Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-])(=[O:3])=[O:2].FC(F)(F)C(O)=O.CC[N:21](C(C)C)C(C)C>>[CH3:9][C:8]1[CH:7]=[CH:6][C:5]([S:1]([NH2:21])(=[O:3])=[O:2])=[CH:11][CH:10]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(N)(=O)=O)cc1

Procedure:
Referring to reaction Scheme I, trans-1,2-di-carbomethoxy-4-methylene-cyclopentane is reacted with sodium hydroxide followed with acid to produce trans-4-methylene-1,2-cyclopentanedicarboxylic acid. The dicarboxylic acid is reacted with acetic anhydride to produce cis-tetrahydro-5-methylene-1H-cyclopenta[c]furan-1,3(3H)-dione. The ammonium salt 4 is prepared by reacting the anhydride 3 in dry methylene chloride with ammonia gas. The imide 5 is prepared from the ammonium salt by reacting the ammonium salt with acetyl chloride. The imide is reacted with lithium aluminum hydride and ditertiarybutyl dicarbonate to produce cis-1,1-dimethylethylhexahydro-5-methylenecyclopenta[c]pyrrole-2(1H)carboxylate 6. The term BOC is used herein to refer to t-butyloxy carbonyl. The BOC-amine 6 is reacted with bis(p-toluenesufonyl) sulfodiimide to produce the p-toluenesulfonamide 7. The term Tos is used herein to represent p-toluenesulfonyl. The p-toluenesulfonamide is reacted with thexyl borane to produce the endo alcohol 8. The endo alcohol is reacted with p-toluenesulfonyl chloride to produce the tosylate 9. The tosylate 9 is reacted with trifluoroacetic acid and treated with Hunig's base to provide the p-toluenesulfonamide tetracycle 10. The sulfonamide tetracycle 10 was reductively cleaved to produce the aminoazatetracycle 11. Coupling of the aminoazatetracycle 11 with benzoic acid derivative 12 under mixed anhydride conditions gave the protected benzamide tetracycle 13. Basic hydrolysis of the acetamide 13 gives the benzamide tetracycle 14 which upon treatment with HCl produces the hydrochloride salt of the benzamide tetracycle 15.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.Cl.[CH3:21][NH2:22]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH3:21])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: Clc1ccc(C2COCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CN
Agent: Cl
Product: CNc1nc(Cl)nc2c1COCC2c1ccc(Cl)cc1
Yield: 30.6 %

Procedure:
2,4-dichloro-8-(4-chlorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation K) (500 mg, 1.584 mmol) and methanamine hydrochloride (160 mg, 2.377 mmol) were combined and purified as per Preparation Ha to give 2-chloro-8-(4-chlorophenyl)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (150 mg, 0.484 mmol, 30.5% yield). LC-MS (M+H)+=310.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.22-7.31 (2 H, m), 7.13 (2 H, d, J=8.55 Hz), 4.46-4.64 (1 H, m), 4.43 (1 H, br. s.), 3.97-4.14 (1 H, m), 3.91 (1 H, d, J=3.36 Hz), 3.09 (3 H, d, J=4.88 Hz).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.Br[CH2:16][CH2:17][CH2:18][OH:19]>>[CH2:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[O:14][CH2:16][CH2:17][CH2:18][OH:19])[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: OCCCBr
Reactant: Oc1ccccc1Cc1ccccc1
Product: OCCCOc1ccccc1Cc1ccccc1

Procedure:
By using 2-hydroxydiphenylmethane and 3-bromopropanol, the title compound was obtained as colorless oil by similar procedures to those of Example 60b (yield: 28%).
Reaction SMILES: [C:1]([NH:9][C:10](=[N:13][CH2:14][CH2:15][CH2:16][N:17]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)[C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1)SC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:36]1[CH:40]=[C:39]([CH2:41][CH2:42][CH2:43][NH2:44])[N:38]=[CH:37]1>N1C=CC=CC=1>[Br:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:17]([CH2:16][CH2:15][CH2:14][NH:13][C:10]([NH:44][CH2:43][CH2:42][CH2:41][C:39]2[N:38]=[CH:37][NH:36][CH:40]=2)=[N:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:30][CH:31]=1
Reactant: NCCCc1c[nH]cn1
Reactant: CSC(=NCCCN(Cc1ccc(Br)cc1)c1ccc2ccccc2n1)NC(=O)c1ccccc1
Solvent: c1ccncc1
Product: O=C(N=C(NCCCc1c[nH]cn1)NCCCN(Cc1ccc(Br)cc1)c1ccc2ccccc2n1)c1ccccc1
Yield: 58 %

Procedure:
To a solution of the above isothiourea (5.0 g, 9.133 mmol) in dry pyridine (70 ml) was added 3-(1H-imidazol-4-yl)propyl amine (1.26 g, 10.05 mmol) and the resulting mixture was stirred at reflux temperature for 10 h followed by stirring at room temperature for 48 h. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel (600 ml) using a mixture of dichloromethane/methanol/triethylamine 9:0.5:0.5 as eluent affording 3.31 g (58%) of the title compound as an amorphous solid.
Reaction SMILES: [CH:1]([N:4]([CH3:29])[C:5]1[C:6](OS(C(F)(F)F)(=O)=O)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([O:19][CH3:20])[CH:9]=2)([CH3:3])[CH3:2].[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:6]2[C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[CH3:29])=[N:14][C:13]3[C:8](=[CH:9][C:10]([O:19][CH3:20])=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=3)[N:7]=2)=[CH:33][CH:32]=1
Reactant: COC(=O)c1cc2nc(N(C)C(C)C)c(OS(=O)(=O)C(F)(F)F)nc2cc1OC
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc2nc(N(C)C(C)C)c(-c3ccc(F)cc3)nc2cc1OC
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-7-methoxy-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (2.5 g, crude) in dioxane (5.0 mL) and water (3 drops) was added (4-fluorophenyl)boronic acid (2.40 g, 17.15 mmol), Pd(PPh3)4 (320 mg, 0.28 mmol), and K3PO4 (3.58 g, 16.87 mmol) with stirring for 1.5 h at 95° C. under an atmosphere of nitrogen. The reaction mixture was concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford methyl 2-(4-fluorophenyl)-3-(isopropyl(methyl)amino)-7-methoxyquinoxaline-6-carboxylate as a light yellow solid (0.9 g, 36% 2 steps).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:41]=[CH:40][C:26]([C:27]([N:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([C:35]([O:37]CC)=[O:36])[CH2:30]2)=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)=[N:13]2)=[CH:8][C:7]=1[CH3:21].C1COCC1.[OH-].[Na+]>C(O)C>[F:43][C:2]([F:1])([F:42])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:41]=[CH:40][C:26]([C:27]([N:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([C:35]([OH:37])=[O:36])[CH2:30]2)=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)=[N:13]2)=[CH:8][C:7]=1[CH3:21]
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(CCC(F)(F)F)c3ccc(-n4cc5c(n4)CCCC5)cc3C)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(-n2cc3c(n2)CCCC3)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)N2CCC[C@@H](C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of ethyl (3R)-1-(4-((4,4,4-trifluoro-1-(2-methyl-4-(4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)butyl)amino)benzoyl)piperidine-3-carboxylate (9.61 g), THF (32 mL) and ethanol (32 mL) was added 1M aqueous sodium hydroxide solution (32.2 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, the reaction mixture was neutralized with 1M hydrochloric acid (32.2 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a crudely purified product. The crudely purified product obtained here and separately synthesized crudely purified product (1.68 g) were combined, and recrystallized from a mixed solvent of ethyl acetate-hexane to give the title compound (8.49 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:18][CH2:19][O:20]S(C1C=CC(C)=CC=1)(=O)=O.C([O:33][C:34](=[O:56])[C:35]([CH3:55])([O:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:47][CH:46]=1)[CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=1)C>C(O)C>[CH3:55][C:35]([O:44][C:45]1[CH:46]=[CH:47][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:49][CH:50]=1)([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:20][CH2:19][CH2:18][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]4[CH:17]=[CH:16][S:15][CH:14]=4)[CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:39][CH:38]=1)[C:34]([OH:56])=[O:33]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C(C)(C)C)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccsc4)c3)oc2C)cc1
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccsc3)c2)nc1CCOc1ccc(CC(C)(Oc2ccc(C(C)(C)C)cc2)C(=O)O)cc1
Temperature: 55 °C
Yield: 8 %

Procedure:
Toluene-4-sulfonic acid 2-(5-methyl-2-(3-thiophen-3-yl-phenyl)-oxazol-4-yl)-ethyl ester(0.132 mmol) (see Ex. 6, Part B) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxyphenyl)-2-methyl-2-(4-tert-butylphenoxy)-propionic acid ethyl ester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) (see Ex. 15, Part B) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by preparative thin-layer silica chromatography eluting with 95:5 CH2Cl2:MeOH to produce a white solid (8%). MS [EI+] 596 (M+H)+, [EI−] 594 (M−H)+
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][OH:13])[CH:6]=1)[CH2:3][NH2:4].[C:14]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](=O)[CH3:32])=[CH:26][CH:25]=1)([O:16]CC1C=CC=CC=1)=[O:15].O>C1(C)C(C)=CC=CC=1>[C:14]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][OH:13])[CH:6]=2)[CH3:32])=[CH:26][CH:25]=1)([OH:16])=[O:15]
Reactant: NCC(O)c1ccc(O)c(CO)c1
Reactant: CC(=O)Cc1ccc(C(=O)OCc2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(Cc1ccc(C(=O)O)cc1)NCC(O)c1ccc(O)c(CO)c1
Reaction time: 3 h

Procedure:
2-Hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl) ethanamine (1.09 g) and 1-(4-carbobenzyloxyphenyl) propan-2-one (1.6 g) were refluxed in xylene in a Dean and Stark apparatus until the theoretical amount of water had been collected. The solvent was removed, ethanol added and the mixture hydrogenated at 70 psi and 50° for 3 hours using 10% Pd/c as catalyst. Filtration of the catalyst and evaporation of the solvent gave the title compound as a foam τ(d6DMSO) 8.95 (3H, d, J=7 Hz), 6.8-7.4 (5H, m), 5.5 (2H, s+1H, t), 3.65 (5H, broad), 2.3-3.3 (5H, m), 2.0 (2H, d, J=8 Hz).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)([CH3:5])[C:3]#[N:4]>C(OCC)(=O)C.[Pd]>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:2]([CH3:5])([CH3:1])[C:3]#[N:4])=[CH:11][CH:10]=1
Reactant: CC(C)(C#N)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 101.1 %

Procedure:
To a solution of 2-methyl-2-(4-nitrophenyl)propanenitrile (0.95 g, 5.0 mmol) in ethyl acetate (10 mL) was added 10% palladium/carbon (100 mg), and the mixture was stirred at room temperature for 14 hr under hydrogen atmosphere. The residual catalyst was filtered through celite, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound (0.81 g, 99%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][C:10]1[C:11]([O:40][CH3:41])=[CH:12][C:13]([O:38][CH3:39])=[C:14](/[CH:16]=[CH:17]/[C:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH:29][CH2:30][CH2:31][CH2:32][N:33]3[CH:37]=[CH:36][N:35]=[CH:34]3)(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:19])[CH:15]=1>C(#N)C.[Pd](Cl)Cl>[N:33]1([CH2:32][CH2:31][CH2:30][NH:29][S:26]([C:23]2[CH:22]=[CH:21][C:20]([C:18](=[O:19])/[CH:17]=[CH:16]/[C:14]3[CH:15]=[C:10]([C:9]4[NH:1][C:2]5[C:3]([CH:8]=4)=[CH:4][CH:5]=[CH:6][CH:7]=5)[C:11]([O:40][CH3:41])=[CH:12][C:13]=3[O:38][CH3:39])=[CH:25][CH:24]=2)(=[O:28])=[O:27])[CH:37]=[CH:36][N:35]=[CH:34]1
Reactant: COc1cc(OC)c(/C=C/C(=O)c2ccc(S(=O)(=O)NCCCn3ccnc3)cc2)cc1C#Cc1ccccc1N
Agent: Cl[Pd]Cl
Solvent: CC#N
Product: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)NCCCn2ccnc2)cc1
Reaction time: 0.08 h
Yield: 99.5 %

Procedure:
A suspension of 4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}-N-(3-imidazol-1-ylpropyl)benzenesulfonamide (Ex-50A, 210 mg, 0.37 mmol) in acetonitrile (130 mL) was purged with nitrogen gas for 10 minutes. Palladium(II) chloride (5.0 mg, 0.029 mmol) was added to the reaction vessel. The reaction mixture was refluxed for 16 hrs. The cooled reaction mixture was stirred with 3-mercaptopropyl functionalized silica gel (500 mg) for 5 minutes. The filtrate was collected via suction filtration and concentrated to an orange solid to give 210 mg (100%) of the title compound, mp 197–200° C. 1H-NMR (300 MHz, DMSO-d6) 11.19 (br s, 1H), 8.28 (m, 3H), 8.11 (m, 2H), 7.95 (m, 4H), 7.45 (m, 3H), 7.00 (m, 5H), 4.08 (s, 3H), 4.03 (s, 3H), 3.89 (m, 2H), 2.69 (br s, 2H), 1.78 (br s, 2H). HRMS (ESI) Calcd. for C31H30N4O5S: 571.2015 [(M+H)+]; Found: 571.2016.
Reaction SMILES: [N:1]1([CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:21](=[O:36])[CH:22]=[C:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:1]1([CH:6]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:21](=[O:36])[CH:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1
Reactant: O=C(Cl)C=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(C=C(c1ccccc1)c1ccccc1)Nc1ccc(C(c2ccccc2)n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 140.2 %

Procedure:
A mixture of intermediate (1-b) (8.92 g) and 1-chloro-3,3-diphenyl-2-propen-1-one (10.42 g) in DCM (100 ml) was stirred at room temperature overnight. The mixture was poured into a 10% NaHCO3 -solution. This mixture was extracted with DCM and separated. The organic layer was dried (MgSO4), filtered and evaporated, yielding 22.85 g (100%) of (±)-N-[4-[(1H-imidazol-1-yl)phenylmethyl]phenyl]-3,3-diphenyl-2-propenamide (interm. 1-c). The product was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([CH2:14][NH2:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC1CN(Cc2ccccc2)CC1CN
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H]1CN(Cc2ccccc2)C[C@H]1CNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
c is-1-Benzyl-4-methyl-3-aminomethylpyrrolidine (1000 mg) was dissolved in methanol (10 mL). While this solution was cooled on an ice bath, benzaldehyde (0.50 mL) was added dropwise and the mixture was stirred at room temperature for 1 hour. Subsequently, sodium cyanoborohydride (184 mg) was added and the mixture was stirred at room temperature for 1.5 hours. This was followed by a second addition of sodium cyanoborohydride (123 mg) and stirring for additional 5.5 hours. Subsequently, a 2mol/L aqueous solution of sodium hydroxide (5 mL) was added to the reaction mixture and the mixture was refluxed for 2 hours while heated. Following concentration under reduced pressure, the resulting residue was extracted with toluene (2×30 mL) and the toluene extracts were combined. The combined toluene layer was then washed with water, followed by drying over anhydrous sodium sulfate and concentration under reduced pressure. The resulting residue was purified on a silica gel column (hexane:ethyl acetate=4:1) to give 690 mg of cis-1-benzyl-3-benzylaminomethyl-4-methylpyrrolidine as a pale yellow oil.
Reaction SMILES: FC(F)(F)S(O[CH:7]([CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:8]([F:11])([F:10])[F:9])(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CS(C)=O.O>[N:26]([CH:7]([C:8]([F:11])([F:10])[F:9])[CH2:12][NH:13][C:14](=[O:15])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N+:27]=[N-:28]
Reactant: O=C(NCC(OS(=O)(=O)C(F)(F)F)C(F)(F)F)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NC(CNC(=O)OCc1ccccc1)C(F)(F)F
Temperature: 40 °C
Reaction time: 5 h

Procedure:
To a solution of 3-{[(benzyloxy)carbonyl]amino}-1,1,1-trifluoropropan-2-yl trifluoromethanesulfonate (150 g, 380 mmol) in DMSO (1200 mL) was added sodium azide (36.5 g, 562 mmol). The reaction mixture was heated to 40° C. After 5 hours, the reaction mixture was diluted with water (1000 mL) and extracted with diethyl ether (3×1200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford benzyl (2-azido-3,3,3-trifluoropropyl)carbamate. The material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[OH:13][C@@H:14]([CH3:28])[CH2:15][CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCCCCC>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:16][CH2:15][C@@H:14]([OH:13])[CH3:28])[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@H](C)O)cc1
Reactant: COC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCC[C@H](C)O)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 44.2 %

Procedure:
To a stirring solution of (3-hydroxy-phenyl)-acetic acid methyl ester (0.93 g, 0.0056 mole) and toluene-4-sulfonic acid-(S)-3-hydroxy-butyl ester (1.5 g, 0.0061 mole) in anhydrous DMF (10 mL) was added Cs2CO3 (2.0 g, 0.006 mole). The reaction was heated to 100° C. and stirred for 4 hours. The mixture was cooled to RT and filtered. The filtrate was poured into H2O (50 mL) and extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography over silica gel (silica gel 60, EM Science) using 30% EtOAc:hexane as eluent to afford 0.59 g (44% yield) of the title compound as an oil: MS (ESI) 239.0 (M+H+).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:44]2([CH3:45])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:46])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24][C:25]#[C:26][C:27]([CH2:38][CH3:39])([O:30][Si](CC)(CC)CC)[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([O:47][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:44]2([CH3:45])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:43]2[CH2:42][CH2:41][C@@:40]2([CH3:46])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24][C:25]#[C:26][C:27]([CH2:38][CH3:39])([OH:30])[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([OH:47])[CH2:10]1
Reactant: CCC(C#CCO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(C#CCO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C)CC
Yield: 96.5 %

Procedure:
By the same procedure as in Example 9, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-(4-ethyl-4-triethylsilyloxy-2-hexynyloxy)pregna-5,7,16-triene (79.0 mg, 0.0991 mmol), tetrahydrofuran (3 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted (heating under reflux for 5.5 hours) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, dichloromethane:ethyl acetate:ethanol 20:80:1, developed once) to give the title compound as a colorless oil (43.5 mg, 96%).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:17]([O:19]CC)=[CH2:18])CCC.O>CN(C=O)C>[N:7]1([C:4]2[N:3]=[C:2]([C:17](=[O:19])[CH3:18])[S:6][N:5]=2)[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: Clc1nc(-n2ccnc2)ns1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1nc(-n2ccnc2)ns1
Temperature: 67.5 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
A catalytic amount of dichloropalladium(II)bis(triphenylphosphine) (189 mg, 268 μmol) was added to a solution of 5-chloro-3-imidazol-1-yl-[1,2,4]thiadiazole (500 mg, 2.68 mmol) and tributyl-(1-ethoxy-vinyl)-stannane (904 μL, 2.68 mmol) in DMF (10 mL) under a nitrogen atmosphere at r.t. prior to heating at 65-70° C. for 21 h. The reaction was then cooled to r.t., H2O (70 mL) was added, filtered through celite, and washed with EtOAc (200 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated to a yellow residue. The yellow residue was diluted with a 5:1 mixture of 5N HCl/THF (48 mL) and stirred at r.t. for a period of 2 hours prior to concentrating to a white residue. The crude product was diluted with EtOAc (100 mL), washed with 1M NaOH (75 mL), brine (75 mL), dried over Na2SO4, filtered and concentrated to a white solid. Purification was achieved using column chromatography (CH2Cl2 to 9:1 CH2Cl2/MeOH) to afford 398 mg (77%) of 1-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-ethanone as a white solid. [M+H]+ 195.35.
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[NH:14][C:10]=2[N:9]=[CH:8]1.[Li+].[OH-]>C1COCC1.CO>[CH3:1][Si:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[NH:14][C:10]=2[N:9]=[CH:8]1
Reactant: CCOC(=O)c1cc2c(ncn2COCC[Si](C)(C)C)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[Si](C)(C)CCOCn1cnc2[nH]c(C(=O)O)cc21
Temperature: 60 °C
Yield: 153.9 %

Procedure:
Ethyl 1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1,4-dihydropyrrolo[2,3-d]imidazole-5-carboxylate (0.088 g, 0.284 mmol) was dissolved in THF and MeOH. LiOH (1 mL, 1 mmol) was added to the solution and the reaction was heated to 60° C. When starting material was no longer evident by TLC the reaction was evaporated to afford the title compound (0.123 g, 77%) a white solid. This was used with no further purification. LCMS: m/z=280.0 (M−1).