Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](O)=[O:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([NH2:34])[CH2:31][CH2:32][OH:33]>>[OH:33][CH2:32][CH2:31][C:30]1[N:34]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][S:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:26][N:29]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: NC(CCO)=NO
Product: O=C(N1CCSCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(CCO)no2)C1

Procedure:
According to General Method 6A, 600 mg (1.491 mmol) of the compound from Example 16A and 201 mg (1.938 mmol) of N′,3-dihydroxypropanimidamide were reacted Yield: 494 mg (68% of theory)
Reaction SMILES: O=C1N(C)C(=O)N(C)[CH:4]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:13][C:12]=2[OH:27])N1C.[OH-:29].[Na+]>O>[C:21]1([S:18]([NH:17][C:14]2[CH:13]=[C:12]([OH:27])[C:11](=[CH:16][CH:15]=2)[CH:4]=[O:29])(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [OH-]
Reactant: CN1C(=O)N(C)C(c2ccc(NS(=O)(=O)c3ccccc3)cc2O)N(C)C1=O
Agent: [Na+]
Solvent: O
Product: O=Cc1ccc(NS(=O)(=O)c2ccccc2)cc1O
Yield: 98.8 %

Procedure:
432 g (1 mol) of 2,4-dioxo-hexahydro-1,3,5-trimethyl-6-[2-hydroxy-4-benzenesulphonamido-phenyl]-s-triazine (93.5% pure product) are introduced into a solution of 280 g (7 mols) of sodium hydroxide in 600 ml of water. The mixture is boiled under reflux and under nitrogen for 6 hours. A pale brown solution is formed, from which small single crystals separate out. The contents of the flask are then poured onto a mixture of 700 ml of concentrated hydrochloric acid and 2 kg of ice and the yellow product which has separated out is filtered off. After washing with water and drying at 80° C, 274 g of 4-benzene-sulphonamido-salicylaldehyde of melting point 150° to 157° C are obtained. According to the oxime titration, the aldehyde is 94.8% pure and the yield is thus 93.6%. After recrystllisation from xylene (1 : 10), the aldehyde is obtained as colourless crystals of melting point 160° to 163° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=3)=[N:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([CH:34]=O)=[C:29]([CH3:36])[CH:28]=1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>CS(C)=O>[CH3:22][O:23][C:24](=[O:37])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([CH3:33])[C:30]([C:34]2[NH:21][C:16]3[CH:15]=[C:14]([C:12]4[O:13][C:9]([NH:8][C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=5)=[N:10][N:11]=4)[CH:19]=[CH:18][C:17]=3[N:20]=2)=[C:29]([CH3:36])[CH:28]=1
Reactant: Nc1ccc(-c2nnc(Nc3cccc(Cl)c3)o2)cc1N
Reactant: COC(=O)CCc1cc(C)c(C=O)c(C)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCc1cc(C)c(-c2nc3ccc(-c4nnc(Nc5cccc(Cl)c5)o4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-[5-(3-chlorophenylamino)-[1,3,4]oxadiazol-2-yl]-benzene-1,2-diamine (210 mg, 0.7 mmol) and 3-(4-formyl-3,5-dimethylphenyl)-propionic acid methyl ester (169 mg, 0.77 mmol) (from step D) in DMSO (2.5 mL) was added Yb(OTf)3 (86 mg, 0.14 mmol) and the mixture was stirred at RT for 72 h. The mixture was poured into water and the resulting precipitate was filtered and washed with water. The solid was purified by flash chromatography using 10% MeOH/CH2Cl2 as eluent to give the title compound as a tan solid. MS: m/z 502.0 (M+1). H1-NMR (DMSO-d6): δ ppm 12.91 (m, 0.6H), 10.93 (s, 0.3 H), 10.48 (dd, 0.3H), 8.33 (s, 0.4H), 8.13 (s, 0.6H), 7.89-7.73 (M, 2.3H), 7.68 (d, 0.3 H), 7.59 (d, 0.4H), 7.52 (m, 1 H), 7.46-7.35 (m, 1H), 7.08 (s, 3H), 3.61 (s, 3H), 2.87 (t, 2H), 2.69 (t, 2H), 2.10 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH3:32])[CH:30]=3)[C:13]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCn1cc(Br)cn1
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CC)c3)c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][N:19]=[CH:18]4)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].O>CN(C=O)C>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:19]=[CH:18]4)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3c(cnn3CC(=O)OCC)c2)ncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(1H-indazol-5-yl)pyrimidine-4-carboxamide (Example 45, 350 mg; 1 mmol) in DMF (4 ml) was treated with potassium carbonate (140 mg; 1 mmol), and ethyl 2-bromoacetate (184 mg; 1.1 mmol). After stirring at RT for 18 hours the mixture was poured into water (20 ml) and stirred at RT for 30 minutes. The solid was removed by filtration and purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid, together with ethyl {5-[({6-[(cyclopropylmethyl)(propyl)amino]pyrimidin-4-yl}carbonyl)amino]-2H-indazol-2-yl}acetate (Example 120 below).
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:15]=[CH:14][C:13]3[C:12]([C:16]([NH:18][CH2:19]C4CCCCC4)=[O:17])=[C:11]([Cl:26])[CH:10]=[CH:9][C:8]=3[N:7]=2)[CH2:3]1.[C:27]([O:31]CC)(=[O:30])[CH:28]=[CH2:29].[OH-].[Na+].Cl>CO>[Cl:26][C:11]1[C:12]([C:16]([NH:18][CH2:19][CH2:16][CH:12]2[CH2:13][CH2:8][CH2:9][CH2:10][CH2:11]2)=[O:17])=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([N:4]1[CH2:5][CH:2]([NH:1][CH2:29][CH2:28][C:27]([OH:31])=[O:30])[CH2:3]1)[CH:15]=[CH:14]2
Reactant: NC1CN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1
Reactant: C=CC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCNC1CN(c2ccc3c(C(=O)NCCC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 2-(3-amino-1-azetidinyl)-6-chloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide (Example 97(a)) (0.1 g) in methanol (1 mL) was added ethyl acrylate (0.032 mL). The mixture was stirred at room temperature for 20 hours. Sodium hydroxide (1 mL, 1M) was added and the reaction mixture was stirred for 72 hours. Hydrochloric acid (0.5 mL, 2M) was added and the reaction mixture was concentrated under vacuum. Purification (HPLC—Symmetry, 0.1% aqueous ammonium acetate:acetonitrile as eluant) gave the title compound as a solid (0.026 g).
Reaction SMILES: [CH:1]([Cl:4])(Cl)Cl.[F:5][C:6]1[CH:36]=[CH:35][C:9]2[S:10][C:11]([S:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[S:25][CH:26]=[C:27](CO)[N:28]=4)=[CH:20][C:19]=3[S:31]([CH3:34])(=[O:33])=[O:32])(=[O:16])=[O:15])=[C:12]([CH3:13])[C:8]=2[CH:7]=1.S(Cl)(Cl)=O>C(N(CC)CC)C>[Cl:4][CH2:1][C:27]1[N:28]=[C:24]([C:21]2[CH:22]=[CH:23][C:18]([NH:17][S:14]([C:11]3[S:10][C:9]4[CH:35]=[CH:36][C:6]([F:5])=[CH:7][C:8]=4[C:12]=3[CH3:13])(=[O:15])=[O:16])=[C:19]([S:31]([CH3:34])(=[O:32])=[O:33])[CH:20]=2)[S:25][CH:26]=1
Reactant: ClC(Cl)Cl
Reactant: Cc1c(S(=O)(=O)Nc2ccc(-c3nc(CO)cs3)cc2S(C)(=O)=O)sc2ccc(F)cc12
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3nc(CCl)cs3)cc2S(C)(=O)=O)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Into 20 mL of chloroform was suspended 159 mg of Compound 63, and 47 μL of thionyl chloride was added at 0° C., followed by 21 hours of stirring at room temperature. Further, 1 mL of thionyl chloride was added, followed by 1 hour of heating under refluxing. After 2 mL of triethylamine was added at 0° C. and the mixture was stirred for 3 hours, the reaction was terminated with 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, successively and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform) to obtain 104 mg of the title compound as light brown powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[CH:8][C:9]=1I)=[O:4].C([Mg]Cl)(C)C.CC1OCCC1.Br[C:24]1[CH:52]=[CH:51][C:27]([C:28]([N:30]([C:44]2[C:49]([CH3:50])=[CH:48][CH:47]=[CH:46][N:45]=2)[CH:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]2)=[O:29])=[CH:26][CH:25]=1>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[CH:8][C:9]=1[C:24]1[CH:52]=[CH:51][C:27]([C:28]([N:30]([C:44]2[C:49]([CH3:50])=[CH:48][CH:47]=[CH:46][N:45]=2)[C@@H:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:38])[CH2:32]2)=[O:29])=[CH:26][CH:25]=1)=[O:4]
Reactant: Cc1cccnc1N(C(=O)c1ccc(Br)cc1)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)c1c(I)cnn1C
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccc(C(=O)N(c3ncccc3C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc2)cnn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a solution of 4-iodo-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (8.1 g, 30.45 mmol) in THF (anhydrous, 60 mL) was added isopropyl magnesium chloride (16.5 mL, 16.5 mmol) at −45° C. The solution turned from clear to light green-yellowish. Stirred at this temperature for 30 min, GC-MS (sample in CD3OD) indicated all halogen-metal exchange completed. To the mixture was added 1.9 N ZnCl2 in 2-MeTHF (9.62 mL, 18.3 mmol) dropwise and the reaction was warmed to room temperature. The mixture was stirred for 2 h, over which time it turned from clear yellowish to an opaque yellowish mixture. To this reaction was added Preparation 2 tert-butyl 3-[(4-bromobenzoyl)(3-methylpyridin-2-yl)amino]piperidine-1-carboxylate (12.04 g, 25.37 mmol) as a solid in one batch. The reaction temperature was then raised to 50° C., 1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (166 mg, 0.254 mmol) was added. The reaction was then stirred at 60° C. for 2 h then cooled to room temperature. The reaction was quenched with water and extracted 3× EtOAc. The organic layer was dried and concentrated. Purification was performed by Combiflash ISCO column (220 g) 0-75% EtOAc/heptane to isolate the desired title compound (12.8 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[NH2:19][O:20][CH2:21][CH2:22][NH2:23].N1C=CC=CC=1>C(O)C>[ClH:1].[NH2:23][CH2:22][CH2:21][O:20][N:19]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCCCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: NCCON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COCCCCC(=NOCCN)c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 14 mmol (3.65 g) of 3', 4'-dichloro-5-methoxyvalerophenone, 14 mmol (2.1 g) of 2-aminooxyethylamine dihydrochloride, 7 ml of pyridine and 14 ml of absolute ethanol was refluxed for 2 hours. The reaction mixture was then further processes as described in Example 4. After crystallization from a mixture of ether and petroleum ether (boiling point 40°-60° C) the above entitled compound was obtained with a melting point of 93°-94° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:21][S:22][C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1.[C:32](Cl)(=[O:36])[O:33][CH2:34][CH3:35].CC1C(CSC2NC3C=CC=CC=3N=2)=NC=CC=1SCCN1CCOCC1>>[CH3:1][C:2]1[C:3]([CH2:21][S:22][C:23]2[N:24]([C:32]([O:33][CH2:34][CH3:35])=[O:36])[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1
Reactant: Cc1c(SCCN2CCc3ccccc3C2)ccnc1CSc1nc2ccccc2[nH]1
Reactant: CCOC(=O)Cl
Agent: Cc1c(SCCN2CCOCC2)ccnc1CSc1nc2ccccc2[nH]1
Product: CCOC(=O)n1c(SCc2nccc(SCCN3CCc4ccccc4C3)c2C)nc2ccccc21

Procedure:
The same reaction as in Example 17 was carried out except that 2-((3-methyl-4-(2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethylthio)-2-pyridyl)methylthio)-1H-benzimidazole was reacted with ethyl chlorocarbonate, in place of 2-((3-methyl-4-(2-morpholinoethylthio)-2-pyridyl)methylthio)-1H-benzimidazole, to give ethyl 2-((3-methyl-4-(2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethylthio)-2-pyridyl)methylthio)-1H-benzimidazole-1-carboxylate 1/2 ·ethanol as crystals, melting point 134°-136° C. (dec.).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]2([CH:15]([Br:16])[CH2:14][CH2:13][C:12]3[N:11]([S:17]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:10]=[CH:9][C:8]2=3)[O:4]1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.N1C=CC=CC=1>ClCCl>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([O:1][CH2:2][CH:3]2[CH2:7][O:6][C:5]3([CH:15]([Br:16])[CH2:14][CH2:13][C:12]4[N:11]([S:17]([C:20]5[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=5)(=[O:19])=[O:18])[CH:10]=[CH:9][C:8]3=4)[O:4]2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CO)O2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COC3(O2)c2ccn(S(=O)(=O)c4ccc(C)cc4)c2CCC3Br)cc1
Reaction time: 10 h
Yield: 87 %

Procedure:
To a solution of 4'-hydroxymethyl-5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-[1,3]-dioxolane (100 parts) in dichloromethane (2000 parts) is added a solution of p-toluenesulfonyl chloride (1.1 molar equivalent) and pyridine (1.2 molar equivalents) in dichloromethane (500 parts), and the mixture is kept at room temperature for 10 hours. The mixture is evaporated, and the residue is dissolved in ethyl acetate, washed with water, dried and evaporated to give 4'-p-toluenesulfonyloxymethyl-5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-[1,3]dioxolane in 87% yield. The physical constants are given in Table I, No. 18.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([PH:17](=[O:34])[C:18]2[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([O:28][CH3:29])=[C:20]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:19]=2)[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(PCCCPC2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(O[C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][C:77]=1[Br:82])(=O)=O.C(N(CC)C(C)C)(C)C.Cl>C1(C)C=CC=CC=1>[C:24]([C:22]1[CH:23]=[C:18]([P:17](=[O:34])([C:7]2[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([O:11][CH3:12])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=2)[C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][C:77]=2[Br:82])[CH:19]=[C:20]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:21]=1[O:28][CH3:29])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=S(=O)(Oc1ccccc1Br)C(F)(F)F
Reactant: COc1c(C(C)(C)C)cc([PH](=O)c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)cc1C(C)(C)C
Agent: Cl
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: c1ccc(PCCCPc2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1c(C(C)(C)C)cc(P(=O)(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccccc2Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
Into a four-neck flask were weighed 28.71 g (59.0 mmol) of bis(3,5-di-t-butyl-4-methoxyphenyl)phosphine oxide, 1.27 g (2.5 mmol) of Pd2(dba)3CHCl3 (dba represents dibenzylideneacetone), and 1.01 g (2.5 mmol) of 1,3-diphenylphosphinopropane. The atmosphere of the reaction vessel which was fitted with a thermometer, a condenser tube, and a dropping funnel with a pressure-equalizing tube was completely replaced with nitrogen. Thereto were added 150 mL of toluene, 15.00 g (49.2 mmol) of the 2-(trifluoromethanesulfonyl)oxy-bromobenzene (5), and 9.53 g (73.8 mmol) of N,N-diisopropylethylamine, followed by 16 hours of heating at reflux. After the completion of the reaction, the reaction mixture was cooled to room temperature and poured into 150 mL of 5% hydrochloric acid aqueous solution. After 30 minutes of stirring, the layers were separated from each other. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. Toluene was removed by evaporation and the residue was purified by silica gel column chromatography to obtain the title compound (30.83 g, a white viscous solid). Yield 97.7%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:16][CH:15]([OH:17])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:18][NH:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([OH:31])=[CH:28][CH:29]=2)[N:24]([CH3:32])[C:23]=1[CH3:33])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:18][NH:19][C:20]([C:22]1[C:30]2[C:25](=[CH:26][C:27]([O:31][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:16][CH:15]([OH:17])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:28][CH:29]=2)[N:24]([CH3:32])[C:23]=1[CH3:33])=[O:21]
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC(O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N5CC(O)C5)sc34)ccc12

Procedure:
This material was prepared by the reaction of (7-chloro-thieno [3,2-b]pyridin-2-yl)-(3-hydroxy-azetidin-1-yl)-methanone 9d with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid methylamide 16e and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) δ 8.41 (1H, d, J=5.5 Hz), 7.78–7.74 (2H, m), 7.29 (1H, d, J=2.1 Hz), 6.95(1H, dd, J=2.1, 8.6 Hz), 6.62 (1H, d, J=5.5 Hz), 4.76–4.73 (2H, m), 4.63 (1H, bs), 4.35–4.32 (2H, m), 3.9.7–3.94(1H, m), 3.62(3H, s), 2.89(3H, s), 2.57 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 451. found 451.
Reaction SMILES: [CH3:1][N:2]([C@@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[CH3:32][C:33]1[N:37]([CH2:38][C:39](O)=[O:40])[N:36]=[C:35]([C:42]([F:45])([F:44])[F:43])[CH:34]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][N:2]([C@@H:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:17][CH3:18])[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:39](=[O:40])[CH2:38][N:37]3[C:33]([CH3:32])=[CH:34][C:35]([C:42]([F:45])([F:44])[F:43])=[N:36]3)[CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4]
Reactant: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCNCC2)n1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methyl-N-[(1R)-1-phenylpropyl]-2-(4-piperidinyl)-4-thiazolecarboxamide (i.e. the product of Example 1, Step E) (150 mg, 0.44 mmol) was dissolved in 3 mL of dry dichloromethane. To this solution was added triethylamine (30 μL, 0.22 mmol), 5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-acetic acid (83 mg, 0.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol) and a catalytic amount of 4-(dimethylamino)pyridine (˜1 mg). The reaction mixture was shaken overnight at ambient temperature, concentrated under reduced pressure and passed through a silica gel column (2 g) using 1:1 hexanes/ethyl acetate as eluant. The dichloromethane/hexanes/ethyl acetate solution was concentrated under reduced pressure, and the residue was purified by preparative reverse phase High Pressure Liquid Chromatography (HPLC) using a solvent gradient going from 100% water to 100% acetonitrile to give 85 mg of the title product, a compound of the present invention as an oil. 1H NMR (CDCl3) δ 0.9-1.1 (br m, 3H), 1.7-1.9 (m, 2H), 1.9-2.2 (m, 4H), 2.31 (s, 3H), 2.7-3.0 (m, 4H), 3.2-3.4 (m, 2H), 3.9-4.6 (br m, 2H), 4.96 (br s, 2H), 5.6-6.0 (m, 1H), 6.3 (s, 1H) 7.20-7.45 (m, 5H), 7.8 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:26]=2)/[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:14]=[CH:13]3)=[CH:4][CH:3]=1.[CH3:40][O:41][CH2:42][CH2:43]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:40][O:41][CH2:42][CH2:43][O:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:26]=[CH:27][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][CH:30]=2)/[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:14]=[CH:13]3)=[CH:6][CH:7]=1
Reactant: COCCO
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(O)cc2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(OCCOC)cc2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of (E)-ethyl 3-(4-((E)-2-(4-hydroxyphenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (222 mg, 0.42 mmol), 2-methoxyethanol (0.1 mL, 1.26 mmol), diisopropyl azidocarboxylate (0.24 mL, 1.26 mmol), and triphenylphosphine (330 mg, 1.26 mmol) in THF (5 mL) was stirred at room temperature overnight. The reaction mixture was absorbed on silica gel and purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate/hexanes to afford 139 mg of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.11 (s, 1H), 7.72 (d, 1H), 7.62 (s, 1H), 7.48 (d, 1H), 7.40 (d, 2H), 7.21 (d, 1H), 7.08 (d, 2H), 6.88 (d, 2H), 6.79 (d, 2H), 6.47 (d, 1H), 5.85 (dd, 1H), 4.13 (qt, 2H), 4.02 (m, 2H), 3.90 (m, 1H), 3.74 (m, 1H), 3.62 (m, 2H), 3.29 (s, 3H), 2.47-2.37 (m, 3H), 2.01 (m, 2H), 1.76 (m, 1H), 1.59 (m, 2H), 1.22 (t, 3H), 0.89 (t, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[CH3:15])=O.CNC(C1CC2C(C=1C)=CC=CC=2)=O>>[CH3:15][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[CH2:3][NH:2][CH3:1]
Reactant: CNC(=O)c1ccc2ccccc2c1C
Agent: CNC(=O)C1=C(C)c2ccccc2C1
Product: CNCc1ccc2ccccc2c1C
Yield: 36 %

Procedure:
According to the procedure of Preparation 20(b), except substituting N,1-dimethylnaphthalene-2-carboxamide (0.3 g, 1.5 mmole) for the N,3-dimethylindene-2-carboxamide, the title compound (0.1 g, 36%) was prepared as a colorless oil: MS (ES) m/e 186 (M+H)+.
Reaction SMILES: [CH3:1]S(C1N(CCCCC2C=CC=CC=2)C(=O)C1)=O.[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:47])[CH2:33][N:34]2[CH:37]([S:38]([CH2:40]CCCCC)=[O:39])[CH2:36][C:35]2=[O:46])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.OCCS(C1N(CC(=O)CCC2C=CC=CC=2)C(=O)C1)=O>>[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:47])[CH2:33][N:34]2[C@@H:37]([S:38]([CH3:40])=[O:39])[C@H:36]([CH3:1])[C:35]2=[O:46])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCCCCS(=O)C1CC(=O)N1CC(=O)NCCCCCCc1ccccc1
Reactant: CS(=O)C1CC(=O)N1CCCCc1ccccc1
Agent: O=C(CCc1ccccc1)CN1C(=O)CC1S(=O)CCO
Product: C[C@@H]1C(=O)N(CC(=O)NCCCCCCc2ccccc2)[C@H]1S(C)=O

Procedure:
4-Methylsulfinyl-1-(4-phenylbutyl)-azetidin-2-one; N-(6-Phenylhexyl )-(4-n-hexylsulfinyl-2-oxoazetidin-1-yl )acetamide; 4-(2-Hydroxyethylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one (Diastereoisomer 2);