Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Ag:1]Br.[C:3]([OH:16])(=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[Na+].[N+]([O-])([O-])=O.[Ag+]>C1(C)C=CC=CC=1.O>[C:3]([O-:16])(=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Ag+:1]
Reactant: Br[Ag]
Reactant: CCCCCCCCCCCC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)[O-]

Procedure:
An aqueous solution prepared by dissolving 0.8 g of cetylethyldimethylammonium bromide in 100 ml of water was mixed with 100 ml of toluene and emulsified. To this emulsion there was added a solution prepared by dissolving 0.425 l g of silver nitrate in 10 ml of water to thereby form silver bromide in an emulsified state. To the silver bromide emulsion there was added an emulsion prepared by mixing a solution (prepared by dissolving 12 g of lauric acid in 100 ml of toluene) with a solution (prepared by dissolving 1.9 l g of sodium hydroxide in 100 ml of toluene), whereafter a solution prepared by dissolving 8.5 g of silver nitrate in 50 ml of water was added thereto to thereby form silver laurate. There was thus obtained a mixture wherein silver bromide was in intimate contact with silver laurate.
Reaction SMILES: [C:1]12([C:11](O)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:45]1[NH:50][CH2:49][CH2:48][N:47]2[CH:51]=[C:52]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH:53]=[C:46]12.FC(F)(F)C(O)=O.C1NCCN2C=C(C(OCC)=O)C=C12>CN(C=O)C>[C:1]12([C:11]([N:50]3[CH2:49][CH2:48][N:47]4[CH:51]=[C:52]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH:53]=[C:46]4[CH2:45]3)=[O:12])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CCOC(=O)c1cc2n(c1)CCNC2
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2n(c1)CCN(C(=O)C13CC4CC(CC(C4)C1)C3)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a microwave vial containing 1-adamantanecarboxylic acid (0.05 g, 0.283 mmol) was added HATU (0.11 g, 0.283 mmol), triethylamine (0.11 mL, 0.772 mmol) and DMF (1.5 mL). The solution was allowed to stir at rt for 30 minutes before ethyl 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate Intermediate 5 (0.05 g, 0.257 mmol) was added to the solution. The solution was then allowed to stir at rt overnight and then evaporated. To the resulting residue was added DCE (3 mL) and water (1 mL). After separation, the aqueous phase was extracted with DCE (2×3 mL). The combined organic phases were concentrated to give a crude ethyl 2-(1-adamantylcarbonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate as a solid.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.[OH:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]([C@@H:27]2[CH2:31][C@H:30]([S:32]CC3C=CC(OC)=CC=3)[CH2:29][N:28]2[C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][C:49]([N+:52]([O-:54])=[O:53])=[CH:48][CH:47]=2)=[O:43])=[O:26])[CH2:21][CH2:20]1>C1(OC)C=CC=CC=1>[OH:16][CH2:17][CH2:18][N:19]1[CH2:20][CH2:21][N:22]([C:25]([C@@H:27]2[CH2:31][C@H:30]([SH:32])[CH2:29][N:28]2[C:42]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][C:49]([N+:52]([O-:54])=[O:53])=[CH:50][CH:51]=2)=[O:43])=[O:26])[CH2:23][CH2:24]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCO)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C([C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 168.1 %

Procedure:
2.8 ml of trifluoroacetic acid and 91 μl of trifluoromethanesulfonic acid were added, whilst ice-cooling, to a solution of 288 mg of (2S,4S)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine in 580 μl of anisole, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was washed with diethyl ether by decantation and dried in vacuo, to give 380 mg of the title compound, as a powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([O:17][C:18]3([CH3:35])[CH2:21][N:20](C(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:19]3)[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:36])[CH3:6])[CH3:2]>CCO.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4](=[O:37])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([O:17][C:18]3([CH3:35])[CH2:19][NH:20][CH2:21]3)[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:36])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)N1C(=O)COc2ccc(OC3(C)CN(C(c4ccccc4)c4ccccc4)C3)cc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)N1C(=O)COc2ccc(OC3(C)CNC3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 1068.1 %

Procedure:
A suspension of 2-[6-(1-benzhydryl-3-methyl-azetidin-3-yloxy)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-propionic acid ethyl ester (0.300 g, 0.070 mmol) and Pd(OH)2/C (10%, 0.170 g) in EtOH (15 mL) was stirred under H2 (50 psi) at ambient temperature overnight. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give 2-[6-(3-methyl-azetidin-3-yloxy)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-propionic acid ethyl ester (0.250 g, crude) as an oil, which was used in the next step directly. LC/MS (Table 1, Method 2) Rt=0.806 min.; MS m/z: 335 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[C:14]([C:16]3[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[N:17]=3)[S:13][C:12]=2[CH:34]=1)(C)(C)C.C(O)(C(F)(F)F)=O.CO>ClCCl>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[C:14]([C:16]3[C:21]([CH3:22])=[CH:20][N:19]=[C:18]([NH:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)[N:17]=3)[S:13][C:12]=2[CH:34]=1
Reactant: Cc1cnc(NCCCN2CCN(C)CC2)nc1-c1cc2ccc(NC(=O)OC(C)(C)C)cc2s1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(NCCCN2CCN(C)CC2)nc1-c1cc2ccc(N)cc2s1
Reaction time: 20 h
Yield: 64 %

Procedure:
(2-{5-Methyl-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophen-6-yl)-carbamic acid tert-butyl ester (0.33 g, 0.66 mmol) is dissolved in dichloromethane (6 mL) and TFA (0.78 mL) is added. The solution is stirred for 20 hours before adding methanol. The mixture is passed through an SCX column. After eluting with methanol, 20% of 2.0 M NH3/MeOH in EtOAc is used to elute the product which is then chromatographed on silica gel, eluting with 2.0 M NH3/MeOH in dichloromethane 0-15%, to give the title compound as a yellow oil. (166 mg, 64% yield). ES+(m/z) 397 [M+H].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:5][C:6]=1[C:7]#[N:8].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>COCCOC.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[C:2]1[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:5][C:6]=1[C:7]#[N:8]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: N#Cc1sc(N2CCOCC2)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: N#Cc1sc(N2CCOCC2)nc1-c1ccc(Cl)cc1Cl
Yield: 15.2 %

Procedure:
4-chloro-2-morpholin-4-yl-1,3-thiazole-5-carbonitrile (0.200 g, 0.871 mmol), 2,4-dichlorophenylboronic acid (0.249 g, 1.31 mmol), bis(triphenylphosphine)palladium dichloride (0.061 g, 0.0871 mmol), sodium carbonate (0.184 g, 1.74 mmol) were taken up in DME (3 mL), ethanol (1 mL) and water (1 mL) and microwaved at 125° for 30 minutes. Mixture was diluted with ethyl acetate (10 mL) and extracted. The organic phase was dried with sodium sulfate, filtered and evaporated. ISCO purification on silica gel using 10% ethyl acetate in hexane to 50% ethyl acetate in hexane afforded the title compound (45 mg, 15%). LCMS: (FA) ES+, 340. 1H NMR (400 MHz, d6-DMSO) δ: 7.44 (d, 1H), 7.20-7.17 (m, 2H), 3.43-3.28 (m, 4H), 3.16-2.93 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.CN(CCN(C)C)C.[Li]CCCC.ClCC[I:34]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:34])[N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Reactant: ClCCI
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(I)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 90.5 %

Procedure:
A suspension of 2-chloro-9-methyl-6-morpholin-4-yl-9H-purine (2.95 g, 11.7 mmol) and TMEDA (2.6 mL, 2.03 g, 17.5 mmol) in THF (80 mL) was cooled to −78° C. before the drop wise addition of n-BuLi (9.8 mL, 24.5 mmol, 2.5 M solution in hexanes). The resulting mixture was warmed to −40° C. and stirred for 40 mins. The mixture was cooled back to −78° C. before the addition of 1-chloro-2-iodoethane (3.7 mL, 7.8 g, 40.8 mmol). The resulting mixture was allowed to warm to r.t. over 2 h then quenched with NH4Cl and extracted with EtOAc (×4). The combined organics were dried (Na2SO4) and concentrated in vacuo affording 2-Chloro-8-iodo-9-methyl-6-morpholin-4-yl-9H-purine as a yellow solid (4.02 g, 91%). LCMS (method H): RT 4.09 min [M+H]+ 379.9
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C:17]([C@@H:18]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=4)[CH2:19][C@:3]12[CH3:4])=[C:16]1[C:11](=[CH:12][C:13](=[O:28])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.C1C(=O)N([Br:36])C(=O)C1>C1COCC1>[Br:36][C:12]1[C:13](=[O:28])[CH2:14][CH2:15][C:16]2[C:11]=1[CH2:10][CH2:9][C@@H:8]1[C:17]=2[C@@H:18]([C:20]2[CH:21]=[CH:22][C:23]([CH:24]=[O:25])=[CH:26][CH:27]=2)[CH2:19][C@@:3]2([CH3:4])[C@H:5]1[CH2:6][CH2:7][C@@H:2]2[OH:1]
Reactant: C[C@]12C[C@H](c3ccc(C=O)cc3)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: C[C@]12C[C@H](c3ccc(C=O)cc3)C3=C4CCC(=O)C(Br)=C4CC[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
4-(17β-Hydroxy-3-oxoestra-4,9-dien-11β-yl)benzaldehyde is reacted according to Example 5 in THF with NBS to form 4-(4′-bromo-17β-hydroxy-3-oxoestra-4,9-dien-11β-yl)benzaldehyde and purified by chromatography. The purified product is incorporated directly into the oximization.
Reaction SMILES: N=[C:2]1[C:6]2([CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[NH:5][C:4](=[O:12])[N:3]1[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=1.C[OH:26].C(Cl)(Cl)Cl.Cl>O>[O:12]=[C:4]1[N:3]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:22])[F:23])[CH:14]=2)[C:2](=[O:26])[C:6]2([CH2:7][CH2:8][O:9][CH2:10][CH2:11]2)[NH:5]1
Reactant: N#Cc1ccc(N2C(=N)C3(CCOCC3)NC2=O)cc1C(F)(F)F
Reactant: CO
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#Cc1ccc(N2C(=O)NC3(CCOCC3)C2=O)cc1C(F)(F)F

Procedure:
1.66 g of the product of Example 1 were introduced into 30 ml of methanol, 10 ml of chloroform and 10 ml of 2N hydrochloric acid, and the mixture was refluxed for 50 minutes. 100 ml of water were added and extraction was carried out 3 times with ethyl acetate. The organic phase was washed with salt water, dried and purified on silica with methylene chloride-acetone: 85-15 as eluant. The resultant product was dissolved in 100 ml of isopropanol at about 70° C. and filtration was carried out, followed by concentrating, ice-cooling for one hour, separating and drying to obtain 1,425 g of the expected product (white crystals) melting at 192°-193° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:35][C:36](=[NH:55])[C:37]1[CH:54]=[CH:53][C:40]2[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45][C:39]=2[CH:38]=1>CN(C=O)C>[F:18][C:2]([F:1])([F:19])[C:3]1[CH:8]=[C:7]([C:9]2[O:11][N:35]=[C:36]([C:37]3[CH:54]=[CH:53][C:40]4[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])[CH2:44][CH2:45][C:39]=4[CH:38]=3)[N:55]=2)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=N)NO)cc2CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(C(F)(F)F)c4)n3)cc2CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.5 %

Procedure:
2-(Trifluoromethyl)-4-biphenylcarboxylic acid (Preparation 40) (284 mg, 1.07 mmol), HOBT (159 mg, 1.18 mmol) and EDC (225 mg, 1.18 mmol) were stirred in DMF (10 ml) under argon for 20 minutes. 1,1-Dimethylethyl 7-[(hydroxyamino)(imino)methyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 41) (326 mg, 1.07 mmol) was added and the mixture stirred at room temperature for 2.5 h before it was heated to 80° C. for 16 h. The reaction mixture was partitioned between EtOAc (30 ml) and water (30 ml) and the organic layer washed with aqueous sodium bicarbonate and water before it was dried (phase separator) and evaporated. The residue was triturated with methanol to give the title compound as a white solid (370 mg, 0.69 mmol). The filtrate was purified by Biotage Horizon, reverse phase cartridge, eluting with 5-100% acetonitrile in water to give further title compound (70 mg, 0.13 mmol). δH (d6DMSO, 400 MHz): 8.52 (1H, s), 8.50 (1H, d), 7.93 (1H, s), 7.90 (1H, dd), 7.74 (1H, d) 7.56-7.48 (3H, m), 7.41-7.38 (3H, m), 3.55-3.47 (4H, m), 3.02-2.93 (4H, m), 1.41 (9H, s).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:15])[C:8]2[NH:13][N:12]=[C:11](I)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[Cl:23][CH2:24][CH2:25][CH2:26][C:27]#[CH:28]>CN(C)C=O.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([C:5]1[NH:6][C:7](=[O:15])[C:8]2[NH:13][N:12]=[C:11]([C:28]#[C:27][CH2:26][CH2:25][CH2:24][Cl:23])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C#CCCCCl
Reactant: CCCCc1nc2c(I)n[nH]c2c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(C#CCCCCl)n[nH]c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.7 %

Procedure:
To a nitrogen degassed solution of 5-butyl-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (250 mg, 0.786 mmol) in anhydrous N,N-dimethylformamide (6 mL) under nitrogen atmosphere at room temperature was added copper(I) iodide (30 mg, 0.158 mmol), bis(triphenylphosphine)palladium(II)dichloride (62 mg, 0.088 mmol) and finally triethylamine (0.219 mL, 1.572 mmol). The mixture was stirred at room temperature under nitrogen atmosphere for 10 minutes and then a solution of 5-chloro-1-pentyne (161 mg, 1.572 mmol) in anhydrous N,N-dimethylformamide (1.5 mL) was added. The reaction mixture was stirred at 60° C. for 80 minutes. The reaction was evaporated in-vacuo to yield a brown oil. The oil was partitioned between water/brine (1:1) and ethyl acetate. The organic layer was separated, passed through a hydrophobic frit and evaporated in-vacuo to yield a brown solid. The solid was absorbed onto Florisil, loaded onto a 50 g silica cartridge and purified by chromatography using a 0-100% ethyl acetate in cyclohexane gradient over 60 minutes. Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a pale yellow solid (172 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22].[C:23](NC1C=C(Cl)N=C(C(OC)=O)C=1Cl)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22])(=[O:25])[CH3:24]
Reactant: COC(=O)c1nc(Cl)cc(NC(C)=O)c1Cl
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1Cl
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1Cl

Procedure:
Methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate is produced from a 4-chloro-2-fluoro-3-substituted-phenylboronic acid derivative, such as PBA. As shown in the reaction scheme below, the methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate (Compound 1) is produced by reacting PBA (Compound 2) with methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate (Compound 3) to produce methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate (Compound 4), which is deacetylated to produce Compound 1:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([N:5]1[CH2:24][CH2:23][C:9]2[C:10]3[C:11](O)([C:17]4[S:18][CH:19]=[CH:20][N:21]=4)[CH2:12][CH2:13][C:14]=3[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]>Cl.O1CCOCC1>[F:26][C:2]([F:1])([F:25])[C:3]([N:5]1[CH2:24][CH2:23][C:9]2[C:10]3[C:11]([C:17]4[S:18][CH:19]=[CH:20][N:21]=4)=[CH:12][CH2:13][C:14]=3[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CCc2ccc3c(c2CC1)C(O)(c1nccs1)CC3)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: O=C(N1CCc2ccc3c(c2CC1)C(c1nccs1)=CC3)C(F)(F)F
Temperature: 60 °C
Yield: 5.3 %

Procedure:
The product from step (b) (1.13 mmol) was dissolved in 4N HCl/dioxane and heated to 60° C. for 1 hour after which time LCMS indicated no starting material. The reaction mixture was cooled to RT and the solvent was evaporated in vacuo to give the crude product as a brown semi-solid. Purification by flash silica-gel chromatography (gradient elution: 0-50% EtOAc in hexanes) gave the sub-title compound (22 mg) as a yellow oil. MS: ESI (positive): 365 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([Sn](CCCC)(CCCC)CCCC)=[CH:5][N:4]=[CH:3]1.[C:20]([N:23]1[C:32]2[C:27](=[CH:28][C:29](Br)=[CH:30][CH:31]=2)[C@H:26]([NH:34][C:35](=[O:40])[O:36][CH:37]([CH3:39])[CH3:38])[CH2:25][C@@H:24]1[CH3:41])(=[O:22])[CH3:21]>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.CCOC(C)=O.CCCCCC>[CH3:39][CH:37]([O:36][C:35](=[O:40])[NH:34][C@H:26]1[C:27]2[C:32](=[CH:31][CH:30]=[C:29]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)[CH:28]=2)[N:23]([C:20](=[O:22])[CH3:21])[C@@H:24]([CH3:41])[CH2:25]1)[CH3:38]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)N1c2ccc(-c3cncn3C)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 140 °C
Reaction time: 16 h
Yield: 13 %

Procedure:
A mixture of 1-methyl-5-(tributylstannyl)-1H-imidazole (200 mg, 0.54 mmol), 1-methylethyl [(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Example 4) (199 mg, 0.54 mmol) and tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.027 mmol) in dry, degassed DMF (5 mL) was stirred at 140° C. under nitrogen for 16 h then was cooled to room temperature and diluted with AcOEt (20 mL). The solution was washed with water (×2) then brine. The organic phase was dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 6% MeOH in DCM) gave 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(1-methyl-1H-imidazol-5-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (27 mg, 0.073 mmol, 13%) as a colourless solid after trituration with AcOEt/hexane. LCMS (method G): Retention time 0.59 min, [M+H]+=402.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:32]#[N:33])[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:8]=[C:7]2[CH:30]=[CH2:31].C(N(CC)CC)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.Br[C:63]1[CH:64]=[N:65][CH:66]=[CH:67][CH:68]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:32]#[N:33])[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[N:8]=[C:7]2/[CH:30]=[CH:31]/[C:63]1[CH:64]=[N:65][CH:66]=[CH:67][CH:68]=1
Reactant: Brc1cccnc1
Reactant: C=Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2c(F)cc(C#N)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1cc(F)c2c(c1)c(/C=C/c1cccnc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Under nitrogen atmosphere, 2.59 g of 7-fluoro-1-trityl-3-vinyl-1H-indazole-5-carbonitrile was dissolved in 50 mL of acetonitrile, added with 10 mL of triethylamine, 271 mg of palladium acetate (II), 450 mg of 2-(di-tert-butylphosphino)biphenyl and 726 μl of 3-bromo pyridine, and refluxed overnight. The solution was cooled to room temperature, added with 10 g of silica gel, the solvent was evaporated, followed by purification by silica gel column chromatography, to afford 2.00 g of the title compound as yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]2=[N:10]1.C(N(CC)CC)C.[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[CH2:28]>C(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:26](=[O:30])[C:27]([CH3:29])=[CH2:28])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]2=[N:10]1
Reactant: Nc1ccc(O)c(-n2nc3ccc(Cl)cc3n2)c1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)Nc1ccc(O)c(-n2nc3ccc(Cl)cc3n2)c1
Reaction time: 1 h

Procedure:
To 10.4 g. (0.04 mole) of 2-(2-hydroxy-5-aminophenyl)-5-chlorobenzotriazole and 4.1 g. triethylamine in 400 ml. methylene chloride (no preservative) was added at 0°-5° C., under nitrogen, with stirring, 4.2 g. methacryloyl chloride in 30 ml. methylene chloride. The dropwise addition required about 30 minutes. The mixture was stirred at 0°-5° C. for an additional 30 minutes and then at room temperature for one hour. The mixture was then washed with equal volumes of water, 5% hydrochloric acid and water. The organic phase was dried over magnesium sulfate and poured onto a 2" column of silica gel (120 g.) which had been slurry packed with methylene chloride. The column was eluted with methylene chloride and 100 ml. fractions were taken. The fractions were examined by thin layer chromatography (TLC) on silica gel plates using 1:5, ethyl acetate:chloroform as the developing solvent. The fractions containing the product (r.f. 0.36) were combined and evaporated. The residual solid was crystallized from ethanol to give 2.2 g. of product, m.p. 204°-205° C.