Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]([NH:20]C(=O)OC(C)(C)C)[CH:17]=[CH:18][CH:19]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[ClH:28]>O1CCOCC1>[ClH:28].[NH2:20][C:16]1[CH:15]=[C:14]([NH:13][C:11](=[O:12])[CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(NC(=O)Cc2cccc([N+](=O)[O-])c2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cccc(NC(=O)Cc2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Into the reaction was added tert-butyl (3-{[(3-nitrophenyl)acetyl]amino}phenyl)carbamate (0.46 g, 1.2 mmol) and 4.0 M of hydrogen chloride in 1,4-dioxane (3 mL). The mixture was stirred at rt for 2 h. The solvent was removed under vacuum to give the desired product (0.34 g, 100%) as a white powder. LCMS for C14H13N3O3 (M+H)+: m/z=272.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1B1OCC(C)(C)CO1.Br[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Reactant: Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C)cc3)cc12
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 177.9 %

Procedure:
A mixture of methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (80 mg, 0.15 mmol), 4-bromotoluene (56 mg, 0.30 mmol), 2.0M aqueous potassium carbonate (0.5 mL, 1.0 mmol), and Pd(dppf)Cl2 (10 mg, 0.01 mmol) in toluene/ethanol (1.44 mL/0.48 mL) was stirred at 110° C. for 2.5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated to give a residue, which was purified by preparative TLC to give the title compound (80 mg, 100% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.51 (br. s, 1H), 8.15 (s, 1H), 7.98 (s, 1H), 7.55 (s, 1H), 7.42 (d, 2H), 7.25 (d, 2H), 3.90 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:34])[C:20]([C:27]4[N:31]([CH3:32])[N:30]=[N:29][C:28]=4[CH3:33])=[CH:21][C:22]=3[Cl:26])[C:17]2=[O:35])=[C:13]([CH3:36])[CH:12]=[C:11]([CH3:37])[N:10]=1)C1C=CC=CC=1.ClCCl.CO>FC(F)(F)C(O)=O>[Cl:26][C:22]1[CH:21]=[C:20]([C:27]2[N:31]([CH3:32])[N:30]=[N:29][C:28]=2[CH3:33])[C:19]([Cl:34])=[C:18]2[C:23]=1[CH2:24][CH2:25][N:16]([CH2:15][C:14]1[C:9](=[O:8])[NH:10][C:11]([CH3:37])=[CH:12][C:13]=1[CH3:36])[C:17]2=[O:35]
Reactant: Cc1cc(C)c(CN2CCc3c(Cl)cc(-c4c(C)nnn4C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cc1cc(C)c(CN2CCc3c(Cl)cc(-c4c(C)nnn4C)c(Cl)c3C2=O)c(=O)[nH]1
Temperature: 45 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
A solution of 229a (1.1 g, 2.1 mmol) was dissolved in trifluoroacetic acid (25 mL) and stirred at 45° C. for 3 hours. TLC (dichloromethane/methanol=10:1, Rf: 0.5) showed the reaction was complete. The mixture was concentrated and diluted with dichloromethane (30 mL), washed with aqueous sodium bicarbonate (4×50 mL) and brine (2×20 mL), dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (eluting with 10:1 dichloromethane methanol) to afford 5,8-dichloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 229, 514 mg, 51% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 11.73 (s, 1H), 7.31 (s, 1H), 5.95 (s, 1H), 4.77 (s, 2H), 3.85 (s, 3H), 3.77 (t, J=12.8 Hz, 2H), 3.06-3.02 (m, 2H), 2.38 (s, 3H), 2.29 (s, 3H), 2.21 (s, 3H). MS: 446.1 [M+1].
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[C:40]([C:42]([NH:44][CH2:45][C:46]([OH:48])=O)=[O:43])[N:39]=[N:38]2)[CH:32]=1.NC1C=NC=CC=1.Cl.[NH:57]1[CH2:60][CH:59]([O:61][C:62]2[CH:63]=[C:64]([CH:67]=[CH:68][C:69]=2[CH3:70])[C:65]#[N:66])[CH2:58]1>CN(C=O)C>[C:65]([C:64]1[CH:67]=[CH:68][C:69]([CH3:70])=[C:62]([CH:63]=1)[O:61][CH:59]1[CH2:58][N:57]([C:46](=[O:48])[CH2:45][NH:44][C:42]([C:40]2[N:39]=[N:38][N:37]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)[CH:41]=2)=[O:43])[CH2:60]1)#[N:66]
Reactant: O=C(O)CNC(=O)c1cn(-c2cccnc2)nn1
Reactant: Cc1ccc(C#N)cc1OC1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C#N)cc1OC1CN(C(=O)CNC(=O)c2cn(-c3cccnc3)nn2)C1
Reaction time: 0.03 h
Yield: 7 %

Procedure:
DIPEA (193.9 mg, 1.5 mmol) followed by HOBt (53 mg, 0.29 mmol) and EDCI (75 mg, 0.39 mmol) were added to a stirred solution of [(1-pyridin-3-yl-1H-[1,2,3]triazole-4-carbonyl)-amino]-acetic acid (prepared by the method used for the synthesis of Intermediate 64, starting from 3-aminopyridine, and subsequently, application of Step 3 of the General Scheme) (93 g, 0.37 mmol) in DMF (3 mL). After 2 minutes of stirring, 3-(azetidin-3-yloxy)-4-methyl-benzonitrile hydrochloride (prepared by the method used for the synthesis of Intermediate 71) (84 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between cold water and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by preparative HPLC afforded 11 mg (7% Yield) of 1-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid {2-[3-(5-cyano-2-methyl-phenoxy)-azetidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 418, 96.08%. 1H NMR (300 MHz, DMSO-d6): δ 9.42 (s, 1H), 9.2 (d, 1H), 8.7 (m, 2H), 8.38 (m, 1H), 7.62 (m, 1H), 7.4 (s, 1H), 7.16 (s, 1H), 5.1 (m, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 4.2 (m, 1H), 4.0 (d, 2H), 3.8 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12]CC2C=CC=CC=2)=[O:11])=[N:8][CH:9]=1)([CH3:3])=[CH2:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])=[CH2:2]
Reactant: C=C(C)c1ccc(C(=O)OCc2ccccc2)nc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C=C(C)c1ccc(C(=O)O)nc1
Yield: 95.6 %

Procedure:
A solution of benzyl 5-isopropenylpicolinate (1.27 g, 5 mmol) in MeOH (25 mL) was subjected to hydrogenation with 20% Pd(OH)2/C (200 mg) with a H2 balloon for 2 h. The product 5-isopropenylpicolinic acid (780 mg) was obtained by filtration and concentration.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[CH3:2].Cl.[CH3:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1>>[CH3:19][C:20]1[C:21]([N:27]2[CH2:28][CH2:29][N:30]([C:13]([C:12]3[CH:11]=[CH:10][C:9]([N:4]4[C@H:3]([CH2:1][CH3:2])[CH2:7][O:6][C:5]4=[O:8])=[CH:17][CH:16]=3)=[O:15])[CH2:31][CH2:32]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: CC[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Agent: Cl
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1
Yield: 38.2 %

Procedure:
By reaction and treatment in the same manner as in Example 49 and using (R)-4-(4-ethyl-2-oxooxazolidin-3-yl)benzoic acid (470 mg) described in Preparation Example 78 and 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (455 mg) described in Preparation Example 64, the title compound (312 mg) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH:22]([NH:21][C:20]([N:17]1[CH2:18][CH2:19][CH:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:15][CH2:16]1)=[O:25])([CH3:24])[CH3:23]
Reactant: CC(C)NC(=O)N1CCC(N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)N1CCC(N2CCNCC2)CC1

Procedure:
In a manner analogous to the method described in example 27, 4-(1-isopropylcarbamoyl-piperidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester was treated with trifluoroacetic acid to give 4-piperazin-1-yl-piperidine-1-carboxylic acid isopropylamide trifluoroacetate as a yellow solid. LR-MS: 255 [(M+H)+]
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]1(C)[C:17](C)(C)OB(C(C)=C)O1.C(=O)([O-])[O-].[Na+].[Na+]>O.O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]([CH3:17])=[CH2:12])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)c1ccc(C)cc1[N+](=O)[O-]
Temperature: 140 °C
Yield: 95.4 %

Procedure:
1-Chloro-4-methyl-2-nitrobenzene (0.771 mL, 5.83 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.32 mL, 6.99 mmol), bis(triphenyl phosphine)palladium(II) chloride (0.327 g, 0.466 mmol), sodium carbonate (0.741 g, 6.99 mmol) in water (2.9 mL) and dioxane (11.4 mL) was capped in two separate 10-20 mL vials and heated on a Biotage Initiator® microwave reactor for 30 minutes at 140° C., with external IR-sensor temperature monitoring from the side of the vessel. The contents of the two vials were combined and diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography using 1-5% ethyl acetate/hexanes provided the title compound as a yellow oil (0.986 g, 95%): IR (thin film) 3084 (w), 2976 (m), 2919 (w), 1641 (w), 1560 (w), 1526 (vs), 1349 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.68-7.65 (m, 1H), 7.37-7.32 (m, 1H), 7.21 (d, J=7.9 Hz, 1H), 5.15 (p, J=1.5 Hz, 1H), 4.91 (p, J=1.0 Hz, 1H), 2.42 (s, 3H), 2.06 (t, J=1.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 148.06, 142.71, 138.30, 136.15, 133.38, 130.32, 124.29, 115.17, 23.32, 20.81.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[C:4]2[N:5]([C:19]([C:22](O)=[O:23])=[CH:20][N:21]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1.O[NH:28][C:29](=[NH:40])[C:30]1[CH:35]=[CH:34][C:33]([S:36](=[O:39])(=[O:38])[NH2:37])=[CH:32][CH:31]=1>>[F:26][C:2]([F:1])([F:25])[C:3]1[C:4]2[N:5]([C:19]([C:22]3[O:23][N:40]=[C:29]([C:30]4[CH:31]=[CH:32][C:33]([S:36]([NH2:37])(=[O:38])=[O:39])=[CH:34][CH:35]=4)[N:28]=3)=[CH:20][N:21]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][CH:10]=2)[CH:8]=1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnc4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)cn34)n2)cc1

Procedure:
The title compound was prepared from 8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.32) (187 mg, 0.5 mmol) and N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane) as a yellow solid (143 mg, 52%). MS (EI) 553.1 [(M)+]; mp 292° C.
Reaction SMILES: O=[C:2]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]#[N:16])=[CH:5][C:4]=2[NH:3]1.P(Cl)(Cl)([Cl:19])=O>C(#N)C>[Cl:19][C:2]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]#[N:16])=[CH:5][C:4]=2[N:3]=1
Reactant: N#Cc1ccc2c(c1)[nH]c(=O)c1sccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: N#Cc1ccc2c(c1)nc(Cl)c1sccc12
Yield: 89.3 %

Procedure:
4-oxo-4,5-dihydrothieno[2,3-c]quinoline-7-carbonitrile (1.0 eq, 1.22 g, 5.40 mmol) was stirred under reflux in acetonitrile (12 ml) and phosphorus oxychloride (5.0 eq, 2.5 ml, 26.8 mmol) for 6 hours. The volatiles were removed in vacuo, water and ice were added. The resulting solid was filtered, washed with water and dried to afford 4-chlorothieno[2,3-c]quinoline-7-carbonitrile as a light brown solid (1.18 g, 90% yield). LCMS (ES)>95% pure, m/z 245 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br)[CH3:3].CC1(C)C(C)(C)OB([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>C1(C)C=CC=CC=1.CCCCO.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>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[CH3:3]
Reactant: CN(C)Cc1ccccc1Br
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
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: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: O
Product: CN(C)Cc1ccccc1-c1ccc(N)cc1
Yield: 51.8 %

Procedure:
To a solution of 2-dimethylaminomethyl-bromobenzene (588 mg, 2.75 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (560 mg, 2.56 mmol) in toluene (10 mL) and n-BuOH (3 mL), Cs2CO3 (2.50 g, 7.67 mmol) in H2O (5 mL) was added, followed by addition of Pd(Ph3P)4 (200 mg, 0.17 mmol, 6%). The mixture was then heated at reflux for 4 h. EtOAc and H2O were added. The organic layer was separated, filtered, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel flash column using 50% EtOAc/hexanes (containing 1% TEA) as eluent to give a solid (300 mg). MS 182.0 (M—Me2N).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].[NH:18]1[CH2:25]CC[C@H:19]1[C:20](O)=[O:21]>CS(C)=O.CC(=O)OCC.O.[Cu]I>[OH:21][CH:20]1[CH2:19][N:18]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:25]1
Reactant: COC(=O)c1cccc(I)c1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cccc(N2CC(O)C2)c1
Temperature: 90 °C
Yield: 164.3 %

Procedure:
To a solution of methyl 3-iodobenzoate (4.5 g, 17.2 mmol) in DMSO (30 mL) was added 3-azetidin-3-ol hydrogen chloride salt (1.3 g, 11.8 mmol), Cs2CO3 (9.5 g, 29.2 mmol), CuI (446 mg, 2.3 mmol) and L-proline (540 mg, 4.7 mmol) and then the mixture was heated at 90° C. for 18 h under argon atmosphere. The solution was diluted with EA and water and the organic layer was washed with brine three times, concentrated under reduced pressure and purified by CC (PE/EA=2:1) to give compound 3a (1.6 g, 66%) as a yellow solid.
Reaction SMILES: Cl.C[O:3][C:4](=O)[C@H:5]([CH3:7])[NH2:6].[NH2:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[NH2:14].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>B([O-])([O-])[O-]>[NH2:6][C@H:5]([C:4]([NH:9][C@H:10]([C:16]([OH:18])=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[NH2:14])=[O:3])[CH3:7]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [O-]B([O-])[O-]
Product: C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)O

Procedure:
3 μl of the same enzyme fraction as used in Example 5 was added to 100 μl of 100 mM borate buffer (pH 9.0) containing 100 mM L-alanine methyl ester hydrochloride, 200 mM L-glutamine and 10 mM EDTA, and allowed to react at 18° C. As a result, as shown in FIG. 3, 83 mM L-alanyl-L-glutamine (L-Ala-L-Gln) was formed in the case of an enzyme-added lot, and the concentration of by-product L-Ala-L-Ala-L-Gln was 1.3 mM. On the other hand, there was scarcely any production of L-Ala-L-Gln observed in an enzyme-non-added lot, and L-Ala-L-Gln production was only about 0.07 mM after reaction for 120 minutes.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1.[CH3:21][N:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:26]=1[C:32]([F:35])([F:34])[F:33])[CH3:23]>C(Cl)Cl.CO>[CH3:23][N:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:17](=[O:19])[CH2:16][C:13]2[CH:14]=[CH:15][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:11][C:12]=2[CH3:20])=[CH:27][C:26]=1[C:32]([F:33])([F:35])[F:34])[CH3:21]
Reactant: CN(C)Cc1ccc(N)cc1C(F)(F)F
Reactant: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)Nc1ccc(CN(C)C)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 7 but using (4-imidazo[4,5-b]pyridin-3-yl-2-methyl-phenyl)-acetic acid (Step 60.1) and 4-dimethylaminomethyl-3-trifluoromethyl-phenylamine (disclosed in WO2005/051366). Title compound: ES-MS: 468.2 [M+H]+; tR=2.97 min (System 1); Rf=0.37 (CH2Cl2/MeOH, 9:1+0.1% NH3aq).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])#[CH:2].S(Cl)([Cl:14])=O>>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:14])=[O:7])#[CH:2]
Reactant: C#Cc1cccc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: C#Cc1cccc(C(=O)Cl)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Air in a 20 ml Schlenk tube was replaced by Ar gas and 1.02 g (7 mmol) of m-ethynylbenzoic acid and 5 g (42 mmol) of thionyl chloride were added to the tube and the mixture was stirred at 50° C. for 2 hours and then excess thionyl chloride was removed by distillation under reduced pressure to obtain m-ethynylbenzoyl chloride. To the m-ethynylbenzoyl chloride obtained was added a solution having 2.44 g (14.4 mmol) of diphenylamine dissolved in 7 ml of dichloromethane under ice-cooling and then the resultant mixture was stirred at room temperature for one hour. After completion of the stirring, dichloromethane was removed by distillation under reduced pressure and 35 ml of water was added to the resultant residue. The mixture was extracted with 35 ml of ethyl acetate, the extract was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure using an evaporator. The resultant crude reaction product was purified by column chromatography (hexane/AcOEt10/1) using silica gel to obtain 0.7 g of 3-ethynyl-N,N-diphenylbenzamide which is a desired product as pale yellow liquid. (Yield: 35%)
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:33])[CH2:7][O:8][CH2:9][C:10]1[CH:32]=[C:13]2[C:14]([C:18](=[O:31])[NH:19][CH2:20][C:21]34[CH2:30][CH:25]5[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]5)[CH2:22]3)[CH2:28]4)=[CH:15][CH:16]=[CH:17][N:12]2[N:11]=1)C>CCO>[C:21]12([CH2:20][NH:19][C:18]([C:14]3[C:13]4[N:12]([N:11]=[C:10]([CH2:9][O:8][CH2:7][C:6]([OH:33])=[O:5])[CH:32]=4)[CH:17]=[CH:16][CH:15]=3)=[O:31])[CH2:30][CH:25]3[CH2:24][CH:23]([CH2:29][CH:27]([CH2:26]3)[CH2:28]1)[CH2:22]2
Reactant: CCOC(=O)COCc1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COCc1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Reaction time: 18 h

Procedure:
3 M Aq. KOH (50 μL) is added to a solution of {4-[(adamantan-1-ylmethyl)carbamoyl]-pyrazolo[1,5-a]pyridin-2-ylmethoxy}acetic acid ethyl ester (11 mg, 25 μmol) and EtOH (250 μL). After 18 h, the volatiles are removed under reduced pressure. The residue is diluted with H2O (0.3 mL) and then acidified with 1 M aq. HCl. The title compound is collected by filtration. 1H NMR (400 MHz, ((CD3)2SO) δ: 8.74 (d, 1H), 8.42 (bs, 1H), 7.62 (d, 1H), 6.93 (t, 1H), 6.84 (s, 1H), 4.70 (s, 2H), 4.08 (s, 2H), 2.99 (d, 2H), 1.86-2.00 (m, 3H), 1.48-1.73 (m, 12H). LC-MS m/z (M+H+): 398.3; RT=1.26.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[C:16]([O:20][C:21](ON=C(C1C=CC=CC=1)C#N)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CO>[NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:3]1
Reactant: NC1CCNC1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(N)C1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
In methanol (30 ml), 3-aminopyrrolidine (0.54 g) was dissolved under ice cooling, followed by the addition of diisopropylethylamine (720 μl) and 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (0.84 g). The resulting mixture was gradually heated to room temperature and stirred for 11 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane˜5% methanol-dichloromethane), whereby the title compound (0.59 g, 94%) was obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16]([C:18]1([C@H:21]2[CH2:25][N:24]([C@H:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH3:27])[C:23](=[O:34])[C@@H:22]2[F:35])[CH2:20][CH2:19]1)=[O:17])[CH3:14].C(C1C=CC=C(C(C)(C)C)C=1O)(C)(C)C.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:13]([O:15][C:16]([C:18]1([C@H:21]2[CH2:25][N:24]([C@H:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH3:27])[C:23](=[O:34])[C@H:22]2[F:35])[CH2:19][CH2:20]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@@H]2F)CC1
Agent: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@H]2F)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 74.3 %

Procedure:
Under a nitrogen atmosphere, diisopropylamine (7.22 ml, 51.52 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml) to which, after cooling to -78° C., was subsequently added dropwise an n-hexane solution of 1.68 M n-butyl lithium (28.1 ml, 47.21 mmol) over a period of 15 minutes. After 10 minutes of stirring at 0° C. and subsequent cooling to -78° C., to the resulting reaction solution was added dropwise an anhydrous tetrahydrofuran solution (40 ml) of 4-(S)-(1-ethoxycarbonylcyclopropyl)-3-(R)-fluoro-1-[1-(S)-phenylethyl]-2-pyrrolidone (13.72 g, 42.96 mmol) over a period of 20 minutes. After an additional 20 minutes of stirring at -78° C., to the reaction solution was added dropwise 2,6-di-tert-butylphenol (10.63 g, 51.52 mmol) dissolved in anhydrous tetrahydrofuran (40 ml) over a period of 20 minutes. The reaction solution was stirred at -78° C. for 10 minutes and then warmed to room temperature. While cooling in an ice bath, the resulting reaction solution was mixed with a saturated ammonium chloride aqueous solution (200 ml), the organic layer was separated and then the aqueous layer was extracted with diethyl ether (200 ml×2). The organic layers were combined, washed with water (400 ml×2) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane: ethyl acetate=3:1, to thereby obtain 10.19 g (74.2%) of the title compound as a colorless oil.