Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH:12]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(OCC)=[O:2].C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[OH:2][CH2:1][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH:12]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)CCCCCN1CCCC(NCc2ccccc2OC)C1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1CNC1CCCN(CCCCCCO)C1c1ccccc1
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
Under a nitrogen atmosphere in a round-bottom flask were placed 95 mg (0.22 mmol) of the title compound of Example 97 and 1 ml of THF. The system was cooled in an ice/acetone bath, 0.44 ml (0.44 mmol) of 1M lithium aluminum hydride in ether was added to the system and the mixture was stirred for 10 minutes. The cold bath was removed, the mixture was stirred at room temperature for 20 minutes and the cold bath was replaced. To the system was added cautiously ca. 0.4 ml of 2M aqueous sodium hydroxide, and the mixture was stirred at room temperature for 20 minutes. Sodium sulfate was added to the system, the mixture was stirred for 30 minutes, solids were removed by suction filtration and the filtrate was concentrated. The crude material was purified by flash column chromatography (5 g of silica gel) using 3:47 methanol/chloroform as the eluant to obtain 49 mg of the title compound.
Reaction SMILES: C1C=[CH:3][C:4]2[O:11][CH2:10][CH2:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[CH2:12]=O.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(O)C>[CH3:12][C:4]1([CH3:3])[C:5](=[CH2:6])[C:7](=[O:8])[C:9]2[C:15](=[CH:16][CH:17]=[C:18]([C:19]#[N:14])[CH:10]=2)[O:11]1
Reactant: O=C1CCOc2ccccc21
Reactant: C=O
Reactant: C1CCNCC1
Solvent: CCO
Product: C=C1C(=O)c2cc(C#N)ccc2OC1(C)C

Procedure:
A solution of 24 g of the chromanone, 12 g of paraformaldehyde and 24 ml of piperidine in 300 ml of ethanol is heated at 70° for 3 hours and evaporated. The residue is taken up in dichloromethane/petroleum ether 1:1, the mixture is filtered through silica gel and evaporated, and 2,2-dimethyl-3-methylene-6-cyano-4-chromanone is obtained as an unstable oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1>CC#N>[Cl:11][C:4]1[N:3]=[C:2]([NH:27][C@H:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[CH3:26])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: C[C@H](N)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](Nc1nc(Cl)ccc1[N+](=O)[O-])c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.8 %

Procedure:
To a mixture of 2,6-dichloro-3-nitropyridine (2.26 g, 10.8 mmol) and potassium carbonate (1.29 g, 9.34 mmol) in anhydrous CH3CN (20 ml), was added (S)-1-(4-fluoro-phenyl)-ethylamine (1.00 g, 7.19 mmol) dropwise at 0° C. The reaction mixture was stirred at 25° C. for 17 hours. The solid was removed by filtration and the resulted cake was washed with EtOAc (20 ml). The combined filtrate was concentrated and purified by column chromatography (hexane:EtOAc=10:1) to give the title compound as a yellow solid (1.74 g, 82%). NMR (400 MHz) 8.65 (d, J=7.6 Hz, 1H), 8.43 (d, J=8.4 Hz, 1H), 7.51 (m, 2H), 7.16 (m, 2H), 6.81 (d, J=8.8 Hz, 1H), 5.37 (m, 1H), 1.59 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[Si:6]([O:13][NH2:14])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]>C(Cl)Cl>[Si:6]([O:13][N:14]=[CH:1][CH:2]=[CH:3][CH3:4])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: C/C=C/C=O
Reactant: CC(C)(C)[Si](C)(C)ON
Solvent: ClCCl
Product: CC=CC=NO[Si](C)(C)C(C)(C)C
Temperature: 5 °C
Reaction time: 18 h

Procedure:
The procedure followed was that described by Behforouz et al., J. Org. Chem. 58:7089-7091 (1993). In a 50 mL round bottom flask dry, 4 Å molecular sieves (Fisher, 3.4 g) were added to dry CH2Cl2 (distilled from CaH2, 10 mL) and cooled to 5° C. with an ice bath. Freshly distilled crotonaldehyde (Matheson Coleman & Bell, 0.725 mL, 0.618 g, 8.84 mmol) was added. A solution of O-(tert-butyldimethylsilyl)hydroxylamine (Aldrich, used without purification, 1.0 g, 6.80 mmol) in dry CH2Cl2 (distilled from CaH2, 3 mL) was added dropwise over a period of 5 min. The ice bath was removed and the mixture was stirred at rt under N2 for 18 h. The sieves were removed by filtration and the CH2Cl2 was evaporated to dryness (rotovap). Column chromatography on silica gel with CHCl3 as eluent afforded 1-(tert-butyldimethylsilyloxy)-1-aza-1,3-pentadiene as a colorless light oil (1.2 g, 88%, interpretation of the 1H NMR showed a 1:1 anti/syn mixture): 1H NMR (CDCl3) δ (anti) 0.18 (s, 6H), 0.95 (s, 9H), 1.85-1.88 (m, 3H), 5.93-6.23 (m, 1H), 6.7-6.9 (m, 1H), 7.18 (d, 1H); (syn) 0.18 (s, 6H), 0.95 (s, 9H), 1.85-1.88 (m, 3H), 5.93-6.15 (m, 2H), 7.81 (d, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[O:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.O>[Cl:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:14]5[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=5[O:12][CH:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: O=C(O)Cc1cc(F)cc(Cl)c1
Reactant: Nc1nccc2occ(-c3ccc4c(c3)CCN4)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nccc2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)cc(Cl)c3)c12
Temperature: 25 °C
Reaction time: 96 h
Yield: 90 %

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-5-yl)furo[3,2-c]pyridin-4-amine (150 mg, 0.440 mmol), 3-chloro-5-fluorophenylacetic acid (89 mg, 0.472 mmol), HATU (184 mg, 0.484 mmol), and Hunig's base (0.31 mL, 1.775 mmol) in N,N-Dimethylformamide (DMF) (3 mL) was stirred at room temperature for 4 days. Water (10 mL) was added, the mixture was stirred for about an hour, and the precipitate was collected by vacuum filtration. The solid was dried in the vacuum oven overnight to give 3-{1-[(3-chloro-5-fluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (176 mg, 0.396 mmol, 90% yield) as a beige solid. LC/MS (ES) m/z=422, 424 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.27 (t, 2H), 3.96 (s, 2H), 4.26 (t, J=8.46 Hz, 2H), 5.53 (s, 2H), 6.93 (d, J=5.81 Hz, 1H), 7.14-7.22 (m, 1H), 7.27 (s, 1H), 7.28-7.38 (m, 2H), 7.40 (s, 1H), 7.86 (d, J=5.81 Hz, 1H), 7.92 (s, 1H), 8.15 (d, J=8.34 Hz, 1H).
Reaction SMILES: [CH2:1](OC(OCC)OCC)C.[NH2:11][C:12]1[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=1[C:14]([NH:16][C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:20]([NH:22][CH:23]1[CH2:25][CH2:24]1)=[O:21])=[O:15].C(O)(=O)C>C(O)C>[CH:23]1([NH:22][C:20](=[O:21])[C:19]2[CH:26]=[CH:27][C:28]([CH3:29])=[C:17]([N:16]3[C:14](=[O:15])[C:13]4[C:12](=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:11]=[CH:1]3)[CH:18]=2)[CH2:25][CH2:24]1
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccccc1N
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccccc2c1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Triethylorthoformate (0.15 ml) was added to a stirred mixture of 3-[(2-aminobenzoyl)amino]-N-cyclopropyl-4-methylbenzamide (0.093 g) and glacial acetic acid (0.017 ml) in ethanol (10 ml). The mixture was heated to 80° C. and stirred for 16 hours. The reaction mixture was evaporated, dissolved in ethyl acetate (50 ml) and washed with a saturated NaHCO3 solution (100 ml). The organic phase was dried over magnesium sulphate, filtered then concentrated in vacuo onto silica gel (0.1 g). The residue was purified by column chromatography (isolute silica 20 g column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using a gradient of 10% iso-propanol/iso-hexane through to 50% iso-propanol/iso-hexane to give the title compound as a white solid (0.062 g); NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.68 (m, 2H), 2.14 (s, 3H), 2.84 (m, 1H), 7.52 (d, 1H), 7.62 (t, 1H), 7.78 (d, 1H), 7.84 (d, 1H), 7.89 (m, 2H), 8.21 (m, 1H), 8.30 (s, 1H), 8.41 (d, 1H); Mass Spectrum: M+H+ 320.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:30]=[C:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([C:31]1[N:39]=[C:26]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:15][N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]3)=[O:9])[CH2:11]2)[O:27][N:30]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NC(Cc1ccccc1)=NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cc3ccccc3)no2)C1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 41.3 mg (0.275 mmol) of N′-hydroxy-2-phenylethanimidamide were reacted according to the General Method 1. Yield: 61.5 mg (47% of theory).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:20][CH2:21][CH3:22])[N:5]([CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)[C:6](=[O:8])[CH:7]=1.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[N:3]=[C:4]([CH2:20][CH2:21][CH3:22])[N:5]([CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[C:27]3[S:23][C:24](=[O:29])[NH:25][C:26]3=[O:28])=[CH:14][CH:13]=2)[C:6](=[O:8])[CH:7]=1
Reactant: CCCc1nc(C)cc(=O)n1CCOc1ccc(C=O)cc1
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCNCC1
Product: CCCc1nc(C)cc(=O)n1CCOc1ccc(C=C2SC(=O)NC2=O)cc1
Temperature: 25 °C
Yield: 125.7 %

Procedure:
A mixture of 4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde (10 g, 24.5 mmol) (obtained from preparation 1), thiazolidine-2,4-dione (3.5 g, 30 mmol), benzoic acid (388 mg, 3.18 mmol) and piperidine (352 μl, 303 mg, 3.68 mmol) in toluene (50 ml) was refluxed for 1 h with continuous removal of water. The reaction was cooled to room temperature and the resultant crystalline compound was filtered and washed with water and dried to afford the title compound (12.3 g, 99%), mp 240-242° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])=[C:18]([O:28][CH3:29])[CH:17]=3)=[O:14])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.Br[CH2:31][CH2:32]Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C:13](=[O:14])[N:15]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([OH:27])([CH3:25])[CH3:26])=[C:18]([O:28][CH3:29])[CH:17]=4)[CH2:32][CH2:31][N:11]3[CH:12]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1OCC(C)(C)O
Reactant: BrCCBr
Product: COc1cc(N2CCn3cc(-c4ccc(Cl)cc4)cc3C2=O)ccc1OCC(C)(C)O

Procedure:
Following the procedure described in Example 1 step D, the product of step B (11 mg) was alkylated with 1,2-dibromoethane to yield 1.8 mg of the title compound. MS (ESI) 441 (M+H)+.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[CH:38]12[CH2:46][CH2:45][CH:42]([CH2:43][CH2:44]1)[CH2:41][N:40]([C:47](=O)[CH2:48]Cl)[CH2:39]2>>[CH:38]12[CH2:46][CH2:45][CH:42]([CH2:43][CH2:44]1)[CH2:41][N:40]([CH2:47][CH2:48][O:10][C:8]1[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=1)[CH2:39]2
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CC2CCC(CC2)C1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CC4CCC(CC4)C3)cc2)c1
Yield: 11.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (26 mg) and 1-(3-azabicyclo[3.2.2]non-3-yl)-2-chloroethanone (21 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.7 mg) was obtained.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([S:8]([NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:2]=1.N1C=CC=CC=1.Cl[CH:24]([CH3:28])[C:25](Cl)=[O:26].C(Cl)[Cl:30]>>[Cl:30][CH2:28][CH2:24][C:25]([NH:7][C:6]1[CH:1]=[CH:2][C:3]([S:8](=[O:10])(=[O:9])[NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:5]=1)=[O:26]
Reactant: CC(Cl)C(=O)Cl
Reactant: ClCCl
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Solvent: c1ccncc1
Product: O=C(CCCl)Nc1ccc(S(=O)(=O)Nc2nccs2)cc1

Procedure:
Synthesized according to general procedure 1: N′-(2-thiazolyl)sulfanilamide (8.37 g, 32.8 mmol), pyridine (5.3 mL, 65.6 mmol), 2-chloro-propionylchloride (3.8 mL, 39.4 mmol, 1.2 equiv) in DCM (400 mL). Yield: 2.70 g (24%) of a white solid. 1H-NMR (DMSO-d6) δ 10.41 (s, 1H), 7.77-7.72 (m, 4H), 7.25 (d, J=4.6 Hz, 1H), 6.82 (d, J=4.6 Hz, 1H), 3.88 (t, J=6.2 Hz, 2H), 2.86 (t, J=6.2 Hz, 2H). LC/MS (10-99%) M/Z: M+1 obs=346.1; tR=1.94 min.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.O1CCCCC1[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37]([Sn](CCCC)(CCCC)CCCC)[N:36]=[CH:35]1.O1CCCCC1OCCN1C([Sn](CCCC)(CCCC)CCCC)=CN=C1>>[CH:20]([N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:37]5[N:36]=[CH:35][N:34]([CH2:33][CH2:32][OH:31])[CH:38]=5)[CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(CCOC2CCCCO2)cn1
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)C)n1
Agent: CCCC[Sn](CCCC)(CCCC)c1cncn1CCOC1CCCCO1
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(-c4cn(CCO)cn4)ccc2-3)n(C(C)C)n1

Procedure:
Similar to described in General Procedure G: 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with a mixture of 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(tributylstannyl)-1H-imidazole and 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-5-(tributylstannyl)-1H-imidazole to give 440 after THP-removal with aqueous HCl purification by reverse phase HPLC (55 mg). LCMS: 437.1.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:6](=[O:13])[CH:7]=[C:8]([CH2:11][OH:12])O[CH:10]=1.O.[NH3:15]>>[O:13]1[C:6]2[CH:7]=[C:8]([CH2:11][OH:12])[N:15]=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=c1cc(CO)occ1OCCCl
Reactant: N
Solvent: O
Product: OCc1cc2c(cn1)OCCO2
Temperature: 85 °C
Reaction time: 7 h

Procedure:
To 229 g of 5-(2-chloroethoxy)-2-(hydroxymethyl)-4H-pyran-4-one (crude product), 572 mL of 28% ammonia water was added, the mixture was stirred for 7 hours at 85° C. and allowed to stand overnight at room temperature. The reaction mixture was extracted 4 times with 500 mL of 2-propyl acetate. The organic layer was combined therewith and the solvent was evaporated under reduced pressure to give 90.5 g of (2,3-dihydro-(1,4)dioxino(2,3-c)pyridin-7-yl)methanol as a brown oily substance.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:24]([O:25][CH3:26])=[C:23]([S:27][CH3:28])[CH:22]=[CH:21][C:10]=1[C:11]([C:13]1[CH:14]=[N:15][O:16][C:17]=1[CH:18]1[CH2:20][CH2:19]1)=[O:12]>ClCCl>[Br:8][C:9]1[C:24]([O:25][CH3:26])=[C:23]([S:27][CH3:28])[CH:22]=[CH:21][C:10]=1[C:11](=[O:12])[CH:13]([C:14]#[N:15])[C:17]([CH:18]1[CH2:20][CH2:19]1)=[O:16]
Reactant: COc1c(SC)ccc(C(=O)c2cnoc2C2CC2)c1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(SC)ccc(C(=O)C(C#N)C(=O)C2CC2)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
Triethylamine (0.58 g) was added to a stirred solution of 4(2-bromo-3-methoxy-4-methylsulphenylbenzoyl)-5-cyclopropylisoxazole (2.0 g) in dichloromethane and the mixture was stirred at room temperature for 3 hours. The mixture was evaporated to dryness and the residue triturated with ether and filtered. The solid was re-dissolved in dichloromethane and washed with hydrochloric acid (2M). The organic layer was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue triturated with ether and filtered to give 1-(2-bromo-3-methoxy-4-methylsulphenylphenyl)-2-cyano-3-cyclopropylpropan-1,3-dione (COMPOUND 661, 1.33 g) as a white solid, m.p. 128°-129° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.F[C:30]1[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([CH:39]=1)[C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(P(N(C)C)(N(C)C)=O)C.CCOC(C)=O.O>[CH:1]1([C:4]2[C:5]([N:24]([C:30]3[CH:31]=[CH:32][C:33]([N+:40]([O-:42])=[O:41])=[C:34]([CH:39]=3)[C:35]([O:37][CH3:38])=[O:36])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[O:20])[NH:21][CH3:22])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Yield: 91.8 %

Procedure:
A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (1.0 g, 2.49 mmol), methyl 5-fluoro-2-nitrobenzoate (0.99 g, 4.97 mmol), and potassium carbonate (1.03 g, 7.45 mmol) in HMPA (6.2 mL) was stirred at 60° C. for 3 days. The solution was diluted with EtOAc and water and the organic layer was washed with brine, dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-80% EtOAc/hexanes) to afford the title compound (1.33 g, 92%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.99 (d, J=9.09 Hz, 1H), 7.85-7.92 (m, 2H), 7.56 (s, 1H), 7.53 (s, 1H), 7.50 (dd, J=9.09, 2.64 Hz, 1H), 7.43 (d, J=2.64 Hz, 1H), 7.19-7.26 (m, 2H), 5.80 (d, J=4.59 Hz, 1H), 3.90 (s, 3H), 3.34 (s, 3H), 3.02 (d, J=4.98 Hz, 3H), 1.91 (tt, J=8.37, 5.31 Hz, 1H), 1.01 (br. s., 1H), 0.89 (br. s., 1H), 0.73-0.85 (m, 1H), 0.58 (br. s., 1H).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C(O)(=O)C.[CH3:12][S-:13].[Na+]>C1(C)C=CC=CC=1>[CH3:12][S:13][CH:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1
Reactant: C[S-]
Reactant: O=C1C=CCCC1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CSC1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
Cyclohex-2-enone (3.80 g, 95% Aldrich, 39.5 mmol uncorrected), toluene (15.31 g, HPLC grade) and glacial acetic acid (2.85 g, 47.4 mmoles, 1.20 eq, 99.7+% Aldrich) were combined in a 50 mL 3-necked round bottom flask equipped with a magnetic stirrer, reflux condenser with nitrogen oil bubbler vented to a bleach scrubber, thermometer with Therm-o-watch controller and septum. To the stirred solution was added 15 wt % sodium thiomethoxide (19.4 g of solution, 2.91 g, 41.5 mmol, 1.05 eq of NaSCH3) in portions via syringe during 19 min. The reaction temperature increased from 28.0° C. to 36.4° C. during the addition. The two-phase mixture was stirred at ambient temperature overnight. The reaction mixture was heated to about 50° C. and stirred for 7.5 h. The mixture was then allowed to cool to room temperature with stirring overnight. The phases were allowed to settle for 30 min. The lower aqueous phase was removed. The upper organic phase was washed with water (2×10 mL), dried through a cone of anhydrous magnesium sulfate and concentrated on the rotary evaporator (29 in. Hg vacuum/48° C.) to afford 4.91 g of 3-(methylthio)cyclohexanone as a clear pale yellow oil. Area % conversion by GC 95%. Raw area % 91.1%. Mass recovery 86%.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[CH:28](I)([CH3:30])[CH3:29]>C1COCC1>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([CH:28]([CH3:30])[CH3:29])([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)I
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@@]1(C(C)C)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a 1.00 M solution of lithium hexamethyldisilazide in THF (202 mL) at −78° C. was added a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (22.10 g, 91.59 mmol) in THF (36.2 mL) over 10 min. The solution was stirred at −78° C. for 30 min before isopropyl iodide (10.0 mL, 100 mmol) was added in one portion. The mixture was then moved to a freezer reading at −24° C. and kept overnight. The reaction was quenched with aqueous ammonium chloride and the resulting solution was extracted with ether three times. The ether layers were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica eluting with 10% ethyl acetate/hexane to give the title compound (20.2 g). MS calculated for C15H25NO4:(M+H)+284; found 184.2 (M-Boc+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[N:27]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:28]=[O:29]>N1C=CC=CC=1>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][CH2:30][NH:27][C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])[CH:7]=1)=[O:29])[CH3:36]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: CCOC(=O)CCN=C=O
Solvent: c1ccncc1
Product: CCOC(=O)CCNC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in pyridine (0.2 mL) and ethyl 3-Isocyanatopropionate (0.016 mL, 0.12 mmol) was added. The solution was stirred at room temperature for 1.5 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:1 as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (CD3OD) δ 198.4, 173.8, 161.0 (dd), 158.0, 157.8 (dd), 151.1, 141.0, 138.7, 136.1, 135.0, 132.7, 132.2, 128.8, 127.4 (dd), 126.0 (dd), 122.6, 120.9, 116.6, 112.9, 112.6 (dd), 105.8 (dd), 61.7, 36.7, 35.8, 19.7, 14.5