Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([C:21]#[N:22])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][C:12]1[O:13][C:14]2[C:20]([C:21]#[N:22])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2cccc(C#N)c2o1
Product: N#Cc1cccc2nc(CCC#Cc3ccccn3)oc12
Yield: 17.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (161 mg, 1.02 mmol) and 2-(but-3-ynyl)benzo[d]oxazole-7-carbonitrile (200 mg, 1.02 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 48 mg (0.18 mmol, 17%) of 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole-7-carbonitrile as a yellow solid (M.P.=126-126.5° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:21]3[CH:16]([C:17]4[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=4[CH2:19][CH2:20]3)[C:15]3[CH:14]=[C:13]([C:26]#[N:27])[CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][C:3]=1[O:28][CH3:29].[BH4-].[Na+].C(O)(C(F)(F)F)=O>C1COCC1>[NH2:27][CH2:26][C:13]1[CH:12]=[CH:11][C:10]2[NH:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:28][CH3:29])[CH:4]=3)[CH:21]3[CH:16]([C:17]4[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=4[CH2:19][CH2:20]3)[C:15]=2[CH:14]=1
Reactant: COc1cc(C2Nc3ccc(C#N)cc3C3c4ccccc4CCC23)ccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cc(C2Nc3ccc(CN)cc3C3c4ccccc4CCC23)ccc1O

Procedure:
6-(4-Hydroxy-3-methoxy-phenyl)-5,6,6a,7,8,12b-hexahydro-benzo[k]phenanthridine-2-carbonitrile (0.1 mmol; 38.2 mg) was added at 10° C. to a mixture obtained by pre-treating sodium borohydride (600 mg) in 4 mL of THF with a mixture of THF (2 mL) and TFA (1.2 mL). The reaction mixture was reacted overnight before quenching with 1 mL of 10% HCl solution. The mixture was further heated for 1 hour before it was extracted using ammonium hydroxide and water. The organic phase was dried over magnesium sulfate and evaporated to dryness. The residue was purified using HPLC to yield compound 4-(2-Aminomethyl-5,6,6a,7,8,12b-hexahydro-benzo[k]phenanthridin-6-yl)-2-methoxy-phenol. Mass spectrum 369(M−17);in the presence of 0.1M ammonium acetate 385 (M−1) observed for negative ion mode.
Reaction SMILES: CON(C)[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[Mg]Br.C1COCC1>>[C:10]([O:9][C:8](=[O:14])[NH:7][C@@H:5]([CH3:6])[C:4]([C:19]1[CH:18]=[CH:17][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:15])([CH3:11])([CH3:12])[CH3:13]
Reactant: Br[Mg]c1ccc2ccccc2c1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccc2ccccc2c1

Procedure:
The subtitle compound was prepared analogous to the method described in Example 19 (step 19d), starting from (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (1.86 g, 8 mmol) and a freshly prepared 2-Naphthylmagnesiumbromide 1M solution in THF (8 mL, 8 mmol). The obtained material was crystallised from Heptane. Yield 350 mg (14%).
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:19][CH2:20][CH3:21])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Br:22]N1C(=O)CCC1=O.N(C(C)(CC(OC)(C)C)C#N)=NC(C)(CC(C)(OC)C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:22][CH:19]([C:7]1[NH:8][C:9]2[C:14]([C:6]=1[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)[CH2:20][CH3:21]
Reactant: CCCc1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(Br)c1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Yield: 69.9 %

Procedure:
To a solution of methyl 3-isobutyryl-2-propylindole-6-carboxylate (201 mg) in carbon tetrachloride (7 ml) was added N-bromosuccinimide (187 mg) and 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) (20 mg) and refluxed for 30 minutes. The resulting mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (2:1) to give methyl 2-(1-bromopropyl)-3-isobutyrylindole-6-carboxylate (179 mg).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH2:25])(=[O:24])=[O:23])=[CH:9][CH:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C.C(OCC)(=O)C>[CH2:30]([O:29][C:27]([NH:25][S:22]([C:14]1[S:15][C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:17][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1)(=[O:23])=[O:24])=[O:28])[CH2:31][CH2:32][CH3:33]
Reactant: CC(C)Cc1cc(-c2ccc(Cn3cncn3)cc2)c(S(N)(=O)=O)s1
Reactant: CCCCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1ccc(Cn2cncn2)cc1
Reaction time: 8 h
Yield: 9.2 %

Procedure:
59 mg (0.16 mmol) of the crude 3-(4-[1,2,4]triazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide from step (c) above was mixed with butyl chloroformate (31 μL, 0.24 mmol) and 4-dimethylaminopyridine (2 mg, 16 μmol) in 5 mL of triethylamine at 0° C. The reaction mixture was stirred overnight and then diluted with ethyl acetate, washed with water and dried over K2CO3. The reaction mixture was then separated on a silica column (dichloromethane+15% methanol), circular chromatography (dichloromethane+10-15% methanol and preparative LC-MS to yield 7.0 mg of the title compound (9% isolated yield).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[CH:20]=[CH:19][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.[OH-].[Na+].[C:23]([O:27]C)(=[O:26])[CH:24]=[CH2:25].Cl>O1CCOCC1.ClCCl>[N:16]1[CH:17]=[CH:18][C:13]([O:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][C@H:2]3[CH2:3][CH2:4][CH2:5][N:1]3[CH2:25][CH2:24][C:23]([OH:27])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:15]=1
Reactant: c1cc(Oc2ccc(OC[C@H]3CCCN3)cc2)ccn1
Reactant: C=CC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)CCN1CCC[C@@H]1COc1ccc(Oc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 144 (50 mg, 0.15 mmol) was treated with 20% NaOH (5 ml) and extracted with EtOAc, dried over Na2SO4 and dried down to give the free base. Dichloromethane (3 ml) and methyl acrylate (0.4 ml, 2.8 mmol) were added and the mixture was stirred at rt overnight. The reaction mixture was dried down to give an oil. Excess 4.0M HCl in dioxane was added and the mixture was stirred overnight at rt. The solvent was removed in vacuo to give the title compound. (15 mg, 23%); LC/MS; m/z 343 (M+H) 99%; 1H NMR (DMSO-d6, 400 MHz) δ 1.79-2.29 (4H, m), 2.89 (2H, m), 3.16 (1H, m), 3.56-3.71 (3H, m), 3.97 (1H, m) 4.34-4.51 (2H, m), 7.18 (2H, d, J=8.8 Hz), 7.33 (2H, d, J=9.6 Hz), 7.43 (2H, d, J=7.2 Hz), 8.80 (2H, d, J=7.2 Hz)
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][N:6]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2.Cl.C(=O)([O-])[O-].[K+].[K+].[CH2:28]([O:30][P:31](Cl)([O:33][CH2:34][CH3:35])=[O:32])[CH3:29]>CN(C=O)C>[CH2:28]([O:30][P:31]([N:2]([CH2:3][CH2:4][CH2:5][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2)[CH3:1])(=[O:32])[O:33][CH2:34][CH3:35])[CH3:29]
Reactant: CNCCCN1c2ccccc2CCc2ccccc21
Reactant: CCOP(=O)(Cl)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)N(C)CCCN1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Desipramine hydrochloride (1 equivalent, 0.5 gram) was added drop wise to a stirred solution of potassium carbonate (2 equivalents, 0.456 gram) in dry DMF at 0° C. Diethylchlorophosphate (1.2 equivalents, 0.33 ml) which had been dissolved in dry DMF was added drop wise to this mixture and stirred for 12 hours at room temperature. The reaction mixture was quenched with water, extracted with ethyl acetate, the organic layer separated, washed with brine solution and dried over anhydrous sodium sulfate. The dried material was concentrated and purified by column chromatography to provide a pale yellow liquid (yield: 0.33 gram) and analyzed by HPLC (purity 93.1%). The FTIR, MS and 1H NMR spectra were consistent with the assigned with the empirical formula of C22H31N2O3P.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].I[CH2:13][CH2:14][CH2:15][CH3:16].O>CN(C)C=O>[CH2:13]([CH:2]([C:1]#[N:5])[C:3]#[N:4])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCI
Reactant: N#CCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(C#N)C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
26.4 g of malononitrile was dissolved in 60 ml of N,N-dimethylformamide and 56 g of potassium carbonate was added thereto, followed by stirring for 1 hour at room temperature. To the solution was added 40 g of iodobutane at about 0° C. and stirred for 30 minutes at the same temperature and for additional 4 hours at room temperature. Then, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give 17 g of 2-butylmalononitrile.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=O)[C:5]=2[O:4][CH2:3][CH2:2]1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=[CH:14][C:15]([OH:17])=[O:16])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=Cc1cccc2c1OCCO2
Reactant: O=C(O)CC(=O)O
Product: O=C(O)C=Cc1cccc2c1OCCO2

Procedure:
Similar procedure as described in example 343a was used, starting from 2,3-Dihydro-benzo[1,4]dioxine-5-carbaldehyde and malonic acid to give 3-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-acrylic acid. LC-MS: m/e 207 (MH+).
Reaction SMILES: [ClH:1].[CH2:2]([OH:4])[CH3:3].O.[NH2:6][C@H:7]([C:19]([OH:21])=[O:20])[CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:16](O)=[O:17])[CH2:14][SH:15])=[O:11]>CCOCC>[ClH:1].[CH2:2]([O:4][C:16](=[O:17])[C@H:13]([CH2:14][SH:15])[NH:12][C:10](=[O:11])[CH2:9][CH2:8][C@@H:7]([C:19]([OH:21])=[O:20])[NH2:6])[CH3:3]
Reactant: CCO
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)O)C(=O)O
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)[C@H](CS)NC(=O)CC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
After 250 ml of hydrogen chloride-containing ethanol (7N HCl-EtOH) was added to a dehydrated ethanol suspension (750 ml) containing 50 g (about 185 mmol) of γ-L-glutamyl-L-cysteine monohydrate, the mixture was stirred at room temperature for 1 hour. Upon addition of hydrogen chloride, the suspension turned to a solution. The reaction solution was then poured into ether (7.5 l) which had been cooled to 0° C. beforehand and the mixture was kept stirring for 2 hours to make the crystals precipitate. Thus obtained product was separated by filtration to give 48.4 g (83%) of γ-L-glutamyl-L-cysteine ethyl ester hydrochloride salt.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:28]=1[NH:42][C:43]([C:45]1[N:46]([CH3:54])[C:47]2[C:52]([CH:53]=1)=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:31]3[CH:30]=[CH:29][C:28]([NH:42][C:43]([C:45]4[N:46]([CH3:54])[C:47]5[C:52]([CH:53]=4)=[CH:51][CH:50]=[CH:49][CH:48]=5)=[O:44])=[C:27]([O:26][CH3:25])[CH:32]=3)[C:10]=12
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 80 °C
Reaction time: 21.5 h

Procedure:
A suspension of trans-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.227 mmol) in ethylene glycol dimethyl ether (8 mL) was treated with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (0.097 g, 0.238 mmol), tetrakis(triphenylphosphine)palladium (0.016 g, 0.014 mmol), and a solution of sodium carbonate (0.057 g, 0.538 mmol) in water (4 mL). The reaction mixture was stirred for 21.5 h at 80° C. The precipitate was filtered, and the organic layer was evaporated under reduced pressure. Dichloromethane (15 mL) was added and the layers were partitioned. The aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a 10% methanol in dichloromethane to 50% methanol in dichloromethane step gradient on Sq 16× ISCO CombiFlash. The column afforded 0.083 g (68%) of trans-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide. 1H NMR (d6-DMSO) δ 9.4316 (s, 1H), 8.2427 (s, 1H), 8.1207-8.1003 (d, 1H, J=8.16 Hz), 7.7173-7.6974 (d, 1H, J=7.96 Hz), 7.5979-7.5769 (d, 1H, J=8.4 Hz), 7.3507-7.2758 (m, 4H), 7.1695-7.1321 (t, 1H), 4.6893-4.6324 (m, 1H), 4.0400 (s, 3H), 3.9571 (s, 3H), 2.5 (m, 3H), 2.4055-2.3279 (m, 5H), 2.1606 (s, 3H), 2.1094-1.9367 (m, 6H), 1.5214-1.4624 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium Acetate in Water to 95% Acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.12 min (100%), M+ 594.3.
Reaction SMILES: BrC1C=C(CCCC[OH:12])C=CC=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][OH:31])[CH:24]=[CH:25][CH:26]=2)=[O:20])[CH:14]=1>>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][C:30]([OH:12])=[O:31])[CH:24]=[CH:25][CH:26]=2)=[O:20])[CH:14]=1
Reactant: O=C(c1cccnc1)c1cccc(CCCCO)c1
Reactant: OCCCCc1cccc(Br)c1
Product: O=C(O)CCCc1cccc(C(=O)c2cccnc2)c1

Procedure:
4-(3-bromophenyl)butanol and 3-pyridylaldehyde were reacted to synthesize 4-[3-(3-pyridylcarbonyl)phenyl]butanol, then the resultant product was oxidized by a similar method as in Example 2(3) to synthesize the desired compound.
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][CH2:16][C@H:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[F:15][CH2:16][C@H:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([CH:6]3[CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:7]3)=[CH:13][CH:12]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Reactant: C[C@H](CF)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc([C@H](C)CF)cc3)cc2)C1
Yield: 22.5 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (110 mg, 0.57 mmol) in CH2Cl2/pyridine 1:1 (12 ml) was treated with 4-((S)-2-fluoro-1-methyl-ethyl)-benzenesulfonyl chloride (178 mg, 0.75 mmol). Purification of the crude product by flash column chromatography (CH2Cl2:methanol, 95:5) provided the title compound (50 mg, 22%) as a gum.
Reaction SMILES: [NH2:1][CH:2](/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[C:3]([OH:5])=[O:4].Cl.[CH2:14](O)[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([O:4][C:3](=[O:5])[CH:2]([NH2:1])/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[CH:15]([CH3:17])[CH3:16]
Reactant: NC(/C=C/CP(=O)(O)O)C(=O)O
Reactant: CC(C)CO
Agent: Cl
Product: CC(C)COC(=O)C(N)/C=C/CP(=O)(O)O

Procedure:
1.5 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml of isobutanol and the suspension is saturated with hydrogen chloride gas for 31/2 hours at 70°. After concentration, the residue is dissolved in 10 ml of isobutanol, 10 ml of propylene oxide are added and the precipitate is filtered off. Recrystallisation from water/acetone 1:1 yields E-2-amino-5-phosphono-3-pentenoic acid isobutyl ester, m.p. 163°-164°.
Reaction SMILES: O=[C:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=O>CC(O)C.O.O.[Na+].Cl[Au-](Cl)(Cl)Cl>[F:27][C:24]1[CH:23]=[C:22]2[C:21](=[CH:26][CH:25]=1)[N:20]=[C:2]([CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4])[C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[C:28]2[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Cc1ccccn1
Reactant: Nc1ccc(F)cc1C(=O)c1ccccn1
Agent: Cl[Au-](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2c(-c2ccccn2)c1-c1ccccn1
Temperature: 25 °C
Reaction time: 71 h
Yield: 58.9 %

Procedure:
A mixture of (S)-tert-butyl 3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate (0.427 g, 1.615 mmol), (2-amino-5-fluorophenyl)(pyridin-2-yl)methanone (0.384 g, 1.777 mmol), and sodium tetrachloroaurate(III) dihydrate (0.032 g, 0.081 mmol) in 2-propanol (9.50 mL) was heated under reflux. After 71 h, the mixture was cooled to rt and evaporated to dryness. The mixture was dissolved in DCM (50 mL) and washed with brine (1×50 mL), and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography eluting with a gradient of 0% to 50% EtOAc in hexane, to provide tert-butyl 1-(6-fluoro-3,4-di(pyridin-2-yl)quinolin-2-yl)ethylcarbamate (0.423 g, 0.952 mmol, 58.9% yield) as orange syrupy solid: LC-MS (ESI) m/z 445.1 [M+H]+. The orange syrupy solid was used without further purification. Epimerization occurred during the condensation.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:10](Cl)=[N:9][C:8]([Cl:13])=[N:7][C:6]=2[N:5]([C@@H:14]2[O:26][C@H:25]([CH2:27][O:28]C(=O)C)[C@@H:20]([O:21]C(=O)C)[C@H:15]2[O:16]C(=O)C)[CH:4]=1)#[N:2].[NH3:32]>>[CH:4]1[N:5]([CH:14]2[O:26][CH:25]([CH2:27][OH:28])[CH:20]([OH:21])[CH:15]2[OH:16])[C:6]2[N:7]=[C:8]([Cl:13])[N:9]=[C:10]([NH2:32])[C:11]=2[C:3]=1[C:1]#[N:2]
Reactant: N
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C#N)c3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: N#Cc1cn(C2OC(CO)C(O)C2O)c2nc(Cl)nc(N)c12
Reaction time: 12 h
Yield: 51 %

Procedure:
5-Cyano-2,4-dichloro-7-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine (5, 2.85 g) was covered with 50 ml of liquid ammonia and the solution was allowed to stand at room temperature for 12 hr while sealed in a steel vessel. The excess ammonia was allowed to evaporate and the residue was triturated with 50 ml of cold water. The water insoluble solid was collected by filtration, washed with 10 ml of water and dissolved in a minimum amount of boiling methanol. The methanol solution was then concentrated to ~100 ml or until the product began to crystallize. The solution was then allowed to stand at -5° for 12 hr. The white to light tan crystalline solid was collected by filtration, washed with 15 ml of methanol and dried in a vacuum oven for 2 hr at 100° over drierite to yield 1.00 g (51%) of 6, mp 258-260° dec.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:11])[CH:3]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:4]1[CH:3]=[C:2]([Cl:1])[C:9]([Cl:10])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)c(Cl)cc1C#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Cl)c(Cl)cc1CBr
Yield: 44.5 %

Procedure:
To a solution 4,5-Dichloro-2-methyl-benzonitrile 7 (6.3 g, 33.9 mmol) in carbon tetrachloride (50 mL) was added N-bromosuccinimide (9.0 g, 50.8 mmol) and 2,2′-azobisisobutyronitrile (cat.). The reaction mixture was refluxed 6 hrs, filtered, concentrated, and partitioned between ether and water. The ether layer was dried, concentrated, and purified by silica gel chromatography (10% ether/hexanes) to yield the tittle compound 4.0 g. (45%). 1H NMR (400 MHz, CDCl3) δ7.75 (s, 1 H, Ar), 7.66 (s, 1 H, Ar), 2.55 (s, 2 H, CH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20]
Reactant: OCCc1ccccc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
To a solution of 2-(2-fluorophenyl)-ethanol (4.00 g, 28.5 mmol) and triethylamine (6.36 mL, 45.7 mmol) in dichloromethane (15 mL) was added methanesulfonyl chloride (2.88 mL, 37.1 mmol) at −5° C. The mixture was stirred for 4 hours and was allowed to slowly warm to room temperature. The mixture was diluted with dichloromethane and extracted with 1 M HCl and water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography, using dichloromethane as eluent, to afford 5.88 g (94.4%) the title compound.
Reaction SMILES: [F:1][C:2]([F:25])([C:21]([F:24])([F:23])[F:22])[C:3](=O)[CH:4]=[CH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.Cl.[CH:27]1([NH:33][NH2:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.N1CCCCC1>C(O)C>[CH:27]1([N:33]2[CH:5]([C:6]3[CH:7]=[C:8]([C:12]4[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=4)[CH:9]=[CH:10][CH:11]=3)[CH2:4][C:3]([C:2]([F:25])([F:1])[C:21]([F:24])([F:23])[F:22])=[N:34]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CSc1ccc(-c2cccc(C=CC(=O)C(F)(F)C(F)(F)F)c2)cc1
Reactant: NNC1CCCCC1
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: CSc1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3C3CCCCC3)c2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 4 %

Procedure:
4,4,5,5,5-Pentafluoro-1-(4′-methylsulfanyl-biphenyl-3-yl)-pent-1-en-3-one (200.0 mg, 0.54 mmol) prepared in Step 3 of Preparation 4, cyclohexylhydrazine hydrochloride (98.0 mg, 0.59 mmol), and piperidine (107.0 uL, 1.08 mmol) were added to ethanol (5.0 mL). The reaction mixture was stirred at 100° C. for 18 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with distilled water, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/60) to give 10.0 mg of the titled compound as a yellow liquid.