Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:32][CH2:33][CH3:34])[C:5]#[C:6][C:7](=[N:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8](F)(F)[F:9])[CH3:2].[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][NH2:43])=[C:38]([F:44])[C:37]=1[O:45][CH3:46].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCCC1>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:8]([F:9])=[C:7]([NH:12][C:13]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=[C:5]([CH:4]([O:3][CH2:1][CH3:2])[O:32][CH2:33][CH3:34])[N:43]=2)=[C:38]([F:44])[C:37]=1[O:45][CH3:46]
Reactant: CCOC(C#CC(=NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F)OCC
Reactant: COc1c(Cl)ccc(CN)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(-c2ccc(Cl)c(OC)c2F)n1
Temperature: 80 °C

Procedure:
In a typical reaction, N-(5,5-diethoxy-1,1,1-trifluoropent-3-yn-2-ylidene)-1,1,1-triphenylmethanamine is mixed with about a 2.5 to 3 fold excess of (4-chloro-2-fluoro-3-methoxyphenyl)methyl amine and about a 2.5 to 3 fold excess of cesium carbonate in anhydrous terahydrofuran. The mixture is heated at about 80° C. until the reaction is complete. After cooling, an extraction solvent like a halogenated hydrocarbon is added to the mixture along with water. The organic layer is recovered, washed with brine and dried. The solvent is evaporated to provide crude 2-(4-chloro-2-fluoro-3-methoxyphenyl)-6-(diethoxymethyl)-3-fluoro-N-tritylpyridin-4-amine.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][O:24][CH2:25][CH3:26])[N:14]([CH2:15][C:16]([NH:19][C:20](=[O:22])[CH3:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])=[CH:5][C:4]=2[N:3]=1.[C:35](Cl)(=[O:37])[CH3:36].CS(OS(C)(=O)=O)(=O)=O>>[C:35]([NH:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][O:27][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:14]([CH2:15][C:16]([NH:19][C:20](=[O:22])[CH3:21])([CH3:18])[CH3:17])[C:13]([CH2:23][O:24][CH2:25][CH3:26])=[N:12][C:11]=3[C:2]([NH2:1])=[N:3][C:4]=2[CH:5]=1)(=[O:37])[CH3:36]
Reactant: CCOCc1nc2c(N)nc3cc(OCCCCCCN)ccc3c2n1CC(C)(C)NC(C)=O
Reactant: CC(=O)Cl
Agent: CS(=O)(=O)OS(C)(=O)=O
Product: CCOCc1nc2c(N)nc3cc(OCCCCCCNC(C)=O)ccc3c2n1CC(C)(C)NC(C)=O
Yield: 36.7 %

Procedure:
A modification of the method described in Part K of Example 45 was followed using N-{2-[4-amino-7-(6-aminohexyloxy)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}acetamide (1.2 g, 2.5 mmol) as the starting material and acetyl chloride (200 μL, 3 mmol) in lieu of methanesulfonic anhydride. Following chromatographic purification, the solid was recrystallized from acetonitrile, and the crystals were dissolved in dichloromethane:methanol, concentrated under reduced pressure, and further dried under high vacuum at 60° C. to provide 0.47 g of N-(2-{7-[6-(acetylamino)hexyloxy]-4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl}-1,1-dimethylethyl)acetamide as a white powder, mp 190-192° C.
Reaction SMILES: [C:1]([O:9][CH:10]([CH3:33])[CH2:11][CH:12]([CH2:15][S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:13][OH:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C.N(CC(NC(OC)=O)CSCCCCCCCCCCCCCCCC)=[N+]=[N-]>ClCCl>[CH3:34][S:35]([O:14][CH2:13][CH:12]([CH2:11][CH:10]([O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:33])[CH2:15][S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:37])=[O:36]
Reactant: CCCCCCCCCCCCCCCCSCC(CO)CC(C)OC(=O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CCCCCCCCCCCCCCCCSCC(CN=[N+]=[N-])NC(=O)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCSCC(COS(C)(=O)=O)CC(C)OC(=O)c1ccccc1

Procedure:
A mixture of 1.268 g (2.65 mM) of 2-(2-benzoyloxypropan-1-yl)-3-n-hexadecylthiopropanol m12, 0.270 ml (3.45 mM) of methanesulfonyl chloride and 0.56 ml (3.98 mM) of triethylamine in 30 ml of dichloromethane is allowed to react by the same procedure as described in (52) and the crude product of the titled compound m12a is obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[S:40]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:22][CH2:23][N:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:25][CH2:26]2)[CH:6]=[CH:7][CH:8]=1)(=[O:42])=[O:41]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN)c4)cc23)CC1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5cc(Cl)ccc5Cl)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 10.6 %

Procedure:
To a solution of 5-[3-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (40 mg, 0.096 mmol) in DMF (1.0 mL) and DCM (1.0 mL) was added 2,5-dichlorobenzenesulfonyl chloride (86 mg, 0.352 mmol) and DIEA (62 μL, 0.352 mmol). Reaction was stirred at room temperature for 6 h. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 6.6 mg the title compound (11%). LC/MS=m/z 649.2 [M+H] Ret. Time: 2.25 min
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[NH:3]1.C[O:9][C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=O>>[CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH3:7])[N:3]1[C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=[O:9]
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: CC1CCC(C)N1
Product: CC1CCC(C)N1C(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 10 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 2,5-dimethylpyrrolidine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (10%) as amorphous yellow solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]=[C:12]1[CH2:18][CH:17]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:16]2[CH:28]=[C:29]([C:32]([O:34][CH3:35])=[O:33])[CH:30]=[CH:31][C:15]=2[O:14][CH2:13]1.[CH2:36](Br)[CH3:37].Cl>O1CCCC1.ClCCl.O>[CH2:36]([C:17]1([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:16]2[CH:28]=[C:29]([C:32]([O:34][CH3:35])=[O:33])[CH:30]=[CH:31][C:15]=2[O:14][CH2:13][C:12](=[CH2:11])[CH2:18]1)[CH3:37]
Reactant: C=C1COc2ccc(C(=O)OC)cc2C(S(=O)(=O)c2ccccc2)C1
Reactant: CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C1COc2ccc(C(=O)OC)cc2C(CC)(S(=O)(=O)c2ccccc2)C1
Reaction time: 0.25 h
Yield: 58 %

Procedure:
0.030 ml (1.1 equivalents) of 1,3-dimethylpropyleneurea and then 0.246 ml (1.1 equivalents) of 1.06M lithium bis(trimethylsilyl)amide in tetrahydrofuran are added at ambient temperature to 80 mg (0.22 mmol) of methyl 3-methylene-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate, prepared according to example 1, in solution in 2.2 ml of tetrahydrofuran. The reaction medium then assumes a dark yellow color. After stirring for 15 minutes, 0.0185 ml (1.1 equivalents) of ethyl bromide is added. After stirring for 5 minutes, water, 1N hydrochloric acid and dichloromethane are added. After separating the organic and aqueous phases, the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed with brine, are dried and are finally concentrated under vacuum. The crude reaction product is then purified by chromatography on silica gel (ethyl acetate/heptane 25/75) to give 56 mg (58%) of methyl 5-ethyl-3-methylene-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate in the form of an oil; 1H NMR (300 MHz, CDCl3): 0.97 (t, J=7.3 Hz, 3H), 2.41 (q, J=7.3 Hz, 2H), 3.83 (s, 3H), 4.28 (d, J=14.7 Hz, 1H), 4.58 (d, J=14.7 Hz, 1H), 4.86 (s, 1H), 5.02 (s, 1H), 6.82 (d, J=8.5 Hz, 1H), 7.35 (m, 5H), 7.85 (dd, J=8.46 and 2 Hz, 1H), 8.08 (d, J=2.07 Hz, 1H).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[CH3:21][N:22]([CH3:25])C=O>C(O)C.C1C2C(=CC=CC=2)CCN1>[CH2:21]1[C:9]2[C:8](=[CH:7][CH:6]=[CH:11][CH:10]=2)[CH2:12][CH2:25][N:22]1[CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:7]=1
Reactant: CN(C)C=O
Reactant: c1cc(OC[C@H]2CO2)cc(-c2noc3ncccc23)c1
Agent: c1ccc2c(c1)CCNC2
Solvent: CCO
Product: O[C@@H](COc1cccc(-c2noc3ncccc23)c1)CN1CCc2ccccc2C1

Procedure:
The title compound is prepared from a mixture of (R)-3-(3-oxiranylmethoxy-phenyl)-isoxazolo[5,4-b]pyridine in dimethylformamide and ethanol and 1,2,3,4-tetrahydroisoquinoline in ethanol essentially as described above in Example 102. Purity by LC/MS=100%, [M+H]+=402.
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.[CH3:15][C:16]1[CH:34]=[CH:33][CH:32]=[CH:31][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[C:23]([Cl:30])[CH:22]=1)=[O:19].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>ClCCl>[N:1]1[N:10]2[C:4]([CH2:5][N:6]([C:25]([C:24]3[CH:28]=[CH:29][C:21]([NH:20][C:18](=[O:19])[C:17]4[CH:31]=[CH:32][CH:33]=[CH:34][C:16]=4[CH3:15])=[CH:22][C:23]=3[Cl:30])=[O:26])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)c(Cl)c1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C

Procedure:
As described for Example 518, a mixture of 0.185 g of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine, 0.369 g of 4-[(2-methylbenzoyl)amino]2-chlorobenzoyl chloride and 0.158 g of diisopropylethylamine in 10 ml of dichloromethane is stirred at room temperature to give crystals (from ethyl acetate) m.p. 241-244 C.
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[C:12](OC(=O)C)(=[O:14])[CH3:13].O>C(O)(=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:12](=[O:14])[CH3:13])=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(CC(C)C)cc1
Yield: 67.2 %

Procedure:
70.0 g (0.47 mol) of p-isobutylaniline was dissolved in 126 ml of glacial acetic acid. 59.9 g (0.58 mol) of acetic anhydride was then added dropwise to the solution at a temperature of 30° C. After the completion of dropwise addition, the reaction mixture was then allowed to undergo reaction at a temperature of 40° C. for 1 hour. The reaction solution was then poured into 500 ml of water. The resulting crystal was filtered off, washed with water, and then dried. The crystal thus obtained was then recrystallized from a mixture of 140 ml of toluene and 700 ml of n-hexane to obtain 60.4 g (yield: 67.3%) of p-isobutylacetanilide. The melting point of the crystal was from 124.5° C. to 125.0° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:15])[CH:3]=1.[CH2:16]([O:18][CH2:19][C@@H:20]([C:22]1[N:27]=[C:26]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH:25]=[CH:24][CH:23]=1)O)[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([C:26]2[N:27]=[C:22]([C@H:20]([O:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:15])[CH:3]=3)[CH2:19][O:18][CH2:16][CH3:17])[CH:23]=[CH:24][CH:25]=2)=[CH:29][CH:30]=1)#[N:33]
Reactant: CCOC[C@H](O)c1cccc(-c2ccc(C#N)cc2)n1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC[C@@H](Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C#N)cc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A stirred mixture of ethyl [(4-hydroxy-2-methylphenyl)oxy]acetate (664 mg, 3.16 mmol), 4-{6-[(1R)-2-(ethyloxy)-1-hydroxyethyl]-2-pyridinyl}benzonitrile (719 mg, 2.68 mmol) and triphenylphosphine (857 mg, 3.27 mmol) in dry DCM (35 mL) was cooled to 0° C. under nitrogen. DIAD (633 μL, 3.21 mmol) was added dropwise over 10 min, and the reaction mixture stirred at 0° C. for a further 2 h. DCM (120 mL) was added to the reaction mixture, washed with aq 1M NaOH (50 mL) and water (100 mL), dried (Na2SO4) and evaporated to give a yellow oil. Purification by Biotage™ chromatography (silica, 90 g cartridge) eluting with cyclohexane:EtOAc (8:1) afforded the title compound as a colourless oil (765 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.N#N.[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(F)c([N+](=O)[O-])c2)cn1
Temperature: 90 °C
Yield: 79 %

Procedure:
A solution of 4-bromo-1-fluoro-2-nitrobenzene (2 g, 9.095 mmol) in 1,4-dioxane (20 ml) was degassed by N2 bubbling for 5 min. 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.27 g, 10.91 mmol, 1.2 eq.) and aqueous sodium carbonate (2.89 g, 27.27 mmol, 3.0 eq.) were added and the mixture was degassed for another 15 min. Pd(PPh3)2Cl2 (0.638 g, 0.909 mmol, 0.1 eq.) was added sequentially and the mixture was further degassed for 15 min and then heated at 90° C. for 2 h. The mixture was quenched and extracted as in Intermediate Example 5(c). The solvent was distilled off to afford the crude residue which was purified by column chromatography (60-120 silica gel, 40-50% ethyl acetate in hexane) to yield the product in 79% yield (1.6 g). 1H NMR (300 MHz, DMSO-d6): δ 8.32-8.26 (m, 2H), 8.0-7.97 (m, 2H), 7.62-7.55 (m, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:36]([O:35][C:33](=[O:34])[NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Product: CCOC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-Cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A157) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C[Si]([C:14]#[CH:15])(C)C.[F-].[K+].C(Cl)Cl>CCN(CC)CC.O1CCOCC1.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.[Cu]I>[C:14]([C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9])#[CH:15]
Reactant: Cc1ccc(O)c(Br)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [F-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C#Cc1cc(C)ccc1O
Reaction time: 8 h

Procedure:
A flask is flushed with N2 and charged with 2-Bromo-4-methylphenol (20 mmol) and dissolved in 1/1 Et3N/dioxane. Bis(triphenylphosphine)palladium(II) dichloride (PdCl2(PPh3)2) (0.2 mmol) is added, followed by 0.4 mmol of CuI. Trimethylsilylacetylene (24 mmol) is added drop-wise to the reaction mixture. The reaction mixture is stirred overnight under N2. The solvents are removed under vacuum and the resulting liquid is extracted by washing with ethyl ether. The ethyl ether extracts are combined and washed with H2O, then dried over anhydrous sodium sulfate. The solvent was removed under vacuum and the product is purified by column chromatography. The purified product is placed in a N2-flushed flask and dissolved in methanol. Potassium fluoride (65 mmol) is added and the reaction stirred under a N2 blanket for 16 h. The reaction mixture is poured into CH2Cl2 and extracted with H2O, then dried over Na2SO4, filtered and the solvent is removed under vacuum. The resulting product is purified by column chromatography to yield 2-ethynyl-4-methyl-phenol (3).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])[CH:24]=[CH:25][C:26]=1[CH3:27]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:23]3[CH:24]=[CH:25][C:26]([CH3:27])=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: COc1cc(-c2ocnc2C(=O)O)ccc1C
Product: COc1cc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)n2)ccc1C

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-methoxy-4-methyl-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:8][C:7]2[CH2:9][CH2:10][C:11]3[CH2:12][CH:13]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:15][C:16]=3[C:6]=2[CH:5]=1.[C:21]1([C:27]2[C:31]3[CH:32]=[CH:33][C:34](O)=[C:35]([CH2:36][CH2:37][CH3:38])[C:30]=3[O:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([C:27]2[C:31]3[CH:32]=[CH:33][C:34]([O:1][CH2:2][CH2:3][C:4]4[O:8][C:7]5[CH2:9][CH2:10][C:11]6[CH2:12][CH:13]([C:17]([OH:19])=[O:18])[CH:14]=[CH:15][C:16]=6[C:6]=5[CH:5]=4)=[C:35]([CH2:36][CH2:37][CH3:38])[C:30]=3[O:29][N:28]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCCc1c(O)ccc2c(-c3ccccc3)noc12
Reactant: COC(=O)C1C=CC2=C(CCc3oc(CCO)cc32)C1
Product: CCCc1c(OCCc2cc3c(o2)CCC2=C3C=CC(C(=O)O)C2)ccc2c(-c3ccccc3)noc12

Procedure:
Using the procedure from Example 1, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)-4,5,6,7-tetrahydronaphtho[2,1-b]furan-7-carboxylate and 3-phenyl-7-propyl-6-hydroxybenz[4,5]isoxazole as a colorless oil.
Reaction SMILES: [CH3:1][P:2]([C:7]1[CH:12]=[C:11](Cl)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])(=[O:6])[O:3][CH2:4]C.[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+].Cl>C(O)C.O>[CH3:1][P:2]([C:7]1[CH:12]=[C:11]([S:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])(=[O:6])[O:3][CH3:4]
Reactant: Sc1ccccc1
Reactant: CCOP(C)(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COP(C)(=O)c1cc(Sc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
To a mixture of ethyl P-methyl-2-nitro-5-chlorophenylphosphinate (20.0 mmol) and thiophenol (40.0 mmol) in 20 ml of ethanol is added sodium hydroxide (60.0 mmol) in 1 ml of water. The mixture is heated under reflux for 24 hours. The reaction mixture is poured into water, acidified with dilute HCl and extracted with methylene chloride (2X). The combined extracts are washed with brine, dried and evaporated to dryness. The resulting oily residue is treated with diazomethane in methanol, concentrated and purified by preparative TLC to yield methyl P-methyl-2-nitro-5-phenylthiophenylphosphinate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][CH:14]1[CH2:16][CH:15]1[CH2:17][CH2:18][CH3:19].C(O)(=O)C>[Fe].O>[CH3:11][C:5]1[CH:4]=[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH:15]2[CH2:17][CH2:18][CH3:19])[C:2]([CH3:1])=[CH:7][C:6]=1[NH2:8]
Reactant: CCCC1CC1COc1cc(C)c([N+](=O)[O-])cc1C
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CCCC1CC1COc1cc(C)c(N)cc1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
A mixture of 1.58 g of 2,5-dimethyl-4-nitro-1-[(2-propylcyclopropyl)methoxy]benzene, 1.68 g of iron powder, 20 mL of acetic acid and 20 mL of water was stirred at 80° C. for 1 hour. The reaction mixture was cooled to around room temperature, and then concentrated under reduced pressure. The resulting residue was converted into basic with an aqueous 1 N sodium hydroxide solution, then ethyl acetate was added, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water, and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.90 g of 2,5-dimethyl-4-[(2-propylcyclopropyl)methoxy]phenylamine.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(NCc2ccc(Br)cc2)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
The mixture of methyl 4-fluoro-3-nitrobenzoate (2 g, 10.1 mmol), (4-bromophenyl)methanamine (1.87 g, 10.1 mmol) and K2CO3 (2.77 g, 10.1 mmol) in TI-IF (40 mL) was stirred at 40° C. for 2 hrs, then the mixture was filtered and the filtrate was concentrated to get a yellow solid which was washed by MTBE and EtOAc (10/1,100 mL) to give the titled compound.