Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[N:6]([CH3:16])[C:5]1=[O:17])([CH3:3])[CH3:2].[C:18](O)(=[O:20])[CH3:19]>[Ni]>[CH:1]([CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:18](=[O:20])[CH3:19])[CH:11]=2)[N:6]([CH3:16])[C:5]1=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)C1C(=O)N(C)c2ccc([N+](=O)[O-])cc21
Reactant: CC(=O)O
Agent: [Ni]
Product: CC(=O)Nc1ccc2c(c1)C(C(C)C)C(=O)N2C

Procedure:
(rac)-3-Isopropyl-1-methyl-5-nitro-1,3-dihydro-indol-2-one (3.40 g) is dissolved in acetic acid (30 ml) and subjected to a catalytic hydrogenation with Raney-nickel (0.5 g) at 3 bar. After completion of the hydrogenation the mixture is filtered and evaporated. The residue is treated with acetic anhydride (10 ml) for 2 h at RT. The mixture is concentrated in vacuo to give the crude acetamide.
Reaction SMILES: [Cu](C#N)C#N.C([Li])CCC.C([SnH](CCCC)CCCC)CCC.[CH2:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:25]#[CH:26].[Cl-].[NH4+].[OH-].[NH4+]>C1COCC1.ClCCl>[CH2:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:25]=[CH2:26]
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: N#C[Cu]C#N
Agent: CCCC[SnH](CCCC)CCCC
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCNC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 180.5 %

Procedure:
A solution of copper cyanide (1.15 g, 12.9 mmol) in THF (30 mL) at −78° C. was treated slowly with n-butyllithium (16.9 mL, 27.1 mmol), stirred for 15 minutes at −78° C., treated with tributyltin hydride (7.88 g, 7.30 mL, 27.1 mmol) over a period of 5 minutes, stirred for 15 minutes, treated with tert-butyl 2-propynylcarbamate (2.00 g, 12.9 mmol) in tetrahydrofuran (7 mL), stirred at −78° C. for 1 hour, and treated with a 9:1 aqueous solution of ammonium chloride:ammonium hydroxide (250 mL) and dichloromethane (200 mL). The suspension was filtered through a short pad of diatomaceous earth (Celite®). The organic phase of the filtrate was washed with brine and concentrated. The residue was purified on silica gel using 1-2% ethyl acetate/heptane to provide the desired product (3.66 g, 63%). 1H NMR (400 MHz, CDCl3) δ 6.08 (dt, B part of an AB system, J=19.3 Hz, 1.3 Hz, 1H); 5.93 (dt, A part of an AB system, J=19.3 Hz, 4.8 Hz, 1H), 4.59 (br s, 1H), 3.78 (br s, 2H), 1.45 (s, 9H), 1.32-1.26, (m, 12H), 0.90-0.85 (m, 15H).
Reaction SMILES: [CH2:1]([S:4][C:5]1[S:6][CH2:7][C:8](=[O:10])[N:9]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:17][S:18](Cl)(=[O:20])=[O:19].O>C(#N)C>[CH2:1]([S:4][C:5]1[S:6][CH:7]=[C:8]([O:10][S:18]([CH3:17])(=[O:20])=[O:19])[N:9]=1)[CH2:2][CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCSC1=NC(=O)CS1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCSc1nc(OS(C)(=O)=O)cs1
Yield: 78.7 %

Procedure:
8 g of 2-n-propylthio-1,3-thiazoline-4-one and 4.8 g of anhydrous sodium carbonate were suspended in acetonitrile, followed by stirring. 7.9 g of methanesulfonyl chloride was added dropwise to the suspension below 10° C. After the addition, the reaction was continued under stirring at room temperature for 2 hours. The reaction solution was poured into water and extracted by ether. The ether layer was washed with a saturated aqueous solution of common salt and dried over anhydrous sodium sulfate. The oil obtained by concentration was purified by silica-gel column chromatography to 9.1 g of the objective compound as a yellow oil (yield: 78.8%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:33])[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:35][O:36][C:37](=[O:40])[CH2:38][NH2:39]>>[CH3:35][O:36][C:37](=[O:40])[CH2:38][NH:39][C:30]([C:27]1[CH:26]=[CH:25][C:24]([C:21]2[CH:20]=[CH:19][C:18]([C@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[CH2:9][C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[O:33])=[CH:23][CH:22]=2)=[CH:29][CH:28]=1)=[O:31]
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccccc2C)ccn1
Reactant: COC(=O)CN
Agent: Cl
Product: COC(=O)CNC(=O)c1ccc(-c2ccc([C@@H](CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)cc1

Procedure:
In analogy to example 89, step 2, from 4′-[(R)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid (example 95, step 1) and glycine methyl ester hydrochloride was prepared the title compound as light yellow foam, MS (ESI+): m/z=507.2282 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH2:22][OH:23])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H-].[Na+].O>CN(C)C=O>[CH2:24]([O:23][CH2:22][C:11]1[C:12]([CH3:21])=[N:13][N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]=1[S:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1CO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1COCc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
A solution containing 115 mg of [5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazol-4-yl]-methanol, 54 mg of benzyl bromide and 38 mg of sodium hydride (60% in mineral oil) in 3 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen at 100° C. for 2 hours. Water (10 ml) was added and the mixture was extracted three times with 8 ml of dichloromethane. Combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified twice by flash chromatography on silica gel using ethyl acetate/petroleum ether (bp 40-60° C.) (1:4) then dichloromethane for the elution to give 35 mg of 4-benzyloxymethyl-5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole as a colourless gum. Mass spectrum (ES) m/z 455 [M+H]+, 496 [M+H+CH3CN]+. 1H NMR (DMSO-d6) 2.36 (s, 3H), 4.47 (s, 2H), 4.49 (s, 2H), 6.96 (d, 2H), 7.24-7.47 (m, 11H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.CC=CCN.C(N(CC)CC)C.[CH3:23][N:24]1C[CH2:27][CH2:26][C:25]1=O>O>[CH2:25]([N:24]([CH3:23])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH:26]=[CH2:27]
Reactant: CN1CCCC1=O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC=CCN
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCN(C)c1ccc([N+](=O)[O-])cc1
Yield: 96 %

Procedure:
A mixture of p-fluoronitrobenzene (2.8 g, 20 mmol), N-methylallylamine (2.10 g, 30 mmol), triethylamine (2.0 g, 20 mmol), and N-methyl-2-pyrrolidinone (NMP) (20 ml) was heated to 60°-70° C. for 5 hours in an oil bath. The mixture was diluted with distilled water (100 ml) and extracted twice with ether. The extracts were washed with distilled water and brine solution, dried over potassium carbonate and concentrated to an oil. The oil was distilled via Kugelrohr apparatus (forecut taken up to 90° C. discarded, 110°-125° C., 0.1 mm Hg) to give 3.70 g (96%) N-allyl-N-methyl-4-nitroaniline. As is, this material failed to undergo clean hydrosilation, possibly due to residual N-methyl-2-pyrrolidinone present. The remaining material was chromatographed on silica with hexane-ethyl acetate (10:1) and distilled again via Kugelrohr apparatus to give a yellow oil that underwent clean hydrosilation.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[CH:7][C:6]=1[CH3:13])=[O:4].[CH3:14][O-:15].[Na+]>CO>[OH:12][C:8]1[C:9]([CH3:11])=[CH:10][C:5]([C:3](=[O:4])[CH2:2][O:15][CH3:14])=[C:6]([CH3:13])[CH:7]=1
Reactant: C[O-]
Reactant: Cc1cc(C(=O)CCl)c(C)cc1O
Agent: [Na+]
Solvent: CO
Product: COCC(=O)c1cc(C)c(O)cc1C
Yield: 77.2 %

Procedure:
In 30 mL of methanol, 0.4 g (2.0 mmol) 2-chloro-1-(4-hydroxy-2,5-dimethylphenyl)ethanone was reacted with 0.40 g (7.55 mmol) sodium methoxide at room temperature for 5 hours with stirring, and the solvent was removed at a reduced pressure. To the residue was added 20 mL of water, followed by adjusting the pH to 7 with conc. HCl. The aqueous layer was extracted twice with 3 mL of dichloromethane and the organic layer was dried over anhydrous magnesium sulfate and concentrated at a reduced pressure to afford a yellowish solid compound 1-(4-hydroxy-2,5-dimethylphenyl)-2-methoxyethanone (0.30 g, yield: 78%).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][CH2:16][CH2:17][C:18](=[O:25])[N:19]([CH2:21][CH2:22][CH2:23][OH:24])[CH3:20])[CH2:11][CH2:10]1)C)(C)(C)C.[ClH:27]>CC(OC)(C)C>[ClH:27].[OH:24][CH2:23][CH2:22][CH2:21][N:19]([CH3:20])[C:18](=[O:25])[CH2:17][CH2:16][O:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([NH:7][CH3:6])[CH2:14][CH2:13]1
Reactant: CN(CCCO)C(=O)CCO[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: COC(C)(C)C
Product: CN[C@H]1CC[C@H](OCCC(=O)N(C)CCCO)CC1
Temperature: 25 °C

Procedure:
1 g (2.71 mmol) of trans-(4-{2-[(3-hydroxy-propyl)-methyl-carbamoyl]-ethoxy}-cyclohexyl)-methyl-carbamic acid tert-butyl ester was dissolved in 5 mL of TBME and 5.4 mL of 5M HCl in TBME were added at 0° C. The solution was stirred at RT, additional 1.5 mL of 5M HCl in TBME were added and stirring was continued. Evaporation of the solvent yielded the crude trans-N-(3-hydroxy-propyl)-N-methyl-3-(4-methylamino-cyclohexyloxy)-propionamide-hydrochloride, MS: 273 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][O:28][CH2:29][CH2:30][CH2:31][NH:32]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[NH:12][C:11]([CH2:52][C:53]([N:55]2[CH2:60][CH2:59][N:58]([CH:61]3[CH2:67][CH:66]4[N:68]([CH3:69])[CH:63]([CH2:64][CH2:65]4)[CH2:62]3)[CH2:57][CH2:56]2)=[O:54])=[C:10]1[C:70]([O:72][CH3:73])=[O:71].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CO.O>[NH2:32][CH2:31][CH2:30][CH2:29][O:28][CH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][CH2:19][C:13]1[NH:12][C:11]([CH2:52][C:53]([N:55]2[CH2:60][CH2:59][N:58]([CH:61]3[CH2:62][CH:63]4[N:68]([CH3:69])[CH:66]([CH2:65][CH2:64]4)[CH2:67]3)[CH2:57][CH2:56]2)=[O:54])=[C:10]([C:70]([O:72][CH3:73])=[O:71])[CH:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1=C(CCc2ccccc2COCCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(CC(=O)N2CCN(C3CC4CCC(C3)N4C)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C1=C(CCc2ccccc2COCCCN)NC(CC(=O)N2CCN(C3CC4CCC(C3)N4C)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl

Procedure:
A mixture of dimethyl 4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-[2-(2-{[3-(tritylamino)propoxy]methyl}phenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate (355 mg/0.346 mmol) and p-toluenesulfonic acid monohydrate (246 mg/1.29 mmol) in methanol (9.4 ml) and water (3.5 ml) was stirred at reflux temperature for 4 hours. After cooling, the mixture was poured into saturated NaHCO3 aqueous solution. The whole was extracted with dichloromethane (100 ml×2). The combined organic layer was washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (NH2 gel/200-350 mesh/dichloromethane:methanol=100:1-1100:2-100:5) to afford a yellow amorphous (190 mg/70%).
Reaction SMILES: N1C(C)=CC=CC=1C.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([F:45])=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:39][C@@H:40]([OH:44])[C:41]([OH:43])=[O:42])[NH:24][C:25]([C:27]3[O:31][N:30]=[C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[F:38])[CH:28]=3)=[O:26])=[CH:18][CH:17]=2)[CH:15]=1.[CH2:46]([O:48][C:49](=[O:53])[O:50][CH2:51]Cl)[CH3:47].[Na+].[I-]>CN(C=O)C.O>[CH2:46]([O:48][C:49]([O:50][CH2:51][O:42][C:41](=[O:43])[C@H:40]([OH:44])[CH2:39][N:23]([CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[CH:15]=[C:10]([Cl:9])[CH:11]=[CH:12][C:13]=2[F:45])=[CH:17][CH:18]=1)[NH:24][C:25]([C:27]1[O:31][N:30]=[C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[CH:28]=1)=[O:26])=[O:53])[CH3:47]
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cc(-c2ccccc2F)no1
Reactant: CCOC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: CCOC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(-c2ccccc2F)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
2,6-Lutidine (407 mg, 3.8 mmol) was added to a solution of (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid (200 mg, 380 mmol), carbonic acid chloromethyl ester ethyl ester (105 mg, 760 μmol) and NaI (114 mg, 760 μmol) in DMF (10 mL). The mixture was stirred overnight at room temperature. Water (30 mL) was added and the mixture was extracted with EtOAc (3×40 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (MeCN—H2O (0.1% TFA); Gradient 60-70) to yield the title compound as a white solid (56 mg). LC-MS: 630.1 [M+H]+. 1H-NMR: (CD3OD-d4, 400 MHz) δ 1.24 (t, J=5.9 Hz, 3H), 3.30-3.33 (m, 2H), 4.17-4.32 (m, 4H), 4.45 (t, J=4.2 Hz, 1H), 5.78 (br, 2H), 7.20-7.28 (m, 1H), 7.57-7.29 (m, 10H), 7.92-7.95 (m, 1H).
Reaction SMILES: [CH:1]1[C:2]2[N:3]([CH:8]=[N:9][CH:10]=2)[C:4](=[S:7])[NH:5][N:6]=1.C[O-].[Na+].I[CH2:15][CH3:16]>CO>[CH2:15]([N:5]1[C:4](=[S:7])[N:3]2[CH:8]=[N:9][CH:10]=[C:2]2[CH:1]=[N:6]1)[CH3:16]
Reactant: S=c1[nH]ncc2cncn12
Reactant: CCI
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCn1ncc2cncn2c1=S

Procedure:
To a mixture of 3.04 g of imidazo[1,5-d]-as-triazine-4(3H)-thione and 30 ml of methanol is added a solution of 1.08 g of sodium methoxide in 10 ml of methanol. The resulting solution is treated with 1.70 ml (3.28 gm) of iodoethane. Upon evaporation, the residue is purified by preparative thin layer chromatography on silica gel. Recrystallization from acetone gives the desired product, m.p. 143°-144.5° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:15]3[S:16][C:17]([C:19]([N:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[CH3:22])=[O:20])=[CH:18][C:14]=3[CH2:13][CH2:12][O:11][C:10]=2[CH:30]=1)=[O:4].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:21]([CH3:22])[C:19]([C:17]1[S:16][C:15]2[C:9]3[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:30][C:10]=3[O:11][CH2:12][CH2:13][C:14]=2[CH:18]=1)=[O:20]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(NC(=O)CCl)cc1OCC2)c1ccccc1Cl
Reactant: C1COCCN1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(NC(=O)CN3CCOCC3)cc1OCC2)c1ccccc1Cl

Procedure:
Following the procedure in Example 147 for 237, 8-(2-chloroacetamido)-N-(2-chlorophenyl)-N-methyl-4,5-dihydro-benzo[b]thieno[2,3-d]oxepine-2-carboxamide and morpholine were reacted to give 170. MS: (ESI+) 512.2
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:8]([O:24][CH3:25])=[C:9]([NH:11][C:12]([C:14]2[S:18][C:17]3[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:16]=3[CH:15]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[C:8]([O:24][CH3:25])=[C:9]([NH:11][C:12]([C:14]2[S:18][C:17]3[C:19]([NH:23][C:38]([NH:37][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:39])=[CH:20][CH:21]=[CH:22][C:16]=3[CH:15]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=Nc1ccccc1
Reactant: COc1c(NC(=O)c2cc3cccc(N)c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Solvent: CC#N
Product: COc1c(NC(=O)c2cc3cccc(NC(=O)Nc4ccccc4)c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 80 °C
Yield: 50.4 %

Procedure:
To an opaque yellow solution of 7-amino-benzo[b]thiophene-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide (see Example 1) (30 mg, 0.07 mmol) in acetonitrile was added phenyl isocyanate (10 μL, 0.9 mmol). The reaction was heated to 80° C. for 12 h in a sealed tube, then cooled to room temperature. The product precipitated out directly to provide 20 mg (50%) of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([NH:22][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: CC(C)(C)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42 a) and tert-butylamine (CAN 75-64-9) as starting materials. MS (EI): m/e=289.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:16])[CH2:10][CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.Br.[CH3:18][C:19](O)=O>>[CH2:18]([O:13][C:12](=[O:14])[CH:11]([CH3:15])[CH2:10][C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[O:16])[CH3:19]
Reactant: CC(=O)O
Reactant: COc1ccc(C(=O)CC(C)C(=O)O)cc1
Agent: Br
Product: CCOC(=O)C(C)CC(=O)c1ccc(OC)cc1
Yield: 93 %

Procedure:
A solution of 4-(4-methoxyphenyl)-2-methyl-4-oxobutyric acid (10 g, 45 mmol) and 150 mL of 48% HBr in 20 mL of AcOH was heated to 100° C. for 48 h. The solvent was evaporated and EtOH (3×30 mL) was added and evaporated to give 4-(4-methoxyphenyl)-2-methyl-4-oxobutyric acid ethyl ester (9.96 g, 93%); MS m/z 259 (M+23).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH2:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[C:33]1([CH2:39][CH2:40][CH2:41][C:42](O)=[O:43])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.OC1C2N=NNC=2C=CC=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH:25][C:42](=[O:43])[CH2:41][CH2:40][CH2:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Reactant: O=C(O)CCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)CCCc1ccccc1
Temperature: 0 °C
Reaction time: 64 h
Yield: 22.3 %

Procedure:
A solution of 270 mg of N-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester and 98 mg of 4-phenylbutyric acid in 10 ml of dry tetrahydrofuran was cooled in an ice/salt mixture. 81 mg of hydroxybenzotriazole, 69 mg of N-ethylmorpholine and 136 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 64 hours. The mixture was then diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium bicarbonate solution and sodium chloride solution. The solvent was removed by evaporation and the residue was chromatographed on silica gel using System G for the elution to give 79 mg of N-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(4-phenylbutyryl)-L-asparaginyl]amino]butyl]-L-proline tert.butyl ester as a white solid; MS: m/e 595 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13]([OH:15])=O)=[O:5])[CH3:2].[N:16]1([CH2:22][CH2:23][NH2:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.ClCCl.O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=[O:15])[NH:24][CH2:23][CH2:22][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)O
Reactant: NCCN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1c(C)c[nH]c1CC(=O)NCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A stirred solution of 2-carboxymethyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (2.67 g, 12.67 mmol) in N,N-dimethylformamide (6.5 ml) and dichloromethane (65 ml) was added with 2-piperidin-1-yl-ethylamine (1.78 g, 13.9 mmol), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide hydrochloride (4.84 g, 25.34 mmol) and 1-hydroxybenzotriazol (1.71 g, 12.67 mmol) in an ice/water-bath. Upon completion of the addition, the reaction mixture was stirred at room temperature overnight, then added with cold water (50 ml), and extracted with dichloromethane (50 ml×3). The combined organic extracts were washed with saturated sodium bicarbonate (50 ml), water (50 ml), brine (50 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-methyl-2-[(2-piperidin-1-yl-ethyl carbamoyl)-methyl]-1H-pyrrole-3-carboxylic acid ethyl ester (3.46 g, 85%) as a brown oil which was used as such.
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][N:9]1[CH2:12][CH2:11][C:10]1=[O:13].[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17]>O1CCCC1>[CH2:16]([O:15][C:14]([CH:11]1[CH2:12][N:9]([CH3:8])[C:10]1=[O:13])=[O:18])[CH3:17]
Reactant: CCOC(=O)OCC
Reactant: CN1CCC1=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1CN(C)C1=O
Reaction time: 0.42 h

Procedure:
Into tetrahydrofuran (20 ml) containing diisopropylamine (1.82 ml) is added 15% n-butyllithium-hexane (7.5 ml), and the mixture is stirred for 25 minutes. To this solution are added 1-methyl-2-azetidinone dropwise at -70° C. and after 20 minutes, diethyl carbonate (1.33 ml). After 2.5 hours stirring, reaction mixture is quenched with 10% hydrochloric acid (15 ml) and extracted with ethyl acetate. The solvent is evaporated to give 1-methyl-2-oxoazetidine-3-carboxylic acid ethyl ester (476 mg). Colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8](=[O:19])[C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([F:16])=[CH:11][C:10]=2[O:17]C)=[C:4]([F:22])[CH:3]=1.Br.[Na+].[Cl-].C(OCC)(=O)C>C(O)(=O)C>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8](=[O:19])[C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([F:16])=[CH:11][C:10]=2[OH:17])=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc(F)c(C)cc1C(=O)NCc1ccc(Br)cc1F
Agent: Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)NCc2ccc(Br)cc2F)c(O)cc1F
Temperature: 120 °C
Yield: 73 %

Procedure:
A stirring suspension of N-(4-bromo-2-fluoro-benzyl)4-fluoro-2-methoxy-5-methyl-benzamide (2.32 g, 6.51 mmol) in a 25% solution of HBr in acetic acid (60 mL, 0.11 M) was equipped with a reflux condenser and heated to 120° C. for 3.5 h. The mixture was allowed to cool and saturated aq NaCl (50 mL) and ethyl acetate (50 mL) were added. The layers were allowed to separate and the organic layer was collected. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to provide an orange powder. Purification of the solid via silica gel flash chromatography (30% ethyl acetate in heptane) provided N-(4-bromo-2-fluoro-benzyl)-4-fluoro-2-hydroxy-5-methyl-benzamide (1.69, 73%) as a white powder: mp 149-150° C.; Rf 0.51 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 12.20 (d, J=1.5, 1H), 7.30-7.29 (m, 2H), 7.26 (s, 1H), 7.14 (d, J=8.1 Hz, 1H), 6.64 (d, J=10.8, 1H), 6.48 (bd s, 1H), 4.62 (d, J=5.7'Hz, 2H), 2.19 (s, 3H); ESI-LC/MS m/z calcd for C15H12BrF2NO2: 355.0. Found 354.0 (M−1)−. Anal. calcd for C15H12BrF2NO2: C, 50.58; H, 3.40; N, 3.93. Found C, 50.65; H, 3.47; N, 3.87.