Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([Br:18])=[C:9]1[C:19]1[C:20]2[S:33][CH:32]=[CH:31][C:21]=2[N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+]>BrCCCBr>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:19][CH2:9][CH2:10][Br:18])[CH:15]=2)[C:10]([Br:18])=[C:9]1[C:19]1[C:20]2[S:33][CH:32]=[CH:31][C:21]=2[N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:23]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc(-c2c(Br)c3ccc(O)cc3n2C(=O)OC(C)(C)C)c2sccc21
Agent: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)n1nc(-c2c(Br)c3ccc(OCCCBr)cc3n2C(=O)OC(C)(C)C)c2sccc21
Temperature: 75 °C
Reaction time: 1 h
Yield: 144.9 %

Procedure:
To 3-bromo-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-hydroxy-indole-1-carboxylic acid tert-butyl ester [0.22 g, 0.40 mmol, Intermediate (65)] in 1,3 dibromopropane (4 mL) was added cesium carbonate (0.33 g, 1.0 mmol). The resulting suspension was stirred at 75° C. for 1 hour then filtered. The insoluble was filtered off. The filtrate was concentrated. The residue was chromatographed through silica gel (n-heptane/ethyl acetate, 100/0 then 90/10) to provide 3-bromo-6-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [0.19 g, 72%, Intermediate (66)] as a white foam. LC/MS: 654.0 (M+H), RT=4.71 minutes.
Reaction SMILES: CC12CC(CC1)CC2=O.C([C:14]1[CH:19]=[C:18](C)[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])C)N=1)(C)(C)C.[F:25][C:26]([F:39])([F:38])[S:27]([O:30]S(C(F)(F)F)(=O)=O)(=[O:29])=[O:28].O>C(Cl)Cl>[F:25][C:26]([F:39])([F:38])[S:27]([O:30][C:16]12[CH2:17][CH:18]([CH2:19][CH2:14]1)[CH2:24][C:21]2=[CH2:23])(=[O:29])=[O:28]
Reactant: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CC12CCC(CC1=O)C2
Solvent: O
Solvent: ClCCl
Product: C=C1CC2CCC1(OS(=O)(=O)C(F)(F)F)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.5 %

Procedure:
To a solution of methylbicyclo[2.2.1]heptan-2-one (26 g, 0.209 mol) and 2,6-di-tert-butyl-4-methyl-pyridine (64 g, 0.315 mol) in DCM (300 mL) was added dropwise trifluoromethanesulfonic anhydride (88 g, 0.315 mol) in DCM (50 mL) at 0° C. The reaction mixture was stirred at room temperature for 24 h. The mixture was poured into water, and extracted with DCM (2×100 mL). The combined extracts were washed with a 10% hydrochloric acid solution (3×100 mL), saturated aqueous sodium bicarbonate solution (50 mL), brine (50 mL) and dried over sodium sulfate. Concentration under reduced pressure gave the crude product, which was purified by silica gel column chromatography (100% n-pentane) to give the desired product (7.6 g, 0.03 mol, 14%). 1H NMR (400 MHz, CDCl3): δ ppm 5.15 (brs, 1H), 4.89 (brs, 1H), 2.51-2.39 (m, 2H), 2.26-2.17 (m, 2H), 2.12-2.05 (m, 2H), 1.99-1.85 (m, 2H), 1.53-1.50 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[CH3:8][CH2:9][C:10](=O)[CH2:11][CH3:12]>>[CH2:9]([C:10]1([CH2:11][CH3:12])[O:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2][O:1]1)[CH3:8]
Reactant: OCC(CO)CO
Reactant: CCC(=O)CC
Product: CCC1(CC)OCC(CO)CO1
Yield: 46 %

Procedure:
The same procedure as in the step (7a) of Example 7 was repeated using 2-(hydroxymethyl)-1,3-propanediol, and 3-pentanone to obtain the title compound (1.5 g, yield: 46%) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)=[C:4]([O:13][CH3:14])[CH:3]=1.C(N(CC)CC)C.[Cl:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[Cl:22][CH2:23][C:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)=[C:4]([O:13][CH3:14])[CH:3]=1)=[O:25]
Reactant: COc1cc(N)ccc1-c1cnco1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)CCl)ccc1-c1cnco1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1D (500 mg, 2.63 mmol) and triethylamine (370 μL, 2.89 mmol) in dichloromethane (13.0 mL), was added chloroacetyl chloride (0.23 mL, 2.89 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 min. and then at RT for 4 h. The mixture as diluted with dichloromathane, washed with water, brine, and dried over Na2SO4. The mixture was filtered through celite and concentrated in vacuo to give 2A as a yellow solid. LC/MS: ret. timeA=3.123 min., MS (M+H)+=267.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=3)[C:11]3[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1OC
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc(C(F)(F)F)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with yields 2-chloro-6-trifluoromethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-trifluoromethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[Br:9][C:10]1[N:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1.C(O)CO.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]1>C(O)(C)C.[Cu]I>[Br:9][C:10]1[N:14]2[CH:15]=[C:16]([NH:24][CH:25]3[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]3)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1
Reactant: Brc1cnc2ccc(I)cn12
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: OC1CCC(Nc2ccc3ncc(Br)n3c2)CC1
Temperature: 80 °C

Procedure:
Copper (I) iodide (0.1 eq, 1.45 g, 7.68 mmol) and potassium phosphate tribasic (2 eq, 0.153 mol, 32.5 g) are stirred at RT under an atmosphere of argon during the addition of 3-bromo-6-iodo-imidazo[1,2-a]pyridine (Intermediate F) (25 g, 77 mmol, 1 eq) in isopropyl alcohol (200 ml), ethylene glycol (2 eq, 0.153 mol, 8.5 ml) and finally trans-4-aminocyclohexanol (2 eq, 17.5 g, 153 mmol) The reaction is heated at 80° C. for 40 hours. The majority of the solvent is removed in vacuo and the residue is diluted with water (500 ml) and extracted with EtOAc (3×500 ml). The combined organic portions are dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography on silica eluting with 0-15% MeOH in EtOAc gives 4-(3-bromo-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol; [M+H]+=310 (312)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:40][CH3:41])[C:24]([Cl:42])=[CH:23][N:22]=1>>[Cl:42][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:29]=2[O:40][CH3:41])=[N:26][C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=3[CH:19]=2)=[N:22][CH:23]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: COCCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-(2-methoxy-ethyl)-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine to yield an off-white solid (51%). LCMS: m/z=581.26 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.22 (dd, 1H, J=8.8, 1.3 Hz), 8.04 (d, 1H, J=1.5 Hz), 7.78 (m, 1H), 7.60 (d, 2H, J=6.6 Hz), 7.38 (m, 1H), 7.27 (m, 1H), 6.53 (m, 1H), 6.42 (m, 1H), 3.89 (m, 8H), 3.88 (m, 3H), 3.28 (d, 3H, J=1.8 Hz), 2.17 (m, 4H), 1.32 (m, 6H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13](C=O)[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].Cl.[CH3:28][O:29][NH:30][CH3:31].[C:32]([BH3-])#N.[Na+]>O1CCCC1>[F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH2:31][N:30]([O:29][CH3:28])[CH3:32])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: CNOC
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CON(C)Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 17 %

Procedure:
To a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (56.2 mg, 0.117 mmol) in tetrahydrofuran (anhydrous) were added O,N-dimethyl-hydroxylamine hydrochloride (commercially available, 34 mg, 0.351 mmol) and sodium cyanoborohydride (34 mg, 0.541 mmol) under nitrogen atmosphere, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (Mega Bond Elut, Varian, 5% methanol/methylene chloride as an eluent) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(methoxy-methyl-amino)-methyl]-benzamide (9.72 mg, 17%) as a white solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CO[CH:35]1[N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:38]([CH3:48])([CH3:47])[CH2:37][CH2:36]1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C@H:15]([C@H:35]1[N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:38]([CH3:48])([CH3:47])[CH2:37][CH2:36]1)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1CCC(C)(C)N1C(=O)OC(C)(C)C
Reactant: O=C(Cc1cccc(Cl)c1)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2cccc(Cl)c2)CCC1(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
A solution of (R)-4-benzyl-3-(2-(3-chlorophenyl)acetyl)oxazolidin-2-one (0.975 g, 2.96 mmol) in dry DCM (125 mL) was cooled to −78° C., and TiCl4 (3.10 mL, 3.10 mmol) was added. DIEA (0.566 mL, 3.25 mmol) was added to this stirring cold solution for 15 minutes. A solution of tert-butyl 5-methoxy-2,2-dimethylpyrrolidine-1-carboxylate (0.881 g, 3.84 mmol) in DCM (20 mL) was added to the cold mixture. The reaction was stirred for 15 minutes at −78° C. and then warmed to −10° C. (ice/acetone) and stirred for 3 hours. The reaction was quenched with NH4Cl, diluted with DCM (50 mL), water (50 mL), and the layers were separated. The aqueous layer was extracted with DCM (25 mL), dried (MgSO4) and concentrated to an oil. TLC (10% ethyl acetate/hexanes) shows desired product at Rf˜0.2. Purification by flash chromatography (5% ethyl acetate/hexanes-10% ethyl acetate/hexanes) gave (S)-tert-butyl 5-((S)-2-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-(3-chlorophenyl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.98 g, 1.86 mmol, 62.9% yield). HPLC, 254 nm, 100% purity, retention time=3.86 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19]CC)=O)=[C:13]([CH2:22]Br)[N:12]=2)[CH:6]=[N:7][C:8]=1[O:9][CH3:10].[NH2:24][C:25]1[CH:26]=[N:27][N:28]([CH2:30][C:31]#[N:32])[CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:12]=[C:13]3[CH2:22][N:24]([C:25]4[CH:26]=[N:27][N:28]([CH2:30][C:31]#[N:32])[CH:29]=4)[C:17](=[O:19])[C:14]3=[CH:15][CH:16]=2)[CH:6]=[N:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1ccc(-c2cnc(OC)c(OC)c2)nc1CBr
Reactant: N#CCn1cc(N)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2ccc3c(n2)CN(c2cnn(CC#N)c2)C3=O)cnc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
As shown in step 8-iv of Scheme 8, a solution of the above mixture (Compound 2029, 2.2 g, about 60% pure) in DMF (40 mL) at 0° C. was added dropwise over 2 hours to a suspension of 2-(4-amino-1H-pyrazol-1-yl)acetonitrile (844 mg, 6.9 mmol) and sodium carbonate (732 mg, 6.9 mmol) in DMF (20 mL). After addition was complete, the reaction mixture was stirred at 0° C. for 2 hours and heated at 80° C. for 15 hours. Additional sodium carbonate (732 mg) was added and the reaction mixture was heated at 90° C. for an additional 7 hours. After cooling, the mixture was poured into water and a precipitate formed. The solid was collected by filtration, washed with methyl t-butyl ether, and dried under high vacuum to provide 2-(4-(2-(5,6-dimethoxypyridin-3-yl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-1H-pyrazol-1-yl)acetonitrile (Compound 25, 450 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH3:17])=[C:7]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:8]3=[N:9][C:10]=2[CH:11]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19]([N:14]1[CH2:15][CH2:16][C:7]2[C:8](=[N:9][C:10]3[CH:11]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:6]=2[CH3:17])[CH2:12][CH2:13]1)=[O:20])[CH3:23]
Reactant: Cc1ccc2c(C)c3c(nc2c1)CCNCC3
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCc2nc3cc(C)ccc3c(C)c2CC1
Yield: 79 %

Procedure:
8,11-Dimethyl-1,2,4,5-tetrahydro-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester was prepared from 8,11-dimethyl-1,2,4,5-tetrahydro-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 155. Yield: 79% of theory; m.p. 121° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5]([OH:8])=[N:6][CH:7]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)#[CH:11].N#N.CCOCC>C(N(CC)CC)C.[Cu]I.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[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: Oc1ncc(Br)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2cc3cc(Br)cnc3o2)cc1
Temperature: 90 °C
Yield: 65.5 %

Procedure:
5-bromo-3-iodopyridin-2-ol (6.7 g, 22 mmol) (Heterocycles. 57, 1, pp 55), 1-ethynyl-4-fluorobenzene (4.03 g, 33.5 mmol), copper(I) iodide (0.255 g, 1.34 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.784 g, 1.12 mmol) were combined and evacuated/backfilled with N2 (3×) then diluted with triethylamine (223 mL) and heated to 90° C. for 2 hours. The solvent was evaporated and the reaction was dissolved in EtOAc. The organic phase was washed with water (50 mL), brine, dried over Na2SO4, filtered, and concentrated. Trituration with Et2O afforded the expected product 5-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridine (4.2 g, 14.4 mmol, 64% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.35-8.42 (2H, m), 8.03 (2H, dd, J=8.78, 5.27 Hz), 7.46 (1H, s), 7.39 (2H, t, J=8.91 Hz). LC-MS retention time: 2.36 min; m/z (MH+): 292, 294. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11]1)=[O:7])(C)(C)C.[CH3:18][N:19]=[C:20]=[S:21].[NH2:22][C:23]1[C:31]([Cl:32])=[CH:30][C:26](C(O)=O)=[C:25]([O:33][CH3:34])[CH:24]=1>>[NH2:22][C:23]1[C:31]([Cl:32])=[CH:30][C:26]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:20]([NH:19][CH3:18])=[S:21])[CH2:11]2)=[O:7])=[C:25]([O:33][CH3:34])[CH:24]=1
Reactant: CN=C=S
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCN)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: CNC(=S)NCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
2-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)ethylamine (1 g) as starting compound was reacted and treated in the same manner as in Example 34 using methyl isothiocyanate (0.25 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.83 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(2-(3-methylthioureido)ethyl)pyrrolidin-3-ylmethyl)-benzamide.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])(C)C)=[O:8])[CH2:3]1.[C:14]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)O[C:22]([CH3:24])=O.[Na+]>C1COCC1>[CH:14]1([NH:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][CH2:13][CH2:22][CH3:24])=[O:8])[CH2:3]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOC(=O)N1CC[C@@H](NC2CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1.0 g, 5.3 mmol) and cyclopentanone (451 mg, 5.3 mmol) in THF (20 mL) was slowly added NaBH(OAc)3 (1.13 g, 5.3 mmol) and then stirred at the ambient temperature for overnight. The reaction was quenched with H2O (20 mL) and extracted with dichloromethane (3×20 mL). The combined extracts were washed with brine (3×5 mL), dried over anhydrous Na2SO4, filtered and concentrated to give the title compound. MS (m/z): 255 (M+H)+.
Reaction SMILES: Cl[C:2]([C:4]1[C:5]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3].Cl.C[O:18][C:19](=[O:22])[CH2:20][NH2:21].[CH:23](N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:23][N:21]([C:2]([C:4]1[C:5]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:3])[CH2:20][C:19]([OH:18])=[O:22]
Reactant: COC(=O)CN
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)OC(=O)c1ncccc1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(C)OC(=O)c1ncccc1C(=O)N(C)CC(=O)O
Temperature: 0 °C

Procedure:
A solution of isopropyl 3-(chlorocarbonyl)pyridine-2-carboxylate (prepared as in P. Ornstein et. al. J. Med. Chem. 1989, 32, 827) (6.577 g, 31.44 mmol) in CH2Cl2 (50 ml) was added dropwise to a solution of glycine methyl ester hydrochloride (4.34 g, 34.58 mmol) and diisopropylethylamine (12.6 ml, 72.31 mmol) in CH2Cl2 (65 ml) at 0 C. The reaction was stirred for 16 hrs during which time the ice bath was allowed to expire. The solvent was evaporated in vacuo and the residue was used in the next step without further purification.
Reaction SMILES: O=[C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH2:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O.O.[NH2:26][NH2:27]>CCO>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:2]1[CH:3]=[C:4]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[NH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CC(=O)c2ccccn2)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccccn3)n[nH]2)CC1
Temperature: 80 °C

Procedure:
Unpurified tert-butyl 4-(3-oxo-3-pyridin-2-ylpropanoyl)piperidine-1-carboxylate (2.00 g, 6.02 mmol) was dissolved in 20 ml of EtOH and hydrazine hydrate (0.321 ml, 6.62 mmol) was added and the reaction was warmed to 80° C. After 15 h the reaction was concentrated in vacuo and the residue was purified by flash column chromatography (dissolve in DCM, elute with 98:2 to 95:5 DCM/MeOH). tert-Butyl 4-(3-pyridin-2-yl-1H-pyrazol-5-yl)piperidine-1-carboxylate was obtained as a yellow oil. 1H NMR (CDCl3): δ 8.60 (m, 1H), 7.73 (dt, J=1.7, 7.6 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.22 (m, 1H), 6.57 (s, 1H), 4.18 (bs, 2H), 2.89 (m, 4H), 2.00 (d, J=12.5 Hz, 2H), 1.67 (m, 2H), 1.48 (s, 9H). m/z (m+1): 329.2
Reaction SMILES: [C:1]([C:5]1[N:9]=[CH:8][N:7]([CH2:10]O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:14])=O>>[ClH:14].[C:1]([C:5]1[N:9]=[CH:8][N:7]([CH2:10][Cl:14])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1ncn(CO)n1
Product: CC(C)(C)c1ncn(CCl)n1
Product: Cl
Temperature: 25 °C

Procedure:
The mixture of 1.38 g of 3-t-butyl-1H-1,2,4-triazole1-ylmethanol and 2.7 ml of thionyl chloride was stirred under reflux condition for 3 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from hexane to obtain 1.72 g of 3-t-butyl-1-(chloromethyl)-1H-1,2,4-triazole hydrochloride. 1H-NMR (CDCl3, TMS, δ (ppm)): 1.36 (9H, s), 5.83 (2H, s), 8.17 (1H, s)
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][CH3:6])=[O:4].[N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[S:9][C:8]=1[NH2:16].Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25](O)[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[CH3:6][NH:5][C:3]([CH2:2][O:1][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[NH:16][C:8]1[S:9][C:10]2[C:15]([N:7]=1)=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:4]
Reactant: CNC(=O)CO
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Nc1nc2cccnc2s1
Product: CNC(=O)COc1ccc2ncnc(Nc3nc4cccnc4s3)c2c1

Procedure:
The compound of Example 84 was manufactured by the same method as in Example 22, by a similar method thereto or by a combination of such a method with a conventional method using 2-hydroxy-N-methyl-acetamide, thiazolo[5,4-b]pyridin-2-yl-amine and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][C@@H:8]([CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:9][C@H:10]([CH3:14])[CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O.O>[C:1]([O:5][C:6](=[O:27])[CH2:7][C@@H:8]([CH2:15][N:28]=[N+:29]=[N-:30])[CH2:9][C@H:10]([CH3:14])[CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC[C@@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCC[C@@H](C)C[C@H](CN=[N+]=[N-])CC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 78.3 %

Procedure:
Tosylate 104 (2.92 g, 7.3 mmol) and sodium azide (1.43 g, 0.02 mol) were warmed to ˜50° C. in DMSO (30 mL). After 2 hours the solution was cooled to room temperature and diluted with water. The solution was extracted with ether and the combined organic phases dried (MgSO4) and concentrated to give an oil 1.54 g, 79%. Further purification by flash chromatography (95% hexane/EtOAc) gave an oil. [α]D=−8.3 (c 1 in CHCl3). 13C NMR (100 MHz; CDCl3) 172.01, 80.73, 54.89, 39.73, 39.46, 39.00, 33.40, 29.85, 28.30, 20.15, 19.82, 14.52.