Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[O:3]=[C:4]1[NH:12][C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[C:5]21[CH2:20][C:19]1[C:14](=[CH:15][CH:16]=[C:17]([NH:21][C:22]3[N:27]=[CH:26][N:25]=[C:24]([C:28]([O:30]CC)=[O:29])[CH:23]=3)[CH:18]=1)[CH2:13]2.[ClH:33]>C(O)C>[ClH:33].[O:3]=[C:4]1[NH:12][C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[C:5]21[CH2:20][C:19]1[C:14](=[CH:15][CH:16]=[C:17]([NH:21][C:22]3[N:27]=[CH:26][N:25]=[C:24]([C:28]([OH:30])=[O:29])[CH:23]=3)[CH:18]=1)[CH2:13]2
Reactant: CCOC(=O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.0 mL (5.0 mmol) of a 1M aqueous lithium hydroxide solution were added to 1.80 g (4.48 mmol) ethyl 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylate in 5.0 mL ethanol and the mixture was stirred overnight at RT. The reaction mixture was acidified with 1.3 mL of a 4M aqueous HCl solution and the precipitate formed was suction filtered and dried.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:30][CH2:29][N:28](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:27][CH2:26][N:25](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:24][CH2:23][N:22](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:21][CH2:20][N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:18][CH2:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)(=O)=O)=CC=1.OS(O)(=O)=O.C(O)C>C(OCC)C>[NH:10]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOCC
Product: C1CNCCNCCNCCNCCNCCNCCN1
Temperature: 100 °C
Reaction time: 96 h
Yield: 8.2 %

Procedure:
A mixture of 1,4,7,10,13,16,19-hepta(p-toluenesulfonyl)-1,4,7,10,13,16,19-heptaazacycloheneicosane (28.3 g, 0.0205 mole) and concentrated H2SO4 (85 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 4 days. To the resulting solution, ethanol (170 mL) was added dropwise with stirring at 0° C., followed by ethyl ether (430 ml). The solid was filtered and dried in vacuo over P2O5. The solid was then dissolved in H2O (75 ml) and the pH of the solution was adjusted to 10 with 10N NaOH. Insoluble impurities were removed by filtration and the solution was extracted with 6×CHCl3. The extracts were combined, dried (Na2SO4) and the solvent removed in vacuo to give a yellow oil which crystallized on standing. The aqueous layer was taken to dryness in vacuo and the resulting brown oily solid was extracted with hot THF (2×500 ml). The THF extracts were filtered and combined with the yellow solid obtained above. Insoluble impurities were removed by filtration and the solvent was removed in vacuo to give a yellow crystalline solid. The crude solid was crystallized from CHCl3 -acetonitrile to give 505 mg (8% yield) of the product as colorless needles: mp 163°-5° C.; 1H NMR (CDCl3) δ 2.99 (s, 28 H), 4.00 (br s, 7 H); Exact mass (M+H)+ : calcd., 302.3032; Found: 302.3097 (C14H36N7).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[O:8][CH2:9][C:5]=2[C:4]=1[CH3:13])=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH3:13][C:4]1[C:5]2[CH2:9][O:8][C:7](=[O:10])[C:6]=2[CH:11]=[CH:12][C:3]=1[CH:1]1[CH2:2][O:22]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc2c(c1C)COC2=O
Solvent: ClCCl
Product: Cc1c(C2CO2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-ethenyl-4-methyl-2-benzofuran-1(3H)-one (1.46 g, 8.38 mmol) was added to DCM (25 mL) at 0° C. then m-CPBA (2.89 g, 16.8 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was washed once each with saturated aqueous Na2S2O3, NaHCO3, and brine. The organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The crude material was purified by MPLC chromatography through 120 g Redi-sep column eluting with 0-80% EtOAc/hexane solvent system to yield 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one. 1H-NMR (500 MHz, CDCl3): 6 ppm 7.77 (d, J=8 Hz, 1H), 7.43 (d, J=8 Hz, 1H), 5.30 (s, 2H), 4.12 (s, 1H), 3.27 (t, J=4 Hz, 1H), 2.735 (dd, J=2.2, 5.5 Hz, 1H), 2.43 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]#[N:10])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[C:22]([NH2:24])[CH:21]=[C:20]([Cl:25])[C:19]=1[OH:26]>C1(C)C=CC=CC=1>[CH3:8][C:7]1[C:2]([O:26][C:19]2[C:18]([Cl:17])=[CH:23][C:22]([NH2:24])=[CH:21][C:20]=2[Cl:25])=[N:3][CH:4]=[C:5]([C:9]#[N:10])[CH:6]=1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: Cc1cc(C#N)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)cnc1Oc1c(Cl)cc(N)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a 100 mL round bottom flask equipped with a water condenser, thermometer, magnetic stirrer, and under nitrogen atmosphere was added 2-chloro-3-methyl-5-cyanopyridine (7.10 g, 46.6 mmol), potassium carbonate (9.02 g, 65.2 mmol), 2,6-dichloro-4-aminophenol (10.77 g, 60.5 mmol), and dimethylformanide (70 mL). The resulting mixture was stirred at room temperature for 1 hour, 90° for 2 hours, and 110° for 3 hours. It was then cooled, filtered, and concentrated to give a brown mixture. This mixture was dissolved in 500 mL of toluene and washed with four 150 mL portions of 4% sodium hydroxide, water, and brine. It was then dried (Na2SO4) and concentrated to give the desired product as a brown solid (8.00 g, 27.2 mmol). m.p. 211.5°-212.5°.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](Cl)=[O:38])=[CH:32][CH:31]=1>C1COCC1>[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[O:38])=[CH:32][CH:31]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)Cc3ccc(F)cc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (11.0 mg, 0.0280 mmol) and (4-fluorophenyl)acetyl chloride (7.20 mg, 0.0420 mmol) in THF (5 mL) was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC using Hexane:EtOAc (2:1) to give the desired product (13 mg, 90% yield). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, 1H, J=8.4 Hz), 7.59 (s, 1H), 7.31-6.93 (m, 13H), 5.13 (q, 1H, J=6.0 Hz), 3.56 (s, 2H), 3.07 (d, 1H, J=11.7 Hz), 2.91 (d, 1H, J=11.0 Hz), 2.62-2.42 (m, 2H), 2.40-2.30 (m, 1H), 2.12-1.54 (m, 9H), 1.24 (d, 6H, J=6.7 Hz); ESMS m/e: 515.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.C[C:12]([CH3:14])=[O:13]>>[N:3]1([CH:4]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=2)[CH3:5])[CH2:14][CH2:12][O:13][CH2:7][CH2:2]1
Reactant: CC(C)=O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: CC(c1ccc(N)cn1)N1CCOCC1

Procedure:
A4-11 was made using a variation of the above approach from methylketone 35. The methylketone was synthesised from 2-chloro-5-nitropyridine (21).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]1([N:13]2[CH:17]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21]([NH:22][C@@H:23]([CH3:36])[CH2:24][N:25]4[C:28]([O:30][CH:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:29])=[CH:20][CH:19]=3)[CH:15]=[N:14]2)[CH2:12][CH2:11]1.Cl[C:38]([O:40][CH3:41])=[O:39]>ClCCCl>[CH:10]1([N:13]2[CH:17]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21](=[CH:20][CH:19]=3)[N:22]([C:38]([O:40][CH3:41])=[O:39])[C@@H:23]([CH3:36])[CH2:24][N:25]4[C:28]([O:30][CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)=[O:29])[CH:15]=[N:14]2)[CH2:12][CH2:11]1
Reactant: COC(=O)Cl
Reactant: C[C@H]1CN(C(=O)OC2CCCC2)c2cc(-c3cnn(C4CC4)c3)ccc2N1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2N(C(=O)OC2CCCC2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 79.5 %

Procedure:
N,N-Diisopropylethylamine (0.148 mL, 0.846 mmol) was added to a solution of (S)-cyclopentyl 7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.062 g, 0.169 mmol) and methyl chloroformate (0.065 mL, 0.846 mmol) in 1,2-dichloroethane (2.0 mL), and the mixture stirred at 50° C. for 2.5 h. The reaction mixture was concentrated to afford a brown oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford (S)-4-cyclopentyl 1-methyl 6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-2,3-dihydroquinoxaline-1,4-dicarboxylate (0.057 g, 79%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90-1.02 (m, 2 H), 1.02-1.12 (m, 5 H), 1.37-1.93 (m, 9 H), 3.66-3.81 (m, 5 H), 4.49-4.72 (m, 1 H), 5.00-5.21 (m, 1 H), 7.17-7.39 (m, 1 H), 7.67-7.82 (m, 3 H), 8.13 (s, 1 H). MS (ESI, pos. ion) m/z 425. [M+1]+.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].[OH-].[Cs+:10]>O>[C:1]([O-:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].[Cs+:10]
Reactant: CC(=O)CCC(=O)O
Agent: [Cs+]
Agent: [OH-]
Solvent: O
Product: CC(=O)CCC(=O)[O-]
Temperature: 65 °C

Procedure:
46.9 gr. of 99% pure levulinic acid is slurried in 100 cc. distilled water. 97.3 g. of a 4.22 molar, pure cesium hydroxide solution is added and temperature is raised to 65° C. to obtain complete solution. The solution is filtered through No. 40 filter paper to remove dust, etc. The solution is then evaporated on a hot plate to 200 g., which gives a 2 molar concentration, and it is then bottled.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][C:9]2[C:13]3[C:14](=[O:28])[N:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:16]4[N:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]=3[NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-])=O>CN(C=O)C.CO.[C].[Pd]>[NH2:1][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][C:9]2[C:13]3[C:14](=[O:28])[N:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:16]4[N:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]=3[NH:11][N:10]=2)=[CH:6][CH:5]=1
Reactant: O=c1c2c(Cc3ccc([N+](=O)[O-])cc3)n[nH]c2c2cccnc2n1-c1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Reaction time: 72 h
Yield: 65.3 %

Procedure:
To a solution of 3-(4-nitrobenzyl)-5-phenyl-1H-pyrazolo [4,3-c][1,8]naphthyridin-4 (5H)-one (200 mg, 0.50 mmol, prepared in Example 24) in DMF (10 ml) and methanol (10 ml) was added activated carbon-palladium (20 mg), the mixture was stirred under hydrogen atmosphere for 3 days, and filtered. After methanol was distilled off, the resultant solution was admixed with water, and filtered to give precipitates which were dried to afford 3-(4-aminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (120 mg, 65%).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([OH:17])=[C:12]([Cl:18])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][C:27]=1[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C)C=O>O>[C:1]([O:9][C:10]1[CH:11]=[C:12]([Cl:18])[C:13]([O:17][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([F:25])=[C:27]([O:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:28]=2)=[C:14]([Cl:16])[CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1cc(Cl)c(O)c(Cl)c1)c1ccccc1
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1cc(Cl)c(OCc2ccc(F)c(Oc3ccccc3)c2)c(Cl)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.2 %

Procedure:
A reaction vessel was charged with 1.54 g of 3,5-dichloro-4-hydroxyphenyl benzoate, 0.83 g of potassium carbonate, 1.53 g of 4-fluoro-3-phenoxybenzyl bromide, and 10 ml of N,N-dimethylformamide, followed by stirring at room temperature for 5 hours. The reaction mixture was poured into water, and extracted twice with 50 m of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 2.32 g of 3,5-dichloro-4-(4-fluoro-3-phenoxybenzyloxy)phenyl benzoate (88% yield).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].C(N(CC)CC)C.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH2:13]([O:20][S:1]([CH3:4])(=[O:3])=[O:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Mesyl chloride (25.8 mg) and triethylamine (0.055 ml) were added to a chloroform (0.9 ml) solution of benzyl alcohol (16.2 mg), and the mixture was stirred for 3 hours at room temperature. The reaction mixture was eluted by NH-type silica gel (Chromatorex, Fuji Silysia Chemical Ltd.) column chromatography using tetrahydrofuran as a solvent to obtain methanesulfonic acid benzyl ester. To a tetrahydrofuran (0.9 ml) solution of the methanesulfonic acid benzyl ester, 4-chloro-N-[(1R)-1-(4-ethyl-5-mercapto-4H-1,2,4-triazol-3-yl)ethyl]benzenesulfonamide (Compound 90) (17.3 mg) obtained by performing the same procedure as in Example 1 using the corresponding raw materials, and potassium t-butoxide (8.4 mg) were added, followed by stirring the mixture for 20 hours at 40° C. PSA (polymer supported amine) (0.15 ml) was added to the reaction mixture, and the resulting mixture was stirred for 4 hours at room temperature. The reaction mixture was eluted with ethyl acetate and tetrahydrofuran, and the solvents were distilled off. The resulting residue was eluted by NH-type silica gel column chromatography using tetrahydrofuran as a solvent, and the eluate was purified by silica gel column chromatography to obtain Compound 5 (2.3 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[CH3:13][C:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH3:20][C:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=3)[N:3]=2)=[CH:26][CH:27]=1)([CH3:13])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(Oc2ccc3cc(Cl)ccc3n2)cc1

Procedure:
Ethyl 2-methyl-2-[4-(6-chloroquinolin-2-yloxy)phenoxy]-propionate (36) was prepared from 2,6-dichloroquinoline and ethyl 2-methyl-2-(4-hydroxyphenoxy)propionate following essentially the same procedure as that described in Example 1. The product was isolated after chromatography as a low melting point solid. Mass spectrum (m/e): 385 (parent ion; 30%); 312 (35%); 271 (100%); 270 (100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:3]=1.Cl[CH2:21][CH2:22][CH2:23][N:24]1[C:29](=[O:30])[C:28]([CH2:31][OH:32])=[CH:27][N:26]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:25]1=[O:41]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:21][CH2:22][CH2:23][N:24]3[C:29](=[O:30])[C:28]([CH2:31][OH:32])=[CH:27][N:26]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:40])[CH3:39])[C:25]3=[O:41])[CH2:10][CH2:9]2)=[C:4]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(CO)c(=O)n(CCCCl)c1=O
Reactant: Fc1ccc(N2CCNCC2)c(OCC(F)(F)F)c1
Product: C[Si](C)(C)CCOCn1cc(CO)c(=O)n(CCCN2CCN(c3ccc(F)cc3OCC(F)(F)F)CC2)c1=O

Procedure:
substituting 1-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 3-(3-chloropropyl)-5-hydroxymethyl-1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione gave 3-(3-{4-[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-5-hydroxymethyl-1-[2-(trimethylsilyl)ethoxymethyl]-2,4(1H,3H)-pyrimidinedione;
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>C(Cl)Cl>[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:38])=[CH:32][CH:31]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1CN(C(=O)Nc2ccc(F)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.8 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (43.1 mg, 0.102 mmol) and 4-fluorophenyl isocyanate (Aldrich, 71.0 mg, 0.512 mmol) in CH2Cl2 (5 mL) was stirred at rt for 24 hrs. The reaction mixture was then concentrated and purified by flash column to give (2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid (4-fluoro-phenyl)-amide (45.6 mg, 79.8%). HRMS (ES+) m/z Calcd for C29H26Cl2F3N3O+H [(M+H)+]: 560.1478; Found: 560.1479.
Reaction SMILES: [CH:1]1([C:4]#[C:5][CH2:6][OH:7])[CH2:3][CH2:2]1.[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:15][C:14]1[CH:16]=[CH:17][C:11]([S:8]([O:7][CH2:6][C:5]#[C:4][CH:1]2[CH2:3][CH2:2]2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: OCC#CC1CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC#CC2CC2)cc1
Reaction time: 3 h

Procedure:
To a stirred solution of crude 3-cyclopropylprop-2-yn-1-ol (intermediate AT) (0.55 mg) in 10 mL of CH2Cl2 was added TsCl (1.33 g, 6.87 mmol) and DMAP (0.035 g, 0.2865 mmol) at 0° C. Triethylamine (0.96 mL, 6.87 mmol) was added dropwise to the mixture and the reaction temperature was held so as not to exceed 0° C. After stirring for 3 h, the mixture was quenched with 10 mL of water. The aqueous layer was extracted twice with 20 mL each of CH2Cl2. The organic layer was washed with 20% HCl and water prior to drying over anhydrous Na2SO4. The organic phase was concentrated and the crude product was purified by gel column chromatography to obtain intermediate AU (0.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10]=2[CH3:18])=[CH:5][CH:4]=1.[CH2:19](Br)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]=[C:12]3[N:13]([CH2:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:21])[CH:14]=[CH:15][CH:16]=[C:11]3[C:10]=2[CH3:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2[nH]c3ncccc3c2C)cc1
Reactant: O=C(CBr)c1ccccc1
Product: COc1ccc(-c2nc3n(CC(=O)c4ccccc4)cccc-3c2C)cc1

Procedure:
The title compound was prepared from 2-(p-methoxyphenyl)-3-methyl-pyrrolo[2,3-b]pyridine and phenacylbromide on a 10 mmol scale according to the procedure described in example 8 yielding 4.02 g (92% ).
Reaction SMILES: [N:1]1[N:2]=[C:3]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[N:20]=[C:19]([NH2:21])[C:18]([N+:22]([O-])=O)=[CH:17][CH:16]=3)[CH2:10]2)[N:4]2[CH2:8][CH2:7][CH2:6][C:5]=12.[CH:25]1([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]=O)[N:29]=2)[CH2:27][CH2:26]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)C>O>[CH:25]1([C:28]2[N:29]=[C:30]([C:34]3[NH:21][C:19]4=[N:20][C:15]([N:11]5[CH2:12][CH2:13][CH2:14][CH:9]([C:3]6[N:4]7[CH2:8][CH2:7][CH2:6][C:5]7=[N:1][N:2]=6)[CH2:10]5)=[CH:16][CH:17]=[C:18]4[N:22]=3)[CH:31]=[CH:32][CH:33]=2)[CH2:27][CH2:26]1
Reactant: Nc1nc(N2CCCC(c3nnc4n3CCC4)C2)ccc1[N+](=O)[O-]
Reactant: O=Cc1cccc(C2CC2)n1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1cc(-c2nc3ccc(N4CCCC(c5nnc6n5CCC6)C4)nc3[nH]2)nc(C2CC2)c1
Temperature: 110 °C
Yield: 20.6 %

Procedure:
A mixture of 6-(3-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)piperidin-1-yl)-3-nitropyridin-2-amine (Intermediate 45) (300 mg, 0.91 mmol), 2-cyclopropylpyridine-6-aldehyde (187.5 mg, 1.27 mmol), sodium dithionite (602.6 mg, 4.46 mmol), ethanol (15 mL) and water (2.4 mL) in a sealed tube was heated to 110° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was and purified via preparative TLC to afford the title compound (80 mg, 21%) as a racemic mixture. MS (ES+) (M+H) 427.3; LCMS retention time 2.687 min (Method J). 1H NMR (400 MHz, CDCl3) δ 1.02-1.15 (m, 4H), 1.73-1.82 (m, 1H), 1.89-2.13 (m, 3H), 2.21 (d, 1H), 2.74-2.85 (m, 2H), 2.94-3.01 (m, 2H), 3.02-3.12 (m, 2H), 3.21-3.32 (m, 1H), 3.91-4.10 (m, 2H), 4.33 (d, 1H), 4.65 (d, 1H), 6.75 (d, 1H), 7.20 (d, 1H), 7.66 (t, 2H), 7.88 (d, 1H), 8.05 (d, 1H), 10.20 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(NCC)C.[CH2:37]([OH:40])[C:38]#[CH:39]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:39]#[C:38][CH2:37][OH:40])[CH:17]=3)[N:12]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: CC(C)(C)OC(=O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC(C)(C)OC(=O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Reaction time: 8 h

Procedure:
To a dry flask under an atmosphere of argon gas containing 0.23 g of tert-butyl 2-[3-{[(4-chlorobenzyl)amino]carbonyl}-6-iodo-4-oxo-1(4H)-quinolinyl]acetate from Preparation No. 26, 0.01 g of copper (I) iodide and 0.03 g of dichlorobis(triphenylphosphine)palladium (II) is added diethylamine (2.0 mL) and propargyl alcohol (0.03 mL). After 1 hour the reaction is diluted with DMF (1.0 mL) and left to stir overnight. The reaction is concentrated under reduced pressure, diluted with dichloromethane containing a small amount of methanol, and partioned against water. The organic layer is washed with brine, dried and concentrated under reduced pressure. The residue is adsorbed onto silica and chromatographed on silica eluting with 2% to 4% methanol in dichloromethane . The product-containing fractions are combined and concentrated under reduced pressure to afford 0.13 g of the title compound as a solid.