Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[N:22]1([C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][CH:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:34]([C:31]1[CH:30]=[CH:29][C:28]([N:22]2[CH2:23][CH2:24][N:25]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][C:11]=3[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]4=[O:21])[CH2:26][CH2:27]2)=[CH:33][CH:32]=1)(=[O:36])[CH3:35]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Product: CC(=O)c1ccc(N2CCN(c3cc4c(=O)n(NS(C)(=O)=O)c(=O)[nH]c4cc3[N+](=O)[O-])CC2)cc1
Yield: 44 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (20 mg, 0.0628 mmol) is reacted with 1-(4-piperazin-1-yl-phenyl)-ethanone according to the GPA affording 14 mg (44%) of an orange powder. Rt=3.85 min.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:13]C)(=[O:12])/[CH:9]=[CH:10]/[CH3:11].[OH-].[Na+]>CO.O.[Na]>[C:1]1([S:7][CH:10]([CH3:11])[CH2:9][C:8]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: C/C=C/C(=O)OC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(CC(=O)O)Sc1ccccc1
Temperature: 120 °C
Yield: 32.6 %

Procedure:
0.25 g of sodium in small pieces, in 50 ml (0.5 mol) of thiophenol, is heated to 90°-95° C whilst stirring, and 52.5 ml (0.55 mol) of methyl crotonate are added dropwise. The mixture is heated further for 1 hour at 120° C and 85 g (boiling point/5 mm Hg = 137°-138° C) of the resulting ester are distilled in vacuo. 53 g (0.25 mol) of this ester in solution in 200 ml of methanol are hydrolysed with 16 g (0.4 mol) of NaOH in 200 ml of water. The mixture is heated for 2 hours under reflux, the alcohol is evaporated in vacuo, the residue is taken up in water and the product is precipitated with concentrated HCl and extracted with ether. The extract is washed with water and dried, and 32 g (65%) of a white oil are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:36]=[C:37]([C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)[CH3:38]>CN(C=O)C.[Cu]I>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6](/[CH:36]=[C:37](/[C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)\[CH3:38])[C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC(=CBr)c1ccncc1
Reactant: CN1CCc2[nH]c3ccc(C(F)(F)F)cc3c2C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C(F)(F)F)ccc31)CN(C)CC2)c1ccncc1
Temperature: 140 °C

Procedure:
2-Methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (239 mg, 0.94 mmol), and potassium phosphate (399 mg, 1.88 mmol) were mixed in DMF and the suspension was purged with nitrogen. The suspension was heated at 140° C. for 10 min. Copper (I) iodide (17.86 mg, 0.094 mmol) and L-proline (21.64 mg, 0.188 mmol) were added followed by a solution of 4-(1-bromoprop-1-en-2-yl)pyridine (399 mg, 1.88 mmol) in DMF. The contents were purged with nitrogen and heated overnight at 140° C. The contents were cooled to RT and poured into water. The precipitate obtained was filtered, dried and purified by silica gel chromatography (100-200 mesh) eluting with 0-10% MeOH-DCM as eluent. The compound was further purified by HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.82 (d, 2H), 8.30 (d, 2H), 7.95 (s, 1H), 7.70 (s, 1H), 7.58 (d, 1H), 7.45 (d, 1H), 4.50 (m, 1H), 3.95 (m, 1H), 3.62 (m, 1H), 3.30 (m, 3H), 3.18 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C.O>O1CCCC1>[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:16]2[CH2:17][CH2:18][N:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:3]([CH3:6])([CH3:4])[CH3:5])[CH2:14][CH2:15]2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (10.0 g, 34.3 mmol), 4-bromobenzoyl chloride (8.2 g, 37.4 mmol) and triethylamine (16.7 mL, 120.0 mmol) in tetrahydrofuran (200 mL) was stirred at room temperature for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to purify the residue by NH-silica gel column chromatography (hexane/ethyl acetate 50:50 to 0:100). Solvent was removed to obtain a solid (14.2 g, quant.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:15](Cl)(=[O:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH:6]=[C:7]([C:15](=[O:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:8]=[CH:9]2
Reactant: COc1cc2ccccc2cc1OC
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCC(=O)c1ccc2cc(OC)c(OC)cc2c1

Procedure:
The solution of 2,3-dimethoxynaphthalene (1.9 g), palmitoyl chloride (3.2 ml) and aluminium chloride (1.5 g) in methylene chloride (40 ml) was stirred at ambient temperature overnight. The reaction mixture was worked up as described in example 4(a). The crude product was recrystallized from ethyl acetate-heptane. Yield 2.0 g.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:2].[N+:15]([O-])([OH:17])=[O:16].O.N>S(=O)(=O)(O)O>[CH2:1]([O:3][CH2:4][C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:10][CH:9]=2)[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOCc1cc2ccccc2cn1
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOCc1cc2c([N+](=O)[O-])cccc2cn1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3-Ethoxymethylisoquinoline (31 g) is dissolved in 95% sulphuric acid (density 1.83; 100 cc). The solution is cooled to 0° C. and a mixture of 95% sulphuric acid (density 1.83; 35 cc) and 70% nitric acid (density 1.42; 10.2 cc) is added dropwise in the course of 30 minutes so as not to exceed 10° C. Stirring is continued for 16 hours whilst allowing the temperature to return to about 20° C. The mixture is then poured into a mixture of ice and water (1 liter), and an ammonia solution containing 20% of NH3 (density 0.9) is added, without exceeding 30° C., until a pH of about 10 is obtained. The yellow suspension is extracted with methylene chloride (4×200 cc). The organic extracts are combined, washed with water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg). 3- Ethoxymethyl-5-nitroisoquinoline (24 g), melting at 54° C., is obtained.
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C:5]1[N:10]2[C:11]([C:15]([O:17]CC)=O)=[C:12]([CH3:14])[N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.O>CN(C=O)C>[CH3:14][C:12]1[N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[N:10]2[C:11]=1[C:15](=[O:17])[NH:4]3
Reactant: CCOC(=O)c1c(C)nc2cccc(N)n12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2cccc3[nH]c(=O)c1n23
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a suspension of 4.8 g (120 mmol) of sodium hydride (60% dispersion in oil) in 60 ml of DMF was added 10.23 g (40 mmol) of 5-amino-3-ethoxycarbonyl-2-methylimidazo[1,2-a]pyridine-hydrochloride with small portions. The mixture was stirred for 0.5 hour, then for 0.5 hour at 100° C., which was left standing for cooling. To the reaction mixture was added 60 ml of water. The mixture was washed with chloroform, to which was added, while stirring at room temperature, conc. HCl to make the pH of the solution 8. The resulting precipitate was collected by filtration, washed with water and ether, successively to give 5.97 g of the desired compound (86.1%, pale brown solid).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].Cl>C(OCC)C.O>[CH2:21]([O:20][C:18]([NH:11][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc(O)cc1C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(Nc1ccc(O)cc1C(=O)O)OCc1ccccc1
Yield: 96.6 %

Procedure:
To a mixture of 5-hydroxyanthranilic acid (50 g, 0.33 mol), sodium hydrogen carbonate (109 g, 1.3 mol) and water (200 ml) was added dropwise a solution of benzyl chloroformate (52 ml, 0.36 mol) in diethyl ether (200 ml) with stirring, and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was acidified by adding conc. hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained crystals were washed with diisopropyl ether and hexane to give 2-{[(benzyloxy)carbonyl]amino}-5-hydroxybenzoic acid (91.6 g, yield 98%) as brown crystals.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:19]1([CH2:22][C:23]([NH2:31])([CH3:30])[C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)[CH2:21][CH2:20]1>>[CH:19]1([CH2:22][C:23]([NH:31][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])([CH3:30])[C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)[CH2:21][CH2:20]1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 63b, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 66e) as starting materials and the racemate was isolated (43 mg, 32%) as a colorless oil. The racemate was separated into its enantiomers by preparative chiral HPLC (Chiralpak AD, isopropanol/heptane) and the title compound was the first enantiomer collected and isolated as a colorless oil; MS (ESI, m/z): 425.5 (M+H+). The collected enantiomer shows levorotation properties according to the observed optical activity measured during preparative chiral HPLC.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:19]([CH:21]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)#[CH:20]>>[CH:21]1([C:19]#[C:20][C:2]2[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C#CC1CCCCCC1
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Product: O=C(NCCC(O)c1cccc(C#CC2CCCCCC2)c1)C(F)(F)F

Procedure:
Sonogashira coupling of N-(3-(3-bromophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide (43) with ethynylcycloheptane, followed by flash chromatography (5-40% EtOAc/hexanes gradient), gave N-(3-(3-(cycloheptylethynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide as an amber oil. Yield (0.507 g, 51%): 1H NMR (400 MHz, CDCl3) δ 7.42 (br s, 1H), 7.34-7.36 (m, 1H), 7.19-7.33 (m, 3H), 4.81 (q, J=4.0 Hz, 1H), 3.48-3.68 (m, 1H), 3.32-3.42 (m, 1H), 2.74-2.82 (m, 1H), 2.48 (br s, 1H), 1.85-2.00 (m, 4H), 1.70-1.80 (m, 4H), 2.46-1.64 (m, 6H).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH2:29][CH:28]3[CH2:30][CH:25]([CH2:26][CH2:27]3)[C:24]=2[CH:31]=[CH:32][CH:33]=[O:34])=[CH:19][CH:18]=1>C1COCC1.CCCCC>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH2:29][CH:28]3[CH2:30][CH:25]([CH2:26][CH2:27]3)[C:24]=2/[CH:31]=[CH:32]/[CH:33]([OH:34])[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH3:10])=[O:8])=[CH:21][CH:22]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=CC=CC1=C(c2ccc(F)cc2)CC2CCC1C2
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CC(O)/C=C/C1=C(c2ccc(F)cc2)CC2CCC1C2
Reaction time: 0.5 h

Procedure:
To a 0°-5° C. suspension of pentane-washed sodium hydride (0.43 g, 10.6 mmoles) in 10 ml anhydrous THF was added dropwise methyl acetoacetate. The solution was stirred for 30 minutes and n-butyl lithium (5.8 ml of a 1.6M solution in hexanes, 9.31 mmoles) was added dropwise. The solution was stirred for 20 minutes and a solution of 3-[3-(4-fluorophenyl)bicyclo [3.2.1]oct-2-en-2-yl]propenal (2.50 g, 9.75 mmoles) in 15 ml anhydrous THF was added. The resulting solution was stirred for 60 minutes and quenched with ether and aqueous HCl. The organic layer was washed with water and brine and dried (MgSO4). Removal of the volatiles in vacuo provided 3.3 g of the solid product which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1.[P:24]([O:31]CC)([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>C1(C)C(C)=CC=CC=1>[C:13]([O:12][C:10]([N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]1[CH:5]=[CH:4][C:3]([CH2:2][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[N:8][CH:7]=1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(CBr)nc1
Solvent: Cc1ccccc1C
Product: CCOP(=O)(Cc1ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cn1)OCC
Temperature: 140 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of di-tert-butyl [6-(bromomethyl)pyridin-3-yl]imidodicarbonate (Compound 260C, 3.0 g, 7.7 mmol) in dry xylene (100 mL) was added a triethyl phosphite (6.0 g, 36 mmol). The reaction mixture was stirred at 140° C. for 4 h, then concentrated. The residue was purified by column chromatography to give the desired compound (2.5 g, yield: 92%) as a liquid. 1H NMR (CDCl3, 400 MHz): δ=1.34 (t, J=7.6 Hz, 6 H), 1.39 (s, 18 H), 3.43 (d, J=22.0 Hz 2 H), 4.09-4.18 (m, 4 H), 7.43 (dd, J=2.0, 8.0 Hz, 1 H), 7.67 (s, 1 H), 8.33 (d, J=8.0 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][C@@H:22]([C:25]1[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1)[CH2:23][OH:24].C(N(CC)C(C)C)(C)C>C(#N)C>[OH:24][CH2:23][C@@H:22]([NH:21][C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:25]1[CH:26]=[N:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: N[C@H](CO)c1ccc(C(F)(F)F)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(N[C@H](CO)c4ccc(C(F)(F)F)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (160 mg, 0.56 mmol) and (S)-2-amino-2-(6-(trifluoromethyl)pyridin-3-yl)ethanol (118 mg, 0.57 mmol) (prepared similarly according to the method for Intermediate 10) in acetonitrile (2 mL) and N,N-diisopropylethylamine (0.4 mL) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by semi-preparative HPLC (100×20.2 mm, C18 column; 40-60% acetonitrile-water [10 mM diethylamine]) to yield a light brown solid.
Reaction SMILES: [CH:1]([NH:3][C@H:4]([C:9]([OH:11])=O)[CH2:5][C:6]([OH:8])=[O:7])=[O:2].[CH3:12][O:13][C:14](=[O:24])[C@H:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH2:16].COC(=O)C(CC1C=CC=CC=1)N>O>[CH3:12][O:13][C:14](=[O:24])[C@H:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:16][C:9](=[O:11])[C@H:4]([CH2:5][C:6](=[O:7])[OH:8])[NH:3][CH:1]=[O:2]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=CN[C@@H](CC(=O)O)C(=O)O
Agent: COC(=O)C(N)Cc1ccccc1
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC=O

Procedure:
An enzymatic method for producing N-formyl-α-L-aspartyl-L-phenylalanine methyl ester by a condensation reaction between N-formyl-L-aspartic acid and L-phenylalanine methyl ester or D,L-phenylalanine methyl ester, which comprises: supplying an organic phase comprising a water-immiscible solvent containing N-formyl-L-aspartic acid and L- or D,L-phenylalanine methyl ester onto an aqueous phase comprising a thermolysin-like metalloprotease; proceeding the condensation reaction in the aqueous phase to produce N-formyl-α-L-aspartyl-L-phenylalanine methyl ester; and extracting the N-formyl-α-L-aspartyl-L-phenylalanine methyl ester thus produced from the aqueous phase to the organic phase.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]2[OH:25])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].C(N(CC)CC)C.C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C:13]2=[O:25])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)nc1Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Reaction time: 15 h

Procedure:
tert-Butyl trans(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-hydroxypiperidine-1-carboxylate obtained in Example (77b) (300 mg, 0.80 mmol) was dissolved in DMSO (3 mL). Triethylamine (1.2 mL, 8.61 mmol) and sulfur trioxide-pyridine complex (737 mg, 4.63 mmol) were added, and the mixture was stirred for 15 hours. Ethyl acetate was added, to the reaction solution. This was washed with 5% saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2>>[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Yield: 64.8 %

Procedure:
The title compound was prepared under the same conditions as described in step 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d obtained from step 4 of Example 32 and 5-chloro-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 35 (44 mg, yield 64.8%) as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:11][OH:12].C(=O)([O-])[O-].[Na+].[Na+].O>CO>[OH:12][NH:11][C:8](=[NH:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N=C(Cc1ccccc1)NO
Temperature: 25 °C

Procedure:
Phenyl acetonitrile (20 g, 170 mmol), hydroxylamine hydrochloride (60 g, 850 mmol) and sodium carbonate (71 g, 850 mmol) were heated under reflux in methanol (300 ml) and water (300 ml) for 5 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate was evaporated and extracted with dichloromethane (3×). The combined organic solutions were washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure to give the title compound as a white solid, 15.5 g.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4](I)[CH:3]=1.[CH2:18]([C:21]1([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1)[CH:19]=[CH2:20].CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=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.C(Cl)Cl>[CH2:18]([C:21]1([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:22][CH2:23][N:24]([C:27]2[N:28]=[CH:29][C:30]([C:4]3[CH:3]=[C:2]([Br:1])[C:10]4[S:9][C:8]([NH:11][C:12](=[O:13])[NH:14][CH2:15][CH3:16])=[N:7][C:6]=4[CH:5]=3)=[CH:31][N:32]=2)[CH2:25][CH2:26]1)[CH:19]=[CH2:20]
Reactant: CCNC(=O)Nc1nc2cc(I)cc(Br)c2s1
Reactant: C=CCC1(C(=O)OCC)CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCC1(C(=O)OCC)CCN(c2ncc(-c3cc(Br)c4sc(NC(=O)NCC)nc4c3)cn2)CC1
Temperature: 80 °C
Yield: 27 %

Procedure:
To a solution of 1-(7-bromo-5-iodobenzothiazol-2-yl)-3-ethylurea (0.55 g, 1.29 mmol) and ethyl 4-allyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperidine-4-carboxylate (0.79 g, 1.97 mmol) in 1,4-dioxane:MeOH (30:20 mL) was added potassium phosphate (0.41 g, 1.97 mmol) at rt and the mixture degassed for 15-20 min by purging N2 followed by addition of tetrakis(triphenylphosphine)palladium(0) (0.15 g, 0.13 mmol). The reaction mixture was again degassed for another 15-20 min then heated up to 80° C. for 5 h. After completion of reaction (by TLC), the reaction mixture was cooled to rt, diluted with EtOAc (500 mL) and passed through celite. The filtrate was evaporated and the crude residue was purified over 100-200 M silica-gel using 1.50% MeOH: DCM to obtain the desired product as a beige solid (0.20 g, 27% yield). 1H NMR (DMSO-d6): δ 1.09 (t, J=7.20 Hz, 3H), 1.21 (t, J=6.80 Hz, 3H), 1.47 (m, 2H), 2.05 (m, 2H), 2.29 (m, 2H), 3.18 (m, 2H), 3.21 (q, J=7.20, 2H), 4.17 (q, J=6.80 Hz, 2H), 4.46 (m, 2H), 5.05 (m, 2H), 5.72 (m, 1H) 6.74 (br s, 1H), 7.69 (s, 1H), 7.87 (s, 1H); 8.77 (s, 2H) and 10.90 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:25][CH3:26])[N:6]2[CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#N)=[CH:19][CH:18]=1.C1C[O:30]CC1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:25][CH3:26])[N:6]2[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH:21]=[O:30])=[CH:23][CH:24]=1
Reactant: C1CCOC1
Reactant: COCCOc1nc(N)c2nc(OC)n(Cc3ccc(C#N)cc3)c2n1
Product: COCCOc1nc(N)c2nc(OC)n(Cc3ccc(C=O)cc3)c2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product of example 5 (100 mg) is dissolved in dry THF (3 mL) and cooled to 0° C. under argon. The reagent generated in example 6 (0.72 mL) is added to the reaction flask and the mixture is stirred at 0-5° C. for 1 h and then quenched by addition of 3 M HCl. The mixture is then extracted with ethyl acetate and then dichloromethane and concentrated in vacuo to yield 85 mg. NMR is consistent with structure assignment.