Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[C:2]=1[NH2:8].C1(C)C=CC=CC=1.[O:16]=[CH:17][C:18](OCC)=O.C(OCC)C>O1CCOCC1>[NH:7]1[C:17](=[O:16])[CH:18]=[N:8][C:2]2[N:1]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: Nc1cccnc1N
Reactant: CCOC(=O)C=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=c1cnc2ncccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3.8 g of pyridine-2,3-diamine in 100 mL of dioxane, 7.1 g of a 45 to 50% toluene solution of ethyl oxoacetate was added, and the mixture was stirred at room temperature for 1 hour, and then heated under reflux while stirring for 1 hour. The reaction mixture was cooled with ice bath, and diethyl ether was added thereto. The solid was filtered off to obtain 3.9 g of pyrido(2,3-b)pyrazin-2(1H)-one as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([O:17][CH3:18])=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:23]=1.Cl[C:32]1[N:37]=[N:36][C:35]([N:38]([CH3:49])[CH:39]2[CH2:44][C:43]([CH3:46])([CH3:45])[NH:42][C:41]([CH3:48])([CH3:47])[CH2:40]2)=[CH:34][CH:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>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.O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([C:32]2[N:37]=[N:36][C:35]([N:38]([CH3:49])[CH:39]3[CH2:44][C:43]([CH3:45])([CH3:46])[NH:42][C:41]([CH3:48])([CH3:47])[CH2:40]3)=[CH:34][CH:33]=2)[C:5]([O:17][CH3:18])=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH:23]=1
Reactant: COc1cc(-c2cnn(C(=O)OC(C)(C)C)c2)c(F)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cnn(C(=O)OC(C)(C)C)c2)c(F)cc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 100 °C
Yield: 101.7 %

Procedure:
To a microwave vial was added tert-butyl 4-(2-fluoro-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole-1-carboxylate (98 mg, 0.23 mmol), 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (Intermediate 1-1, 66.3 mg, 0.23 mmol), potassium phosphate (199 mg, 0.94 mmol), Pd2(dba)3 (21.5 mg, 0.02 mmol), and SPhos (9.62 mg, 0.02 mmol), followed by addition of 1,4-dioxane (0.4 mL)/H2O (0.9 mL). The vial was purged with N2 for 5 minutes and then heated at 100° C. in the microwave for one hour. The reaction mixture was concentrated in vacuo. The crude material was adjusted to pH 3 using 1 M HCl aqueous solution and loaded on an SCX column. The crude material was washed with methanol then eluted with 2 N ammonia in methanol. The product-containing fractions were concentrated to afford tert-butyl 4-(2-fluoro-5-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenyl)-1H-pyrazole-1-carboxylate (126 mg) MS [M+H+]=539.2.
Reaction SMILES: Br[CH:2]1[C:10](=O)[C:6]2=[N:7][O:8][N:9]=[C:5]2[CH2:4][CH2:3]1.[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C>[N:7]1[O:8][N:9]=[C:5]2[CH2:4][CH2:3][C:2]3[S:14][C:13]([NH2:15])=[N:12][C:10]=3[C:6]=12
Reactant: O=C1c2nonc2CCC1Br
Reactant: NC(N)=S
Solvent: CCO
Product: Nc1nc2c(s1)CCc1nonc1-2
Temperature: 60 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution commercially available 5-bromo-6,7-dihydro-5H-benzo[1,2,5]oxadiazol-4-one (1.1 g, 5.1 mmol) in absolute ethanol (60 mL) was added thiourea. The mixture was stirred at 60° C. overnight and then concentrated. The residue was triturated in hexanes and then collected by filtration to afford 1.3 g (90%) of the title compound MS (ESI+) m/z 195 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[C:21]([F:29])[CH:20]=[CH:19][C:18]=1B(O)O>>[F:29][C:21]1[C:22]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)=[C:17]([F:16])[CH:18]=[CH:19][C:20]=1[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2
Reactant: OB(O)c1ccc(F)c(-c2ccncc2)c1F
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)c(F)c1-c1ccncc1
Yield: 35.2 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 2,4-difluoro-3-(pyridin-4-yl)benzeneboronic acid (66 mg, 0.28 mmol) as described in Example 7 part g), affording 5-(2,4-difluoro-3-pyridin-4-ylphenyl)-2-trifluoromethyl-[1,8]naphthyridine (30 mg, 36%). δH (360 MHz, CDCl3) 7.29 (1H, m), 7.41-7.50 (3H, m), 7.62 (1H, d, J 4.6), 7.85 (1H, d, J 8.8), 8.33 (1H, dd, J 2.3 and 8.6), 8.75-8.77 (2H, m), 9.34 (1H, d, J 4.6). m/z (ES+) 388 [MH]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]3[C:24]([NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[C:25]4[CH:33]=[N:32][N:31]([CH2:34][CH3:35])[C:26]4=[N:27][C:28]=3[CH2:29][CH3:30])=[O:20])[N:14]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:43][N:44]1[CH2:49][CH2:48][CH:47]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53](B3OC(C)(C)C(C)(C)O3)[CH:52]=2)[CH2:46][CH2:45]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:8][C:7]1[C:2]([C:55]2[CH:54]=[CH:53][CH:52]=[C:51]([CH2:50][CH:47]3[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]3)[CH:56]=2)=[CH:3][C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]3[C:24]([NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[C:25]4[CH:33]=[N:32][N:31]([CH2:34][CH3:35])[C:26]4=[N:27][C:28]=3[CH2:29][CH3:30])=[O:20])[N:14]=2)=[O:12])=[CH:5][CH:6]=1
Reactant: CN1CCC(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(Br)c2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(-c3cccc(CC4CCN(C)CC4)c3)c2)n1
Temperature: 100 °C
Yield: 17.2 %

Procedure:
A mixture of N-[(3-bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (50 mg, 0.076 mmol), 1-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}piperidine (30.6 mg, 0.076 mmol), Na2CO3 (24.27 mg, 0.229 mmol) and PdCl2(dppf) (5.59 mg, 7.63 μmol) was diluted in a mixture of 1,4-dioxane (3 mL) and water (1 mL) in a 2-5 mL Biotage microwave reaction tube. The mixture was degassed by bubbling argon through it for 5 minutes and was then heated in a Biotage microwave at normal absorption for 10 minutes at 100° C. The crude mixture was filtered through a PL-Thiol MP SPE+ and was then washed with ethyl acetate and water. The organic layer was concentrated under vacuum to obtain the crude residue. It was purified with a Gilson HPLC (with 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined and converted to the free base with saturated 1 N NaOH, and the basified solution was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N-({6-chloro-3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide as a solid (10 mg, 17.2%). LC-MS m/z 763 M+, 0.81 min (ret time).
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:22]([C:24]1[CH:29]=[C:28]([CH2:30][O:31][Si](C)(C)C)[CH:27]=[CH:26][N:25]=1)#[N:23]>O1CCCC1>[C:22]([C:24]1[CH:29]=[C:28]([CH2:30][OH:31])[CH:27]=[CH:26][N:25]=1)#[N:23]
Reactant: C[Si](C)(C)OCc1ccnc(C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(CO)ccn1
Yield: 32 %

Procedure:
Tetra-n-butylammonium fluoride trihydrate (1.1 g, 3.5 mmol) was added to a solution of 2-cyano-4-(trimethylsilyloxymethyl)pyridine (600 mg, 2.9 mmol, Reference compound No. 10-1) in tetrahydrofuran (15 mL) at room temperature, then the mixture was stirred for 3 hours. The solvent was evaporated under reduced pressure, and then the resulting residue was purified by silica gel column chromatography to give 120 mg of the title reference compound as a yellow solid. (Yield 32%)
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][N:19]2[C:24](=[O:25])[C:23]3[S:26][C:27]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)=[CH:28][C:22]=3[N:21]=[CH:20]2)=[CH:13][CH:12]=1)[CH3:9])(C)(C)C.C(OCC)(=O)C.[ClH:43]>>[ClH:35].[ClH:43].[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:27]2[S:26][C:23]3[C:24](=[O:25])[N:19]([CH2:18][CH2:17][C:14]4[CH:13]=[CH:12][C:11]([CH2:10][N:8]([CH3:9])[CH2:7][C:6]([OH:36])=[O:5])=[CH:16][CH:15]=4)[CH:20]=[N:21][C:22]=3[CH:28]=2)=[CH:30][CH:31]=1
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(CC(=O)O)Cc1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the compound (0.92 g) obtained in Example 29 and 4N hydrogen chloride-ethyl acetate solution was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (115 mg) as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[C:34]([O:36][CH3:37])=[O:35].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[CH3:37][O:36][C:34]([C:33]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[CH2:9][C:10]([C:12]3[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=3)=[O:11])=[CH:6][CH:7]=2)=[CH:29][C:28]=1[F:27])=[O:35]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccccc3C)cc2)cc1F

Procedure:
In analogy to example 166, step 1, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-methyl-1H-pyridin-2-one (example 162, step 3) was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid in the presence of dichloro(1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane adduct in a mixture of 1,4-dioxane, water and 2 M aqueous sodium carbonate solution to give the title compound as an off-white solid, MS (ESI+): m/z=484.3 [M+H]+.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][Br:13].C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][Br:13]
Reactant: O=C(CCCCBr)NCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(CCCCBr)NCCCCCBr
Reaction time: 12 h
Yield: 33.6 %

Procedure:
Part A. A solution of N-(5-hydroxypentyl)-5-bromopentanamide (4.07 g, 15.3 mmol) and carbon tetrabromide (7.61 g, 22.9 mmol) in methylene chloride (75 mL) was cooled to 0° C., and treated with a solution of triphenylphosphine (6.02 g, 22.9 mmol) in methylene chloride (30 mL) dropwise. After stirring for 12 hours, the reaction mixture was evaporated, and the residual oil was separated by flash chromatography (1:1 ethyl acetate-hexane) to afford the oily product, N-(5-bromopentyl)-5-bromopentanamide (1.69 g, 5.14 mmol, 34%). 1H NMR (CDCl3): 5.96 (1H, br s); 3.40 (4H, t, J=6.6 Hz); 3.24 (2H, q, J=6.2 Hz); 2.20 (2H, t, J=7.0 Hz); 1.94-1.74 (6H, m); 1.58-1.42 (4H, m).
Reaction SMILES: C([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1[CH2:19][CH2:20][C:21]([F:31])([F:30])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[F:31][C:21]([F:30])([CH2:22][O:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:20][CH2:19][C@@H:11]1[C@@H:12]2[C@@H:13]([O:14][C:15](=[O:17])[CH2:16]2)[CH2:18][C@H:10]1[OH:9]
Reactant: O=C1C[C@@H]2[C@@H](CCC(F)(F)COc3ccccc3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1C[C@@H]2[C@@H](CCC(F)(F)COc3ccccc3)[C@H](O)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(3aR,4R,5R,6aS)-4-(3,3-Difluoro-4-phenoxybutyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate (prepared in Step C, 1.0 g, 2.4 mmol) is dissolved in methanol (0.2 M) and potassium carbonate (194 mg, 1.41 mmol) is added. The reaction mixture is stirred at room temperature and the progress is monitored by TLC every 30 minutes. After complete consumption of starting material, the reaction mixture is acidified with 5% KHSO4 and diluted with brine. The product is extracted with ethyl acetate twice. The combined organic layers are dried over sodium sulfate, filtered and evaporated. The crude product is purified by flash chromatography on regular silica gel eluted with ethyl acetate-hexanes (1:1) to afford the title intermediate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[N:11]=[C:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:9]=1.P(=O)(O)O.[CH3:31]CC.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:31][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[N:11]=[C:10]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:9]=1
Reactant: CCC
Reactant: Oc1ccccc1-c1nc(-c2ccccc2)nc(-c2ccccc2O)n1
Agent: O=C([O-])[O-]
Agent: O=[PH](O)O
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1-c1nc(-c2ccccc2)nc(-c2ccccc2O)n1
Temperature: 150 °C
Yield: 94.5 %

Procedure:
9.6 g (0.028 mol) of 2,4-bis(2'-hydroxyphenyl)-6-phenyl-s-triazine, 25 ml (0.234 mol) of dimethylmethane phosphonate and 4.0 g (0.028 mol) of sodium carbonate are mixed and the mixture is heated to 150° C. After 2 hours the clear, pale red reaction solution is stirred into 150 ml of ethanol. The precipitate is filtered with suction, rinsed with 20 ml of ethanol and water and dried in an exsiccator, giving 9.4 g (94.1%) of the compound of formula ##STR7##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=1.S(Cl)([Cl:20])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]([C:15]([Cl:20])=[O:17])=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccccc1-c1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: COc1ccccc1-c1ccccc1C(=O)Cl

Procedure:
2'-Methoxy-[1,1'-biphenyl]-2-carboxylic acid (32 g., 100 mmole) was dissolved in thionyl chloride (40 ml) and the solution was refluxed for 3 hours. The solution was evaporated to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=3)=[N:14][NH:13][C:12](=[O:25])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:13]1[C:12](=[O:25])[CH:11]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[C:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=2)=[N:14]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(-c2cc(=O)[nH]nc2-c2ccc(OC)c(F)c2)cc1F
Reactant: BrCc1ccccc1
Product: COc1ccc(-c2cc(=O)n(Cc3ccccc3)nc2-c2ccc(OC)c(F)c2)cc1F
Yield: 99.9 %

Procedure:
Using 5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one and benzyl bromide as starting materials, the procedures of Example 12 were repeated likewise, whereby the title compound was obtained in a yield of 99.9%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4](Cl)[N:3]=1.O.[NH2:19][NH2:20]>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH:19][NH2:20])[N:3]=1
Reactant: NN
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Solvent: CCCCO
Solvent: O
Product: NNc1nc(Cl)nc2c1ncn2C1CCCCO1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a suspension of 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (5 g, 20 mmol) in 1-butanol (75 mL) was added hydrazine hydrate (2.0 ml, 40 mmol) at room temperature. The mixture was stirred at 80° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to give the desired product. LCMS calculated for C10H14ClN6O (M+H): 269.1; found: 269.0.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([N:25]4[CH2:34][CH2:33][C:28]5(OCC[O:29]5)[CH2:27][CH2:26]4)(=[O:24])=[O:23])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[ClH:40]>>[ClH:40].[ClH:40].[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([N:25]4[CH2:34][CH2:33][C:28](=[O:29])[CH2:27][CH2:26]4)(=[O:24])=[O:23])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2ccc(-c3ccc(S(=O)(=O)N4CCC5(CC4)OCCO5)cc3)cn2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)N1CCN(c2ccc(-c3ccc(S(=O)(=O)N4CCC(=O)CC4)cc3)cn2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A suspension of 400 mg of the product obtained in Step C (0.82 mmol) in 5 ml of 1N HCl is stirred for 1 hour at 80° C. After neutralisation of the reaction mixture using 10% NaHCO3, the precipitate is filtered off, washed with water and dried. The white solid is suspended in ethanol and dissolved by adding methanolic HCl. The solution is evaporated to dryness and the residue is taken up in an ethanol/ethyl ether mixture to yield the expected product after filtration.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:5]([CH3:8])[C:6]=1[Br:7].C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]([CH3:23])=O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:13][CH:21]([CH3:23])[CH3:20])=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:5]([CH3:8])[C:6]=1[Br:7]
Reactant: COC(=O)c1c(O)c(Br)c(Br)n1C
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(OC(C)C)c(Br)c(Br)n1C

Procedure:
Methyl 4,5-dibromo-3-hydroxy-1-methyl-1H-pyrrole- 2-carboxylate (9.6 g, 0.03 moles) and potassium carbonate (5.0 g, 0.036 moles) are stirred in a mixture of acetone (100 mL) and DMF (15 mL) and heated to reflux under argon. After 22 hours the solvent is removed under reduced pressure and the residue is partitioned between CH2Cl2 (500 mL) and water (400 mL). The layers are separated and the aqueous phase is extracted with CH2Cl2 (300 mL). The combined organic extracts are washed with saturated brine (2×300 mL) and dried over MgSO4. Removal of the solvent under reduced pressure afforded the crystalline product (10.6 g); mp 42°-45° C.
Reaction SMILES: [CH3:1][C:2]1[N:3](C(=O)C)[CH:4]=[CH:5][N:6]=1.[O:10]1CC[CH2:12][CH2:11]1>>[CH3:1][C:2]1[NH:6][CH:5]=[C:4]([C:11](=[O:10])[CH3:12])[N:3]=1
Reactant: CC(=O)n1ccnc1C
Reactant: C1CCOC1
Product: CC(=O)c1c[nH]c(C)n1
Reaction time: 18 h
Yield: 45 %

Procedure:
5.75 g (46.3 mmol) of 1-(2-methyl-1-imidazolyl)ethanone was dissolved in 600 ml tetrahydrofuran and photolyzed in a quartz flask with a short wave u.v. light source (2537 nm) for 18 hours. The tetrahydrofuran solution was concentrated in vacuo to an oil and chromatographed on silica gel using 5% methanol in chloroform as eluent to give 2.6 g (45%) 1-(2-methyl-4-imidazolyl)ethanone, mp 123°-5°.
Reaction SMILES: [C:1]([N:9]([CH2:24][CH2:25][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:10][CH2:11][NH:12][C:13]([C:15]1[C:16]2[CH2:17][CH2:18][NH:19][C:20]=2[CH:21]=[CH:22][CH:23]=1)=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.Br[CH2:58][C:59]([O:61][CH2:62][CH3:63])=[O:60]>CN(C=O)C.CCOC(C)=O>[C:1]([N:9]([CH2:24][CH2:25][CH:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:10][CH2:11][NH:12][C:13]([C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][CH2:18][N:19]2[CH2:58][C:59]([O:61][CH2:62][CH3:63])=[O:60])=[O:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(NCCN(CCC(c1ccccc1)c1ccccc1)C(=O)c1ccccc1)c1cccc2c1CCN2
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCc2c(C(=O)NCCN(CCC(c3ccccc3)c3ccccc3)C(=O)c3ccccc3)cccc21
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a solution of N-{2-[benzoyl(3,3-diphenylpropyl)amino]ethyl}-4-indolinecarboxamide (77.0 mg) and 2-(tert-butylimino)-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (106 μL) in DMF (2.3 mL) was added ethyl bromoacetate (39 μL) and the mixture was stirred at ambient temperature for 40 hours. The resulting mixture was diluted with EtOAc (20 mL), washed successively with 1M HCl aqueous solution, saturated NaHCO3 aqueous solution and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform: MeOH=99:1) to afford ethyl {4-[({2-[benzoyl(3,3-diphenylpropyl)amino]ethyl}amino)-carbonyl]-2,3-dihydro-1H-indol-1-yl}acetate (87 mg) as an yellow syrup.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[C:5]([CH:12]=C)[CH:4]=1.I([O-])(=O)(=O)=[O:17].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:12]([C:5]1[CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=1)=[O:17]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(C(=O)O)nc(C(F)(F)F)c1
Agent: O=[Os](=O)(=O)=O
Agent: Cl
Agent: O=S([O-])([O-])=S
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1cc(C(=O)O)nc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 20 %

Procedure:
6-(Trifluoromethyl)-4-vinylpyridine-2-carboxylic acid (0.30 g, 0.69 mmol, the crude product from Step A) was dissolved in 1,4-dioxane (20. mL) and water (5.0 mL), then sodium periodate (0.44 g, 2.1 mmol, Aldrich) was added, followed by 4 wt % osmium tetraoxide in water (0.152 mL, 0.0240 mmol, Aldrich). The reaction was stirred overnight. Sodium thiosulfate solution was added and the mixture was stirred for 30 minutes. 1N HCl was added to adjust the pH to between 4 and 5, and the product was extracted with ten portions of 10% isopropanol in CHCl3. The combined extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-10% MeOH in DCM afforded a partially purified product (94 mg, 20% yield over Steps A & B). 1H NMR (300 MHz, CDCl3) δ 10.25 (s, 1H), 8.83 (d, J=0.8 Hz, 1H), 8.38 (d, J=1.3 Hz, 1H).