Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([C:30]([O:32][CH3:33])=[O:31])[C:7]=2[C:10]2[C:11]([C:26]([O:28][CH3:29])=[O:27])=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:16]CC3C=CC=CC=3)[CH:15]=2)[O:2]1.[H][H]>O1CCCC1.CO.[C].[Pd]>[CH2:1]1[O:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([C:30]([O:32][CH3:33])=[O:31])[C:7]=2[C:10]2[C:11]([C:26]([O:28][CH3:29])=[O:27])=[CH:12][C:13]([O:24][CH3:25])=[C:14]([OH:16])[CH:15]=2)[O:2]1
Reactant: COC(=O)c1cc(OC)c(OCc2ccccc2)cc1-c1c(C(=O)OC)ccc2c1OCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC)c(O)cc1-c1c(C(=O)OC)ccc2c1OCO2
Yield: 93.5 %

Procedure:
Dimethyl 5,6-methylenedioxy-4'-methoxy-5'-benzyloxy-2,2'-biphenyldicarboxylate (1.15 g) is dissolved in tetrahydrofuran (50 ml) and methanol (50 ml), and the solution is sitrred under 40 psi hydrogen gas atmosphere in the presence of palladium-carbon (0.2 g) for 16 hours. After the reaction, the catalyst is filtered off, and the filtrate is evaporated into dryness under reduced pressure. The residue is treated with methanol to give dimethyl 5,6-methylenedioxy-4'-methoxy-5'-hydroxy-2,2'-biphenyldicarboxylate (0.86 g) as colorless crystal. M.p. 172°-173° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9](OC)(=[O:14])[CH2:10][C:11]([CH3:13])=O>>[CH3:13][C:11]1[CH:10]=[C:9]([OH:14])[C:5]2[C:3](=[C:2]([CH3:1])[CH:8]=[CH:7][CH:6]=2)[N:4]=1
Reactant: Cc1ccccc1N
Reactant: COC(=O)CC(C)=O
Product: Cc1cc(O)c2cccc(C)c2n1
Yield: 37.5 %

Procedure:
Following a procedure similar to (454a), 2-methylaniline (21.4 g, 0.2 mol) was condensed with methyl acetoacetate (23.2 g, 0.2 mol) to provide the desired 2,8-dimethyl-4-hydroxyquinoline (456a) (13.0 g, 38%). MS (AP+): 173 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:33])[C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]=2)[C:6](=[O:34])[C:5]([CH:35]=O)=[CH:4]1)[CH3:2].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([F:33])[C:9]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:10]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH:11]=2)[C:6](=[O:34])[C:5]([CH2:35][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C=O)c(=O)c2c(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCn1cc(CN2CCCC2)c(=O)c2c(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
To a solution of 1-ethyl-5-fluoro-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (18 g, 36.6 mmol) in 1,2-Dichloroethane (DCE) (100 mL) was added pyrrolidine (4.53 mL, 54.9 mmol), sodium triacetoxyborohydride (15.52 g, 73.2 mmol) and AcOH (0.105 mL, 1.831 mmol). The reaction mixture was stirred at 25° C. for 3 h. LCMS indicated completion of the reaction. The mixture was extracted with DCM and washed with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by normal phase automatic silica column chromatography (Combinflash RF), using a 40 g gold column and eluting with MeOH/DCM (0-20%). The product was further purified by reverse phase automatic chromatography (Combinflash RF), using a 150 g gold C18 column and eluting with acetonitrile/Water (0%-60%) to afford 1-ethyl-5-fluoro-6,7-bis((4-methoxybenzyl)oxy)-3-(pyrrolidin-1-ylmethyl)quinolin-4(1H)-one (9.4 g, 17.20 mmol, 47.0% yield) as a pale yellow solid. LCMS: (M+H)+: 547.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:18]=[C:17](F)[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[Cl:20].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[Cl:20]
Reactant: C1CNCCN1
Reactant: COC(=O)c1ccc(F)cc1Oc1cnc(N)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cnc(N)c(Cl)c1
Reaction time: 3 h

Procedure:
A solution of EXAMPLE 318C (8.90 g) and piperazine (10.34 g) in dimethylsulfoxide (100 mL) was heated to 85° C. After stirring for 3 hours, the reaction was cooled, diluted with ethyl acetate (400 mL) and washed with water (2×250 mL), brine (250 mL), dried over magnesium sulfate and concentrated to give the title compound.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:31]([C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[N:37][CH:38]=1)#[CH:32]>>[C:16]([C:14]1[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]([O:25][CH3:26])=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:4]([N:1]3[CH:32]=[C:31]([C:33]4[CH:38]=[N:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[N:3]=[N:2]3)[CH:5]=2)[CH:15]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: C#Cc1ccc(OC)nc1
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1ccc(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4OC)ccc3C)nn2)cn1

Procedure:
Example 22 was prepared from 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide and 5-ethynyl-2-methoxy-pyridine in the same manner as Example 15. ESI MS m/z 565 [C28H32N6O5S+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.O>C(Cl)(Cl)Cl>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH:7]([N:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12][CH2:11]3)[CH2:6][CH2:5]2)(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: NCCN1CCC(N2CCc3ccccc32)CC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)NCCN2CCC(N3CCc4ccccc43)CC2)cc1
Yield: 23.6 %

Procedure:
1-[1-(2-Aminoethyl)piperidin-4-yl]indoline (113 mg) was dissolved in chloroform (3 ml). Under ice cooling, 4-methoxybenzenesulfonyl chloride (95 mg) was added thereto and the resultant mixture was stirred at room temperature overnight. After adding water, the reaction solution was extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. After evaporating the solvent, the resulting residue (80 mg) was purified by NH-silica gel column chromatography (methanol/methylene chloride system) to give the title compound (45 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:12][O:13][CH3:14])[C:8]([O:10][CH3:11])=[O:9])[N:6]=1.[Cl:15][CH2:16][C:17](Cl)=[O:18].O>CN(C)C(=O)C>[Cl:15][CH2:16][C:17]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:12][O:13][CH3:14])[C:8]([O:10][CH3:11])=[O:9])[N:6]=1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: CON=C(C(=O)OC)c1csc(N)n1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CON=C(C(=O)OC)c1csc(NC(=O)CCl)n1
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
In 90 ml of N,N-dimethylacetamide is dissolved 21.5 g of methyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (syn-isomer) and, under ice-cooling, 13.6 g of chloroacetyl chloride is added dropwise. The mixture is stirred under ice-cooling for 30 minutes and, then, at room temperature for 30 minutes, after which 500 ml of water is added. The mixture is extracted twice with ethyl acetate and the combined extract is washed with a 5% aqueous solution of sodium hydrogen carbonate and water in that order and dried. On removal of the solvent, there is obtained 25 g of methyl 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetate(syn-isomer) as crystals melting at 130.8° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1.[CH2:23]([O:25][C:26](=[O:31])[CH:27]=[C:28]([CH3:30])[CH3:29])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:29][C:28]([N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1)([CH3:30])[CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:31]
Reactant: CCOC(=O)C=C(C)C
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(C)(C)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
4-(1H-Pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (220 mg, 0.0006996 mol) and 3-methyl-2-butenoic acid ethyl ester (292 μL, 0.00210 mol) were dissolved in DMF (10 mL). Cesium carbonate (912 mg, 0.00280 mol) was added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, and the product was extracted with MTBE several times. The combined extracts were dried over sodium sulfate and concentrated. The crude residue was purified by flash column chromatography (0-60% EtOAc/Hexanes) to afford ethyl 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butanoate (244 mg, 79%). 1H NMR (300 MHz, CDCl3): δ 8.37 (d, 1H), 8.11 (s, 1H), 8.09 (s, 1H), 7.45 (d, 1H), 7.24 (d, 1H), 6.79 (d, 1H), 5.77 (s, 2H), 4.10 (q, 2H), 3.62 (dd, 2H), 3.04 (s, 2H), 1.88 (s, 6H), 1.20 (t, 3H), 0.98 (dd, 2H), 0.00 (s, 9H); MS(ES): 443 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.[CH:16]1([Mg]Br)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:11])=[CH:4][CH:3]=1
Reactant: Br[Mg]C1CCCCC1
Reactant: CON(C)C(=O)CCc1ccc(Br)cc1
Solvent: CCOCC
Product: O=C(CCc1ccc(Br)cc1)C1CCCCC1
Reaction time: 1.25 h

Procedure:
To a solution of 25.02 g 3-(4-Bromophenyl)-N-methoxy-N-methylpropanamide from Step A above in 500 mL anhydrous ether cooled in an ice bath was added 115 mL 2 M cyclohexylmagnesium bromide in ether over 30 minutes. The cooling bath was removed after finishing addition. After 75 minutes, an additional 30 mL 2 M cyclohexylmagnesium bromide in ether was added. The reaction mixture was stirred for 40 minutes and poured into a mixture containing 500 mL ether, 500 mL cold water, 200 mL saturated brine, and 175 mL 2 N HCl. The layers were separated. The aqueous layer was extracted with 4×75 mL ether. The combined ether solution was washed with 200 mL 1:1 5% NaHCO3 and saturated brine followed by 200 mL saturated brine, dried over anhydrous Na2SO4, and evaporated to give a crude product. It was purified on silica gel using 20-100% EtOAc in hexanes and re-purified using 5-10% EtOAc in hexanes to give the title compound as yellow oil. 1H NMR (CDCl3, 500 MHz) δ 7.39˜7.42 (m, 2H), 7.06˜7.09 (m, 2H), 2.84˜2.87 (m, 2H), 2.74˜2.78 (m, 2H), 2.32 (tt, J=3.3 & 11.3 Hz, 1H), 1.76˜1.84 (m, 4H), 1.65˜1.70 (m, 1H), 1.15˜1.36 (m, 5H).
Reaction SMILES: O[C:2]1([CH3:13])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:13][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: CC1(O)CCCCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=CCCCc2ccccc21
Yield: 80.2 %

Procedure:
Following the procedure of Example 1, step 2, 26.65 g (0.151 mol) of 5-hydroxy-5-methyl-6,7,8,9-tetrahydro-5H-benzocycloheptene in 300 ml of toluene was reacted with 0.30 g of p-toluenesulphonic acid monohydrate. Vacuum distillation yielded 19.17 g (80%) of the title product as a colourless oil, b.p. 62°-65° C./1.0 mm of Hg. NMR δ(CDCl3) 1.81 (2H, q, J=7.1 Hz), 2.07 (2H, m), 2.09 (3H, s), 2.56 (2H, t, J=6.9 Hz), 6.97 (1H, m), 7.14-7.26 (4H, m).
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13](=[O:18])[C:14]([O:16]C)=O)=[C:5]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:4]=1[C:23]([O:25][CH3:26])=[O:24].[OH-].[NH4+:29].[Na+].[Cl-]>C(Cl)Cl>[F:1][CH:2]([F:27])[C:3]1[N:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[C:6]([C:13](=[O:18])[C:14]([NH2:29])=[O:16])=[C:5]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:4]=1[C:23]([O:25][CH3:26])=[O:24]
Reactant: [NH4+]
Reactant: COC(=O)C(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1CC(C)C
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)C(N)=O)c1CC(C)C
Reaction time: 2 h

Procedure:
To 16.5 g of methyl 6-(difluoromethyl)-4-(2-methylpropyl) -5-(methoxycarbonyl)-2-(trifluoromethyl)-a-oxo-3-pyridineacetate (prepared by example E of U.S. Pat. No. 5,298,479) in 60 ml of methylene chloride was added 25 ml of concentrated ammonium hydroxide. The reaction mixture was stirred for 2 h and the aqueous layer was saturated with NaCl and the organic was extracted into methylene chloride. The methylene chloride layer was dried (MgSO4) and concentrated in vacuo. The residue was recrystallized from 20% EtOAc-benzene to give 12.5 g of 6-(difluoromethyl) -4-(2-methylpropyl)-5-(methoxycarbonyl)-2-(trifluoromethyl)-a-oxo-3-pyridineacetamide. A mixture of 2.4 g of this material, 2.0 g of phosphorus pentasulfide , 2 g of Celite and 16 ml of toluene was held at reflux for 2 h. The mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20% EtOAc in hexane) to give an oil which crystallized from 3% EtOAc in hexane as a solid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2].[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1>>[CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:23]([CH:20]3[CH2:22][CH2:21]3)=[O:24])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: O=C(Cl)C1CC1
Product: CCc1noc(-c2sc(NC(=O)C3CC3)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and cyclopropanecarbonyl chloride.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][CH:11]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])=[CH:21][CH:22]=1)[C:12]([O:14]C)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.CO>[C:3]([O:7][C:8]([NH:10][CH:11]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])=[CH:21][CH:22]=1)[C:12]([OH:14])=[O:13])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)C(Cc1ccc(-c2cccc(F)c2F)nc1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(-c2cccc(F)c2F)nc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
Lithium hydroxide (10 mg, 0.5 mmol) in water (1 mL) was added to a solution of methyl 2-[(tert-butoxycarbonyl)amino]-3-[6-(2,3-difluorophenyl)pyridin-3-yl]propanoate (70 mg, 0.2 mmol) in methanol (3 mL). The reaction was stirred at rt for 3 h. The reaction was concentrated under reduced pressure to remove methanol and was partitioned between EtOAc and ammonium chloride water. The organic was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give crude 2-[(tert-butoxycarbonyl)amino]-3-[6-(2,3-difluorophenyl)pyridin-3-yl]propanoic acid (0.07 g, 100%) as a semisolid residue. Analytical LCMS (M+H)+: m/z=378.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].[NH:29]1[CH2:34][CH2:33][CH2:32][C@@H:31]([C:35]([OH:37])=[O:36])[CH2:30]1>>[F:1][C:2]1[CH:3]=[C:4]([C:5]([N:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([C:35]([OH:37])=[O:36])[CH2:30]2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:22]1)[N:14]=2
Reactant: O=C(O)[C@@H]1CCCNC1
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Product: O=C(O)[C@@H]1CCCN(C(=O)c2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1

Procedure:
The title compound was synthesized using the procedure described in Example 105 above, with 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzoic acid (111 mg, 0.284 mmol) and (R)-piperidine-3-carboxylic acid (44 mg, 0.341 mmol). MS (ESI) m/z: Calculated: 501.2; Observed: 502.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[C:21]([C:25]1[O:29][N:28]=[C:27]([NH2:30])[CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[O:29][N:28]=[C:27]([NH:30][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:6]([Cl:20])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:16])[CH:26]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CC(C)(C)c1cc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)no1

Procedure:
Prepared according to the procedure described for example 50 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxylic acid (200 mg, 0.57 mmol) and 5-tert-butylisoxazol-3-amine (95 mg, 0.68 mmol). The title compound was obtained as a yellow solid (45 mg, 17% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.78 (1H, s), 9.01 (2H, s), 8.75 (1H, m), 8.01 (2H, m), 7.82 (2H, m), 2.51 (3H, s). MS m/z: 466.03, 468.03 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH:11]=[O:12])[CH2:6][CH2:5][C:4]2([CH2:10][CH2:9][CH2:8][O:7]2)[O:3]1>O1CCCC1>[CH3:1][C:2]1([CH2:11][OH:12])[CH2:6][CH2:5][C:4]2([CH2:10][CH2:9][CH2:8][O:7]2)[O:3]1
Reactant: CC1(C=O)CCC2(CCCO2)O1
Solvent: C1CCOC1
Product: CC1(CO)CCC2(CCCO2)O1
Yield: 83.1 %

Procedure:
A solution of 1.70 g of 2-methyl-1,6-dioxaspiro[4.4]nonane-2-carboxaldehyde in tetrahydrofuran was hydrogenated at 60 p.s.i. and 20° C. for 5 hours in the presence of 1.0 g triethylamine promoter and Raney nickel, that had been rinsed in tetrahydrofuran. When all of the starting material had disappeared, the mixture was treated with magnesium sulfate and filtered. Distillation of the filtrate gave 1.43 g of the desired product as a colorless liquid, b.p. 65°-70° C. (1 torr.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[N:3]=1
Reactant: Clc1cccc(Cl)n1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cccc(-n2ccnc2)n1
Temperature: 85 °C

Procedure:
A mixture of 2,6-dichloropyridine (5 g, 33.78 mmol), imidazole (2.3 g, 33.78 mmol) and potassium carbonate (4.66 g, 33.78 mmol) in DMF (50 ml) is heated to 85° C. over night. The cooled mixture is poured into ice-water and unreacted starting material is filtered off. The filtrate is acidified with diluted hydrochloric acid and is extracted once with ethyl acetate. The aqueous phase is rendered alkaline by addition of aqueous sodium hydroxide (10 M) and extracted with ethyl acetate. The organic extract is dried over sodium sulfate, concentrated under reduced pressure and eluted through silica gel with a mixture of ethyl acetate and methanol (9:1). Evaporation of solvent leaves 15a. Yield: 2.37 g (39%). Mp 71-73° C.
Reaction SMILES: [CH2:1]([S:3]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:13][CH2:14][CH3:15])[CH:12]=1)[CH:8]=[O:9])=[O:4])[CH3:2].[OH:16]O.O.[OH-].[Na+]>C(O)(=O)C>[CH2:1]([S:3]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:13][CH2:14][CH3:15])[CH:12]=1)[CH:8]=[O:9])(=[O:16])=[O:4])[CH3:2]
Reactant: OO
Reactant: CCOc1cc(C=O)cc(S(=O)CC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc(C=O)cc(S(=O)(=O)CC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
To a solution of (±)-3-ethanesulfinyl-5-ethoxy-benzaldehyde (0.39 g, 1.72 mmol, 1.0 equiv) in conc. acetic acid (10 mL) was added a solution of 35% hydrogen peroxide in water (0.60 mL, 0.67 g, 6.89 mmol, 4.0 equiv). After stirring the reaction mixture for 18 h at rt, the pH was adjusted to 10 by addition of a 1 M solution of NaOH, extracted with ethyl acetate (3×50 mL) and the combined organic phases dried over MgSO4. The organic solvent was removed by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with heptane/ethyl acetate (1:1) providing 0.09 g (22%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.31 (t, J=7.4 Hz, 3H), 1.48 (t, J=7.0 Hz, 3H), 3.17 (q, J=7.4 Hz, 2H), 4.17 (q, J=7.0 Hz, 2H), 7.63-7.66 (m, 2H), 7.94-7.95 (m, 1H), 10.04 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 11.46, 18.59, 54.59, 68.89, 122.74, 123.94, 125.68, 142.60, 145.26, 164.29, 194.24. MS (ISP): 243.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)=[O:14]>CN(C=O)C.[Pd]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc([N+](=O)[O-])ccc1NC(=O)Nc1cnccn1
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1cc(N)ccc1NC(=O)Nc1cnccn1
Yield: 41.4 %

Procedure:
A solution of (2-methoxy-4-nitrophenyl)-3-pyrazin-2-yl-urea (Compound 65, Example 9) (7.9 g, 27 mmol) in DMF (300 mL) was shaken under H2in the presence of Pd/C catalyst (1.6 g, 10% Pd) at 110° C. for 4 h. The mixture was filtered through a pad of celite using an additional 200 mL of DMF. The filtrate was concentrated in vacuo and the residue was recrystallized from ethanol (with a hot filtration step) to yield the light gray product (2.9 g, 41%). 1H NMR (300 MHz, d6-DMSO) δ: 9.83 (s, 1H), 9.50 (s, 1H), 8.86 (s, 1H), 8.28 (s, 1H), 8.19 (d, J=2.5 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 6.31 (d, J=2.0 Hz, 1H), 6.13 (dd, J=8.5, 2.0 Hz, 1H), 4.92 (s, 2H), 3.79 (s, 3H). 13C NMR (75 Mhz, d6-DMSO) δ: 151.6, 150.0, 149.6, 145.2, 140.9, 136.9, 135.1, 121.6, 116.8, 105.5, 98.0, 55.4.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][CH:8]=1)(=[O:5])=[O:4].[NH2:18][C@@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH:23]=[CH:24][CH:25]=2)[CH2:20]1>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:35][N:32]1[CH2:33][CH2:34][N:29]([C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:21]=2[CH2:20][C@H:19]([NH:18][C:13](=[O:15])[C:10]2[CH:9]=[CH:8][C:7]([O:6][S:3]([C:2]([F:1])([F:17])[F:16])(=[O:4])=[O:5])=[CH:12][CH:11]=2)[CH2:28][CH2:27]3)[CH2:30][CH2:31]1
Reactant: O=C(O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc2)CC3)CC1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
4-Carboxyphenyl trifluoromethanesulfonate (0.40 g, 1.5 mmol; described in: Looker, J. H.; Hayes, C. H.; Thatcher, D. N. J. Am. Chem. Soc. 1957, 79, 741-4) was dissolved in thionyl chloride (10 mL) and heated at 40° C. for 45 min. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. The crude acid chloride (280 mg, 0.96 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.46 mmol) and triethylarine (96 μL, 0.69 mmol) in methylene chloride (20 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with water. The phases were separated and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 100 mg (44%) of the title compound as white crystals: mp 178-180° C.; [α]21D −31° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 497 (17, M+).