Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9]([C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])[CH:8]=3.CC1(C)C(C)(C)OB([C:34]2[N:35]=[CH:36][S:37][CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[N:17]1([C:15]([C:9]2[CH:8]=[C:7]3[C:12]([C:13]4[CH:14]=[C:2]([C:34]5[N:35]=[CH:36][S:37][CH:38]=5)[CH:3]=[C:4]([C:23]([NH2:25])=[O:24])[C:5]=4[NH:6]3)=[CH:11][CH:10]=2)=[O:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: CC1(C)OB(c2cscn2)OC1(C)C
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(-c2cscn2)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 105 °C
Yield: 42.6 %

Procedure:
3-Bromo-7-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide (50 mg, 0.112 mmol, Example 144A), Pd(Ph3P)4 (7 mg, 6.06 nmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (37 mg, 0.175 mmol), aqueous Na2CO3 (0.15 mL, 0.300 mmol), MeOH (1 mL) and Toluene (2 mL) were combined in a 5 ml microwave vial. The vial was sealed, flushed with nitrogen and heated to 105° C. for 4 hours in an oil bath. Additional Pd(Ph3P)4 (20 mg, 15 nmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (65 mg, 0.308 mmol) and aqueous Na2CO3 (0.30 mL, 0.60 mmol) were added, the vial flushed with nitrogen again and heat to 105° C. for 5 additional hours. The reaction mixture was evaporated to dryness, suspended in water and the crude product was collected by filtration through a medium porosity glass frit. The crude was washed with water, then dissolved off the frit with DMSO and purified by prep HPLC. Product containing fractions were combined and concentrated in vacuum to give 19.4 mg 7-(morpholine-4-carbonyl)-3-(thiazol-4-yl)-9H-carbazole-1-carboxamide. MS (ESI) m/e+=407, m/e−=405, consistent with [M−H]− and [M+H]+. 1H NMR (CD3OD+CDCl3) δ ppm 9.11 (d, 1H, J=2.1), 8.91 (d, 1H, J=1.5), 8.57 (d, 1H, J=1.5), 8.26 (d, 1H, J=8.0), 7.96 (d, 1H, J=1.8), 7.72 (s, 1H), 7.32 (dd, 1H, J=7.9, 1.2), 3.90-3.50 (b, 8H). HPLC retention time 8.02 min. (Sunfire C18 3.5 μm, 4.6×150 mm column, 15 min gradient, 10-100% B, 1 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[S:3]([C:6]1[C:7]2[C:8]3[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=S)[C:9]=3[CH:16]=[CH:17][CH:18]=2)(=[O:5])=[O:4].[N:20]1([CH2:25][CH2:26][CH2:27][NH2:28])[CH:24]=[CH:23][N:22]=[CH:21]1>C(O)C>[N:20]1([CH2:25][CH2:26][CH2:27][NH:28][C:10]2[C:9]3[CH:16]=[CH:17][CH:18]=[C:7]4[C:8]=3[C:12](=[CH:13][CH:14]=[C:6]4[S:3]([N:2]([CH3:19])[CH3:1])(=[O:5])=[O:4])[N:11]=2)[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: NCCCn1ccnc1
Reactant: CN(C)S(=O)(=O)c1ccc2c3c(cccc13)C(=S)N2
Solvent: CCO
Product: CN(C)S(=O)(=O)c1ccc2c3c(cccc13)C(NCCCn1ccnc1)=N2
Yield: 41.2 %

Procedure:
A mixture 5 g of 1,2-dihydro-N,N-dimethyl-2-thioxobenz[cd]indole-6-sulfonamide, 2.3 g of 3-(1H-imidazol-1-yl)propanamine, 100 ml of ethanol and 5.4 g of mercuric acetate was reacted as described in Example 1, giving 2.7 g of the desired product, mp 199°-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[CH:10][C:4]=2[C:3]=1/[C:27](=[N:29]/[O:30][C:31]([C:33]1([OH:37])[CH2:36][CH2:35][CH2:34]1)=O)/[NH2:28]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:27]2[N:28]=[C:31]([C:33]3([OH:37])[CH2:34][CH2:35][CH2:36]3)[O:30][N:29]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:8]([S:17]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=3)(=[O:18])=[O:19])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(/C(N)=N/OC(=O)C4(O)CCC4)c(Cl)cnc32)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(-c4noc(C5(O)CCC5)n4)c(Cl)cnc32)cc1
Temperature: 110 °C

Procedure:
A mixture of (Z)-5-chloro-N′-(1-hydroxycyclobutanecarbonyloxy)-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-carboximidamide (Example 138C) (53.8 mg, 0.099 mmol) in anhydrous toluene (1 mL) was heated for 4 hours at 110° C. under nitrogen. The reaction was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel, eluting with a gradient of 40 to 50% ethyl acetate in hexanes, to provide the title compound. MS ESI(+) m/z 525.4 [M+H]+.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[N:24]=[N:25][S:26][CH:27]=2)=[O:22])=[CH:16][CH:15]=1>O1CCCC1>[N:13]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]2[N:24]=[N:25][S:26][CH:27]=2)=[O:22])=[CH:18][CH:19]=1)=[C:1]=[S:2]
Reactant: Nc1ccc(NC(=O)c2csnn2)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(N=C=S)cc1)c1csnn1
Temperature: 0 °C

Procedure:
To a ice cooled solution of 1,1′-thiocarbonyldiimidazole (7.28 g) in tetrahydrofuran (50 mL) is added [1,2,3]-thiadiazole-4-carboxylic acid (4-amino-phenyl) amide (9.0 g) in tetrahydrofuran (100 mL). After approximately one hour the solvent is removed by evaporation and the residue is dissolved in ethyl acetate. Diethyl ether is added to precipitate the crude product, which is then collected by filtration, dissolved in dichloromethane, and passed through a plug of hydrous magnesium silicate. After removal of solvents, the residue is recrystallized from ethyl acetate-hexanes to provide the desired product as a slightly yellow solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:25][CH2:26][CH2:27][C:28]([OH:30])=O)[C:20]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:66]([CH2:68][NH2:69])[OH:67]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:25][CH2:26][CH2:27][C:28]([NH:69][CH2:68][CH2:66][OH:67])=[O:30])[C:20]([C:31]([CH3:32])([CH3:34])[CH3:33])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NCCO
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2n1CCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2n1CCCC(=O)NCCO
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 53.1 %

Procedure:
To a solution of 4-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butyl-1H-indol-1-yl)butanoic acid (10 mg) in anhydrous DMF (0.25 mL) were successively added Et3N (9.5 mL, 0.069 mmol) and HBTU (8.2 mg, 0.022 mmol). After stirring for 10 min at 60° C., ethanolamine (1.3 μL, 0.022 mmol) was added, and the mixture was stirred for another 4 h at 60° C. 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(4-(2-hydroxyethyl-amino)-4-oxobutyl)-1H-indol-5-yl)cyclopropanecarboxamide (5.8 mg, 64%) was obtained after purification by preparative HPLC. MS (ESI) m/e (M+H+) 506.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[NH:34][C:35]1[S:36][CH:37]=[CH:38][N:39]=1>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:23])=[C:28]([NH:34][C:35]2[S:36][CH:37]=[CH:38][N:39]=2)[CH:29]=1
Reactant: NCc1ccc(F)cc1Nc1nccs1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1Nc1nccs1)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and N-(2-(aminomethyl)-5-fluorophenyl)thiazol-2-amine, derived from reduction of intermediate 123, 4-fluoro-2-(thiazol-2-ylamino)benzonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.92 (1H, s), 9.10 (1H, t, J=6.3 Hz), 8.19 (1H, dd, J=2.8, 12.3 Hz), 7.41-7.38 (2H, m), 7.32-7.28 (5H, m), 6.99 (1H, d, J=3.8 Hz), 6.71 (1H, ddd(dt), J=2.8, 8.3), 5.05 (2H, s), 4.45 (2H, d, J=6.3 Hz), 4.01-3.98 (2H, m), 3.88-3.85 (2H, m), 1.54 (6H, s) LCMS (+ESI, M+H+) m/z 536.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Cl.Cl[CH2:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:12][CH2:13][C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: ClCCc1c[nH]cn1
Reactant: N#Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCc2c[nH]cn2)cc1

Procedure:
360 mg (3 mmol) of 4-cyanophenol, 251 mg (1.5 mmol) of 4-[2-chloroethyl]imidazole hydrochloride, 500 mg (3.6 mmol) of potassium carbonate and sodium iodide (catalyst) are stirred at 80° C. for 5 days in 5 ml of dimethylformamide. The mixture is cooled and filtered. The filtrate is evaporated under reduced pressure to give an oily residue. The unreacted 4-cyanophenol is precipitated with a methanol/diethyl ether (1/10) mixture. After filtration, the filtrate is evaporated under reduced pressure to give the title compound which is crystallized from a methanol/water (10/3) mixture, M.p.: 181°-183° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[NH:40][C:39]2=[O:47])[CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([N:32]3[CH2:33][CH2:34][CH:35]([N:38]4[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=5[NH:40][C:39]4=[O:47])[CH2:36][CH2:37]3)=[O:23])=[CH:17][C:9]1=2
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1,3-dihydro-1-(4-piperidinyl)benzoimidazol-2-one as in General Procedure 10 to give the title compound. LCMS: m/z=647.02 (M+H+); retention time=0.83 minutes.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:9]=1[C:10](OCC)=[O:11].O>C1COCC1.C(O)C>[CH3:7][C:8]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:9]=1[CH2:10][OH:11]
Reactant: CCOC(=O)c1c(C)cccc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C)c1CO
Yield: 97.9 %

Procedure:
To a solution of 1.0 M lithium aluminium hydride in anhydrous THF (3.6 ml, 3.6 mmol), under nitrogen, was added anhydrous THF (12 ml). Ethyl 2-methyl-6-(methyloxy)benzoate (1 g, 5.2 mmol, ABCR) in anhydrous THF (2 ml) was then added over 5 min with stirring. The solution was stirred for 15 min and then heated at gentle reflux for 100 min. The solution was allowed to cool. A 5% solution of water in ethanol was added dropwise. The solvent was removed in vacuo and acidified using 1 to 2M aqueous HCl. The mixture was extracted with chloroform and the organic solvent removed in vacuo to give the title compound as yellow solid (0.775 g); LCMS: (System 4) MH+=152, tRET=1.78 min.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.[Br:27][C:28]1[CH:29]=[C:30]([CH:35]=[C:36]([CH2:39]O)[C:37]=1[CH3:38])[C:31]([O:33][CH3:34])=[O:32]>ClCCl>[Br:27][C:28]1[CH:29]=[C:30]([CH:35]=[C:36]([CH2:39][I:20])[C:37]=1[CH3:38])[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)c1cc(Br)c(C)c(CO)c1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(C)c(CI)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a dichloromethane (0.05 M) solution of triphenylphosphine (1.1 eq) was added iodine (1.1 eq.). The resulting orange-yellow suspension was stirred at RT for 30 min before imidazole (1.2 eq.) and finally methyl 3-bromo-5-(hydroxymethyl)-4-methylbenzoate (1 eq.) from the previous step were added. The now pale yellow solution was stirred at RT for another 30 min. The volatiles were removed in vacuo and the residue was triturated with a 1:1 (v/v) mixture of hexanes and ether. The insolubles were then removed via filtration through a pad of silica gel. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1>C(Cl)Cl>[N:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([Cl:3])=[O:19])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCN(c2ccncc2)CC1
Solvent: ClCCl
Product: O=C(Cl)C1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (1.6 ml) was added dropwise to a stirred suspension of 1-(4-pyridyl)piperidine-4-carboxylic acid (2.17 g) in methylene chloride (30 ml) and the mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated to give 1-(4-pyridyl)piperidine-4-carbonyl chloride which was used without further purification.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[N:7]=[C:8]2[N:13]([CH:14]=1)[CH2:12][C@H:11]([OH:15])[CH2:10][O:9]2)([O-:5])=[O:4].Br[CH2:17][C:18]1[N:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=1>CN(C=O)C>[Cl:24][C:21]1[N:20]=[N:19][C:18]([CH2:17][O:15][C@@H:11]2[CH2:10][O:9][C:8]3=[N:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][N:13]3[CH2:12]2)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cn2c(n1)OC[C@@H](O)C2
Reactant: Clc1ccc(CBr)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn2c(n1)OC[C@@H](OCc1ccc(Cl)nn1)C2
Temperature: -42 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
Sodium hydride (60% w/w, 0.30 g, 7.6 mmol) was added to a solution of (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ol (0.89 g, 4.8 mmol) in DMF (20 mL) at 0° C. The resultant solution was cooled to −42° C. and a solution of 3-(bromomethyl)-6-chloropyridazine (1.05 g, 5.1 mmol) in DMF (5 mL) was added. The mixture was stirred at −42° C. for 1 h and then quenched with ice. EtOAc (200 mL) was added, the organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel, initially eluting with hexanes/EtOAc (1:1) to remove unreacted 3-(bromomethyl)-6-chloropyridazine and then EtOAc to give the title compound (0.84 g, 56%) as a white solid. APCI MS m/z 312.6 (M+H). 1H NMR (400 MHz, (CD3)2SO) δ 8.02 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 4.97 (d, J=13.2 Hz, 1H), 4.94 (d, J=13.2 Hz, 1H), 4.69 (dt, J=12.0, 2.6 Hz, 1H), 4.50 (d, J=12.1 Hz, 1H), 4.30-4.39 (m, 2H), 4.25 (dd, J=13.5, 3.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:18])[N:4]([CH2:10][C:11]2[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Br>CC(N(C)C)=O>[Cl:1][C:2]1[C:3](=[O:18])[N:4]([CH2:10][C:11]2[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:28][C:27]1[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:26]=1[F:25]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: Cc1cnc(Cn2c(C)cc(O)c(Cl)c2=O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-chloro-4-hydroxy-6-methyl-1-[(5-methylpyrazin-2-yl)methyl]pyridin-2(1H)-one (2.48 g, 9.3 mmol) in DMA (7 mL)was added K2CO3 (1.54 g, 11.0 mmol) followed by 2,4-difluorobenzyl bromide (1.2 mL, 9.3 mmol). The reaction mixture stirred at room temperature under nitrogen for 1.5 hours. The solvent was distilled in vacuo. The resulting residue was diluted in dichloromethane and washed with water. The organic extracts were concentrated and the resulting residue was purified by flash column chromatography (ethyl acetate). The appropriate fractions were combined, and concentrated. 1H NMR (CD3OD, 400 MHz) δ 8.49 (d, 1H, J=1.2 Hz), 8.40 (s, 1H), 7.59 (m, 1H), 7.04 (m, 2H), 6.54 (s, 1H), 5.41 (s, 2H), 5.28 (s, 2H), 2.54 (s, 3H), 2.40 (s, 3H); ES-HRMS m/z 392.1014 (M+H calculated for C19H17N3O2ClF2 requires 392.0972).
Reaction SMILES: [OH:1][C@@H:2]1[C@@:21]2([CH3:22])[C@@H:14]([CH2:15][CH2:16][C@@H:17]2[C:18](=[O:20])[CH3:19])[C@H:13]2[C@@H:4]([C@:5]3([CH3:24])[C:10]([CH2:11][CH2:12]2)=[CH:9][C:8](=[O:23])[CH:7]=[CH:6]3)[CH2:3]1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].Cl>N1C=CC=CC=1>[S:26]([O:1][C@@H:2]1[C@@:21]2([CH3:22])[C@@H:14]([CH2:15][CH2:16][C@@H:17]2[C:18](=[O:20])[CH3:19])[C@H:13]2[C@@H:4]([C@:5]3([CH3:24])[C:10]([CH2:11][CH2:12]2)=[CH:9][C:8](=[O:23])[CH:7]=[CH:6]3)[CH2:3]1)([CH3:25])(=[O:28])=[O:27]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3C[C@H](OS(C)(=O)=O)[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
12α-Hydroxypregna-1,4-diene-3,20-dione (3.3 g) was dissolved in 17 mlof pyridine. To the solution was added 3.4 g of methanesulfonyl chloride, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was then poured into 300 ml of diluted hydrochloric acid, and the resulting mixture was extracted with three 300 ml portions of benzene. Theextracts were combined and washed in sequence with diluted hydrochloric acid, aqueous sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate. Low-boiling fractions were distilled off under reduced pressure from the extract to give 3.8 g of crude 12α-mesyloxypregna-1,4-diene-3,20-dione, which was recrystallized from ethyl acetate. The physical properties for the thus-purified product were as follows:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:16][C:17](=[O:29])[CH:18]([CH3:28])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([Cl:27])[CH:21]=1)C>>[Cl:27][C:22]1[CH:21]=[C:20]([CH2:19][CH:18]([CH3:28])[C:17]([OH:29])=[O:16])[CH:25]=[CH:24][C:23]=1[O:26][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1
Reactant: ClCc1cccc(SC2CCC2)n1
Reactant: CCOC(=O)C(C)Cc1ccc(O)c(Cl)c1
Product: CC(Cc1ccc(OCc2cccc(SC3CCC3)n2)c(Cl)c1)C(=O)O
Yield: 78.6 %

Procedure:
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (50 mg, 0.25 mmol) obtained in Step C of Preparation Example 37 and 3-(3-chloro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (60 mg, 0.28 mmol) obtained in Step B of Preparation Example 46 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (77 mg, 85%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3]OS(C(F)(F)F)(=O)=O.CN(C)C=O.[Cl:19][C:20]1[N:28]=[C:27]2[C:23]([N:24]=[CH:25][NH:26]2)=[C:22]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]2[CH3:35])[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:19][C:20]1[N:28]=[C:27]2[C:23]([N:24]=[CH:25][N:26]2[CH2:3][C:2]([F:13])([F:12])[F:1])=[C:22]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]2[CH3:35])[N:21]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1ncn2CC(F)(F)F
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
2,2,2-Trifluoroethyltrifluoromethyl sulfonate (83 μl, 0.57 mmol) was added to an N,N-dimethylformamide (5 ml) suspension of 2-chloro-6-[(3S)-3-methylmorpholin-4-yl]-9H-purine (132 mg, 0.52 mmol) and potassium carbonate (86 mg, 0.62 mmol) with ice cooling. The reaction mixture was stirred at 50° C. for 2 hours and returned to room temperature. Water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate and, after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (30% ethyl acetate:hexane) to give the title compound (133 mg, 76%) as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[CH2:4][CH2:3]1.CC1(C)C2C(=CC(C#CC3C=CC(C([O-])=O)=CC=3)=CC=2)N(C2C=CC(C)=CC=2)CC1.[Li+].[OH-]>O1CCCC1.CO>[CH3:1][C:2]1([CH3:32])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)N(c2ccc(C)cc2)CCC3(C)C)cc1
Agent: Cc1ccc(N2CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)[O-])cc4)cc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N2CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 4-(2-(4,4-dimethyl-1,2,3,4-tetrahydro-N-(4-methylphenyl)quinolin-7-yl)ethynyl)benzoate (Compound 4) (0.105 g, 0.25 mmol) in 10.0 mL of tetrahydrofuran and 0.5 mL of methanol was added 1.0 mL (1.5 mmol) of 1.5M aqueous LiOH. The resulting solution was stirred at room temperature for 24 hours. The mixture was concentrated in vacuo, water was added, and the mixture was extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give the title compound as a yellow solid, which was recrystallized from 2:1 acetonitrile:ethyl acetate to give yellow needles. PNMR (300 MHz, DMSO) d 1.31 (6 H, s), 1.80 (2 H, t, J=5.9 Hz), 2.31 (3 H, s), 3.53 (2 H, t, J=5.9 Hz), 6.50 (1 H, d, J=1.6 Hz), 6.83 (1 H, dd, J=8.0, 1.6 Hz), 7.16 (2 H, d, J=8.4 Hz), 7.25 (2 H, J=8.4 Hz), 7.29 (1 H, d, J=8.0 Hz), 7.55 (2 H, d, J=8.4 Hz), 7.89 (2 H, d, J=8.4 Hz)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[O:8])=[O:5])[CH3:2].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[NH:18][C:19](=[NH:22])[O:20][CH3:21])=[CH:12][CH:11]=1>O1CCCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]([N:18]=[C:19]([NH:22][C:7](=[O:8])[NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:20][CH3:21])=[O:23])=[CH:14][CH:15]=1
Reactant: CCOC(=O)N=C=O
Reactant: COC(=N)NC(=O)Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCOC(=O)NC(=O)NC(=NC(=O)Nc1ccc(Cl)cc1)OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
12 Parts ethoxycarbonyl isocyanate was added dropwise to 23 parts of methyl 4-(4-chlorophenyl)allophanimidate (prepared as above) in 230 parts of tetrahydrofuran at 20°C. The mixture was stirred for six hours at room temperature and then evaporated under reduced pressure. The residue was triturated with boiling 1-chlorobutane, cooled, and the solid collected by filtration affording 16 parts of ethyl 4-[1-(4-chlorophenylcarbamoylimino)-1-(methoxy)methyl]allophanate, m.p. 140.5-142°C.