Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=1.Cl.CN.C[CH2:25][N:26](CC)CC>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([NH:26][CH3:25])=[O:20])[N:9]=1
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2I)n1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1cc2ccccc2c(-c2ccccc2I)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 63.7 %

Procedure:
To a mixture of 1-(2-iodophenyl)-3-isoquinolinecarboxylic acid (0.1868 g, 0.5 mmol), benzotriazol-1-yloxy-tris (demethylamino) phosphonium hexafluorophosphate (BOP) (0.2219 g, 0.5 mmol), Methylamine hydrochloride (0.1019 g, 1.5 mmol) in DMF (8 mL) was added Et3N (0.42 mL, 4.5 mmol). The resulting mixture was stirred under Ar at room temperature for 7 h and quenched by adding H2O (10 mL). The mixture was extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried (MgSO4), filtered. The filtrate was concentrated in vacuo. The residue was purified on column (SiO2, 50% ethyl acetate/hexane, 0.1% Et3N), thereby giving a white foam (0.1237 g, 65%). mp: 167-168° C. 1H NMR (CDCl3) d 3.03, 3.05 (two s, 3 H, N-methyl), 7.25 (t, J=10.5 Hz, 1 H, aromatic), 7.39 (d, J=7.5 Hz, 1 H), 7.48-7.68 (m, 3 H, aromatic), 7.75 (t, J=9 Hz, 1 H, aromatic), 8.02-8.06 (m, 2 H, aromatic), 8.18 (br s, 1 H, NH), 8.65 (s, aromatic). 13C NMR (CDCl3) d 26.13 (q, N-methyl), 97.79 (s, C--I), 120.02 (d, aromatic), 127.29 (d, aromatic), 127.75 (d, aromatic), 127.98 (d, aromatic), 128.53 (d, aromatic), 128.76 (d, aromatic), 130 13 (d, aromatic), 130.31 (d, aromatic), 130.81 (d, aromatic), 136.81 (s, aromatic), 139.42 (d, aromatic), 142.59 (s, aromatic), 143.30 (s, aromatic), 160.79 (s, aromatic), 165.32 (s, --CO--). HRMS calcd. for C17H13IN3IN2O: 388.0073. Found: 388.0070.
Reaction SMILES: O=O.[C:3]([C:7]1[CH:8]=[C:9](O)[C:10](=[CH:12][CH:13]=1)O)(C)(C)[CH3:4].[CH2:15]=[CH:16][CH:17]=[CH2:18]>O>[CH2:4]=[CH:3][C:7]1[CH:8]=[CH:9][CH:10]=[CH:12][CH:13]=1.[CH2:15]=[CH:16][CH:17]=[CH2:18]
Reactant: CC(C)(C)c1ccc(O)c(O)c1
Agent: C=CC=C
Agent: O=O
Solvent: O
Product: C=Cc1ccccc1
Reaction time: 20 h

Procedure:
A pressure-resistant glass bottle, specifically an empty bottle for carbonated drink was used as a reactor; 60 g of ion-exchanged water was charged in this glass bottle; and dissolved oxygen was removed with a nitrogen gas. This glass bottle was cooled in an iced water bath; the emulsifier that is the invention product or comparative product and polyfunctional monomers shown in Table 4 were added; 0.12 g of a naphthalenesulfonic acid formalin condensate, 0.12 g of sodium carbonate, and 0.12 g of dodecyl mercaptan were added; and the glass bottle was temporarily plugged with a rubber stopper. This glass bottle was lightly manually shaken to make the contents uniform and then opened; 20 g of styrene and 0.12 g of potassium persulfate were charged; and the glass bottle was again temporarily plugged with a rubber stopper and allowed to stand for cooling in an iced water bath. Subsequently, butadiene was introduced from a butadiene cylinder into a graduated sample collecting tube in a methanol dry ice bath and liquefied. And 20 g of the liquefied butadiene was weighed out and charged in the glass bottle by using a stop cock-equipped syringe; and immediately after charging, a prescribed metal-made crown was covered and capped, thereby preparing a bottle polymerization reactor. Subsequently, the capped glass bottle was vigorously shaken, thereby making the content liquid in the glass bottle in an emulsified state. Subsequently, the glass bottle was set in a holder within a rotary polymerization tank for bottle polymerization adjusted at a water temperature of 50° C., polymerization was conducted for 20 hours at a rotation number of 50 rpm, thereby conducting emulsion polymerization by the bottle polymerization method. The glass bottle was then put in an iced water bath and cooled. Then, after opening the glass bottle, 0.12 g of p-tert-butyl catechol was added, and unreacted butadiene was vaporized and distilled off by means of bubbling of a nitrogen gas within a draft, thereby obtaining a polymer dispersion.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:16](O)[C@@H:15]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:14][C@@H:11]1[O:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCN(S(F)(F)[F:48])CCOC>ClCCl>[C:1]([O:9][C@@H:10]1[C@@H:17]([O:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:16]([F:48])[C@@H:15]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:14][C@@H:11]1[O:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1O[C@H](COC(=O)c2ccccc2)[C@H](O)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: CO[C@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](F)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: -30 °C
Reaction time: 8 h

Procedure:
3 g of methyl 2,3,6-tri-O-benzoyl-α-D-galactopyranoside 57 (Reist et al., J. Org. Chem 1965, 30, 2312) are introduced into dichloromethane and cooled to −30° C. Then 3.06 ml of [bis(2-methoxyethyl)amino]sulfur trifluoride (BAST) are added dropwise. The reaction solution is warmed to room temperature and stirred overnight. The mixture is diluted with dichloromethane, and the organic phase is extracted with H2O, NaHCO3 solution and saturated NaCl solution. The organic phase is dried over Na2SO4 and concentrated. The crude product is crystallized from ethyl acetate and heptane. 1.95 g of 58 are obtained as a colorless solid. C28H25FO8 (508.51) MS (ESI+) 526.18 (M+NH4+). Alternatively, the reaction can also be carried out using 2.8 eq. of diethylaminosulfur trifluoride (DAST); in this case, the reaction solution is refluxed for 18 h after the addition. The working up takes place in analogy to the above description.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].C=O.[CH:12](=[O:14])C.[OH-].[Na+].[OH:17]CC(CO)(CO)C=O>C1C=CC=CC=1.CCOCC.ClC(Cl)(Cl)Cl.O>[OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[CH:12]([O-:14])=[O:17]
Reactant: O=CC(CO)(CO)CO
Reactant: CC=O
Agent: C=O
Agent: OCC(CO)(CO)CO
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C[O-]

Procedure:
Pentaerythritol[2,2-bis(hydroxymethyl)-1,3-propane diol, Penta, PE] is a white, crystalline powder with a sweet taste and is neither hygroscopic nor inflammable, density 1.399, melting point 262° C. and boiling point 276° C. (40 hPa). Pentaerythritol is highly soluble in boiling water, is poorly soluble in alcohol, and insoluble in benzene, tetrachloromethane, ether, petroleum ether. Pentaerythritol is manufactured industrially by reacting formaldehyde with acetaldehyde in an aqueous solution of Ca(OH)2 or NaOH at 15-45° C. The reaction takes place initially as an aldol reaction, whereby the formaldehyde reacts as the carbonyl component and the acetaldehyde as the methylene component. Due to the high carbonyl activity of the formaldehyde, the reaction of acetaldehyde with itself hardly occurs. Finally, the tris(hydroxymethyl)acetaldehyde undergoes a crossed Cannizzaro reaction with formaldehyde to afford pentaerythritol and formate.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH2:7])[NH:4][N:3]=1.CN(C)C=O.[CH3:13][N:14]=[C:15]=[S:16]>C(OCC)(=O)C>[NH2:1][C:2]1[N:6]=[C:5]([NH2:7])[N:4]([C:15]([NH:14][CH3:13])=[S:16])[N:3]=1
Reactant: Nc1n[nH]c(N)n1
Reactant: CN=C=S
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=S)n1nc(N)nc1N
Yield: 68 %

Procedure:
The synthesis method of Example 1-(3) was applied. 3,5-Diamino-1H-1,2,4-triazole (11.0 g), dimethylformamide (100 ml) and methyl isothiocyanate (10.0 g) were used as reagents. After the reaction, recrystallization from ethyl acetate gave 13.0 g of white powdery crystals (yield (68%).
Reaction SMILES: [N:1]1[CH:6]=CC=C[CH:2]=1.Cl.C([C:11]1[N:15]2[CH2:16][CH2:17][CH2:18][N:19]=[C:14]2SC=1C(Cl)=O)CC.C(OC(CCNC1C=C(Cl)C=C(Cl)C=1)=O)C>CN(C)C=O>[CH3:11][NH:15][C:16]1[CH:2]=[N:1][CH:6]=[C:18]([NH:19][CH3:14])[CH:17]=1
Reactant: CCCC1=C(C(=O)Cl)SC2=NCCCN21
Reactant: c1ccncc1
Agent: CCOC(=O)CCNc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Product: CNc1cncc(NC)c1

Procedure:
In the mixture of 30 ml of pyridine and 3 ml of dimethylformamide was suspended 1.09 g of 3-propyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonylchloride hydrochloride (described in Example 13). To the suspension was added 1.02 g of N-(2-ethoxycarbonylethyl)-3,5-dichloro-aniline obtained in Reference Example 5 and 47.4 mg of 3,5-dimethylaminopyridine, followed by stirring at 70° C. for 20 hours. The reaction mixture was concentrated and to the mixture was added saturated sodium hydrogencarbonate aqueous solution. The organic layer was extracted with chloroform. The extact was washed with water and dried, followed by removing the solvent. The residue was dissolved in ethanol and to the solution was added saturated hydrogenchloride diethylether solution. The mixture was stirred at room temperature and the solvent was removed under reduced pressure. The residue was purified by column chromatography using a mixed solvent of chloroform and methanol (10:1 by volume) as an eluent. The resulting substance was crystallized from a mixed solvent of ethanol and diethylether. The formed crystals were recrystallized from a mixed solvent methanol and diethylether to obtain 109 mg of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[OH:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH2:15]([N:17]([CH2:22][CH3:23])[C:18](=[O:21])[CH2:19]Cl)[CH3:16].C(N(C(C)C)C(C)C)C.[I-].[Na+]>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH2:19][C:18](=[O:21])[N:17]([CH2:22][CH3:23])[CH2:15][CH3:16])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\O)c1csc(N)n1
Reactant: CCN(CC)C(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)/C(=N\OCC(=O)N(CC)CC)c1csc(N)n1
Yield: 77.9 %

Procedure:
57.3 g of ethyl 2-(2-amino-4-thiazolyl)-2-(Z)-hydroxyimino-acetate, 80 g of N,N-diethylchloroacetamide, 138.7 ml of N-ethyldiisopropylamine and 80 g of sodium iodide are stirred at room temperature for 12 hours in 1.1 l of acetonitrile. The mixture is subsequently diluted with 5 l of ethyl acetate, washed with water, dried over magnesium sulphate and concentrated to a small volume. The compound which crystallizes out is filtered off and dried. There are obtained 68.1 g of ethyl 2-(2-amino-4-thiazolyl)-2-[(Z)-[(diethylcarbamoyl)methoxy]imino]-acetate of melting point 161° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(Br)c1Nc1ccccc1
Temperature: 100 °C

Procedure:
A solution of 1-bromo-2-fluoro-3-nitrobenzene (5 g, 22.7 mmol) and aniline (4.2 mL, 45 mmol) in DMSO (10 mL, 2M) in a sealed flask was evacuated and purged with argon. The mixture was heated at 100° C. for 12 h. The cooled mixture was diluted with KHSO4 (aq. satd. solution, 100 mL) and brine, dried (Na2SO4) and concentrated to give the product (2-bromo-6-nitrophenyl)phenylamine as a bright orange solid (6.5 g, quant.). 1H NMR (400 MHz, CDCl3): δ 7.96 (1H, dd, J=8.5, 1.7 Hz), 7.86 (1H, br s), 7.75 (1H, dd, J=8.2, 1.5 Hz), 7.16-7.22 (2H, m), 6.90-6.99 (2H, m), 6.77 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=2)[N:20]=[C:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:18]=1[CH3:34].[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[N:8]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]=[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:18]=3[CH3:34])[CH2:9][C:10]3([CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)NCC21CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ccc(Br)cc21
Temperature: 130 °C

Procedure:
Prepared according to procedure M using 6-bromo-2′,3′,5′,6′-tetrahydrospiro-[indoline-3,4′-pyran] (98 mg, 367 μmol), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (100 mg, 367 μmol) in DMF (4.5 mL) and sodium hydride (18 mg, 0.73 mmol) and heating the reaction mixture at 130° C. for 8 h. After purification 6-bromo-1-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.74 (1H, d, J=5.1 Hz), 7.89-7.98 (2H, m), 7.85 (1H, dd, J=10.0, 2.5 Hz), 7.75 (1H, dd, J=9.2, 6.1 Hz), 7.41 (1H, ddd, J=6.7, 4.5, 2.5 Hz), 7.28-7.33 (1H, m), 7.07 (1H, d, J=7.8 Hz), 6.89 (1H, dd, J=7.8, 2.0 Hz), 6.11 (1H, d, J=2.0 Hz), 3.93-4.10 (4H, m), 3.45-3.60 (2H, m), 2.38 (3H, s), 2.08-2.25 (2H, m), 1.91 (1H, dd, J=13.9, 2.5 Hz), 1.81 (1H, dd, J=13.7, 2.3 Hz). Mass Spectrum (ESI) m/e 504 [(M+1) (79Br)] and 506 [(M+1) (81Br)].
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:9]([F:10])=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH:7]=[CH:6][C:5]=1[C:18](=[O:30])[C:19](P(=O)(OCC)OCC)([F:21])[F:20]>CO>[F:3][C:4]1[C:9]([F:10])=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH:7]=[CH:6][C:5]=1[C:18](=[O:30])[CH:19]([F:21])[F:20]
Reactant: CCOP(=O)(OCC)C(F)(F)C(=O)c1ccc(-c2ccc(F)cn2)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(c1ccc(-c2ccc(F)cn2)c(F)c1F)C(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1 M Aqueous sodium hydroxide (1 mL, 1 mmol) was added to a solution of diethyl {2-[2,3-difluoro-4-(5-fluoropyridin-2-yl)phenyl]-1,1-difluoro-2-oxoethyl}phosphonate (872 mg, 2 mmol) in methanol (8 mL) at room temp. After stirring at rt for 30 min, the reaction was quenched with 1 N hydrochloric acid. The reaction mixture was extracted with ethyl acetate washed with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate) and concentrated. Chromatography over silica eluting with 0-60% ethyl acetate/hexane afforded the title compound as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[Li+].CC([N-]C(C)C)C.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29](Cl)[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:24]=1>C1COCC1>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:24]=1
Reactant: c1cncc(Cc2cccnc2)c1
Reactant: Fc1ccc(C(Cl)c2cccc(Br)n2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(C(c2cccc(Br)n2)C(c2cccnc2)c2cccnc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(pyridine-3-ylmethyl)pyridine (2.5 g, 14.69 mmol) in anhydrous THF (75 mL) under N2. The mixture was cooled to −78° C. and LDA (12.24 mL, 1.8 M) was added dropwise. The mixture was stirred @ −78° C. for 1 hr and 2-bromo-6-[chloro(4-fluorophenyl)methyl]pyridine (4.64 g, 15.42 mmol) was added. The mixture was warmed to 0° C. and stirred for 2 hr. The reaction was quenched with saturated aqueous NH4Cl and extracted 3× with EtOAc. The combined organics were dried (anhd. Na2SO4) filtered, and concentrated. The resulting residue was purified by silica gel chromatography (1-3% MeOH in CH2Cl2) to give 2-bromo-6-[1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]pyridine. 1H NMR (500 MHz, CDCl3) δ 8.55 (d, 1H, J=2.0), 8.45 (d, 1H, J=2.0), 8.35-8.29 (m, 2H), 7.60 (dt, 1H, J=7.9, 1.9), 7.49 (dt, 1H, J=7.9, 1.9), 7.35-7.24 (m, 3H), 7.17 (d, 1H, J=7.8), 7.14-7.07 (m, 2H), 7.05 (d, 1H, J=7.6), 6.86 (t, 2H, J=8.7), 5.13 (d, 1H, J=12.2), 4.78 (d, 1H, J=12.0) LRMS m/z (M+H) Calcd.: 434.0, found: 434.0. The racemic mixture was separated by ChiralPak AD (30% iPrOH in Hexane+DEA 1 mL/L). The first peak was enantiomer A of 2-bromo-6-[1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]pyridine; HRMS m/z (M+H) Calcd.: 434.0663, found: 434.0648. And the second peak was enantiomer B of 2-bromo-6-[1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]pyridine; HRMS m/z (M+H) Calcd.: 434.0633, found: 434.0646.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)=[CH:6][C:3]=1[C:4]#[N:5].C([OH:21])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:21])[NH:14]3)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(-c2cccc3[nH]ccc23)ccc1F
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: N#Cc1cc(-c2cccc3c2CC(=O)N3)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To the suspension of 2-fluoro-5-(1H-indol-4-yl)-benzonitrile (2.68 g, 11.34 mmol) in t-BuOH: ethanol: acetic acid (72 mL: 43 mL: 23 mL) was added pyridinium tribromide (10.91 g, 34.1 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (55 mL). Zinc dust (4 g, 61.2 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (3×), sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 1.93 g (68%) of 2-fluoro-5-(2-oxo-2,3-dihydro-1H-indol-4-yl)-benzonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=1[C:16]#[C:17][Si](C)(C)C)=[O:5])[CH3:2].[OH:22]S(O)(=O)=O.CC(C)=O>O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=1[C:16](=[O:22])[CH3:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c(C)c(=O)n(C)c1C#C[Si](C)(C)C
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1c(Cl)c(C)c(=O)n(C)c1C(C)=O
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-1,5-dimethyl-6-oxo-2-trimethylsilanylethynyl-1,6-dihydropyridine-3-carboxylic acid ethyl ester (1.00 equivalent), HgSO4 (1.00 equivalent) and H2SO4 (2.00 equivalents) in ˜6:1 acetone:water is refluxed for 3 hours. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is diluted with a mixture or THF and ethyl acetate and washed with water and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure. The desired product is obtained by flash column chromatography as necessary.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:27])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[CH:14][C:13]=2[Cl:26])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:28]([OH:32])[CH2:29][C:30]#[CH:31]>>[Cl:26][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:31]=[C:30]([CH2:29][CH2:28][OH:32])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:27])=[O:11]
Reactant: Cc1cccc(Nc2ccc(C(=O)c3cc(N=[N+]=[N-])ccc3C)c(Cl)c2)c1
Reactant: C#CCCO
Product: Cc1cccc(Nc2ccc(C(=O)c3cc(-n4cc(CCO)nn4)ccc3C)c(Cl)c2)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 465 (0.25 mmol) and but-3-yn-1-ol (0.30 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 6:1 as the eluent to afford the title compound as light yellow foam. 13C NMR (CDCl3) δ 194.8, 148.9, 146.3, 141.1, 139.7, 139.6, 138.1, 135.6, 134.8, 134.0, 132.5, 129.5, 127.5, 125.2, 122.3, 122.2, 120.7, 119.9, 118.7, 116.3, 112.8, 61.6, 28.7, 21.5, 19.9
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[CH:13][Cl:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=O)(C)(C)C.[CH2:18]([N:20]1[C:32]2[CH:31]=[CH:30][C:29]([NH2:33])=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH3:19]>>[Cl:14][CH:13]=[C:11]1[CH2:12][NH:8][C@H:9]([C:15]([NH:33][C:29]2[CH:30]=[CH:31][C:32]3[N:20]([CH2:18][CH3:19])[C:21]4[C:26]([C:27]=3[CH:28]=2)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:17])[CH2:10]1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CC(C)(C)OC(=O)N1CC(=CCl)C[C@H]1C(=O)O
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=CCl)CN3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(chloromethylene)-2-pyrrolidinecarboxylic acid, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 73% purity by LC/MS. MS(ESI+): m/z=354.4.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[N:6][CH:7]=1.[C:13]([C:15]1[CH:16]=[C:17]([CH:39]=[CH:40][C:41]=1[CH3:42])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[C:23]([C:35]([F:38])([F:37])[F:36])[CH:22]=1)=[O:19])#[CH:14]>>[CH3:42][C:41]1[CH:40]=[CH:39][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:23]([C:35]([F:36])([F:38])[F:37])[CH:22]=2)=[O:19])=[CH:16][C:15]=1[C:13]#[C:14][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Brc1ccc(-c2nc[nH]n2)nc1
Reactant: C#Cc1cc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)ccc1C
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1ccc(-c2nc[nH]n2)nc1

Procedure:
The title compound was prepared using 5-bromo-2-(1,2,4-triazol-3-yl)pyridine and 3-ethynyl-4-methyl-N-[4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide as raw materials, according to the method described in Step 4 of Example 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[C:13]([O:15]C)=[O:14])=[CH:5][CH:4]=1.O[Li].O>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1
Reactant: COC(=O)C1=CCCc2ccc(OC)cc21
Agent: [Li]O
Solvent: O
Product: COc1ccc2c(c1)C(C(=O)O)=CCC2

Procedure:
The sub-title compound was prepared according to the method described in Example 1(ii) above from 7-methoxy-3,4-dihydronaphthalen-1-yl-carboxylic acid, methyl ester (0.39 g; 1.79 mmol; from step (i) above) and LiOH.H2O (0.15 g; 3.57 mmol). Yield 148 mg (40%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[C:27]([Cl:29])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]3)[C:15]2=[O:26])=[C:11]([Cl:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[CH:36]([Si:39](Cl)([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41])([CH3:38])[CH3:37]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Cl:30])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:20][CH2:21][C@H:22]([O:25][Si:39]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:36]([CH3:38])[CH3:37])[CH2:23][CH2:24]3)[C:15]2=[O:26])=[C:27]([Cl:29])[CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1[C@H]1CC[C@H](O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C

Procedure:
Mix (R)-3-(4-Benzyloxy-2,6-dichloro-benzyl)-trans-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one (Preparation 16) (1.37 g, 3.07 mmol) and imidazole (0.527 g, 68.08 mmol) in 10 ml of dry DMF. Add triisopropylsilylchloride (0.81 ml, 3.07 mmol) dropwise and stir at room temperature for 5 hours. Quench with 1N HCl and extract with ethyl acetate. Wash the extract with NaHCO3 and brine. Dry over magnesium sulfate, filter, and concentrate. After flash column chromatography, receive 1.83 g (99%) of the title compound: Mass spectrum (apci) m/z=604 (M+H).