Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([NH2:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.ClC(Cl)Cl.[C:26](Cl)(=[O:34])[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([NH:15][C:26](=[O:34])[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(N2CCN(N)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(N2CCN(NC(=O)Oc3ccccc3)CC2)cc1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a stirred solution of 8 parts of 4-(4-methoxyphenyl)-1-piperazinamine in 5 parts of pyridine and 45 parts of trichloromethane are added dropwise during a 30 minutes period 7.8 parts of phenyl carbonochloridate. Upon completion, stirring is continued for 30 minutes at room temperature. Water is added to the reaction mixture and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is triturated in 4-methyl-2-pentanone. The product is filtered off and crystallized from 1,4-dioxane, yielding 9 parts (70%) of phenyl [4-(4-methoxyphenyl)-1-piperazinyl]carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11](Cl)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(O[C:21]([CH:23]([CH3:25])[CH3:24])=[CH2:22])C>C(=O)([O-])[O-].[Na+].[Na+].O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]([CH:23]([CH3:25])[CH3:24])=[CH:22][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10]1
Reactant: C=C(OCC)C(C)C
Reactant: CCOC(=O)C(Cl)=NNc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(C(C)C)n(-c2ccc(Cl)cc2Cl)n1
Temperature: 70 °C
Yield: 94.7 %

Procedure:
1550 g of ethyl 2-chloroglyoxalate 2,4-dichlorophenylhydrazone are dissolved in 600 g of 2-ethoxy-3-methylbut-1-ene and 325 g of sodium carbonate, dissolved in 300 ml of water, are added such that a pH of greater than 8.0 is always maintained. After a reaction time of 4 hours (60°-80° C.), the aqueous phase is separated off and 200 ml of hydrochloric acid (pH~1) are added to the organic phase and the mixture is heated to reflux for 1 hour. After cooling to 70° C., the organic phase is separated off and crystallized using methanol/water. 1694 g of product having a purity of 96.3% are obtained, which corresponds to a yield of 94.7% of theory. The melting point is 95°-96° C.
Reaction SMILES: C([O:3][P:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:5][CH2:6][CH3:7])C.Br[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29]>>[CH2:6]([O:5][P:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2[C:21](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]1=[O:29])=[O:3])[CH3:7]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: CCOC(=O)CP(OCC)OCC
Product: CCOC(=O)CP(=O)(CCCCN1C(=O)c2ccccc2C1=O)OCC

Procedure:
Heat 12.5 gm of ethyl (diethoxyphosphino)acetate with 16.9 gm of N-(4-bromobutyl)phthalimide in a melt at 180° for 5 hours under a nitrogen atmosphere. After cooling, chromatograph the mixture on a silica gel column, eluting with a gradient of 1% to 2% CH3OH in EtOAc. Isolate the major product by vacuum evaporation of the solvent from the combined fractions to obtain the title compound. Rf (silica gel; EtOAc:CH3OH, 99:1)=0.40.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([CH3:16])([CH3:15])[C:11]([O:13]C)=[O:12]>O.CO.C1COCC1>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([CH3:16])([CH3:15])[C:11]([OH:13])=[O:12]
Reactant: COC(=O)C(C)(C)c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C(=O)O)c1ccccc1F
Temperature: 40 °C

Procedure:
A solution of sodium hydroxide (1 g) in water (50 mL) was added to a solution of methyl 2-(2-fluorophenyl)-2-methylpropanoate (example 90, step b) (2.6 g) in methanol (50 mL) and THF (50 mL). The reaction mixture was heated at 40° C. for 40 hours. The organics were removed under reduced pressure and the remaining aqueous solution washed with ethyl acetate. The aqueous layer was cooled and acidified by addition of concentrated HCl. The mixture was extracted with ethyl acetate and the organic layer washed with brine before being dried over sodium sulphate, filtered and the solvent removed under reduced pressure to afford the subtitled compound. Yield 1.5 g.
Reaction SMILES: [OH-].[K+].[F:3][CH2:4][C:5]([CH2:15][F:16])([C:7](=[O:14])[CH2:8][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)[CH3:6].[CH:17]1([CH2:23]Br)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O.CS(C)=O>[F:16][CH2:15][C:5]([CH2:4][F:3])([C:7](=[O:14])[CH:8]([N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)[CH2:23][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:6]
Reactant: BrCC1CCCCC1
Reactant: CC(CF)(CF)C(=O)Cn1cncn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(CF)(CF)C(=O)C(CC1CCCCC1)n1cncn1
Yield: 54.9 %

Procedure:
A solution of 101.4 g (1.81 moles) of potassium hydroxide in 217.2 ml of water was added to a solution of 369.4 g (1.81 moles) of 2,2-bis-fluoromethyl-4-(1,2,4-triazol-1-yl)-butan-3-one in 2 liters of dimethyl sulfoxide at room temperature, with stirring. 320.5 g (1.81 moles) of cyclohexylmethyl bromide were added dropwise to this mixture, with stirring, the temperature of the reaction mixture being kept between 20° and 40° C. by cooling. The reaction mixture was stirred at 60° C. for a further 15 hours and then poured into 2 liters of water. The resulting mixture was extracted twice with 1 liter of methylene chloride each time, the combined organic phases were washed four times with 2 liters of water each time and dried over sodium sulphate and the solvent was stripped off. The oily product which remained was taken up in acetone and 326 g of naphthalene-1,5-disulphonic acid were added to the solution. The precipitate which thereby formed was filtered off with suction and suspended in 2 liters of methylene chloride. This suspension was shaken twice with 2 liters of saturated aqueous sodium bicarbonate solution each time. The organic phase was then washed with 2 liters of water and, after drying over sodium sulphate, was concentrated under reduced pressure. 297.5 g (63% of theory) of 2,2-bis-fluoromethyl-5-cyclohexyl-4-(1,2,4-triazol-1-yl)-pentan-3-one were obtained in this manner in the form of an oil.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:9])([C:5](=[O:8])[CH2:6][CH3:7])[CH3:4].[N:10](OCCCC)=[O:11]>C(OCC)C.C1(C)C=CC=CC=1>[OH:11][N:10]=[C:6]([CH3:7])[C:5](=[O:8])[C:3]([CH3:9])([CH3:4])[CH3:2]
Reactant: CCC(=O)C(C)(C)C
Reactant: CCCCON=O
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(=NO)C(=O)C(C)(C)C
Temperature: -10 °C
Reaction time: 4 h
Yield: 54.9 %

Procedure:
A solution of 40 g of hydrogen chloride in 156 g of diethyl ether is added dropwise at room temperature to 96 g (0.84 mol) of 2,2-dimethyl-3-pentanone in 960 g of toluene. After cooling to -10° C., a solution of 95 g of n-butyl nitrite in 470 g of diethyl ether is added dropwise. The mixture is stirred at from -10° C. to 0° C. for 4 hours and then allowed to come to room temperature. After a total of 16 h, the reaction mixture is washed three times with 1 l of ice-water each time and then extracted twice with 1 l of 1M sodium hydroxide solution each time. The alkaline phase is separated off and neutralized with 20% strength sulfuric acid. The crude product is filtered off with suction and, after drying, recrystallized from n-hexane. 66 g (55%) of the title compound are obtained as a pale yellow powder of melting point 107°-110° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[C:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:21])[CH3:20].C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[C:19]([N:22]1[CH2:27][CH2:26][N:25]([C:16]([C:13]2[S:14][CH:15]=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[N:12]=2)=[O:17])[CH2:24][CH2:23]1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reactant: CC(=O)N1CCNCC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCN(C(C)=O)CC3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above (160 mg, 0.53 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 1-Acetylpiperazine (Aldrich) (81.5 mg; 0.64 mmol; 1.20 eq.) and triethylamine (0.22 ml; 1.59 mmol; 3 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is purified by preparative HPLC, affording Compound (45) as a pale yellow powder (127.9 mg; 61%). 1H NMR (DMSO-d6, 300 MHz) δ 2.04 (s, 3H), 2.13 (s, 3H), 2.49 (s, 3H), 3.57 (m, 4H), 3.65 (m, 1H), 3.70 (m, 1H), 4.25 (m, 1H), 4.35 (m, 1H), 8.01 (s, 1H), 12.16 (s, 1H). M− (ESI): 392.14; M+ (ESI): 394.15. HPLC (method A), Rt: 2.41 min (purity: 100%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[C:20](F)=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([N+:22]([O-:24])=[O:23])[CH:11]=1.CCN(CC)CC>C1COCC1>[CH2:1]([O:8][C:20]1[C:10]([F:9])=[CH:11][C:12]([N+:22]([O-:24])=[O:23])=[C:13]([CH:19]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)c1cc(F)c(F)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(OCc2ccccc2)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.5 %

Procedure:
8.25 g of Verkade base are added to a solution of 2.61 g of benzyl alcohol in 20 ml of THF. The mixture is stirred for 10 minutes at room temperature, and a solution of 5.3 g of ethyl 4,5-difluoro-2-nitrobenzoate and 2.55 g of Et3N in 150 ml of THF is added to this solution. The mixture is stirred for 1 hour at room temperature. The reaction medium is evaporated under reduced pressure. The residue is taken up in DCM and washed three times with aqueous 1N HCl solution, and then with water. The organic phase is dried over MgSO4 and filtered, and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a PE/DCM mixture from (100/0, v/v) to (0/100, v/v) to give 4.5 g of the expected product.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][O:23][CH:22]([C:26](O)=[O:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:26]([CH:22]3[O:23][CH2:24][CH2:25][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:21]3)=[O:27])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (350 mg, 1.52 mmol), 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (739 mg, 3.20 mmol), BOP—Cl (813 mg, 3.20 mmol), and triethylamine (1.06 mL, 7.61 mmol) in DCM (5 mL) was stirred at room temperature for 1 hour. 3M LiOH (3 mL) was then added, and stirred for an additional 10 minutes. Water (10 mL) and DCM (10 mL) were then added, and the solid formed was filtered. The solid product was washed with DCM (10 mL) and dried to give tert-butyl 2-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbamoyl)morpholine-4-carboxylate (660 mg, 97.9% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[C:13](=O)[CH2:14][CH2:15][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(O)(=O)C.C([BH3-])#N>ClCCl>[CH2:1]([N:8]1[CH2:12][C@H:11]2[C@@H:13]([NH:20][CH:17]3[CH2:19][CH2:18]3)[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: O=C1CCC2CN(Cc3ccccc3)CC12
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(CN2C[C@@H]3CC[C@H](NC4CC4)[C@@H]3C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one (0.578 g, 2.68 mmol), cyclopropylamine (0.189 mL, 2.68 mmol), and acetic acid (10 mL) were combined in dichloromethane (20 mL). PS-Cyanoborohydride (1.147 g, 2.68 mmol) was added. The reaction was stirred at room temperature for 2 hours, then filtered and the resin was washed with dichloromethane. The solvent was removed in vacuo, and the crude material was applied to a silica gel column and was eluted with 1-10% methanol(2 N ammonia)/dichloromethane to give the title compounds.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10](=[S:20])[NH:9]2)=[CH:4][CH:3]=1.[CH3:21][I:22]>CCO>[IH:22].[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:12]2[C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[NH:9][C:10]([S:20][CH3:21])=[N:11]2)=[CH:14][CH:15]=1
Reactant: CI
Reactant: S=C1N[C@H](c2ccc(Cl)cc2)[C@H](c2ccc(Cl)cc2)N1
Solvent: CCO
Product: CSC1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1
Product: I
Temperature: 25 °C
Yield: 75.3 %

Procedure:
A mixture of cis-4,5-bis-(4-chlorophenyl)imidazolidine-2-thione (34) (30 g, 0.0928 mol) and methyl iodide (11.5 mL, 0.186 mol) in abs. EtOH (100 mL) is heated at 90° C. for 8 h. The reaction mixture is cooled to rt, concentrated in vacuo, and the residue triturated with abs EtOH. The insoluble material is filtered to give 32.5 g of the product 51.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[CH3:12][S-:13](C)[C:14](=[N:16][C:17]#[N:18])[S-]>>[C:17]([NH:16][C:14](=[N:6][C:5]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[S:13][CH3:12])#[N:18]
Reactant: C[S-](C)C([S-])=NC#N
Reactant: COc1ccc(N)cc1OC
Product: COc1ccc(N=C(NC#N)SC)cc1OC

Procedure:
South African OPI specification No. 79/1059 describes a process for the production of 4-amino-6,7-dimethoxy-2-[4-(furo-2-yl)-piperazin-1-yl]-quinazoline (prazosin), in which 3,4-dimethoxyaniline is reacted with S,S-dimethyl-N-cyanodithioimidocarbonate to form N-cyano-N'-(3,4-dimethoxyphenyl)-S-methylisothiourea which is then condensed with 1-(furo-2-yl)-piperazine to form 4-(furo-2-yl)-piperazine-1-[N-cyano-N'-(3,4-dimethoxyphenyl)]-carboximide amide which, in turn, is closed at 180° C. to form the 4-amino-6,7-dimethoxy-2-[4-(furo-2-yl)-piperazin-1-yl]-quinazoline ring.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[F:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=1[OH:35]>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:35][C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=2[F:27])=[N:3][CH:4]=1
Reactant: Oc1cccc(F)c1F
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1cccc(F)c1F)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 2,3-difluorophenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.7 Hz), 8.11 (1H, d, J=2.7 Hz), 7.98–7.92 (3H, m), 7.43–7.40 (2H, m), 7.23–7.07 (3H, m), 5.43–5.32 (1H, m), 1.61–1.56 (12H, m); MS (ESI) m/z 489 (M+H)+, 487 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([NH:12][CH2:13][C:14]#[CH:15])(=[O:11])[CH3:10].[OH2:16]>C(NC(C)C)(C)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>[C:9]([NH:12][CH2:13][C:14]#[C:15][C:5]1[CH:6]=[CH:7][C:2]([C:6]#[C:7][CH2:2][NH:3][C:4](=[O:16])[CH3:5])=[N:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: C#CCNC(C)=O
Reactant: O
Reactant: Brc1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)NC(C)C
Product: CC(=O)NCC#Cc1ccc(C#CCNC(C)=O)nc1
Reaction time: 1 h

Procedure:
A mixture of 2,5-dibromopyridine (15.0 g, 63.9 mmol), N-acetyl-propargylamine (15.51 g), and PdCl2(PPh3)2 (453 mg) in diisopropylamine (510 mL) was refluxed for 3 hours under a nitrogen atmosphere. To the mixture was added water (200 ml) and diisopropylamine was removed from the mixture by distillation under reduced pressure. The resulting suspension was aged at ambient temperature for 1 hour, and precipitates were collected by filtration and dried under reduced pressure to provide 2-1 (14.0 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][C:38]([O:40][CH3:41])=[O:39])[CH:12]=[CH:13][C:14]=1[C@H:15]1[C@H:18]([CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](=[O:28])[N:16]1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)C1C=CC=CC=1>CCOC(C)=O.CO>[OH:8][C:9]1[CH:10]=[C:11]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:12]=[CH:13][C:14]=1[C@H:15]1[C@H:18]([CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](=[O:28])[N:16]1[C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1
Reactant: COC(=O)C=Cc1ccc([C@H]2[C@H](CCCc3ccccc3)C(=O)N2c2ccc(F)cc2)c(OCc2ccccc2)c1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc([C@H]2[C@H](CCCc3ccccc3)C(=O)N2c2ccc(F)cc2)c(O)c1
Reaction time: 8 h
Yield: 70.4 %

Procedure:
Dissolve the product of Example 5 (0.266 g, 0.48 mmol) in EtOAc (16 mL), dilute with CH3OH (20 mL) and purge with N2. Add 20% Pd/C (0.05 g), purge the mixture with H2 and then stir under a balloon of H2 overnight. Filter the reaction mixture through celite. Wash the filter cake with EtOAc and concentrate the filtrate to give 0.156 g of the title compound as a colorless oil. HRMS calc'd for C28H28 NO4 :M+H 462.2081; found 462.2070.MS (CI): 462 (M+1,37), 351 (17), 293(41 ), 138(100).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C@@:22]2([CH3:25])[CH2:24][O:23]2)=[O:21])=[CH:15][C:14]=1[CH3:26])#[N:12].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH2:25][C@@:22]([OH:23])([CH3:24])[C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([C:11]#[N:12])=[C:14]([CH3:26])[CH:15]=2)=[O:21])=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: Cc1cc(NC(=O)[C@@]2(C)CO2)ccc1C#N
Reactant: N#Cc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)[C@@](C)(O)COc2ccc(C#N)c(F)c2)ccc1C#N
Temperature: 50 °C
Reaction time: 25.5 h
Yield: 70.8 %

Procedure:
2-Fluoro-4-hydroxy benzonitrile (0.81 g, 5.9 mmol) and (2R)-2-methyl-oxirane-2-carboxylicacid-(4-cyano-3-methylphenyl)amide (0.905 g, 4.2 mmol) were dissolved in 17.6 ml of EtOAc. Anhydrous K2CO3 (0.29 g; 2.1 mmol) was added and the mixture heated to 50° C. and stirred for 25.5 hours. The mixture was cooled to room temperature, 30 ml of EtOAc added and washed first with 2×24 ml of 1M Na2CO3 and then 2×24 ml of water. Organic layer was dried over Na2SO4, filtered and evaporated to give 1.05 g of crude product.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][CH3:16])[C:8]([O:13][CH3:14])=[C:9]([CH:12]=1)[C:10]#[N:11])=[O:4].[Se](=O)=[O:18].[CH2:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(Cl)Cl>[C:10]([C:9]1[CH:12]=[C:5]([C:3](=[O:4])[C:2]([O:26][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:18])[CH:6]=[C:7]([O:15][CH3:16])[C:8]=1[O:13][CH3:14])#[N:11]
Reactant: O=[Se]=O
Reactant: COc1cc(C(=O)CBr)cc(C#N)c1OC
Reactant: CCCCCCO
Solvent: ClCCl
Product: CCCCCCOC(=O)C(=O)c1cc(C#N)c(OC)c(OC)c1
Temperature: 25 °C

Procedure:
1.45 g of 5-(bromoacetyl)-2,3-dimethoxybenzonitrile and 1.12 g of selenium dioxide are stirred at 120° for 18 hours in 10 ml of n-hexanol. After cooling to room temperature the mixture is diluted with 20 ml of methylene chloride and filtered. The filtrate is washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed on 70 g of silica gel with hexane/ether (2:1). There is obtained hexyl (3-cyano-4,5-dimethoxy-phenyl)glyoxylate as an oil.
Reaction SMILES: [O:1]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:18]([OH:20])=[O:19])[CH:12]=[CH:13][CH:14]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[C:27]([NH2:28])=[C:26]([NH2:29])[CH:25]=[CH:24][N:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:28][C:27]1[C:22]([Cl:21])=[N:23][CH:24]=[CH:25][C:26]=1[NH:29][C:18]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]=[C:8]([O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:17]=[CH:16]2)=[O:20].[NH2:29][C:26]1[CH:25]=[CH:24][N:23]=[C:22]([Cl:21])[C:27]=1[NH:28][C:18]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[N:9]=[C:8]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:17]=[CH:16]2)=[O:19]
Reactant: O=C(O)c1cccc2ccc(Oc3ccccc3)nc12
Reactant: Nc1ccnc(Cl)c1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1c(NC(=O)c2cccc3ccc(Oc4ccccc4)nc23)ccnc1Cl
Product: Nc1ccnc(Cl)c1NC(=O)c1cccc2ccc(Oc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-phenoxyquinoline-8-carboxylic acid (119 mg, 0.449 mmol), 2-chloropyridine-3,4-diamine (97 mg, 0.673 mmol, Waterstone Technology, Carmel, Ind.), HATU (341 mg, 0.897 mmol), and DIPEA (235 μl, 1.346 mmol) in DMF (449 μl) was stirred at RT for 2 h. The mixture was diluted with EtOAc (100 ml), added to a separatory funnel, and washed with saturated aq. NaHCO3 (3×75 ml) before the organic layer was separated, dried over Na2SO4, and concentrated. Purification by silica chromatography (100% DCM to 5% MeOH/DCM) provided N-(3-amino-2-chloropyridin-4-yl)-2-phenoxyquinoline-8-carboxamide (or N-(4-amino-2-chloropyridin-3-yl)-2-phenoxyquinoline-8-carboxamide; regioisomer not determined; 178d, 49% yield). MS (ESI, pos. ion) m/z: 391.2 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:10]=[C:11]([N:14]([C:21]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][CH3:13].C(N(CC)CC)C.CN(C)C(=[O:43])C.[OH2:45]>>[OH2:10].[C:27]([OH:29])(=[O:28])[C:21]([OH:43])=[O:45].[O:10]=[C:11]([N:14]([C:21]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][CH3:13].[CH2:30]([O:29][C:27]([C:21]1([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11](=[O:10])[CH2:12][CH3:13])[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:23][CH2:22]1)=[O:28])[CH3:31].[C:27]([OH:29])(=[O:28])[C:21]([OH:43])=[O:45]
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)C1(N(C(=O)CC)c2ccccc2)CCNCC1
Reactant: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1(N(C(=O)CC)c2ccccc2)CCN(CCc2ccccc2)CC1
Product: O=C(O)C(=O)O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 3.1 parts of (2-bromoethyl)benzene, 4.6 parts of ethyl 4-[N-(1-oxopropyl)-N-phenylamino]-4-piperidinecarboxylate, 2.7 parts of N,N-diethylethanamine and 67.5 parts of N,N-dimethylacetamide is stirred for 2 hours at 70° C. The reaction mixture is poured onto 600 parts of water, whereupon an oil is precipitated. The supernatant phase is decanted and discarded. The oily product is dissolved in 210 parts of 1,1'-oxybispropane. The solution is washed twice with water, dried, filtered and evaporated. The residue is converted into the ethanedioate salt in 2-propanol. The salt is filtered off and dried at 120° C., yielding ethyl 4-[N-(1-oxopropyl)-N-phenylamino]-1-(2-phenylethyl)-4-piperidinecarboxylate ethanedioate hemihydrate; mp. 197.1° C.