Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)[OH:4].[NH2:14][C:15]1[C:23]2[C:18](=[N:19][C:20]([N:27]3[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]3)=[CH:21][C:22]=2[CH2:24][CH2:25][CH3:26])[S:17][C:16]=1[C:34]([NH2:36])=[O:35].[BH4-].C(O)(=O)C>C1COCC1.CO>[NH2:14][C:15]1[C:23]2[C:18](=[N:19][C:20]([N:27]3[CH2:28][CH2:29][CH:30]([NH:1][CH2:2][CH:3]([C:5]4[S:9][C:8]5[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=5[CH:6]=4)[OH:4])[CH2:31][CH2:32]3)=[CH:21][C:22]=2[CH2:24][CH2:25][CH3:26])[S:17][C:16]=1[C:34]([NH2:36])=[O:35]
Reactant: CCCc1cc(N2CCC(=O)CC2)nc2sc(C(N)=O)c(N)c12
Reactant: NCC(O)c1cc2ccccc2s1
Agent: [BH4-]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCc1cc(N2CCC(NCC(O)c3cc4ccccc4s3)CC2)nc2sc(C(N)=O)c(N)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
The above 2-amino-1-benzo[b]thiophen-2-yl-ethanol (57.9 mg, 0.300 mmol), 3-amino-6-(4-oxo-piperidin-1-yl)-4-propyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (50.0 mg, 0.15 mmol), MP-borohydride (100 mg) and acetic acid (0.075 mL, 1.31 mmol) were mixed in a 2-dram vial in THF (4 mL) and shaken at room temperature for 21 h overnight. The reaction was filtered, and the borohydride resin was rinsed with MeOH, and then filtered again. The combined filtrates were concentrated in on a rotary evaporator to afford crude product. The residue was dissolved into a minimal amount of MeOH, applied to a 1 mm prep plate (Merck) and eluted with 5% MeOH/CH2Cl2, 1% NH3 to give 21.3 mg, 27.9% of the title compound. ES+ 510.1 m/z (MH+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[C:16]([C:20]1[CH:29]=[C:28]2[C:23]([C:24]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=3)=[N:25][C:26]([S:30][CH3:31])=[N:27]2)=[C:22]([NH2:39])[C:21]=1[C:40]([NH2:42])=[O:41])([CH3:19])([CH3:18])[CH3:17]>CC(C)=O>[C:16]([C:20]1[CH:29]=[C:28]2[C:23]([C:24]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:9][CH2:10][N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)[CH:33]=3)=[N:25][C:26]([S:30][CH3:31])=[N:27]2)=[C:22]([NH2:39])[C:21]=1[C:40]([NH2:42])=[O:41])([CH3:19])([CH3:17])[CH3:18]
Reactant: CSc1nc(-c2cccc(O)c2)c2c(N)c(C(N)=O)c(C(C)(C)C)cc2n1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1nc(-c2cccc(OCCN3CCCC3)c2)c2c(N)c(C(N)=O)c(C(C)(C)C)cc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of K2CO3 (1.0 g), 1-(2-chloroethyl)pyrrolidine hydrochloride (66 mg) and tert-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-quinazoline-6-carboxamide (example 26a, 121 mg) in acetone was heated overnight at reflux. The mixture was cooled to room temperature, the solids were removed by filtration and the filtrate concentrated under reduced pressure. The residue was taken up in EtOAc and washed with water and brine. The organic phase was dried (MgSO4) and concentrated in vacuo. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: 10% aq. CH3CN/CH3CN/0.1% aq. TFA=72/25/3 to 27/70/3 (v/v/v) in 30 min. The title compound was lyophilized from a nixture of water, TFA is and CH3CN.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:16])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1>C(O)C.[Pd]>[ClH:1].[CH3:2][N:3]([CH3:16])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1
Reactant: CN(C)CCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN(C)CCOc1ccc(N)cc1
Yield: 92.3 %

Procedure:
A solution of dimethyl-[2-(4-nitro-phenoxy)-ethyl]-amine hydrochloride (0.29 g, 1.2 mmol) in ethanol (20 mL) is hydrogenated at atmospheric pressure over 10% palladium on carbon. The reaction mixture is filtered through a pad of diatomaceous earth and concentrated to give 4-(2-dimethylamino-ethoxy)-phenylamine hydrochloride (0.24 g, 96%).
Reaction SMILES: [Cl:1][C:2]([CH2:4]Cl)=[CH2:3].[CH:6](=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1(C)C=CC=CC=1>[Zn].C(O)(=O)C>[Cl:1][C:2](=[CH2:3])[CH2:4][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[OH:13]
Reactant: CCCCCCC=O
Reactant: C=C(Cl)CCl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C=C(Cl)CC(O)CCCCCC

Procedure:
58.30 Grams of 2,3-dichloro-1-propene were added dropwise to a mixture of 30.00 g of heptanal, 90 g of toluene, 120 g of 5% acetic acid and 34.35 g of zinc powder at 45° C., and then the mixture was allowed to react at the same time temperature for 3 hours. After the reaction was completed zinc-derived insolubles were filtered off, and the resultant filtrate was subjected to separation. The organic phase was washed with a 7% sodium carbonate aqueous solution an dried over sodium sulfate. The desiccant was filtered off, and then the toluene was distilled off under reduced pressure to give 46.31 g of 2-chloroallyl-n-hexylcarbinol. The yield thereof was 92.4%.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14](=[O:19])[NH:15][CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]([NH:15][C:14]([C@H:11]1[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]1)=[O:19])([CH3:18])[CH3:17]
Reactant: CC(C)NC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)[C@H]1CC[C@H](N)CC1

Procedure:
A mixture of trans (4-isopropylcarbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (1.35 g, 4.75 mmoll) in DCM (25 ml) was treated with TFA (5 ml) at ambient temperature for 1 hour. The solvent was evaporated under vacuum and the residues diluted with water and extracted into ethyl acetate. The combined organic extracts were washed with 1M sodium hydroxide, water and brine, dried with magnesium sulfate and concentrated under vacuum affording 400 mg (46%) of trans 4-amino-cyclohexanecarboxylic acid isopropylamide as a white solid. LCMS (Method B, ESI): RT=0.43 min, m+H=185.21; 1H NMR (400 MHz, DMSO) δ: 7.50 (d; 1H); 3.81-3.75 (m; 1H); 2.55 (m, 1H); 1.94 (m; 1H); 1.79 (m; 2H); 1.69-1.58 (m; 2H); 1.35 (m; 2H); 1.01 (d; 6H) 0.99 (m; 2H).
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[CH:5]=[N:4][C:3]1=2.[NH2:18][CH2:19][CH2:20][CH2:21][NH2:22].CCOCC.C(#N)C>CO>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:18][CH2:19][CH2:20][CH2:21][NH2:22])=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: NCCCN
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CCOCC
Solvent: CO
Solvent: CC#N
Product: NCCCNC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was added to 1.85 g (25.0 mmol) of 1,3-diaminopropane in a 10 ml round bottom flask equipped with a magnetic stirring bar. The solution was stirred at room temperature for two hours. 10 ml ether was added and the solution was stirred for a few minutes. The ether solution was decanted, leaving an oil residue. 5 ml of acetonitrile and 4 ml of ether were added and the solution was stirred. Methanol was added dropwise until a precipitate had formed. The solution was filtered and washed with acetonitrile and ether, to yield 205 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-(3-aminopropyl)propanamide (AIT-0074). m.p. 172°-175° C. Yield: 73%
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1.[OH-].[K+]>C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])(O)(=O)=O.C1(C)C=CC=CC=1.O>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][O:1][C:2]2[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:16][C:17]=3[CH3:18])[CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])=[CH:29][CH:28]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)c(O)c1
Reactant: COc1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(COc2cc(OCCc3nc(-c4ccccc4)oc3C)ccc2C=O)cc1
Temperature: 80 °C

Procedure:
A mixture of 2-hydroxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (54 mg, 0.167 mmol), 4-methoxy-benzylchloride (58 mg, 0.368 mmol), KOH (56 mg, 1 mmol) and tetrabutylammonium-hydrogensulfate (50 mg) in 6 ml toluene and 5 ml water was heated at 80° C. during 6 hours. The reaction mixture was then cooled to 0° C., washed with water/ice and brine, the aqueous layer extracted with AcOEt, the combined organic layers dried over Na2SO4 and evaporated. The crude product was purified by chromatography (SiO2; AcOEt/heptane) and the product was crystallized from heptane to yield 25 mg (34%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[NH:10][C:9]1=S)([CH3:4])([CH3:3])[CH3:2].[NH2:23][CH2:24][CH:25]([OH:31])[C:26]([O:29][CH3:30])([CH3:28])[CH3:27].C(N(CC)CC)C>C(O)C.[Hg](Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[NH:10][C:9]1=[N:23][CH2:24][CH:25]([OH:31])[C:26]([O:29][CH3:30])([CH3:28])[CH3:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1NC(=S)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Reactant: COC(C)(C)C(O)CN
Agent: Cl[Hg]Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(C)(C)C(O)CN=C1N[C@H](C)[C@H](c2ccccc2)C[C@@H]1NC(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To as solution of tert-butyl[(3S,5S,6R)-6-methyl-5-phenyl-2-thioxopiperidin-3-yl]carbamate (150 mg, 0.47 mmol) in ethanol (4.7 mL) was added 1-amino-3-methoxy-3-methylbutan-2-ol (156 mg, 1.17 mmol), mercury (II) chloride (165 mg, 0.61 mmol), and triethylamine (163 μL, 1.17 mmol). The mixture was stirred 20 min, and then concentrated, giving the crude title compound. MS 420.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[C:31]3[C:26](=[CH:27][C:28]([CH:32]([CH3:39])[CH2:33][C:34]([O:36]CC)=[O:35])=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:23]2[C:31]3[C:26](=[CH:27][C:28]([CH:32]([CH3:39])[CH2:33][C:34]([OH:36])=[O:35])=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: CCOC(=O)CC(C)c1ccc2c(c1)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(CC(=O)N2CCc3cc(C(C)CC(=O)O)ccc32)ccc1NC(=O)Nc1ccccc1C
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 86.7 %

Procedure:
A solution of ethyl (R/S) 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-2,3-dihydro-1H-indol-5-yl)-butyrate [2.8 g, Reference Example 4(a)] in methanol (about 150 ml) was treated with aqueous sodium hydroxide solution (15 ml, 1M). The mixture was warmed at about 50° C. for 3 hours, then treated with a further aliquot of aqueous sodium hydroxide solution (7.5 ml). After a further 2-3 hours at 50° C. TLC analysis indicated complete reaction. The bulk of the methanol was removed by evaporation and the residue was diluted with hydrochloric acid (about 200 ml, 1M). The resulting mixture was stirred for about 30 minutes, then the solid was collected by filtration, washed with water, and dried to give the title compound (2.3 g) as a very light orange powder. LC-MS: RT=3.84 minutes (100% total area by ELS); MS (ES+) 502 (MH+), 524 (MNa+).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH2:21]([O:28][C:29]1[CH:30]=[CH:31][C:32](B2OC(C)(C)C(C)(C)O2)=[C:33]([NH2:35])[CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+].[Cl-].[NH4+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:35][C:33]1[CH:34]=[C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:30]=[CH:31][C:32]=1[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: CC1(C)OB(c2ccc(OCc3ccccc3)cc2N)OC1(C)C
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
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: [Cl-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OCc4ccccc4)cc3N)[nH]c2c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 136.4 %

Procedure:
To a suspension of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (3.38 g, 10.0 mmol) obtained in the same manner as in the method described in WO03/010140 and 5-benzyloxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (3.93 g, 12.1 mmol) in 1,2-dimethoxyethane (70 ml) and water (35 ml) were added sodium hydrogen carbonate (2.49 g, 30.0 mmol) and tetrakis(triphenylphosphine)palladium (582 mg, 0.50 mmol), and the mixture was stirred at 90° C. for 3 hr. The reaction mixture was allowed to cool to room temperature, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The obtained crude product (6.20 g) was used for Step 5 without further purification.
Reaction SMILES: O[CH2:2][C-:3]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4]1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15].[CH:16]([PH:19][CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17]>C(O)(=O)C>[CH:16]([P:19]([CH2:2][C-:3]1[CH:7]=[CH:6][C:5]([CH2:8][P:19]([CH:14]([CH3:13])[CH3:10])[CH:16]([CH3:18])[CH3:17])=[CH:4]1)[CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17].[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15]
Reactant: CC(C)PC(C)C
Reactant: OCc1cc[c-](CO)c1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CC(=O)O
Product: CC(C)P(Cc1cc[c-](CP(C(C)C)C(C)C)c1)C(C)C
Temperature: 80 °C
Yield: 175.6 %

Procedure:
2.46 g (10 mmol) of 1,3-bis(hydroxymethyl)ferrocene and 4.72 g (40 mmol) of diisopropylphosphine were added to 40 ml of acetic acid. The resulting mixture was heated at 80° C. for 3.5 hours and extracted with benzene after cooling. The organic phase was then washed with water and then dried over Na2SO4. After evaporation an orange residue was chromatographed on an alumina column. Elution with an ether-light petroleum mixture yielded 3.92 g (88%) of the product. Selected NMR data (CDCl3, 22° C.) 1H: δ0.92 (m, 24H, CH3), 1.63 (m, 4H, CH(CH3)2), 2.49 (bs, 4H, CH2P), 3.92 (s, 5H, C5H5), 3.95 (bs, 2H, 4.5-H), 4.06 (bs, 1H, 2-H). 31P NMR (CDCl3, 22° C.): δ 10.97(s, 2P).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[Br:6][CH2:7][C:8](Br)=[O:9].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)C>[CH3:1][N:2]([CH2:3][C:4]#[CH:5])[C:8](=[O:9])[CH2:7][Br:6]
Reactant: O=C(Br)CBr
Reactant: C#CCNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: C#CCN(C)C(=O)CBr
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 13.8 g (0.2 mol) of N-methylpropargylamine in 20 ml methylene chloride was added dropwise to a stirred and cooled (below 15° C) solution of 40.2 g (0.2 mol bromoacetyl bromide and 16 g (0.2 mol) sodium bicarbonate in 250 ml methylene chloride. The reaction mixture was allowed to warm to about 25° C and stirred for 2 hours. The reaction mixture was then filtered and evaporated under reduced pressure to give an oily residue. The residue was diluted with 150 ml ethyl ether to form a two-phase mixture consisting of an ether phase and a dark oil. The ether phase was separated, dried over magnesium sulfate, and evaporated to give 32.3 g of N-methyl-N-propargyl-alpha-bromoacetamide.
Reaction SMILES: C(O[C:6](=[O:30])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:12]2[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:11]=2[O:10][C@@H:9]1[CH3:29])(C)(C)C.N[C@@H]1C(=O)N(CCN2CCOCC2)C2C=C(F)C=CC=2O[C@@H]1C.[CH3:54][C:55](C)([C:59]([NH:61][CH2:62][C:63]([F:69])([F:68])[C:64]([F:67])([F:66])[F:65])=[O:60])[C:56](O)=O>>[F:28][C:25]1[CH:26]=[CH:27][C:11]2[O:10][C@H:9]([CH3:29])[C@H:8]([NH:7][C:6](=[O:30])[C:55]([CH3:56])([CH3:54])[C:59]([NH:61][CH2:62][C:63]([F:68])([F:69])[C:64]([F:67])([F:65])[F:66])=[O:60])[C:14](=[O:15])[N:13]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:12]=2[CH:24]=1
Reactant: C[C@H]1Oc2ccc(F)cc2N(CCN2CCOCC2)C(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: CC(C)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Agent: C[C@H]1Oc2ccc(F)cc2N(CCN2CCOCC2)C(=O)[C@H]1N
Product: C[C@H]1Oc2ccc(F)cc2N(CCN2CCOCC2)C(=O)[C@H]1NC(=O)C(C)(C)C(=O)NCC(F)(F)C(F)(F)F

Procedure:
[(6R,7S)-2-fluoro-6-methyl-9-(2-morpholin-4-yl-ethyl)-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-carbamic acid tert-butyl ester was deprotected according to the procedure in example 42b. The resulting (6R,7S)-7-amino-2-fluoro-6-methyl-9-(2-morpholin-4-yl-ethyl)-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one was reacted with 2,2-dimethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in analogy to the procedure described in example 2b to yield N-[(6R,7S)-2-fluoro-6-methyl-9-(2-morpholin-4-yl-ethyl)-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-2,2-dimethyl-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide, MS m/e (%): 569.3 (M+H+, 100).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([CH3:10])[CH:4]=1.[Br:11][C:12]1[S:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=1.C(N(CC)CC)C>C1COCC1>[CH3:10][C:5]1[CH:4]=[C:3]([CH2:2][NH:1][S:17]([C:15]2[S:16][C:12]([Br:11])=[CH:13][CH:14]=2)(=[O:19])=[O:18])[CH:8]=[C:7]([CH3:9])[N:6]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: Cc1cc(CN)cc(C)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(CNS(=O)(=O)c2ccc(Br)s2)cc(C)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.9 %

Procedure:
To a stirred solution of commercially available 4-aminomethyl-2,6-dimethyl-pyridine [CAS-No. 324571-98-4] (0.24 g, 1.76 mmol) in THF (8 ml) was added at 0° C. (ice water bath) commercially available 5-bromo-thiophene-2-sulfonyl chloride (0.46 g, 1.76 mmol) dissolved in THF (8 ml) and triethylamine (0.27 ml, 1.94 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) and crystallization from dichloromethane/hexane to yield the title compound (0.33 g, 52%) as a light red solid. MS (ISN) 359.0 [(M−H)−], mp 138° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7][N:6]1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:19][CH:18]=1)=[O:4].Br[CH2:30][CH:31]1[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([CH:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:30][CH:31]3[CH2:33][CH2:32]3)=[CH:12][CH:13]=2)[CH2:8][CH2:7][N:6]1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C@@H:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:21][CH:22]=1)=[O:4]
Reactant: BrCC1CC1
Reactant: COC(=O)C1c2ccc(O)cc2CCN1Cc1ccc([C@H](C)NC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1c2ccc(OCC3CC3)cc2CCN1Cc1ccc([C@H](C)NC(C)=O)cc1

Procedure:
15 mg (39 μmol) 2-[4-((S)-1-Acetylamino-ethyl)-benzyl]-6-hydroxy-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid methyl ester (example XXXVIII), 5.8 mg (43 μmol) (bromomethyl)cyclopropane and 10 mg (78 μmol) K2CO3 in 2 mL DMF are stirred at 80° C. over night. The reaction mixture is diluted with water and extracted with DCM. The organic layer is concentrated by evaporation and the residue is purified by HPLC.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]([NH:16][C:17](=[O:29])[C@@H:18]([N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:21])[CH3:19])[N:8]=1)[CH3:5]>C1COCC1.C(O)(=O)C.CO.[Pd]>[C:25]([O:24][C:22](=[O:23])[N:20]([CH3:21])[C@H:18]([C:17](=[O:29])[NH:16][C:9]1[CH:10]=[CH:11][C:12]2[NH:13][C:3](=[O:2])[C@H:4]([CH3:5])[NH:6][C:7]=2[N:8]=1)[CH3:19])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)[C@H](C)Nc1nc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1Nc2nc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)ccc2NC1=O
Reaction time: 3 h
Yield: 43.2 %

Procedure:
To a solution of (S)-2-{6-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-nitro-pyridin-2-ylamino}-propionic acid methyl ester (90 mg, 0.21 mmol) in THF (3 mL) and acetic acid (3 mL) and MeOH (3 mL) was added Pd/C (10%, 90 mg) and the reaction mixture was hydrogenated for 3 h. The catalyst was filtered and the filtrate evaporated. The residue was partitioned between saturated NaHCO3 and EtOAc. The organic phase was dried (MgSO4), filtered and evaporated. The crude material was purified by preparative HPLC to afford methyl-[(S)-1-((S)-3-methyl-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-6-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (33 mg). MS: [M+H]+=364.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([C:27](=[O:36])[NH:28][C:29]5([C:32](=[NH:35])[NH:33][OH:34])[CH2:31][CH2:30]5)[CH:24]=[CH:23][C:22]=4[CH3:37])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.N1C=CC=[CH:40][CH:39]=1.C(Cl)(=O)C>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([C:27](=[O:36])[NH:28][C:29]5([C:32]6[N:35]=[C:39]([CH3:40])[O:34][N:33]=6)[CH2:30][CH2:31]5)[CH:24]=[CH:23][C:22]=4[CH3:37])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C(=N)NO)CC4)ccc3C)cc12
Solvent: CO
Solvent: CC(=O)Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5noc(C)n5)CC4)ccc3C)cc12
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-fluorophenyl)-5-(5-(1-(N-hydroxycarbamimidoyl)cyclopropylcarbamoyl)-2-methylphenyl)-N-methylbenzofuran-3-carboxamide (46.5 mg, 0.093 mmol, crude) in pyridine (0.5 mL, 6.18 mmol) at r.t. under N2 was added acetyl chloride (0.020 mL, 0.279 mmol). The mixture was stirred at 115° C. for 2 hours. The mixture was cooled to r.t., diluted with MeOH and purified by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, Fraction Collection: 7.64-7.95 min. (UV detection at 220 nm). The residue obtained after evaporation of the combined fractions was further purified by preparative TLC, 10% MeOH/CH2Cl2, two 20 cm×20 cm×0.5 mm plates. Rf about 0.67 (10% MeOH/CH2Cl2). 1H NMR (500 MHz, CD3OD) δ 7.98 (m, J=9.00, 5.34, 2H), 7.81 (s, 1H), 7.80 ((m overlapped with s, J=2.14, 1H), 7.66 (d, J=8.55, 1H), 7.65 (d, J=1.22, 1H), 7.43 (d, J=8.55, 1H), 7.36 (dd, J=8.55, 1.83, 1H), 7.28 (m, J=8.70, 2H), 2.96 (s, 3H), 2.54 (s, 3H), 2.35 (s, 3H), 1.59 (m, 2H), 1.43 (m, 2H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=525.07, HPLC Rt=1.682 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H2O-0.1% TFA, Solvent B=95% MeCN-5% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, Rt=6.67 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=5.22 min. Analytical HPLC method: Solvent A=5% MeOH-95% H2O-10 mM NH4HCO3, Solvent B=95% MeOH-5% H2O-10 mM NH4HCO3, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=12.36 min.