Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)CCCC1.[CH:28]1([NH:35][C@H:36]2[CH2:41][CH2:40][C@H:39]([CH:42]([CH3:44])[CH3:43])[CH2:38][CH2:37]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:28]1([N:35]([C@H:36]2[CH2:37][CH2:38][C@H:39]([CH:42]([CH3:44])[CH3:43])[CH2:40][CH2:41]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:13]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Reactant: CC(C)[C@H]1CC[C@H](NC2CCCCCC2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC(C)[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid (Example 38) via cycloheptyl-(trans-4-isopropyl-cyclohexyl)-amine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[CH:22]=O.N1CCCC1.ClC1C=C2C(/C(=C/C3C=C(Cl)C=CC=3O)/C(=O)N2)=CC=1>CO>[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[CH:22]=[C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: COC(=O)c1ccc(Cl)cc1C=O
Agent: O=C1Nc2cc(Cl)ccc2/C1=C/c1cc(Cl)ccc1O
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)c1ccc(Cl)cc1C=C1C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C

Procedure:
To the mixture of 6-chlorooxindole (1.2 g, 7 mmol) and 4-chloro-2-formyl-benzoic acid methyl ester (1.4 g, 7 mmol) in methanol (10 mL) was added pyrrolidine (490 mg, 7 mmol) dropwise. The mixture was then heated at 70° C. for 3 h. After cooled to 4° C., the mixture was filtered and the precipitate was collected, dried to give a mixture of E/Z-6-chloro-3-(5-chloro-2-hydroxy-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid (500 mg).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8](=[O:12])[CH2:9][CH2:10][CH3:11])[N:6]=1.C([O-])(=O)C.[Na+].[H][H]>CO.[Pd]>[C:8]([NH:7][C:5]1[N:6]=[CH:2][S:3][CH:4]=1)(=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: [H][H]
Reactant: CCCC(=O)Nc1csc(Br)n1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCCC(=O)Nc1cscn1
Yield: 40.2 %

Procedure:
A solution of 2-bromo-4-butyramidothiazole (4 g) and sodium acetate (1.35 g) in methanol (100 ml) was hydrogenated at atmospheric pressure over 10% Pd/C (1 g) as catalyst until theoretical uptake of hydrogen had occurred. The catalyst was removed by filtration and washed with methanol and the extracts evaporated in vacuo. The residue was recrystallised from hexane and the crystals sublimed at 50° C. at 0.2 mm and the sublimate recrystallised from carbon tetrachloride to give the title compound (1.1 g) m.p. 63°-6° C. (Found: C, 49.0; H, 5.9; N, 16.5. C7H10N2OS requires C, 49.4; H, 5.9; N, 16.5%).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([C:17]([N:19]([CH:33]([CH3:35])[CH3:34])[C@@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)=[O:18])[C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:4]=2[O:3]1.[CH2:37]([O:39][C:40](=[O:44])[CH2:41][CH2:42]Br)[CH3:38].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH2:37]([O:39][C:40](=[O:44])[CH2:41][CH2:42][N:6]1[C:5]2[CH:9]=[C:10]([C:17]([N:19]([CH:33]([CH3:34])[CH3:35])[C@@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)=[O:18])[C:11]([C:13]([F:14])([F:15])[F:16])=[CH:12][C:4]=2[O:3][C:2]([CH3:36])([CH3:1])[C:7]1=[O:8])[CH3:38]
Reactant: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21

Procedure:
To tert-Butyl (3R)-3-[{[2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (460 mg) were added 3-bromopropionic acid ethyl ester (0.19 ml), potassium carbonate (298 mg) and acetonitrile (5 ml), and the mixture was refluxed for 5 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (350 mg) as a colorless liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].Cl[CH2:20][C:21]1[S:25][C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[S:25][C:24]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=3)=[N:23][C:22]=2[CH3:36])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCOC(=O)C(Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 14 b], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole [PCT Int. Appl. (2002), WO 0292590 A1] in the presence of cesium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-{2-methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionic acid ethyl ester as colorless liquid.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([NH:35][C:36](=[O:53])[CH2:37][CH:38]([NH:42][C:43]([NH:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])[CH2:39][CH:40]=[CH2:41])[C:14](=[O:34])[N:15]([CH2:26][CH:27](OCC)OCC)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:25]=2[NH:24][N:23]=[CH:22]3)=[CH:8][CH:7]=1)(C)(C)C>C(O)=O>[CH2:46]([NH:45][C:43]([N:42]1[CH:38]([CH2:39][CH:40]=[CH2:41])[CH2:37][C:36](=[O:53])[N:35]2[CH:13]([CH2:12][C:9]3[CH:10]=[CH:11][C:6]([OH:5])=[CH:7][CH:8]=3)[C:14](=[O:34])[N:15]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][N:23]=[CH:22]4)[CH2:26][CH:27]12)=[O:44])[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: C=CCC(CC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2cn[nH]c12)CC(OCC)OCC)NC(=O)NCc1ccccc1
Solvent: O=CO
Product: C=CCC1CC(=O)N2C(Cc3ccc(O)cc3)C(=O)N(Cc3cccc4cn[nH]c34)CC2N1C(=O)NCc1ccccc1
Yield: 34.9 %

Procedure:
A solution of crude 3-(3-Benzyl-ureido)-hex-5-enoic acid {2-(4-tert-butoxy-phenyl)-1-[(2,2-diethoxy-ethyl)-(1H-indazol-7-ylmethyl)-carbamoyl]-ethyl}-amide (3.60 g, 4.95 mmol) in formic acid (100 mL) was stirred at room temperature for 13 h. The solvent was removed under reduced pressure and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The residue was purified by chromatography and recrystallized on ethyl acetate and hexane to give the 2-Allyl-6-(4-hydroxy-benzyl)-8-(1H-indazol-7-ylmethyl)-4,7-dioxo-hexahydro-pyrazino[1,2-a]pyrimidine-1-carboxylic acid benzylamide (1.0 g, 3 step yield: 30%). 1H NMR (CDCl3, 300 MHz) δ 8.20 (s, 1H), 7.4˜7.26 (m, 3H), 7.2 (d, J=7.01, 2H), 6.98 (t, J=8.0, 1H), 6.80 (m, 3H), 6.75 (t, J=7.0, 1H), 6.5 (d, J=8.76, 2H), 5.6 (m, 1H), 5.25 (t, J=4.7, 1H), 5.05 (d, J=10.75, 1H), 5.0 (d, J=18.54, 1H), 4.87 (d, J=14.51, 1H), 4.55 (m, 1H), 4.5˜4.25 (m, 4H), 3.5˜3.3 (m, 2H), 3.25˜3.1 (m, 2H), 2.6˜2.4 (m, 2H), 2.2 (t, J=7.2, 2H) MS ESI 579 (M+H), 601 (M+Na).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][OH:26])[CH:19]=2)=[O:17])[NH:13][C:12]1=[O:27])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:29].[Na+]>CC(C)=O.O.[Ru](Cl)(Cl)Cl>[Si:1]([O:8][C@@H:9]([C@H:11]1[C:12](=[O:27])[NH:13][C@@H:14]1[CH2:15][C:16]([C:18]1[CH:19]=[C:20]([CH2:24][C:25]([OH:29])=[O:26])[CH:21]=[CH:22][CH:23]=1)=[O:17])[CH3:10])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)c1cccc(CCO)c1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)c1cccc(CC(=O)O)c1
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
(3S,4R)-3-((1R)-1-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-4-{2-[3-(2-hydroxyethyl)phenyl]-2-oxoethyl}azetidin-2-one (3.0 g) prepared by reference example 15 and ruthenium trichloride (79 mg) were dissolved in acetone (77 ml) and to the solution was added at room temperature a solution of sodium periodate (3.3 g) in water (40 ml). The solution was stirred for 30 minutes. Further, a solution of sodium periodate (0.66 g) in water (4 ml) was added thereto and the solution was stirred for 3 hours. After removal of insoluble materials by filtration with celite, acetone was removed under reduced pressure. To the aqueous layer (about 50 ml) was added a saturated aqueous sodium chloride solution (100 ml) and the mixture was extracted with ethyl acetate (3×50 ml). The organic layers were combined, dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure to give (3-{[(2R,3S)-3-((1R)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-oxoazetidin-2-yl]acetyl}phenyl)acetic acid (2.72 g).
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:40])[C:12]3[S:19][C:18]([CH2:20][N:21]([CH2:23][CH:24]([OH:31])[C:25]4[CH:30]=[N:29][CH:28]=[CH:27][N:26]=4)[CH3:22])=[C:17]([CH2:32][O:33]CC[Si](C)(C)C)[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:40])[C:12]3[S:19][C:18]([CH2:20][N:21]([CH2:23][CH:24]([OH:31])[C:25]4[CH:30]=[N:29][CH:28]=[CH:27][N:26]=4)[CH3:22])=[C:17]([CH2:32][OH:33])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1COCC[Si](C)(C)C)CC(O)c1cnccn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CO)CC(O)c1cnccn1
Yield: 94.2 %

Procedure:
A solution of 144 mg of N-(4-chlorobenzyl)-2-{[(2-hydroxy-2-pyrazin-2-ylethyl)(methyl)amino]methyl}-4-methyl-7-oxo-3-{[2-(trimethylsilyl)ethoxy]methyl}-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide in 3 mL of 75% TFA in CH2Cl2 is stirred at room temperature for 3 h, then diluted with CHCl3 and added to stirred aq. NaHCO3. The aqueous phase is adjusted to pH 10-11 with added NaOH, then extracted with 6 portions of CHCl3. The combined organic phase is dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica gel (compound pre-loaded onto silica gel using CHCl3-MeOH) using 5-8% MeOH in CH2Cl2 provides 114 mg of the title compound as a white solid. Trituration with boiling acetonitrile affords white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:8]=2)[N:3]=1.[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1)#[CH:20].C(N(CC)CC)C>CN(C=O)C.C(#N)C.[Cu]I.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>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([C:20]#[C:19][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=2)[CH:11]=[CH:10]3)=[CH:13][CH:14]=1
Reactant: Clc1ccc(-c2ccc3nc(Br)ccc3c2)cc1
Reactant: C#Cc1ccc(C=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=Cc1ccc(C#Cc2ccc3cc(-c4ccc(Cl)cc4)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Under a nitrogen atmosphere 0.6 mg CuI, 9.3 mg Pd(PPh3)2Cl2 and 318 mg (1 mmol) 2-bromo-6-(4-chloro-phenyl)-quinoline are added successively to a solution of 85 mg (0.66 mmol) 4-ethynyl-benzaldehyde and 2.6 mL (18.67 mmol) triethylamine in 5 mL absolute DMF and 10 mL acetonitrile. The reaction mixture is stirred for 14 hours at RT and evaporated down. The purification is carried out by column chromatography on silica gel (PE/EtOAc 1:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>C1C=CC=CC=1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[CH:20]([C:19]1[CH:22]=[CH:23][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1)[O:12][CH2:11][CH2:10]2
Reactant: COc1ccc(CCO)cc1Br
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COc1cc2c(cc1Br)CCOC2c1ccc([N+](=O)[O-])cc1
Yield: 67 %

Procedure:
Hydrogen chloride gas that is dried for 5 hours is introduced into a suspension of 7.50 g (32.4 mmol) of 2-(3-bromo-4-methoxy-phenyl)-ethanol, 4.90 g (32.4 mmol) of 4-nitro-benzaldehyde and 4.39 g (32.4 mmol) of freshly melted zinc chloride in anhydrous benzene (96 ml). The reaction mixture is then diluted with ethyl acetate and washed neutral with water. After drying and concentration by evaporation, the solid residue is recrystallized from ethyl acetate (25 ml). 7.91 g (67%) of 6-bromo-7-methoxy-l-(4-nitrophenyl)-isochroman, melting point 144-147° C., is obtained.
Reaction SMILES: C([NH:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:7]([CH3:21])([CH3:20])[CH2:6]1)(=O)C>O.Cl>[NH2:4][CH:5]1[CH2:10][C:9]([CH3:11])([CH3:12])[N:8]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:7]([CH3:21])([CH3:20])[CH2:6]1
Reactant: CC(=O)NC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Agent: Cl
Solvent: O
Product: CC1(C)CC(N)CC(C)(C)N1OC1CCCCC1

Procedure:
A solution of 5.0 g of the acetamide from Example 47 in 7.5 ml of water and 7.5 ml of conc. hydrochloric acid is heated at reflux for 10 hours. The reaction mixture is then quenched with saturated sodium carbonate and extracted with ethyl acetate. The combined organic extracts are washed with water, brine, dried (MgSO4) and evaporated to leave a light brown oil. Distillation (Kugelrohr, 140° C. @ 1.5 mm) affords the title compound as a clear colorless oil.
Reaction SMILES: C(COC)OC.[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:26]([C:28]3[N:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[CH:30][N:29]=3)=O)[CH2:22][CH2:21]1)(=[O:19])=[O:18])=[CH:11]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:49])=CC=1>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:26]([C:28]3[N:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=4)=[CH:30][N:29]=3)=[S:49])[CH2:22][CH2:21]1)(=[O:19])=[O:18])=[CH:11]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(c1ncc(-c2ccncc2)cn1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCN(C(=S)c2ncc(-c3ccncc3)cn2)CC1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
In a mixed solvent of dimethoxyethane (10 ml) and toluene (10 ml) was suspended 1-[(5-chloroindol-2-yl)sulfonyl]-4-[[5-(pyridin-4-yl)pyrimidin-2-yl]carbonyl]piperazine (100 mg) at room temperature, followed by the addition of Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide, 42 mg). The resulting mixture was heated under reflux for 2 days. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by chromatography on a silica gel column (3→5% methanol—methylene chloride). 1N hydrochloric acid (in ethanol) was added to make acidic the purified product. After concentration, ethyl acetate was added. Yellow powder so precipitated was collected by filtration and dried, whereby the title compound (34 mg) was obtained.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[N:21]=[C:22]([Cl:24])[CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:24][C:22]1[CH:23]=[C:18]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]3)=[CH:15][N:14]=2)[C:19](=[O:26])[N:20]([CH3:25])[N:21]=1
Reactant: CC(C)N1CCN(c2ccc(N)nc2)CC1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)N1CCN(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 82.9 %

Procedure:
In a 50 mL round-bottomed flask, 5-(4-isopropylpiperazin-1-yl)pyridin-2-amine (200 mg, 908 μl mmol, Eq: 1.00), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (243 mg, 1.09 mmol, Eq: 1.2) and cesium carbonate (887 mg, 2.72 mmol, Eq: 3) were combined with dioxane (20 ml) to give a orange suspension. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (78.8 mg, 136 mmol, eq: 0.15) was added. Tris(dibenzylideneacetone)dipalladium(0) (41.6 mg, 45.4 μmol, Eq: 0.05) was added. The solution was degassed with Ar for 10 min. The solution was heated at 95-105° C. for 48 h. The solution was diluted with 200 ml DCM. MgSO4 was added and the suspension stirred for 10 min. The solid was filtered and washed several times with DCM. The organics were concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 50% to 100% EtOAc/hexanes gradient) to give 6-chloro-4-(5-(4-isopropylpiperazin-1-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one (273 mg, 83%). LC/MS-ESI observed [M+H]+ 363.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH:13]1([S:18][C:19]2[N:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=3)[N:22]=[CH:21][C:20]=2[C:34](O)=[O:35])[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.[CH:38]12[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:46][CH:40]([CH2:41]3)[CH:39]1[NH2:48])[CH2:45]2.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH:38]12[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:46][CH:40]([CH2:41]3)[CH:39]1[NH:48][C:34]([C:20]1[CH:21]=[N:22][N:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=3)[C:19]=1[S:18][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:35])[CH2:45]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)O)c2SC2CCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2SC2CCCC2)cc1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (199 mg, 1.04 mmol) was added in one portion to 5-(cyclopentylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylic acid (Intermediate#93) (300 mg, 0.87 mmol), 2-Adamantanamine hydrochloride (179 mg, 0.95 mmol), 1-Hydroxybenzotriazole (140 mg, 1.04 mmol) and N-Ethyldiisopropylamine (0.450 mL, 2.60 mmol) in DMF (7 mL) at 20° C. under nitrogen. The resulting mixture was stirred at 20° C. for 18 hours.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:13][NH:14][CH3:15].C(N(CC)CC)C.Cl>C(Cl)Cl.O>[CH3:13][N:14]([CH3:15])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
7.00 g of 4-methylbenzenesulfonyl chloride was dissolved in 70 mL of methylene chloride, to which 3.59 g of dimethylamine hydrochloride was added at room temperature and 12.8 mL of triethylamine was added dropwise in an ice bath, and then this solution was stirred for one hour at room temperature. The reaction mixture, to which water was added, was adjusted to pH 3 with 6M hydrochloric acid, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out thereof under reduced pressure to yield 6.75 g of N,N,4-trimethylbenzenesulfonamide as white solid.
Reaction SMILES: C([O:4][C@H:5]([C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[CH2:6][CH2:7][C@H:8]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[C@@H:9]1[C:20]1[CH:25]=[CH:24][C:23]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:22][CH:21]=1)(=O)C.[C-]#N.[Na+]>CO>[Si:27]([O:26][C:23]1[CH:22]=[CH:21][C:20]([C@H:9]2[N:10]([C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)[C:11](=[O:12])[C@@H:8]2[CH2:7][CH2:6][C@@H:5]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[OH:4])=[CH:25][CH:24]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(=O)O[C@@H](CC[C@H]1C(=O)N(c2ccc(I)cc2)[C@@H]1c1ccc(O[Si](C)(C)C(C)(C)C)cc1)c1ccc(F)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H]2[C@@H](CC[C@H](O)c3ccc(F)cc3)C(=O)N2c2ccc(I)cc2)cc1
Temperature: 50 °C

Procedure:
To a solution of 15 mg (0.022 mmol) (1S)-3-[(2S,3R)-2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-(4-iodophenyl)-4-oxoazetidin-3-yl]-1-(4-fluorophenyl)propyl acetate (Alternate Example 6, step A) in 1 mL anhydrous methanol under nitrogen atmosphere was added 2 mg of sodium cyanide. The reaction mixture was heated at 50° C. for 1.25 hr at which time the volatiles were removed by a nitrogen stream. The residue was purified by prep. Tlc eluting with EtOAc/hexanes (1/3) to afford the title compound. m/z (ES) 632.3 (MH+), 614.3 (MH−H2O+).