Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5](=[O:13])[NH:6][NH:7][C:8](OCC)=[O:9].[OH-].[K+]>O>[Cl:1][CH2:2][CH2:3][N:4]1[C:5](=[O:13])[NH:6][NH:7][C:8]1=[O:9]
Reactant: CCOC(=O)NNC(=O)NCCCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH][nH]c(=O)n1CCCl
Yield: 42.7 %

Procedure:
23.9 g (0.114 mol) of 4-(2-chloroethyl)-1-ethoxycarbonyl-semicarbazide and 57 ml (0.228 mol) of 4-M potassium hydroxide solution were stirred together at room temperature for 2 hours. The mixture was diluted with 100 ml of water, applied to an ion-exchange column (Dowex 50X-8, H+ form) and eluted with water. The eluate was evaporated in vacuo to give a colourless solid which was recrystallized from water to give 7.97 g (43%) of 4-(2-chloroethyl)-1,2,4-triazolidine-3,5-dione of melting point 192°-193° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:14](N1C=CN=C1)(N1C=CN=C1)=[S:15].C(O)(=O)C>C1(C)C=CC=CC=1>[S:15]=[C:14]1[NH:1][C:2]2[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=2[O:8]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)Cc1ccc(O)c(N)c1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc2oc(=S)[nH]c2c1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
Methyl 3-amino-4-hydroxyphenylacetate (5.43 g, 0.03 mol) was suspended in toluene (60 ml) and 1,1′-thiocarbonyldiimidazole (5.34 g, 0.03 mol) was added. The resultant mixture was stirred for 30 minutes, then acetic acid (10 ml) was added and the mixture was heated under reflux for 3 hours. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was partitioned between water and ethyl acetate The organic extract was dried over magnesium sulfate, filtered and the filtrate was evaporated to give methyl (2,3-dihydro-2-thioxo-5-benzoxazolyl)acetate (6,2 g) as a light brown solid, m.p. 120-122° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:11]=2)[C:6]1=[O:19].Cl.C(N(CC)CC)C.[CH3:28][C:29]([CH3:34])([CH3:33])[C:30](Cl)=[O:31]>C(Cl)Cl>[CH3:28][C:29]([CH3:34])([CH3:33])[C:30]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:11]=2)[C:6]1=[O:19])=[O:31]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)c1ccc2ccn(CCCN)c(=O)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2ccn(CCCNC(=O)C(C)(C)C)c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of methyl 2-(3-aminopropyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate.HCl (0.13 g, 0.44 mmol) dissolved in methylene chloride (8 mL) was added triethylamine (0.18 mL, 1.3 mmol) and 2,2-dimethylpropanoyl chloride (0.08 mL, 0.66 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was then concentrated to dryness and the residue was purified by flash silica gel chromatography (40% to 90% EtOAc/hexanes) to afford methyl 2-{3-[(2,2-dimethylpropanoyl)amino]propyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.14 g, 92%). LC-MS: (FA) ES+ 345.
Reaction SMILES: [NH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[S:2]1(=[O:14])=[O:13].[H-].[Na+].Cl[CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.O>CN(C)C=O.C(OCC)(=O)C>[C:27]1([C:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][N:1]3[C:11]4=[C:12]5[C:7](=[CH:8][CH:9]=[CH:10]4)[CH2:6][CH2:5][CH2:4][N:3]5[S:2]3(=[O:13])=[O:14])[CH2:22][CH:23]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S1(=O)Nc2cccc3c2N1CCC3
Reactant: ClCCCN1CC=C(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S1(=O)N(CCCN2CC=C(c3ccccc3)CC2)c2cccc3c2N1CCC3
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 73.1 %

Procedure:
A solution of 5,6-dihydro(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (2.6 g) in dry N,N-dimethylformamide (10 cc) is added dropwise to a suspension of sodium hydride (0.45 g, 80% suspension in oil) in N,N-dimethylformamide (20 cc). After 15 minutes, stirring, a solution of 1-(3-chloropropyl)-4-phenyl-1,2,3,6-tetrahydropyridine (3.51 g) in N,N-dimethylformamide (10 cc) is added. The reaction mixture is heated to 80° C. for 90 minutes and is then cooled and poured into a mixture of water (100 cc) and ethyl acetate (200 cc). The organic phase is washed with water, is dried over magnesium sulphate and is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063-mm particle size, 4-cm diameter, 50-cm height) with ethyl acetate as eluent and with 125-cc fractions being collected. Fractions 2 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization from ethyl acetate, 1-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-5,6-dihydro(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (3.7 g) is obtained, melting at 120° C.
Reaction SMILES: C([Li])CCC.[CH3:6][Si:7]([C:10]#[CH:11])([CH3:9])[CH3:8].[CH:12](=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>O1CCCC1.C(OCC)C>[CH3:6][Si:7]([CH3:9])([CH3:8])[C:10]#[C:11][CH:12]([OH:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCC=O
Reactant: C#C[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCC(O)C#C[Si](C)(C)C
Temperature: -70 °C

Procedure:
173 mol of n-butyllithium solution (1.6 mol in hexane) is instilled in a solution of 25 g of trimethylsilylacetylene in 500 ml of tetrahydrofuran with stirring and argon atmosphere at -40° C., is stirred for 30 minutes at -40° C., cooled to -70° C. and 48.1 ml of nonanal is instilled at this temperature. After an hour at -70° C., the mixture is allowed to come to -30° C., 300 ml of 2 n hydrochloric acid is added and shaken with diethyl ether. The organic phases are dried (Na2SO4), concentrated by evaporation and the residue is distilled in a bulb tube at 120°-130° C./0.2 mbar. Thus 48.5 of (3RS)-1-(trimethylsilyl)-1-undecin-3-ol is obtained as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][CH2:4][OH:5]>[Ni].O>[CH3:1][CH:2]([CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:3][CH2:4][OH:5]
Reactant: CC(CCO)CCc1ccccc1
Agent: [Ni]
Solvent: O
Product: CC(CCO)CCC1CCCCC1
Yield: 96 %

Procedure:
3-Methyl-5-phenylpentanol (50 g., 0.28 mol.) and 1 g. of 50% Ni on silica catalyst (2 wt %, G-49-C, United Catalyst) were stirred at 700 rpm in a Parr reactor at 180° C. and 200-600 psi of hydrogen until hydrogen absorption stopped (12 hours). The reaction mixture was filtered through a filter bed (Celite™) using toluene as a rinse solvent and concentrated to a clear, colorless liquid. The odor grade product was isolated by fractional distillation, 96% yield; bp 84-86° C. at 0.8 mm. Odor: powerful green, rosy. Mass Spectrum form 5313-24. MS (EI) m/z (relative intensity) 166 (M+−H2O, 5), 151 (M+−Me and H2O, 2).
Reaction SMILES: P(OP(O)(O)=O)(O)(O)=O.O.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:16]([C:18](=[CH:23]O)[C:19]([O:21][CH3:22])=[O:20])[CH:17]=1>C(OC)(C)(C)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:16]=2[CH:17]=1
Reactant: COC(=O)C(=CO)c1cc(Cl)ccc1Oc1ccccc1
Agent: O=P(O)(O)OP(=O)(O)O
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)C1=Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
A mixture of 415.23 g (2.33 mol) of pyrophosphoric acid and 22.14 g of water at 0° C. was added over methyl 2-(5-chloro-2-phenoxyphenyl)-3-hydroxyacrylate (compound IXa) as obtained in Example 16. The reaction mixture was stirred at 60° C. for 2 hours. After cooling to 20° C., 500 mL of water and 1.4 L of methyl tert-butyl ether were added. The aqueous layer was extracted and washed with 200 mL of methyl tert-butyl ether. The organic phases were combined, washed with 400 mL of an aqueous saturated solution of sodium bicarbonate and 400 mL of saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was suspended in 400 mL of n-butanol and stirred at room temperature for 1 hour, and at 0° C. for 2 hours. The resulting suspension was filtered, and the solid was dried until constant weight to obtain 161 g of methyl 2-chlorodibenzo[b,f]oxepin-11-carboxylate (compound Xa) as an off-white solid. Yield: 77.7%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[S:16]1[CH:20]=[CH:19][N:18]=[C:17]1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:24]2[CH2:25][CH2:26][N:21]([C:17]3[S:16][CH:20]=[CH:19][N:18]=3)[CH2:22][CH2:23]2)=[CH:4][CH:5]=1)[CH3:11]
Reactant: CC(=O)NC(C)(C)c1ccc(CCl)cc1
Reactant: c1csc(N2CCNCC2)n1
Product: CC(=O)NC(C)(C)c1ccc(CN2CCN(c3nccs3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)-1-methylethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(thiazol-2-yl)piperazine instead of phenylpiperazine, the title compound was obtained as pale-yellow crystals, m.p.=118-120° C.
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[I:28]N1C(=O)CCC1=O.C(Cl)Cl>CCOC(C)=O>[CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[C:19]([I:28])=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1I
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1cc(-c2cc3ncc(I)n3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.7 %

Procedure:
3-cyclopropyl-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (Example 2; 84.6 mg, 0.236 mmol) and 1-iodopyrrolidine-2,5-dione (79.7 mg, 0.354 mmol) were suspended in DCM (2.36 mL, 0.236 mmol) and stirred at ambient temperature for 15 hours. The reaction mixture was diluted in EtOAc and washed with saturated sodium bicarbonate and brine. The organic layer was dried with MgSO4, filtered and concentrated in vacuo. Purification of the resulting crude material by silica chromatography using 0-5% MeOH/EtOAc gradient afforded 3-cyclopropyl-3-(4-(3-iodo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (86.5 mg, 75.7% yield). MS (apci) m/z=485.2 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([Br:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br-].[OH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[N+:22]([CH3:27])[CH:21]=[CH:20]2>C(#N)C>[Br-:14].[CH2:7]([O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[N+:22]([CH3:27])[CH:21]=[CH:20]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: C[n+]1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CC#N
Product: C[n+]1ccc2cc(OCc3ccccc3)ccc2c1

Procedure:
Sodium carbonate (5 g.), benzyl bromide (2 ml), 6-hydroxy-2-methylisoquinolinium bromide (2.5 g.) in acetonitrile (100 ml) were heated under reflux for 2 hr. The suspension was filtered hot and the filtrate was diluted with ether. The solid that precipitated was crystallised from acetonitrile, and had m.p. 210°-213°.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:11])([CH:8]1[CH2:10][CH2:9]1)[C:6]#[N:7])(=[O:3])[CH3:2].[OH-].[Na+]>[Cl-].[Na+]>[C:1]([O:4][C@:5]([CH3:11])([CH:8]1[CH2:10][CH2:9]1)[C:6]#[N:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)(C#N)C1CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)O[C@@](C)(C#N)C1CC1
Temperature: 10 °C
Reaction time: 118 h
Yield: 15 %

Procedure:
(Warning: Highly toxic hydrogen cyanide is formed in the experiment; use adequate protection). 119.8 g (782 mmol) racemic α-(acetyloxy)-α-methyl-cyclopropaneacetonitrile was emulsified in 7.0 L 0.1 M sodium chloride/3.8 mM sodium phosphate buffer pH 7.0 by stirring. The emulsion was cooled to 10° C. and the hydrolytic reaction started by adding 8.0 g of triacylglycerol lipase from wheat germ (Sigma L-3001) and the pH maintained at 7.0 by the controlled addition of 1.0 N sodium hydroxide solution under vigorous stirring at 10° C. After a consumption of 605.8 mL solution (corresponding to 78% conversion), after 118 h, the reaction was stopped by adding 6 L dichloromethane under vigorous stirring. The emulsion was allowed to stand overnight for phase separation. The organic phase was removed (the turbid part was filtered through silicon-treated Phase Separator (1 PS; Whatman) and the filtrate stirred with ca. 1 L of Speedex filter aid). The aqueous phase was extracted again with 2×6 L dichloromethane. The combined organic phases were concentrated in vacuo down to a volume of ca. 40 mL and distilled (final temp. 68–69° C./4 mbar) to give 17.88 g (117 mmol; 15%) of (R)-α-(acetyloxy)-α-methyl-cyclopropaneacetonitrile as a colorless oil. Analysis: purity >99% GC; 98.0% ee (column: BGB-176; 30 m×0.25 mm; 100–140° C. with 2° C./min; H2; 90 kPa; Inj. 200° C.; Det. 210° C.); αD20:+32.92° (c=1.00; EtOH).
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+]>O>[CH3:11][C:4]1[NH:3][C:2](=[O:13])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])c(N)n1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(=O)[nH]1

Procedure:
A solution of 24 g. of 2-amino-6-methyl-3-nitropyridine in 25 ml. of concentrated sulfuric acid and 380 ml. of water was cooled to 0° C. and treated with 11 g. of sodium nitrite in 25 ml. of water. The temperature spontaneously rose to 45° C. After cooling, the precipitate of 6-methyl-3-nitro-2-pyridone was collected (m.p. 222°-223° C.) and used directly in the next step.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:37])[CH2:7][C@@H:8]([C:35]#[CH:36])[NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:34])/[CH:19]=[CH:20]/[CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH2:13]1)=[O:11])C.CCO>O.O1CCCC1>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][CH:21](/[CH:20]=[CH:19]/[C:18]([N:14]2[CH2:15][CH2:16][CH2:17][C@@H:12]([C:10]([NH:9][C@H:8]([C:35]#[CH:36])[CH2:7][C:6]([OH:37])=[O:5])=[O:11])[CH2:13]2)=[O:34])[CH2:26][CH2:25]1)=[O:28])([CH3:31])([CH3:33])[CH3:32]
Reactant: C#C[C@H](CC(=O)OCC)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: C#C[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Reaction time: 3 h
Yield: 97.4 %

Procedure:
A solution of LiOH (79 mg) in H2O (10 ml) was added to a solution of N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine ethyl ester (1.34 g) in tetrahydrofuran (10 ml)-EtOH (10 ml) at 0° C. The reaction mixture was stirred for 3 hours at the same condition, and the solvent was evaporated in vacuo. The residue was resolved in ethyl acetate-water, and acidified with 10% aq. KHSO4. The whole was washed with water, brine, dried over MgSO4, and evaporated in vacuo to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine (1.23 g).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([CH3:14])[C:5]=1[S:15][CH2:16][CH:17]1[CH2:19][CH2:18]1>CO>[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:14])[C:5]=1[S:15][CH2:16][CH:17]1[CH2:19][CH2:18]1
Reactant: COC(=O)c1ccc(Cl)c(SCC2CC2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)ccc(Cl)c1SCC1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3 ml of 20% strength aqueous sodium hydroxide solution were added to 1.20 g (4.43 mmol) of methyl 4-chloro-3-cyclopropylmethylthio-2-methylbenzoate in 30 ml of methanol, and the mixture was stirred at RT for 16 h. For work-up, the mixture was concentrated on a rotary evaporator, and the residue was taken up in water. The mixture was acidified with 1M HCl, and the product was then filtered off as a solid. This gave 1.1 g of pure product.
Reaction SMILES: C([O:4][C:5]([C:7]1[C:12]([C:13]#[N:14])=[CH:11][C:10]([Br:15])=[CH:9][N:8]=1)=[O:6])(C)C.O.[OH-].[Li+].Cl>C1COCC1.O>[Br:15][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[C:7]([C:5]([OH:6])=[O:4])=[N:8][CH:9]=1
Reactant: CC(C)OC(=O)c1ncc(Br)cc1C#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(Br)cnc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a solution of 5-bromo-3-cyano-pyridine-2-carboxylic acid isopropyl ester (70 mg, 0.26 mmol) in a mixture of THF (3 ml) and water (3 ml) was added lithium hydroxide monohydrate (32.75 mg, 0.78 mmol, 3 equiv.). The reaction mixture was stirred for 2 hours at 25° C. The mixture was acidified with 2N aqueous HCl solution (pH 5) and extracted with EtOAc (2×15 ml). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to dryness to give 5-bromo-3-cyano-pyridine-2-carboxylic acid (45 mg, 76%) as a yellow solid which was used in next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[Cl:21][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:30]4[CH:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(Br)c2)n1
Product: Nc1ccc(-c2cccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.37) (0.13 g, 0.29 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.083 g, 0.38 mmol) according to the general procedure VI. Obtained as an off-white solid (0.07 g, 52%). MS (ISP) 461.3 [(M+H)+]; mp 179° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[C:15]([O:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]C)=[O:25])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[C:11](=[O:28])[N:10]2[CH2:29][CH2:30][CH2:31][C@H:9]2[CH:8]1[O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)=[O:6])[CH:2]=[CH2:3].[OH-].[Na+]>CO.O>[CH2:1]([O:4][C:5]([N:7]1[C:13]2[CH:14]=[C:15]([O:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[C:11](=[O:28])[N:10]2[CH2:29][CH2:30][CH2:31][C@H:9]2[CH:8]1[O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1c2cc(OCCCC(=O)OC)c(OC)cc2C(=O)N2CCC[C@H]2C1OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCOC(=O)N1c2cc(OCCCC(=O)O)c(OC)cc2C(=O)N2CCC[C@H]2C1OC1CCCCO1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 95.1 %

Procedure:
The methyl ester 18 (2.2 g, 4.26 mmol) was dissolved in MeOH (30 mL). Sodium hydroxide (340 mg, 8.5 mmol) was dissolved in water (7 mL) and added to the ester solution. The reaction mixture was stirred at 70° C. for 15 min. The methanol was then removed under vacuum and water (20 mL) was added. The aqueous solution was allowed to return to room temperature and a 5% aqueous citric acid solution was added to adjust the pH to <4. The precipitate was extracted with EtOAc (100 mL). The organic layer was washed with brine (30 mL) and dried over MgSO4. The solvent was removed under vacuum, then diethylether (50 mL) was added to the residue and removed under vacuum, then dried under vacuum to yield the pure 19 as white foam 2.10 g (98%). 1H NMR (d6-DMSO) as a mixture of 4/5 of diastereoisomers δ 7.10 (2H, s×2), 6.90-6.84 (2H, s×2), 5.84-5.68 (4H, m), 5.45-4.91 (6H, m), 4.72-4.30 (4H, m), 4.09-3.93 (4H, m), 3.91-3.75 (8H, m), 3.60-3.44 (4H, m), 3.44-3.22 (8H, m), 2.46-2.33 (4H, m), 2.20-1.76 (14H, m), 1.76-1.31 (12H, m). 13C NMR (d6-DMSO) δ 173.9, 173.9, 171.9, 166.1, 166.0, 149.6, 148.4, 148.3, 132.6, 116.5, 114.4, 110.5, 110.3, 99.2, 67.5, 67.4, 65.6, 65.5, 62.8, 59.4, 55.7, 45.9, 30.5, 30.2, 29.8, 29.7, 28.4, 28.3, 24.9, 24.8, 23.9, 23.8, 22.9, 22.7; MS (ES+) m/z (relative intensity) 519.2 ([M+H]+, 100). This compound was proved optically pure at C11a by reesterification (EDCI, HOBt, then MeOH), THP removal (AcOH/THF/H2O) and chiral HPLC, as in Tercel et al., J. Med. Chem., 2003, 46, 2132-2151).
Reaction SMILES: [CH2:1]([C@H:3]1[O:8][C@@H:7]([CH2:9][CH3:10])[CH2:6][N:5]([C:11]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=2[CH:13]=O)[CH2:4]1)[CH3:2].[NH:22]1[C:29](=[O:30])[CH2:28][C:26](=[O:27])[NH:25][C:23]1=[O:24]>CO>[CH2:9]([C@H:7]1[O:8][C@@H:3]([CH2:1][CH3:2])[C@@H:4]2[C:28]3([CH2:13][C:12]4[C:11]([N:5]2[CH2:6]1)=[CH:18][CH:17]=[C:16]([N+:19]([O-:21])=[O:20])[CH:15]=4)[C:26](=[O:27])[NH:25][C:23](=[O:24])[NH:22][C:29]3=[O:30])[CH3:10]
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: CC[C@@H]1CN(c2ccc([N+](=O)[O-])cc2C=O)C[C@H](CC)O1
Solvent: CO
Product: CC[C@@H]1CN2c3ccc([N+](=O)[O-])cc3CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](CC)O1
Temperature: 80 °C
Yield: 47.9 %

Procedure:
2-(cis-2,6-Diethylmorpholin-4-yl)-5-nitrobenzaldehyde (1.58 g, 5.39 mmol) is combined with barbituric acid (767 mg, 5.39 mmol, Aldrich) in a flask with MeOH (17 mL). The sealed reaction is stirred with heating at 80° C. overnight. The solvent is removed by rotary evaporation and the product is purified on a Biotage Flash 40M+ using a 10% MTBE in CH2Cl2 as eluent. The product is dried under vacuum and re-crystallized from CH3OH/heptane. The large crystals are crushed and dried under vacuum @100° C. yielding 1.04 g (48%) of bright yellow crystalline solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 0.86, 0.97, 1.08, 1.24, 1.45, 1.58, 2.84, 3.03, 3.34, 3.60, 3.97, 4.26, 7.01, 7.84, 7.98, 11.56, 11.87.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[C:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])#[N:23].[H-].[Na+].Cl>O.O1CCOCC1>[C:22]([CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:11]1[CH:12]=[C:13]2[C:8]([C:7](=[O:16])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[CH:9][C:10]=1[F:15])#[N:23]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2cc(C(C#N)C(=O)OCC)c(F)cc2c1=O
Reaction time: 3 h

Procedure:
8.8 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylate and 5.1 g of ethyl cyanoacetate are initially introduced into 120 ml of dioxane. 1.74 g of NaH are added in portions. The mixture is then boiled for 3 hours, diluted with water and rendered acidic using HCl. It is extracted using methylene chloride. The organic phase is dried and concentrated. The residue is recrystallized from ethanol.