Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [FH:1].[FH:2].F.C(N(CC)CC)C.O=[C:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1.C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[F:1][C:12]1([F:2])[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)C1CCC(F)(F)CC1
Temperature: 25 °C
Yield: 69 %

Procedure:
A solution of triethylamine trihydrofluoride (0.479 mL, 2.94 mmol) in DCE (6 mL) at RT was treated with XtalFluor-M (1.071 g, 4.41 mmol) followed by ethyl 4-oxocyclohexanecarboxylate (0.500 g, 2.94 mmol) and the mixture heated to reflux for 2.5 h. The mixture was cooled to RT, treated with satd. NaHCO3 and stirred overnight. The mixture was diluted with DCM, the layers separated, the aqueous layer extracted with additional DCM (1×) and the combined organics were dried over MgSO4 and filtered through a small pad of silica gel, rinsing well with DCM. The filtrate was concentrated to dryness and purified via silica gel chromatography (DCM/Hex) to afford ethyl 4,4-difluorocyclohexanecarboxylate (390 mg, 69%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 4.05 (q, J=7.1 Hz, 2H), 2.49 (m, 1H), 2.02-1.77 (m, 6H), 1.65-1.50 (m, 2H), 1.16 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[CH3:8][N:9]([CH2:13][C:14]#[CH:15])[C:10](=[O:12])[CH3:11].[CH2:16]=O.[OH-].[Na+]>O.O1CCOCC1.C(O)(=O)C>[CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:16][C:15]#[C:14][CH2:13][N:9]([CH3:8])[C:10](=[O:12])[CH3:11])[CH2:4]1
Reactant: C#CCN(C)C(C)=O
Reactant: C=O
Reactant: COC1CCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: COC1CCN(CC#CCN(C)C(C)=O)C1
Yield: 75.4 %

Procedure:
A mixture of 365 mg of (racemic)-3-methoxypyrrolidine, 480 mg of N-methyl-N-propargyl acetamide, 180 mg of paraformaldehyde, 0.6 ml of acetic acid, 20 ml of dioxane and cuprous chloride catalyst was stirred at reflux under argon for 1 hour. The mixture was treated with 3 ml of 5N sodium hydroxide and 2 ml of water and extracted twice with dichloromethane. The extracts were combined, concentrated and purified by chromatography (alumina), giving 610 mg of the desired product.
Reaction SMILES: [C:1]12([CH2:11][NH2:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:13][C@@H:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](O)=[O:16].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]12([CH2:11][NH:12][C:15](=[O:16])[C@@H:14]([OH:13])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(O)[C@@H](O)c1ccccc1
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)[C@@H](O)c1ccccc1
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a solution of (1-adamantyl)methylamine (100 mg, 0.61 mmol), (S)-2-hydroxy-2-phenylacetic acid (92 mg, 0.61 mmol), EDCI (239 mg, 1.22 mmol) and HOBt (164 mg, 1.22 mmol) in CH2Cl2 (15 mL) was added DIEA (391 mg, 3.03 mmol) and the resulting mixture was stirred overnight. The solution was concentrated under vacuum to give the crude product, which was purified by preparative TLC to afford (S)—N-((1-adamantyl)methyl)-2-hydroxy-2-phenylacetamide (85 mg, 47%). 1H NMR (CDCl3, 400 MHz): δ=1.34-1.91 (m, 15H), 2.86 (q, 1H), 3.02 (q, 1H), 5.04 (s, 1H), 5.93 (s, 1H), 7.25-7.43 (m, 5H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1)#[N:2].C[Si]([N:37]=[N+:38]=[N-:39])(C)C.C([Sn](=O)CCCC)CCC.C(O)CO>C1(C)C=CC=CC=1>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]2[C:11]3[C:10]([O:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][C:1]4[NH:39][N:38]=[N:37][N:2]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:16][C:17]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCCOCCC#N)c23)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: OCCO
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(OCCCOCCc4nnn[nH]4)c23)cc1

Procedure:
Stir 200 mg (0.47 mmol) 4-[3-(2-cyanoethoxy)propoxy]-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]-pyrimidine, 804 mg (7.0 mmol) trimethylsilylazide and 174 mg (0.70 mmol) di-n-butyltin oxide in 10 ml toluene overnight at 80° C. Concentrate the mixture by evaporation, take up the residue in water and acidify with dilute hydrochloric acid. Next, extract with methylene chloride. Wash the organic extracts with sodium chloride solution, dry over magnesium sulphate and concentrate by evaporation. Purify the residue that remains by RP-HPLC (column: Gromsil 250 mm×30 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-50 min 5%→98% acetonitrile, 50-55 min 98% acetonitrile). To remove organotin compounds, dissolve the beige foam obtained in 10 ml toluene and add 1 ml ethylene glycol. After heating for 1 h under reflux, remove the solvent under vacuum. Dissolve the residue in methylene chloride, wash with dilute hydrochloric acid and with sodium chloride solution, dry, and concentrate by evaporation. Purification of the residue by RP-HPLC (column: Gromsil 250 mm×30 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-34 min 5%→98% acetonitrile, 34-38 min 98% acetonitrile) gives 46 mg (21% of theor.) of the title compound as a beige foam.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]([NH2:11])=[NH:10])=[CH:7][N:6]=[C:5]([O:12][CH3:13])[CH:4]=1.C(=O)(O)[O-].[K+].Br[CH2:20][C:21]([C:23]1[N:24]([CH:29]([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[N:27]=1)=O>C1COCC1.O>[Cl:2][C:3]1[C:8]([C:9]2[NH:11][CH:20]=[C:21]([C:23]3[N:24]([CH:29]([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[N:27]=3)[N:10]=2)=[CH:7][N:6]=[C:5]([O:12][CH3:13])[CH:4]=1
Reactant: Cc1nc(C(=O)CBr)n(C(C)C)n1
Reactant: COc1cc(Cl)c(C(=N)N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)c(-c2nc(-c3nc(C)nn3C(C)C)c[nH]2)cn1
Yield: 96.5 %

Procedure:
A suspension of 4-chloro-6-methoxy-nicotinamidine hydrochloride (18.4 mmol) and potassium bicarbonate (7.37 g, 73.6 mmol) in THF (42 mL) and water (8.5 mL) was heated to reflux and treated with a solution of 2-bromo-1-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-ethanone (4.53 g, 18.4 mmol) in THF (14 mL) added dropwise. The reaction mixture was heated at reflux for 18 h before removal of volatile solvent in vacuo. The resultant suspension was filtered and the residue washed with water then dried to give the title compound as a brown solid (5.91 g, 97%). LCMS: RT=2.68 min, [M+H]+=333/335. 1H NMR 400 MHz (CDCl3) δ: 10.41 (1 H, s), 9.02 (1 H, s), 7.81 (1 H, s), 6.87 (1H, s), 5.91 (1 H, m), 4.00 (3 H, s), 2.41 (3 H, s), 1.55 (6 H, d, J=6.71 Hz).
Reaction SMILES: C(O)(=O)C.O.[NH2:6][NH2:7].[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[CH:16]([C:21]#[N:22])[CH2:17][C:18](=O)[CH3:19]>C(O)C>[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[C:16]1[CH:17]=[C:18]([CH3:19])[N:7]=[N:6][C:21]=1[NH2:22]
Reactant: CC(=O)CC(C#N)c1ccc(C)cc1C
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2cc(C)nnc2N)c(C)c1

Procedure:
Acetic acid (5 mL) and hydrazine monohydrate (2.52 g, 0.05 mol) were added to a solution of 1-(2,4-dimethylphenyl)-3-oxobutyl cyanide (10.13 g, 0.05 mol) in ethanol (100 mL), and the mixture was heated under reflux for 8 hours. The reaction mixture was evaporated as it was. Water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated, to give 4-(2,4-dimethylphenyl)-6-methyl-3-pyridazinamine as a crude product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[C:4](O)[CH:5]=[CH:6][CH:7]=1.[ClH:10].[N:11]([O-])=O.[Na+].[Sn](Cl)Cl.[OH2:18]>>[ClH:9].[Cl:10][C:4]1[CH:3]=[C:2]([NH:1][NH2:11])[CH:7]=[CH:6][C:5]=1[OH:18]
Reactant: O
Reactant: Nc1cccc(O)c1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: NNc1ccc(O)c(Cl)c1
Reaction time: 2 h

Procedure:
At 0° C., to a mixture of 3-amino-2-chlorophenol 100 g and concentrated hydrochloric acid 250 ml was added slowly aqueous solution 300 ml containing sodium nitrite 67.0 g and followed by addition of water 400 ml. The resulting mixture was stirred for two hours and thereto was added slowly anhydrous tin(II) chloride 292 g and concentrated hydrochloric acid 250 ml and the resulting mixture was stirred for one hour. At room temperature, the resulting mixture was stirred for additional twelve hours, and then the reaction mixture was filtered and was washed with aqueous 10% hydrochloric acid and hexane to give 2-chloro-4-hydrazinophenol hydrochloride salt 105 g.
Reaction SMILES: COC(N[C@H](C(N1[C@@H](C)CC[C@H]1C1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43]C([C@@H]3C[C@H](COC)CN3C(OC(C)(C)C)=O)=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=O)C(C)C)=O.[CH3:59][O:60][C:61]([NH:63][C@@H:64]([CH:79]([CH3:81])[CH3:80])[C:65]([N:67]1[CH2:71][C@@H:70]([C:72]([F:75])([F:74])[F:73])[CH2:69][C@H:68]1[C:76](O)=O)=[O:66])=[O:62].[C:82]([O:86][C:87]([N:89]1[CH2:93][C@@H:92]([CH2:94][O:95][CH3:96])[CH2:91][C@H:90]1[C:97](O)=O)=[O:88])([CH3:85])([CH3:84])[CH3:83]>>[CH3:59][O:60][C:61]([NH:63][C@H:64]([C:65]([N:67]1[CH2:71][C@@H:70]([C:72]([F:75])([F:74])[F:73])[CH2:69][C@H:68]1[C:76]1[NH:43][C:39]([C:34]2[CH:35]=[C:36]3[CH2:37][O:38][C:25]4[CH:24]=[C:23]5[C:28]([CH:29]=[CH:30][C:20]6[N:19]=[C:97]([C@@H:90]7[CH2:91][C@H:92]([CH2:94][O:95][CH3:96])[CH2:93][N:89]7[C:87]([O:86][C:82]([CH3:83])([CH3:84])[CH3:85])=[O:88])[NH:22][C:21]=65)=[CH:27][C:26]=4[C:31]3=[CH:32][CH:33]=2)=[CH:40][N:41]=1)=[O:66])[CH:79]([CH3:81])[CH3:80])=[O:62]
Reactant: COC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C(F)(F)F)C[C@H]1C(=O)O)C(C)C
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3cnc([C@@H]4C[C@H](C(F)(F)F)CN4C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]3)ccc2-5)N(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared as in example OF for compound tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate, by using (2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid in place of (2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid and (2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid in place of (2S,5S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylic acid.
Reaction SMILES: C1CO[C:3]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11]C3CCCCO3)[CH2:9][C@H:8]([OH:18])[C@@H:7]2[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[O:2]1.C(O)(=O)C.C1COCC1>O>[OH:11][C@@H:10]1[CH2:9][C@H:8]([OH:18])[C@H:7]([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[C@H:6]1[CH2:5][CH2:4][C:3](=[O:2])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCC1(CC[C@@H]2[C@@H](C/C=C\CCCCCC(=O)OC(C)C)[C@@H](O)C[C@H]2OC2CCCCO2)OCCO1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCC(=O)CC[C@@H]1[C@@H](C/C=C\CCCCCC(=O)OC(C)C)[C@@H](O)C[C@H]1O
Reaction time: 14 h

Procedure:
The compound (43) (0.305 g) was dissolved in a mixed solvent (6 ml) consisting of acetic acid, THF and water (2:1:1) and kept at 50° C. for 14 hours. The resultant mixture was worked up with the conventional procedure and the obtained crude product was subjected to silicagel column chromatography to give the titled compound (44). Yield: 0.213 g (90%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]1[C@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@@H:12]([CH3:22])[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]([O:31][C:32](ON1C(=O)CCC1=O)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl.CCOC(C)=O>[CH2:24]([O:31][C:32]([N:10]1[CH2:11][C@H:12]([CH3:22])[C@@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:23])[CH2:9]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
To a solution of tert-butyl-((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (3.2 g, 9.4 mmol) (40% purity) in DCM (25 mL), N-(benzyloxycarbonyloxy)succinimide (2.6 g, 10 mmol) was added, followed by triethylamine (1.4 mL, 10 mmol). The mixture was stirred for 16 h at room temperature. The reaction mixture was then diluted with EtOAc, washed with water and brine and dried over Na2SO4. The solvent was evaporated under reduced pressure and the resulting crude product was purified by silica gel chromatography eluting with 25% EtOAc in hexanes to give the sub-title compound as a white solid (1.71 g, 38%). LCMS calc. for C25H42N2O5SiNa (M+Na)+ m/z=501.3. found 501.0.
Reaction SMILES: [CH2:1]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[C:16]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:34][CH3:35]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[CH:17]=[C:16]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:15]=[CH:14][C:13]=3[N:12]([CH2:34][CH3:35])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc2[nH]c3c(c2c1)CCN(Cc1ccccc1)CC3
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)CCN(Cc1ccccc1)CC2

Procedure:
A 0° mixture of 3-benzyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (EXAMPLE 1, Step II, 301 mg, 0.723 mmol) in dry DMF (5 ML) is treated with sodium hydride (60% in oil, 32 mg, 0.795 mmol), and allowed to warm to 20-25° over 1.5 hr. The mixture is then cooled (0°), treated with iodoethane (64 μL, 0.795 mmol) and allowed to slowly warm to 20-25° under nitrogen over 72 hr. The resultant mixture is diluted with ethyl acetate (50 mL) and washed with H2O (3 X 25 mL) and saline (25 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a solid. The solid is purified via chromatography (20 g SG; ethyl acetate/heptane, 65/35) to give the indole as a solid, mp=188-191°; IR (drift) 1477, 1373, 1300, 1289, 1157, 1148, 1094, 766, 756, 738, 728, 701, 694, 645 and 621 cm−1; NMR (300 MHz, CDCl3) 8.10-8.20,7.90-8.05, 7.65-7.75, 7.20-7.50,4.11, 3.82, 2.85-3.05 and 1.27 δ; MS (EI) m/z 444 (M+), 326, 324, 312, 167, 154, 132, 118, 96, 91 and 64.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.C[Li].[CH2:17](OCC)C.[CH3:22][O:23][C:24]1[C:29]([CH3:30])=[CH:28][C:27]([S:31](Cl)(=[O:33])=[O:32])=[CH:26][C:25]=1[CH3:35]>>[CH3:22][O:23][C:24]1[C:29]([CH3:30])=[CH:28][C:27]([S:31]([N:6]2[CH:7]([CH3:17])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)(=[O:33])=[O:32])=[CH:26][C:25]=1[CH3:35]
Reactant: COc1c(C)cc(S(=O)(=O)Cl)cc1C
Reactant: CCOCC
Reactant: c1ccc2c(c1)cnc1ccccc12
Agent: [Li]C
Product: COc1c(C)cc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)cc1C
Yield: 62 %

Procedure:
The title compound was prepared from phenanthridine (3.58 g, 20 mmol), 1.4 M methyllithium in diethyl ether (14.5 mL, 20.3 mmol), and 4-methoxy-3,5-dimethylbenzenesulfonyl chloride (4.69 g, 20 mmol) according to the procedure and in the same manner as described in Example 1, step a. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:8) to yield 5-[(4-methoxy-3,5-dimethylphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (4.86 g, 12.4 mmol, 62%) as a white solid;
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:12]([NH:13][C:14]2[C:15](=[O:20])[C:16](=[O:19])[C:17]=2[CH3:18])=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:7][NH:8]2)[CH3:2].CCN(CC)CC.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1.C(Cl)Cl.C(Cl)Cl>[CH2:1]([S:3][C:4]1[C:12]([NH:13][C:14]2[C:15](=[O:20])[C:16](=[O:19])[C:17]=2[CH3:18])=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH2:21][CH2:22][CH2:23][O:24][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:7][NH:8]2)[CH3:2]
Reactant: CCSc1c(Nc2c(C)c(=O)c2=O)ccc2[nH]cc(CCCO)c12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCSc1c(Nc2c(C)c(=O)c2=O)ccc2[nH]cc(CCCOS(C)(=O)=O)c12
Temperature: 23 °C
Reaction time: 1.5 h

Procedure:
A cold (5° C.) mixture of 3-(4-ethylthio-5-(4-methyl-1,2-dioxocyclobut-3-en-3-yl) amino-3-indolyl)1-propanol (0.708 g, 2.1 mmol) and Et3N (0.697 ml, 5.0 mmol) in THF:CH2Cl2 (1:2, 45 ml) mixture kept under argon atm. was treated dropwise with MsCl (0.387 ml, 5.0 mmol) and stirred at 23° C. for 1.5 h. The reaction mixture was diluted with CH2Cl2 (40ml) and washed with H2O (10ml) and saturated NaHCO3 solution. The organic phase was dried (MgSO4) and concentrated in vacuo. The crude material was purified on silica gel dry column using a mixture of CH2Cl2 :EtOAc (7.3) as eluting solvent. Appropriate fractions were concentrated in vacuo giving a yellow oil, 0.70 g, 79%. 1H NMR (DMSO-d6) δ (ppm): 11.26, 11.20, 10.81 and 10.53 (4 br s, 2H, indolic NH and 5-NH), 7.42 (br s, 1H), 7.32 (s, 1H), 7.09 (d, J=8.2 Hz, 1H), 4.27 (t, J=6.4 Hz, 2H, CH2OSO2), 3.17 (s, 3H, CH3SO2), 3.11 (t, J=7 Hz, 2H, CH2CH2CH2O), 2.67 (br s, 2H, CH3CH2S), 2.28 (br, s, 1H, CH3 of dioxocyclobutene), 2.0-2.15 (m, 2H, CH2CH2CH2O), 1.59 (br s, 2H CH3 of dioxocyclobutene), 0.9-1.1 (m, 3H, CH3CH2S). IR (film) n:3710, 3180, 1783, 1728, 1590, 1340 and 1170 cm-1.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]([O-:10])([CH3:9])[CH3:8].[K+].C(NC(C)C)(C)C.[C:19]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:24]=[CH:23][C:22]([CH:25]([N:27](C(OC(C)(C)C)=O)[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH3:26])=[CH:21][CH:20]=1.C1C[O:51][CH2:50]C1>Cl>[C:19]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:24]=[CH:23][C:22]([C@@:25]([C:50]([O:10][C:7]([CH3:9])([CH3:8])[CH3:6])=[O:51])([CH3:26])[NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[CH:21][CH:20]=1
Reactant: CC(c1ccc(-c2ccccc2)cc1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N[C@@](C)(C(=O)OC(C)(C)C)c1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
n-BuLi (4.09 ml, 6.5 mmol, 1.6 M in hexane) was added to a suspension of t-BuOK (735 mg, 6.55 mmol) and diisopropyl amine (926 ul, 6.55 mmol) in THF (20 ml) at −78° C. The mixture was stirred at −78° C. for 15 min. before a solution of bis(1,1-dimethylethyl) [1-(4-biphenylyl)ethyl]imidodicarbonate (2.08 g, 5.24 mmol) in THF (20 ml) was added dropwise and stirring was continued for 30 min at −78° C. The reaction mixture was diluted with HCl (2M, 50 ml) and the product was extracted with ether (3×30 ml). The ether extracts were concentrated and then purified by silica gel chromatography (120 g Redisep column, silica, 40 um, 60 Å, 85 mL/min, A: hexane, B: ethyl acetate, B: 4% for 2 min, 10% for 30 min, detection at 214 nm) which gave 1.15 g (55%) as a clear oil. 1H NMR (CDCl3): delta 7.38-7.63 (m, 9H, arom), 5.95 (1H), 2.01 (3H), 1.41 (S, 18H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[S:6][CH:7]=1>CO.C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH:2]([C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[S:6][CH:7]=1)=[O:1]
Reactant: CC(=O)Nc1nc(CO)cs1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc(C=O)cs1
Temperature: 25 °C
Reaction time: 7 h
Yield: 72.6 %

Procedure:
N-(4-(Hydroxymethyl)-1,3-thiazol-2-yl)acetamide (2.8 g) was dissolved in methanol (10 ml) and chloroform (200 ml). Then manganese (IV) oxide (28.3 g) was added to the solution under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 7 hours, and filtered through a celite pad. The filtrate was concentrated in vacuo. The resulting solid was washed with ethyl ether to give N-(4-formyl-1,3-thiazol-2-yl)acetamide (2.01 g) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:25])[C:18]([O:21][C:22](=[O:24])[CH3:23])([CH3:20])[CH3:19].C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].C(OCC)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:33](=[O:35])[CH3:34])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:25])[C:18]([O:21][C:22](=[O:24])[CH3:23])([CH3:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CC(=O)OC(C)(C)C(=O)Nc1ccc(Sc2ccc(N)cc2)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(Sc2ccc(NC(=O)C(C)(C)OC(C)=O)c(Cl)c2)cc1
Temperature: 2.5 °C

Procedure:
N-[2-Chloro-4-(4-aminophenylsulphanyl)phenyl]-2-acetoxy-2-methylpropanamide (Method 22) (0.50 g) was dissolved in DCM (10 ml) and cooled to 0-5° C. in an ice bath. Triethylamine (0.46 ml) was added followed by dropwise addition of acetyl chloride (0.1 ml) and the mixture was allowed to warm to ambient temperature over 2 hours. Ethyl acetate (20 ml) was added and the solution was washed with water (2×10 ml) and brine then dried. Volatile material was removed by evaporation and the residue was purified by flash chromatography eluting with 40-80% ethyl acetate/hexane to give the title compound (0.470 g) as a solid. NMR (CDCl3): 1.8 (s, 6H), 2.2 (d, 6H), 7.2-7.3 (m, 5H), 7.5 (d, 2H), 8.3 (d, 1H), 8.4 (s, 1H); MS (ESP−): 419; EA: found: C, 56.7; H, 5.0; N, 6.0%; C20H21ClN2O4S.0.4 EtOAc requires C, 56.9; H, 5.3; N, 6.1%.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].O>CS(C)=O>[C:9]([O:13][C:14]([N:16]1[CH2:17][CH2:18][C:19]2([O:22][CH2:4]2)[CH2:20][CH2:21]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 62.5 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Oil free sodium hydride (2.16 g, 0.09 M) was added to dry dimethyl sulfoxide (250 mL) under nitrogen gas and the mixture was heated to 60-65° C. until a uniform black solution was formed, about 1 h. Then 19.83 g (0.09 M) of trimethylsulfoxonium iodide was added (slight exotherm) and the mixture was stirred until a brown solution occurred, about 30 min. Then a solution of 13.40 g (67.3 mM) of N-t-butyloxycarbonyl-4-piperidone in 50 mL of dimethyl sulfoxide was stirred at room temperature for 1 h. The reaction mixture was then poured into 1 L of cold water and the whole was extracted 4× with 100 mL portions of hexane. The combined hexane extracts was back-washed with 50 mL of water and with brine solution and was dried with magnesium sulfate, filtered and evaporated to give 11.75 g of white crystalline product, 6-t-butyloxycarbonyl-1-oxa-6-azaspiro[2.5]octane, (78% yield).