Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-])=O)=[C:6]([CH:18]=1)[O:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11].O.O.Cl[Sn]Cl.O.C(=O)(O)[O-]>C(O)C.C(OCC)(=O)C>[NH2:19][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][C:6]=1[O:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccccc1Oc1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccccc1Oc1cc(Cl)ccc1N
Temperature: 80 °C
Reaction time: 3 h
Yield: 52.9 %

Procedure:
A mixture of compound 50 (4.40 g, 14.30 mmol) and SnCl2.2H2O (16.13 g, 71.5 mmol) in ethanol (100 mL) was stirred at 80° C. for 3 h. Water and saturated bicarbonate solution (˜250 ml) was added (very effervescent). The reaction mixture was diluted with ethyl acetate and then Celite® was added and the mixture was stirred for 15 min then filtered. The filtrate was extracted with ethyl acetate twice, and the organic extract was dried over Na2SO4, filtered and concentrated. The crude was purified by flash chromatography, dry loaded with THF onto 80 g SiO2 and eluted with 0% to 50% ethyl acetate in hexanes to afford title compound 51 (2.10 g, 51%) as a beige solid. LRMS (ESI): (calc) 277.05 (found) 278.2 (MH)+. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.89 (dd, J=7.9, 1.7 Hz, 1H), 7.46 (ddd, J=7.9, 7.4, 1.8 Hz, 1H), 7.17 (td, J=7.6, 1.2 Hz, 1H), 6.97 (dd, J=8.3, 0.9 Hz, 1H), 6.94 (dd, J=8.4, 2.3 Hz, 1H), 6.79 (d, J=2.3 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 4.05 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=O)[C:5]2[C:6]([CH:29]=1)=[N:7][N:8]([CH2:10][C:11]([NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)([C:13]#[N:14])[CH3:12])[N:9]=2.[CH3:32][NH:33][CH3:34].[B][B][B][B][B][B][B][B][B][B]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:30][N:33]([CH3:34])[CH3:32])[C:5]2[C:6]([CH:29]=1)=[N:7][N:8]([CH2:10][C:11]([NH:15][C:16](=[O:28])[C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:19][CH:18]=1)([C:13]#[N:14])[CH3:12])[N:9]=2
Reactant: CC(C#N)(Cn1nc2cc(Cl)cc(C=O)c2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: CNC
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CN(C)Cc1cc(Cl)cc2nn(CC(C)(C#N)NC(=O)c3ccc(OC(F)(F)F)cc3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a solution of N-[2-(6-Chloro-4-formyl-2H-benzotriazol-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (0.18 g) in methanol (3 mL) was added a 2 molar methanolic solution of dimethylamine (0.24 mL). After one hour stirring at room temperature, decaborane was added (15 mg) and the mixture stirred one more hour before being concentrated under reduced pressure. The residue was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (100 mg, 52%). Rf=0.2 (3:1 EA/heptane). MS (ES): M/Z [M+H]=481. 1H NMR: (400 MHz, CHLOROFORM-d): 1.81 (s, 3H), 2.31 (s, 6H), 3.75 (d, J=13.5 Hz, 1H), 3.92 (d, J=13.5 Hz, 1H), 5.12 (d, J=13.8 Hz, 1H), 5.52 (d, J=13.7 Hz, 1H), 7.32 (d, J=8.1 Hz, 2H), 7.36 (s, 1H), 7.81 (d, J=1.7 Hz, 1H) and 7.95 (br. d, J=8.7 Hz, 3H). 19F NMR (376 MHz, CHLOROFORM-d): −58.1 (s, 3F).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][C:10](=O)[CH2:11][O:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:14]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH:10]([N:17]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:15][CH3:16])[CH2:11][O:12][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCCNCCC
Reactant: COc1cccc2c1CC(=O)CO2
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCN(CCC)C1COc2cccc(OC)c2C1

Procedure:
A mixture of 6.4 g of 5-methoxy-3,4-dihydro-2H-[1]-benzopyran-3-one, 30 ml of dipropylamine, 0.5 ml of trifluoroacetic acid and 200 ml of toluene is refluxed in a Dean-Stark apparatus for 3 hours. The solution concentrated in vacuo and the residue is added to a solution of 7 g of sodium cyanoborohydride in 160 ml of ethanol and 40 ml of acetic acid. After 15 minutes at room temperature most of the solvent is removed in vacuo. The residue is dissolved in 6N hydrochloric acid and washed with ether. The aqueous layer is made basic and the product is extracted with ether. The aqueous layer is made basic and the product is extracted with ether. The ether layer is dried over magnesium sulfate and the solvent is removed in vacuo, to afford 5-methoxy-3,4-dihydro-N,N-dipropyl-2H-[1]-benzopyran-3-amine which is treated with ethanolic hydrochloric acid to afford 5-methoxy-3,4-di-hydro-N,N-dipropyl-2H-[1]-benzopyran-3-amine hydrochloride, m.p. 219°-221°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][N:29]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[S:38]([CH3:37])(=[O:40])=[O:39])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCNCc4ccccc4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCN(Cc4ccccc4)S(C)(=O)=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-{4′-[4-(2-benzylamino-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and methane sulfonyl chloride.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:21][C:20](=[O:22])[CH:19]=[C:18]([OH:23])[CH2:17]2)=[CH:12][CH:11]=1)(C)(C)C.[C:34]([C:38]1[CH:43]=[C:42]([O:44][CH2:45][CH2:46][O:47][Si](C(C)(C)C)(C)C)[C:41]([CH3:55])=[CH:40][C:39]=1[S:56]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:37])([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+].Cl>CO.CN(C=O)C>[C:34]([C:38]1[CH:43]=[C:42]([O:44][CH2:45][CH2:46][OH:47])[C:41]([CH3:55])=[CH:40][C:39]=1[S:56][C:19]1[C:20](=[O:22])[O:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][OH:6])=[CH:11][CH:12]=2)([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:17][C:18]=1[OH:23])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(C2(CCc3ccccc3)CC(O)=CC(=O)O2)cc1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OCCO[Si](C)(C)C(C)(C)C)cc2C(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccccc3)(c3ccc(OCCO)cc3)OC2=O)c(C(C)(C)C)cc1OCCO

Procedure:
To a round bottom flask equipped with a magnetic stirrer were added 6-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenyl} -4-hydroxy-6-phenethyl-5,6-dihydro-pyran-2-one (prepared in Example SS; 0.260 g, 0.555 mmol), toluene-4-thiosulfonic acid S-{2-tert-butyl-4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-methyl-phenyl) ester (prepared in Example PPP; 0.282 g, 0.555 mmol), K2CO3 (0.346 g, 2.50 mmol), and DMF (5 mL), as described in General Method 9. The mixture was stirred at room temperature for 2 days at which time MeOH (150 mL) was added and the solution taken to pH 3.0 with conc. HCl. The reaction was quenched with H2O (500 mL) and extracted with EtOAc. The organics were dried over MgSO4 and concentrated; the residue was taken up in a small amount of EtOAc and triturated with hexane. The solid was filtered and dried under high vacuum to yield the title compound, m.p. >190° C. (dec.). 1H NMR (DMSO-d6) δ 1.45 (s, 9 H), 1.68 (s, 3 H), 2.22 (br m, 4 H), 2.51 (br m, partially obscured by DMSO, 2 H), 3.34 (d of ABX q, partially obscured by H2 0, 1 H), 3.40 (d of ABX q, partially obscured by H2O, 1 H), 3.67 (br m, 2 H), 3.72 (br m, 2 H)3.91 (t, 2 H), 3.98 (t, 2 H), 6.76 (s, 1 H), 6.96 (s, 1 H), 6.99 (d, 2 H), 7.08-7.22 (m, 1 H), 7.10 (d, 2 H), 7.24 (d, 2 H), 7.30 (d, 2 H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:2]=1.[O:16]1[CH2:18][CH:17]1[CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.[H-].[Na+]>CN(C)C=O>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[CH:2]=[CH:1][C:6]([O:7][CH2:18][CH:17]([OH:16])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:5][CH:4]=2)=[CH:10][CH:11]=1
Reactant: c1cncc(CCC2CO2)c1
Reactant: Oc1ccc(Oc2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1ccc(Oc2ccc(OCC(O)CCc3cccnc3)cc2)cc1
Yield: 14 %

Procedure:
Prepared according to the method described in Example 5 from 4,4'-dihydroxydiphenyl ether (1.68 g), (±)-3-(2-oxiranylethyl)pyridine (1.24 g) and sodium hydride (60% dispersion in oil; 0.319 g) in dimethylformamide (20 ml) at 100° C. for 2 hours to give the title compound as a white solid (0.41 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:18])[CH3:17])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[Br:19]Br>CCOCC.C(Cl)(Cl)Cl>[Br:19][CH2:17][C:16]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1)=[O:18]
Reactant: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Reaction time: 1 h

Procedure:
A mixture of (3,5-Di-t-butyl-4-hydroxyphenyl)ethanone (EXAMPLE 58, 800 mg) in ether (15 ml) and chloroform (10 ml) is cooled to 0° and then treated in a dropwise manner with a mixture containing 0. 17 ml of bromine dissolved in 5 ml of chloroform. The reaction mixture is allowed to warm to 20°-25° and stirred for 1 hr. Standard work-up gives the crude product (1.21 g) which is chromatographed on 180 g of silica gel. The column is packed and eluted with chloroform. An initial fraction of 200 ml is collected, followed by 7 ml fractions. Based on their TLC homogeneity, fractions 36-65 are combined and concentrated. Recrystallization from hexane gives the title compound, mp 105°-106°; IR (mineral oil) 3590, 2955, 2925, 2871, 2856, 1685, 1594, 1581, 1466, 1459, 1451, 1438, 1426, 1366, 1328, 1302, 1282, 1242, 1194, 1153, 1139, 1121, 860 and 615 cm-1 ; NMR (CDCl3 ; TMS) 7.88, 5.85, 4.40 and 1.47δ; CMR (CDCl3 ; TMS) 190.6, 159.0, 135.9, 126.8, 125.6, 34.2, 30.6 and 29.9δ; MS (m/z) M+ found=327, other ions at m/z 326, 311,233, 219, 203, 189, 175, 115, 101, 87, 57 and 40.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:17]([O:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:16]([Br:37])=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH2:5]([O:4][C:2]([NH:12][C:13]1[C:18]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[C:17]([O:26][S:27]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)(=[O:29])=[O:28])[C:16]([Br:37])=[CH:15][CH:14]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(Br)ccc(N)c2C(=O)OC(C)(C)C)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Oc2c(Br)ccc(NC(=O)OCc3ccccc3)c2C(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 99.1 %

Procedure:
Benzyl chloroformate (1.705 g) was added to a stirred solution of tert-butyl 6-amino-3-bromo-2-(4-methylbenzensulfonyloxy)-benzoate (Intermediate 50, 3.8 g) in pyridine (50 mL) with cooling in ice. The mixture was stirred for 1 hour and further benzyl chloroformate (1.70 g) was added. The mixture was stirred for a further 1 hour and further benzyl chloroformate (1.70 g) was added. After stirring for a further 30 minutes, the solution was concentrated in vacuo and the residue was dissolved in DCM and 1M hydrochloric acid and filtered through a phase separator. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15% to give tert-butyl 6-benzyloxycarbonylamino-3-bromo-2-(4-methylbenzenesulfonyloxyl)benzoate (4.91 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[F:16][CH2:17][C:18]([C:22]1[O:26][N:25]=[C:24]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[CH:23]=1)([CH3:21])[CH2:19][F:20].CCN(C(C)C)C(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[F:20][CH2:19][C:18]([C:22]1[O:26][N:25]=[C:24]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:6][CH:7]=2)[CH:23]=1)([CH3:21])[CH2:17][F:16]
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)Nc2cc(C(C)(CF)CF)on2)cc1
Temperature: 65 °C
Yield: 100.3 %

Procedure:
To a stirred solution of tert-butyl 4-aminophenylcarbamate (176 mg, 0.85 mmol) in 5 mL of THF was added phenyl 5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (250 mg, 0.85 mmol), DIEA (147 mL, 0.85 mmol), and DMAP (5.2 mg, 0.043 mmol). The resulting mixture was heated at 65° C. for 90 min. LC-MS indicated that the reaction was complete. The organic solvent was removed under reduced pressure and the residue was purified with silica gel column chromatography, eluting with 0-50% EtOAc in hexanes, to give tert-butyl 4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenylcarbamate (350 mg, 95%). LC-MS (ESI) m/z 411 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:13][C@H:14]1[C@@H:19]2[O:20]S(=O)O[C@@H:18]2[CH:17]=[C:16]([C:24]([O:26][CH3:27])=[O:25])[CH2:15]1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C=O)C.CCOC(C)=O>[C:5]([O:13][C@H:14]1[C@H:19]([OH:20])[C@@H:18]([N:1]=[N+:2]=[N-:3])[CH:17]=[C:16]([C:24]([O:26][CH3:27])=[O:25])[CH2:15]1)(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)C1=C[C@H]2OS(=O)O[C@H]2[C@H](OC(=O)c2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1=C[C@H](N=[N+]=[N-])[C@@H](O)[C@H](OC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
Sodium azide (2.3 g, 36.0 mmol) was added to a solution of Example 13F in DMF (30 mL). After stirring at room temperature overnight, the reaction mixture was diluted with EtOAc, washed with brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by flash chromatography using hexanes/ethyl acetate (3/2) to afford 1.36 g (36%) of the desired product as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:16]([O:18]CC)=[O:17])[CH:4]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:16]([OH:18])=[O:17])[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(CC)n(Cc2ccc(C)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(C(=O)O)nn1Cc1ccc(C)cc1
Temperature: 70 °C
Yield: 92.2 %

Procedure:
To a solution of ethyl 5-ethyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboxylate (Step 2, 1.85 g, 6.79 mmol) in ethanol (43 mL) was added NaOH (1N aq., 13.6 mL, 13.6 mmol), and the mixture was heated at 70° C. for 3 h. The organic solvent was evaporated under vacuum and the residue was acidified with HCl (3N aq.) at 0° C. until a white solid completely precipitated from solution. The solid was filtered, washed with water, and was dried in a vacuum oven to afford the title compound as a white solid (1.53 g, 92%): 1H NMR (500 MHz, CDCl3) 7.07 (d, 2H), 6.94 (d, 2H), 6.63 (s, 1H), 5.23 (s, 2H), 2.47 (quart, 2H), 2.30 (s, 3H), 1.17 (t, 3H); ES-MS m/z 245 (MH)+, 262 (M+NH4)+; HPLC RT (Method I) 4.12 min.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.BrC1C=CC=C(C)[N:32]=1.IC1C=CC=CC=1>>[CH3:29][C:28]1[N:32]=[C:24]([N:4]2[CH:5]=[CH:6][C:7]([CH2:9][N:10]3[C:14]([CH2:15][C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=4)=[CH:13][N:12]=[CH:11]3)=[CH:8][C:3]2=[O:2])[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cccc(Br)n1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Agent: Cl
Solvent: Ic1ccccc1
Product: Cc1cccc(-n2ccc(Cn3cncc3Cc3ccc(C#N)cc3)cc2=O)n1

Procedure:
4-[3-(6'-Methyl-2-oxo-2H-[1,2']bipyridinyl-4-ylmethyl)-3H-imidazol-4-ylmethyl]-benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 2-bromo-6-methylpyridine for the iodobenzene in Step 3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:28]1[CH:36]=[N:35][CH:34]=[CH:33][C:29]=1[C:30]([NH2:32])=[O:31].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.C(Cl)Cl.O.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>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:33]3[CH:34]=[N:35][CH:36]=[CH:28][C:29]=3[C:30](=[O:31])[NH2:32])=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)c1ccncc1Br
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCc2cc(-c3cnccc3C(N)=O)cnc21
Yield: 23.5 %

Procedure:
6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (100 mg, 0.36 mmol), 3-bromo-isonicotinamide (80 mg, 0.40 mmol), saturated Na2CO3 aqueous solution (1.0 mL) and Pd(PPh3)2Cl2 (24 mg, 0.034 mmol) are mixed in DME (5.0 mL) and EtOH (5.0 mL). The reaction mixture is microwaved at 140° C. for 45 mins. Then mixture is diluted with DCM and water. The organic layer is separated and concentrated to give the crude product. Purification by flash column chromatography affords 30 mg 6-(4-carbamoyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester. It is then used to prepare 3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-isonicotinamide according to the procedure for Step 2 of Example 27 using 20% trifluoroacetic acid in DCM as the reagent.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[N:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: COc1ccc(CON)cc1
Product: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Yield: 85 %

Procedure:
The same method as employed in the preparation of Intermediate 2, but starting from (2S)-1-(tert-butoxycarbonyl)-4-oxo-2-pyrrolidinecarboxylic acid (Intermediate 1) and 1-[(aminooxy)methyl]-4-methoxybenzene (intermediate 6), gave the title compound as a gum in a 85% yield.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:12][O:13][CH3:14])[C:3]=1[C:15]1[S:16][CH:17]=[CH:18][N:19]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[Cl:1][C:2]1[C:10]2[C:5](=[C:6]([NH:11][S:25]([C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)(=[O:27])=[O:26])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:12][O:13][CH3:14])[C:3]=1[C:15]1[S:16][CH:17]=[CH:18][N:19]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COCn1c(-c2nccs2)c(Cl)c2cccc(N)c21
Solvent: c1ccncc1
Product: COCn1c(-c2nccs2)c(Cl)c2cccc(NS(=O)(=O)c3cccs3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a mixture of 3-chloro-1-(methoxymethyl)-2-(1,3-thiazol-2-yl)-1H-indole-7-amine (0.25 g) and pyridine (8 mL) was added thiophene-2-sulfonyl chloride (0.19 g) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.36 g, yield 96%) was obtained as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). melting point 128-129° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[NH:12][CH2:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>[O-2].[O-2].[Mn+4].[N+](C1C=CC=CC=1)([O-])=O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[NH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C2CNc3ccc([N+](=O)[O-])cc32)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)N1CCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Temperature: 150 °C
Yield: 47 %

Procedure:
A mixture of 3-(1-acetyl-4-piperidyl)-5-nitroindoline (10.0 g), manganese dioxide (17 g) and nitrobenzene (100 ml) was heated at 150° C. for 1 hour, with nitrogen gas being bubbled into the reaction mixture. The reaction mixture was cooled and the insoluble material was filtered off. The residue was washed with a mixture of chloroform and methanol (10:1 V/V) and the washings and the filtrate were combined and concentrated. The residue was dissolved in a mixture of chloroform and methanol (400 ml, 1:1 V/V) and the insoluble material was filtered off. The filtrate was concentrated to give 3-(1-acetyl-4-piperidyl)-5-nitroindole (4.67 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[N:13][C:12]([O:16][CH3:17])=[CH:11][CH:10]=2)=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:17][O:16][C:12]1[N:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:15]2
Reactant: CCOC(=O)c1cnc2ccc(OC)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2ncc(C(=O)O)cc2n1
Yield: 161.2 %

Procedure:
A mixture of 6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester (32.0 g, 74.45 mmol, 1.0 eq) and sodium hydroxide (10.12 g, 137.51 mmol, 1.85 eq) in ethanol (110 mL) is refluxed for 3 hours. The solvent is evaporated and the residue is dissolved in water, washed with ethyl acetate, then acidified with 3N hydrochloric acid aqueous solution to pH=3-4. The precipitate is collected by filtration, dried under 50° C. overnight to afford 6-methoxy-[1,5]naphthyridine-3-carboxylic acid as a white solid (24.5 g, 82% yield).