Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][CH:12]([F:14])[F:13])[CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:4].[Li+].[OH-].Cl.BrC[C:27]([C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:28].C(N(CC)CC)C>CO>[C:18]([O:17][C:15]([N:6]1[CH2:7][CH:8]([CH2:10][O:11][CH:12]([F:14])[F:13])[CH2:9][CH:5]1[C:3]([O:2][CH2:1][C:27]([C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:28])=[O:4])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: COC(=O)C1CC(COC(F)F)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(COC(F)F)CC1C(=O)OCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.6 %

Procedure:
4-Difluoromethoxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (398 mg, 1.29 mmol) was dissolved in MeOH (8 mL) and LiOH (1 M in H2O, 2 mL, 2 mmol) was added. After stirring at RT for 5 h, the MeOH was removed under reduced pressure. The aqueous solution was poured into a separatory funnel, diluted with 1 M HCl (2 mL, 2 mmol) and extracted with DCM (3×). The combined organics were dried over MgSO4, filtered and concentrated. The residue was dissolved in MeCN (4 mL) and treated with 2,4′-dibromoacetophenone (200 mg, 0.719 mmol), and triethylamine (0.100 mL, 0.719 mmol). After stirring for 15 h, the solvent was removed. The crude residue was purified by silica column chromatography (10% to 35% EtOAc/Hex) to afford the title compound (303 mg, 94%).
Reaction SMILES: C(O[CH:5]([C:12]1[CH:13]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:15]=[N:16][C:17]=1[O:18][CH3:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.C(N(CC)CC)C.[H][H]>[C].[Pd].C(O)C>[C:20]1([C:14]2[N:15]=[N:16][C:17]([O:18][CH3:19])=[C:12]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:13]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1nnc(-c2ccccc2)cc1C(OC(C)=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1nnc(-c2ccccc2)cc1Cc1ccccc1
Yield: 100.3 %

Procedure:
600 mg of 10% palladium carbon was added to a mixture of 1.58 g of 5-(α-acetoxybenzyl)-3-phenyl-6-methoxypyridazine, 2.0 ml of triethylamine and 10 ml of ethanol, and the mixture was subjected to hydrocracking in a hydrogen atmosphere. The catalyst was filtered off, and the solvent was removed. Then, the residue was subjected to NH-silica gel (Fuji Silicia) and eluted with ethyl acetate, to give 1.31 g of the target compound.
Reaction SMILES: [N:1]([CH2:4][C:5]([NH:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=[O:27])[N:12]([CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[NH:21][C:20]1=[O:26])[C:13]2=[O:18])=[O:6])=[N+]=[N-].[H][H].[ClH:30]>CO.[Pd]>[ClH:30].[NH2:1][CH2:4][C:5]([NH:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=[O:27])[N:12]([CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[NH:21][C:20]1=[O:26])[C:13]2=[O:18])=[O:6]
Reactant: [N-]=[N+]=NCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 84 %

Procedure:
A mixture of 2-azido-N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}acetamide (1.2 g, 3.24 mmol), and 10% Pd/C (0.15 g) in 4N HCl (20 ml) and CH3OH (50 ml) was hydrogenated in Parr shake apparatus under 50 psi of hydrogen for 3 hours. The mixture was then filtered through celite and the filtrate was concentrated to a solid residue. The solid was slurried in ethanol (20 ml) and the suspension filtered to give 2-amino-N-{[2-(2,6-dioxo(3-piperidyl))1,3-dioxoisoindolin-4-yl]methyl}acetamide hydrochloride (0.86 g, 84%) as a white solid: mp 270–272° C.; 1H NMR (DMSO-d6) δ d 11.16 (s, 1H), 9.28 (t, J=5.7 Hz, 1H), 8.33 (s, 3H), 7.83 (s, 3H), 5.20–5.13 (dd, J=5.3 and 12.5 Hz, 1H), 4.81 (d, J=5.7 Hz, 2H), 3.69 (s, 2H), 2.92–2.87 (m, 1H), 2.65–2.51 (m, 2H), 2.09–2.05 (m, 1H); 13C NMR (DMSO-d6) δ d 172.76, 169.80, 167.44, 166.91, 166.52, 138.24, 134.74, 133.53, 131.51, 127.17, 122.08, 48.89, 37.89, 30.94, 21.99; Anal. Calcd. For C16H17N4O5Cl: C, 50.47; H, 4.50; N, 14.71; Cl, 9.31. Found: C, 50.39; H, 4.61; N, 14.42; Cl, 9.25.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[CH:5][CH:4]=1.[C:11](O)(=O)[C:12]([OH:14])=[O:13]>C1COCC1>[C:3]([O:13][C:12]([CH2:11][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:11][C:12]([O:14][C:6]([CH3:9])([CH3:7])[CH3:5])=[O:13])=[CH:5][CH:4]=1)=[O:14])([CH3:8])([CH3:4])[CH3:2]
Reactant: O=C(O)C(=O)O
Reactant: BrCc1ccc(CBr)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1ccc(CCC(=O)OC(C)(C)C)cc1
Reaction time: 12 h
Yield: 75 %

Procedure:
To a mixture of 200 ml of THF and 44 ml (0.315 mol) of diisopropylamine was added 168 ml (286 mmols) of hexane solution of 1.70 mol dm-3 butyl lithium at 0° C. The mixture was stirred at 0° C. for 10 minutes and then cooled to -78° C. To the mixture was added 35 ml (260 mmols) of t-butyl acetate, followed by stirring for 1 hour. To the lithium enolate thus formed was added 300 ml of THF solution of 26.4 g (0.1 mol) of α,α'-dibromo-p-xylene. The reaction mixture was stirred at -78° C. to room temperature for 12 hours, and 100 ml of saturated aqueous solution of oxalic acid was thereafter added thereto. The organic layer was separated off and subjected to extraction with ether. The organic layer was dried over MgSO4 and concentrated to obtain an oil, which was then subjected to silica gel column chromatography (90:10 hexane-ether), affording 25.0 g (yield 75%) of t-butyl 3-[4-(2-t-butoxycarbonylethyl)phenyl]propionate in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>CC#N>[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([N:11]2[C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=3[NH:1][C:23]2=[O:25])(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2cccc([N+](=O)[O-])c2N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2c(=O)[nH]c3c([N+](=O)[O-])cccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-(2-amino-3-nitrophenyl)-4-methylbenzenesulfonamide from Step A (2.00 g, 6.51 mmol) in CH3CN (100 mL) was added triphosgene (966 mg, 3.25 mmol) and the mixture was stirred at ambient temperature for 30 min. The precipitate was isolated by filtration and dried in vacuo to give the title compound. MS: m/z=334 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[CH:7][CH:6]=[CH:5]2.[Li][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]=[C:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:6]=[CH:5]2
Reactant: Cc1cc2ncccc2cc1Cl
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2nc(-c3ccccc3)ccc2cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Into a solution of 6-chloro-7-methylquinoline (1000 mg, 5.644 mmol) in THF (5 mL), which was cooled in ice/water bath under N2, was added PhLi (1.9 M in THF, 2.971 mL) dropwise over 5 min. After stirring at 0° C. for 15 min, the ice/water bath was removed and the reaction mixture was stirred at rt. After 4 h, MeOH (5 mL) was added to quench the reaction and the reaction mixture was stirred at rt overnight. After that time, the mixture was poured into water (20 mL) and extracted with EtOAc (3×30 mL). The organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in acetonitrile (30 mL) and DDQ (1282 mg) was added and the solution was stirred under N2 at rt for 24 h. After that time, the reaction mixture was poured into aqueous NaOH (3 N, 50 mL) and extracted with EtOAc (2×75 mL). The extracts were washed with aqueous NaOH (3N, 2×50 mL), water (2×50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford the title compounds; 1H NMR (CDCl3, 400 MHz) δ 2.60 (s, 3H), 7.47-7.55 (m, 3H), 7.83-7.86 (m, 2H), 8.04 (s, 1H), 8.10-8.16 (m, 3H); MS (ES): 254.1/256.1 (M/M+2).
Reaction SMILES: Cl.[NH:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH2:3].C(N(CC)CC)C.[C:17](OCC)(=[O:22])[CH2:18][C:19]([CH3:21])=O>C(O)C>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][N:2]1[C:17](=[O:22])[CH2:18][C:19]([CH3:21])=[N:3]1)[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1N=C(C)CC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
To an ethanol (250 mL) solution of ethyl hydrazinoacetate monohydrochloride (19.4 g, 125 mmol) was added triethylamine (19.2 mL, 138 mmol), and the mixture was stirred at room temperature for 10 minutes, and then ethyl acetoacetate (16.6 mL, 131 mmol) was added, and the mixture was heated to reflux for four hours. After returning the mixture to room temperature, the solvent was distilled off under reduced pressure. N-heptane (100 mL) was added to the residue to yield a solid, and the obtained solid was filtered and washed with n-heptane to obtain primary crystals of the title compound (17.1 g, 93.0 mmol). Furthermore, the solvent in the filtrate was distilled off under reduced pressure, and to the residue, n-heptane/acetone mixture (1:1) was added to yield a solid, and the obtained solid was filtered. Thus, secondary crystals of the title compound (0.44 g, 2.39 mmol) were obtained.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[N:6]1.[Cl:26][C:27]1[CH:43]=[CH:42][C:30]2[N:31]([CH3:41])[C:32](=[O:40])[N:33]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:29]=2[CH:28]=1.C(N(CC)CC)C>CCO>[Cl:26][C:27]1[CH:43]=[CH:42][C:30]2[N:31]([CH3:41])[C:32](=[O:40])[N:33]([CH:34]3[CH2:39][CH2:38][N:37]([CH2:3][CH:2]([OH:1])[CH2:4][N:5]4[CH:9]=[C:8]([C:10]5[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=5)[C:7]([C:16]5[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=5)=[N:6]4)[CH2:36][CH2:35]3)[C:29]=2[CH:28]=1
Reactant: Cn1c(=O)n(C2CCNCC2)c2cc(Cl)ccc21
Reactant: FC(F)(F)c1ccc(-c2nn(CC3CO3)cc2-c2ccncc2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cn1c(=O)n(C2CCN(CC(O)Cn3cc(-c4ccncc4)c(-c4ccc(C(F)(F)F)cc4)n3)CC2)c2cc(Cl)ccc21
Temperature: 80 °C
Yield: 21.6 %

Procedure:
To a solution of 4-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-pyridine (68 mg, 0.197 mmol) and 5-chloro-1-methyl-3-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (0.055 g, 0.207 mmol) in EtOH (1 mL) was added triethylamine (0.027 mL, 0.197 mmol). The reaction mixture was heated at 80° C. overnight, concentrated, and purified by column chromatography (silica, 2-10% MeOH/CH2Cl2) to afford the title compound (0.026 g, 22%). MS (electrospray): exact mass calculated for C31H30ClF3N6O2, 611.2 [M+H]+, m/z found, 611.2. 1H NMR (400 MHz, CDCl3): 8.59 (br s, 2H), 8.20 (s, 1H), 7.67 (d, J=8.2 Hz, 2H), 7.61 (d, J=5.9 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.35 (br s, 1H), 7.09 (dd, J=8.2,1.8 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 4.55-4.60 (m, 2H), 4.39 (d, J=14.2, 4.1 Hz, 1H), 4.31 (d, J=14.2, 6.1 Hz, 1H), 3.80-3.90 (m, 2H), 3.37 (s, 3H), 3.18-3.33 (m, 2H), 3.02-3.17 (m, 2H), 2.77-2.95 (m, 2H), 1.99 (t, J=12.4 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([C:10]([OH:12])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:13]([NH:20][CH2:21][C:22]([CH3:24])=[CH2:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.[O-]P1(OP([O-])(=O)OP([O-])(=O)OP([O-])(=O)O1)=O.[Na+].[Na+].[Na+].[Na+]>C(Cl)Cl>[CH2:13]([N:20]([CH2:21][C:22]([CH3:24])=[CH2:23])[C:10]([CH:9]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=2[CH2:8]1)=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=C(C)CNCc1ccccc1
Reactant: O=C(O)C1Cc2c(Cl)cccc21
Agent: O=P1([O-])OP(=O)([O-])OP(=O)([O-])OP(=O)([O-])O1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)CN(Cc1ccccc1)C(=O)C1Cc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 3-chloro-1,2-dihydrocyclobutabenzene-1-carboxylic acid (7.67 mmol, 1.4 g) in DCM (20 ml) was added N-benzyl-2-methylprop-2-en-1-amine (11.50 mmol, 1.854 g), triethylamine (15.33 mmol, 2.131 ml, 1.552 g) and cyclophos (50 wgt % solution in EtOAc) (9.20 mmol, 2.74 ml, 2.93 g). The mixture was stirred at ambient temperature overnight then cyclophos (50 wgt % solution in EtOAc) (0.5 ml) added and the mixture stirred for a further 1 hr. The mixture was diluted with DCM (10 ml), washed with 2 N HCl (20 ml) then 2 N NaOH (20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to afford N-benzyl-3-chloro-N-(2-methylallyl)-1,2-dihydrocyclobutabenzene-1-carboxamide as a brown oil (1.8 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14].C(N(CC)CC)C>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:18][CH2:17][CH2:16][CH:12]2[C:13]([OH:15])=[O:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(O)C1CCCN1c1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Yield: 20.1 %

Procedure:
A mixture of 1-chloro-4-nitrobenzene (3 g, 19 mmol), L-proline (2.19 g, 19.0 mmol) and triethylamine (10.6 ml, 76 mmol) were dissolved in DMSO (15 ml) then heated at 90° C. for 24 hr. The reaction mixture was concentrated under reduced pressure, the residue treated with water and extracted with dichloromethane. The organic layer was washed with brine, dried and evaporated to a residue. Purification by column chromatography using dichloromethane/methanol (97:3) gave 1-(4-nitro-phenyl)-pyrrolidine-2-carboxylic acid (0.9 g, 20%).
Reaction SMILES: C([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]([C:25](O)=[O:26])=[C:17]2[CH2:28][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:30](=[O:31])[C:16]=12)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:40][NH:41][CH3:42].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:40][N:41]([CH3:42])[C:25]([C:18]1[C:19]2[CH:20]=[CH:21][CH:22]=[N:23][C:24]=2[C:15]([OH:14])=[C:16]2[C:30](=[O:31])[N:29]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[CH2:28][C:17]=12)=[O:26]
Reactant: O=C(O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.9 %

Procedure:
9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid 213 (0.02 g, 0.0386 mmol) was dissolved in 0.3 mL of dimethylformamide. To this was added dimethylamine (2M in THF) (0.0386 mL, 0.0772 mmol), diisopropylethylamine (0.027 mL, 0.1544 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.03 g, 0.0772 mmol) and stirred at room temperature. After 15 hours, starting material was consumed. Purified by reverse phase HPLC (0.1% TFA, H2O/ACN) to give 7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid dimethylamide 321 (0.014 g, 0.037 mmol, 97%.) 1H NMR (CDCl3) o9.07 (dd, 1H), 8.18 (d, 1H), 7.65 (dd, 3H), 7.03(dd, 2H), 4.79 (dd, 2H), 4.53 (d, J=17 Hz, 1H), 4.25 (d, J=17 Hz, 1H), 3.24 (s, 3H), 3.21 (s, 3H.) MS: 380 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[CH:12]=[C:13]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])[N:22]=3)[C:14]3[N:15]([CH:17]=[CH:18][N:19]=3)[N:16]=2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[OH-].[Na+]>O1CCOCC1.O>[CH3:1][C:2]1[C:10]([C:11]2[CH:12]=[C:13]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:31][CH2:30][CH2:29][C@@H:28]4[CH3:32])[N:22]=3)[C:14]3[N:15]([CH:17]=[CH:18][N:19]=3)[N:16]=2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1c(C(=O)[O-])cccc1-c1cc(Nc2cccc(N3CCC[C@@H]3C)n2)c2nccn2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(C(=O)O)cccc1-c1cc(Nc2cccc(N3CCC[C@@H]3C)n2)c2nccn2n1
Temperature: 40 °C
Reaction time: 4 h
Yield: 59.8 %

Procedure:
To a solution of (S)-2-methyl-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (72 mg, 0.16 mmol) in dioxane (5 mL) and water (4 mL) was added NaOH (64 mg, 1.6 mmol), then the mixture was heated to 40° C. with stirring for 4 h. The solution was concentrated in vacuo, water (10 mL) was added and the solution was washed with dichloromethane (10 mL×3). The aqueous layer was adjusted to pH=4 by the addition of concentrated HCl. The solid formed was collected by filtration and was purified by prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 40% acetonitrile/60% water (0.1% TFA, v/v) in a linear fashion over 9 min) to give the final product (S)-2-methyl-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (41 mg, 59%). 1H NMR (300 MHz, DMSO): δ 10.43 (s, 1H), 8.72 (s, 1H), 8.45 (s, 1H), 8.12 (s, 1H), 7.90 (d, 1H, J=7.5 Hz), 7.62-7.42 (m, 3H), 6.68 (d, 1H, J=7.8 Hz), 6.10 (d, 1H, J=8.1 Hz), 4.04-4.00 (m, 2H), 3.40-3.35 (m, 1H), 3.18-3.15 (m, 1H), 2.47 (s, 3H), 1.96-1.88 (m, 2H), 1.55-1.51 (m, 1H), 0.86 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 429, tR=1.619 min, HPLC: 100% at 214 nm, 99.42% at 254 nm, tR=5.838 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:26](=[CH:27][CH:28]=1)[C:12]1[NH:13][C:14]([C:16]3[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])=[N:15][C:11]=1[C:10]1[CH:9]=[CH:8][C:7]([C:29]#[C:30][C:31](O)([CH3:33])[CH3:32])=[CH:6][C:5]2=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:28]=[CH:27][C:26]2[C:12]3[N:13]=[C:14]([C:16]4[C:17]([C:18]#[N:19])=[CH:20][CH:21]=[CH:22][C:23]=4[C:24]#[N:25])[NH:15][C:11]=3[C:10]3[C:5](=[CH:6][C:7]([C:29]#[C:30][C:31]([CH3:33])=[CH2:32])=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)(O)C#Cc1ccc2c(c1)c1cc(Cl)ccc1c1[nH]c(-c3c(C#N)cccc3C#N)nc21
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: C=C(C)C#Cc1ccc2c(c1)c1cc(Cl)ccc1c1nc(-c3c(C#N)cccc3C#N)[nH]c21
Yield: 78.2 %

Procedure:
To a stirred suspension of 2-[9-chloro-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-1H-phenanthro[9,10-d]imidazol-2-yl]isophthalonitrile from Example 40 (120 mg, 0.26 mmol) in benzene (4 mL) was added Burgess Reagent (70 mg, 0.29 mmol) and refluxed for 2 hours under N2. The resulting reaction mixture was diluted with EtOAc (20 mL). This EtOAc solution washed with water, brine and dried over MgSO4. After removing the drying agent via filtration, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 50/50 EtOAc/hexane) to yield 90 mg of 2-[6-chloro-9-(3-methylbut-3-en-1-yn-1-yl)-1H-phenanthro[9,10-d]imidazol-2-yl]isophthalonitrile as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:10]2[C:11]3[CH:18]=[CH:17][N:16]([C@@H:19]4[O:25][C@H:24]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C@@H:22]([OH:23])[C@@:20]4([CH3:35])[OH:21])[C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:56](Cl)(=[O:64])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:10]2[C:11]3[CH:18]=[CH:17][N:16]([C@@H:19]4[O:25][C@H:24]([CH2:26][O:27][Si:28]([C:31]([CH3:32])([CH3:33])[CH3:34])([CH3:30])[CH3:29])[C@@H:22]([O:23][C:56](=[O:64])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[C@@:20]4([CH3:35])[OH:21])[C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: CCCCCCCC(=O)Cl
Reactant: COc1ccc(N(c2ncnc3c2ccn3[C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@@]2(C)O)C(c2ccccc2)c2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC(=O)O[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H](n2ccc3c(N(c4ccc(OC)cc4)C(c4ccccc4)c4ccccc4)ncnc32)[C@]1(C)O
Reaction time: 1.5 h
Yield: 71.5 %

Procedure:
To a solution of the compound from Step H (400 mg, 0.6 mmol) and anhydrous DMAP (73 mg, 0.6 mmol) in anhydrous CH2Cl2 (7 mL) was added slowly triethylamine (250 μL, 1.8 mmol). To the stirred solution was added octanoyl chloride (200 μL, 1.2 mmol) over 15 min. The reaction mixture was stirred for an additional 1.5 h. It was then diluted with methylene chloride (30 mL) and washed with saturated aqueous sodium bicarbonate solution (3×10 mL) and water (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was subjected to column chromatography on silica gel eluting with 5% MeOH in CH2Cl2 to afford the title compound as a light yellow foam (340 mg).
Reaction SMILES: [NH3:1].CO.[CH3:4][C:5]1[CH:6]=[C:7]([C@@H:12]([OH:20])[CH2:13][CH2:14][C:15](OCC)=[O:16])[CH:8]=[C:9]([CH3:11])[CH:10]=1>>[CH3:4][C:5]1[CH:6]=[C:7]([C@@H:12]([OH:20])[CH2:13][CH2:14][C:15]([NH2:1])=[O:16])[CH:8]=[C:9]([CH3:11])[CH:10]=1
Reactant: N
Reactant: CCOC(=O)CC[C@H](O)c1cc(C)cc(C)c1
Solvent: CO
Product: Cc1cc(C)cc([C@@H](O)CCC(N)=O)c1

Procedure:
A solution of ammonia in methanol (2.0M; 4.02 mL; 8.03 mmol) was treated with ethyl (4S)-4-(3,5-dimethylphenyl)-4-hydroxybutanoate (Step A; 474 mg; 2.01 mmol) and the resultant solution was stirred at 50° C. for 16 h. The reaction was concentrated in vacuo and the residue purified by flash silica gel chromatography (0-100% EtOAc/hexanes gradient) to afford (4S)-4-(3,5-dimethylphenyl)-4-hydroxybutanamide as a white solid. LCMS=190.3 (M+1−18)+. 1H NMR (CDCl3, 500 MHz): δ 7.00 (s, 2H), 6.94 (s, 1H), 5.61 (br s, 1H), 5.40 (br s, 1H), 4.75 (dd, J=7.6, 2.8 Hz, 1H), 2.43-2.39 (m, 2H), 2.34 (s, 6H), 2.12-2.07 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([Sn](C)(C)C)[S:17][C:10]=12>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:2]3[CH:3]=[N:4][CH:5]=[N:6][CH:7]=3)[S:17][C:10]=12
Reactant: C[Sn](C)(C)c1cc2nccc(Cl)c2s1
Reactant: Brc1cncnc1
Solvent: Cc1ccccc1
Product: Clc1ccnc2cc(-c3cncnc3)sc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
Tereakis(triphenylphosphine)palladium (17 mg) was added to a solution of 5-bromopyrimidine (0.057 g, 0.36 mmole) and 7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.119 g, 0.36 mmole) in toluene (10 ml). The reaction mixture was stirred at 90° C. overnight. After cooling to room temperature, the mixture was filtered, washed with CH2Cl2 and was partitioned between H2O (20 ml) and CH2Cl2 (2×20 ml). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 0–1% MeOH in CH2Cl2 to give white solid (0.045 g, 51%); 1H NMR (300 MHz, C6D6) δ 9.25 (1H, s), 9.10 (2H, s), 8.64 (1H, d, J=5.1 Hz), 7.89 (1H, s), 7.34 (1H, d, J=5.1 Hz); ESIMS (MH+): 248.00.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4].[C:10](Cl)(=[O:14])[C:11]([CH3:13])=[CH2:12]>O>[C:10]([NH:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: NCC(=O)NCC(=O)O
Reactant: C=C(C)C(=O)Cl
Solvent: O
Product: C=C(C)C(=O)NCC(=O)NCC(=O)O
Yield: 75 %

Procedure:
Using Example 1, glycylglycine was reacted with methacryloyl chloride in water at -10° C. After adjustment to a pH of 3, the white slurry was washed with ethanol to remove sodium chloride and water. The product was dried at 80° C. to obtain a good yield (>75%) product with a melting point of 200°-201° C.