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:23])[C:16](=[O:22])[N:17]2[CH2:31][C:32]1[O:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: COc1cccc2c1C(=O)C(=O)N2
Agent: Brc1cccc2[nH]ccc12
Solvent: CCCCCBr
Product: COc1cccc2c1C(=O)C(=O)N2Cc1ccc(C(F)(F)F)o1

Procedure:
Following the procedure as described in PREPARATION 1A, and making non-critical variations to replace 4-bromoindole with 4-methoxy-1H-indole-2,3-dione, and 1-bromopentane with 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (26%): MS (ES+) m/z 348.2 (M+23).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([OH:38])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:40](OC(=O)C)(=[O:42])[CH3:41].N1C=CC=CC=1>C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([O:38][C:40](=[O:42])[CH3:41])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4[C@@H](O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@H](O)[C@H]2[C@@H](CC[C@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]32C)[C@@H]2C[C@@H]3O[C@]4(CC[C@@H](C)CO4)[C@@H](C)[C@@H]3[C@@]12C

Procedure:
(3β,5α,11β,12β,25R)-3-(t-butyldimethylsilyloxy)spirostan-11,12-diol was selectively acetylated with acetic anhydride, pyridine and dimethylaminopydriine in methylene chloride to give the title compound.
Reaction SMILES: C(Cl)Cl.[C:4]([O:8][C:9]([N:11]1[CH2:14][CH:13]([O:15][C:16]2[CH:17]=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])[CH:19]=[CH:20][C:21]=2[CH:22]=[O:23])[CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].C1C=C(Cl)C=C(C(OO)=[O:42])C=1>CCOC(C)=O>[C:4]([O:8][C:9]([N:11]1[CH2:12][CH:13]([O:15][C:16]2[CH:17]=[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:31])[F:32])[CH:19]=[CH:20][C:21]=2[C:22]([OH:42])=[O:23])[CH2:14]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(-c3ccccc3C(F)(F)F)ccc2C=O)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(-c3ccccc3C(F)(F)F)ccc2C(=O)O)C1
Reaction time: 15 h
Yield: 37.2 %

Procedure:
To a CH2Cl2 (6 mL) solution of the title compound of Step A (0.236 g, 0.560 mmol) was added m-CPBA (77 wt %, 0.189 g, 0.840 mmol). After 15 h, 10% Na2S2O5 was added and the solution allowed to stir until the aqueous was Kl paper negative and extracted with CH2Cl2 (2×). The combined organic layers were dried and treated with MeOH (10 mL) and 1N NaOH (10 mL). After 15 h, the reaction was partially concentrated to remove the MeOH and acidified with 1M HCl (220 mL) then extracted with EtOAc (2×). The combined organic layers were dried and concentrated. Silica gel chromatography (0-30% EtOAc in hexanes) gave 0.091 g (37% yield) of the title compound. (MS (ESI): mass calcd. for C22H22F3NO5, 437.15. m/z found, 382.1 [M-56]+, 460.1 [M+Na]+. 1H NMR (CDCl3): 7.73 (d, J=7.8 Hz, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 6.87 (dd, J=8.2, 1.9 Hz, 1H), 6.52 (d, J=1.0 Hz, 1H), 4.97-4.88 (m, 1H), 4.30 (dd, J=9.8, 6.4 Hz, 2H), 4.05 (dd, J=9.9, 3.7 Hz, 2H), 1.45 (s, 9H)) and 0.091 g (39% yield) of 3-(4-Hydroxy-2′-trifluoromethyl-biphenyl-3-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (MS (ESI): mass calcd. for C21H22F3NO4, 409.15. m/z found, 354.1 [M-56]+, 432.1 [M+Na]+. 1H NMR (CDCl3): 8.19 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.61 (t, J=7.2 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.32 (d, J=7.5 Hz, 1H), 7.12 (dd, J=8.0, 1.3 Hz, 1H), 6.63 (s, 1H), 5.11-5.00 (m, 1H), 4.36 (dd, J=10.1, 6.4 Hz, 2H), 4.12 (dd, J=10.6, 3.6 Hz, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11](O)=[O:12])[CH2:6]1)=[O:4].S(C)C>C1COCC1>[OH:12][CH2:11][CH:7]1[CH2:8][CH2:9][CH2:10][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1
Reactant: COC(=O)C1CCCC(C(=O)O)C1
Solvent: C1CCOC1
Solvent: CSC
Product: COC(=O)C1CCCC(CO)C1
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a cold (−78° C.) solution of 3-(methoxycarbonyl)cyclohexanecarboxylic acid (1.25 g, 6.71 mmol) in THF (20 mL) was added BH3.Me2S (0.7 mL, 7.38 mmol). The resulting mixture was stirred at −78° C. to room temperature overnight. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give methyl 3-(hydroxymethyl)cyclo-hexanecarboxylate as a colorless oil (845 mg, yield; 73%). To a solution of methyl 3-(hydroxymethyl)cyclohexanecarboxylate (840 mg, 4.88 mmol) in Et3N (4.4 mL, 32 mmol) and DMSO (10 mL) was added sulfur trioxide-pyridine complex (2.56 g, 16.1 mmol). The mixture was stirred at room temperature for 1 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give methyl 3-formylcyclohexanecarboxylate as a pale yellow oil (795 mg, yield; 96%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCCSc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)CCCCCSc1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.4 %

Procedure:
To a degassed solution of 6-(4-bromo-phenylsulfanyl)-hexanoic acid methyl ester (500 mg, 1.58 mmol) in ethylene glycol dimethyl ether (20 mL) was added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (131 mg, 0.16 mmol). The resulting mixture was stirred for 5 min at room temperature under an argon atmosphere. 4-Chlorophenylboronic acid (494 mg, 3.16 mmol) was added. A solution of cesium carbonate (1.8 g, 5.54 mmol) in water (3 mL) was added. The mixture was stirred at reflux for 1 hour, allowed to cool down to room temperature and concentrated under reduced pressure. The residue was taken up in ethyl acetate (75 mL). This solution was washed with saturated aqueous sodium hydrogen carbonate (2×50 mL), distilled water (2×50 mL) and brine (2×50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (5:95 to 10:90 diethyl ether:40-60° C. petroleum ether) to give a solid that was recrystallised from diethyl ether/40-60° C. petroleum ether to give the title compound (465 mg, 84%) as a solid, mp 87-88° C.