Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S].[CH3:2][NH:3][C:4]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[N:12]=[CH:13][NH:14][C:15]=1[CH3:16])=[S:5].[N:17]#[C:18][NH2:19]>[Hg].N#CN.[Cd]>[C:18]([NH:19][C:4]([NH:3][CH3:2])=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[N:12]=[CH:13][NH:14][C:15]=1[CH3:16])#[N:17].[CH3:2][NH:3][C:4]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[N:12]=[CH:13][NH:14][C:15]=1[CH3:16])=[S:5]
Reactant: N#CN
Agent: CNC(=S)NCCSCc1nc[nH]c1C
Agent: [Cd]
Agent: [Hg]
Product: CNC(=NCCSCc1nc[nH]c1C)NC#N

Procedure:
The compounds of Formula I wherein E is sulphur are also useful as intermediates for the production of compounds of Formula I wherein E is NCN, for example, N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea may be reacted with a heavy metal salt of cyanamide such as lead, mercury or cadmium cyanamide to yield N-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]guanidine or N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-thiourea may be alkylated and the product reacted with cyanamide and a suitable strong base such as potassium t-butoxide to yield N-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]guanidine.
Reaction SMILES: [OH:1][C:2]([CH3:11])([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH2:12]([O:19][C:20]([NH:22][C@H:23]([C:28](O)=[O:29])[CH2:24][CH2:25][S:26][CH3:27])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN(C1C=CN=CC=1)C.ClCCl>[CH2:12]([O:19][C:20]([NH:22][C@@H:23]([CH2:24][CH2:25][S:26][CH3:27])[C:28]([O:1][C:2]([CH2:3][N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1)([CH3:11])[CH3:10])=[O:29])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(O)CN1CCOCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)CN1CCOCC1
Yield: 40 %

Procedure:
A solution of N-(2-hydroxy-2-methylpropyl)morpholine (9.8 g, 62 mmol), N-benzyloxycarbonyl-L-methionine (12.6 g, 44 mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (25 g, 54 mmol), DMAP (5.4 g, 44 mmole) in dichloromethane (250 ml) was stirred, in the presence of 4 Å molecular sieves (5 g), at ambient temperature for 48 h. After evaporation to dryness, the mixture was taken up in diethyl ether and the insoluble material eliminated by filtration. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated solution of brine, evaporated to dryness and purified by flash column chromatography eluting with dichloromethane/ethanol (98:2) to give 2-(morpholinomethyl)prop-2-yl (2S)-2-(benzyloxycarbonylamino)-4-methylsulfanylbutyrate (40%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[N:23]=[C:22]([NH2:27])[N:21]=1>>[F:19][C:20]1[CH:25]=[C:24]([F:26])[N:23]=[C:22]([NH:27][CH2:3][C:4]2[N:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:21]=1
Reactant: ClCc1c(-c2ccccc2)nc2ccccn12
Reactant: Nc1nc(F)cc(F)n1
Agent: Cl
Product: Fc1cc(F)nc(NCc2c(-c3ccccc3)nc3ccccn23)n1
Yield: 17 %

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-2-phenylimidazo[1,2-a]pyridine hydrochloride and 4,6-difluoropyrimidin-2-amine. (0.10 g, 17% yield), M/e− 338.2 for C18H13F2N5 (M+H)+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:6][C:7]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10].Cl>C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:9]([C:8]1[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:7]=1[Cl:6])=[O:10]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: c1ccsc1
Agent: Cl
Solvent: c1ccccc1
Product: O=C(c1cccs1)c1ccc(F)cc1Cl
Reaction time: 3 h

Procedure:
To a stirred mixture of 25.25 parts of thiophene, 58.1 parts of 2-chloro-4-fluorobenzoyl chloride and 200 parts of anhydrous benzene are added dropwise 78.16 parts of stannic chloride (fuming) at room temperature (slightly exothermic reaction: the temperature is kept for 3 hours at 25° C). The reaction mixture is poured onto a mixture of crushed ice and concentrated hydrochloric acid solution. The whole is stirred for a few minutes and the layers are separated. The organic layer is diluted with 80 parts of toluene, washed successively with 200 parts of sodium hydroxide solution 5% and with 200 parts of water, dried and evaporated. The residue is distilled, yielding 2-chloro-4-fluorophenyl 2-thienyl ketone; bp. 129°-130° C at 0.5 mm pressure. 7.2 parts of sodium hydride dispersion 55% are suspended three times in benzene and the latter is decanted each time. Then there are added successively 150 parts of hexamethylphosphoramide and dropwise 26.1 parts of diethyl 2-methylmalonate. The mixture is slightly heated and when the reaction is ceased, there are added 36.1 parts of 2-chloro-4-fluorophenyl 2-thienyl ketone. The whole is stirred for 6 hours at 100° C. The reaction mixture is cooled and 320 parts of benzene are added. The organic phase is washed twice with water, dried and evaporated. The residue is distilled, yielding diethyl 2-[3-chloro-4-(2-thenoyl)phenyl]-2-methylmalonate; bp. 225°-235° C at 0.6-0.8 mm pressure.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:13])[CH2:5][CH2:6][CH2:7][C:8]([O:11][CH3:12])([CH3:10])[CH3:9].[CH3:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>>[CH3:12][O:11][C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:13])[CH2:3][CH2:2][O:24][C:21]1[CH:20]=[CH:19][C:18]([S:15]([CH3:14])(=[O:17])=[O:16])=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: COC(C)(C)CCCC(C)CCBr
Product: COC(C)(C)CCCC(C)CCOc1ccc(S(C)(=O)=O)cc1

Procedure:
By use of the process of either Example 1(B) or 10(D), 1-bromo-7-methoxy-3,7-dimethyloctane is reacted with 4-(methylsulfonyl)phenol to yield 1-(7'-methoxy-3',7'-dimethyloctyloxy)-4-(methylsulfonyl)benzene. ##STR16##
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:9]2[C:8](=[O:31])[NH:7][C:6]1=[O:32])[CH:2]([CH3:4])[CH3:3].Cl.Cl[CH2:35][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([N:5]1[C:10]2=[N:11][N:12]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[C:9]2[C:8](=[O:31])[N:7]([CH2:35][C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[C:6]1=[O:32])[CH:2]([CH3:4])[CH3:3]
Reactant: ClCc1ccncc1
Reactant: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc21
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)Cn1c(=O)n(Cc2ccncc2)c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc21

Procedure:
This compound was synthesized by the reaction of 7-isobutyl-2-(1-naphthylmethyl)-3-pyridin-4-yl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 4-(chloromethyl)pyridine hydrochloride using DBU as a base. Mass: 516.88 (M+H).
Reaction SMILES: C(N(CC)C([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([C:14]1[C@H:15]([CH3:45])[C@@H:16]2[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=O)=O)C.C1(S)C=CC=CC=1>>[Si:37]([O:36][C@@H:34]([C@H:33]1[C:32](=[O:44])[N:17]2[C:18]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)=[O:20])=[C:14]([S:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:6]=3)[C@H:15]([CH3:45])[C@H:16]12)[CH3:35])([C:40]([CH3:41])([CH3:42])[CH3:43])([CH3:39])[CH3:38]
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2[C@H]1C
Agent: Sc1ccccc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccccc3)[C@H](C)[C@H]12
Yield: 72 %

Procedure:
Following a procedure similar to that described in Example 21(b), but using 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 39) and thiophenol as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as crystals in a yield of 72%. Recrystallization of this product from a mixture of ethyl acetate and hexane afforded crystals of the title compound melting at 149° to 150° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCc1oc(N2CCN(c3ccccc3)CC2)nc1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 52.8 %

Procedure:
A mixture of 3-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]propionic acid (1.0 g), 1-phenylpiperazine (2.27 g), potassium carbonate (2.42 g) and N,N-dimethylformamide (20 mL) was stirred at 100° C. for 3 hrs. The reaction mixture was poured into aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography and 3-[4-(4-chlorophenyl)-2-(4-phenyl-l-piperazinyl)-5-oxazolyl]propionic acid (0.76 g, yield 53%) was obtained as a powder from a fraction eluted with ethyl acetate-chloroform-methanol (10:10:1, volume ratio). Recrystallization from ethyl acetate gave colorless prism crystals. melting point: 177–178° C.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].Br[C:8]1[CH:13]=[CH:12][C:11]([B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)=[CH:10][CH:9]=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]([OH:6])([C:4]#[C:5][C:8]1[CH:13]=[CH:12][C:11]([B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)=[CH:10][CH:9]=1)[CH3:3]
Reactant: C#CC(C)(C)O
Reactant: CC1(C)OB(c2ccc(Br)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1

Procedure:
2-Methyl-but-3-yn-2-ol (24 ml; 247 mmol), 2-(4-bromo-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (8.7 g; 30.85 mmol) (J.Organomet. Chem. 2006, 691(26), 5725), Pd(PPh3)2Cl2 (4.33 g; 6.17 mol) Cul (1.17 g; 6.17 mmol) in DMF (140 ml) and triethylamine (60 ml) are heated to 110° C. for 20 minutes. The reaction mixture is evaporated to dryness and the residue taken up in hexanes/acetone (85:15), filtered and the filtrate purified via chromatography ((SiO2; hexaneslacetone 85:15) to deliver the target compound as light-brown crystals. 1H-NMR (400 MHz; DMSO-d6): 7.65 (d, 2H); 7.40 (d, 2H); 5.51 (s, 1H); 1.48 (s, 6H); 1.31 (s, 12H). MS (m/z) ES+: 269 (100).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@H:10]([OH:25])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:33]([Si:37]([CH3:40])([CH3:39])Cl)([CH3:36])([CH3:35])[CH3:34].N1C=CN=C1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CO.C1COCC1.O>[C:1]([NH:8][C@@H:9]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@H:10]([O:25][Si:37]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:40])[CH3:39])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@@H](Cc1ccc(C#N)cc1)C(=O)O)O[Si](C)(C)C(C)(C)C

Procedure:
In analogy with Example 1j), 0.62 g of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(p-cyano-phenyl)methyl]hexanoic acid in 6.2 ml of DMF is silylated with 0.98 g of tert-butyldimethylchlorosilane and 0.79 g of imidazole. Hydrolysis of the silyl ester function with 1.2 g of potassium carbonate in 31 ml of methanol/THF/water, 3:1:1, yields the title compound, after acidifying with citric acid solution and extracting with ethyl acetate: TLC Rf (D)=0.29; FAB-MS (M+H)+ =553.
Reaction SMILES: C([O:5][C:6](=[O:46])[CH:7]([NH:12][C:13](=[O:45])[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[S:21][S:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:30](=[O:44])[NH:31][CH:32]([C:37]([O:39]C(C)(C)C)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>ClCCl>[C:37]([CH:32]([NH:31][C:30]([C:24]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=1[S:22][S:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:13]([NH:12][CH:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:46])=[O:5])=[O:45])=[O:44])[CH2:33][CH:34]([CH3:36])[CH3:35])([OH:39])=[O:38]
Reactant: CC(C)CC(NC(=O)c1ccc(F)cc1SSc1cc(F)ccc1C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC(NC(=O)c1ccc(F)cc1SSc1cc(F)ccc1C(=O)NC(CC(C)C)C(=O)O)C(=O)O
Yield: 62.5 %

Procedure:
This compound was prepared according to the procedure described in Example 50 using [S-(R*,R*)]-2-[2-[2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-5-fluoro-phenyldisulfanyl]-4-fluorobenzoylamino]-4-methyl-pentanoic acid tert-butyl ester (3.1 g, 4.5 mmol) from Example 27, 30 mL dichloromethane, 30 mL trifluoroacetic acid, and 3.0 mL anisole. The crude product was recrystallized from dimethylformamide/methanol/water to afford 1.6 g of the title compound, mp 261-262° C.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Ce+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[C:26]1([CH3:35])[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH3:35][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:35])=[CH:27][CH:28]=2)=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Ce+3]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)c2ccc(C)cc2)cc1
Reaction time: 48 h
Yield: 60.9 %

Procedure:
Cerium(III) trifluoromethanesulfonate (3.23 g as a wet solid) and para-toluic acid (1.36 g) were refluxed together in 125 mL toluene as in Example 3, but for 48 hours., After work-up (as in Example 3) crude 4,4′-dimethylbenzophenone (0.64 g, 30% yield) was obtained as a cream-colored crystalline solid.
Reaction SMILES: CC1C=CC(S([N:11]2[C@H:20]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)(=O)=O)=CC=1.[Mg]>CO>[N:24]1([CH2:23][CH2:22][CH2:21][C@@H:20]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][NH:11]2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccccc3C[C@H]2CCCN2CCOCC2)cc1
Agent: [Mg]
Solvent: CO
Product: c1ccc2c(c1)CN[C@H](CCCN1CCOCC1)C2
Reaction time: 96 h

Procedure:
To a solution of 1.50 g (3.62 mmol) of the compound obtained in Step E in 20 mL of anhydrous methanol there are added 2.0 g (82.3 mmol), in portions, of magnesium turnings. The batch is stirred in the presence of ultrasound for 96 hours. The reaction mixture is then filtered, the solid is washed several times with methanol, and the filtrate is concentrated to dryness. After purification by chromatography over silica gel using dichloromethane and ammonia-in-ethanol as eluants, the expected product is obtained in the form of an oil.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:13][C:14]([F:25])([F:26])[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])[CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCCCc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C1c2ccccc2CN1CCCc1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (1.13 g, 4.9 mmol), 3-(3-trifluoromethyl-phenyl)-propylamine (1 g, 4.9 mmol), and K2CO3 (1.13 g, 8.17 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[3-(3-trifluoromethyl-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.658 g, 49%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.02 (m, 2H), 2.76 (t, 2H), 3.69 (t, 2H), 4.36 (s, 2H), 7.36-7.56 (m, 7H), 7.84 (d, 1H). GC-MS: m/z 319 (M)+.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][C:22](O)=[O:23])[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35])(C(C)(C)C)(C)C.[NH3:37].C(O)C.Cl>>[OH:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][C:22]([NH2:37])=[O:23])[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35]
Reactant: N
Reactant: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Agent: Cl
Solvent: CCO
Product: C[C@H](CCC(N)=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24 oic acid (1.0 g) is reacted with ammonia and hydrolysed with ethanol/HCl following the procedure outlined in example to give the title compound (147 mg). Melting point: 233-235° C. 1H-NMR (CDCl3, 400 MHz)): δ=5.36 (1H, s); 5.45-5.2 (2H, broad d); 3.25 (1H, m). MS: Calculated: 399.6. Found 399.3.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].C(O)(=O)C.C(O)(=O)C.[CH:64]1[C:73]2[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH:67]=[CH:66][C:65]=1[Bi](C1C=CC2C(=CC=CC=2)C=1)C1C=CC2C(=CC=CC=2)C=1.C(O)(=O)C.C(=O)(O)O.C1C2C(=CC=CC=2)C=CC=1[Bi](C1C=CC2C(=CC=CC=2)C=1)C1C=CC2C(=CC=CC=2)C=1>C(Cl)Cl.C([O-])(O)=O.[Na+].CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:66]3[CH:65]=[CH:64][C:73]4[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=4)[CH:67]=3)[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: c1ccc2cc([Bi](c3ccc4ccccc4c3)c3ccc4ccccc4c3)ccc2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(Oc4ccc5ccccc5c4)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 40 °C

Procedure:
To a stirred mixture of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,-10,16-tetraone (250 mg, 0.32 mmol, 1 eq) and Cu(OAc)2 (10 mg, 0.055 mmol, 0.17 eq) in CH2Cl2 (5.5 ml) in a round bottom flask equipped with a magnetic stir-bar was added tri(2-naphthyl) bismuth diacetate [prepared immediately prior to use by addition of acetic acid (0.100 ml, 1.75 mmol, 5.46 eq) to a suspension of tri(2-naphthyl)bismuth carbonate (350 mg, 0.538 mmol, 1.7 eq) in CH2Cl2 (5.5 ml)]. The reaction flask was fitted with a reflux condenser and the mixture warmed to 40° C. for 4 hours then stirred at room temperature. After 3 days the reaction mixture was diluted with saturated aqueous NaHCO3 and extracted 3 times with CH2Cl2. The extracts were combined, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The products were separated and purified by preparative TLC on silica gel (eluted with 3:1 hexanes/acetone) to give 63 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(napth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone and 49 mg of 17-ethyl-1,14-dihyroxy-12-[2'-(4"-(naphth-2-yloxy)- 3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 octacos-18-ene-2,3,10,16-tetraone. (1H NMR was consistent with the desired structure).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@H:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][OH:8])=[O:4].[H-].[Na+].[NH4+].[Cl-]>C1COCC1>[C:9]1([C@H:6]2[NH:5][C:3](=[O:4])[CH2:2][O:8][CH2:7]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(CCl)N[C@@H](CO)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1COC[C@@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-N-[(1R)-2-hydroxy-1-phenylethyl]acetamide from Step A (12.0 g, 56 mmol) in THF (750 mL) at 0° C. was added NaH (4.48 g of a 60% dispersion in oil, 112 mmol) in portions over 1 h and the mixture was stirred at ambient temperature for 1 h. Saturated aqueous NH4Cl (100 mL) was added and the mixture was extracted with EtOAc (2×200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=178 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:17]([C:18]3[C:19](=O)[NH:20][C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[C:10]3[N:11]=[C:12]([CH3:16])[N:13]([CH2:14][CH3:15])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:27]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:17]([C:18]3[C:19](=[S:37])[NH:20][C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[C:10]3[N:11]=[C:12]([CH3:16])[N:13]([CH2:14][CH3:15])[C:9]=3[CH:8]=[CH:7][C:6]=2[CH:27]=1
Reactant: CCn1c(C)nc2c1C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CCn1c(C)nc2c1C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=S

Procedure:
A mixture of the product of step (i) (0.065 g) and Lawesson's reagent (0.343 g) in 1,4-dioxane (5 ml) was heated at reflux for 20 hours. The solvent was evaporated under reduced pressure and the residue partitioned between dichloromethane and water. Purification was by chromatography eluting with 0.2% 880 ammonia, 4% methanol in dichloromethane to give the title compound.