Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:7]=1.[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>[Cl-].[Na+].O.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:6]1[CH:7]=[C:2]([C:31]2[CH:32]=[N:27][CH:28]=[N:29][CH:30]=2)[CH:3]=[CH:4][C:5]=1[F:26])[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1cc(C2(c3cc(Br)ccc3F)N=C(N)c3c(F)cccc32)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C2(c3cc(-c4cncnc4)ccc3F)N=C(N)c3c(F)cccc32)ccn1
Temperature: 150 °C
Yield: 43.3 %

Procedure:
1-(5-Bromo-2-fluorophenyl)-4-fluoro-1-(2-methylpyridin-4-yl)-1H-isoindol-3-amine (80 mg, 0.19 mmol), 5-pyrimidinylboronic acid (31.1 mg, 0.25 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.77 mg, 0.02 mmol), potassium carbonate (2.5 M, aq, 0.290 mL, 0.58 mmol) and DMF (2 mL) were added to a vial and heated in a microwave reactor at 150° C. for 15 min. Brine was added and the product mixture was extracted EtOAc. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification by preparative HPLC afforded 34.0 mg (43% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[N:15]1[C:19]([NH:20][C:21]([CH2:23][O:24][C:25]([CH3:27])=[O:26])=[O:22])=[CH:18][CH:17]=[N:16]1.[N+:28]([O-])([OH:30])=[O:29].C(OC(=O)C)(=O)C>C(O)(=O)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:11])([F:10])[F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[N:15]1[C:19]([NH:20][C:21]([CH2:23][O:24][C:25]([CH3:27])=[O:26])=[O:22])=[C:18]([N+:28]([O-:30])=[O:29])[CH:17]=[N:16]1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OCC(=O)Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3.63 grams of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-5-methylcarbonyloxymethylcarbonylaminopyrazole, 0.5 mL of concentrated nitric acid, and 1.53 grams (0.0150 mole) of acetic anhydride in 9.4 mL of glacial acetic acid was stirred at room temperature for two hours. This mixture was poured into ice-water, forming a yellow solid. This solid was collected by filtration and was dried to yield 3.50 grams of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-5-methylcarbonyloxymethylcarbonylamino-4-nitropyrazole. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:24])=[C:19]([CH:23]=1)[C:20](Cl)=[O:21]>C(Cl)Cl>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:24])=[C:19]([C:20]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)=[O:21])[CH:23]=1
Reactant: CCOc1ccccc1
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Temperature: -2.5 °C
Reaction time: 1 h

Procedure:
At −5-0° C., ethoxybenzene (20.5 g) and AlCl3 (22.3 g) were added into a solution of 5-bromo-2-chlorobenzoyl chloride (from step 2) in dry DCM (200 mL). Then the mixture was stirred at −5-0° C. for 1 h. The mixture was poured into ice-H2O (200 mL) and extracted with DCM. The organic phase was washed with 1M HCl, H2O, IM NaOH and brine. And the organic phase was concentrated, and the crude was purified by silica-gel column chromatography (PE/EA=80/1-40/1), to obtain 30 g of (5-bromo-2-chloro phenyl)(4-ethoxyphenyl)methanone.
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:24][O:25][CH3:26])[C:12]([NH:14][CH:15]2[CH2:18][N:17]([S:19]([O-:22])(=[O:21])=[O:20])[C:16]2=[O:23])=[O:13])[N:10]=1)=O.[Na+:27].CNC(=S)[S-].[Na+]>O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:24][O:25][CH3:26])[C:12]([NH:14][CH:15]2[CH2:18][N:17]([S:19]([O-:22])(=[O:20])=[O:21])[C:16]2=[O:23])=[O:13])[N:10]=1.[Na+:27]
Reactant: CON=C(C(=O)NC1CN(S(=O)(=O)[O-])C1=O)c1csc(NC(=O)CCl)n1
Agent: CNC(=S)[S-]
Agent: [Na+]
Solvent: O
Product: CON=C(C(=O)NC1CN(S(=O)(=O)[O-])C1=O)c1csc(N)n1

Procedure:
The crude sodium 3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonate (syn-isomer) obtained above (0.556 g) is dissolved in 8 ml of water, and to the solution is added 0.172 g of sodium N-methyldithiocarbamate under ice-cooling and stirring. The mixture is stirred for 3 hours, after which any insoluble matter is filtered off. The filtrate is purified by XAD-II chromatography to yield 0.174 g of sodium 3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonate (syn-isomer).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].O[CH2:6][C@@:7]12[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C@@H:19]([O:25][C:26]3([O:32][CH3:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:18][CH2:17]4)[CH2:14][CH:13]=[C:12]1[CH2:11][C:10](=[O:34])[CH2:9][CH2:8]2.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1>[C:1]([O:4][CH2:6][C@@:7]12[C@@H:24]3[C@H:15]([C@H:16]4[C@@:20]([CH2:22][CH2:23]3)([CH3:21])[C@@H:19]([O:25][C:26]3([O:32][CH3:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[CH2:18][CH2:17]4)[CH2:14][CH:13]=[C:12]1[CH2:11][C@@H:10]([OH:34])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: COC1(O[C@H]2CC[C@H]3[C@@H]4CC=C5CC(=O)CC[C@]5(CO)[C@H]4CC[C@]23C)CCCCC1
Reactant: CC(=O)O
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: COC1(O[C@H]2CC[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(COC(C)=O)[C@H]4CC[C@]23C)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A tetrahydrofuran solution of 19-hydroxy-17β-(1'-methoxycyclohexyloxy)androst-5-en-3-one acetate is added under nitrogen to a solution of lithium tri-t-butoxyaluminum hydride in tetrahydrofuran. After stirring at room temperature overnight, an aqueous solution of potassium sodium tartrate is added with stirring to form a readily filterable white solid. The reaction mixture is filtered and the filtrate dried over magnesium sulfate and the solvent removed. The residue which remains is recrystallized from acetone to yield 17β-(1'-methoxycyclohexyloxy)-5-androstene-3β,19-diol 19-acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]([C:15]([O:17][CH3:18])=[O:16])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.CC(C)(C([O-])=O)C([O-])=O.[N+](C1C=CC(C=O)=CC=1)([O-])=O.C([BH3-])#N.[Na+].Cl>CO.O>[CH3:1][O:2][C:3](=[O:19])[CH:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1
Reactant: COC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)OC
Agent: CC(C)(C(=O)[O-])C(=O)[O-]
Agent: Cl
Agent: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: O
Product: COC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
2-Carbomethoxy-3-(4-nitrophenyl)propenoic acid methyl ester was made from the Knovenagle condensation of dimethylmalonate and p-nitrobenzaldehyde according to the method of J. Chem. Soc., 2125 (1927): Melting point observed (mpobs)=133-134° C. Melting point reported in the literature (mplit)=136-137° C. 2-Carbomethoxy-3-(4-nitrophenyl)propenoic acid methyl ester (23.0 grams (g), 86.7 millimoles (mmole)) was dissolved in 175 milliliters (mL) of methanol (MEOH) under nitrogen and sodium cyanoborohydride (6.0 g, 95.5 mmole) was cautiously added to the stirred solution with cooling. The pH was adjusted to 4.0 with concentrated hydrochloric acid and the solution was stirred at 25° C. overnight. During the first 8 hrs the pH was readjusted from 6 to 4 on several occasions. The yellow methanol solution was poured into 700 mL of water and extracted with 3×200 mL portions of methylene chloride. The combined organic fractions were washed with 400 mL of saturated sodium bicarbonate and 400 mL of water, dried over magnesium sulfate and evaporated to a pale yellow oil on a rotary evaporator. The oil crystallized (mp=82-83° C.) upon standing and gave 2-carbomethoxy-3-(4-nitrophenyl)propanoic acid methyl ester (p-nitrobenzyl malonate dimethyl ester) in 93 percent yield (21.3 g, 81 mmole).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([NH2:31])=[O:30])=[CH:15][CH:14]=2)=O)(C)(C)C.[ClH:37]>C(OCC)(=O)C>[ClH:37].[NH2:8][CH2:9][C:10]1[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:12](=[O:32])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([NH2:31])=[O:30])=[CH:15][CH:14]=2
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c3ccc(/C=C/C(N)=O)cc23)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2c(CN)n(CC(C)C)c(=O)c3ccc(/C=C/C(N)=O)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
(E)-3-[3-[[(Tert-butoxycarbonyl)amino]methyl-]-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide (0.15 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml) and the mixture was stirred at room temperature, for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate-diisopropyl ether to give (E)-3-[3-(aminomethyl)-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenamide hydrochloride (0.12 g, 92.3%) as crystals.
Reaction SMILES: [F:1][C:2]1([F:38])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[CH:25][CH:24]=5)[C:20]([CH2:36][CH3:37])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.FC(F)(F)C(O)=O>ClCCl>[F:38][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:35]=[CH:34][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=5)[C:20]([CH2:36][CH3:37])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: CCc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(C(=O)O)cc1
Reaction time: 3 h

Procedure:
Crude tert-butyl 4-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-3-ethylpyridin-2-yl)benzoate (from step a) was taken up in 1 mL of dichloromethane and 1 mL of trifluoroacetic acid (TFA) and allowed to stir for 3 hours. The crude product was then evaporated to dryness, re-dissolved in 1 mL of N,N-dimethylformamide and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% TFA to yield 4-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-3-ethylpyridin-2-yl)benzoic acid. ESI-MS m/z calc. 466.1, found 467.3 (M+1)+. Retention time 1.94 minutes.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]([F:17])([F:16])[F:15])[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][C:14]([F:15])([F:16])[F:17])[C:3]=1[C:18]([N:43]1[CH2:42][CH2:41][N:40]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[F:33])[CH2:45][CH2:44]1)=[O:20]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Nc1onc(-c2ccccc2OC(F)(F)F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccccc2OC(F)(F)F)c1C(=O)N1CCN(c2ccccc2F)CC1
Yield: 69.6 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (576 mg, 1.28 mmol, 70%) was obtained.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH3:11][S:12]([NH:15][C:16]1[C:28]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][C:19]2[C:20](=[O:26])[C:21]([NH:24][CH3:25])=[CH:22][O:23][C:18]=2[CH:17]=1)(=[O:14])=[O:13].C(OC(C)C)(C)C>C(Cl)Cl>[CH3:11][S:12]([NH:15][C:16]1[C:28]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][C:19]2[C:20](=[O:26])[C:21]([N:24]([CH:1]=[O:3])[CH3:25])=[CH:22][O:23][C:18]=2[CH:17]=1)(=[O:13])=[O:14]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O
Solvent: O=CO
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: CN(C=O)c1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O
Reaction time: 1.5 h
Yield: 76.6 %

Procedure:
340 mg of acetic anhydride and 310 mg of formic acid were mixed. The mixture was stirred for 1.5 hours at 40°-45° C. Thereto was added 10 ml of methylene chloride. There was further added 400 mg of 7-methylsulfonylamino-3-methylamino-6-phenoxy-4H-1-benzopyran-4-one. The resulting mixture was stirred for 1 hour at 25°-30° C. 10 ml of diisopropyl ether was added thereto. The resulting crystal was collected by filtration and then recrystallized from acetonitrile to obtain 330 mg (yield: 76.7%) of 7-methylsulfonylamino-3-(N-formyl-N-methylamino)-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[OH:5][CH:6]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:31][CH:32]([CH3:34])[CH3:33])[N:25]=3)[O:21][N:20]=2)=[CH:15][CH:14]=1)[CH2:7]OS(C)(=O)=O>O1CCOCC1>[OH:2][CH2:1][CH2:3][NH:4][CH2:7][CH:6]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:31][CH:32]([CH3:34])[CH3:33])[N:25]=3)[O:21][N:20]=2)=[CH:15][CH:14]=1)[OH:5]
Reactant: NCCO
Reactant: Cc1cc(-c2nc(-c3ccc(C(O)COS(C)(=O)=O)cc3)no2)nc(NC(C)C)n1
Solvent: C1COCCO1
Product: Cc1cc(-c2nc(-c3ccc(C(O)CNCCO)cc3)no2)nc(NC(C)C)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
Ethanolamine (3.0 mL, 49.85 mmol) is added to a solution of methanesulfonic acid 2-hydroxy-2-{4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethyl ester (152 mg, 0.35 mmol) in dioxane (2.0 mL). The reaction mixture is stirred at 80° C. for 18 h, is then evaporated and purified by prep. TLC (eluting with DCM/MeOH 10:1) to give 99 mg of the title compound as a yellow oil; LC-MS: tR=0.74 min; [M+H]+=399.07. 1H NMR (CDCl3) δ 1.29 (d, J=6.5 Hz, 6H), 2.48 (s, 3H), 2.84 (m, 3H), 2.97 (dd, J=12.3, 3.5 Hz, 1H), 3.73 (t, J=5.0 Hz, 1H), 4.31 (m, 1H), 4.85 (dd, J=8.8, 3.3 Hz, 1H), 5.30 (s br, 1H), 7.29 (s, 1H), 7.53 (d, J=8.3 Hz, 2H), 8.17 (d, J=8.0 Hz, 2H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:27]=1[CH:28]=[CH:29][C:30]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:31]
Reactant: O=C(O)C=Cc1c(F)cccc1F
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1c(F)cccc1F
Yield: 86.1 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 2,6-difluorocinnamic acid (2.6 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (3.9 g, 85%) as an oily product.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:18][C:19]([CH3:33])([CH3:32])[CH2:20][CH2:21][NH:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[SH:30].CCCCCC.CC(=O)OCC>CC(C)=O>[CH3:18][C:19]([CH3:33])([CH3:32])[CH2:20][CH2:21][NH:22][C:23]([C:24]1[C:25]([S:30][CH2:8][C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:31]
Reactant: O=C(CCl)Cc1ccccc1
Reactant: CC(C)(C)CCNC(=O)c1cccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CC(C)(C)CCNC(=O)c1cccnc1SCC(=O)Cc1ccccc1
Temperature: 50 °C
Yield: 55 %

Procedure:
840 mg (6.1 mmol) of K2CO3 and 340 mg (2.0 mmol) of 1-chloro-3-phenylpropan-2-one were added to a solution of 450 mg (2.0 mmol) of N-(3,3-dimethylbutyl)-2-mercapto-nicotinamide in acetone (10 ml), and the mixture was then heated for 1 h at 50° C. Dilution with water (20 ml) and extraction with EA (2×30 ml) were then carried out. The combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 4:1) of the residue yielded 420 mg (1.1 mmol, 56%) of N-(3,3-dimethyl-butyl)-2-[(2-oxo-3-phenyl-propyl)sulfanyl]-pyridine-3-carboxylic acid amide. MS: m/z 371.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.CCCCC.C([Li])(C)(C)C.[C:21]([O:29][CH2:30][CH2:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[O:37])=[CH:34][CH:33]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>C(OCC)C>[C:21]([O:29][CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH:36]([C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[O:4][CH2:3][O:2][CH3:1])[OH:37])=[CH:38][CH:39]=1)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COCOc1cccnc1
Reactant: O=Cc1ccc(CCOC(=O)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCC
Product: COCOc1cnccc1C(O)c1ccc(CCOC(=O)c2ccccc2)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
Next, to a mixture of 3-(methoxymethoxy)pyridine (2.4 g, 17.4 mmol) and diethyl ether (240 ml), a 1.47 mol/L t-butyllithium n-pentane solution (15 ml, 22.0 mmol) was added dropwise at −70° C. over 15 minutes. After stirring at −70° C. for 1 hour, a diethyl ether solution of 4-(2-benzoyloxyethyl)benzaldehyde (5.35 g, 21.0 mmol) was added over 10 minutes and stirred at −70° C. for 1.5 hours. After warming to room temperature, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:80) to give [4-(2-benzoyloxyethyl)phenyl]-[3-(methoxymethoxy)pyridin-4-yl]-methanol (2.2 g, 32%) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[C:16][C:17]2[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][N:20]=[C:19]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]4)=[CH:30][CH:29]=3)[N:18]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]>CCOC(C)=O.CCN(CC)CC.[Pd]>[CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][CH2:16][C:17]2[C:22]([C:23]([F:24])([F:26])[F:25])=[CH:21][N:20]=[C:19]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:45])([CH3:46])[CH3:44])=[O:41])[CH2:36][CH2:35]4)=[CH:30][CH:29]=3)[N:18]=2)[CH2:6][CH2:7][CH2:8]1)=[O:4]
Reactant: COC(=O)C1(c2ccccc2C#Cc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)CCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)CCC1
Reaction time: 8 h

Procedure:
Pd/C 10% (40 mg) was added to a solution of tert-butyl 4-(4-((4-((2-(1-(methoxycarbonyl)cyclobutyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate A54 (33 mg, 0.052 mmol) in EtOAc (10 mL) and Et3N (0.5 mL). The mixture was stirred under a hydrogen atmosphere overnight and then filtered through Celite. The filter cake was washed with EtOAc (50 mL) and the volatiles were removed in vacuo to give the title compound A55 as a yellow oil (31 mg, 93%). LCMS-A: rt 8.013 min; m/z 639.3 [M+H]+.
Reaction SMILES: [C:1](=[O:17])([O-])[O:2][CH2:3][CH:4](N1C(=O)CCC1=O)[Si:5]([CH3:8])([CH3:7])[CH3:6].[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][NH:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:24])([CH3:21])([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][N:28]([C:1]([O:2][CH2:3][CH2:4][Si:5]([CH3:6])([CH3:7])[CH3:8])=[O:17])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)CNCCNC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)C(COC(=O)[O-])N1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2,5-Dioxopyrrolidin-1-yl(2-(trimethylsilyl)ethyl) carbonate (5.44 g, 20.99 mmol) was added to a mixture of ethyl 2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)acetate (intermediate 126, 4.70 g, 19.08 mmol) and K2CO3 (5.80 g, 42.0 mmol) in DCM (60 ml) and water (30 ml) at room temperature. The reaction mixture was vigorously stirred for 20 h at room temperature, partitioned between saturated aqueous NaHCO3 solution and DCM, the mixture extracted with DCM (2×), the combined organic layers dried over Na2SO4 and evaporated to give the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 6.71 (d, br, 1H), 4.16-3.93 (m, 6H), 3.30-3.21 (m, 2H), 3.09-3.00 (m, 2H), 1.37 (s, 9H), 1.19 (t, 3H), 0.99-0.94 (m, 1H), 0.90-0.85 (m, 1H), 0.05 (s, 9H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][NH:8][C:9]([N:11]=[N:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[S:10])=[CH:3][CH:2]=1.NC(O[CH2:23][CH3:24])=O>C(OCC(C)C)(=O)C1C(=CC=CC=1)C(OCC(C)C)=O>[CH:16]1[CH:15]=[CH:14][C:13]([NH:12][NH:11][C:9]([N:8]=[N:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)=[S:10])=[CH:18][CH:17]=1.[C:24]1([N:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:11][C:9]([N:8]=[NH:7])=[S:10])[CH:23]=[CH:3][CH:2]=[CH:1][CH:6]=1
Reactant: CCOC(N)=O
Agent: CC(C)COC(=O)c1ccccc1C(=O)OCC(C)C
Agent: S=C(N=Nc1ccccc1)NNc1ccccc1
Product: N=NC(=S)NN(c1ccccc1)c1ccccc1

Procedure:
A solution of dithizone, (diphenylthiocarbazone, C6H5NHNHCSN.NC6H5) was prepared by dissolving 0.025 gr. dithizone in 50 ml of di-isobutyl phthalate. Washed urethane foam cubes (prepared or described above) were impregnated by placing 1.0g cubes and 3ml of dithizone solution in a plastic bag and kneading until a uniform color developed on the cube. Excess solution was removed by blotting with sheets of whatman filter paper to give a finished cube of bright green color.