Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([C@H:23]5[C@@H:27]([F:28])[CH2:26][NH:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH3:36][C:37]([CH3:39])=O>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([C@H:23]5[C@@H:27]([F:28])[CH2:26][N:25]([CH:37]([CH3:39])[CH3:36])[CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:34])([F:35])[F:33])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CNC[C@@H]1F
Reactant: CC(C)=O
Product: CC(C)N1C[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@@H](F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3R,4S)-4-fluoro-1-(1-methylethyl)pyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(cis)-4-fluoropyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione (Example 322) and acetone (in place of formaldehyde) following General Procedure R2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([NH:14][C:15]2[CH:27]=[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:25]=[CH:24][C:16]=2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1Nc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To toluene 3.0 mL solution of 4-bromobiphenyl 0.43 g were added 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 17 mg, tert-butyl 2-amino-4-phenylbenzoate 0.20 g, cesium carbonate 0.48 g, palladium acetate 1.7 mg and tris(dibenzylideneacetone)dipalladium(0) 6.8 mg at room temperature, and it was heated and refluxed for 5 hours and 40 minutes. 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 17 mg, tris(dibenzylideneacetone)dipalladium(0) 6.8 mg and palladium acetate 1.7 mg were added to it, and it was heated and refluxed for 2 hours and 20 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=50:1] to give tert-butyl 2-((biphenyl-4-yl)amino)-4-phenylbenzoate 0.24 g of a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C1COCC1>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][NH:1][C:20](=[O:22])[CH3:21])=[CH:5]1
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tryptamine (192 mg/1.2 mmol) was initially introduced into abs. THF (5 ml), and triethylamine (179 μl/1.3 mmol) was added. Acetic anhydride (132 mg/1.3 mmol) was then added and the mixture was stirred at RT for 4 h. The mixture was concentrated to dryness i. vac. The residue was taken up in ethyl acetate and this solution was washed with saturated NaHCO3 solution (two times 20 ml) and with NaCl solution (two times 20 ml). The organic phase was dried over Na2SO4 and concentrated i. vac.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14](C(=O)NCC(C2C=CC(Br)=CC=2)=O)[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)CC1C(=O)NCC(=O)c1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC2)C1
Temperature: 140 °C
Yield: 130.1 %

Procedure:
15 mL Xylenes was added to 6-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (424 mg, 0.97 mmol) and ammonium acetate (20 eq., 1.5 g). The mixture was heated in microwave at 140° C. for 60 minutes. The mixture was diluted with EtOAc and washed with sat.NaHCO3 aqueous solution. The organic layer was concentrated down and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 645-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (249 mg, yield 61%). LCMS-ESI−: calc'd for C20H24BrN3O2: 418.33. Found: 418. (M+H+).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([C:18]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[N:21][N:20]4[CH2:29][CH2:30][CH2:31][C:19]=34)=[CH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1)=[O:7]>O1CCCC1.O>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]1[C:18]([C:12]2[C:11]3[C:16](=[CH:17][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=3)[N:15]=[CH:14][CH:13]=2)=[C:19]2[CH2:31][CH2:30][CH2:29][N:20]2[N:21]=1
Reactant: COC(=O)c1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Lithium hydroxide monohydrate (0.65 g, 15.6 mmol) is added to a solution of 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinoline-7-carboxylic acid methyl ester (1.44 g, 3.89 mmol) in 2:1 tetrahydrofuran/water (30 mL), stirred at room temperature for 18 h, and concentrated in vacuo. The residue is purified by SCX resin, (2 N ammonia in methanol), to yield the title compound, 1.22 g (88%), as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.C(Cl)Cl.O.[CH3:31][N:32](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:31]#[N:32]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: ClCCl
Product: N#Cc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Yield: 90 %

Procedure:
Combine 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (5.015 g, 11.8 mmol), zinc cyanide (2.09 g, 17.7 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.59 g, 0.59 mmol) and DPPF (0.659 g, 1.18 mmol) in anhydrous DMF (40 mL), and stir at 95° C. for 3 h. Cool the reaction mixture to room temperature, add DCM and water. Extract the aqueous phase with DCM. Dry the combined organic extracts over anhydrous Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (20:1, 10:1 and 5:1) to obtain the desired intermediate (3.2 g, 90%). MS (ES+) m/z: 303 (M+H)+.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[Br:11][C:12]1[CH:13]=[C:14]2[C:20]([CH2:21]N(C)C)=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1.C(O)(=[O:28])CC>>[Br:11][C:12]1[CH:13]=[C:14]2[C:20]([CH:21]=[O:28])=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1
Reactant: CN(C)Cc1c[nH]c2ncc(Br)cc12
Reactant: CCC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81 %

Procedure:
To a refluxing (oil bath temp. 140° C.) solution of hexamethylenetetramine (8.83 g, 63 mmol) in 66% aqueous propionic acid (31.5 mL) was added a mixture of 5 (16.0 g, 63 mmol) and hexamethylenetetramine (8.83 g, 63 mmol) in 66% propionic acid (47 mL) over 2.5 h. The reflux was continued for 2.5 h, the reaction mixture allowed to cool to room temperature, then poured onto water (220 mL) and the suspension cooled in an ice-bath. The solid was filtered off, washed with ice-cold water (2×), and dried under high vacuum overnight to give 6 as a white solid (11.47 g, 81%); 1H NMR (400 MHz, CDCl3+4 drops d4-MeOH) δ 9.91 (s, 1H), 8.69 (d, J=2.2 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H), 7.95 (s, 1H).
Reaction SMILES: N#N.[CH3:3][S:4](Cl)(=[O:6])=[O:5].[C:8]([O:12][C:13]([N:15]1[CH2:18][CH2:17][C@H:16]1[CH2:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[CH:28]=[C:29]([CH2:33][CH2:34][CH2:35][NH2:36])[CH:30]=[CH:31][CH:32]=2)[CH:24]=[N:25][CH:26]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.COC(C)=O>C(Cl)Cl.O.CCOC(C)=O.C(Cl)Cl.CO.CCN(CC)CC>[C:8]([O:12][C:13]([N:15]1[CH2:18][CH2:17][C@H:16]1[CH2:19][O:20][C:21]1[CH:22]=[C:23]([C:27]2[CH:28]=[C:29]([CH2:33][CH2:34][CH2:35][NH:36][S:4]([CH3:3])(=[O:6])=[O:5])[CH:30]=[CH:31][CH:32]=2)[CH:24]=[N:25][CH:26]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccc(CCCN)c2)c1
Agent: N#N
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2cccc(CCCNS(C)(=O)=O)c2)c1
Temperature: 0 °C
Reaction time: 0.92 h
Yield: 140 %

Procedure:
In a 25 mL round-bottom flask with magnetic stirrer, septum, and N2 balloon, methanesulfonyl chloride (12 μL, 0.16 mmol, 1.3 equiv.) was added dropwise in 4 min with ice cooling to a solution of 3-[3-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]phenyl]propanamine (43.1 mg, 81.1 μmol) and triethylamine (30 μL, 0.22 mmol, 1.8 equiv.) in anhydrous CH2Cl2 (0.8 mL). The reaction mixture was stirred at 0° C. for 55 min. After 45 min, TLC (SiO2, CH2Cl2/MeOH/Et3N 90:10:5, UV detection) demonstrated disappearance of the starting material. On SiO2 with EtOAc, the product spot was detected at Rf approx. 0.25; with MeOAc, at Rf approx. 0.5. Water (100 μL) was added to the reaction mixture, and stirring was continued at room temperature for 1 h. After evaporation, the residue was chromatographed on SiO2 (21×1.3 cm, EtOAc, then MeOAc). Product-containing fractions were evaporated, and the residue was dried (50° C./oil pump) to furnish 54 mg of the sulfonamide, which was taken up in 1 mL of DMSO. The solution was filtered over a cotton plug (0.2 mL rinse) before purification by prep. HPLC (Supelco Discovery C18 column, 250×21.2 mm, 5 μm particle size; UV detection at 270 nm; flow 12.5 mL/min; 0-8 min, 20% CH3CN in water, then 20 to 100% within another 40 min; run aborted after elution of major peak and column washed with CH3CN; tR 32.0-33.0 min). The eluate was partially evaporated to remove CH3CN, and the product was extracted into CH2Cl2 (3×8 mL). The combined organic phases were dried over MgSO4 and evaporated, and the residue was dried (50° C./oil pump vacuum) to yield 39.9 mg (78%) of a colorless glass. [α]D−36.3, [α]546−43.3 (c 6.0 g/L, EtOAc). 1H NMR (CDCl3, TMS, 400 MHz) δ 8.45 (s, 1H), 8.33 (d, 1H, J=2.3 Hz), 7.46-7.37 (m, 4H), 7.23 (d, 1H, J=7.4 Hz), 4.61 (m, 1H), 4.55 (br m, 1H), 4.41 (br, 1H), 4.21 (dd, 1H, J=2.8, 10.1 Hz), 3.96-3.87 (m, 2H), 3.20 (q, 2H, J=6.7 Hz), 2.95 (s, 3H), 2.79 (t, 2H, J=7.6 Hz), 2.43-2.27 (m, 2H), 1.97 (quint, 2H, J=7.2 Hz), 1.40 (s, 9H). MS (EI) m/z 475 (M+, 0.4%), 402 (2.3%), 346 (5.3%), 320 (12%), 319 (31%), 307 (12%), 198 (12%), 113 (14%), 100 (30%), 70 (11%), 57 (94%), 56 (100%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3].[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][C:28](=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:19]1.C([BH3-])#N.[Na+]>>[C:29]([CH:28]([NH:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3])[CH2:27][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:18][CH:19]=1)([O:31][CH2:32][CH3:33])=[O:30]
Reactant: C[C@H](N)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Reactant: CCOC(=O)C(=O)Cc1c[nH]c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOC(=O)C(Cc1c[nH]c2ccccc12)N[C@@H](C)C(=O)N1C2CCCCC2C[C@H]1C(=O)O

Procedure:
As described in Example 1, react 1-[(S)-alanyl]octahydroindole-2(S)-carboxylic acid and ethyl indole-3-pyruvate with sodium cyanoborohydride to obtain the title compound.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].N1C=CC=CC=1.[CH2:12]([C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:19][CH3:20])[C:16](Cl)=[O:17])[CH:13]=[CH2:14]>C1C=CC=CC=1>[CH2:12]([C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:19][CH3:20])[C:16]([O:5][CH2:1][CH2:2][C:3]#[CH:4])=[O:17])[CH:13]=[CH2:14]
Reactant: C=CCC(OC)(C(=O)Cl)c1ccccc1
Reactant: C#CCCO
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C#CCCOC(=O)C(CC=C)(OC)c1ccccc1
Yield: 89.2 %

Procedure:
Into a solution of 1.4 g of 3-butyn-1-ol and 20 g of pyridine in 20 cc of benzene, was added a solution of 4.5 g of α-allyl-α-methoxyphenyl acetic chloride in 10 cc of benzene while being cooled with ice, whereby white precipitates were deposited immediately. The reaction mixture was washed with a diluted hydrochloric acid, 5% aqueous solution of sodium carbonate and an aqueous solution saturated with sodium chloride, and dried over anhydrous sodium sulfate. Evaporation of benzene gave 4.6 g of oily 3-butynyl α-allyl-α -methoxyphenylacetate, nD25 1.5137.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:26])=[CH:3]\[C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][N:13]2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)=[CH:9][CH:8]=1)=[O:5].[C:27](OCC)(OCC)(OCC)[CH3:28]>>[CH3:27][C:28]1[N:6]([C:7]2[CH:15]=[C:14]3[C:10]([CH:11]=[CH:12][N:13]3[CH2:16][O:17][C:18]3[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=3)[C:24]#[N:25])=[CH:9][CH:8]=2)[C:4](=[O:5])[CH:3]=[C:2]([CH3:26])[N:1]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: C/C(N)=C/C(=O)Nc1ccc2ccn(COc3cccc(C#N)c3)c2c1
Product: Cc1cc(=O)n(-c2ccc3ccn(COc4cccc(C#N)c4)c3c2)c(C)n1
Temperature: 130 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A mixture of (Z)-3-amino-N-(1-((3-cyanophenoxy)methyl)-1H-indol-6-yl)but-2-enamide (1.04 g, 3.00 mmol) and triethyl orthoacetate (20 mL) was stirred at 130° C. overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (272 mg, 25%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:17])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)S[CH2:9][CH2:8][CH:7]2[CH2:15][CH3:16])(=[O:3])[CH3:2].OO.[S:20]([O-:23])(O)=[O:21].[Na+]>C(O)(=O)C>[C:1]([C:4]1[C:5]([CH3:17])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[S:20](=[O:23])(=[O:21])[CH2:9][CH2:8][CH:7]2[CH2:15][CH3:16])(=[O:3])[CH3:2]
Reactant: CCC1CCSc2c(C)cc(C(C)=O)c(C)c21
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC1CCS(=O)(=O)c2c(C)cc(C(C)=O)c(C)c21
Temperature: 25 °C
Yield: 55 %

Procedure:
A mixed solution containing 1.66 g (6.68 mmol) of the 6-acetyl-4-ethyl-5,8-dimethylthiochroman, 2.28 g (20.1 mmol) of a 30% hydrogen peroxide aqueous solution and 2.0 ml of acetic acid was allowed to react at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, a 2% sodium hydrogensulfite aqueous solution was added, and the mixture was extracted with ethyl acetate and washed with a saturated sodium hydrogencarbonate and then with a saturated sodium chloride aqueous solution. An organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel; hexane/ethyl acetate=2:1) to give 1.03 g (yield 55%) of 6-acetyl-4-ethyl-5,8-dimethylthiochroman-1,1-dioxide.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].[H-].[Na+].[N:28]1[CH:33]=[CH:32][C:31](ON2C3C=CC=CC=3N=N2)=[N:30][CH:29]=1>CS(C)=O>[CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C:33]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Reactant: c1ccc2c(c1)nnn2Oc1ccncn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ccncn2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 71, Step D) (100 mg, 0.27 mmol) in 1.3 mL of DMSO was added sodium hydride (60% suspension in mineral oil, 13 mg, 0.32 mmol) at room temperature. The reaction mixture was stirred for 5 minutes, and was treated with 1-(pyrimidin-4-yloxy)-1H-benzo[d][1,2,3]triazole (Example 110, Step A) (170 mg, 0.80 mmol). The reaction mixture was stirred at 110° C. for 13 hours. The reaction mixture was cooled to room temperature, quenched with water and extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography (0 to 45% EtOAc/hexanes) provided the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)([O:4]COCC[Si](C)(C)C)[CH3:3].[Br:18]Br.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:18][C:15]1[S:14][C:13]([C:2]([OH:4])([CH3:3])[CH3:1])=[N:17][CH:16]=1
Reactant: CC(C)(OCOCC[Si](C)(C)C)c1nccs1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(O)c1ncc(Br)s1
Reaction time: 1 h

Procedure:
To a solution of 2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)thiazole from Step 2 in chloroform (2 mL mmol) at room temperature was added bromine (2 molar eq) and the resulting mixture was stirred for 1 hour. Solid sodium bicarbonate (0.55 eq) was added and the mixture was stirred for 5 hours. More sodium bicarbonate was added (0.55 eq) and stirring was continued for 18 hours. After a final addition of sodium bicarbonate (0.55 eq) the mixture was stirred for a further 5 hours, diluted with chloroform and the organic phase was washed with saturated aqueous sodium bicarbonate, then with water, dried and evaporated. The crude material was chromatographed, eluting with a 3:7 mixture of ethyl acetate and hexane to afford the desired product.
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]([Cl:18])=[N:10][CH:9]=1.C([Sn](CCCC)(CCCC)[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)CCC>CCOC(C)=O>[Cl:18][C:11]1[CH:12]=[C:13]([C:8]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)=[CH:9][N:10]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1cc(Cl)ncc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)ncc1-c1nccs1
Temperature: 65 °C

Procedure:
To a 100 mL round bottom flask was added bis(tri-tertbutylphosphine)palladium(0) (204 mg, 0.40 mmol, 0.1 equiv). The flask was then flushed with nitrogen and charged with 1,4-dioxane (20 mL), methyl 5-bromo-2-chloroisonicotinate (7-1, 1000 mg, 4.0 mmol, 1 equiv) and 2-(tributylstannyl)-1,3-thiazole (1.5 mL, 4.8 mmol, 1.2 equiv). The reaction mixture was heated for 3 hours at 65° C., diluted with EtOAc (20 mL) and filtered through celite. The filtrate was concentrated and the residue purified by normal phase column chromatography (0-40% EtOAc in hexanes) to afford the title compound (7-2) as a yellow solid. ESI+MS[M+H]+C10H8ClN2O2S=255.0
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[N:12]1C=CC=C[CH:13]=1.[Cu]C#N>CN(C=O)C>[NH2:4][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[C:13]#[N:12]
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: c1ccncc1
Agent: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1ccc([N+](=O)[O-])cc1N
Temperature: 160 °C
Yield: 74.2 %

Procedure:
A solution of 2-bromo-5-nitroaniline (10 g, 46 mmol) in DMF (100 mL) and pyridine (40 mL, 490 mmol) was treated with copper(I) cyanide (11.5 g, 128 mmol). The mixture was heated at 160° C. for 2 days under a reflux condenser. After the mixture had cooled to room temperature, it was filtered through celite and washed with ethyl acetate. Concentration and silica gel chromatography using methylene chloride gave 5.57 g of 2-amino-4-nitro-benzonitrile (74%): 1H NMR (300 MHz, CDCl3) δ 7.72 (d, 1H), 7.67 (m, 2H), 4.9 (br, 2H); MS (m/e): 164.1 (M+1).
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:74][O:73][C@@:6]2([O:10][C@H:9]3[CH2:11][C@H:12]4[C@@H:17]5[CH2:18][CH2:19][C@@H:20]6[CH2:25][C@@H:24]([O:26][C@@H]7O[C@H](CO[C@@H]8O[C@H](CO)[C@@H](O)[C@H](O)[C@H]8O)[C@@H](O[C@@H]8O[C@@H](C)[C@H](O)[C@@H](O)[C@H]8O)[C@H](O)[C@H]7O[C@@H]7O[C@H](CO)[C@@H](O)[C@H](O)[C@H]7O)[CH2:23][CH2:22][C@:21]6([CH3:70])[C@H:16]5[CH2:15][CH2:14][C@:13]4([CH3:71])[C@H:8]3[C@@H:7]2[CH3:72])[CH2:5][CH2:4]1>>[CH3:2][C@@H:3]1[CH2:74][O:73][C@@:6]2([O:10][C@H:9]3[CH2:11][C@H:12]4[C@@H:17]5[CH2:18][CH2:19][C@@H:20]6[CH2:25][C@@H:24]([OH:26])[CH2:23][CH2:22][C@:21]6([CH3:70])[C@H:16]5[CH2:15][CH2:14][C@:13]4([CH3:71])[C@H:8]3[C@@H:7]2[CH3:72])[CH2:5][CH2:4]1
Reactant: C[C@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5C[C@@H](O[C@@H]6O[C@H](CO[C@@H]7O[C@H](CO)[C@@H](O)[C@H](O)[C@H]7O)[C@@H](O[C@@H]7O[C@@H](C)[C@H](O)[C@@H](O)[C@H]7O)[C@H](O)[C@H]6O[C@@H]6O[C@H](CO)[C@@H](O)[C@H](O)[C@H]6O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: Cl
Product: C[C@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C

Procedure:
hydrochloric acid hydrolysis of sarsasaponin to afford sarsasapogenin;
Reaction SMILES: O[CH2:2][CH:3]([N:8]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[NH2:17])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>ClCCl>[CH3:36][O:37][CH2:38][C:39]([NH:17][C:11]1[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=1[CH2:9][N:8]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:3](=[CH2:2])[C:4]([O:6][CH3:7])=[O:5])=[O:40]
Reactant: COCC(=O)Cl
Reactant: COC(=O)C(CO)N(Cc1cc(C)ccc1N)S(=O)(=O)c1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C(=O)OC)N(Cc1cc(C)ccc1NC(=O)COC)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.3 %

Procedure:
To a cooled (0° C.) mixture of 1.598 g (3.91 mmol) of methyl 3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(2-amino-5-methylbenzyl)amino]propionate and 1.97 g (19.5) mmol) of triethylamine in 15 ml of dichloromethane was added 0.787 ml (8.60 mmol) of methoxyacetylchloride. The mixture was stirred at room temperature overnight. The mixture was then diluted with CH2Cl2 and washed with H2O, 2N citric acid, H2O, brine and dried with Na2SO4. The solution was filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to give 1.94 g of crude methyl 2-{[2-(methoxyacetylamino)-5-methylbenzyl]-(4-methoxy-benzenesulfonyl)-amino}acrylate as a brown oil. Mass spectrum (ES) 463.4 (M+H).