Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([Br:12])[C:9]2[C:4](=[C:5]([Br:22])[CH:6]=[C:7]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:14])[CH:8]=2)[N:3]=1.C1(C)C=CC=CC=1.[O:30]([CH3:32])[Na]>O1CCCC1>[Br:12][C:10]1[C:9]2[C:4](=[C:5]([Br:22])[CH:6]=[C:7]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:14])[CH:8]=2)[N:3]=[C:2]([O:30][CH3:32])[CH:11]=1
Reactant: CO[Na]
Reactant: O=C(c1ccc(Cl)cc1)c1cc(Br)c2nc(Br)cc(Br)c2c1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(Br)c2cc(C(=O)c3ccc(Cl)cc3)cc(Br)c2n1
Temperature: 66 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed 2,4,8-tribromo-6-[(4-chlorophenyl)carbonyl]quinoline (2 g, 3.97 mmol, 1.00 equip), toluene (20 mL), and tetrahydrofuran (2 mL). To the resulting mixture was then added NaOCH3 (642 mg, 11.89 mmol, 3.00 equip). The resulting solution was stirred for 2 h at 66° C. Then another batch of NaOCH3 (642 mg, 11.89 mmol, 3.00 equip) was added to the solution. The resulting solution was allowed to react, with stirring, for an additional 2 h at 66° C. And then a final batch of NaOCH3 (642 mg, 11.89 mmol, 3.00 equip) was added to the solution. The resulting solution was allowed to react, with stirring, for an additional 2 h at 66° C. The reaction was then quenched by the addition of saturated sodium bicarbonate (200 mL). The resulting solution was extracted with DCM (2×100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 4,8-dibromo-6-[(4-chlorophenyl)carbonyl]-2-methoxyquinoline as a yellow solid. LCMS (ES, m/z) 456 [M+H]+
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=1>C(O)C>[CH3:24][C:23]1[C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cccnc1N
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1-c1cn2cccc(C)c2n1
Yield: 40 %

Procedure:
A mixture of 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (112 mg, 0.4 mmol) and 2-amino-3-methylpyridine (43 mg, 0.4 mmol) in ethanol (2.5 mL) was heated under reflux under argon for 5 h. The mixture was then poured onto water and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated to leave a yellow oil. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 25:75) afforded the title compound (46 mg, 40%) which was obtained as a colourless oil. MS: m/e=290.3 [M+H]+.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([N+:21]([O-])=O)=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)#[CH:3].CO.C(Cl)(Cl)Cl.P([O-])(O)O.[Na+]>O1CCCC1.[Pd].O>[NH2:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([NH:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([C:2]#[CH:3])[CH:5]=3)=[N:12][CH:13]=[N:14]2)=[CH:19][CH:18]=1
Reactant: C#Cc1cccc(Nc2ncnc3cc([N+](=O)[O-])ccc23)c1
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C#Cc1cccc(Nc2ncnc3cc(N)ccc23)c1

Procedure:
The title product of example 12 (1.039 g, 3.18 mmol) was dissolved in 50 mL of tetrahydrofuran, 10 mL of methanol and 5 mL of chloroform at 50° C. Sodium dihydrogen phosphite (NaH2PO2, 3.822 g, 36 mmol) and 10% palladium on carbon (0.19 g) were added followed by dropwise addition of 10 mL of water. When 3 mL of water had been added the mixture became noticeably more homogeneous. After 1 hour the mixture was filtered through Celite. The Celite was washed thoroughly with methanol and chloroform. The combined organic solutions were vacuum evaporated to a residue which was triturated with water, 3% aqueous sodium bicarbonate and filtered. The solid title product was washed with water then diethyl ether and dried in vacuo, 1.054 gm (127%, wet). A portion of the above product was recrystallized from a minimum amount of hot ethanol and water to give, after removal of a small first crop of impure material, pure title product, (43%), mp 180° C. (dec).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1(/[CH:15]=[CH:16]/[C:17](=[O:19])[CH3:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.C(OCC)(=O)C>C1COCC1>[OH:19][C:17]([CH3:18])(/[CH:16]=[CH:15]/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC(=O)/C=C/c1ccccc1
Reactant: CCOC(=O)C[Zn]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(O)/C=C/c1ccccc1
Yield: 100 %

Procedure:
Under nitrogen atmosphere, 15 mL of THF was added to 3.05 g (5 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.73 g (5 mmol) of trans-4-phenyl-3-buten-2-one in 2.5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 3 hours. 8.5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.17 g of the desired product (yield 100%). 1H NMR (CDCl3), (ppm): δ 1.23 (3H, t, J=7.1 Hz), 1.42 (3H, s), 2.66 (2H, dd, J=19.5, 15.6 Hz), 4.05 (1H, s), 4.15 (2H, q, J=7.1 Hz), 6.27 (1H, d, J=16.0 Hz), 6.64 (1H, d, J=16.0 Hz), 7.20-7.39 (5H, m).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:14])[C:5]2[C:10]([N:11]=1)=[C:9]([CH3:12])[CH:8]=[C:7]([CH3:13])[N:6]=2.O[C:16]1[CH:48]=[CH:47][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[O:46])=[CH:18][CH:17]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:14][N:4]1[C:5]2=[N:6][C:7]([CH3:13])=[CH:8][C:9]([CH3:12])=[C:10]2[N:11]=[C:3]1[CH2:2][O:1][C:16]1[CH:48]=[CH:47][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[O:46])=[CH:18][CH:17]=1
Reactant: Cc1cc(C)c2nc(CO)n(C)c2n1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2nc(COc3ccc(CC4SC(=O)N(C(c5ccccc5)(c5ccccc5)c5ccccc5)C4=O)cc3)n(C)c2n1
Yield: 71.3 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.47 g of 2-hydroxymethyl-3,5,7-trimethylimidazo[5,4-b]pyridine (prepared as described in Preparation 86), 3.58 g of 5-(4-hydroxy-benzyl)-3-triphenylmethyl-thiazolidine-2,4-dione, 1.87 g of tributylphosphine, 2.33 g of 1,1'-(azodicarbonyl) dipiperidine and 50 ml of toluene were used. After working up the product as described in Preparation 4, the resulting crude product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.5 g of the title compound, melting at 96-990° C. (softening).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=1)[C:12]([OH:14])=O)=[O:7].[CH3:23][NH:24][CH3:25].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][N:17]=1)[C:12]([N:24]([CH3:25])[CH3:23])=[O:14])=[O:7]
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cc(C(=O)O)ccn1
Reactant: CNC
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccnc(NC(=O)COc2ccc(Cl)cc2Cl)c1
Yield: 46.3 %

Procedure:
To solution of 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-isonicotinic acid (100.0 mg, 0.31 mmol), dimethylamine (0.24 ml, 0.47 mmol, in 2.0 M tetrahydrofuran), EDC (90.1 mg, 0.47 mmol) and HOBt (63.5 mg, 0.47 mmol) in DMF 4 ml was added DIPEA (60.8 mg, 0.08 ml, 0.47 mmol), and stirred. Reaction mixture was then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried over anhydrous MgSO4, and concentrated. The residue was purified by preparative-TLC (n-Hexane:EtoAC:MeOH=6:3:1) to afford 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-N,N-dimethyl-isonicotinamide as a yellow solid (52.9 mg, 46.5% yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C1COCC1>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine trans-(4-hydroxy-cyclohexyl)-carbamic acid benzyl ester (16.0 g, 0.064 mol), imidazole (13.9 g, 0.10 mol), and anhydrous THF (300 mL), add tert-butyldimethylsilyl chloride (14.5 g, 0.10 mol) and stir at room temperature for 18 hours. Wash the reaction mixture with water (250 mL), saturated aqueous NaHCO3 (250 mL) and dry the organic layer over anhydrous Na2SO4. Remove the solvent and purify the residue by chromatography over silica gel (eluting with 0 to 30% EtOAc in hexane) to obtain the desired intermediate as clear oil (23.0 g, 98%).
Reaction SMILES: [F:1][C:2]1[C:21](F)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([O:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.O.CS(O)(=O)=O.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CS(C)=O>[F:1][C:2]1[C:21]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([O:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1
Reactant: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: C1CNCCN1
Agent: CS(=O)(=O)O
Solvent: CS(C)=O
Solvent: O
Product: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNCC4)cc3nc21
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
A suspension of 2 g of 7,8-difluoro-1-methoxy-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid in 2.8 g of piperazine and 40 cm3 of dimethyl sulphoxide is stirred for 15 minutes at a temperature close to 40° C. After cooling to about 20° C., the reaction mixture is poured into 150 cm3 of water and 27.75 cm3 of 2N methanesulphonic acid are added. A very small amount of insoluble matter is removed by filtration through diatomaceous silica. 15 cm3 of 2N aqueous potassium hydroxide solution are added to the solution obtained. The precipitate formed is drained, washed with 3 times 15 cm3 of water and taken up in 100 cm3 of dimethylformamide and the mixture is heated, with stirring, for 10 minutes at a temperature close to 150° C. The suspension is cooled to about 100° C.; the insoluble matter is drained and taken up in 100 cm3 of ethanol and the mixture is heated at a temperature close to 75° C. for 1 hour. The insoluble matter is drained at about 50° C. and washed with 40 cm3 of the same solvent at the same temperature as above. 1.8 g of 7-fluoro-1-methoxy-4-oxo-8-(1-piperazinyl)-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a brown solid melting at 298°-300° C., solvated by 2.4% of water.
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5])C.[CH2:25]([CH2:27][NH2:28])[OH:26]>>[OH:26][CH2:25][CH2:27][NH:28][C:4]([C:6]1[S:10][C:9]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5]
Reactant: CCOC(=O)c1cnc(OCc2c(-c3ccccc3)noc2C)s1
Reactant: NCCO
Product: Cc1onc(-c2ccccc2)c1COc1ncc(C(=O)NCCO)s1
Yield: 59 %

Procedure:
As described for example 127, 2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-thiazole-5-carboxylic acid ethyl ester (100 mg, 0.28 mmol) was converted, using ethanolamine instead of isopropylamine, to the title compound (62 mg, 59%) which was obtained as a colourless gum after purification by chromatography (silica, 0 to 3% methanol in dichloromethane). MS: m/e=360.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:14]=[O:15].[Cl-].C[Al+]C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]([CH2:14][OH:15])[CH2:12][O:11][CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(C2=CCOCC2)c1
Reactant: C=O
Agent: C[Al+]C
Agent: [Cl-]
Solvent: ClCCl
Product: OCC1COCC=C1c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 56 %

Procedure:
A 0° C. solution of 4-(3-bromophenyl)-3,6-dihydro-2H-pyran (0.50 g, 2.09 mmol) in CH2Cl2 (15 mL) is treated with paraformaldehyde (0.208 g, 2.20 mmol) and stirred for 5 minutes at 0° C. A 1 M solution of dimethylaluminum chloride in hexanes (3.03 mL, 3.03 mmol) is added drop-wise to the slurry. The reaction is warmed to room temperature and stirred for 1 hour. The reaction is cooled to 0° C. and more paraformaldehyde (0.208 g, 2.20 mmol) and 1 M solution of dimethylaluminum chloride in hexanes (3.03 mL, 3.03 mmol) is added. The reaction is warmed to room temperature and stirred overnight. The reaction is quenched by pouring into an ice/1 N HCl mixture and is extracted three times with EtOAc. The combined organic layers are dried over Na2SO4 and the solvent is removed under reduced pressure to afford a residue that is purified on silica gel chromatography eluting with a linear gradient of 5% to 100% EtOAc in hexanes to give the title compound (0.315 g, 53%). 1H NMR (400 MHz, CDCl3) δ 7.50 (t, J=2.0 Hz, 1H), 7.40 (dd, J=2.2, 7.9 Hz, 1H), 7.29-7.27 (m, 1H), 7.20 (t, J=7.9 Hz, 1H), 6.11 (t, J=2.9 Hz, 1H), 4.32-4.29 (m, 2H), 4.28-4.25 (m, 1H), 3.76 (dd, J=3.1, 11.4 Hz, 1H), 3.70-3.64 (m, 2H), 2.70 (d, J=2.2 Hz, 1H), 1.89 (dd, J=4.6, 6.4 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]([NH:24][C:25]([C@@H:27]2[CH2:32][CH2:31][CH2:30][N:29]([C:33](=[O:49])[CH2:34][CH2:35][CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)[CH2:28]2)=[O:26])[CH2:19][C:20]([O:22]C)=[O:21])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][F:17])=[CH:10][CH:9]=2)[CH:7]=1.[OH-].[Na+]>O1CCCC1.O>[C:45]([O:44][C:42]([N:39]1[CH2:38][CH2:37][CH:36]([CH2:35][CH2:34][C:33]([N:29]2[CH2:30][CH2:31][CH2:32][C@@H:27]([C:25]([NH:24][CH:18]([C:4]3[CH:5]=[C:6]([C:8]4[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][F:17])=[CH:12][CH:13]=4)[CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:19][C:20]([OH:22])=[O:21])=[O:26])[CH2:28]2)=[O:49])[CH2:41][CH2:40]1)=[O:43])([CH3:48])([CH3:47])[CH3:46]
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cc(F)cc(-c2ccc(OCCF)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)NC(CC(=O)O)c3cc(F)cc(-c4ccc(OCCF)cc4)c3)C2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.8 %

Procedure:
220 mg (0.32 mmol) tert-butyl 4-{3-[(3R)-3-({1-[5-fluoro-4′-(2-fluoroethoxy)biphenyl-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate were dissolved in 10.4 ml tetrahydrofurane. 3.85 ml (0.39 mmol) 0.1N sodium hydroxide solution were added. The mixture was stirred at room temperature for 20 hours, diluted with water and a small amount of 1N sodium hydroxide solution and extracted with ethyl acetate. The aqueous layer was brought to pH=4.5 with 10% aqueous citric acid solution and extracted with dichloromethane and dichloromethane/2-propanol 8/2. The organic layer was dried over sodium sulfate and concentrated in vacuum to give 150 mg (70%) 3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-[5-fluoro-4′-(2-fluoroethoxy)biphenyl-3-yl]propanoic acid.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.N1(CC2C=C(C=CC=2)OCCCN)CCCCC1>>[CH3:8][N:7]1[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=[CH:2]1
Reactant: CN1C(Cl)=NS(=O)(=O)c2ccccc21
Agent: NCCCOc1cccc(CN2CCCCC2)c1
Product: CN1C=NS(=O)(=O)c2ccccc21

Procedure:
The 3-chloro-4-methyl-1,2,4-benzothiadiazine-1,1-dioxide obtained in Reference Example 4 was reacted with 3-[3-(piperidinomethyl)phenoxy]propylamine in the same manner as in Example 1 to obtain 3-[N-]3-[3-(piperidinomethyl)phenoxy]-propyl]amino)-4-methyl-1,2,4-benzothiadiazine-1,1-dioxide. In an argon stream with ice cooling, 0.18 g of 60% sodium hydride was added to a solution of 1.78 g of this dioxide in 10 ml of N,N-dimethylformamide. To the mixture was added dropwise 0.6 g of acetoxyacetyl chloride, and the resulting mixture was stirred at room temperature for 12 hours. Ice-cold water was added to the reaction mixture, and the mixture was made alkaline with sodium hydroxide and subjected to extraction with ethyl acetate, followed by distillation to remove the solvent. The residue was purified by silica gel column chromatography using chloroform:methanol (10:1) to isolate 0.33 g of 3-[N-[3-[3-(piperidinomethyl)phenoxy]-propyl]acetoxyacetylamino]-4-methyl-1,2,4-benzothiadiazine-1,1-dioxide (yield 15% ). The oily product obtained was converted to an oxalic acid salt in the same manner as in Example 1 to obtain 0.28 g of a compound 21 listed in Table 1 (yield 71% ). M.p.: 86°~89° C.
Reaction SMILES: N#N.[OH:3][CH:4]([C:6]1[O:7][C:8]([CH2:11][N:12]2[N:16]=[C:15]([NH:17][C:18]([C:20]3[N:21]=[CH:22][O:23][C:24]=3[C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)=[O:19])[CH:14]=[N:13]2)=[CH:9][N:10]=1)[CH3:5]>C(C#N)(C)=O.O=[Mn]=O>[C:4]([C:6]1[O:7][C:8]([CH2:11][N:12]2[N:16]=[C:15]([NH:17][C:18]([C:20]3[N:21]=[CH:22][O:23][C:24]=3[C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)=[O:19])[CH:14]=[N:13]2)=[CH:9][N:10]=1)(=[O:3])[CH3:5]
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(Cc3cnc(C(C)O)o3)n2)c1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: CC(=O)c1ncc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(C)c3)n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-m-tolyl-oxazole-4-carboxylic acid {2-[2-(1-hydroxy-ethyl)-oxazol-5-ylmethyl]-2H-[1,2,3]triazol-4-yl}-amide (44 mg, 0.11 mmol) in AcCN (1.5 mL) was treated at rt with MnO2 (81 mg, 0.84 mmol) and the reaction mixture was stirred at rt overnight before being filtered through Celite. The solvent was removed under reduced pressure and the residue was dissolved in EA (10 mL), washed with water (10 mL), and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a white solid. LC-MS-conditions 02: tR=1.01 min; [M+H]+=392.97.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][C:16]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=3[F:38])=[C:17]([C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25]([CH:28]([CH3:30])[CH3:29])=[N:26][N:27]=4)[N:24]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])(=O)C.[OH-].[Na+].Cl>C1COCC1>[F:38][C:32]1[CH:33]=[C:34]([F:37])[CH:35]=[CH:36][C:31]=1[C:16]1[NH:15][C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[CH2:5][OH:4])[CH2:9][CH2:10]2)=[N:18][C:17]=1[C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([CH:28]([CH3:30])[CH3:29])=[N:26][N:27]=2)[N:24]=1
Reactant: CC(=O)OCC(=O)N1CCC(c2nc(-c3ccc4nnc(C(C)C)n4n3)c(-c3ccc(F)cc3F)[nH]2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(-c3nc(C4CCN(C(=O)CO)CC4)[nH]c3-c3ccc(F)cc3F)nn12
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
A 100 mL round-bottomed flask equipped with rubber septum and nitrogen inlet needle was charged with 2-(4-(5-(2,4-difluorophenyl)-4-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-imidazol-2-yl)piperidin-1-yl)-2-oxoethyl acetate (0.145 g, 0.277 mmol, prepared using General Procedure T from 6-(3-(2,4-difluorophenyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (Example #Q.1.2) and acetoxyacetyl chloride) in THF (5.0 mL). A 2.5M aqueous NaOH solution (0.274 mL, 0.685 mmol) was added dropwise via syringe to give a yellow solution. The reaction mixture was stirred at about ambient temperature for about 20 min. Additional 2.5M aqueous NaOH (0.274 mL, 0.685 mmol) was added dropwise via syringe. The reaction mixture was stirred at about ambient temperature for about 1 h. The solution was acidified with 1N HCl to about pH 5. The reaction mixture was partitioned between DCM and water. The layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography using DCM/MeOH (gradient, 1:0 to 9:1) to provide the title compound (0.107 g, 80%): LC/MS (Table 1, Method b) Rt=1.7 min; MS m/z: 482.2 (M+H)+.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12]([OH:14])=[O:13]>C(Cl)Cl.CO>[NH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12]([O:14][CH3:1])=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1cc(C(=O)O)ccc1[N+](=O)[O-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 25 °C

Procedure:
(Trimethylsilyl)diazomethane (6 mL, 2M solution in hexanes) was added to a solution of 3-amino-4-nitro-benzoic acid in CH2Cl2 (25 mL) and methanol (25 mL). Stirred at room temperature until bubbling ceased. Concentrated under vacuum to provide 1.2 g of desired product. MS (DCI) m/e 197 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([OH:5])=[O:4].[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>O1CCOCC1.CCOC(C)=O>[CH3:16][O:15][C:13]([NH:1][C@@H:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([OH:5])=[O:4])=[O:14]
Reactant: CSCC[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)N[C@@H](CCSC)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a solution of (S)-2-amino-4-(methylthio)butanoic acid (1.0 g, 6.7 mmol) in dioxane at 0° C. was added NaOH (11.06 g, 22.12 mmol) followed by dropwise addition of methyl chloroformate (1.04 mL, 13.4 mmol) and the solution was warmed to room temperature with stirring over 2 h. The solution was diluted with EtOAc, washed with 1 N HCl, brine, dried (Na2SO4), filtered and solvent removed in vacuo to give the title compound (1.3 g, 6.27 mmol, 94%). 1H NMR (400 MHz, CDCl3) δ ppm 1.95-2.07 (m, 1H) 2.07-2.13 (m, 3H) 2.14-2.28 (m, 1H) 2.59 (t, J=7.4 Hz, 2H) 3.71 (s, 3H) 4.52 (br s, 1H) 5.33 (br s, 1H).