Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[F:13])=[O:3].O.O.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>C(OCC)(=O)C>[CH3:1][C:2]([C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[F:13])=[O:3]
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(N)ccc1F
Temperature: 70 °C
Yield: 48.4 %

Procedure:
25.4 g (152 mmol) of 2-fluoro-5-nitroacetophenone, 343 g (1.52 mol) of tin chloride dihydrate and 250 ml of ethyl acetate are introduced into a 1-liter three-necked flask. The reaction mixture is heated to 70° C. for 30 minutes and then poured onto 1 liter of crushed ice, 30% sodium hydroxide solution is added and the mixture is extracted with 3 times 350 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulphate and concentrated. 11.26 g of product are obtained in the form of an oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:28])[CH:12]([CH2:15][C:16]3[N:17]=[CH:18][N:19](S(=O)(=O)N(C)C)[C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12.Cl>C(O)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:28])[CH:12]([CH2:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1c2n(c3ccccc13)C(=O)C(Cc1ncn(S(=O)(=O)N(C)C)c1C)CC2
Agent: Cl
Solvent: CCO
Product: Cc1[nH]cnc1CC1CCc2c(C)c3ccccc3n2C1=O
Temperature: 90 °C
Yield: 61.7 %

Procedure:
A mixture of 8,9-dihydro-10-methyl-7-[[5-methyl-1-(N,N-dimethylsulfamoyl)-1H-imidazol-4-yl]methyl]pyrido[1,2-a]indol-6(7H)-one (93 mg), 3N hydrochloric acid (3 ml), and ethanol (2 ml) was heated at 90° C. for 2.5 hours. After evaporation of the solvent, the residue was neutralized with aqueous sodium bicarbonate solution and extracted three times with chloroform. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Chromatography of the residue (solvent, 4% methanol-chloroform) gave 8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (42 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:9][CH2:10][CH2:2][CH2:3][CH3:4])[C:5]([O:7][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:6])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCOC(=O)c1ccc(OCCCCC)c(OCCCCC)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 166.8 %

Procedure:
3,4-Dihydroxybenzoic acid (462 mg, 3 mmol) was dissolved in DMF (10 ml). Potassium carbonate (3.73 g, 27 mmol, 9 eq) and 1-bromopentane (1.70 ml, 13.5 mmol, 4.5 eq) were successively added to this solution at room temperature, and the mixture was stirred at 110° C. for 24 hours. This reaction mixture was filtered, and the residual potassium carbonate was washed with ethyl acetate (50 ml). The filtrate was washed with water (15 ml×3) and saturated brine (15 ml). The organic layer was dried over anhydrous sodium sulfate. After the drying agent was filtered off; the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (heaxane/ethyl acetate=95/5) to give pentyl 3,4-dipentyloxybenzoate (912 mg, 83%).
Reaction SMILES: N[C@H](C(O)=O)CCC(=O)N.N1CCC[C@H]1C(O)=O.C([S:22][CH2:23][CH:24]([CH2:37][S:38]C(=O)C)[C:25]([NH:27][C@H:28]([C:34]([OH:36])=[O:35])[CH2:29][CH2:30][C:31](=[O:33])[NH2:32])=[O:26])(=O)C>>[SH:22][CH2:23][CH:24]([CH2:37][SH:38])[C:25]([NH:27][C@H:28]([C:34]([OH:36])=[O:35])[CH2:29][CH2:30][C:31](=[O:33])[NH2:32])=[O:26]
Reactant: CC(=O)SCC(CSC(C)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: NC(=O)CC[C@H](N)C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Product: NC(=O)CC[C@H](NC(=O)C(CS)CS)C(=O)O

Procedure:
By substituting L-glutamine for the L-proline in the procedure of Example 3B, and then submitting the product to the procedure of Example 4, N-[2-(acetylthiomethyl)-3-(acetylthio)propanoyl]-L-glutamine and 1-[2-(mercaptomethyl)-3-mercaptopropanoyl]-L-glutamine are obtained.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]2[C:8]([O:14]C(=O)C)=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[C:4]=1[C:18](=[O:31])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1.[CH3:32][NH:33][CH3:34]>C1COCC1>[CH3:32][N:33]([CH:2]=[C:3]1[O:7][C:6]2[C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[CH:4]1[C:18](=[O:31])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1)[CH3:34]
Reactant: CNC
Reactant: COc1cc(C(=O)c2c(CBr)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Solvent: C1CCOC1
Product: COc1ccc2c(c1O)OC(=CN(C)C)C2C(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71 %

Procedure:
To a stirred solution of 2-bromomethyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-acetoxy-benzo[b]furan (Example 33) (25 mg, 0.051 mmol) in dry THF (0.5 mL) was added solution of dimethylamine (0.5 mL, excess, 2M solution in THF) and the mixture was stirred for 6 hours at room temperature (tlc). The solvent was distilled and the crude was purified over silica gel to afford the title compound as a light yellow solid (15 mg, 71%). 1H NMR (300 MHz, CDCl3) δ—7.14 (s, 2H, benzoyl Hs), 6.85 (s, 2H, Ar—Hs), 3.93 (s, 3H, OMe), 3.92 (s, 3H, OMe), 3.81 (s, 6H, 2×OMe), 3.75 (s, 2H), 2.31 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:30][C:31]1[S:35][C:34]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:32]=1.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:36]([C:34]2[S:35][C:31]([Cl:30])=[CH:32][CH:33]=2)(=[O:38])=[O:37])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccc(Cl)s2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Example 13w from {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, prepared in Step A of Example 13a, and 5-chlorothiophene-2-sulfonyl chloride with the following exception. The sulfonyl chloride was dissolved in CH2Cl2 (1 mL) and 0.28 mL was added to the reaction mixture. MS 574 (M+).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[C:41]([NH:43][C:44]([CH3:47])([CH3:46])[CH3:45])[N:40]=[C:39]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)[CH:38]=2)[CH:34]=[N:35][CH:36]=1>COCCOC.C(Cl)Cl>[C:44]([NH:43][C:41]1[N:40]=[C:39]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)[CH:38]=[C:37]([C:33]2[CH:34]=[N:35][CH:36]=[C:31]([C:12]3[CH:11]=[CH:10][C:9]([C:7]([N:1]4[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]4)=[O:8])=[CH:14][CH:13]=3)[CH:32]=2)[CH:42]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCNCC3)cc2)OC1(C)C
Reactant: CC(C)(C)Nc1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)Nc1cc(-c2cncc(-c3ccc(C(=O)N4CCNCC4)cc3)c2)cc(-c2ccccn2)n1

Procedure:
To a solution of piperazin-1-yl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (1.2 eq, 0.25 mmol, 0.079 g) and 2M Na2CO3 (3 eq, 0.624 mmol, 0.3 ml) in dry DME (1.5 ml) are added (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-tert-butyl-amine (Ex. 2.48; step 1) (1 eq, 0.208 mmol, 80 mg) and PdCl2dppf (0.1 eq, 0.0208 mmol, 15 mg). The reaction mixture is heated using microwave radiation at 90° C. for 1 hour. The reaction mixture is dissolved in DCM and washed with water. The organic solvent is reduced in vacuo and the residue is purified by reverse phase column chromatography (Isolute™ C18, 0-40% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 493.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([NH:23][CH:24]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:25](O)=[O:26])=[O:22])=[CH:15]2>>[CH2:28]([CH:24]([NH:23][C:21]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:11])=[CH:20][CH:19]=2)=[O:22])[C:25]([N:8]1[CH2:9][CH2:10][CH:5]([O:4][CH2:3][O:2][CH3:1])[CH2:6][CH2:7]1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COCOC1CCNCC1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Product: COCOC1CCN(C(=O)C(Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1

Procedure:
4-Methoxymethoxy-piperidine (1.0 mmol) and 2-[(5-chloro-1H-indole-2carbonyl)-amino]-3-phenyl-propionic acid (1.0 mmol) were coupled according to Procedure A and the product purified by chromatography on silica gel eluted with 1:1 ethyl acetate-hexanes:
Reaction SMILES: [CH2:1]([CH:10]1[C:15](=O)[CH2:14][CH2:13][S:12][CH2:11]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][NH2:22].C(O)C.[ClH:27]>Cl.CCOCC>[ClH:27].[CH3:17][N:18]([CH3:23])[CH2:19][CH2:20][CH2:21][N:22]1[C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:1][C:10]2[CH2:11][S:12][CH2:13][CH2:14][C:15]1=2
Reactant: O=C(CC1CSCCC1=O)c1ccccc1
Reactant: CN(C)CCCN
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CN(C)CCCn1c(-c2ccccc2)cc2c1CCSC2
Temperature: 25 °C

Procedure:
A solution of 3.0 g (0.013 mole) of 3-phenacyl-2,3,5,6-tetrahydrothiopyran-4-one, 1.33 g of 3-dimethylaminopropylamine, 20 ml. of ethanol, and one drop of concentrated hydrochloric acid is heated under reflux under nitrogen for 1.5 hours, and then cooled to ambient temperature. The reaction mixture is treated with 4 ml. of saturated ethereal hydrogen chloride and diluted to the cloud point with ether. The solid which separates is collected and recrystallized from ethanol to provide colorless crystals of 1-(3-dimethylaminopropyl)-2-phenyl-1,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrole hydrochloride, m.p. 225° to 227° C. dec.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH2:19][C:20]([NH2:22])=[O:21])=[C:9]1[CH3:23].C(OC(=O)CC1C2C(=CC=C(OC)C=2)[N:37](CC2C=CC=CC=2C2C=CC=CC=2)C=1C)C.NN.O>C(O)C>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH2:19][C:20]([NH:22][NH2:37])=[O:21])=[C:9]1[CH3:23]
Reactant: COc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1-c1ccccc1
Reactant: CCOC(=O)Cc1c(C)n(Cc2ccccc2-c2ccccc2)c2ccc(OC)cc12
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1ccccc1-c1ccccc1

Procedure:
1-([1,1'-Biphenyl]-2-ylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetamide. A mixture of 1.18 g (2.86 mmol) of 1-([1,1'-biphenyl]-2-ylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester and 3 mL of hydrazine in 20 mL of ethanol was heated to maintain reflux for 16 hours. After cooling, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgSO4), and concentrated to give 1.02 g of 1-([1,1'-biphenyl]-2-ylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid hydrazide. A mixture of 576 mg (1.44 mmol) of this material and 300 mg of Raney Ni in 20 mL of ethanol was heated to maintain reflux for 3 hours. After cooling the solvent was decanted and the Raney Ni washed twice with methylene chloride. The combined organic solvents were concentrated at reduced pressure and the residue chromatographed on silica gel and eluted with ethyl acetate to give 369 mg (67% yield) of 1-([1,1'-biphenyl]-2-ylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetamide.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][CH:28]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:33]([C:30]3[CH:31]=[CH:32][C:27]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:28][CH:29]=3)=[O:34])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(-c2ccccc2)cc1

Procedure:
The title compound, yellow solid (119 mg, 94%), MS (ISP) m/z=507.3 [(M+H)+], mp 235° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and biphenyl-4-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][N:11]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C@@H:10]([CH2:29][OH:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:32].[Na+]>CC(C)=O.O.O.[Ru](=O)=O>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][N:11]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C@@H:10]([C:29]([OH:32])=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(S(=O)(=O)N2C[C@@H](CC(C)C)N(C(=O)OC(C)(C)C)C[C@@H]2CO)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(S(=O)(=O)N2C[C@@H](CC(C)C)N(C(=O)OC(C)(C)C)C[C@@H]2C(=O)O)cc1
Reaction time: 0.67 h
Yield: 102.4 %

Procedure:
Ruthenium (IV) oxide hydrate (238 mg) was added to a solution of (2R,5R)-4-(tert-butoxycarbonyl)-2-hydroxymethyl-1-(4-methoxybenzenesulfonyl)-5-(2-methylpropyl)piperazine (5.3 g) in acetone (50 ml) and H2O (20 ml), followed by addition of sodium periodate (5.1 g) with cooling on an ice bath. After stirring at the same temperature for 40 minutes, the reaction was quenched with 2-propanol (50 ml). Insoluble matter was removed by filtration through a celite pad, and the filtrate was washed with acetone and AcOEt. The filtrate and combined washings were concentrated in vacuo, and the residue was partitioned by dissolving same in 5% aqueous sodium bisulfite and AcOEt. The organic layer was washed with saturated NaCl solution, dried over MgS04, and concentrated in vacuo to give 5.6 g of (2R,5R)-4-(tert-butoxycarbonyl)-1-(4-methoxybenzenesulfonyl)-5-(2-methylpropyl)piperazine-2-carboxylic acid as an amorphous powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[CH:15]([C:21]([OH:23])=[O:22])[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:13]=2[CH:12]=[C:11]([C:24]([CH3:32])([CH3:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O[C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=O.N1C=CC=CC=1>CCCCC>[CH2:1]([O:8][C:9]1[C:14]2[CH:15]([C:21]([O:23][C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=3)=[O:22])[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:13]=2[CH:12]=[C:11]([C:24]([CH3:31])([CH3:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: CCCCCCC(C)(C)c1cc(OCc2ccccc2)c2c(c1)OC(C)(C)CC2C(=O)O
Solvent: c1ccncc1
Solvent: CCCCC
Product: CCCCCCC(C)(C)c1cc(OCc2ccccc2)c2c(c1)OC(C)(C)CC2C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
A mixture of 3.3 g (7.53 mmole) 5-benzyloxy-2,2-dimethyl-7-(1,1-dimethylheptyl)-3,4-dihydro-2H-benzopyran-4-carboxylic acid, 5.0 g (21.3 mmole) p-nitrophenyl trifluoroacetate and 100 ml dry pyridine, under nitrogen, is stirred at room temperature for three hours. The pyridine is evaporated in vacuo, ethyl ether is added to the residue and this is washed with 1N sodium hydroxide, water, 10% hydrochloric acid, brine, dried (MgSO4) and the solvent evaporated to obtain 4.5 g crude oil. This is taken up in pentane and cooled to obtain 3.38 g of crystals, m.p. 87°-87.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:10][CH:11](OCC)[CH2:12][NH:13][C:14]([C:16]1[S:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)=[O:15])C>O>[O:10]=[CH:11][CH2:12][NH:13][C:14]([C:16]1[S:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)=[O:15]
Reactant: CCOC(CNC(=O)c1ccc(-c2ccc(Cl)cc2)s1)OCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=CCNC(=O)c1ccc(-c2ccc(Cl)cc2)s1
Reaction time: 4 h
Yield: 95.2 %

Procedure:
Add water (21 mL) followed by trifluoroacetic acid (100 g) to a 250 mL three-necked round bottom flask equipped with an overhead stirrer, nitrogen inlet/outlet, and thermocouple. To the stirring TFA solution, add 5-(4-chlorophenyl)-thiophene-2-carboxylic acid (2,2-diethyoxyethyl) amide (25 g, 0.07 mol) in one portion. Stir the reaction mixture for 4 h, pour onto ice/water (1200 mL), and stir for 1.25 h. Filter the resulting slurry and rinse the solid with water (500 mL) and heptane (500 mL), and then dry to give 18.65 g (95%) of the title compound as a yellow-white solid. LC-MS/ES m/z (35Cl)=278 (M−H)−. 1H NMR (500 MHz, CDCl3): δ 4.40 (d, J=4.0 Hz, 2H), 6.69 (bs, 1H), 7.26 (d, J=3.0 Hz, 1H), 7.40 (d, J=9.0 Hz, 2H), 7.53-7.58 (m, 3H), 9.78 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]([C:5]1[C:9]([CH3:10])=[CH:8][NH:7][N:6]=1)=[O:4].C1C(=O)N([I:19])C(=O)C1>CC#N>[I:19][C:8]1[NH:7][N:6]=[C:5]([C:3]([N:2]([CH3:11])[CH3:1])=[O:4])[C:9]=1[CH3:10]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1c[nH]nc1C(=O)N(C)C
Solvent: CC#N
Product: Cc1c(C(=O)N(C)C)n[nH]c1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
To a solution of N,N,4-trimethyl-1H-pyrazole-3-carboxamide (compound 374.1, 0.98 g, 6.40 mmol) in CH3CN (10 mL) was added NIS (1.59 g, 7.04 mmol). The mixture was stirred at room temperature for 16 hours then quenched with sat. Na2SO3 solution (5 mL). The mixture was partitioned between EtOAc (200 mL) and water (30 mL). The EtOAc layer was washed with brine (30 mL), dried (MgSO4) and concentrated. The residue was purified with column chromatography (50% EtOAc in hexanes to 100% EtOAc) to give the product as a brown solid (1.79 g, 100%). m/z (ES+) 280 (M+H)+.
Reaction SMILES: CCCCCCC=CCCC.[C:12]([O:16][C:17]([NH:19][CH:20](P(OC)(OC)=O)[C:21]([O:23][CH3:24])=[O:22])=[O:18])([CH3:15])([CH3:14])[CH3:13].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O>C(Cl)Cl>[C:12]([O:16][C:17]([NH:19][C:20](=[CH:36][C:35]1[CH:38]=[CH:39][CH:40]=[C:33]([O:32][CH3:31])[CH:34]=1)[C:21]([O:23][CH3:24])=[O:22])=[O:18])([CH3:13])([CH3:14])[CH3:15]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Reactant: COc1cccc(C=O)c1
Agent: CCCC=CCCCCCC
Solvent: ClCCl
Product: COC(=O)C(=Cc1cccc(OC)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.70 mL (4.7 mmol) of 1,8-diazabicyclo[5.4.0.]undec-7-ene (DBU) and 1.40 g (4.7 MMOL) of tert-butoxycarbonylamino-(dimethoxyphosphoryl)acetic acid, methyl ester of Example 29 in 14 mL of methylene chloride is stirred at room temperature for 25 minutes. A quantity of 0.64 g (4.7 mmol) of 3-methoxybenzaldehyde is added and the solution is stirred at room temperature overnight. Methylene chloride (100 mL) is added and the solution is washed with 80mL of 1N hydrochloric acid and then with 80 mL of brine. The dried (magnesium sulfate) organic phase is evaporated and the product is purified by silica gel chromatography, eluting with 18% ethyl acetate to give pure product as a white powder; wt 1.25 g (86%);
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[F:18])=[O:22])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: Nc1ccc(-c2cc3c(cc2Cl)OCC3)cn1
Reactant: O=C(Cl)c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2cc3c(cc2Cl)OCC3)cn1)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a solution of 5-(6-chloro-2,3-dihydrobenzo[3,4-b]furan-5-yl)-2-pyridylamine (144) (19 mg, 0.045 mmol) in 1 ml DCM was added 2-fluorobenzoyl chloride (16 μl, 3 eq) followed by addition of DIEA (39 μl). The resulting solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (100 μl) at r.t. for 2 h and before worked up with EA/aq. NaHCO3. Prep HPLC purification furnished N-[5-(6-chloro(2,3-dihydrobenzo[3,4-b]furan-5-yl))(2-pyridyl)](2-fluorophenyl)carboxamide (146) (7.6 mg, yield: 45.8%, purity>95%) as white solid.
Reaction SMILES: [CH2:1]([C@H:3]1[N:8](C(OC(C)(C)C)=O)[CH2:7][C@@H:6]([C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[O:5][CH2:4]1)[CH3:2].O1CCOCC1.[ClH:32]>>[ClH:32].[CH2:1]([C@H:3]1[NH:8][CH2:7][C@@H:6]([C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[O:5][CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1CO[C@H](C(=O)NCc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@@H]1CO[C@H](C(=O)NCc2ccccc2)CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl(2S,5R)-5-ethyl-2-{[(phenylmethyl)amino]carbonyl}-4-morpholinecarboxylate (0.551 g, 1.581 mmol) was taken up in HCl in 1,4-dioxane (4 M, 5 mL, 165 mmol) and was stirred at room temperature overnight. The reaction was concentrated to afford a HCl salt of the title compound (0.400 g) as a brown oil. LC-MS (ES) m/z=249 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(O)C>[N:12]1([C:2]2[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: C1CNCCN1
Solvent: CCO
Product: CCOC(=O)c1cnc(N2CCNCC2)s1
Yield: 92 %

Procedure:
1.02 g (5.0 mmol) of ethyl 2-bromothiazole-5-carboxylate and 4.31 g (50 mmol) of piperazine were dissolved in ethanol (20 ml) and the mixture was heated under reflux over a period of 4 h. The solution was then concentrated in vacuo, taken up in EA and washed successively with water and a satd aq. NaCl solution. Following drying of the organic phase over MgSO4, filtration and removal of solvent in vacuo there were obtained 1.12 g (4.6 mmol, 93%) of ethyl 2-piperazin-1-ylthiazole-5-carboxylate.