Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][CH2:14][S:15]([O-:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].CN(C)C=O.S(Cl)(Cl)=O.[CH2:31](O)[CH3:32]>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][CH2:14][S:15]([O:18][CH2:31][CH3:32])(=[O:16])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)([O-])CCc1ccc(OCc2ccccc2)cc1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOS(=O)(=O)CCc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of sodium 4-benzyloxyphenethyl sulfonate (4.84 g) and dimethylformamide (0.5 ml) in toluene (40 ml) is added dropwise thionyl chloride (1.35 ml) and the mixture heated at 90° C. for about 5 hours. The mixture is cooled to room temperature and is added portionwise to a solution of absolute ethanol (30 ml) and pyridine (15 ml) at -20° C. The mixture is stirred for 5 hours while being allowed to warm to 0° C. The mixture is diluted with ethyl acetate and 10% aqueous hydrochloric acid. The organic layer is washed with dilute HCl, water, saturated sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give ethyl 4-benzyloxyphenethyl sulfonate.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][C:19](OCC)=[O:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(N(C(C)C)CC)(C)C>[C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][C:19]([NH:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Reactant: NCCN1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1ncc(-c2ccccc2)c1-c1ccccc1)NCCN1CCCCC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 15 g (0.049 mol) of ethyl 4,5-diphenyl-1H-pyrazole-1-acetate of example 1 and 10.2 mL (0.072 mol) of N-(2-aminoethyl)piperidine in 62 ml of diisopropylethylamine was stirred at 100° C. for 18 hr. Upon cooling and standing a solid precipitate was formed which was filtered off and recyrtallized very slowly from 250 mL of 1:3 THF-ether to yield 10.6 of 4,5-Diphenyl-N-[2-(1-piperidinyl)ethyl]-1H-pyrazole-1-acetamide mp 95°-97° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[CH:10]1([CH:16]=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CC1OCCC1>[CH:10]1([CH2:16][NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(CN)OCC
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC1CCCO1
Product: CCOC(CNCC1CCCCC1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2,2-diethoxyethylamine (209 mL, 1.43 mol) and MeTHF (1050 L) was added cyclohexanecarbaldehyde (107 mL, 0.89 mol). The reaction mixture was stirred for 30 min at room temperature and cooled to 0° C. Sodium triacetoxyborohydride (378 g, 1.79 mol) was added over 40 min and the reaction mixture was stirred for 2 h and cooled to 0° C. 1 M NaOH (1 L) was added. The organic layer was washed with brine in water (1:1, 2×1 L) and the volume was reduced to ˜20%. MeTHF (1 L) was added and the volume reduced to ˜20%. The solution of the crude title intermediate was used directly in the next step.
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@@H:17]([CH2:28][OH:29])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C([C@@H]1C2[C@](C)(CCC(=[O:50])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[OH:29][CH2:28][C@H:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:50])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:2])[CH2:8][CH2:7]3)[CH2:16]1
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[C@]12CCCCC1[C@H](CO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1[C@H](CO)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
The title compound (II-ai) was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-6β-hydroxymethylandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.71-3.47 (m, 3H), 2.82-0.79 (m, 21H), 1.08 (s, 3H), 0.89 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH:27]([OH:39])[C:28]([P:31](=[O:38])([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34])([F:30])[F:29])=[CH:26][C:4]=2[N:3]=1.CS(C)=O.C(OCC)(=O)C>C(OCC)(=O)C>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([C:27](=[O:39])[C:28]([P:31](=[O:38])([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34])([F:29])[F:30])=[CH:26][C:4]=2[N:3]=1
Reactant: CCOP(=O)(OCC)C(F)(F)C(O)c1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3C)cc12
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOP(=O)(OCC)C(F)(F)C(=O)c1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3C)cc12
Temperature: 80 °C

Procedure:
To a solution of diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1,1-difluoro-2-hydroxyethylphosphonate (2-3) (1.0 equiv.) in 1:1 DMSO/ethyl acetate (0.07 M) was added IBX (1.5 equiv.). The reaction was heated to 80° C. for 1 hour, and then cooled to room temperature. The mixture was diluted with ethyl acetate and filtered through celite. The filtrate was washed with water (2×), brine, dried over anhydrous MgSO4, and concentrated in vacuo. The resulting residue was purified by a COMBIFLASH® system (ISCO) using a gradient of 0-5% MeOH/DCM to provide diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)-1,1-difluoro-2-oxoethylphosphonate (2-4) as a solid.
Reaction SMILES: [Cl-].[CH2:2]([NH+:9]1[CH2:13][CH:12]([S:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[C:11]([C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)([C:22]([F:25])([F:24])[F:23])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OCC)(=O)C>[OH-].[Na+]>[CH2:2]([N:9]1[CH2:13][CH:12]([S:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:15])[C:11]([C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)([C:22]([F:23])([F:24])[F:25])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(c1ccccc1)C1C[NH+](Cc2ccccc2)CC1(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=S(c1ccccc1)C1CN(Cc2ccccc2)CC1(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Yield: 80 %

Procedure:
Trifluoroacetic acid (9 μL, 128 μmol) was added to (1E)-2-(3,5-dichlorophenyl)-3,3,3-trifluoroprop-1-en-1-yl phenyl sulfoxide (1.00 g, 93% purity, 2.56 mmol) in toluene (1.28 mL). N-Benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (911 mg, 3.84 mmol) in toluene (8.75 mL) was added at room temperature over one hour. The solvents of the reaction mixture were removed and the crude product was taken up in iso-propanol and the pH was adjusted to 3 with 3.6% hydrochloric acid. After two hours the formed crystals were filtered off. 1-Benzyl-3-(3,5-dichlorophenyl)-4-(phenylsulfinyl)-3-(trifluoro-methyl)pyrrolidinium chloride (1.17 g, 95% purity, 86% yield) was obtained. The hydrochloride was suspended in aqueous sodium hydroxide (2 N, 5 mL) and ethyl acetate was added. The mixture was stirred until two clear phases were formed. The organic phase was separated, dried over sodium sulfate, filtered and evaporated. This procedure yielded 1-benzyl-3-(3,5-dichlorophenyl)-4-(phenylsulfinyl)-3-(trifluoromethyl)pyrrolidine (1.07 g, 95% purity, 80% yield).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[N:8]=[C:9]([CH2:24][CH2:25][CH3:26])[N:10]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][C:12]=3[C:20]([F:23])([F:22])[F:21])[C:6]=2[CH:5]=[CH:4][NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:58][C:59]1[CH:73]=[CH:72][C:62]2[NH:63][C:64]([C@@H:66]([NH2:71])[CH2:67][CH2:68][S:69][CH3:70])=[N:65][C:61]=2[CH:60]=1>O1CCCC1.ClCCl.C(O)C>[Cl:58][C:59]1[CH:73]=[CH:72][C:62]2[NH:63][C:64]([C@@H:66]([NH:71][C:15](=[O:16])[C:14]3[CH:18]=[CH:19][C:11]([N:10]4[C:6]5[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=5[N:8]=[C:9]4[CH2:24][CH2:25][CH3:26])=[C:12]([C:20]([F:21])([F:23])[F:22])[CH:13]=3)[CH2:67][CH2:68][S:69][CH3:70])=[N:65][C:61]=2[CH:60]=1
Reactant: CSCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCCc1nc2c(=O)[nH]ccc2n1-c1ccc(C(=O)O)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCc1nc2c(=O)[nH]ccc2n1-c1ccc(C(=O)N[C@@H](CCSC)c2nc3cc(Cl)ccc3[nH]2)cc1C(F)(F)F
Yield: 40 %

Procedure:
Prepared analogously to Example 1 g from 4-(4-oxo-2-propyl-4,5-dihydroimidazo[4,5-c]-pyridin-1-yl)-3-trifluoromethylbenzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulfanylpropylamine in tetrahydrofuran. Yield: 40%; Rf value: 0.35 (silica gel: dichloromethane/ethanol=9:1); C28H26ClF3N6O2S (603.066).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:60][CH3:61])=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]3[NH:32][C:33]([C:35]4[CH2:40][C@@H:39]([CH2:41][O:42][Si](C(C)C)(C(C)C)C(C)C)[N:38]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:37][CH:36]=4)=[CH:34][C:27]=23)[CH:25]=1>O1CCCC1>[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:60][CH3:61])=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]3[NH:32][C:33]([C:35]4[CH2:40][C@@H:39]([CH2:41][OH:42])[N:38]([C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54])[CH2:37][CH:36]=4)=[CH:34][C:27]=23)[CH:25]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(C(=O)OC(C)(C)C)[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)C3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(C(=O)OC(C)(C)C)[C@H](CO)C3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1M tetrabutylammonium fluoride in tetrahydrofuran (3.1 mL, 3.10 mmol) was added to a solution of Example 260E (627 mg, 1.028 mmol) in tetrahydrofuran (5 mL) and the mixture was stirred at room temperature for 1 hour and concentrated. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0-7% methanol-dichloromethane to give the title compound. MS (ESI+) m/z 454.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]2([CH3:19])[CH3:18])[C:3]([OH:5])=O.[CH3:21][O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.CCN(CC)CC.[NH4+].[Cl-]>O=S(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:20][C:2]([F:1])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH3:16])([CH3:17])[CH2:11][CH2:10][C:9]2([CH3:19])[CH3:18])[C:3]([NH:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]([O:22][CH3:21])=[O:31])=[CH:29][CH:28]=1)=[O:5]
Reactant: CC1(C)CCC(C)(C)c2cc(C(F)(F)C(=O)O)ccc21
Reactant: COC(=O)c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)C(F)(F)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
2,2-Difluoro-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)acetic acid 16 (0.70 g, 2.48 mmol) was dissolved in SOCl2 and two drops of DMF were added at 0° C. This mixture was stirred at 0° C. for 30 min and evaporated in vacuo. The resulting acid chloride was dissolved in CH2Cl2 (5 mL). Methyl-4-aminobenzoate (0.38 g, 2.48 mmol) and DMAP (30 mg, 0.25 mmol) were dissolved in CH2Cl2 (5 mL) and Et3N (2.9 mL) was added at 0° C. The solution of the acid chloride in CH2Cl2 was added and this mixture stirred for 10 min at 0° C. and then abandoned to RT for 1 h. A solution of aqueous NH4Cl 5% was added (200 mL) and the mixture was extracted with EtOAc (3×100 mL). The organic layer was washed with aqueous NaHCO3 5% (2×20 mL), brine (2×20 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude product was purified by chromatography on silica using as eluent cyclohexane:EtOAc=9:1. After evaporation, methyl 4-(2,2-difluoro-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)acetamido)benzoate 17 (0.67 g, 65% yield) was obtained as a beige solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25]>>[CH2:11]1[CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3][CH:2]1[NH:1][C:24]([NH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[Cl:16])=[O:25]
Reactant: O=C=Nc1ccccc1Cl
Reactant: NC1CCN2CCc3ccccc3C2C1
Product: O=C(Nc1ccccc1Cl)NC1CCN2CCc3ccccc3C2C1

Procedure:
By a procedure analogous to that of Example 1, 2-amino-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine is reacted with o-chlorophenyl isocyanate to give the title compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH2:4][CH2:3]1.BrC1C=CC=CC=1C#N.CC1(C)C(C)(C)OB(C2CCC3(OCCO3)CC=2)O1.[NH:44]1[CH2:47][CH:46]([NH:48][C:49](=[O:66])[CH2:50][NH:51][C:52]2[C:61]3[C:56](=[CH:57][CH:58]=[C:59]([C:62]([F:65])([F:64])[F:63])[CH:60]=3)[N:55]=[CH:54][N:53]=2)[CH2:45]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:10]([C:9]1[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=1[CH:5]1[CH2:6][CH2:7][CH:2]([N:44]2[CH2:45][CH:46]([NH:48][C:49](=[O:66])[CH2:50][NH:51][C:52]3[C:61]4[C:56](=[CH:57][CH:58]=[C:59]([C:62]([F:63])([F:65])[F:64])[CH:60]=4)[N:55]=[CH:54][N:53]=3)[CH2:47]2)[CH2:3][CH2:4]1)#[N:11]
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: N#Cc1ccccc1C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: N#Cc1ccccc1Br
Product: N#Cc1ccccc1C1CCC(N2CC(NC(=O)CNc3ncnc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
Reaction of 2-(4-oxocyclohexyl)benzonitrile (prepared by the reaction of 2-bromobenzonitrile with 8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec-7-ene using the sequence described in Example 1 Step A-C) with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]([CH2:18][C@@H:19]2[O:23][CH2:22][C@@H:21]([S:24][C:25](=[O:27])[CH3:26])[CH2:20]2)[C:10](OCC(Cl)(Cl)Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28](OC(=O)C)(=O)C>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[C:10]([N:9]([CH2:18][C@@H:19]1[O:23][CH2:22][C@@H:21]([S:24][C:25](=[O:27])[CH3:26])[CH2:20]1)[O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:11])[CH3:28]
Reactant: CC(=O)S[C@@H]1CO[C@@H](CN(OCc2ccccc2)C(=O)OCC(Cl)(Cl)Cl)C1
Reactant: CC(=O)OC(C)=O
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)S[C@@H]1CO[C@@H](CN(OCc2ccccc2)C(C)=O)C1
Reaction time: 0.17 h

Procedure:
To a room temperature solution, under argon, of 0.188 g of product from Example 71 in 2.3 ml of glacial acetic acid is added 0.269 g of zinc dust. The reaction is stirred 10 minutes and 155 microliter of acetic anhydride is added. The reaction is stirred at room temperature overnight, diluted with ethyl acetate and filtered. The filtrate is concentrated in vacuo to give 0.110 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11]C)=[O:10])=[CH:4][C:3]=1[OH:14].[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22](F)=[C:21]([Cl:26])[CH:20]=1)(=[O:18])=[O:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:14][C:22]1[CH:23]=[CH:24][C:19]([S:16]([CH3:15])(=[O:18])=[O:17])=[CH:20][C:21]=1[Cl:26]
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: COC(=O)C(C)c1ccc(Cl)c(O)c1
Product: CC(C(=O)O)c1ccc(Cl)c(Oc2ccc(S(C)(=O)=O)cc2Cl)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of step (iii) and 3-chloro-4-fluorophenyl methyl sulfone.
Reaction SMILES: [Li]CCCC.[O:6]1[C:10]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:21])[O:19][CH3:20])[CH:14]=[CH:15][CH:16]=2)=[CH:9][N:8]=[CH:7]1.[Cl:22]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:22][C:7]1[O:6][C:10]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:21])[O:19][CH3:20])[CH:14]=[CH:15][CH:16]=2)=[CH:9][N:8]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COC(=O)Nc1cccc(-c2cnco2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)Nc1cccc(-c2cnc(Cl)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
1.6 M nBuLi (9.60 mL, 15.35 mmol) was added dropwise to −78° C. solution of methyl 3-(oxazol-5-yl)phenylcarbamate (1.34 gm, 6.14 mmol) in THF (50 mL). Upon addition the reaction mixture turned red in color. After 60 min, a solution of hexachloroethane (2.18 gm, 9.21 mmol) in THF (10 mL) was slowly added. The reaction was slowly warmed to rt over 30 min. After 2 h at rt the reaction was quenched by slow addition of sat. NH4Cl (20 mL). The mixture was concentrated to remove most of the THF. The mixture was then partitioned between EtOAc (80 mL) and water (30 mL). The organic phase was isolated, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography eluting with a gradient of 0-100% EtOAc/Hexanes to give the product, Methyl 3-(2-chlorooxazol-5-yl)phenylcarbamate, (1.20 gm, 4.75 mmol, 77% yield) as a light yeloow solid. Anal. Calcd. for C11H9ClN2O3 m/z 252.0, found: 253.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH3:32][NH:33][CH:34]1[CH2:38][N:37]([CH3:39])[CH2:36][CH2:35]1>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:33]([CH3:32])[CH:34]4[CH2:35][CH2:36][N:37]([CH3:39])[CH2:38]4)/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CNC1CCN(C)C1
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/N(C)C2CCN(C)C2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To a solution of 50 mg (0.12 mmol) 17-hydroxywortmannin in 0.5 mL CH2Cl2 is added 27.4 mg (0.24 mmol) N,N′-dimethyl-3-aminopyrrolidine. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 25 mg (38%) product as an orange powder.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH2:20]1>CCCCCC.CS(C)=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][CH2:27][CH2:26][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]2[CH2:19][N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=3[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]2=3)=[CH:34][CH:33]=1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: COc1ccc(CCCN2CCCC[C@@H](Cl)C2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(CCCN2CCCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Sodium hydride (39 mg, 0.99 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (6 ml). The obtained suspension was stirred at room temperature for 30 minutes. 5,11-Dihydrodibenzo[b,e][1,4]oxazepine (178 mg, 0.90 mmol) was added to the suspension, and they were stirred at room temperature for 20 minutes and then at 50° C. for 30 minutes. A solution of (R)-3-chloro-1-[3-(4-methoxyphenyl)propyl]homopiperidine (278 mg, 0.99 mmol) in dimethyl sulfoxide (3 ml) was added dropwise into the obtained solution, and they were stirred at 50° C. for 3 hours. The reaction liquid was distributed in saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduce pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (10:1) and then with hexane and ethyl acetate (3:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-[3-(4-methoxyphenyl) propyl]piperidine-2-ylmethyl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (196 mg, 49%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:18]O>>[CH3:18][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:2]([Br:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To an ice cold solution of 3-bromo-5-nitro-benzoic acid (D5) (2.5 g, 10 mmol, 1 equiv) in MeOH (25 ml) was added SOCl2 (1 ml, 15 mmol, 1.5 equiv) dropwise. The resulting solution was allowed to warm to room temperature and was then stirred at 60° C. for 3 h, cooled to room temperature and concentrated in vacuo. The residue was dissolved in AcOEt and the organic layer was washed with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo to give 3-bromo-5-nitro-benzoic acid methyl ester (D11) (2.6 g, 100%) as a yellow solid. RT=3.22 min
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]([OH:8])[C@@H:6]([O:9][CH3:10])[C:5]([CH3:12])([CH3:11])[O:4][C@H:3]1[O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([NH:25][C:26](=[O:28])[CH3:27])[C:20](=[O:24])[O:21]2)=[CH:16][CH:15]=1.[CH3:29][OH:30]>C(Cl)Cl>[CH3:10][O:9][C@H:6]1[C:5]([CH3:11])([CH3:12])[O:4][C@@H:3]([O:13][C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([NH:25][C:26](=[O:28])[CH3:27])[C:20](=[O:24])[O:21]3)=[CH:16][CH:15]=2)[C@@H:2]2[O:1][C:29](=[O:30])[O:8][C@H:7]12
Reactant: CO
Reactant: CO[C@@H]1[C@@H](O)[C@@H](O)[C@H](Oc2ccc3cc(NC(C)=O)c(=O)oc3c2)OC1(C)C
Solvent: ClCCl
Product: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](Oc2ccc3cc(NC(C)=O)c(=O)oc3c2)OC1(C)C

Procedure:
More specifically, triethylamine (0.2 mL) was added to a solution of noviosylated coumarin (45 mg, 0.10 mmol) in methanol (2 mL) at 25° C. After stirring for 48 hours, the solvent was evaporated and the residue purified by preparative TLC (SiO2, DCM-acetone; 4:1) to afford KU-1/A4 (35 mg, 0.086 mmol, 83%) as a white solid. N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy)-2-oxo-2H-chromen-3-yl)acetamide (KU-1/A4). [α]25D=−351.6° (c, 0.06, 50% MeOH in CH2Cl2); 1HNMR (CD3OD 400 MHz) δ 8.58 (s, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.03 (s, 1H), 7.02 (d, J=8.3 Hz, 1H), 5.55 (d, J=2.3 Hz, 1H), 4.10 (dd, J=3.3, 9.6 Hz, 1H), 4.03 (dd, J=2.4, 3.3 Hz, 1H), 3.60 (s, 3H), 3.38 (d, J=9.6 Hz, 1H), 2.21 (s, 3H), 1.30 (s, 3H), 1.13 (s, 3H); 13CNMR (CD3OD 100 MHZ) δ 171.6, 158.9, 158.8, 151.8, 128.9, 125.7, 122.5, 114.3, 114.1, 103.1, 99.2, 84.2, 78.8, 71.5, 68.4, 61.1, 28.2, 22.9, 22.4; IR (film) νmax 3326, 1714, 1674, 1613, 1558, 1553, 1108 cm−1; HRMS (FAB+) m/z 394.1492 (M+H+, C19H24O8 requires 394.1502).