Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]([C:7]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:26][N:25]=[C:24]([CH3:27])[C:23]=4[NH:28][C:29]([O:31][C@@H:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH3:33])=[O:30])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1)=[O:6])(C)C.[OH-].[Na+]>C1COCC1.CO.O>[CH3:27][C:24]1[C:23]([NH:28][C:29]([O:31][C@@H:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH3:33])=[O:30])=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([C:13]3[CH:12]=[CH:11][C:10]([C:7]4([C:5]([OH:6])=[O:4])[CH2:9][CH2:8]4)=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)[O:26][N:25]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)OC(C)C)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Temperature: 65 °C
Yield: 72.5 %

Procedure:
To the isopropyl ester from Step 7 (5.2 g, 10 mmol) in THF (30 mL), MeOH (10 mL) was added NaOH (2 g, 50 mmol) in water (10 mL). The solution is heated to 65° C. for 5 hours. The solution was cooled to room temperature, extracted with methylene chloride and dilute hydrochloric acid. The organic was dried and evaporated and the product was purified by column chromatography (0 to 60% EtOAc/hexanes) to yield ˜3.5 grams of product.
Reaction SMILES: O[CH:2]([CH3:13])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.N1C(C)=CC=CC=1C.C(N(C(C)C)CC)(C)C.Cl.Cl.[F:48][C:49]1[CH:50]=[C:51]([C:55]2([CH2:61][CH2:62][N:63]3[C@H:68]4[CH2:69][CH2:70][C@@H:64]3[CH2:65][CH:66]([N:71]3[C:75]5[CH:76]=[CH:77][CH:78]=[CH:79][C:74]=5[N:73]=[C:72]3[CH3:80])[CH2:67]4)[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH:52]=[CH:53][CH:54]=1>C(Cl)Cl>[F:48][C:49]1[CH:50]=[C:51]([C:55]2([CH2:61][CH2:62][N:63]3[C@H:68]4[CH2:69][CH2:70][C@@H:64]3[CH2:65][CH:66]([N:71]3[C:75]5[CH:76]=[CH:77][CH:78]=[CH:79][C:74]=5[N:73]=[C:72]3[CH3:80])[CH2:67]4)[CH2:56][CH2:57][N:58]([CH:2]([CH3:13])[C:3]([O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:4])[CH2:59][CH2:60]2)[CH:52]=[CH:53][CH:54]=1
Reactant: CC(O)C(=O)OCc1ccccc1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCNCC1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(C)C(=O)OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 36.3 %

Procedure:
To a −78° C. solution of benzyl 2-hydroxypropanoate (250 mg, 1.39 mmol) and 4A molecular sieves in 2 mL CH2Cl2 was added trifluoromethanesulfonic anhydride (0.33 mL, 1.97 mmol). After stirring for 10 min at this temperature, 2,6-lutidine (0.31 mL, 2.62 mmol) was added. After 15 min, diisopropylethylamine (0.46 mL, 2.62 mmol) was added and after another 15 min, a solution of 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (400 mg, 0.66 mmol) in 3 mL CH2Cl2 was added. The reaction mixture was stirred at −78° C., then allowed to warm to room temperature overnight, washed with saturated aqueous NaHCO3, and purified by chromatography (3% (2M NH3/MeOH) in CHCl3) to provide benzyl 2-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)propanoate (146 mg, 37%) as a solid. 1H NMR (400 MHz, CDCl3), δ 7.68 (m, 1H), 7.37-7.26 (m, 7H), 7.22-7.13 (m, 2H), 7.08 (m, 1H), 6.98 (m, 1H), 6.92 (m, 1H), 5.09 (s, 2H), 4.62 (m, 1H), 3.39-3.17 (m, 2H), 2.89-1.26 (m, 27H); ESI-MS 609 (M+H).
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6]2([C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:15][C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:5][CH2:4]1.[Cl:22]N1C(=O)CCC1=O>ClCCl>[ClH:22].[Cl:1][C:11]1[CH:12]=[CH:13][C:14]2[O:15][C:16]3[C:21]([C:6]4([CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]4)[C:9]=2[CH:10]=1)=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3
Reactant: CN1CCC2(CC1)c1ccccc1Oc1ccccc12
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: ClCCl
Product: CN1CCC2(CC1)c1cc(Cl)ccc1Oc1ccc(Cl)cc12

Procedure:
A mixture of 1'-methylxanthene-9-spiro-4'-piperidine hydrochloride (5 g.), N-chlorosuccinimide (4.5 g.) and dichloromethane (100 ml.) is refluxed for 72 hours. The solution is washed with saturated sodium bicarbonate solution then water and dried with MgS04. The solution is evaporated to give a gummy residue which is chromatographed on grade 3 aluminium oxide, Woelm basic. The product is eluted with 30% petroleum-ether (b.p. 60°-80° C.)/chloroform, taken up in ether and the solution treated with ethereal hydrochloric acid. The precipitate is filtered and recrystallised from ethanol-ether to give 2,7-dichloro-1'-methylxanthene-9-spiro-4'-piperidine hydrochloride, m.p. 285° C.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:41][CH:42]1[CH2:47][CH2:46][N:45]([CH2:48][C:49]2[CH:56]=[CH:55][C:52]([C:53]#[N:54])=[CH:51][CH:50]=2)[CH2:44][CH2:43]1>CN(C)C=O.O>[Br:1][C:2]1[S:3][C:4]([C:7]([NH:41][CH:42]2[CH2:47][CH2:46][N:45]([CH2:48][C:49]3[CH:56]=[CH:55][C:52]([C:53]#[N:54])=[CH:51][CH:50]=3)[CH2:44][CH2:43]2)=[O:9])=[CH:5][N:6]=1
Reactant: N#Cc1ccc(CN2CCC(N)CC2)cc1
Reactant: O=C(O)c1cnc(Br)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CN2CCC(NC(=O)c3cnc(Br)s3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a stirred mixture of 2-bromothiazole-5-carboxylic acid (500 mg, 2.4 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added triethylamine (1.1 mL, 7.92 mmol), HATU (1 g, 2.64 mmol), and 4-((4-aminopiperidin-1-yl)methyl)benzonitrile (762 mg, 2.64 mmol). The mixture was stirred at room temperature overnight and then poured into water. The resulting solids were collected by filtration and purified by column chromatography to yield 972 mg (100%) of 2-bromo-N-(1-(4-cyanobenzyl)piperidin-4-yl)thiazole-5-carboxamide as a yellow solid. LCMS (m/z): 406 (MH+).
Reaction SMILES: C([O:8][C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:15]([O:17][C@@H:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:19][C:20]([NH2:22])=[O:21])=[O:16])=[O:10])C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:9]([CH2:11][CH2:12][CH2:13][C@H:14]([NH:36][C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[C:15]([O:17][C@@H:18]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:19][C:20]([NH2:22])=[O:21])=[O:16])([OH:10])=[O:8]
Reactant: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)O)NC(=O)OC(C)(C)C
Yield: 47 %

Procedure:
A solution of (3S)-3-[(2S)-5-benzyloxycarbonyl-2-(tertiarybutoxycarbonylamino)pentanoyl]oxyhexadecanamide (100 mg) in methanol (2 ml) was hydrogenated over 10% palladium on carbon (20 mg) under atmospheric pressure of hydrogen for 3.5 hours at room temperature. Then, the catalyst was filtered off with celite and the filtrate was concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate (0.5 ml) and n-hexane (1 ml) to give (3S)-3-[(2S)-5-carboxy-2-(tertiarybutoxycarbonylamino)-pentanoyl]oxyhexadecanamide (40 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[CH:3]=[N:2]1.C(N(CC)CC)C.[C:16](=O)([O-:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>CN(C)C1C=CN=CC=1.ClCCl>[OH:8][CH2:7][CH2:6][C:4]1[CH:5]=[N:1][N:2]([C:16]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])[CH:3]=1
Reactant: OCCc1cn[nH]c1
Reactant: CC(C)(C)OC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1cc(CCO)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.10 g (9.81 mmol) 2-(1H-pyrazol-4-yl)-ethanol, 0.20 g (1.64 mmol) 4-dimethylaminopyridine and 1.50 ml (10.3 mmol) triethylamine were placed in 30 ml dichloromethane, the reaction mixture was cooled to 0° C. and 2.20 g (9.88 mmol) tert. butyl carbonate was slowly added. The mixture was stirred for 2 h at ambient temperature and then overnight at ambient temperature. It was diluted with 50 ml dichloromethane and washed with 10% citric acid solution and 15% potassium carbonate solution, the organic phase was dried, filtered and the solvent was eliminated from the filtrate.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[N:10][C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>COCCOC.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>[Cl:26][C:27]1[CH:32]=[C:31]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[N:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1nc(-c2cccc(C#N)c2)c(Br)s1
Reactant: OB(O)c1cccc(Cl)c1
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: COCCOC
Product: N#Cc1cccc(-c2nc(C(=O)O)sc2-c2cccc(Cl)c2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
At room temperature, 2.2 ml of an aqueous 2M sodium carbonate solution and 30.8 mg (0.027 mmol) of tetrakis(triphenylphosphine)palladium are added to 300 mg (0.890 mmol) of the compound from Example 35A and 209 mg (1.34 mmol) of (3-chlorophenyl)boronic acid in 12 ml of DME, and the mixture is subsequently stirred at 80° C. overnight. The crude product is filtered through a short kieselguhr column and the filtrate is concentrated under reduced pressure. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 132 mg (37% of theory) of the title compound having a purity of 85% are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[C:13]12(O)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2.ClCCl.S(=O)(=O)(O)O>CCCCCCC>[C:13]12([C:6]3[C:7]([OH:12])=[CH:8][C:9]4[C:4]([CH:5]=3)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=4)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCCCCCC
Product: Oc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
56 g (0.25 mol) of 6-bromo-2-naphthol, 38.2 g (0.25 mol) of 1-adamantanol and 500 ml of a mixture of dichloromethane and heptane (40/60) were introduced into a round-bottomed flask. 15 ml of concentrated sulfuric acid were added and the reaction mixture was stirred at room temperature for 48 hours. The solid was filtered off, washed with heptane (3×100 ml) and dissolved in ethyl ether and the organic phase was washed with water, separated by settling, dried over magnesium sulfate and evaporated. 60.1 g (67%) of the expected compound were collected, which compound had a melting point of 215°-6° C.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3](=[O:6])[CH:4]=[CH2:5].[CH3:15][C:16]([C:19]1[CH:24]=[C:23]([SH:25])[CH:22]=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]=1[OH:30])([CH3:18])[CH3:17].C(N(CC)CC)C>CO>[CH3:29][C:26]([C:21]1[CH:22]=[C:23]([S:25][CH2:5][CH2:4][C:3]([N:2]([CH3:1])[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:6])[CH:24]=[C:19]([C:16]([CH3:18])([CH3:17])[CH3:15])[C:20]=1[OH:30])([CH3:27])[CH3:28]
Reactant: C=CC(=O)N(C)CCc1ccccn1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(CCc1ccccn1)C(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-methyl-N-[2-(2-pyridinyl)ethyl]-2-propenamide (0.95 g, 0.005 mole) was dissolved in methanol (200 ml) containing 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (1.19 g, 0.005 mole). After addition of triethylamine (0.5 ml), the solution was stirred at room temperature overnight. The solvent was removed by a nitrogen stream to give a residue which was purified by chromatography on silica to give the title compound, m.p. ca. 82°-84° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Sn](C)(C)C)=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:3]1.Br[C:23]1[S:27][C:26]([C:28]2[CH2:32][CH:31]([CH2:33][OH:34])[O:30][N:29]=2)=[CH:25][CH:24]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[OH:34][CH2:33][CH:31]1[O:30][N:29]=[C:28]([C:26]2[S:27][C:23]([C:10]3[CH:11]=[CH:12][C:7]([N:6]4[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:3][C:2]4=[O:1])=[CH:8][CH:9]=3)=[CH:24][CH:25]=2)[CH2:32]1
Reactant: OCC1CC(c2ccc(Br)s2)=NO1
Reactant: CC(=O)NC[C@H]1CN(c2ccc([Sn](C)(C)C)cc2)C(=O)O1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(CO)C4)s3)cc2)C(=O)O1
Temperature: 90 °C
Yield: 42.1 %

Procedure:
N-({(5S)-2-Oxo-3-[4-(trimethylstannyl)phenyl]-1,3-oxazolidin-5-yl}methyl)acetamide (500 mg, 1.26 mM), [3-(5-bromothien-2-yl)-4,5-dihydroisoxazol-5-yl]methanol (330 mg, 1.26 mM), tris(dibenzylideneacetone)dipalladium (0)-chloroform adduct (130 mg, 0.126 mM) and tri-2-furylphosphine (58 mg, 0.252 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (10 ml) was added and the suspension was heated at 90° C. for 16 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (220 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:6][C:7](O)=[O:8])=[O:4].CN(C=O)C.C(Cl)(=O)C([Cl:29])=O>C1COCC1>[CH2:14]([O:13][C:11]([NH:10][C@@H:5]([CH2:6][C:7]([Cl:29])=[O:8])[C:3]([O:2][CH3:1])=[O:4])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(=O)Cl)NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Z-asp-OMe (175 g, 622 mmol) was dissolved in THF (1750 ml) and admixed with 2 ml of DMF. 86.9 g (684 mmol) of oxalyl chloride were dissolved in 200 ml of THF (slightly exothermic), cooled back to room temperature (RT) and added dropwise to the solution of the amino acid over 1 hour (h). After a further hour at RT, the solution was initially sparged with nitrogen for 10 min, concentrated on a rotary evaporator at a maximum of 30° C. and coevaporated repeatedly with toluene. The resulting dirty white solid was dried to constant weight under in-house vacuum (about 1.5 mbar) and reacted further without further purification. Yield: 186.6 g (quantitative).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:29]1[C:33]2[CH:34]=[CH:35][C:36]([CH2:38][C:39](O)=[O:40])=[CH:37][C:32]=2[O:31][CH2:30]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>C(#N)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH:18][C:39](=[O:40])[CH2:38][C:36]3[CH:35]=[CH:34][C:33]4[O:29][CH2:30][O:31][C:32]=4[CH:37]=3)[N:13]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Reactant: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CNC(=O)Cc2ccc3c(c2)OCO3)cc1
Reaction time: 16 h
Yield: 64 %

Procedure:
To a mixture of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (300 mg, 0.74 mmol), benzo[1,3]dioxol-5-yl-acetic acid (134 mg, 0.74 mmol), 1-hydroxybenzotriazole hydrate (111 mg, 0.82 mmol), and N,N-diisopropyl-ethylamine (258 μL, 1.48 mmol) in acetonitrile (5 ml) at room temperature was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (157 mg, 0.82 mmol). The reaction mixture was stirred for 16 hours and the solvent evaporated in vacuo. The residue was taken into ethylacetate (50 ml), washed with water, 1 N hydrochloric acid, saturated sodium bicarbonate, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was subjected to flash chromatography using a gradient of 10-20% ethylacetate/hexanes as eluent, which afforded 268 mg (64%) of 2-amino-5-((2-benzo[1,3]dioxol-5-yl-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1)[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2]>C(O)C.ClCCl.[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:9][OH:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CO)c1ccc(O)cc1
Reaction time: 8 h
Yield: 90.8 %

Procedure:
[(R)-1-(4-Benzyloxy-phenyl)-2-hydroxy-ethyl]-carbamic acid t-butyl ester (2.013 g, 5.87 mmol) and 10% Palladium on active carbon (0.300 g, 0.294 mmol) were mixed in ethanol (15 ml) and dichloromethane (5 ml). The hydrogenation was carried at 1 atmosphere at room temperature overnight. The catalyst was filtered out. The filtrate was concentrated to a white solid (1.350 g, 91% yield): 1H NMR (400 MHz, MeOD) δ ppm 7.36 (d, 2H), 6.97 (m, 2H), 3.83 (m, 1H), 3.54 (dt, J=3.2, 1.5 Hz, 2 H), 1.66 (m, 9H); LCMS (ESI) m/e 254.1 [(M+H), calcd. for C13H20NO4 254.3].
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[CH3:13][O:14][C:15]1[CH:35]=[CH:34][CH:33]=[CH:32][C:16]=1[CH2:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:10][C:7]([N:18]([CH2:17][C:16]1[CH:32]=[CH:33][CH:34]=[CH:35][C:15]=1[O:14][CH3:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:6]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccccc1CNc1ccccc1Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CN(C(=O)Cl)c1ccccc1Oc1ccccc1
Yield: 267.5 %

Procedure:
To a solution of 775 mg of triphosgene in 14 ml of methylene chloride was added gradually dropwise a solution of 2.16 g of N-(2-methoxybenzyl)-2-phenoxyaniline and 1.10 g of diisopropylethylamine in 25 ml of methylene chloride with stirring, followed by stirring at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure, poured into ethyl acetate, washed with 5% hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane=1:15) to give 2.57 g of N-chlorocarbonyl-N-(2-methoxybenzyl)-2-phenoxyaniline.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]#[C:3][CH3:4].[CH2:8]([SH:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>C1CCN2C(=NCCC2)CC1.CCOCC>[CH2:8]([S:16]/[C:3](/[CH3:4])=[CH:2]/[C:1]([O:6][CH3:7])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CC#CC(=O)OC
Reactant: CCCCCCCCS
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCCCS/C(C)=C/C(=O)OC
Reaction time: 8 h

Procedure:
Two drops of DBU is added to methyl 2-butynoate (6.0 g) under N2. 1-Octanethiol (8.96 g, 61.2 mmol) is added dropwise over 20 min. with cooling with an ice bath. The mixture is allowed to come to RT and is stirred overnight. It is then diluted with ether, washed, dried and stripped and the product is purified by prep. TLC to give methyl (E)-3-octylthio-2butenoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O[NH:17][C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[NH:19]>C1(C)C=CC=CC=1>[CH:20]1([C:18]2[N:19]=[C:13]([CH:12]=[CH:11][C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[O:15][N:17]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: N=C(NO)C1CCCCC1
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Solvent: Cc1ccccc1
Product: COc1ccc(C=Cc2nc(C3CCCCC3)no2)cc1OC
Reaction time: 1.25 h

Procedure:
To a solution of 1.43 g (6.9 mmol) of 3-(3,4-dimethoxy-phenyl)-acrylic acid (compound of Example 2; Step 1) in 22 mL of toluene, 1.21 g (7.5 mmol) of 1,1-carbonyldiimidazole was added in portions at 25° C. to 30° C. under inert atmosphere. To the thickened mixture, 22 mL of toluene was added and the resulting mixture was stirred at 25° C. to 30° C. for 60 to 90 min. A solution of N-hydroxycyclohexanecarboximidamide (compound of Example 59; 2 g, 14 mmol) in 5 mL of toluene was added to the above reaction mixture at 25° C. to 30° C. The reaction mixture was stirred at 25° C. to 30° C. under nitrogen for 12-14 h, followed by stirring at 100° C. to 105° C. for 6-8 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C. and quenched with 10 mL of chilled water under stirring at 25° C. to 30° C. The organic layer was separated, and the aqueous layer was washed with 5 mL of toluene. The organic layers were combined and washed with 10 mL of 1N HCl solution, 10 mL of 5% sodium bicarbonate solution and 10 mL of 10% sodium chloride solution. The organic layer was distilled completely to obtain a crude residue, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])([O-:3])=[O:2].[OH-].[CH2:19]([N+:26](C)(C)C)[C:20]1C=CC=C[CH:21]=1>C(#N)C=C.CO>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([CH2:21][CH2:20][C:19]#[N:26])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1Nc1ccccc1F
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C=CC#N
Solvent: CO
Product: N#CCCN(c1ccccc1F)c1ccccc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 3 h

Procedure:
N-(2-Nitrophenyl)-2-fluoroaniline (17.8 g) was dissolved in acrylonitrile (100 ml), triton B (40% benzyltrimethylammonium hydroxide in methanol) (1.0 ml) was added, the mixture was stirred at 50-60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby obtain 6.37 g of the titled compound as a orange color crystal.