Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(=O)(O)(O)O.CO>O>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CO
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 55 °C
Reaction time: 0.33 h
Yield: 86.7 %

Procedure:
To 300 g of polyphosphoric acid (117% phosphoric acid) heated to 80° C. was added 68.2 g of 2,5-dianilinoterephthalic acid. The reaction mixture was heated at 120°-125° C. for two hours. After the melt was cooled to 90°-95° C., the acid strength was adjusted to 112% by the dropwise addition of phosphoric acid. The resultant melt was stirred for 20 minutes and then slowly poured into 453 g of methanol at 24° C. During the drown, the temperature was allowed to increase to 55° C., with the temperature being controlled by external cooling and adjustment of melt addition rate. The slurry was heated at reflux (68°-72° C.) for one hour, diluted with water, and stirred at 60° C. for 30 minutes. The solid component was collected by filtration and washed with water until acid free. The resultant presscake was reslurried in water. After adjustment of the pH to about 7, 7.5 g of 50% sodium hydroxide was added and the resultant slurry was heated at 90°-95° C. for one hour. The slurry was cooled, filtered, and washed with water until alkali free, then reslurried in water (595 g total, including water from the presscake). After adjustment of the pH to 9.0-9.5, 3.2 g of a cycloaliphatic carboxylic acid was added. The resultant slurry was heated at about 140°-145° C. for two hours in a closed system, cooled, acidified with phosphoric acid, and stirred. The solid component was collected by filtration and washed with water. The wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 53 g of quinacridone as a violet pigment.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.Cl.[NH2:10][C@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]([NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[O:18].C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.[Cu]I>[Br:8][C:6]1[CH:7]=[C:2]([NH:10][C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([NH:19][CH2:20][C:21]([F:22])([F:23])[F:24])=[O:18])[CH:3]=[N:4][CH:5]=1
Reactant: N[C@H]1CCCC[C@H]1C(=O)NCC(F)(F)F
Reactant: Brc1cncc(Br)c1
Agent: [Cu]I
Agent: Cl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Product: O=C(NCC(F)(F)F)[C@@H]1CCCC[C@@H]1Nc1cncc(Br)c1
Temperature: 80 °C

Procedure:
To a nitrogen degassed mixture of 3,5-dibromopyridine (8.5 g, 35.9 mmol), (cis)-2-amino-N-(2,2,2-trifluoroethyl)cyclohexanecarboxamide hydrochloride, I-5b, (9.35 g, 35.9 mmol), potassium carbonate (19.84 g, 144 mmol) and L-proline (0.826 g, 7.18 mmol), in DMSO (70 ml) was added copper(i) iodide (Strem® crushed) (0.683 g, 3.59 mmol). The reaction was sealed and heated at 80° C. for 64 hrs. Reaction was quenched into water (500 mL) and resulting solid product filtered and then slurry washed with water (50 mL). The wet solid was dissolved in ethyl acetate (400 mL), dried over sodium sulfate, filtered thru pad of silica to remove baseline material and filtrate concentrated to give 7.4 gm tan solid. Solid slurried in ˜50 mL diethyl ether for 15 min, filtered washed with hexane and solid sucked dry under nitrogen to give 5.73 gm product, I-5. LRMS (ESI) m/z 380.1 [(M+H)+; calcd for C14H17BrF3N3O: 380.1].
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]([C:16]#[N:17])([CH3:15])[CH3:14])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:18][C:19]1[N:20]=[CH:21][N:22](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:23]=1>C(#N)C>[C:16]([C:13]([C:11]1[CH:12]=[C:3]([CH2:2][N:20]2[C:19]([CH3:18])=[CH:23][N:22]=[CH:21]2)[CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7])([CH3:15])[CH3:14])#[N:17]
Reactant: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(=O)c1cc(CBr)cc(C(C)(C)C#N)c1
Solvent: CC#N
Product: COC(=O)c1cc(Cn2cncc2C)cc(C(C)(C)C#N)c1

Procedure:
A mixture of methyl 3-bromomethyl-5-(1-cyano-1-methylethyl)benzoate (0.7 g), 4-methyl-1-tritylimidazole (0.8 g) and acetonitrile (2 ml) was heated under reflux for 48 h, then evaporated to dryness. The residue of 3-[3-(1-cyano-1-methylethyl)-5-methoxycarbonylbenzyl]-4-methyl-1-tritylimidazolium bromide was washed with diethyl ether (2×10 ml), and the residue was treated with glacial acetic acid (4 ml) and water (1 ml) and heated at 90° for 15 minutes. The mixture was diluted with water (20 ml), and washed with diethyl ether, and the aqueous phase was basified with 10N aqueous sodium hdroxide and extracted three times with ethyl acetate. The extracts were combined and evaporated to dryness, and the residue was purified by flash column chromatography, eluting with methanol:chloroform (1:49 by volume), to give methyl 5-(1-cyano-1-methylethyl)-3-(5-methylimidazol-1-ylmethyl)benzoate, mp 101°-104°.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:10])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1>[Pt]=O.C(O)C>[CH3:1][NH:2][C:3](=[O:10])[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: CNC(=O)c1ccncc1
Agent: O=[Pt]
Solvent: CCO
Product: CNC(=O)C1CCNCC1
Reaction time: 8 h
Yield: 98.1 %

Procedure:
A mixture of 20 g (0.147 mol) of N-methylisonicotinamide, 100 ml of ethanol, and 1.2 g of platinum oxide was hydrogenated in a Parr shaker at 60° and 60 psi for 8 hr. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was crystallized from ether to give 20.5 g of crude product, mp 115°-121°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C1C=CC(C2(C[O:29][S:30]([CH3:33])(=O)=[O:31])CCCC2)=CC=1>>[CH3:33][S:30]([O:14][CH2:13][C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:31])=[O:29]
Reactant: OCC1(c2cccc(Cl)c2)CCCC1
Reactant: CS(=O)(=O)OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: CS(=O)(=O)OCC1(c2cccc(Cl)c2)CCCC1

Procedure:
(1-(3-Chlorophenyl)cyclopentyl)methyl methanesulfonate (497) was synthesized from (1-(3-chlorophenyl)cyclopentyl)methanol (496) following the procedure described for Methanesulfonic acid 1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl ester (240).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[C:13]([C:20]([O:22][CH3:23])=[O:21])=[CH:12][C:11]=1[NH:24]N>[Cl-].[Zn+2].[Cl-].C(O)(=O)C>[Cl:9][C:10]1[C:11]2[NH:24][C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][C:1]=3[C:12]=2[C:13]([C:20]([O:22][CH3:23])=[O:21])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:15]=1
Reactant: COC(=O)c1cc(Cl)c(NN)cc1C(=O)OC
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c2[nH]c3c(c2c1C(=O)OC)CCCC3
Yield: 31 %

Procedure:
To 10 ml of acetic acid were added 320 mg of cyclohexanone, 500 mg of zinc chloride and 800 mg of 2-chloro-4,5-bis(methoxycarbonyl)phenylhydrazine hydrochloride. The mixture was refluxed for 6 hours. Then, acetic acid was removed by distillation under reduced pressure. The residue was dissolved in 100 ml of ethyl acetate. The solution was washed with 1 N hydrochloric acid, an aqueous saturated sodium chloride solution and an aqueous saturated sodium hydrogen-carbonate solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=1/0 to 40/1) to obtain 270 mg (yield: 31%) of dimethyl 1-chloro-5,6,7,8-tetrahydrocarbazole-3,4-dicarboxylate as colorless crystals.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[C:11]([OH:13])=O.S(Cl)([Cl:16])=O>>[F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[C:11]([Cl:16])=[O:13]
Reactant: Cn1nc(C(F)F)c(C(=O)O)c1F
Reactant: O=S(Cl)Cl
Product: Cn1nc(C(F)F)c(C(=O)Cl)c1F

Procedure:
9.1 g of 5-fluoro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid and 75.5 ml of thionyl chloride were refluxed for 1.5 hours. After cooling down, the reaction mixture was evaporated under vacuum to yield 10 g of 5-fluoro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride as a yellow oil.
Reaction SMILES: [Br-:1].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]([CH2:31][CH2:32]O)=[CH:23]1.[Br-]>C1CCCCC1.C(#N)C.O>[Br:1][CH2:32][CH2:31][C:24]1[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:22][CH:23]=1
Reactant: OCCc1coc2ccccc12
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCCCC1
Solvent: O
Solvent: CC#N
Product: BrCCc1coc2ccccc12
Reaction time: 12 h

Procedure:
Triphenylphosphane dibromide (5.52 g, 14.41 mmol) was suspended in abs. acetonitrile (15 ml) under argon, the suspension was brought to 19° C. in a water batch and 2-(benzofuran-3-yl)ethanol (2.11 g, 13.1 mmol), dissolved in abs. acetonitrile (7 ml) was added in the course of 15 min. During the addition the temperature of the reaction mixture was kept between 19 and 21° C. The mixture was then left to stand for 12 h without further cooling. The triphenylphosphane which had precipitated out during this period of time was removed from the reaction mixture by filtration. The filtrate obtained was concentrated. For complete removal of the phosphane, the residue obtained was taken up in cyclohexane (20 ml) and the mixture was filtered over a layer of silica gel (15 g) about 3 cm thick. The silica gel was washed with cyclohexane (5×20 ml). The solution obtained in t his way, which contains the desired bromide in a pure form, was concentrated on a rotary evaporator. This was isolated in a yield of 2.47 g (87%) as a yellowish oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O)#[N:36]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=5[C:35]#[N:36])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: N#Cc1ccccc1B(O)O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5C#N)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-cyanophenylboronic acid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15].[CH3:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31](O)[CH:30]=2)[C:18]=1[C:19]([O:21][CH3:22])=[O:20]>>[CH3:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:15][CH2:14][CH2:13][C:3]3[N:4]=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[O:6][C:2]=3[CH3:1])[CH:30]=2)[C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1c(C)cccc1COc1cccc(O)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Product: COC(=O)c1c(C)cccc1COc1cccc(OCCc2nc(-c3ccccc3)oc2C)c1

Procedure:
MS (ESI) 458 (M+H)+. Prepared from 2-(5-methyl-2-phenyloxazol-4-yl)ethanol (example 11a) and methyl 2-(3-hydroxyphenoxymethyl)-6-methylbenzoate (example 5).
Reaction SMILES: [F:1][C:2]1([F:20])[O:19][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]#[C:30][CH3:31]>CN(C)C=O.C(OCC)(=O)C>[CH2:28]([N:4]1[CH2:3][C:2]([F:1])([F:20])[O:19][C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)[CH2:5]1)[C:29]#[C:30][CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(F)(F)O2
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCN1CC(F)(F)OC2(CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 45 °C
Yield: 65.4 %

Procedure:
To a mixture of crude tert-butyl 10,10-difluoro-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (65.0 mg, 0.222 mmol) and K2CO3 (61.5 mg, 0.445 mmol) in N,N-dimethylformamide (1.0 mL) was added 1-bromobut-2-yne (29.2 μL, 0.334 mmol) and the reaction heated at 45° C. for 48 h. The reaction was diluted with ethyl acetate and filtered. The filtrate was dried over Na2SO4, filtered and concentrated. Silica gel chromatography (4 g silica, 1-100% ethyl acetate/hexane) provided tert-butyl 8-but-2-ynyl-10,10-difluoro-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (50.0 mg, 65%) as a colorless oil. ESI-MS m/z calc. 344.2. found 345.3 (M+1)+; Retention time: 1.91 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 3.80 (br s, 2H), 3.35 (q, J=2.2 Hz, 2H), 3.23 (t, J=12.1 Hz, 2H), 2.80 (t, J=8.5 Hz, 2H), 2.48 (s, 2H), 2.02 (d, J=13.2 Hz, 2H), 1.84 (t, J=2.3 Hz, 3H), 1.54-1.48 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](=[O:21])[NH:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.N1C=CC=CC=1.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>ClCCl>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([O:21][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28])=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCC[C@H]3C)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@H]3C)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-methyl 3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200 mg, 0.70 mmol) in dichloromethane (30 mL) was added pyridine (221 mg, 2.79 mmol) and then Tf2O (395 mg, 1.40 mmol) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature, then quenched by the addition of ice-water (50 mL), extracted with dichloromethane (3×20 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford (R)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (250 mg, crude).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:33].[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1>C1COCC1>[N:41]1([C:38]2[CH:37]=[CH:36][C:35]([NH:34][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([C:29]([CH3:31])([CH3:30])[CH3:32])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:33])=[CH:40][CH:39]=2)[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C(C)(C)C)n1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCOCC4)cc3)c2)n(C(C)(C)C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
A small screw cap test tube was charged with 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 50, 70 mg, 0.157 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (34 mg, 0.1907 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 mL of i-prOH affording the title compound in 73% yield (0.069 g, 0.1141 mmol).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].I([Cl:26])(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.ClC(Cl)C.C(=O)([O-])[O-].[Na+].[Na+].S(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[CH2:15]([O:14][C:12]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)=[C:4]([C:1](=[O:3])[CH2:2][Cl:26])[CH:13]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)cc2[nH]c(=O)ccc12
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: O
Product: O=C(CCl)c1cc(OCc2ccccc2)cc2[nH]c(=O)ccc12

Procedure:
7.0 g (23.9 mmol) 5-acetyl-7-benzyloxy-1H-quinolin-2-one and 19.0 g (54.6 mmol) benzyltrimethylammonium dichloriodate are stirred in 43 mL acetic acid, 7 mL water and 147 mL dichloroethane at 65° C. After 4.5 hours the reaction is stopped by the addition of 400 mL sodium carbonate solution and 50 mL 5% sodium bisulphite solution. The insoluble constituents are suction filtered, washed with water and dried.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]4[NH:25][C:24]([C:26]([F:29])([F:28])[F:27])=[N:23][C:20]4=3)[O:15][CH2:14]2)(=O)=O)=CC=1.[C:30]1([CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CS(C)=O.C(OCC)(=O)C>[C:30]1([CH2:36][CH2:37][CH2:38][CH2:39][NH:40][CH2:12][CH:13]2[O:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]4[NH:25][C:24]([C:26]([F:28])([F:29])[F:27])=[N:23][C:20]4=3)[O:15][CH2:14]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]c(C(F)(F)F)nc4c3O2)cc1
Reactant: NCCCCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: FC(F)(F)c1nc2c3c(ccc2[nH]1)OCC(CNCCCCc1ccccc1)O3
Temperature: 85 °C
Yield: 49.3 %

Procedure:
A mixture of 0.50 g (1.2 mmole) of [(8R)-2-trifluoromethyl-7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalen-8-yl]methyl 4-methylbenzenesulfonate and 0.75 g (5.0 mmole) of 4-phenylbutylamine in 25.0 mL of DMSO was heated at 80-90° C. under nitrogen for 4 hours. The reaction was allowed to come to room temperature, diluted to 500 mL with ethyl acetate, washed with 500 mL portions of saturated aqueous sodium bicarbonate and water, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel with 2% methanol in chloroform as eluant and the product fractions evaporated to give 0.24 g of the desired product. This was recrystallized from ethanol with the addition of oxalic acid to give 0.092 g of the (S)-enantiomer of the title compound as a white solid oxalate, hydrate, m.p. 124-127° C.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH2:17][CH3:18].CC(C)(O)C#N.Cl>C(Cl)Cl.O>[C:16]([CH:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]1=[O:8])(=[O:19])[CH2:17][CH3:18]
Reactant: O=C1CCCC(=O)C1
Reactant: CCC(=O)Cl
Agent: CC(C)(O)C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCC(=O)C1C(=O)CCCC1=O
Temperature: 25 °C
Yield: 84.3 %

Procedure:
To a mixture of 3.0 g (0.027 mole) of 1,3-cyclohexanedione and 3.8 ml (0.027 mole) of triethylamine in 15 ml methylene chloride, there was added dropwise 2.3 ml (0.027 mole) of propionyl chloride with stirring and cooling in a room temperature water bath. After continued stirring at ambient temperature for about 4 hours, an additional 7.5 ml (0.054 mole) of triethylamine and 0.25 ml (10 mole percent with respect to enol ester) of acetone cyanohydrin were added. The mixture was stirred at ambient temperature overnight, and was then diluted with water and acidified with 6N hydrochloric acid. The phases were separated, and the aqueous phase was extracted with methylene chloride. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4.68 g of crude product as a mixture of solid and liquid. The crude product was dissolved in methylene chloride and was extracted with 2.5N sodium hydroxide solution followed by water. The combined aqueous phases were acidified with 6 N hydrochloric acid and extracted with methylene chloride. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3.83 g of oily product (84% of theoretical). Structure of the product was confirmed by infrared, nuclear magnetic resonance and mass spectroscopy.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1)CCC.[F-].[Cs+]>[Cu]I.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>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[N:3]=[C:2]([C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)[CH:7]=1
Reactant: CC(C)Oc1ccc(-c2cc(Cl)cc(Cl)n2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Product: CC(C)Oc1ccc(-c2cc(Cl)cc(-c3cnccn3)n2)cc1
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a 2 dram vial equipped with a stir bar was added 2,4-dichloro-6-(4-isopropoxyphenyl)pyridine (50 mg, 0.18 mmol), 2-(tributylstannyl)pyrazine (65 mg, 0.18 mmol), CuI (9.0 mg, 0.047 mmol), CsF (82 mg, 0.54 mmol), and Pd(PPh3)4 (10.2 mg, 8.86 μmol). The vial was capped with a septum screw-cap and then placed under N2 atmosphere. To the vial was added degassed DMF (1 mL). The vial was placed in a 80° C. heating block with stirring for 1 hour. The reaction mixture was directly purified by C18 chromatography (water:MeOH w/0.1% TFA) to afford 2-(4-chloro-6-(4-isopropoxyphenyl)pyridin-2-yl)pyrazine as a dark solid (37 mg, 64%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10](O)[CH:9]=[N:8]2)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:18])=O.O>C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([Cl:18])[CH:9]=[N:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccc2nc(O)cnc2c1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc2nc(Cl)cnc2c1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A solution of 250 mg (1.236 mmol) of 6-tert-Butyl-quinoxalin-2-ol in 1.07 mL (11.43 mmol) phosphorus oxychloride under nitrogen was heated at 110° C. for 3 h. The solution was cooled to room temperature and added drop wise to water (10-15° C.). Ethyl acetate was added. The aqueous layer was extracted with ethylacetate. The combined organic phases were washed with water, dried over Na2SO4 and concentrated. The crude compound was purified with flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate to provide 219 mg (80.3%) of the title compound as a green solid. MS(m/e): 220 (M+H+).