Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([O:23]CC)=O)[N:9]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH2:35])[CH2:29][CH2:28]1>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([NH:35][CH2:34][CH2:33][N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)=[O:23])[N:9]=1
Reactant: CN1CCN(CCN)CC1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Solvent: CCO
Product: CN1CCN(CCNC(=O)Cn2nc(-c3ccccc3O)nc2-c2ccccc2O)CC1

Procedure:
3 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 2.5 g of 2-(4-methylpiperazin-1-yl)ethylamine are boiled under reflux for 20 h in 40 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is chromatographed on silica gel. After concentration and drying, 2-[3,5-bis(2-hydroxy-phenyl)-[1,2,4]triazol-1-yl]-N-[2-(4-methylpiperazin-1-yl)ethyl]acetamide is obtained as a colorless foam. Rfvalue: 0.17 (silica gel 60, methylene chloride/methanol=9/1). 1H-NMR (DMSO-d6): 2.1 (s, 3H), 2.3 (m, 10H), 3.15 (m, 2H), 4.9 (s, 2H), 7.0 (m, 4H), 7.4 (m, 3H), 8.0(m, 2H), 11.0 ppm (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1.Br[CH:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:10]([O:11][CH:31]([C:32]([O:34][CH3:35])=[O:33])[CH3:36])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)C(C)Br
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ncccc3O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)Oc1cccnc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
200 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxypyridine and 80 mg of methyl 2-bromopropionate were dissolved in acetonitrile, to this was added 66 mg of potassium carbonate, and the mixture was stirred for 2 hours at 60° C. This reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 77 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-{1-(methoxycarbonyl)ethoxy}pyridine [present compound 2-2].
Reaction SMILES: C(C[O:4][C:5](=O)[CH:6]=[CH:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[CH:12]=1)#N.CO.O.[NH2:21][NH2:22]>O>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[CH:12]=[C:8]1[CH:7]=[CH:6][C:5]([NH:21][NH2:22])=[O:4]
Reactant: NN
Reactant: N#CCOC(=O)C=Cc1cc2ccccc2o1
Solvent: O
Solvent: CO
Product: NNC(=O)C=Cc1cc2ccccc2o1
Yield: 90.1 %

Procedure:
187 g of the β-(2-benzofuryl)acrylic acid cyanomethyl ester were added to 2 liters of methanol, and to the mixture, with stirring, were added 76.8 g of hydrazine hydrate, and then the resulting mixture was refluxed by heating for 30 minutes. After the reaction, 2 liters of water were added to cool the reaction product, and the deposited crystals were filtered by a suction filter, then washed, and then recrystallized from methanol, thereby obtaining 150 g of β-(2-benzofuryl)acrylic acid hydrazide having a melting point between 173° C. and 174° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:14]([S:17](Cl)(=[O:19])=[O:18])[CH2:15][CH3:16]>>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:17]([CH2:14][CH2:15][CH3:16])(=[O:19])=[O:18])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 41, step 41.1, 1-Boc-piperazine replacing piperazine-1-carboxylic acid benzyl ester and 1-propanesulfonyl chloride replacing benzoyl chloride.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:21]3[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=3[Cl:19])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(F)cc1Cl
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccc(F)cc3Cl)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-4-fluoro-phenyl)-acrylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[C:11]([OH:13])=O.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>CN(C)C=O.O>[C:15]1(=[O:24])[N:14]([CH:10]2[CH2:9][CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:11]2=[O:13])[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]12
Reactant: Nc1ccccc1CCC(C(=O)O)N1C(=O)c2ccccc2C1=O
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccccc2CCC1N1C(=O)c2ccccc2C1=O
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
In 80 ml of N,N-dimethylformamide is dissolved 10 g of 4-(2-aminophenyl)-2-phthalimidobutyric acid, and 6.7 g of diethyl phosphorocyanidate is added dropwise to the solution under ice-cooling with stirring. After the addition is complete, stirring is continued for 15 minutes, and 3.1 g of triethylamine is added dropwise to the mixture under ice cooling, followed by stirring under ice-cooling for 45 minutes and then at room temperature for 30 minutes. The reaction solution is diluted with 200 ml of water, followed by stirring for 1 hour, and the crystals, which separate out, are collected by filtration, dried and added to 100 ml of ethanol, followed by heating. After the solution is concentrated to about half of the original volume, the colorless prisms which separate out are collected by filtration to give 8.3 g of 3-phthalimido-1,3,4,5-tetrahydro-1-benzazepin-2-one. m.p. 261°-263° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[CH:20][C:21]([C:23]3[S:24][C:25]([N:33]([CH3:43])[CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[C:26]([C:28]([O:30]CC)=[O:29])[N:27]=3)=[CH:22][C:14]1=2)=[O:12].[OH-].[K+].CO>O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[CH:20][C:21]([C:23]3[S:24][C:25]([N:33]([CH3:43])[CH2:34][CH2:35][O:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=3)=[CH:22][C:14]1=2)=[O:12]
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCO3)sc1N(C)CCOc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(CCOc1ccccc1)c1sc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCO3)nc1C(=O)O
Temperature: 55 °C
Reaction time: 24 h
Yield: 7.5 %

Procedure:
The title compound 2-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(methyl(2-phenoxyethyl)amino)thiazole-4-carboxylic acid (20) was prepared by the following procedure: To ethyl 2-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(methyl(2-phenoxyethyl)amino)thiazole-4-carboxylate (20C) (0.210 g, 0.34 mmol) and KOH (0.1 g, 1.8 mmol) was added MeOH (2 mL) and water (5 mL). The reaction mixture was allowed to heat to 55° C. and stirred 24 hours. The reaction was monitored by LCMS. To the reaction mixture was added (0.1 g, 1.8 mmol). The reaction mixture was allowed to heat to 55° C. and stirred for 24 hours. The reaction mixture was cooled to rt and concentrated under reduced pressure. To the crude residue was added EtOAc and water. The layers were separated and extracted with EtOAc and the combined organic extracts were washed sequentially with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC to provide 0.015 g (8%) of the desired product 2-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(methyl(2-phenoxyethyl)amino)thiazole-4-carboxylic acid (20): LC/MS (APCI): m/z 588.1 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[NH:10][C@@H:11]([C:13]#[N:14])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][OH:18].C(N(CC)CC)C>C(O)C>[CH2:1]([O:8][C:9](=[O:15])[NH:10][C@H:11]([CH3:12])/[C:13](/[NH2:14])=[N:17]/[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](C#N)NC(=O)OCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@@H](NC(=O)OCc1ccccc1)/C(N)=N/O
Temperature: 75 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a solution of benzyl[(1R)-1-cyanoethyl]carbamate (2.52 g, 12.3 mmol) in ethanol (30 ml) was added hydroxylamine hydrochloride salt (0.90 g, 13.0 mmol) and triethylamine (3.43 ml, 24.6 mmol) and the mixture heated to 75° C. After 16 h, the solution was concentrated and the residue was dissolved in 200 mL of dichloromethane. The mixture was washed with 100 ink, of saturated aquous sodium bicarbonate (2×) and saturated aqueous sodium chloride (100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give benzyl[(1R,2Z)-2-amino-2-(hydroxyimino)-1-methylethyl]carbamate (2.9 g). MS 238.2 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]([C@H:9]1[C:31](=[O:32])[N:11]2[CH:12]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])[C:13]([OH:17])([CH3:16])[CH2:14][S:15][C@H:10]12)=[N+:7]=[N-:8].CCN(CC)CC>C(Cl)Cl>[N:6]([C@H:9]1[C:31](=[O:32])[N:11]2[CH:12]([C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=3)=[O:19])[C:13]([O:17][S:2]([CH3:1])(=[O:4])=[O:3])([CH3:16])[CH2:14][S:15][C@H:10]12)=[N+:7]=[N-:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(O)CS[C@@H]2[C@@H](N=[N+]=[N-])C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(OS(C)(=O)=O)CS[C@@H]2[C@@H](N=[N+]=[N-])C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 97.3 %

Procedure:
A solution of CH3SO2Cl (34 μl, 0.44 mMol) in anhydrous CH2Cl2 (0.5 ml.) is added dropwise over 4 min. to an ice-cold, stirring solution of p-nitrobenzyl 7α-azido-3-hydroxy-3-methyl-cepham-4-carboxylate (135 mg., 0.34 mMol) and Et3N (71 μl, 0.51 mMol) in anhydrous CH2Cl2 (2 ml.). After stirring 15 more min. in the cold, the reaction mixture is diluted with cold CH2Cl2 (2 ml.), washed with ice-cold H2O (2 ml.), ice-cold 5% HCl (2 ml.), and ice-cold 5% NaHCO3 (2 ml.), dried over MgSO4, and filtered. Evaporation of the solvent in vacuo gives p-nitrobenzyl 7α-azido-3-methanesulfonyloxy-3-methyl-cepham-4-carboxylate (156 mg.) as a pale yellow oil: ir (CHCl3) 4.76, 5.62, 5.75, 6.57, 7.40, 8.47, and 11.1μ; nmr (CDCl3) δ2.10 (s, 3, CH3), 2.93 (s, 3, SO2CH3), 3.02 (d, l, J=14Hz, SCH), 3.87 (d, l, J=14Hz, SCH), 4.53 (d, l, J=1.2Hz, H7), 4.80 (s, l, H4), 4.97 (d, l, J=1.2Hz, H6), 5.35 (s, 2, CH2Ar), and 7.60, 8.28 (two d's 4, J=8.7Hz, ArH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[N:15]#[C:16]Br>C(O)C>[CH3:13][C:5]1([CH3:14])[C:4]2[C:8](=[CH:9][C:10]3[NH:11][C:16]([NH2:15])=[N:1][C:2]=3[CH:3]=2)[NH:7][C:6]1=[O:12]
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Reactant: N#CBr
Solvent: CCO
Product: CC1(C)C(=O)Nc2cc3[nH]c(N)nc3cc21

Procedure:
3.00 g. (0.016 mole) 5,6-diamino-3,3-dimethylindolin-2-one are suspended in 100 ml. ethanol and mixed at ambient temperature with 1.82 g. (0.017 mole) cyanogen bromide and stirred for 2 hours. The solvent is removed in a vacuum and the residue is dissolved in ethanol, treated with active charcoal and the product precipitated out by the addition of acetone. The product is crystallised from acetone and a little ethanol to give 1.05 g. (22% of theory) of the title compound in the form of the hydrobromide; m.p. 300°-305° C.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[C:25]([Cl:26])=[C:24]([CH3:27])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: NCCc1ccccc1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3cccnc3)nc(NCCc3ccccc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-3-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-phenethylamino-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][N:13]1CCCC1=O.CN>O>[CH3:12][NH:13][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1
Reactant: CN1CCCC1=O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: CN
Solvent: O
Product: CNc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 18.2 of 2-chloro-5-trifluoromethylpyridine and 100 ml of N-methylpyrrolidone was added 23.3 g of a 40% methylamine aqueous solution, and the mixture was stirred for 3 hours at room temperature. Water was poured, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 17.3 g of N-methyl-(5-trifluoromethylpyridine-2-yl)-amine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:8][CH2:9][CH2:10][O:11][C:12]([F:15])([F:14])[F:13])=[CH:6][CH:7]=1.[C:17]([CH2:21][C:22](Cl)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][O:11][C:12]([F:13])([F:15])[F:14])=[C:4]([NH:16][C:22](=[O:23])[CH2:21][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1
Reactant: Nc1cc(Br)ccc1NCCOC(F)(F)F
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)CC(=O)Nc1cc(Br)ccc1NCCOC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of 4-bromo-N1-[2-(trifluoromethoxy)ethyl]benzene-1,2-diamine (step B, 752 mg, 2.51 mmol) in ethyl acetate (22 mL) was added tert-butylacetyl chloride (355 mg, 2.64 mmol) at room temperature. After stirring for 2 h at room temperature, the mixture was diluted with ethyl acetate. The organic solution was washed with saturated sodium hydrogencarbonate aqueous solution, brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1 as eluent) to afford the title compound (728 mg, 73%) as a white solid.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[I:12]I.CCCCCC.CCOCC>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[I:12][C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:10])[Cl:11])[NH:6][CH:7]=1
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(c1cc(I)c[nH]1)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
The title compound was prepared from 2-(trichloroacetyl)pyrrole according to the method of Bélanger, Tetrahedron Lett., 1979, 2505. Thus, iodine (12.0 g, 47.2 mmol) was added portionwise (approximately 1 g per portion) over 0.17 h to a magnetically stirred mixture of silver trifluoroacetate (11.0 g, 49.8 mmol) and 2-(trichloroacetyl)pyrrole (10.0 g, 47.1 mmol) in dry chloroform (70 ml) maintained at 0° C. (ice-bath). After addition was complete the reaction mixture was allowed to warm to 18° C. and stirred at this temperature for a further 2 h. The resultant suspension was filtered through a sintered glass funnel (No. 3 porosity) and the filtrate washed with Na2S2O5 (1×80 ml of 5% w/v aqueous solution) and water (2×80 ml) then dried (MgSO4), filtered and concentrated under reduced pressure. The solid residue thus obtained was treated with hexane/ether (50 ml of a 4:1 v/v mixture) and the resulting suspension stirred at 18° C. for 5 h then the solid was filtered off to give the title compound (13.1 g, 82%) as a cream solid, m.p. 129-130° C. (lit. m.p. 128-130° C.). 1H n.m.r. d 9.45, broad s, 1H; 7.44, dd, J 2.6 and 1.3 Hz, 1H; 7.19, dd, J 2.6 and 1.3 Hz, 1H.
Reaction SMILES: C(Cl)(=O)C.C([O:8][CH:9]([CH2:22][Cl:23])[C:10]1[CH:15]=[C:14]([S:16](=[O:19])(=[O:18])[NH2:17])[CH:13]=[CH:12][C:11]=1[O:20][CH3:21])(=O)C>CO>[Cl:23][CH2:22][CH:9]([C:10]1[CH:15]=[C:14]([S:16](=[O:19])(=[O:18])[NH2:17])[CH:13]=[CH:12][C:11]=1[O:20][CH3:21])[OH:8]
Reactant: COc1ccc(S(N)(=O)=O)cc1C(CCl)OC(C)=O
Solvent: CO
Solvent: CC(=O)Cl
Product: COc1ccc(S(N)(=O)=O)cc1C(O)CCl
Reaction time: 0.25 h
Yield: 87.7 %

Procedure:
61 μl of acetyl chloride are added to 100 ml of methanol and the mixture is stirred for 15 minutes. 1.32 g (−)-α-chloromethyl-2-methoxy-5-sulphamoylbenzyl acetate are then added and the mixture is heated to reflux for 1 hour (degree of conversion of 97% shown by HPLC). The mixture is thereafter evaporated, the residue is then taken up in 100 ml of ethyl acetate and the medium is neutralized with 5 ml of 2% ethyl hydrogen carbonate. The carbonate phase is extracted with 2 times 5 ml of ethyl acetate, the organic phases are then combined, dried and concentrated to 30 ml and cyclohexane is added. After one night at room temperature, the product which has crystallized is filtered off. 1 g of (−)-α-chloromethyl-2-methoxy-5-sulphamoylbenzenemethanol is obtained.
Reaction SMILES: [C:1]1([P:7](=S)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=[O:23])C>>[C:1]1([P:7](=[O:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(C)=O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Through a mixture of triphenylphosphine sulfide (11.03 g) and ethyl acetate (200 ml) is bubbled chlorine gas (ca. 2.2 molar equivalents) at room temperature. The resulting mixture is neutralized with aqueous 6% sodium hydrogen carbonate (350 ml) and stirred at room temperature for 10 minutes. The reaction mixture is then worked up as in the case of Example 1 to give triphenylphosphine oxide (10 g). m.p. 154°-157° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[C:12](O)(=O)[CH3:13].[ClH:16]>>[ClH:16].[CH3:12][C:13]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][C:10]=2[N:11]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: Cl
Product: Cc1nc2ccc(C(=O)O)cc2[nH]1
Temperature: 100 °C
Yield: 94.5 %

Procedure:
After a mixture of 5.0 g (32.8 mmols) of 3,4-diaminobenzoic acid, 50 ml of conc. hydrochloric acid and 10 ml (0.175 mol) of acetic acid was heated at 100° C. for 24 hours, the solvent was distilled off under reduced pressure to give 6.6 g (94.5%) of 2-methylbenzimidazole-5-carboxylic acid hydrochloride.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>C1COCC1>[F:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:30][C:29]3[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[N:9]=[C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)c1n[nH]c2nc(F)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C(=O)OC(C)(C)C)c3ccc(F)nc32)cc1
Temperature: 7.5 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 6-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (29.55 g, 125 mmol) in THF (300 mL) cooled in an ice bath was added KOtBu (13.98 g, 125 mmol) at such a rate as to maintain the temperature between 5-10° C., and then 4-methoxybenzyl bromide (18.2 mL, 125 mmol) was added. The resulting mixture was stirred in an ice bath for 1 hour and then stirred at room temperature for 18 hours. The resulting suspension was quenched with saturated aqueous NH4Cl (200 mL) and then extracted with EtOAc (2×300 mL). The combined organic extracts were washed with brine, dried with MgSO4 and the solvent removed in vacuo. The resulting residue was purified on a silica gel (1000 g) column (0-11% EtOAc/hexanes) to give the title compound I-B. LRMS (M+1)=380.1
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([CH3:24])=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])=[CH:10][CH:9]=1)[NH2:6].[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:30]=1[C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([CH3:24])=[CH:18][C:19]=2[C:20]([F:21])([F:22])[F:23])=[CH:12][CH:13]=1)[NH:6][C:31]([C:30]1[C:34]([CH3:38])=[CH:35][CH:36]=[CH:37][C:29]=1[Cl:28])=[O:32]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Reaction time: 72 h
Yield: 75.3 %

Procedure:
To a suspension of 4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester hydrochloride salt (100 mg, 0.25 mmol), 2-chloro-6-methylbenzoic acid (60 mg, 0.35 mmol) and HBTU (132 mg, 0.35 mmol) in DMF (2 mL) was added DIEA (174 μL, 1.0 mmol) at room temperature. The resulting mixture was stirred for 72 h. Then, the mixture was poured into water (25 mL) and was extracted with ethyl acetate (2×15 mL). The combined ethyl acetate extracts were washed successively with 0.5 N HCl (25 mL), saturated NaHCO3 solution (25 mL), brine solution (25 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product which was purified by silica gel chromatography using a Biotage (40s) column to afford 98 mg (75% yield) of N-[(2-chloro-6-methylphenyl)carbonyl] -4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C26H24ClF3N2O4 (M+Na) 543.1268, found 543.1275.