Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[NH:22][CH:23]=[CH:24]4)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a stirred suspension of 5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.35 g, 0.73 mmol) and 1H-indol-5-ylboronic acid (0.14 mg, 0.88 mmol) in CH3CN (10 mL) was added 1 M Na2CO3 (10 mL) followed by bis(triphenylphosphine)palladium(II) dichloride (0.050 g, 0.071 mmol). The resulting mixture was stirred overnight at 60° C. After the mixture was evaporated to dryness in vacuo, it was dissolved in DMF (3 mL), absorbed onto Celite, and dried. The residue was purified via silica gel chromatography using CH2Cl2 as the eluent to obtain the title compound (0.26 g, 76%). 1H NMR (CDCl3, 300 MHz): δ 8.48 (d, J=2.1 Hz, 1H), 8.27 (bs, 1H), 8.26 (d, J=2.4 Hz, 1H), 8.08 (d, J=8.1 Hz), 7.85 (s, 1H), 7.81 (m, 1H), 7.50 (d, J=8.7 Hz, 1 H), 7.37 (dd, J=1.8, 8.4 Hz), 7.30 (m, 3H), 6.63 (m, 1 H), 2.39 (s, 3H); MS ESI (m/z): 466.2/468.2 (M+1)+, calc. 465.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:15])[CH:4]=1.S(Cl)(Cl)=O.[CH3:20]O>>[CH3:1][O:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:6]([C:7]([O:9][CH3:20])=[O:8])=[C:5]([CH3:15])[CH:4]=1
Reactant: CO
Reactant: COc1cc(C)c(C(=O)O)cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1C
Yield: 89 %

Procedure:
To 4-methoxy-2-methyl-5-nitrobenzoic acid (1.06 g, 5 mmol) in methanol (10 mL) was added thionyl chloride (0.36 mL, 5 mmol) dropwise. The mixture was heated to reflux for 5 h and then allowed to cool. The solvent was removed in vacuo and the residue was partitioned between DCM (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give methyl 4-methoxy-2-methyl-5-nitrobenzoate (998 mg, 89%) as an off-white solid. LCMS (10 cm_ESCI_Bicarb_MeCN): [M+H]+=226 at 3.25 min. 1H NMR (400 MHz, CDCl3): δ 8.56 (s, 1H), 6.91 (s, 1H), 4.01 (s, 3H), 3.90 (s, 3H), 2.71 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24](O)=[O:25])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24]([N:27]4[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]4)=[O:25])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Reactant: OCCC1CCNCC1
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1cc(C(=O)N2CCC(CCO)CC2)n[nH]1

Procedure:
The title compound was prepared as in the previous Example starting from 5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylic acid and 4-piperidine ethanol. The crude product was purified by flash chromatography using CH2Cl2-MeOH as a gradient eluent (100:0-95:5). 1H NMR (400 MHz, CDCl3): 1.27 (3H, m), 1.57 (2H, m), 1.85 (3H, m), 2.81 (1H, m), 3.01 (2H, t), about 3.21 (1H, m), 3.76 (4H, m), about 4.41 (1H, m), about 4.67 (1H, m), 6.20 (1H, d), 6.59 (1H, d), 7.02 (1H, s), 7.29 (1H, broad s), 7.40 (1H, distorted d), 7.43 (1H, distorted dd), 7.75 (1H, d), 11.4 (1H, broad s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](OS(C(F)(F)F)(=O)=O)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:30][C:31]([F:46])([F:45])[C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)C.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][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:34]4[CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=[C:32]([C:31]([F:30])([F:46])[F:45])[CH:33]=4)[C:15]=3[O:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(OS(=O)(=O)C(F)(F)F)c3O2)cc1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
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: CCOCC
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)c3O2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 65.7 %

Procedure:
To a solution of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.0 g, 2.21 mmol) and 3,5-bis(trifluoromethyl)phenylboronic acid (0.86 g, 3.32 mmol) in dioxane (25 mL) heated to 90° C. was added tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.22 mmol) and potassium phosphate (0.94 g, 4.42 mmol). The reaction mixture was allowed to stir at 90° C. for 12 h. The reaction mixture was allowed to cool and was diluted with diethyl ether (100 mL), filtered (celite), and the solvent was removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, ethylacetate:hexanes 1:9) afforded 0.75 g (66%) of (±)-{7-[3,5-bis(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.49 (silica, ethyl acetate:hexanes 1:3); mp 100-105° C.; Anal. calcd. for C24H18F6O4S2: C, 55.82; H, 3.51. Found: C, 55.75; H, 3.35.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([O:12][CH2:13][CH3:14])=[C:10](Cl)[N:9]=[C:8]([Cl:16])[N:7]=1)=[O:5])[CH3:2].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:11]([O:12][CH2:13][CH3:14])=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:9]=[C:8]([Cl:16])[N:7]=1)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1nc(Cl)nc(Cl)c1OCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(Cl)nc(N2CCOCC2)c1OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
2,6-dichloro-5-ethoxy-pyrimidine-4-carboxylic acid ethyl ester (2 g, 1 eq.) was stirred in toluene (80 ml) and a solution of morpholine (0.73 ml, 1.1 eq.) in toluene (20 ml) was added dropwise in about 10 minutes at −10˜0° C., after stirring the resulting solution for 3 h at r.t. Water was added and extracted with EA. The combined organic layers were washed with brine, dried and evaporated in vacuo. Purification by flash chromatography gave a product (1.79 g, 75%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:18]=[C:17]3[C:11]([CH2:12][CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:16]3)=[N:10]2)=[CH:5][CH:4]=1)#N.[OH-:26].[Na+].Cl.C(OCC)(=O)C.[OH2:35]>C(O)C>[CH3:24][C:22]([O:21][C:19]([N:14]1[CH2:15][CH2:16][C:17]2=[CH:18][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]([OH:35])=[O:26])=[CH:8][CH:7]=3)[N:10]=[C:11]2[CH2:12][CH2:13]1)=[O:20])([CH3:23])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C#N)cc3)nc2CC1
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C(=O)O)cc3)nc2CC1
Temperature: 25 °C

Procedure:
To 1,1-dimethylethyl 2-(4-cyanophenyl)-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 10) (750 mg, 2.22 mmol) in ethanol (7.5 ml) was added 10% sodium hydroxide solution (7.5 ml), and the reaction heated at reflux, under argon, for 5 hours. 10% sodium hydroxide solution (10 ml) was added and stirring continued at reflux, under argon, overnight. The reaction was cooled to room temperature and the solvent partially reduced in vacuo. The resulting crude product was dissolved in water and acidified with 5N hydrochloric acid. Ethyl acetate was added, and the product extracted into ethyl acetate (×3). The combined organic fractions were dried over magnesium sulphate and solvent evaporated in vacuo to afford the title compound (D23). MS (ES−) m/e 356 [M−H]−.
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:9](O)=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([N:24](CC)CC)C.C(Cl)(=O)C(C)(C)C>O1CCCC1>[NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:9]([NH2:24])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCN(CC)CC
Reactant: O=C(N[C@H](C(=O)O)c1ccccc1)OCc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
27.6 g (97 mmoles) of Z-L-Phg-OH are dissolved in 300 ml of dry tetrahydrofuran, and 13.55 ml (97 mmoles) of triethylamine are added to the solution. The mixture is cooled to -10° C., and 12.1 ml (97 mmoles) of pivaloyl chloride are introduced. The suspension of the mixed anhydride is stirred for 10 minutes at -10° C., thereafter cooling is stopped and ammonia is bubbled through the suspension for one hour. Next day the reaction mixture is evaporated, and the residue is processed as described for the D enantiomer. 18.90 g (68.7%) of Z-L-Phg-NH2 are obtained; m.p.: 172°-173° C., Rf4 =0.75, [α]D =+80.7° (c=1.0, in dimethyl formamide).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([C:33](Cl)=[O:34])=[C:31]([CH3:36])[N:30]=[CH:29][CH:28]=2)=[C:23]([F:37])[C:22]=1[O:38][CH3:39]>C(Cl)Cl>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([C:33]([NH:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:34])=[C:31]([CH3:36])[N:30]=[CH:29][CH:28]=2)=[C:23]([F:37])[C:22]=1[O:38][CH3:39]
Reactant: COc1c(Cl)ccc(-c2ccnc(C)c2C(=O)Cl)c1F
Reactant: COc1ccc(CN)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)c2c(-c3ccc(Cl)c(OC)c3F)ccnc2C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 34.9 %

Procedure:
To a stirred solution of (4-methoxyphenyl)methanamine (0.437 g, 3.18 mmol) in CH2Cl2 (25 mL) was added DIEA (0.556 mL, 3.18 mmol) and the reaction mixture was stirred at 0° C. for 15 min. 4-(4-chloro-2-fluoro-3-methoxyphenyl)-2-methylnicotinoyl chloride (1 g, 3.18 mmol) (prepared by treatment of carboxylic acid with thionyl chloride) dissolved in 10 mL of DCM was then added to the reaction mixture and the reaction was stirred at rt for 10 h. The reaction was quenched by addition of water (50 mL) and the solution was extracted with DCM (2×50 mL). The combined organic layers were washed with brine solution 50 mL, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate in hexanes as eluant to yield 4-(4-chloro-2-fluoro-3-methoxyphenyl)-N-(4-methoxybenzyl)-2-methylnicotinamide (800 mg, 1.109 mmol, 35% yield) as a brown oil. LC/MS (ESI) m/e 415.1 [(M+H)+, calcd for C22H21ClFN2O3 415.1]; LC/MS retention time (method D): tR=0.78 min.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.CN(C)P(N(C)C)(N(C)C)=O.[CH:24]1([C:33]([O:35][CH3:36])=[O:34])[CH2:28][CH2:27][CH:26]([C:29]([O:31][CH3:32])=[O:30])[CH2:25]1.BrCCCl>C1COCC1>[C:26]12([C:29]([O:31][CH3:32])=[O:30])[CH2:25][C:24]([C:33]([O:35][CH3:36])=[O:34])([CH2:1][CH2:2]1)[CH2:28][CH2:27]2
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C1CCC(C(=O)OC)C1
Agent: [Li]CCCC
Solvent: ClCCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C12CCC(C(=O)OC)(CC1)C2
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
A 22-L, 3-neck, round bottom flask was equipped with a J-KEM temperature controller, a mechanical stirrer, a nitrogen inlet, and an addition funnel. The flask was flushed with nitrogen then charged with anhydrous THF (5 L) and diisopropylamine (731 mL, 5.219 mol). The solution was cooled to −20° C. using a dry ice/acetone bath. The stirring mixture was slowly treated with 1.6 M n-butyllithium in hexanes (3.02 L, 4.833 mol) via cannula over 1 h maintaining the temperature between −20° C. and −27° C. The reaction mixture was cooled to −40° C. and hexamethylphosphoramide (2.7 L, 16.317 mol) was slowly added via addition funnel over 40 min. The reaction mixture was cooled to −73° C. and dimethyl cyclopentane-1,3-dicarboxylate (360 g, 1.933 mol) dissolved in anhydrous THF (2 L) was slowly added via addition funnel over 2 h. The reaction mixture was warmed to −10° C. and stirred at that temperature for 30 min, then cooled to 70° C. and treated with 1-bromo-2-chloroethane (267 mL, 3.209 mol) via addition funnel over 4 h. The reaction mixture was allowed to slowly warm to room temperature over 12 h and then was quenched with saturated aqueous ammonium chloride (2 L) over 90 min. The reaction mixture was diluted with hexane (2 L), the layers were separated, and the aqueous layer was further extracted with hexane (3×2 L). The combined organic layers were washed with brine (2×1 L), dried over sodium sulfate, filtered, and concentrated to a brown oil. The crude product was purified by silica gel purification (0-10% ethyl acetate/hexane). The product containing fractions were concentrated to near dryness and diluted with hexanes. The resulting crystalline solids were filtered and washed with hexane (200 mL) providing pure product as a clear crystalline solid. Additional batches of product were obtained from the filtrate in a similar manner. All product batches were combined to provide 208 g (51%) of dimethyl bicyclo[2.2.1]heptane-1,4-dicarboxylate as a clear crystalline solid. 1H NMR (500 Hz, CDCl3) δ ppm 3.68 (s, 6H), 2.03 (d, J=6.4 Hz, 4H), 1.90 (s, 2H), 1.67 (d, J=7.0, 4H).
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[S:58][CH:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>CN(C=O)C.O>[Cl:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[S:58][CH:59]1[CH2:64][CH2:63][N:62]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:61][CH2:60]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Clc1ccccc1SC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Sc2ccccc2Cl)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.04 g, 0.00014 mol) in DMF (1 mL) was added DIPEA (0.05517 g, 0.00043 mol), HOBt (0.023 g, 0.00017 mol) and EDCI.HCl (0.0326 g, 0.00017 mol) at ambient temperature. After 2 minutes 4-(2-chloro-phenylsulfanyl)-piperidine hydrochloride (0.0449 g, 0.00017 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.054 g (84%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-chlorophenylsulfanyl)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 455.12 (M+1)+, 83.96%, 1H NMR (DMSO-d6): δ 13.65 (s, 1H), 8.1 (s, 1H), 7.8 (d, 2H), 7.5 (m, 4H), 7.38 (t, 2H), 7.24 (t, 2H), 7.15 (s, 1H), 4.2 (m, 3H), 3.85 (m, 1H), 3.65 (m, 1H), 3.25 (m, 1H), 3.0 (m, 1H), 2.0 (m, 2H), 1.56 (m, 1H), 1.4 (m, 1H).
Reaction SMILES: C1C2C(COC([N:18]=[C:19]=[S:20])=O)C3C(=CC=CC=3)C=2C=CC=1.Cl.[CH2:22]([O:24][C:25](=[O:35])[C:26]([CH3:34])([CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:27])[CH3:23].C(=O)([O-])O.[Na+].N1CCCCC1>C(Cl)(Cl)Cl.C(OCC)C>[CH2:22]([O:24][C:25](=[O:35])[C:26]([CH3:34])([CH:28]1[CH2:33][CH2:32][N:31]([C:19](=[S:20])[NH2:18])[CH2:30][CH2:29]1)[CH3:27])[CH3:23]
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: CCOC(=O)C(C)(C)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)C1CCN(C(N)=S)CC1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a solution of 9-fluorenylmethoxycarbonylisothiocyanate (2.62 g, 9.32 mmol) in chloroform (20 ml), a solution of 2-methyl-2-piperidin-4-yl-propionic acid ethyl ester hydrochloride (2.27 g, 9.61 mmol) in chloroform (10 ml) and sodium hydrogen carbonate (4.03 g, 48.0 mmol) were added and the mixture was stirred at room temperature. Further, piperidine (30 ml) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated in vacuo, and the solid obtained by adding diethyl ether was collected by filtration. The solid was dissolved in N,N-dimethylformamide (20 ml) and piperidine (20 ml) was added and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and the solution was extracted with ethyl acetate. The organic layer was washed with a saturated brine and dried over sodium sulfate, and the residue obtained by vacuum concentration was purified by silica gel chromatography (n-hexane:ethyl acetate) and the title compound (2.4 g, 98%) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]#[N:12].[C:13]([O-:16])(=[O:15])C.[Na+].[CH3:18]N(C)C=O>CO>[C:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:13]([O:16][CH3:18])=[O:15])[CH:3]=2)[NH:7][N:6]=1)#[N:12]
Reactant: CN(C)C=O
Reactant: N#Cc1n[nH]c2ccc(Br)cc12
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2[nH]nc(C#N)c2c1
Yield: 68 %

Procedure:
A suspension of 5-bromo-3-cyanoindazole (3 g, 13.51 mmol) palladium dichloride 1,1′-bis(diphenylphosphino)ferrocene (1.76 g, 2.16 mmol), sodium acetate (3.32 g, 40.5 mmol), dimethylformamide (1 mL) in methanol (100 mL) was degassed, and kept under carbon monoxide (80 psi) pressure at 80° C. in a autoclave for 16 hours. The mixture was diluted with water (50 mL), filtered through Celite® bed and the filtrate was concentrated. The obtained residue was acidified with 10% citric acid solution and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by column chromatography (100-200 mesh silica gel) using 10% ethyl acetate in chloroform as eluent to afford methyl 3-cyano-1H-indazole-5-carboxylate (1.8 g, 68%) as a solid. 1HNMR (CDCl3) δ ppm 10.8 (s, 1H), 8.7 (s, 1H), 8.22 (d, 1H), 7.64 (d, 1H), 4.0 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH3:11][O:12][C:13](Cl)=[O:14].Cl>O>[CH3:11][O:12][C:13]([NH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])=[O:14]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
A mixture of (S)-2-amino-3-methyl-butyric acid (10 g, 85 mmol), NaOH (10.3 g, 255 mmol) in water (100 mL) was treated with methylchloridocarbonate (8 g, 85 mmol) at 0° C. The reaction mixture was stirred for 24 h at room temperature and then 5 N aqueous HCl was added to the reaction mixture to adjust pH to 4. The mixture was filtered through a pad of Celite to give the product (10 g, 67% yield) as a white solid. 1H NMR(CH3OD, 400 MHz) δ (ppm) 4.05 (d, 1H), 3.65 (s, 3H), 2.14 (m, 1H), 0.95 (m, 6H).
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23](OCC)=[O:24])[C:5]1=[O:28])#[N:2].[CH3:29][O:30][CH2:31][CH2:32][NH2:33]>>[C:1]([CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:33][CH2:32][CH2:31][O:30][CH3:29])=[O:24])[C:5]1=[O:28])#[N:2]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC#N)c1=O
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC#N)c1=O
Yield: 40 %

Procedure:
In a similar manner to that described in example 196, from ethyl 1-(cyanomethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (33 mg, 0.087 mmol) and [2-(methyloxy)ethyl]amine (0.05 mL) was prepared 1-(cyanomethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(methyloxy)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (14 mg, 40% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 9.95 (s, 1 H), 8.62 (s, 1 H), 7.38 (s, 1 H), 7.18-7.15 (m, 2 H), 7.05-7.01 (m, 2 H), 5.12 (s, 2 H), 4.17 (s, 2 H), 3.63 (m, 2 H), 3.57 (m, 2 H), 3.41 (s, 3 H); MS m/z 411 (M+1).
Reaction SMILES: [OH-].[Na+:2].[SH:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[O:6].C(CN(CC([O-])=O)CC(O)=O)N(CC(O)=O)CC([O-])=[O:25].[Na+].[Na+]>O1CCCC1>[OH2:6].[OH2:25].[Na+:2].[SH:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[C:11]([NH:13][CH2:14][C:15]([O-:17])=[O:16])=[O:12])=[O:6]
Reactant: O=C(O)CNC(=O)c1cccc(NC(=O)CS)c1
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O
Product: O=C([O-])CNC(=O)c1cccc(NC(=O)CS)c1
Temperature: 0 °C
Yield: 66 %

Procedure:
An aqueous solution of 10% sodium hydroxide (7.5 ml., 0.01875 mole) is slowly added to a mixture of N-[3-(mercaptoacetylamino)benzoyl]glycine (5 g., 0.0186 mole) and 5 mg. of disodium edetate in 60 ml. of tetrahydrofuran with cooling at ice water temperature. The mixture stirred and equilibrated to room temperature first provides a complete solution and subsequently a solid precipitate which is stirred for an additional 0.5 hr. and filtered. The collected solid is washed with three 20 ml. portions of tetrahydrofuran and then dried under vacuum over calcium chloride to provide 4 g. (66% yield) of N-[3-(mercaptoacetylamino)benzoyl]-glycine sodium salt dihydrate, m.p. 108°-136.0° C. (dec.).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][CH2:10][C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[CH:19]=1>C(Cl)Cl>[Cl:1][C:19]1[N:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[CH2:10][Cl:9]
Reactant: ClCc1cn2ccccc2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: ClCc1nc2ccccn2c1Cl
Reaction time: 2 h
Yield: 90.4 %

Procedure:
N-Chloro succinimide (329 g, 2.46 mmol) was added to a solution of 2-(chloromethyl)imidazo[1,2-a]pyridine (450 mg, 2.2 mmol) in DCM (15 ml) at RT under an atmosphere of nitrogen. Stirring was continued for 2 h (reaction was monitored by TLC) upon which the reaction mixture was diluted with DCM and washed with water and brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 10% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 3-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (400 mg, 76%,) as Off-white solid. 1H NMR: 200 MHz, CDCl3: δ 8.4 (d, 1H), 7.7 (d, 1H), 7.5 (t, 1H), 7.1 (t, 1H), 4.85 (s, 2H). MS: [M+H]+: m/z=201.8. HPLC: (98.3%, Condition-A).