Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[C:11]([OH:30])[CH:10]=1)=[O:8].[CH2:32]([O:34][C:35](=[O:38])[CH2:36]Br)[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]/[C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[C:11]([O:30][CH2:36][C:35]([O:34][CH2:32][CH3:33])=[O:38])[CH:10]=1)=[O:8]
Reactant: CCOC(=O)CBr
Reactant: COC(=O)CCCC(=O)c1ccc(OCCCC/C=C/c2ccc(OC)cc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C(=O)CCCC(=O)OC)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 111.3 %

Procedure:
Under the conditions of example 1A, 420 mg of 5-(3-hydroxy-4-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-phenyl}-5-oxopentanoic acid methyl ester is reacted with 167 mg of bromoacetic acid ethyl ester in 4 ml of dimethylformamide in the presence of 650 mg of cesium carbonate and worked up. 562 mg of 5-{3-(1-ethoxycarbonylmethoxy)-4-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-phenyl}-5-oxo-pentanoic acid methyl ester is obtained as colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]2.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+].Cl>O.N1C=CC=CC=1>[OH:29][C:26]1[CH:27]=[CH:28][C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2
Reactant: Nc1ccc(O)c2ncccc12
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(O)c4ncccc34)c2cc1OC
Yield: 56.3 %

Procedure:
A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinolin-3-carbonitrile, 0.233 g of 5-amino-8-hydroxyquinoline dihydrocholride, 0.158 g of pyridine, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 2 hours. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate and concentrated hydrochloric acid to adjust pH to 7. The product was collected, washed with water, and dried to give 0.210 g of 4-(8-hydroxy-quinolin-5-ylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 150° C. (decomposed); mass spectrum (EI, m/e): M 372.1228.
Reaction SMILES: Br[C:2]1[C:3]([NH2:13])=[N:4][C:5]([C:9]([F:12])([F:11])[F:10])=[C:6]([Br:8])[N:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[Br:8][C:6]1[N:7]=[C:2]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)[C:3]([NH2:13])=[N:4][C:5]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1nc(C(F)(F)F)c(Br)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 66.6 %

Procedure:
To a mixture of 6.08 g 3,5-dibromo-6-trifluoromethyl-pyrazin-2-ylamine, 3.25 g 4-chlorophenylboronic acid and 1.095 g tetrakis(triphenylphosphine)palladium(0) in 60 ml 1,2-dimethoxyethane was added a solution of 4.016 g sodium carbonate in 22.74 ml water and the mixture was heated to reflux for 18 h. The reaction mixture was cooled to room temperature and partitioned between 10% aqueous citric acid and ethyl acetate, the phases were separated and the organic phase was purified by chromatography on silica gel with a gradient of 9:1 heptane: dichloromethane to 1:1 heptane: dichloromethane to yield 4.45 g of the title compound as white solid. MS (M−H) at 352.0 and 350.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:32])=[C:6]2[C:11]=1[CH:10]([C:12]([OH:14])=[O:13])[N:9]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:8][CH2:7]2.OS(O)(=O)=O.[CH2:38](O)[CH3:39]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:32])=[C:6]2[C:11]=1[CH:10]([C:12]([O:14][CH2:38][CH3:39])=[O:13])[N:9]([S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:22][CH:23]=1)(=[O:16])=[O:17])[CH2:8][CH2:7]2
Reactant: CCO
Reactant: O=C(O)C1c2c(Br)ccc(O)c2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1c2c(Br)ccc(O)c2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 5 h

Procedure:
0.60 g (1.2 mmol) of 8-bromo-2-[4-(4-fluorophenoxy)benzenesulfonyl]-5-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (crude product, 21C) are mixed with 0.25 ml of conc. H2SO4 in 10 ml of ethanol and heated to reflux. After five hours, a further 0.25 ml of conc. H2SO4 is added, and heating to reflux is continued for one hour. For workup, the mixture is concentrated, and the residue is taken up in sat. Na2CO3 solution and extracted twice with dichloromethane. The organic phases are dried with MgSO4, and the solvent is removed in vacuo. The crude product obtained in this way can be reacted further without purification.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:32][C@H:33]([CH:38]([CH3:40])[CH3:39])[C:34]([O:36][CH3:37])=[O:35].[Br:41][C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1>C1(C)C=CC=CC=1>[Br:41][C:42]1[CH:47]=[CH:46][C:45]([O:32][C@@H:33]([CH:38]([CH3:40])[CH3:39])[C:34]([O:36][CH3:37])=[O:35])=[CH:44][CH:43]=1
Reactant: COC(=O)[C@H](O)C(C)C
Reactant: Oc1ccc(Br)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](Oc1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
Diethylazodicarboxylate (17.5 ml) in dry toluene (60 ml) was added dropwise over 30 minutes to a cooled, stirred solution of triphenylphosphine (34 g), methyl (R)-2-hydroxy-3-methylbutanoate (17 g, J.Am. Chem. Soc., (1990), 112, 21, 7659) and 4-bromophenol (24 g) in dry toluene (180 ml). The resulting solution was stirred at room temperature for 30 minutes and was then concentrated under reduced pressure to approximately half the original volume. A mixture of isohexane (700 ml) was added and the mixture stirred at room temperature for 20 minutes. The solution was filtered to remove triphenylphosphine oxide and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with isohexane: dichloromethane (1:4) then (2:3) to give the sub-title compound as an oil (28 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[NH:9]1[CH2:14][CH2:13][S:12][CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][S:12][CH2:11][CH2:10]2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: C1CSCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(N2CCSCC2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 74.9 %

Procedure:
A mixture of 1,4-dibromobenzene (1.0 g), thiomorpholine (0.44 g), tris(dibenzylideneacetone)dipalladium(0) (0.097 g), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.20 g) and sodium tert-butoxide (0.49 g) in toluene (10 mL) was stirred at 80° C. for 16 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.82 g).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[N:12]=1.B(Br)(Br)Br.C1CCCCC=1>>[CH2:28]([CH:25]([CH2:26][CH3:27])[CH2:24][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[C:11]([C:4]2[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]=2[OH:2])=[N:12]1)[CH3:29]
Reactant: CCC(CC)Cn1nc(-c2ccc(OC)cc2OC)c2cccc(C(F)(F)F)c21
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CCC(CC)Cn1nc(-c2ccc(O)cc2O)c2cccc(C(F)(F)F)c21
Yield: 33.1 %

Procedure:
Prepared according to Method D step C from 3-(2,4-dimethoxyphenyl)-1-(2-ethylbutyl)-7-(trifluoromethyl)-1H-indazole (0.720 g, 1.77 mmol), boron tribromide (1.01 mL, 10.7 mmol) and 0.5 mL of cyclohexene to give the product (0.222 g) as an off-white solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[N+:5]([O-:9])[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:12])=O>ClCCl>[Cl:12][CH2:2][C:3]1[CH:4]=[N+:5]([O-:9])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: [O-][n+]1cccc(CO)c1
Solvent: ClCCl
Product: [O-][n+]1cccc(CCl)c1
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To a solution of 3-hydroxymethyl-pyridine N-oxide (1.0 g, 8.0 mmol) in dichloromethane (40 mL) was added thionyl chloride (10 mL, 137 mmol). After stirring for 2 hours, the reaction mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer was repeatedly extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.60 g of the title product as a white solid, m.p. 133–137° C.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[Li]CCCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:26]=[C:25]([CH3:35])[C:24]=2/[CH:36]=[CH:37]/[CH:38]=[O:39])=[CH:19][CH:18]=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1.O.CCCCCC.CCOC(C)=O.CCOCC>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:26]=[C:25]([CH3:35])[C:24]=2/[CH:36]=[CH:37]/[CH:38]([OH:39])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6])=[CH:19][CH:18]=1
Reactant: COC(=O)CC(C)=O
Reactant: Cc1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1/C=C/C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C
Reaction time: 0.25 h
Yield: 29.1 %

Procedure:
Methyl acetoacetate (324 mg, 2.79 mmol) was added dropwise to a slurry of NaH (60% in mineral oil, 111.7 mg, 2.79 mmol) in dry THF (7 ml) at 0° C. After 15 minutes, n-BuLi (1.5M in hexanes, 1.46 ml, 2.19 mmol) was added and the mixture was stirred an additional 15 minutes. Addition of a solution of (E)-3-[4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-2-propenal (633 mg, 1.99 mmol) in THF (7 ml) to the reaction mixture resulted in the formation of a bright red solution. Twenty minutes after the addition, the solution was poured into a biphasic mixture of Et2O (40 ml) and 1N HCl (5.5 ml) in H2O (20 ml). The aqueous layer was made basic with saturated NaHCO3 and the phases were separated. The aqueous layer was extracted again with Et2O, neutralized with 1N HCl and extracted once more. The combined Et2O layers were washed with brine, dried (Na2SO4), filtered and stripped to yield an oil. Flash chromatography (Merck SiO2, 1:1 EtOAc:hexane) afforded (E)-7-[4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-5-hydroxy-3-oxo-6-heptenoic acid, methyl ester (251 mg, 29%) as a yellow oil
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][CH:42]=3)[CH:39]=[C:38]([NH:43][C:44](=[O:46])[CH3:45])[CH:37]=[CH:36]4)(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:48])(=[O:47])[N:20]=1.[OH-].[Na+:50]>O>[C:44]([NH:43][C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([S:30]([NH:29][C:27]1[CH:26]=[CH:25][C:23]3[NH:24][C:19]([C:3]4[C:4](=[O:18])[C@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]=4[O-:1])=[N:20][S:21](=[O:48])(=[O:47])[C:22]=3[CH:28]=1)(=[O:32])=[O:31])[CH:42]=[CH:41]2)(=[O:46])[CH3:45].[Na+:50]
Reactant: CC(=O)Nc1ccc2cc(S(=O)(=O)Nc3ccc4c(c3)S(=O)(=O)N=C(C3=C(O)c5ccccc5[C@@](C)(CCC(C)C)C3=O)N4)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccc2cc(S(=O)(=O)Nc3ccc4c(c3)S(=O)(=O)N=C(C3=C([O-])c5ccccc5[C@@](C)(CCC(C)C)C3=O)N4)ccc2c1
Yield: 99.9 %

Procedure:
A mixture of Example 104A (5.0 mg, 0.0072 mmol) and 0.998 M sodium hydroxide (0.0072 mL, 0.0072 mmol) in water (1 mL) was stirred at rt for 16 h. The reaction mixture was concentrated in vacuo to give the title compound (5.1 mg, quant. yield). 1H NMR (300 MHz, DMSO-d6) δ 0.42 m, 1 H) 0.66 (t, J=6.80 Hz, 6 H) 0.75 m, 1 H) 1.26 (m, 1 H) 1.36 (s, 3 H) 1.73 m, 1 H) 2.10 m, 4 H) 7.21 (d, J=9.93 Hz, 1 H) 7.31 (m, J=8.46, 2.21 Hz, 2 H) 7.38 (d, J=2.21 Hz, 1 H) 7.46 m, 2 H) 7.67 m, 2 H) 8.01 m, 3 H) 8.30 (s, 1 H) 8.37 (s, 1 H) 10.31 (s, 1 H) 10.51 (s, 1 H) 15.31 (s, 1 H). MS (ESI+) m/z 709.1 (M+H)+, 687.6 (M+H—Na)+, 704.1 (M−Na+ NH4)+, (ESI−) m/z 707.1 (M−H)−, 685.0 (M−H—Na)−.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]2[CH:18]=[C:19]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=3)[C:20]([OH:30])=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[CH:22]=2)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47].CCOC(C)=O>CN(C=O)C.O>[C:49]([O:48][C:46](=[O:47])[CH2:45][O:30][C:20]1[C:19]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)=[CH:18][C:17]([C:15](=[O:16])[NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:22][C:21]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cccc(-c2cc(C(=O)NCCCCCCCc3ccccc3)cc(-c3cccc(C)c3)c2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2cc(C(=O)NCCCCCCCc3ccccc3)cc(-c3cccc(C)c3)c2OCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a solution of 2′-hydroxy-3,3″-dimethyl-[1,1′:3′,1″]terphenyl-5′-carboxylic acid (7-phenyl-heptyl)-amide (240 mg, 0.516 mmol) in 2.5 mL anhydrous DMF was added solid K2CO3 (84 mg, 0.613 mmol). The reaction mixture was stirred at room temperature for 2 min before t-butyl bromoacetate (158 mg, 0.812 mmol, 812 μL) was added. The reaction was stirred overnight at room temperature after which point it was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with water to remove DMF. Then they were dried with Na2SO4 and the solvent was removed in vacuo to give an oil that was subjected to flash column chromatography (15% EtOAc: 85% Hexanes) to yield 180 mg, 60% of a colorless oil. 1H NMR (CDCl3) δ 1.25 (s, 9H); 1.25–1.40 (m, 6H); 1.28–1.47 (m, 4H); 2.40 (s, 6H); 2.57 (t, J=8.18 Hz, 2H); 3.43 (quartet, J=8.18 Hz, 2H); 3.73 (s, 2H); 6.06 (t, J=5.73 Hz, 1H); 7.08–7.20 (m, 5H); 7.20–7.32 (m, 4H); 7.37–7.46 (m, 4H); 7.68 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[N:9]O)=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.O=S(Cl)Cl>>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: CSc1nc(Cl)c(C=NO)c(Cl)n1
Solvent: O=S(Cl)Cl
Product: CSc1nc(Cl)c(C#N)c(Cl)n1
Temperature: 75 °C
Yield: 92.7 %

Procedure:
To 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (2.38 g, 10 mmol) was added SOCl2 (21.8 mL, 0.30 mol) slowly at room temperature. The solution was then heated at 75° C. for about 3 hours before it was concentrated under vacuum. The residue SOCl2 was removed by evaporation with toluene (5 mL) under vacuum. The resulting solid was washed with EtOH/H2O (10 mL, 1:1) to afford 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbonitrile (2.04 g, 93%). LC-MS m/z 220 (M+H)+1.99 minute; 1H-NMR (CDCl3) δ 2.64(3 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].Br[CH2:21][CH2:22][CH2:23][C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:14]1([C:7]2([CH3:13])[CH2:6][C:5]3[C:9](=[C:10]([Cl:11])[C:2]([Cl:1])=[C:3]([O:19][CH2:21][CH2:22][CH2:23][C:24]#[N:25])[CH:4]=3)[C:8]2=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C2CCCC2)Cc2cc(OCCCC#N)c(Cl)c(Cl)c2C1=O
Reaction time: 4 h

Procedure:
A mixture of 6,7-dichloro-2-cyclopentyl-5-hydroxy-2-methyl-2,3-dihydro-1H-inden-1-one (6.0 g, 20 mmole), 4-bromobutanenitrile (3.28 g, 22 mmole), and potassium carbonate (3.1 g, 22 mmole) in dimethylformamide (50 ml) was stirred at 60°-65° for four hours. The reaction mixture was poured into water and extracted with diethyl ether. The organic layer was washed successively with water and brine, dried over magnesium sulfate, and concentrated in vacuo to a solid residue (4.7 g). Recrystallization from butyl chloride-hexane afforded the analytically pure title compound, m.p. ca. 112°.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:9][CH2:10][CH3:11])=[CH:4][C:5](N)=[N:6][CH:7]=1.[BrH:12].BrBr.N([O-])=O.[Na+].[OH-].[Na+]>O>[Br:12][C:5]1[CH:4]=[C:3]([CH2:9][CH2:10][CH3:11])[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: Br
Reactant: CCCc1cc(N)ncc1Br
Agent: BrBr
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCCc1cc(Br)ncc1Br
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
5-Bromo-4-propylpyridine-2-amine (5.67 g, 26.3 mmol) was added 48% hydrogen bromide (21 mL) at 10° C. The mixture was added bromine (4.0 mL) under ice-cold conditions, and added dropwise with an aqueous solution (4.5 mL) of sodium nitrite (4.54 g) at −10° C. The mixture was stirred at −10° C. for 0.5 hours, then added 1N aqueous solution of sodium hydroxide (10 mL), and stirred at room temperature for 2 hours. The reaction solution was added water, extracted with diethylether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (diethylether), and the title compound (6.96 g (yield 95%)) was obtained as a brown oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[N:5]=[C:4]([CH3:11])[N:3]=1.O.[NH2:13][NH2:14]>O>[Cl:8][C:7]1[C:6]([O:9][CH3:10])=[N:5][C:4]([CH3:11])=[N:3][C:2]=1[NH:13][NH2:14]
Reactant: NN
Reactant: COc1nc(C)nc(Cl)c1Cl
Solvent: O
Product: COc1nc(C)nc(NN)c1Cl

Procedure:
4,5-Dichloro-6-methoxy-2-methylpyrimidine (21 g, 0.11 mol), 25 ml of hydrazine hydrate, and 25 ml of water were combined and heated to reflux for 25 min. The mixture was then cooled and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The solid residue was extracted with hexane and dried to obtain 12.8 g (62 percent of theory) of the title compound as a fluffy white solid melting at 158°-159° C.
Reaction SMILES: [NH2:1][C:2]1([CH2:9][C:10]#[CH:11])[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[O:8].I[C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:14]=1.C(NC(C)C)(C)C>COC(C)(C)C.[Cu](I)I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1([CH2:9][C:10]#[C:11][C:13]2[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=3)[N:14]=2)[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[O:8]
Reactant: C#CCC1(N)CCN(C)C1=O
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(I)n1
Agent: I[Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: COC(C)(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CCC2(N)CCN(C)C2=O)n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 80.3 %

Procedure:
To a stirred solution of 3-amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (which may be prepared as described in Description 3) (2.3 g, 15.11 mmol) in tert-butyl methyl ether (50 mL) was added 2-iodo-4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidine (which may be prepared as described in Description 6) (6.05 g, 16.62 mmol). diisopropylamine (6.35 mL, 45.34 mmol) was then added, followed by copper iodide (57.56 mg, 0.300 mmol) and bis(triphenylphosphine)palladium (II) dichloride (106.07 mg, 0.1500 mmol). The reaction was then stirred at room temperature for 5 days. The reaction mixture was transferred to a separating funnel and the flask washed with an additional quantity of tert-butyl methyl ether (15 ml). The organic solution was washed with water (2×50 mL) and brine (50 mL). The organic phase was dried over magnesium sulphate, filtered, and then the magnesium sulphate washed with dichloromethane (30 ml). The filtrate was concentrated at reduced pressure to give a yellow foam. The product was purified by silica gel chromatography eluting with ethyl acetate followed by an increasing percentage of a solution of 10% 0.880 ammonia in methanol, to give the title compound (D8a) as a yellow foam (4.71 g). This racemate was consistent by NMR and mass spectroscopy with the S isomer prepared in Description 8.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][N:23]=1)[C:19]#[N:20].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][N:23]=2)[C:19]#[N:20])[CH2:4][CH2:3]1
Reactant: CN1CCC(CCCCO)CC1
Reactant: N#Cc1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(CCCCOc2cc(C#N)ccn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.5 %

Procedure:
To a stirred solution of 4-(1-methyl-piperidin-4-yl)-butan-1-ol (1.0 g, 5.85 mmol) in DMF (12 mL) at 0° C. was added NaH (60%; 280 mg, 7.02 mmol). The mixture was warmed to rt for 1 h, then cooled to 0° C. A solution of 2-chloro-isonicotinonitrile (810 mg, 5.85 mmol) in DMF (4 mL) was added dropwise. The mixture was stirred at rt for 18 h, and then was diluted with water (5 mL) and satd. aq. NaHCO3 (25 mL). The mixture was extracted with CHCl3 (3×25 mL), dried (Na2SO4), filtered, and. Purification by Method 1 afforded 440 mg (28%) of a yellow oil.