Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14]C)=[O:12])[N:8]=1)([CH3:3])[CH3:2].CO.[Mg].C(C1(CCC(OC)=O)NC=CS1)(C)C>C1COCC1>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/c1csc(C(C)C)n1
Agent: COC(=O)CCC1(C(C)C)NC=CS1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCc1csc(C(C)C)n1

Procedure:
A solution of 225 mg (1 mmol) of (E)-ethyl 3-(2-isopropyl-4-thiazolyl)propenoate in 10 ml of freshly distilled (from calcium hydride) methanol and 1 ml of dry THF was treated with 49 mg (2 mmol) of magnesium turnings. The mixture was stirred for 20 min, during which the magnesium was consumed. The resulting solution was poured over cold aqueous HCl, basified to pH 8 with NaHCO3, extracted with ethyl acetate, dried over Na2SO4, and concentrated. Silica gel chromatography using 10% ethyl acetate in hexane provided a mixture of the desired compound and methyl 3-(2-isopropyl-4-thiazolinyl)propanoate.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]([CH:20]3[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][CH:9]=2)[N:4]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])[N:3]=1.[CH:28]1([B-](F)(F)F)[CH2:30][CH2:29]1.[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=CC=1.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>[CH:20]1([N:12]([CH2:11][C:7]2[CH:6]=[C:5]3[C:10]([C:2]([CH:28]4[CH2:30][CH2:29]4)=[N:3][N:4]3[CH2:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:9][CH:8]=2)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:22][CH2:21]1
Reactant: COCCCn1nc(Br)c2ccc(CN(C(=O)OC(C)(C)C)C3CC3)cc21
Reactant: F[B-](F)(F)C1CC1
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: Cc1ccccc1
Solvent: O
Product: COCCCn1nc(C2CC2)c2ccc(CN(C(=O)OC(C)(C)C)C3CC3)cc21
Temperature: 100 °C
Reaction time: 24 h
Yield: 41.7 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (20 mg) was added to a solution of tert-butyl {[3-bromo-1-(3-methoxypropyl)-1H-indazol-6-yl]methyl}cyclopropylcarbamate (150 mg), potassium cyclopropyltrifluoroborate (73 mg) and potassium phosphate (254 mg) in toluene (3 ml)-water (1 ml) under argon atmosphere and the mixture was stirred at 100° C. for 24 hours. Potassium cyclopropyltrifluoroborate (24 mg), potassium phosphate (73 mg) and tetrakis(triphenylphosphine)palladium(0) (20 mg) were added to the reaction mixture and it was stirred further at 100° C. for 24 hours. Water was added to the reaction mixture under ice-cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane to n-hexane/ethyl acetate=2/1) to give tert-butyl cyclopropyl{[3-cyclopropyl-1-(3-methoxypropyl)-1H-indazol-6-yl]methyl}carbamate (57 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][C@H:16]3[CH2:20][N:19](C(OC(C)(C)C)=O)[C@H:18]([C:28]([O:30][CH3:31])=[O:29])[CH2:17]3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.[ClH:38]>>[Cl-:38].[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][C@H:16]3[CH2:20][NH2+:19][C@H:18]([C:28]([O:30][CH3:31])=[O:29])[CH2:17]3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@@H](OCc2cccc(-c3cccc(Br)c3)c2)CN1C(=O)OC(C)(C)C
Reactant: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1C[C@@H](OCc2cccc(-c3cccc(Br)c3)c2)C[NH2+]1
Product: [Cl-]

Procedure:
1-tert-Butyl 2-methyl (2S,4R)-4-[(3′-bromobiphenyl-3-yl)methoxy]pyrrolidine-1,2-dicarboxylate 96 (1.0 eq.) was dissolved at 0° C. in a 4M solution of HCl in dioxane (3.0 eq.) to give a 1.0 M solution. The reaction mixture was stirred at RT for 2 h then the solvent was evaporated under reduced pressure to afford the title compound 97 as a white foam (96%). 1H NMR (400 MHz, DMSO-d6, 300 K) δ 10.33-9.33 (bs, 1H), 7.89 (s, 1H), 7.77-7.71 (m, 2H), 7.67 (d, J 7.7, 1H), 7.62 (d, J 7.7, 1H), 7.54-7.43 (m, 3H), 4.63 (s, 2H), 4.55 (dd, J 10.7, 7.4 Hz, 1H), 4.41 (bs, 1H), 3.81 (s, 3H), 3.51-3.40 (m, 2H), 2.59-2.51 (m, 1H), 2.27-2.16 (m, 1H). MS (ES) m/z 390, 392 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]([C:12]3[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:14][CH:13]=3)[N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH3:30]OC(N(C)C)(OC)C>>[CH3:30][C:9]1[CH:8]=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[N:11]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:28][CH:29]=2)[N:10]=1
Reactant: c1ccc2nc(COc3ccc(-n4nccc4-c4ccncc4)cc3)ccc2c1
Reactant: COC(C)(OC)N(C)C
Product: Cc1cc(-c2ccncc2)n(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(5-Pyridin-4-yl-pyrazol-1-yl)-phenoxymethyl]-quinoline but substituting (1,1-Dimethoxy-ethyl)-dimethyl-amine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=6.2 Hz, 2H), 8.20 (d, J=8.3 Hz, 1H), 8.06 (d, J=8.7 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.74 (m, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.54 (m, 1H), 7.18 (d, J=8.7 Hz, 2H), 7.07 (d, J=6.2 Hz, 2H), 7.00 (d, J=9.1 Hz, 2H), 6.40 (s, 1H), 5.38 (s, 2H), 2.35 (s, 3H); MS: (M+H m/z=393.4).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[NH3:16]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[C:10]1([CH2:9][O:8][C:4]2[CH:3]=[C:2]([NH2:16])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1cncc(OCc2ccccc2)c1
Reactant: N
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Nc1cncc(OCc2ccccc2)c1
Temperature: 180 °C

Procedure:
A thick-walled glass pressure tube was charged with copper(II) sulfate pentahydrate (1.96 g, 7.85 mmol), 5-bromo-3-(phenylmethoxy)pyridine (4.00 g, 15.15 mmol) and concentrated aqueous ammonia (29.7%, 14.8 M, 37 mL). The tube was sealed and the dark blue suspension was stirred and heated at 180° C. (oil bath temperature) for 24 h. The mixture was allowed to cool to ambient temperature. After further cooling in an ice-water bath, the mixture was concentrated on a rotary evaporator to a small volume (˜20 mL) of a dark-blue solution. The solution was diluted with water (40 mL) and saturated K2CO3 solution (40 mL) and extracted with CHCl3 (4×40 mL). The combined, turbid-brown CHCl3 extracts were washed with saturated NaCl solution (2×100 ml), dried (Na2SO4), filtered and concentrated (rotary evaporator). The resulting dark-brown oil, was briefly dried on the vacuum pump to give a dark-brown solid (2.06 g). The product was purified by column chromatography on silica gel (100 g) eluting with CHCl3—MeOH (3:1, v/v). Selected fractions, based on TLC (Rf 0.65) analysis, were combined and concentrated to give a 1.64 g (54.1%) of a tan-brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([F:41])[C:27]=1[OH:42]>>[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)[CH:29]=[C:28]([F:41])[C:27]=1[OH:42]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N(C)C)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure F, 1-{6-bromo-4-[trans-4-(dimethylamino)cyclohexylamino]quinolin-3-yl}ethanone (30 mg, 0.077 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (42 mg, 0.154 mmol) to afford the desired product (24 mg, 68%) as a yellow-orange solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.13 (s, 1H), 8.48 (s, 1H), 8.29 (dd, J=8.8, 1.8 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.63 (s, 1H), 7.56 (dd, J=11.4, 2.3 Hz, 1H), 4.65-4.61 (m, 1H), 3.50-3.46 (m, 1H), 2.91 (s, 6H), 2.75 (s, 3H), 2.58-2.54 (m, 2H), 2.34-2.28 (m, 2H), 1.91-1.81 (m, 4H); ESI MS m/z 456 [C25H27ClFN3O2+H]+; HPLC 97.1% (AUC), tR=9.52 min.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:12][CH:13]([O:20]CC)[CH2:14][C:15](OCC)=O)[CH3:11]>[Ti](Cl)(Cl)(Cl)Cl.[N+](C)([O-])=O>[CH:15]1([CH2:14][C:13]([O:12][CH2:10][CH3:11])=[O:20])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][O:9]1
Reactant: OCCc1ccccc1
Reactant: CCOC(=O)CC(OCC)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C[N+](=O)[O-]
Product: CCOC(=O)CC1OCCc2ccccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Titanium tetrachloride (1M in methylene chloride, 90 ml, 90.0 mmol) is added over a period of 20 minutes to an ice-cooled mixture of phenethyl alcohol (XLV, 4.9 ml, 41.0 mmol), ethyl 3,3-diethoxypropionate (LXXV, 9.1 ml, 46.8 mmol) and nitromethane (17 ml). The mixture is stirred for 2 hr and then concentrated, diluted with ether, poured into ice/hydrochloric acid (1N), and allowed to stir. The phases are separated and the aqueous phase is extracted three times with ether. The combined organic phases are backwashed with saline, dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel eluting with ethyl acetate/hexane (10/90). The appropriate fractions are pooled and concentrated to give ethyl (±)-(isochroman-1-yl)acetate (LXXVII), NMR (CDCl3) 1.28, 2.68-3.04, 3.82, 4.13, 4.22, 5.26, 7.05 and 7.16 δ.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([OH:17])([CH2:12][C:13]([CH2:15]Br)=[CH2:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH-].[Na+].C1COCC1>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2([O:17][CH2:14][C:13](=[CH2:15])[CH2:12]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=C(CBr)CC1(O)CCN(C(=O)OCC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: C=C1COC2(CCN(C(=O)OCC)CC2)C1
Reaction time: 8 h

Procedure:
The product of step b) (1.50 g, 0.0066 mmol), 50% NaOH (15 ml) and THF (20 ml) were mixed and stirred overnight. The reaction mixture was diluted with CH2Cl2 /H2O and separated. The aqueous layer was further extracted with CH2Cl2 (50 ml×2) and worked-up to give 1.42 g of a tan oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CN(C)C=O>[CH2:17]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[OH:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3,4-Dihydroxybenzaldehyde (21.6 g) and potassium carbonate (21.56 g) were suspended in N,N-dimethylformamide (200 mL). To the mixture was added dropwise benzylbromide (18.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added dropwise 2 mol/L hydrochloric acid (400 mL), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5) to give the title compound (19.0 g).
Reaction SMILES: [CH:1]1([CH2:6][S:7]([O-:10])(=O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].S(Cl)([Cl:14])=O>>[CH:1]1([CH2:6][S:7]([Cl:14])(=[O:10])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])CC1CCCC1
Agent: [Na+]
Product: O=S(=O)(Cl)CC1CCCC1

Procedure:
The subtitle compound was prepared by the method of Preparation 58 from sodium cyclopentylmethanesulfonate [Preparation 64] and thionyl chloride, to afford cyclopentylmethanesulfonyl chloride as a solid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:20]([NH2:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21]>>[C:23]1([C:20]([NH:29][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)([CH3:22])[CH3:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: CC(C)(Nc1nccc(-n2cnc3ccccc32)n1)c1ccccc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with cumylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 330.1 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.37 (d, J=4.8 Hz, 1H); 8.05 (br s, 1H); 7.77 (d, J=7.6 Hz; 1H); 7.54 (d, J=7.8 Hz, 2H); 7.41 (m, 2H); 6.75 (d, J=5.5 Hz; 1H); 5.91 (br s, 1H); 1.81 (s, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][OH:9].[C:10]1([CH3:21])[CH:15]=[CH:14][C:13]([S:16]([O:19]C)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[C:10]1([CH3:21])[CH:11]=[CH:12][C:13]([S:16]([O-:19])(=[O:17])=[O:18])=[CH:14][CH:15]=1.[CH3:1][N+:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][OH:9]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CN1CCCCC1CO
Product: C[N+]1(C)CCCCC1CO
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 157.1 %

Procedure:
The procedures of Reference Example 3 were repeated using 2.58 g of 1-methyl-2-piperidinemethanol and 3.72 g of methyl p-toluenesulfonate to give 4.95 g of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:26]([OH:28])=O)[C:5]2[C:10](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[N:9][N:8]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[C:6]=2[N:7]=1.[C:29]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C(=O)C.O1CCCC1>[C:32]([O:31][C:29]([N:36]1[CH2:41][CH2:40][N:39]([C:26]([C:4]2[C:5]3[C:10](/[CH:11]=[CH:12]/[C:13]4[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=4)=[N:9][N:8]([CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][O:21]4)[C:6]=3[N:7]=[C:2]([Cl:1])[CH:3]=2)=[O:28])[CH2:38][CH2:37]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cc(Cl)nc2c1c(/C=C/c1ccc(Cl)cc1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)nc3c2c(/C=C/c2ccc(Cl)cc2)nn3C2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.7 %

Procedure:
To a solution of 6-chloro-3-[(E)-2-(4-chloro-phenyl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (2 g, 4.79 mmol) in a mixture of anhydrous tetrahydrofuran (42 ml) and N,N-dimethylacetamide (10 ml) were added 1-boc-piperazine (0.98 g, 5.27 mmol), 1-hydroxybenzotriazole (0.06 g, 0.48 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.91 g, 4.79 mmol). The reaction mixture was stirred at room temperature for 4 hours, tetrahydrofuran was evaporated under reduced pressure, water and dichloromethane were then added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The crude residue was purified on a silica gel column chromatography using a gradient of ethyl acetate (0-45%) in cyclohexane to yield the title compound as a yellow foam (1.51 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20](Cl)(=[O:22])=[O:21]>>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[S:20]([NH:9][C:5]1[C:4]([O:10][CH3:11])=[N:3][C:2]([Cl:1])=[C:7]([Cl:8])[N:6]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: COc1nc(Cl)c(Cl)nc1N
Product: COc1nc(Cl)c(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1 g) and 2,3-dichlorobenzenesulphonyl chloride (0.15 g). Yield 0.12 g.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.S(Cl)(Cl)=O.O.[NH2:15][NH2:16]>CO>[Br:1][C:2]1[N:3]=[C:4]([C:7]([NH:15][NH2:16])=[O:9])[S:5][CH:6]=1
Reactant: NN
Reactant: O=C(O)c1nc(Br)cs1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: NNC(=O)c1nc(Br)cs1
Yield: 78.1 %

Procedure:
To a solution of 4-bromothiazole-2-carboxylic acid (2.0 g, 9.8 mmol) in methanol (10 mL) was added thionyl chloride (710 μL, 9.8 mmol) and the mixture was refluxed for 3 hours. The solvent was removed under reduced pressure, and the residue was suspended in ethanol (10 mL). To this suspension was added hydrazine hydrate (2.4 mL, 49 mmol), and the reaction was heated to reflux for 90 minutes. The solvent was removed under reduced pressure, and the residue suspended in acetonitrile, filtered, and the solids were washed with acetonitrile, diethyl ether, and dried under vacuum to afford 1.7 g (77%) of 4-bromothiazole-2-carbohydrazide as a yellow solid. M+1=222.1
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3Br)[CH2:5][C:4]=2[N:3]=1.[F:22][C:23]1[C:28](B(O)O)=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[C:28]3[C:23]([F:22])=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1Br)C2
Reactant: OB(O)c1cccnc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1-c1cccnc1F)C2
Yield: 86.9 %

Procedure:
To a 10 mL recovery flask was added 2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydroquinazolin-5(6H)-one (33 mg, 0.0942 mmol, 1.0 eq.), 2-fluoropyridine-3-boronic acid (27 mg, 0.188 mmol, 2.0 eq.), DME (2 mL), potassium carbonate (2.0M aq., 94 μL, 0.188 mmol, 2.0 eq.), and palladium tetrakis triphenylphosphine (5 mg, 0.00471 mmol, 0.05 eq.). The reaction was refluxed overnight whereupon LC/MS analysis judged the reaction to be complete. The reaction mixture was filtered through Celite and concentrated to a residue. The residue was purified via preparatory-HPLC to give the product white solid (30 mg, 96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.67 (dd, J=3.54, 1.77 Hz, 1H) 2.89 (br. s., 1H) 3.06 (t, J=12.51 Hz, 2H) 3.18 (br. s., 1H) 7.18 (dd, J=9.60, 2.78 Hz, 1H) 7.31-7.53 (m, 4H) 7.72 (dd, J=8.84, 5.81 Hz, 1H) 7.98 (ddd, J=9.79, 7.52, 1.89 Hz, 1H) 8.28 (d, J=4.80 Hz, 1H). ESI-MS: m/z 367.3 (M+H)+. ESI-MS: m/z 367.3 (M+H)+.
Reaction SMILES: [CH3:1][S:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][C:4]1=[O:16].ClC1C=C(C=CC=1)C(OO)=[O:22]>C(Cl)Cl>[CH3:1][S:2]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][C:4]1=[O:16])=[O:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSC1C(=O)Nc2ccc(C(F)(F)F)cc21
Solvent: ClCCl
Product: CS(=O)C1C(=O)Nc2ccc(C(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 0.13 h

Procedure:
To a cooled (ice/water) solution of 9.4 g. of 3 -methylthio-5-trifluoromethyl-2-indolinone predissolved in 318 ml. of methylene chloride is added 7.33 g. of m-chloroperoxybenzoic acid in small portions over a period of one minute. The ice/water bath is then removed; and, after eight minutes stirring, the reaction mixture is filtered (after the peracid is dissolved and before the product precipitates). The reaction mixture is stirred for an additional hour during which product precipitates. The product is then collected by filtration. Recrystallization from ethyl acetate/ligroine gives 3-methylsulfinyl- 5-trifluoromethyl-2-indolinone, m.p. 141°-142°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1N1CCCCC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Br)cnc1N1CCCCC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 5-bromo-3-nitro-2-(piperidin-1-yl)pyridine (5.88 g, 20.5 mmol) in EtOAc (50 mL) was added tin(II) chloride dihydrate (23.5 g, 104 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 90° C. After 1 h, the reaction was cooled in an ice bath, then washed with 1M NaOH, water, and brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was purified with silica gel chromatography (0-15% EtOAc in hexanes) to provide a white solid as 5-bromo-2-(piperidin-1-yl)pyridin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.57 (1H, d, J=2.2 Hz), 7.09 (1H, d, J=2.3 Hz), 5.04 (2H, s), 2.98 (4H, m), 1.73 (4H, m), 1.58 (2H, m).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:33])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12](/[CH:16]=[CH:17]/[C:18](=[O:32])[N:19]([CH3:31])[CH2:20][C:21]1[S:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[C:22]=1[CH3:30])=[CH:11][N:10]=2)=[O:5])C.[OH-].[Na+:35]>CO.C(Cl)Cl.O>[Na+:35].[CH3:31][N:19]([CH2:20][C:21]1[S:25][C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[C:22]=1[CH3:30])[C:18](/[CH:17]=[CH:16]/[C:12]1[CH:13]=[C:14]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:33])[C:6]([C:4]([O-:5])=[O:3])=[CH:15]2)=[O:32]
Reactant: CCOC(=O)c1cc2cc(/C=C/C(=O)N(C)Cc3sc4ccccc4c3C)cnc2[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3[nH]c(=O)c(C(=O)[O-])cc3c2)sc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a suspension of (E)-6-{2-[methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)carbamoyl]vinyl}-2-oxo-1,2-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (349 mg, 0.76 mmol) in MeOH (10 mL) and CH2Cl2 (5 mL) was added NaOH (1.53 mL of a 0.995 M solution in H2O, 1.53 mmol) dropwise. The mixture was stirred at room temperature overnight. The solid was collected by filtration and then dried under vacuum at 50° C. for 2 d. Trituration with 5:1 MeCN/H2O gave the title compound (85 mg, 25%) as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6+TFA-d) δ 9.15 (s, 1H), 8.85 (s, 2H), 7.88 (d, J=7.5 Hz, 1H), 7.76-7.58 (m, 2H), 7.46-7.34 (m, 3H), 5.15-4.92 (m, 2H), 3.20-2.98 (m, 3H), 2.44 (s, 3H); MS (ESI) m/e 434 (M−Na+2H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[CH:3][CH:2]=1.[O:16]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:23][N:22]=2)=[CH:17]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[O:16]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([N:26]3[CH2:27][CH2:28][N:29]([C:8]([NH:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[O:15])[CH2:30][CH2:31]3)[S:23][N:22]=2)=[CH:17]1
Reactant: c1cc(-c2nsc(N3CCNCC3)n2)co1
Reactant: O=C(Nc1ccncc1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1ccncc1)N1CCN(c2nc(-c3ccoc3)ns2)CC1
Yield: 30.8 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-4-ylcarbamate (207 mg, 0.770 mmol), 1-[3-(3-furyl)-1,2,4-thiadiazol-5-yl]piperazine (200 mg, 0.846 mmol) and diisopropylethylamine (0.134 ml, 0.846 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 80° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 84.5 mg (30.8%) of the desired product as a solid.