Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[SH:5][C:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][N:7]=1.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:20][CH2:19]1>C(O)C>[CH3:33][C:30]1[CH:31]=[CH:32][C:27]([S:24]([N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][S:5][C:6]3[N:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]4=[N:8][N:7]=3)[CH2:23][CH2:22]2)(=[O:26])=[O:25])=[CH:28][CH:29]=1
Reactant: Sc1nnc2ccccn12
Reactant: Cc1ccc(S(=O)(=O)N2CCN(CCCl)CC2)cc1
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2CCN(CCSc3nnc4ccccn34)CC2)cc1
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
30 g of postassium carbonate are added to a solution of 32.7 g of 3-mercapto-1,2,4-triazolo(4,3-a)pyridine in 300 ml of ethanol and the mixture is heated to the reflux temperature. After 15 minutes, a solution of 65.5 g of 1-chloro-2-[4-(4-methylphenylsulfonyl)piperazin-1-yl]ethane in 100 ml of ethanol is added and refluxing is continued for 3 hours. The reaction mixture is then cooled, the mineral substances are filtered off and the filtrate is concentrated in vacuo. The residue is taken up with chloroform, which is washed with water, and the chloroform phase is then extracted with a 0.5N solution of hydrochloric acid. The acidic aqueous phase is then rendered basic in the cold with a 0.5N aqueous solution of sodium hydroxide and then extracted with chloroform. The chloroform phase is washed with water, dried over sodium sulfate and then concentrated in vacuo to give 73 g of 3-[2-(4-(4-methylphenylsulfonyl)piperazin-1-yl)ethylmercapto]1,2,4-triazolo(4,3-a)pyridine in the form of a thick oil, which is used in the crude state for the next step.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[CH:48]=[CH:47][C:24]([C:25]([C:27]2[CH:28]=[CH:29][C:30]3[N:36]([CH3:37])[C:35](=[O:38])[CH2:34][NH:33][CH:32]([C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=4)[C:31]=3[CH:46]=2)=[O:26])=[CH:23][CH:22]=1>CCCCCC.C1COCC1>[Cl:45][C:41]1[CH:40]=[C:39]([CH:32]2[C:31]3[CH:46]=[C:27]([C:25]([C:24]4[CH:47]=[CH:48][C:21]([Cl:20])=[CH:22][CH:23]=4)([OH:26])[C:11]4[N:7]([CH3:6])[CH:8]=[N:9][CH:10]=4)[CH:28]=[CH:29][C:30]=3[N:36]([CH3:37])[C:35](=[O:38])[CH2:34][NH:33]2)[CH:44]=[CH:43][CH:42]=1
Reactant: Cn1ccnc1
Reactant: CN1C(=O)CNC(c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1C(=O)CNC(c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc21
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 7.9 %

Procedure:
BuLi 1.6M in hexane (27.4 ml) was added dropwise at −70° C. under N2 flow to a mixture of 1-methyl-1H-imidazole (0.0439 mol) in THF (140 ml). The mixture was stirred for 30 min. ClSiEt3 (0.0439 mol) was added. The mixture was brought slowly to room temperature and cooled again to −70° C. BuLi 1.6M in hexane (27.4 ml) was added dropwise. The mixture was stirred for 1 hour, brought quickly to −15° C. and cooled to −70° C. A solution of intermediate (8) (0.02 mol) in THF (90 ml) was added dropwise. The mixture was stirred at −50° C. for 30 min, then hydrolyzed and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (17.5 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 94/6/0.1 and 93/7/0.1; 20–45 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN, EtOAc and 2-propanone. The precipitate was filtered off and dried, yielding 0.8 g (8.5%) of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,3,4,5-tetrahydro-1-methyl-2H-1,4-benzodiazepin-2-one, mp. 208° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:28])[C:8]2[C:9]([N:14]([CH2:16][C:17]3([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:15]=1)=[N:10][CH:11]=[CH:12][N:13]=2)=[O:5])C.C1(C2C=CC=CC=2)C=CC=CC=1CN1C2C(=NC=CC=2)C(=O)C(C(O)=O)=C1>>[O:28]=[C:7]1[C:8]2[C:9](=[N:10][CH:11]=[CH:12][N:13]=2)[N:14]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[CH:15]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cn(CC2(c3ccccc3)CCCC2)c2nccnc2c1=O
Agent: O=C(O)c1cn(Cc2ccccc2-c2ccccc2)c2cccnc2c1=O
Product: O=C(O)c1cn(CC2(c3ccccc3)CCCC2)c2nccnc2c1=O
Yield: 13.7 %

Procedure:
8-Oxo-5-(1-phenyl-cyclopentylmethyl)-5,8-dihydro-pyrido[2,3-b]pyrazine-7-carboxylic acid (17) (70 mg, 14%) was synthesized as a yellow solid from 550 mg of 8-oxo-5-(1-phenyl-cyclopentylmethyl)-5,8-dihydro-pyrido[2,3-b]pyrazine-7-carboxylic acid ethyl ester (16) following the procedure described for 1-biphenyl-2-ylmethyl-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid (7).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14]([C@@H:15]([O:25]C2CCCCO2)/[CH:16]=[CH:17]/[C:18]([CH3:24])([CH3:23])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([CH3:32])[CH2:12][C:11]1=[O:33].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14]([C@@H:15]([OH:25])/[CH:16]=[CH:17]/[C:18]([CH3:23])([CH3:24])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([CH3:32])[CH2:12][C:11]1=[O:33]
Reactant: CCCCC(C)(C)/C=C/[C@H](OC1CCCCO1)[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCC(C)(C)/C=C/[C@H](O)[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC
Reaction time: 24 h

Procedure:
The crude optically active (5Z,11alpha,13S,14E)-13-(2-tetrahydropyranyloxy)-11,16,16-Tri-methyl-9-oxoprosta-5,14-dien-1-oic acid methyl ester (10.55 g) in methanol (100 mL) solution was treated with pyridinium p-toluenesulfonate (1.0 g) and stirred under argon at 40° for 24 hours. After cooling it, the solution was poured into brine (500 mL) and the product was extracted three times with hexane (150 mL each time). The combined extract was dried over sodium sulfate and stripped of solvent to give 9.5 g (>100%) of optically active (5Z,11alpha,13S,14E)-13-hydroxy-11,16,16-trimethyl-9-oxoprosta-5,14-dien-1-oic acid methyl ester as a yellow oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18](=[N:23][O:24][CH3:25])[C:19]([NH:21][CH3:22])=[O:20])=[N:6][CH:7]=[N:8][C:9]=1F.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33]>CN(C)C=O>[F:3][C:4]1[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18](=[N:23][O:24][CH3:25])[C:19]([NH:21][CH3:22])=[O:20])=[N:6][CH:7]=[N:8][C:9]=1[O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH3:26]
Reactant: Cc1ccccc1O
Reactant: CNC(=O)C(=NOC)c1ccccc1Oc1ncnc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)C(=NOC)c1ccccc1Oc1ncnc(Oc2ccccc2C)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
With cooling, 0.25 g (0.0062 mol) of sodium hydride (60%) are added to a mixture of 2 g (0.0062 mol) of 2-[2-(5,6-difluoropyrimidin-4-yloxy)-phenyl]-2-methoxyimino-N-methyl-acetamide and 0.67 g (0.0062 mol) of 2-methylphenol in 20 ml of dimethylformamide, and the mixture is stirred at 25° C. for 12 hours. The reaction mixture is poured onto water and extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. 1.5 g (58.9%) of 2-[2-(5-fluoro-6-o-tolyloxy-pyrimidin-4-yloxy)-phenyl]-2-methoxyimino-N-methyl-acetamide are obtained.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Cl:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[CH:13][C:14]=1[Cl:15].Cl[C:18]1[N:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]>O>[Cl:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:16][C:18]1[N:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccnc1Oc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.7 %

Procedure:
Sodium hydride dispersion, 60% by weight (2.54 grams, 63.47 mmol) is placed into a 125 ml round bottom flask equipped with a stir bar and condenser under nitrogen and is charged with 32 ml of dimethyl formamide. 3,4-Dichlorophenol (5.17 grams, 31.73 mmol) is added portionwise over five minutes. During this addition, an exotherm and vigorous gas evolution are observed. The reaction is allowed to stir for five minutes. 2-Chloronicotinic acid (5.00 grams, 31.73 mmol) is then added portionwise over five minutes. When gas evolution subsides, the reaction is heated to reflux for 21 hours. It is then cooled to room temperature and 300 ml of water added. The aqueous layer is extracted with diethyl ether (3×200 ml), then pH adjusted to acidic with glacial acetic acid and stirred. After 2 hours, the precipitate which has formed is filtered and washed with (3×100 ml) water then (3×100 ml) pentane to yield 1.78 grams (19.8%) of product as a tan crystalline solid.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[CH2:5].C([O-])([O-])=O.[Na+].[Na+]>O.C(OC(=O)C)(=O)C>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:4][CH2:5][C:1]#[N:2]
Reactant: [C-]#N
Reactant: C=Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: N#CCCc1ccccn1
Temperature: 105 °C

Procedure:
3-(2-Pyridinyl)propionitrile is prepared in this example using the procedure of V. Boekelheide, et al., J. Am. Chem. Soc., 75, 3243 (1953). A solution of potassium cyanide (83.74 g) in water (160 ml) is added to a solution of freshly distilled 2-vinylpyridine (67.59 g) in acetic anhydrid (131.30 g) with the rate of addition adjusted to maintain gentle refluxing. When the addition is complete, the resulting dark red mixture is heated for about 17 hours at 105° C. in an oil bath with vigorous stirring. The cooled reaction mixture is adjusted to pH 8 with a saturated Na2CO3 solution. The mixture is extracted with CHCl3 (4×150 ml), washed with water, dried with Na2SO4, and evaporated to a dark viscous oil. The oil is fractionally distilled in vacuo through a Vigreaux column. After a small forerun containing 2-vinylpyridine (0.35 g), the desired 3-(2-pyridinyl)propionitrile is collected as a clear, fluorescent yellow-green, viscous oil: yield 59.8 g; 70.4%; bp 86° C. at 1.0 mm Hg.
Reaction SMILES: [C:1](=[O:3])=O.Cl.[CH2:5]([O:7][C:8](=[O:15])[C@H:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[NH2:10])[CH3:6].C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>ClCCl.C(OCC)C>[N-:10]=[C:1]=[O:3].[CH2:5]([O:7][C:8](=[O:15])[C@H:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[NH2:10])[CH3:6]
Reactant: O=C=O
Agent: CCOC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: [N-]=C=O

Procedure:
Carbon dioxide was added subsurface to a dichloromethane (40 mL) solution containing leucine ethyl ester hydrochloride salt (0.025 mol, 4.89 g), N-cyclohexyl-N',N',N",N"-tetraethylguanidine (0.025 mol, 6.3 g) and triethylamine (0.10 mol, 10.0 g) at -10° C. (ice and salt bath) for 40 min at a pressure of 0 psig. The reaction mixture was transferred via cannula all at once under carbon dioxide to the precooled solution of phosphorus oxychloride (0.025 mol, 3.9 g) in 40 mL dichloromethane. After stirring for 20 min at -10° C. diethylether (50 mL) was added to the reaction mixture. A white ppt formed and was filtered off. The filtrate was concentrated in vacuo and the residue was extracted with 3×25 mL diethylether. The ether layers were concentrated and the residue was distilled under vacuum collecting product, leucine ethyl ester isocyanate, at 53°-58° C. (3.74 g, 81%) of 98.4 % purity as judged by GC. IR (neat) 2261, 1742 cm-1. 1H NMR (CDCl3) δ 4.23 (q, 2H, J=14.2), 3.98 (dd, 1H, Jgem =8.8, Jvic =5.5), 1.84-1.77 (m, 1H), 1.65-1.59 (m, 2H), 1.29 (t, 3H, J=7.2), 0.92 (t, 6H, J=6.7) ppm.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9](OS(C(F)(F)F)(=O)=O)=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.[CH3:21][C:22]([OH:26])([C:24]#[CH:25])[CH3:23].C(N(CC)CC)C>CN(C)C=O.[Cu]I>[CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:25]#[C:24][C:22]([OH:26])([CH3:23])[CH3:21])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: C#CC(C)(C)O
Reactant: CSc1ncnc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1ncnc2cc(C#CC(C)(C)O)ccc12
Yield: 174.2 %

Procedure:
4-(Methylthio)-7-(trifluoromethanesulphonyloxy)quinazoline (592 mg, 1.82 mmol) in dimethylformamide (20 ml) was reacted with 2-methyl-3-butyn-2-ol (0.53 ml, 0.54 mmol) in the presence of bis dichloro(triphenylphosphine)palladium (64 mg, 0.091 mmol), copper (I) iodide (20 mg) and triethylamine (1.1 ml, 0.8 mmol), at 90° C. for 2.5 hours. The solvent was removed in vacuo, aqueous hydrochloric acid (2N) was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and the solvents were evaporated in vacuo. Purification by flash chromatography on silica gel, eluting with isohexane/ethyl acetate (55:45), yielded, 4-(methylthio)-7-(3-hydroxy-3-methylbut-1-ynyl)quinazoline (243 mg, 51% yield):
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:7]([Cl:24])=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[CH:11]=1)[CH3:2].[CH2:26]([NH2:28])[CH3:27]>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:7]([Cl:24])=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:13]=2[CH2:22][NH:28][CH2:26][CH3:27])[CH:11]=1)[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2C=O)cnc1Cl
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cnc(Cl)c(CC(=O)OCC)c1

Procedure:
[2-Chloro-5-(2-formyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester and ethylamine (2M in THF) were reacted as described in Example 3, Step 3 to provide [2-chloro-5-(2-ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=2[F:24])[O:14][C:15]=1[CH3:16])C1C=CC=CC=1.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>O1CCCC1.[OH-].[OH-].[Pd+2]>[F:24][C:18]1[CH:19]=[C:20]([C:32]2[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=2)[CH:21]=[CH:22][C:17]=1[C:13]1[O:14][C:15]([CH3:16])=[C:11]([CH2:10][CH2:9][OH:8])[N:12]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1oc(-c2ccc(Br)cc2F)nc1CCOCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2F)nc1CCO

Procedure:
Using 4-(2-benzyloxy-ethyl)-2-(4-bromo-2-fluoro-phenyl)-5-methyl-oxazole (see Intermediate 37) and 4-methylsulfonylphenylboronic acid, follow a procedure in substantial accordance with that found in Example 4. Take this product and hydrogenate using 20% palladium hydroxide on carbon in tetrahydrofuran for 36 hours at 40° C. and 60 psi. After this time, filter the reaction and concentrate in vacuo. Purify via radial chromatography eluting with methanol and dichloromethane. MS (m/e): 376.2 (M+1)
Reaction SMILES: [C:1]([O:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[CH3:17])[CH2:14]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:18](#[N:22])[C:19]([CH3:21])=[CH2:20].[C:23]([OH:28])(=[O:27])[C:24]([CH3:26])=[CH2:25].[C:29]1(=[O:34])[O:33][CH:30]1[CH2:31][CH3:32].CCC(N=NC(C#N)(CC)C)(C#N)C>O1CCCC1>[CH3:17][CH:8]1[CH:9]2[CH2:10][CH:11]3[CH2:12][CH:13]([CH2:14][C:7]1([CH:25]=[C:24]([CH3:26])[C:23]([O-:28])=[O:27])[CH2:16]3)[CH2:15]2.[C:18](#[N:22])[C:19]([CH3:21])=[CH2:20].[C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:29]1(=[O:34])[O:33][CH:30]1[CH2:31][CH3:32]
Reactant: C=C(C)C(=O)OC12CC3CC(CC(C3)C1C)C2
Agent: C=C(C)C#N
Agent: C=C(C)C(=O)O
Agent: CCC(C)(C#N)N=NC(C)(C#N)CC
Solvent: C1CCOC1
Product: CC(=CC12CC3CC(CC(C3)C1C)C2)C(=O)[O-]
Temperature: 90 °C
Reaction time: 20 h

Procedure:
2-Methyladamantanyl methacrylate (14.21 g, 0.061 mol), methacrylonitrile (3.05 g, 0.045 mol), and alpha-butyrolactone methacrylate (7.74 g, 0.045 mol) were dissolved in 66 mL of tetrahydrofuran. The resulting colorless solution was deoxygenated by gently bubbling a stream of N2 through the stirring solution for 15 minutes, placed under N2, and heated to 90° C. (oil bath temperature). VAZO67 (0.58 g, 0.0030 mol) dissolved in 7 ml of tetrahydrofuran, was then added to the refluxing mixture over 10 minutes. The polymerization was then refluxed with stirring for 20 hours and cooled to room temperature. The polymer was isolated by precipitation into 800 mL of hexanes, filtered, dried, re-dissolved in 70 mL of tetrahydrofuran, precipitated into 800 mL of hexanes, filtered, washed well with hexanes, and dried in a vacuum oven at 40° C. for 24 hours. Yield 19.8 g (79% of theory). Composition of the title terpolymer was determined by quantitative C-13 NMR and was found to be within experimental error of the monomer feed ratio.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.Br[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[OH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:3][C:4]2=[O:18])=[CH:11][CH:12]=1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Reactant: BrCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1cc(OCc2cccnc2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 500 mg (2.04 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 20 mL DMF is added 0.62 g (2.45 mmol) 3-bromomethyl-pyridine and 0.85 g (6.12 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, diluted with 60 mL of EtOAc and is washed twice with water. The organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1[OH:28]>>[Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([NH:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1[OH:28])=[O:9]
Reactant: O=C(O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Reactant: N[C@@H]1CCCC[C@H]1O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1c, using 5-bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid and (1R,2R)-2-amino-cyclohexanol as starting materials, MS (ISP) 467.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:15])([CH3:14])[CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[CH3:16].[C:17](=[O:20])([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C(OCC)(=O)C.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>[CH3:8][N:9]([CH3:12])[C:10]1[CH:11]=[CH:2][C:3]([CH:17]=[O:20])=[CH:4][C:5]=1[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:15])([CH3:14])[CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[CH3:16]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2c(cc1Br)N(C)C(=O)CC2(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1-c1cc(C=O)ccc1N(C)C)N(C)C(=O)CC2(C)C
Temperature: 25 °C
Yield: 168.7 %

Procedure:
A mixture of 6-dimethylamino-3-formyl-1-phenyl boronic acid (11.5 g, 59.5 mmol), 7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one (Example 1d) (14.0 g, 49.6 mmol) and potassium carbonate (13.7 g, 99.2 mmol) in toluene (140 mL), ethanol (28 mL) and water (21 mL) was degassed with argon for 40 minutes. Tetrakis(triphenylphosphine)palladium(0) (3.5 g, 0.06 mmol) was added and the mixture heated at reflux under argon for 24 hrs. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (30% ethyl acetate in hexane) to give 14.66 g of 4-Dimethylamino-3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-benzaldehyde (84%). 1H NMR (300 MHz; CDCl3): 1.31 (s, 3 H), 1.33 (s, 3 H), 2.10 (s, 3 H), 2.53 (s, 2 H), 2.69 (s, 6 H), 3.36 (s, 3 H), 6.89 (s, 1 H), 6.99 (d, J=8.7 Hz, 1 H), 7.14 (s, 1 H), 7.58 (d, J=2.4 Hz, 1 H), 7.77 (dd, J=2.4 Hz and 8.4 Hz, 1 H), 9.82 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2.[CH:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33](O)=[O:34])[CH2:28][CH2:27]1)([CH3:25])[CH3:24]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:33](=[O:34])[CH2:32][N:29]4[CH2:30][CH2:31][N:26]([CH:23]([CH3:24])[CH3:25])[CH2:27][CH2:28]4)[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2
Reactant: CC(C)N1CCN(CC(=O)O)CC1
Reactant: Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1
Product: CC(C)N1CCN(CC(=O)Nc2ccc3nc(NC4CCc5cc(F)ccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 14 described in example 119 from rac-N2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and (4-isopropyl-piperazin-1-yl)-acetic acid (CAS no: 95470-68-1); MS: m/e=462.5 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:24](=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CCCCCCCCCCCCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and tetradecanoic acid to yield (3aR,4S,7aR)-4-tetradecanoyloxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT=2.01 min; UPLC Method I
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:14]1[S:15][C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=1.C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][N:11]([C:14]2[S:15][C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(N2CC(NC(=O)OC(C)(C)C)C2)nc1C
Yield: 44.6 %

Procedure:
The same operation as in Example (217a) was performed using 3-tert-butoxycarbonylaminoazetidine (300 mg, 1.74 mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (479 mg, 1.92 mmol) and diisopropylethylamine (0.61 mL, 3.48 mmol), to obtain 265 mg of the title compound as a pale yellow solid (45%).