Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[Br-].[Br-].N1C=CC=CC=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]([C:24]2([C:30]3[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:31]=3[F:37])SCCCS2)([OH:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].N1C=CC=CC=1.[OH2:44]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C(Cl)Cl.O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]([C:24](=[O:44])[C:30]2[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:31]=2[F:37])([OH:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C2(c3cc(Br)ccc3F)SCCCS2)CC1
Reactant: O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(C(=O)c2cc(Br)ccc2F)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Pyridine tribromide (12.7 g, 39.6 mmol) and TBAB (850 mg, 2.64 mmol) were added to a stirred solution of 4-[2-(5-bromo-2-fluoro-phenyl)-[1,3]dithian-2-yl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (13 g, 26.42 mmol) and pyridine (2.07 ml, 39.63 mmol) in a mixture of DCM/water (5:1, 180 ml). After stirring for 24 h at RT, the solution was poured into water (150 ml) and the product was extracted with DCM. The combined organic layers were washed with water (400 ml), brine (400 ml), dried over Na2SO4, then filtered and evaporated. The crude product was purified by column chromatography (AcOEt/hexane:20/80) to give 9.5 g of 4-(5-bromo-2-fluoro-benzoyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:19][C:20]([CH3:27])([CH3:26])[CH2:21][C:22]([NH:24][NH2:25])=[O:23]>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](/[C:9](=[N:25]/[NH:24][C:22](=[O:23])[CH2:21][C:20]([CH3:27])([CH3:26])[CH3:19])/[C:7](=[O:8])[N:6]2[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:13]=1
Reactant: CC(C)(C)CC(=O)NN
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Product: CCCCCN1C(=O)/C(=N\NC(=O)CC(C)(C)C)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin obtained in Example 39(A) and 3,3-dimethylbutanohydrazide according to the synthetic method E. NMR (CDCl3): δ 0.91 (t, 3H), 1.10 and 1.12 (s for isomers, 9H), 1.36 to 1.39 (m, 4H), 1.55 (s, 2H), 1.67-1.70 (m, 2H), 2.29 (s, 111), 2.75 (s, 1H), 3.70 (t, 2H), 3.86 and 3.87 (s for isomers, 3H), 6.42 (s, 1H), 6.60 (d, 1H), 7.51 and 7.72 (d and br s for isomers, 1H), 12.39 and 12.98 (s and br s for isomers, 1H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[S:12][CH:13]=1)(=O)=O.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:25][O:24][C:16]1[CH:15]=[C:14]([C:11]2[S:12][CH:13]=[C:9]([CH2:8][CH2:7][CH2:6][N:26]3[CH2:31][CH2:30][N:29]([CH2:6][CH2:7][CH2:8][C:9]4[N:10]=[C:11]([C:14]5[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=5)[S:12][CH:13]=4)[CH2:28][CH2:27]3)[N:10]=2)[CH:19]=[C:18]([O:20][CH3:21])[C:17]=1[O:22][CH3:23]
Reactant: COc1cc(-c2nc(CCCOS(C)(=O)=O)cs2)cc(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc(-c2nc(CCCN3CCN(CCCc4csc(-c5cc(OC)c(OC)c(OC)c5)n4)CC3)cs2)cc(OC)c1OC

Procedure:
4-(3-Methanesulfonyloxypropyl)-2-(3,4,5-trimethoxy-phenyl)thiazole (310 mg) and piperazine (34 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[O:20])=[CH:26][CH:27]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)C(=O)c1ccc(NC2CCCN(Cc3ccccc3)C2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccc(N(c2ccccc2)C2CCCN(Cc3ccccc3)C2)cc1
Temperature: 110 °C
Yield: 137.6 %

Procedure:
A mixture of 4-[N-(1-benzyl-piperidin-3-yl)-amino]-N,N-diethyl benzamide (compound 13) (0.29 mg, 0.79 mmol), Ph3Bi (0.87 g, 1.98 mmol), and Cu(OAc)2 (0.36 g, 1.98 mmol) in toluene (5 mL) was heated at 110° C. for 12 h and allowed to cool to room temperature. Water (5 mL) was added and the mixture filtered through Celite®. The layers in the filtrate were separated and the organic phase washed with water, brine, dried over Na2SO4 and concentrated. Chromatography of the residue (9:1 EtOAc/heptane) gave the title compound 14 (0.24 g, 67%) as a pale yellow viscous oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH2:14][N:15]([CH3:19])[C:16](=[O:18])[CH3:17])[N:5]=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][C:29]([CH3:37])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[CH3:30])[NH2:24]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[O:12][CH2:13][CH2:14][N:15]([CH3:19])[C:16](=[O:18])[CH3:17])[N:5]=[CH:4][N:3]=2)[CH:25]=[CH:26][C:27]=1[O:28][C:29]([CH3:30])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[CH3:37]
Reactant: CC(=O)N(C)CCOc1cccc2ncnc(Cl)c12
Reactant: CC(C)(Oc1ccc(N)cc1Cl)c1ccccn1
Product: CC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(OC(C)(C)c4ccccn4)c(Cl)c3)c12
Yield: 31 %

Procedure:
The procedure described in Example 126 was repeated using N-{2-[(4-chloroquinazolin-5-yl)oxy]ethyl}-N-methylacetamide (obtained as described in Example 126, preparation of starting materials, 47 mg, 0.170 mmol) and 3-chloro-4-(1-methyl-1-pyridin-2-ylethoxy)aniline (49 mg, 0.187 mmol) to give the title compound in 31% yield; NMR Spectrum (DMSO-d6, 400 MHz, 373K) 1.75 (s, 6H), 1.92 (s, 3H), 2.94 (s, 3H), 3.88 (t, 2H), 4.47 (t, 2H), 6.62 (d, 1H), 7.16 (d, 1H), 7.31 (ddd, 1H), 7.35 (d, 1H), 7.39 (dd, 1H), 7.70 (dd, 1H), 7.75 (dd, 1H), 7.83 (ddd, 1H), 7.99 (d, 1H), 8.46 (s, 1H), 8.58 (dd, 1H), 9.70 (s, 1H); Mass spectrum MH+ 506.0.
Reaction SMILES: C([O:8][C:9](=[O:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][C:19]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:13]([F:34])[CH:12]=1)C1C=CC=CC=1.C([Li])CCC.[C:41](OC[C@@H]1OC1)(=[O:45])[CH2:42][CH2:43]C.[NH4+].[Cl-]>C1COCC1>[CH2:27]([O:26][C:19]1[CH:20]=[C:21]([CH2:24][CH3:25])[CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[CH2:43][C@H:42]([CH2:41][OH:45])[O:8][C:9]2=[O:35])=[CH:12][C:13]=1[F:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCC(=O)OC[C@H]1CO1
Reactant: CCc1ccc(Oc2ccc(NC(=O)OCc3ccccc3)cc2F)c(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(N3C[C@H](CO)OC3=O)cc2F)c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 51.6 %

Procedure:
To a solution of [4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-phenyl]-carbamic acid benzyl ester (0.31 mmol; 145 mg), under argon, in dry THF cooled to −78° C., was added n-Butyl lithium 2.3M in THF (0.46 mmol; 200 μL). the reaction mixture was stirred ten minutes and (R)-glycidyl butyrate (0.34 mmol; 48 μL) was added. The reaction was stirred overnight with slow warming to room temperature. The mixture was treated with saturated NH4Cl and extracted with ethyl acetate. Combined organic phases were dried over Na2SO4 and concentrated in vacuo. The title compound (70 mg; 52%) was obtained as . . . after purification by preparative TLC (eluant: dichloromethane/methanol: 95/5).
Reaction SMILES: I.CS[C:4](=[NH:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:19][NH:20][CH3:21]>C(O)C>[CH3:19][N:20]([CH3:21])[C:4]([NH2:18])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Reactant: CNC
Agent: I
Solvent: CCO
Product: CN(C)C(N)=Nc1ccccc1N1CCOCC1
Reaction time: 1152 h

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (1 g), dimethylamine (1 ml of a 33% solution in ethanol) and ethanol (2 ml) was kept at ambient temperature for 48 days. The mixture was then cooled in an ice bath. The resulting solid was separated by filtration, treated with dilute aqueous sodium hydroxide solution (5 ml) and the resulting mixture extracted with dichloromethane (2×50 ml). The extract was washed with brine, dried and the solvent removed by evaporation to give 1,1-dimethyl-2-(2-morpholinophenyl)guanidine (m.p. 143°-144° C.) which was recrystallised from hexane.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>>[I:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH:13]1[CH2:14][O:15]1
Reactant: Oc1ccccc1I
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Product: Ic1ccccc1OCC1CO1
Temperature: 70 °C
Yield: 79.6 %

Procedure:
To a round bottom flask under N2 was added 4.56 g (0.095 mole) of 50% NaH in oil. The NaH was washed twice with hexane, then 220 ml of DMF was added. Aliquots of 20.0 g (0.091 mole) of o-iodophenol were added over 15 minutes then 30.0 ml (0.450 mole) of epichlorohydrin was added and the solution heated to 70° C. After two hours the reaction was evaporated in vacuo, taken into CHCl3, washed with 10% NaOH, water, and brine and dried with MgSO4. The solvent was evaporated in vacuo to give 24.93 g of crude product. Distillation at 110°-114° C., 0.05 mm Hg gave 20.0 g (80.0%) of [(2-iodophenoxy)methyl]-oxirane.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([CH:11]1[CH2:16][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[CH2:14][N:13]([C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[CH2:12]1)=O)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:45][C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][N:13]([C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:29])[CH2:12]2)=[N:8][N:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COCCC(=O)NNC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: COCCc1nnc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)s1

Procedure:
93 mg (0.185 mmol) of the compound from Example 120A and 150 mg (0.371 mmol) of Lawesson reagent were reacted according to the General Method 9. Yield: 9 mg (10% of theory)
Reaction SMILES: [CH2:1]([N:5]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:13])[C:7]2[CH:14]=[N:15][C:16](Cl)=[N:17][C:6]1=2)[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=1[O:29][CH3:30].C(O)C>Cl.O>[CH2:1]([N:5]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:13])[C:7]2[CH:14]=[N:15][C:16]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]=3[O:29][CH3:30])=[N:17][C:6]1=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCC(=O)N(C)c2cnc(Cl)nc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCCN1CCC(=O)N(C)c2cnc(Nc3ccc(C(=O)O)cc3OC)nc21
Yield: 70.1 %

Procedure:
A mixture of 0.08 g (0.0003 mole) of 9-butyl-2-chloro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-44), 0.060 g (0.00036 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.084 g of 4-(9-butyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-44a) as an off-white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][N:13]1C(=O)C2=CC=CC=C2C1=O.NN>CCO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][NH2:13]
Reactant: O=C1c2ccccc2C(=O)N1OCc1ccc2ccccc2n1
Agent: NN
Solvent: CCO
Product: NOCc1ccc2ccccc2n1
Reaction time: 8 h
Yield: 107.2 %

Procedure:
N-(2-quinolyl)methoxy phthalimide (782 mg) was suspended in 95% EtOH and hydrazine (0.15 mL) was added. The reaction mixture was stirred overnight and then filtered. The filtrate was concentrated under reduced pressure and then taken up in a small amount of dichloromethane. The small amount of remaining phthalhydrazide was then removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (480 mg) as a yellow oil. MS(CI) m/e 175 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][N:4]=1.[S:12]([O-:15])([O-:14])=[O:13].[Na+:16].[Na+]>CO.O>[O:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:3]([CH2:2][S:12]([O-:15])(=[O:14])=[O:13])=[N:4]1.[Na+:16]
Reactant: O=S([O-])[O-]
Reactant: BrCc1noc2ccccc12
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=S(=O)([O-])Cc1noc2ccccc12
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of 8.0 of 3-bromomethyl-1,2-benzisoxazole (m.p. 64°-66° C.) in 130 ml of methanol was added a solution of 8.1 g of sodium sulfite in 130 ml of water. The mixture was heated with stirring at 50° C. for 4 hours and concentrated under reduced pressure. The crystalline residue was dissolved in 250 ml of methanol with warming and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the crystalline residue was washed with diethyl ether to give crude sodium 1,2-benzisoxazole-3-methanesulfonate (10.5 g).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH:11]1([CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.C1C[O:30]CC1>>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[OH:30])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C1CCOC1
Reactant: O=C(CC1CCCC1)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(OCc1ccccc1)C(O)C1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A 1.0 M sodium hexamethyldisilazide solution in THF (27.5 ml, 27.5 mmol) was added to anhydrous THF (30 ml), and the mixture was cooled to −78° C. An anhydrous THF solution (20 ml) of benzyl cyclopentylacetate (5.0 g, 22.90 mmol) was added dropwise to the mixture over 30 min, and the mixture was stirred for additional 30 min. Subsequently, an anhydrous THF solution (20 ml) of n-benzyl-benzenesulfonyloxaziridine (7.18 g, 27.5 mmol) was added dropwise to the mixture at −78° C. over one hr, and the mixture was stirred for additional one hr. The reaction mixture was quenched with saturated ammonium chloride and was extracted with ether. The organic layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=94:6) to give the title compound as a light yellow oil (3.2 g, yield 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19][OH:20])[N:10]=1.[C:32]1(=[O:38])[O:37][C:35](=[O:36])[CH2:34][CH2:33]1.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>C(Cl)Cl>[Cl:21][C:6]1[CH:5]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[C:24]([C:30]#[N:31])=[N:23]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:19][O:20][C:32](=[O:38])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[N:10]=1
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CO)c1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(COC(=O)CCC(=O)O)c1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 24 %

Procedure:
A solution of 2-[3,5-dichloro-4-(1-hydroxymethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (200 mg, 0.42 mmol), 4-N,N-dimethyaminopyridine (2.6 mg, 0.02 mmol) and succinic anhydride (47 mg, 0.47 mmol) in methylene chloride (2.53 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.17 mL, 0.98 mmol). The reaction mixture was stirred at 25° C. for 3.5 h. At this time, the reaction mixture was poured onto a saturated aqueous ammonium chloride solution (100 mL) and was then extracted with a 90/10 methylene chloride/methanol solution (3×100 mL). The pH of the aqueous layer was brought to pH=2 with a few drops of a 2N aqueous hydrochloric acid solution and was then extracted with a 90/10 methylene chloride/methanol solution (1×100 mL). The combined organics were dried over sodium sulfate, filtered, rinsed and concentrated in vacuo. ISCO CombiFlash chromatography (12 g, 0.5-4% methanol/methylene chloride) followed by supercritical fluid chromatography (Daicel OJ column, 30% methanol) afforded succinic acid mono-{3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-5-isopropyl-6-oxo-6H-pyridazin-1-ylmethyl}ester (57 mg, 24%) as a light tan solid. ES+-HRMS m/e calcd for C22H18N6O8Cl2 (M+H+) 565.0636, found 565.0633.
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:5][CH:4]([C:6]2[C:14]([C:15]3[NH:19][C:18]([CH2:20][CH3:21])=[N:17][N:16]=3)=[CH:13][C:9]([C:10](O)=[O:11])=[C:8]([CH3:22])[CH:7]=2)[CH2:3]1.Cl.[NH:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:23][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[C:14]([C:15]3[NH:19][C:18]([CH2:20][CH3:21])=[N:17][N:16]=3)=[CH:13][C:9]([C:10]([N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=4)[CH2:27][CH2:26]3)=[O:11])=[C:8]([CH3:22])[CH:7]=2)[CH2:3]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: CCc1nnc(-c2cc(C(=O)O)c(C)cc2C2CC(F)(F)C2)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CC(F)(F)C2)[nH]1
Temperature: 30 °C
Reaction time: 3 h
Yield: 57.6 %

Procedure:
To a round-bottom flask was added a solution of 4-(3,3-difluorocyclobutyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid (compound 231.5, 211 mg, 0.660 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 146 mg, 0.660 mmol, 1.00 equiv), EDC.HCl (252 mg, 1.31 mmol, 2.00 equiv) and 4-dimethylaminopyridine (160 mg, 1.31 mmol, 2.00 equiv) were added to the reaction. The resulting solution was stirred for 3 h at 30° C. in an oil bath, then diluted with 30 mL of ethyl acetate. The mixture was washed with 3×40 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (448 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (48.0% CH3CN up to 62.0% in 6 min, up to 100.0% in 4 min, down to 48.0% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 186 mg (58%) of the title compound as a white solid. m/z (ES+) 490 (M+H)+. 1H-NMR (300 MHz, CD3OD, ppm): δ 7.68 (d, J=8 Hz, 2H), 7.59-7.44 (m, 4H), 4.89-4.80 (m, 1H), 4.03-3.98 (m, 1H), 3.67-3.61 (m, 1H), 3.28-3.24 (m, 1H), 3.04-3.00 (m, 2H), 2.97-2.89 (m, 2H), 2.87-2.83 (m, 2H), 2.62-2.60 (m, 2H), 2.48 and 2.38 (2 singlets, amide rotamers, ArCH3, 3H), 2.05-2.00 (m, 1H), 1.88-1.58 (m, 3H), 1.41 (t, 3H).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[OH-:20].[Na+].Cl>O>[OH:20][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cn1nnnc1-c1cn(C)c2cc(O)ccc2c1=O
Temperature: 25 °C

Procedure:
A mixture of 7-fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone (5 g) and aqueous sodium hydroxide (5N, 80 ml) was stirred and boiled under reflux for 45 hours. Water (180 ml) was added to the mixture which was then cooled to ambient temperature. The solution was acidified with concentrated hydrochloric acid to pH 4. The resulting precipitate was collected by filtration and washed with boiling industrial methylated spirit (300 ml) and then hot butanol (120 ml). The residue was crystallised from 50% aqueous industrial methylated spirit to give the novel compound 7-hydroxy-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone, m.p. >320°.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:9]1([C:13]([C:15]2[CH:16]=[C:17]([Cl:36])[C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:35])[CH2:33][OH:34])[CH:30]=3)[C:25]([OH:27])=[O:26])=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.N12CCCN=C1CCCCC2>C(#N)C>[N:9]1([C:13]([C:15]2[CH:16]=[C:17]([Cl:36])[C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:35])[CH2:33][O:34][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:30]=3)[C:25]([OH:27])=[O:26])=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: C[C@@H](CO)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.6 %

Procedure:
tert-Butyldimethylsilyl chloride (2.78 g, 18.4 mmol) was added to a mixture of 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}benzoic acid (3.74 g, 9.19 mmol) and 1,8-diazabicyclo(5,4,0)undec-7-ene (2.75 mL, 7.36 mmol) in acetonitrile (40 mL) and stirred at RT for 24 hours. The solvent was removed in vacuo and water (80 mL) added to the resultant oil. The mixture was adjusted to pH 10 with 1M sodium bicarbonate solution and washed with ether to remove any impurities. The aqueous layer was adjusted to pH 3 with 1M citric acid and extracted into ethyl acetate (2×100 mL). The combined organics were washed with brine (50 mL), dried (MgSO4), filtered and reduced in vacuo to give the desired compound as a white foam (2.9 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([OH:35])[CH:34]=1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:31]1[CH:32]=[C:33]([OH:35])[CH:34]=[C:29]([F:28])[CH:30]=1
Reactant: C[C@H](Nc1ncnc(N)c1I)c1nn2cccc2c(=O)n1-c1ccccc1
Reactant: OB(O)c1cc(O)cc(F)c1
Product: C[C@H](Nc1ncnc(N)c1-c1cc(O)cc(F)c1)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 3 %

Procedure:
(S)-2-(1-(6-Amino-5-iodopyrimidin-4-ylamino)ethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one and 3-fluoro-5-hydroxyphenylboronic acid (34 mg, 0.22 mmol) were stirred at 80° C. following the experimental procedure described in Example 3. 5 mg (3% yield) of the title compound were obtained as a solid.