Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]2[CH:16]=[C:15]([CH2:17][CH2:18][C:19]3[S:20][CH:21]=[C:22]([CH:24]([CH3:26])[CH3:25])[N:23]=3)[CH:14]=[CH:13][N:5]2[C:6](=[O:12])[C:7]=1/[CH:8]=[CH:9]/[C:10]#[N:11].CN(C)C=O.C(N(C(C)C)CC)(C)C.I[CH2:42][CH:43]1[CH2:47][CH2:46][O:45][CH2:44]1>O.C(Cl)(Cl)Cl>[CH:24]([C:22]1[N:23]=[C:19]([CH2:18][CH2:17][C:15]2[CH:14]=[CH:13][N:5]3[C:6](=[O:12])[C:7](/[CH:8]=[CH:9]/[C:10]#[N:11])=[C:2]([O:1][CH2:42][CH:43]4[CH2:47][CH2:46][O:45][CH2:44]4)[N:3]=[C:4]3[CH:16]=2)[S:20][CH:21]=1)([CH3:26])[CH3:25]
Reactant: ICC1CCOC1
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C#N)c(O)nc3c2)n1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C#N)c(OCC4CCOC4)nc3c2)n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
(E)-2-{2-Hydroxy-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4-oxo-4H-pyrido-[1,2-a]pyrimidin-3-yl}-1-ethenylcyanide (100 mg) was added with dimethylformamide (5 ml), diisopropylethylamine (500 ml) and 3-(iodomethyl)tetrahydrofuran (200 ml), and then the mixture was stirred at 80° C. for 2 hours and further stirred overnight at room temperature. After the reaction mixture was distributed between chloroform and water, the organic layer was dried over magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (51 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=2)=[N:17][C:16]([Cl:29])=[CH:15][N:14]=1)(=[O:11])=[O:10].CN.C(O)(=O)C.[C:36]([BH3-])#[N:37].[Na+]>O1CCCC1.CO.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:37][CH3:36])[CH:22]=2)=[N:17][C:16]([Cl:29])=[CH:15][N:14]=1)(=[O:11])=[O:10]
Reactant: [BH3-]C#N
Reactant: O=Cc1cccc(COc2nc(Cl)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)c1
Agent: CN
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CNCc1cccc(COc2nc(Cl)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
A mixture of 2,3-dichloro-N-[5-chloro-3-(3-formylphenylmethoxy)-2-pyrazinyl]benzenesulphonamide (Example 107a) (0.1 g), methylamine (2 mL of a 2M solution in tetrahydrofuran) and acetic acid (0.2 mL) in methanol (2 mL) was stirred at room temperature. After 2 h, sodium cyanoborohydride (0.03 g) was added. After 0.5 h, water (2 mL) was added and the mixture evaporated to dryness. Chromatography on silica gel eluting with methanol/dichloromethane mixtures gave the title compound as a white solid (0.035 g).
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[CH3:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:20])=[O:19])[CH:15]=[CH:14][CH:13]=1>C(O)(=O)C>[CH2:8]([O:7][C:3](=[O:10])[CH2:20][C:18](=[O:19])[C:16]1[CH:17]=[C:12]([CH3:11])[CH:13]=[CH:14][CH:15]=1)[CH3:9]
Reactant: CC(=O)c1cccc(C)c1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)c1cccc(C)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Sodium hydride (3.1 g, 77.1 mmol) and diethyl carbonate were combined with 3-methylacetophenone (4.5 g, 33.54 mmol). The mixture was stirred for 2 hours at 80° C. After the reaction was completed, ice water and acetic acid were added thereto. Then, the mixture was extracted with ethyl acetate/saturated sodium chloride. The extract was dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography to obtain 3-oxo-3-m-tolylpropionate ethyl ester (5.8 g, yield 84%).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:25]2[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=[C:21]([NH2:28])[C:20]=2[N:19]=[C:18]1[CH2:29][O:30][CH2:31][CH3:32]>>[NH2:28][C:21]1[C:20]2[N:19]=[C:18]([CH2:29][O:30][CH2:31][CH3:32])[N:17]([CH2:16][CH2:15][CH2:14][NH:13][C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[C:25]=2[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCN
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCNC(=O)[C@@H]1C[C@H]1c1ccccc1

Procedure:
Using the method of Examples 94-111, trans-2-phenyl-1-cyclopropanecarbonyl chloride was reacted with 1-(3-aminopropyl)-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired product. The observed accurate mass was 422.2564.
Reaction SMILES: N1C2C(=CC=CC=2C(O)=O)C=CC=1.[C:14]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:15]([C:20]([N:22]2[CH:27]=[C:26]([O:28]C)[CH2:25][CH2:24][CH:23]2[CH2:30][NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[C:38]3[C:43]=2[N:42]=[CH:41][CH:40]=[CH:39]3)=[O:33])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:14]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:15]([C:20]([N:22]2[CH2:27][C:26](=[O:28])[CH2:25][CH2:24][CH:23]2[CH2:30][NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[C:38]3[C:43]=2[N:42]=[CH:41][CH:40]=[CH:39]3)=[O:33])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC1=CN(C(=O)c2ccccc2-c2ccccc2)C(CNC(=O)c2cccc3cccnc23)CC1
Agent: O=C(O)c1cccc2cccnc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCC(CNC(=O)c2cccc3cccnc23)N(C(=O)c2ccccc2-c2ccccc2)C1

Procedure:
N-((1-(Biphenylcarbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide was prepared according general procedure A using quinoline-8-carboxylic acid and N-((1-(biphenylcarbonyl)-5-methoxy-1,2,3,4-tetrahydropyridin-2-yl)methyl)quinoline-8-carboxamide which was synthesized from the product from Part VI above, following ketal cleavage using TFA and CH2Cl2. MS (ESI) 464 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)CC)C.Cl[C:24]1[N:29]([CH3:30])[C:28](=[O:31])[CH:27]=[C:26]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[N:25]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:24]2[N:29]([CH3:30])[C:28](=[O:31])[CH:27]=[C:26]([C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)[N:25]=2)[CH2:12][CH2:11]1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: COc1ccccc1NC1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1NC1CCN(c2nc(-c3ccncc3)cc(=O)n2C)CC1
Reaction time: 12 h
Yield: 85 %

Procedure:
To a solution of 4-(2-methoxyphenylamino)-piperidine (0.8 g, 3.87 mmol) and triethylamine (1.3 g, 12.8 mmol) in tetrahydrofuran (20 mL) was added 2-chloro-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (0.8 g, 3.61 mmol) portionwise. After stirring for 12 h, the resulting suspension was partitioned between chloroform and 1N sodium hydroxide. The aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 2-(4-(2-methoxyphenylamino)-piperidin-1-yl)-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (1.2 g, 3.07 mmol, 85%) as white crystals.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([Cl:14])[C:5]=1[C:6](Cl)=[O:7]>C(Cl)(Cl)Cl>[Cl:3][C:4]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([Cl:14])[C:5]=1[C:6]([NH:1][NH2:2])=[O:7]
Reactant: NN
Reactant: O=C(Cl)c1c(Cl)ccc(Cl)c1Cl
Solvent: ClC(Cl)Cl
Product: NNC(=O)c1c(Cl)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.22 mol. hydrazine in 100 ml. chloroform at -10° C. was added 0.1 mol of 2,3,6-trichlorobenzoyl chloride. The mixture was stirred at ambient temperature for 2 hours, filtered, and the filtrate evaporated in vacuo. The residue was crystallized from methanol and water, then recrystallized from chloroform and hexane to obtain the titled product.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([O:13][Si](C(C)(C)C)(C)C)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([OH:13])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cnn(Cc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1cnn(Cc2ccccc2)c1
Reaction time: 8 h
Yield: 34.8 %

Procedure:
1-Benzyl-4-t-butyldimethylsilyloxypyrazole (3.0 g, 10.4 mmol) was dissolved in THF (20 ml) and tetrabutylammonium fluoride (52 ml of 1M solution in THF) was added. The reaction was stirred overnight and the solvent removed in vacuo. The residue was dissolved in water and extracted into diethylether. The organics dried over sodium sulfate, and the ether removed in vacuo. The residue purified by column chromatography (silica gel, chloroform→2% methanol/chloroform) to yield product (0.63 g, 35%). MS
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:14]=[CH:13][NH:12][CH:11]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([F:24])[F:23])=[CH:18][N:17]=1.O>CN(C)C=O>[C:3]([O:7][C:8]([C:10]1[CH:14]=[CH:13][N:12]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([F:24])[F:23])=[CH:18][N:17]=2)[CH:11]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: FC(F)c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccn(-c2ccc(C(F)F)cn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
Sodium hydride (230 mg) was added to a solution of 1H-pyrrole-3-carboxylic acid tert-butyl ester (804 mg) in N,N-dimethylformamide (9.6 ml) at room temperature and stirred at the same temperature for 0.5 hour. 2-Bromo-5-(difluoromethyl)pyridine (1.0 g) was added and stirred at 60° C. for an hour. After completion of the reaction, the reaction solution was cooled to room temperature, water was added and the precipitated solid was filtered. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-[5-(difluoromethyl)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid tert-butyl ester (1.01 g) as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C>[Si:17]([O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1

Procedure:
A solution of ethyl trans-4-hydroxycyclohexanecarboxylate (5 g), tert-butyl(chloro)diphenylsilane (7.93 mL) and imidazole (2.17 g) in DMF (50 mL) was stirred at room temperature overnight and extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (10.1 g).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1B(O)O>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Product: CSc1ccc(C2=C(c3ccc(Cl)cc3Cl)CCC2)cc1
Yield: 89.8 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 280 mg (0.93 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio)benzene (Example 1, Step 2) was reacted with 350 mg (1.9 mmol) of 2,4-dichlorophenylboronic acid (Lancaster). Purification by silica gel chromatography (MPLC) with hexane gave 280 mg of 1-[2-(2,4-dichlorophenyl)cyclopenten-1-yl]-4-(methylthio)benzene as an oil: NMR (CDCl3) d 2.10 (m, J=7 Hz, 2H) , 2.41 (s, 3H) , 2.81 (t, J=8 Hz, 4H) , 2.92 (m, J=8 Hz, 2H) , 6.95-7.21 (m, 6H) , 7.40 (s, 1H) .
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([O:17][C:18]3[CH:32]=[CH:31][C:21]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)=[C:15](Br)[S:14][C:13]=2[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:41]([S:43]([C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1)(=[O:45])=[O:44])[CH3:42]>O1CCOCC1.C(OCC)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([O:17][C:18]3[CH:32]=[CH:31][C:21]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)=[C:15]([C:49]3[CH:48]=[CH:47][C:46]([S:43]([CH2:41][CH3:42])(=[O:45])=[O:44])=[CH:51][CH:50]=3)[S:14][C:13]=2[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Brc1sc2cc(OCc3ccccc3)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(-c2sc3cc(OCc4ccccc4)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
Dissolve 1-{2-[4-(6-benzyloxy-2-bromo-benzo[b]thiophen-3-yloxy)-phenoxy]-ethyl}-piperidine (700 mg, 1.3 mmol) in dioxane (13 mL) and 10% aqueous sodium carbonate (6.9 mL, 6.5 mmol) and add 4-(ethanesulphonyl)benzene boronic acid (430 mg, 2 mmol) and Pd(PPh3)4 (150 mg, 0.13 mmol). Heat to 70° C. and stir overnight. Dilute with diethyl ether (25 mL) and water (25 mL), filter through Celite, and separate layers. Extract the aqueous layer with diethyl ether (50 mL). Combine the organic layers and wash with water (50 mL) and brine (50 mL). Dry with sodium sulfate, filter, and concentrate in vacuo. Chromatograph residue on a SiO2 column eluting with methanol in dichloromethane (0 to 5%) to give 400 mg of the title compound (49%): mass spectrum (ion spray): m/z=628.3 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][C:13](=O)[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:25][OH:26]>O1CCOCC1>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([C:9]([N:11]2[CH2:14][C:13](=[N:25][OH:26])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NO
Reactant: O=C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Solvent: C1COCCO1
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(=NO)C1
Temperature: 60 °C
Yield: 55.2 %

Procedure:
To a solution of 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one (100 mg, 0.22 mmol), prepared using procedures similar to those described in Example 6, in dioxane (1.0 mL) was added hydroxylamine (0.10 mL, 50% solution in water, 1.5 mmol), and the resulting solution was heated at 60° C. for 18 h. The mixture was cooled to room temperature and the crude product was purified by reverse phase HPLC to afford 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one oxime (56 mg, 54% yield): 1H NMR (400 MHz, CDCl3), 8.43 (br s), 7.43-7.39 (m, 2H), 7.35-7.32 (dd, 1H), 7.19-7.15 (m, 1H), 6.87-6.81 (m, 1H), 6.65-6.59 (m, 1H), 4.89 (br s, 2H), 4.85 (br s, 2H); MS (EI) for C16H11F3IN3O2: 462 (MH+).
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH2:11]([C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]=1)[CH2:12][CH3:13]>>[CH2:11]([C:14]1[S:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]=1[S:6]([Cl:10])(=[O:8])=[O:7])[CH2:12][CH3:13]
Reactant: CCCc1cc2ccccc2s1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: CCCc1sc2ccccc2c1S(=O)(=O)Cl

Procedure:
2-Propylbenzo[b]thiophene-3-sulfonyl chloride was prepared by the method of Example 40B with DMF (3.6 mmoles, 0.28 ml), sulfuryl chloride (3.1 mmoles, 0.25 ml) and 2-propylbenzo[b]thiophene (1.8 mmoles, 0.32 g). Flash chromatography (3% ethyl acetate/hexanes) provided 0.28 g (56%) of a yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:31]3[CH2:35][CH2:34][NH:33][S:32]3(=[O:37])=[O:36])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([O:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[CH:14][CH:13]=4)=[C:9]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:8]=3[CH:30]=2)[CH2:3][CH2:2]1.[H-].[Na+].[CH3:40]I>CN(C=O)C>[CH:1]1([C:4]2[C:5]([N:31]3[CH2:35][CH2:34][N:33]([CH3:40])[S:32]3(=[O:36])=[O:37])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([O:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:14][CH:13]=4)=[C:9]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:8]=3[CH:30]=2)[CH2:3][CH2:2]1
Reactant: CI
Reactant: CCOC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)oc2cc(N3CCNS3(=O)=O)c(C3CC3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)oc2cc(N3CCN(C)S3(=O)=O)c(C3CC3)cc12
Reaction time: 0.25 h
Yield: 51.2 %

Procedure:
To a solution of 62 (0.058 g, 0.11 mmol) and dry DMF (5 mL) was added sequentially NaH (5 mg, 0.12 mmol, 50% mineral oil dispersion) and MeI (0.08 mL, 0.14 mmol). The reaction mixture was stirred for 15 min then quenched with H2O and extracted with EtOAc/Et2O. The organic phase was washed sequentially with H2O and brine, dried (MgSO4), filtered and evaporated to afford 30 mg of ethyl 5-cyclopropyl-6-(5-methyl-1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)-2-(4-phenoxy-phenyl)-benzofuran-3-carboxylate (64). Hydrolysis of the ethyl ester and conversion to the amide was carried out as previously described in steps 12 and 13 of example 3 to afford I-105.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:19]=[C:18]([N:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][C:4]=1[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)=[O:6].[CH3:24][N:25]([CH3:35])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([CH3:34])[CH3:33])[CH:27]=1.C(OC(=O)C)(=O)C.Cl>>[CH3:33][N:32]([CH3:34])[C:28]1[CH:27]=[C:26]([N:25]([CH3:35])[CH3:24])[CH:31]=[CH:30][C:29]=1[C:5]1([C:4]2[CH:16]=[CH:17][C:18]([N:20]([CH3:22])[CH3:21])=[CH:19][C:3]=2[N:2]([CH3:1])[CH3:23])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=[O:11])[O:6]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2C(=O)O)c(N(C)C)c1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)c(N(C)C)c1

Procedure:
A mixture of crude 2-(2,4-bis(dimethylamino)-benzoyl)benzoic acid (7 g.), N,N,N' ,N'-tetramethyl-m-phenylenediamine (1.64 g.) and acetic anhydride was warmed (at 25°-35° C.) during two to three hours, then poured into dilute hydrochloric acid (10%). The resulting mixture was basified and filtered with a filter aid. The filter cake was extracted with hot toluene. Dilution of the toluene extract with hexane afforded 3,3-bis(2,4-bis(dimethylamino)-phenyl)phthalide (I: X=Y2 = Y4 = (CH3)2N, Z4 = Z5 = Z6 = Z7 = H) (m.p. 186°-188° C.).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[C@H:15]1[CH2:21][N:20]([CH2:22][CH2:23][S:24][CH3:25])[C:19](=[O:26])[C@H:18]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:17][CH2:16]1.C(=O)([O-])[O-:36].[Na+].[Na+]>CO.O>[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[C@H:15]1[CH2:21][N:20]([CH2:22][CH2:23][S:24]([CH3:25])=[O:36])[C:19](=[O:26])[C@H:18]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:17][CH2:16]1
Reactant: O=C([O-])[O-]
Reactant: CSCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: CS(=O)CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Reaction time: 18 h

Procedure:
Sodium periodate (11.3 mg, 0.053 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-1-[2-(methylthio)ethyl]-2-oxoazepan-3-ylcarbamate (22 mg, 0.053 mmol) in methanol (2 mL) and water (2 mL). After 30 min excess sodium periodate (22 mg, 0.11 mmol) was added. After 18 h, saturated aqueous sodium carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 431 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[S:23]>CN(C)P(=O)(N(C)C)N(C)C>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[S:23])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: Fc1ccccc1N=C=S
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(=O)c1csc(NC(=S)Nc2ccccc2F)n1

Procedure:
Following a procedure similar to that described in Preparation 1. the desired compound was prepared from 15 g of ethyl 2-aminothiazol-4-ylglyoxylate, 17 g of o-fluorophenyl isothiocyanate and 30 ml of hexamethylphosphoric triamide. The resulting product was a pale yellow powder having the following physical properties.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH3:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:21](=[S:24])[NH:22][NH2:23])[N:10]=1.[CH3:25][C:26](C)(C)C([O-])([O-])[O-]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[S:13][C:12]([CH3:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([C:21]2[S:24][C:25]([CH3:26])=[N:23][N:22]=2)[N:10]=1
Reactant: CC(C)(C)C([O-])([O-])[O-]
Reactant: CC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=S)NN
Product: Cc1nnc(N2N=C(c3cc(F)ccc3F)SC2(C)c2ccccc2)s1
Temperature: 80 °C
Yield: 70.4 %

Procedure:
5-(2,5-difluorophenyl)-2-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothiohydrazide (0.268 g, 0.735 mmol) was weighed into a 25 mL 1 neck flask, and suspended in 9.0 mL of trimethylorthoacetate (0.088 g, 0.74 mmol). P-toluenesulfonic acid hydrate (0.0028 g, 0.015 mmol) was then added, and the reaction heated to 80° C. for 1 hour. The reaction was then concentrated in vacuo, and then purified by flash column chromatography (20-50% ethyl acetate/hexanes) yielding 0.201 g, 70% of the desired product as a white solid. MS ESI (+) m/z 389 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.56 (m, 2H), 7.34 (m, 2H), 7.27 (m, 2H), 7.08 (m, 2H), 2.59 (s, 3H), 2.56 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1.[CH2:15]([O:18][C:19]1[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=1[O:21][CH2:22][CH:23]([OH:26])[CH2:24][NH2:25])[CH:16]=[CH2:17]>C(O)(C)C>[CH2:15]([O:18][C:19]1[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=1[O:21][CH2:22][CH:23]([OH:26])[CH2:24][NH:25][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:14])=[C:9]([C:10](=[O:11])[NH2:12])[CH:13]=1)[CH:16]=[CH2:17]
Reactant: C=CCOc1ccccc1OCC(O)CN
Reactant: NC(=O)c1cc(OCCBr)ccc1O
Solvent: CC(C)O
Product: C=CCOc1ccccc1OCC(O)CNCCOc1ccc(O)c(C(N)=O)c1
Reaction time: 1 h

Procedure:
A mixture of 6.5 g of 5-(2-bromoethoxy)salicylamide and 8.9 g of 1-(2-allyloxyphenoxy)-3-aminopropan-2-ol is melted in an oil bath at 100° and stirred for 1 hour using a magnetic stirrer. The working up is carried out analogously to Example 11 and yields 1-(2-allyloxyphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]propan-2-ol having a melting point of 147°-148° (from isopropanol).