Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12](O)=[O:13])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29].C(OC(Cl)=O)C(C)C.[CH3:38][N:39]1CCOCC1>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH:39][CH3:38])=[O:13])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29]
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Product: CNC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Reaction time: 0.08 h
Yield: 98.4 %

Procedure:
To a solution of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (0.16 g, 0.00034 mol, obtained from Step 5) at 0° C. is added isobutylchloroformate (0.063 g, 0.00046 mol) followed by the addition of N-methylmorpholine (0.064 g, 0.00064 mol). The resulting reaction mixture is stirred for 5 minutes under an argon atmosphere. The ice bath is then removed, the reaction mixture is stirred at room temperature for 20 minutes, then the reaction mixture is recooled to 0° C., and N-methylamine (0.5 mL of 2.0 M soln in THF) is added. The resulting mixture is stirred at room temperature for 10 min, concentrated in vacuo, and the residue is purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=478) are combined, concentrated to a small volume (˜20 mL), cooled, 5% NaHCO3 solution (10 mL) is added and then the combined fractions are extracted with dichloromethane (3×20 mL). The combined organic extracts are dried (Na2SO4), filtered, and concentrated to dryness to afford the title compound (0.16 g, 96%) as a white amorphous substance: 1H NMR (CD3OD/400 MHz) δ 7.87 (dd 1H, J=8.0 Hz), 7.64 (d, 1H, J=1.6 Hz), 7.61 (m, 1H), 7.53 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.55 (m, 2H), 2.89 (s, 3H), 2.16 (s, 3H), and 2.12 (s, 3H); ES-HRMS m/z 478.0586 (M+H calcd for C21H19N2O4F2 requires 478.0572). 19F NMR (CD3OD/400 MHz) −111.84 (m) and −115.91 (m).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Br:10]Br.Cl>[OH-].[Na+].S(=O)(O)[O-].[Na+]>[Br:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: BrBr
Reactant: c1ccc2[nH]ncc2c1
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Product: Brc1n[nH]c2ccccc12
Reaction time: 3 h
Yield: 107.4 %

Procedure:
To a suspension of 1H-indazole (3.00 g, 25.4 mmol) in 2.0 M sodium hydroxide solution (70 mL) at ambient temperature was added a solution of bromine (3.00 g, 18.8 mmol) in 2.0 M sodium hydroxide solution (30 mL) dropwise. After stirring for 3 hours, to the reaction mixture was added sodium bisulfite (0.1 g), followed by 2.0 N hydrochloric acid solution (80 mL). The precipitates were filtered and washed with water to provide the title compound (3.98 g, 80% yield): mp 136° C.; 1H NMR (CDCl3) δ 13.4 (br s, 1H), 7.57 (m, 2H), 7.45 (t, 1H), 7.22 (t, 1H); EI-MS (m/z) 198 [M+2]+, 196 [M]+.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:15][C:16]1[C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=3)[NH:28][C:24]=2[C:23]2[C:22](=[O:39])[NH:21][C:20](=[O:40])[C:19]([CH3:42])([CH3:41])[C:18]=2[CH:17]=1.[CH3:43][O:44][C:45]1[CH:46]=[C:47]([CH2:53][CH2:54][N:55]([CH2:63][CH2:64][CH2:65]O)[C:56](=[O:62])[O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH:48]=[CH:49][C:50]=1[O:51][CH3:52].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.C(Cl)Cl.CC(C)=O>[Br:15][C:16]1[C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=3)[NH:28][C:24]=2[C:23]2[C:22](=[O:39])[N:21]([CH2:65][CH2:64][CH2:63][N:55]([CH2:54][CH2:53][C:47]3[CH:48]=[CH:49][C:50]([O:51][CH3:52])=[C:45]([O:44][CH3:43])[CH:46]=3)[C:56](=[O:62])[O:57][C:58]([CH3:60])([CH3:61])[CH3:59])[C:20](=[O:40])[C:19]([CH3:42])([CH3:41])[C:18]=2[CH:17]=1
Reactant: COc1ccc(CCN(CCCO)C(=O)OC(C)(C)C)cc1OC
Reactant: Cc1ccc(-c2nc3c(Br)cc4c(c3[nH]2)C(=O)NC(=O)C4(C)C)cc1[N+](=O)[O-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CCN(CCCN2C(=O)c3c(cc(Br)c4nc(-c5ccc(C)c([N+](=O)[O-])c5)[nH]c34)C(C)(C)C2=O)C(=O)OC(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
DIAD (1.15 mL, 5.87 mmol) was added dropwise to a solution of 4-bromo-6,6-dimethyl-2-(4-methyl-3-nitrophenyl)-1H-imidazo[4,5-h]isoquinoline-7,9(6H,8H)-dione (1.3 g, 2.93 mmol), tert-butyl [2-(3,4-dimethoxyphenyl)ethyl](3-hydroxypropyl)carbamate (from Example 1) (1.99 g, 5.87 mmol), and PPh3 (1.54 g, 5.87 mmol) in THF (14.7 mL). The reaction mixture was stirred at 25° C. for 30 min, then was concentrated under reduced pressure. The residue was purified twice by flash chromatography (40-63μ silica gel) first with hexane:EtOAc 1:1 and then with CH2Cl2:acetone 95:5 to give the title compound (789.6 mg, 35% yield).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=1[Cl:21].[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:29]([NH2:47])=[N:30][C:31]3[C:36]([CH:37]=2)=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=3)[CH2:24][CH2:23]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Cl:21][C:12]1[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=1[O:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[N:30]=[C:29]([NH2:47])[C:28]([N:25]1[CH2:24][CH2:23][O:22][CH2:27][CH2:26]1)=[CH:37]2
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Reactant: Cc1cccc(COc2cc(C(F)(F)F)ccc2Cl)c1Br
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(COc2cc(C(F)(F)F)ccc2Cl)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1

Procedure:
A degassed solution of 2-bromo-1-((2-chloro-5-(trifluoromethyl)phenoxy)methyl)-3-methylbenzene (64.1 mg, 0.169 mmol), 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (50 mg, 0.141 mmol, prepared as in Example 2, Step 1-2), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (13.42 mg, 0.028 mmol), potassium phosphate (149 mg, 0.704 mmol) and Pd2(dba)3 (6.44 mg, 7.04 μmol) in dioxane (0.94 mL)/water (0.47 mL) was heated in a sealed tube in the microwave at 140° C. for 15 min. The reaction was then quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was then washed with water and brine (3× ea.), dried over Na2SO4 and concentrated in vacuo to remove the solvent. The crude material was purified by column chromatography with 0-100% (10% NH3 in MeOH/DCM)/DCM to afford 6-(2-((2-chloro-5-(trifluoromethyl)phenoxy)methyl)-6-methylphenyl)-3-morpholinoquinolin-2-amine. MS (ESI, pos. ion) m/z: 528 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].FC(F)(F)S(O[C:19]1[CH2:28][CH2:27][C:22]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:21][CH:20]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:23]1[C:22]2([CH2:27][CH2:28][C:19]([C:7]3[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=3)=[CH:20][CH2:21]2)[O:26][CH2:25][CH2:24]1
Reactant: O=S(=O)(OC1=CCC2(CC1)OCCO2)C(F)(F)F
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(C2=CCC3(CC2)OCCO3)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 38.4 %

Procedure:
To a solution of 4-carboxyphenylboronic acid (0.69 g, 3.53 mmol) and 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (1.02 g, 3.53 mmol) in 14 mL of DMF were added 7 mL of 2 N aqueous solution of Na2CO3, triphenylphosphine (159 mg, 0.61 mmol), and tris(dibenzylideneacetone)dipalladium(0) (68 mg, 74.2 μmol). After stirring at 80° C. for 3 h and then at rt for 16 h, the mixture was concentrated and partitioned between 100 mL of Et2O and 150 mL of H2O. The aqueous layer was separated and acidified to pH ˜2-3 using concentrated HCl, and extracted with CH2Cl2 (2×100 mL). The organic layers were combined, dried over Na2SO4, and concentrated. The residue was re-crystallized from 10 mL of EtOAc to give 353 mg (38%) of the title compound.
Reaction SMILES: C[Si]([CH2:5][OH:6])(C)C.[H-].[Na+].[N+]([C:12]1[CH:19]=[CH:18][CH:17]=[C:14]([C:15]#[N:16])[C:13]=1[C:20]#[N:21])([O-])=O>CN(C)C=O>[CH3:5][O:6][C:12]1[CH:19]=[CH:18][CH:17]=[C:14]([C:15]#[N:16])[C:13]=1[C:20]#[N:21]
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Reactant: C[Si](C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C#N)c1C#N
Temperature: 5 °C
Reaction time: 1 h
Yield: 1 %

Procedure:
In 60 ml of N,N-dimethylformamide were dissolved 20 g of trimethylsilylmethanol. This was maintained at 5° C. in a water bath and 4.6 g of sodium hydride were added thereto in the atmosphere of argon. The resulting mixture was stirred at 5° C. for 1 hour. Thereafter, 33.3 g of 3-nitrophthalonitrile dissolved in 160 ml of N,N-dimethylformamide were added dropwise to the mixture. After completion of the addition, the ice bath was removed and the mixture was stirred at room temperature for 24 hours. The reaction product was then added with 200 ml of dilute hydrochloric acid and extracted with 1 liter of toluene. The organic layer was washed well with water, followed by the removal of water with magnesium sulfate and the purification with a toluene/silica gel column. However, the desired compound shown by the above formula (XV) was hardly obtained. The yield was about 1% and 3-methoxyphthalonitrile as a by-product was yielded in an amount of several times that of the compound (XV).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C[C@@H](NC(OC(C)(C)C)=O)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C1C=CC=CC=1.C(C(NC(=O)[C@H](N1C=CC(C2C=CC([C:96]3[CH:101]=[CH:100][C:99]([C:102](=[O:104])[NH2:103])=[CH:98][CH:97]=3)=CC=2)=C1)CC(O)=O)CO)C1C=CC=CC=1>ClCCCl>[CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:96]3[CH:101]=[CH:100][C:99]([C:102](=[O:104])[NH2:103])=[CH:98][CH:97]=3)=[CH:33][CH:34]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(-c2ccc(-c3ccn([C@H](CC(=O)O)C(=O)NC(CO)Cc4ccccc4)c3)cc2)cc1
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccccc2)c1)C(C)(C)C
Agent: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: ClCCCl
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccc(C(N)=O)cc3)cc2)c1)C(C)(C)C
Yield: 55 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)-3(R)-(3-phenyl-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-t-butoxycarbonylamino-N-(2,2-dimethyl-1(S)-methylcarbamoylpropyl)succinamic acid benzyl ester was deprotected. The crude amine salt and crude 3-(4′-carboxamidobiphenyl-4-yl)-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 4(b)) were condensed in wet 1,2-dichloroethane at 90-100° C. to yield 180 mg(55%) of 3(R)-[3-(4′-carbamoylbiphenyl-4-yl)-1H-pyrrol-1-yl]-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester. 1H NMR) δ 7.90 (d, 2H, J=8.4 Hz), 7.70 (d, 2H, J=8.7 Hz), 7.60 (dd, 3H, J=8.7, 11.5 Hz), 7.38-7.22 (m, 8H), 7.10 (t, 1H, J=2.2 Hz), 6.82 (t, 1H, J=2.5 Hz), 6.62 (t, 1H, J=3.0 Hz), 6.32 (d, 1H, J=9.0 Hz), 5.63 (d, 1H, J=4.70 Hz), 5.14 (d, 3H, J=3.7 Hz), 4.00 (d, 1H, J=8.7 Hz), 3.48 (dd, J=7.2, 13.1 Hz), 3.39 (d, 1H, J=5.9 Hz), 3.14 (dd, 1H, J=8.7, 16.8 Hz), 2.78 (d, 3H, J=4.7 Hz), 0.92 (s, 9H). IR (KBr): 3356, 2929, 1735, 1657, 1402 cm−1. Anal. Calculated for C35H39N4O5.0.5H2O: C, 69.63; H, 6.51; N, 9.28. Found: C, 69.85, H, 6.46; N, 9.14.
Reaction SMILES: Br[C:2]1[C:29]([Cl:30])=[CH:28][C:5]([O:6][C:7]2[C:12]([C:13]([N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH:25]4[CH2:27][CH2:26]4)[CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([Cl:31])[CH:3]=1.C(N(C(C)C)C(C)C)C.[C:41]([O:45][CH2:46][CH3:47])(=[O:44])[CH:42]=[CH2:43].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:46]([O:45][C:41](=[O:44])[CH:42]=[CH:43][C:2]1[CH:3]=[C:4]([Cl:31])[C:5]([O:6][C:7]2[C:12]([C:13]([N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH:25]4[CH2:27][CH2:26]4)[CH2:17][CH2:16]3)=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:28][C:29]=1[Cl:30])[CH3:47]
Reactant: O=C(c1cccnc1Oc1cc(Cl)c(Br)cc1Cl)N1CCN(C2CC2)c2ccccc21
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCOC(=O)C=Cc1cc(Cl)c(Oc2ncccc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 95 °C

Procedure:
To a degassed solution of [2-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone (500 mg, 0.96 mmol, 1.0 equiv; Example 163) in propionitrile (10 mL) under Ar was added N-ethyldiisopropylamine (373 mg, 491 μL, 2.89 mmol, 3.0 equiv; [CAS RN 7087-68-5]), ethyl acrylate (0.58 g, 0.63 mL, 5.78 mmol, 6.0 equiv; [CAS RN 140-88-5]), palladium(II) acetate (22 mg, 0.10 mmol, 0.1 equiv; [CAS RN 3375-31-3]) and tri-o-tolyl-phosphane (59 mg, 0.19 mmol, 0.2 equiv; [CAS RN 6163-58-2]). The reaction mixture was heated to 95° C. over night. The crude reaction was filtered over Celite®, a sat. solution of NaCl (50 mL) added and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over Na2SO4 and the product purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate affording 320 mg (62%) of the title compound as a yellow foam. MS (ISN): 538.3 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][C:5]=1[C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O.[NH2:28][NH2:29]>C(O)C>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]2[C:3](=[O:2])[NH:29][N:28]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]=2[N:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: COC(=O)c1ccc(OCc2ccccc2)nc1C(=O)c1ccccc1
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2ccccc2)c2nc(OCc3ccccc3)ccc12

Procedure:
2-Benzoyl-6-benzyloxynicotinic acid methyl ester (1.14 g) and hydrazine monohydrate (0.40 ml) were stirred together in ethanol (50 ml) at reflux overnight. The reaction was cooled (ice bath) precipitating a solid, which was separated by filtration and washed with diethyl ether. This was 2-benzyloxy-8-phenyl-6H-pyrido[2,3-d]pridazin-5-one (0.845 g). 1H NMR (400 MHz, DMSO) δ5.42 (2H, s), 7.33 (6H, m), 7.50 (3H, m), 7.86 (2H, m), 8.51 (1H, d, J=9.7 Hz), 13.04 (1H, s); MS (ES+) m/e 330 [MH]+.
Reaction SMILES: Cl[CH2:2][N:3]1[CH2:8][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][C:4]1=[O:21].[NH3:22].C1(C)C=CC=CC=1.[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34]>C(O)C.CCOCC.C1COCC1>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]\[C:33]([OH:35])=[O:34].[NH2:22][CH2:2][N:3]1[CH2:8][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][C:4]1=[O:21]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)CN1CCl
Reactant: N
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: NCN1CC(c2ccccc2)(c2ccccc2)CCC1=O
Temperature: 25 °C

Procedure:
1-Chloromethyl-5,5-diphenyl-2-piperidinone (16g) was added portionwise over 15 min. to a mixture of ammonia (100 ml), toluene (100 ml) and THF (100 ml) at -40° C. with stirring and the mixture was allowed to warm to room temperature over 3 days. The reaction mixture was partitioned between water and chloroform and the combined organic solvents were washed with water and brine. Concentration of the solvents to dryness gave 15 g of crude product which was dissolved in absolute ethanol (150 ml) and treated with maleic acid (6 g) dissolved in ethanol (15 ml). Ether (50 ml) was added and the precipitated solid (13 g) was filtered off. The solid (13 g) was dissolved in 850 ml. of 40° C. water, filtered and the aqueous solution was freeze-dried to give the title product as a maleate salt (mp 136° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]([F:21])([F:20])C(O)=O.O>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:16]([F:21])[F:20])[CH:3]=1
Reactant: Oc1cncc(Br)c1
Reactant: O=C(O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)Oc1cncc(Br)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 17.2 %

Procedure:
A mixture of 5-bromopyridin-3-ol (3.7 g, 21 mmol) and potassium carbonate (8.8 g, 64 mmol) in DMF (50 ml) was treated with 2-chloro-2,2-difluoroacetic acid (2.16 ml, 25 mmol) and the reaction mixture was heated at 100° C. overnight. Further potassium carbonate (4.4 g, 32 mmol) and 2-chloro-2,2-difluoroacetic acid (1.08 ml, 12.5 mmol) were added and the reaction mixture stirred at 100° C. overnight. Water and ethyl acetate were added and the organic phase was washed with brine, dried over magnesium sulphate and the solvent was removed under vacuum. The resulting crude was purified by flash chromatography using SP1® Purification System (0% to 15% in 25 CV, hexane-ethyl acetate) to obtain 0.81 g (17% yield) of the title compound. Purity: 100%
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].N1C=CC=CC=1.[NH:11]([C:18]1[N:23]=[C:22]([C:24]2[N:28]([CH:29]([CH3:31])[CH3:30])[C:27]([CH:32]=O)=[N:26][CH:25]=2)[CH:21]=[CH:20][N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCO>[NH:11]([C:18]1[N:23]=[C:22]([C:24]2[N:28]([CH:29]([CH3:30])[CH3:31])[C:27]([CH:32]=[N:4][O:2][CH3:3])=[N:26][CH:25]=2)[CH:21]=[CH:20][N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)n1c(-c2ccnc(Nc3ccccc3)n2)cnc1C=O
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=Cc1ncc(-c2ccnc(Nc3ccccc3)n2)n1C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
Methoxylamine hydrochloride (340 mg, 4.07 mmol) and pyridine (322 mg, 4.07 mmol) was added to a solution of 2-anilino-4-(2-formyl-1-isopropylimidazol-5-yl)pyrimidine (Example 10; 250 mg, 0.814 mmol) in EtOH (10 ml) and the mixture was stirred at ambient temperature for 18 hours. The volatiles were removed by evaporation and the residue triturated with water. The solid product was collected by filtration and dried at 50° C. under vacuum to give the title compound (248 mg, 91%) as a white crystalline solid. NMR (CDCl3): 1.54 (d, 6H), 4.07 (s, 3H), 5.65-5.80 (sept, 1H), 6.95 (d, 1H), 7.15 (m, 2H), 7.34 (t, 2H), 7.50 (s 1H), 7.57 (d, 2H), 8.28 (s, 1H), 8.41 (d, 1 H); m/z 337.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1.CCN(C(C)C)C(C)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:26]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(OCc1ccccc1)C1CNCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCOC(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.5 %

Procedure:
Phenylmethyl 2-morpholinecarboxylate (450 mg, 2.034 mmol) was dissolved in dichloromethane (30 ml). DIPEA (0.71 ml, 4.07 mmol) and acetic anhydride (0.23 ml, 2.441 mmol) were added and the mixture was stirred under nitrogen at room temperature for 18 hr. The solvent was removed in vacuo, the residue was portioned between dichloromethane (20 ml) and water (20 ml) and separated by hydrophobic frit. The aqueous layer was washed with dichloromethane (2×10 ml) and to the combined organic phases was added saturated sodium bicarbonate solution (20 ml). The phases were separated by hydrophobic frit and the aqueous layer was washed with dichloromethane (2×10 ml). The solvent was removed in vacuo, the residue was dissolved in dichloromethane (˜5 ml) and the residue was purified by flash chromatography (20 g silica, gradient elution, 0-100% EtOAc-Cyclohexane then 0-20% MeOH). The solvent was removed in vacuo to give the title compound (313 mg, 1.19 mmol) as a colourless oil.
Reaction SMILES: [OH:1][C:2]1[C:3]2[S:10][C:9]3[N:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[N:6][N:7]=1.[C:16]([O-])([O-])=O.[K+].[K+].CN(C=O)C.CI>O>[CH3:16][N:7]1[C:2](=[O:1])[C:3]2[S:10][C:9]3[N:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:8]=3[C:4]=2[N:5]=[N:6]1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc2c(n1)sc1c(O)nnnc12
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1ccc2c(n1)sc1c(=O)n(C)nnc12
Reaction time: 3 h

Procedure:
To a mixture of 6 g. (0.028 M) of 4-hydroxy-7-methylpyrido[3',2':4,5]thieno[3,2-d]-1,2,3-triazine, 12 g. of K2CO3 in 150 ml. DMF at 75° C. was added 6 ml. methyl iodide and stirring at this temperature was continued for 3 hours. The mixture was then diluted with water and the precipitated product was collected by filtration. Crystallization with chloroform gave m.p. 169°-171° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][Si](C(C)(C)C)(C)C)[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1.N1C=CC=CC=1>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][OH:26])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]1n1c(=O)sc2cnc(N)nc21
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](CO)O[C@H]1n1c(=O)sc2cnc(N)nc21
Reaction time: 2 h
Yield: 100.5 %

Procedure:
To a solution of 92 (0.22 g, 0.44 mmol) in THF (5 mL) in a plastic vial was added HF/pyridine (0.70 mL). The reaction was stirred for 2 h, concentrated and purified by flash column chromatography (silica, MeOH/CHCl3: gradient=5-10%) to afford 0.17 g (100%) of the title compound as a white solid: mp 109-111° C.; 1H (400 MHz, d6-DMSO) δ 8.37 (s, 1H), 6.91 (s, 2H), 6.00 (m, 2H), 5.48 (t, J=6.0 Hz, 1H), 4.91 (t, J=6.0 Hz, 1H), 4.04 (dd, J=10.4, 6.0 Hz, 1H), 3.64 (m, 1H), 3.52 (m, 1H), 2.08 (s, 3H), 2.05 (s, 3H); MS (+)-ES [M+H]+ m/z 385.3. Elemental Analysis calc'd for C14H16N4O7S.0.5 CH3OH.0.2 CHCl3: C, 41.61; H, 4.32; N, 13.21; S 7.56: Found: C, 41.73; H, 4.29; N, 12.86; S, 7.33.