Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].C(=O)(OC)[O:16][C:17]1[CH:22]=[C:21]([N:23]=[C:24]=[O:25])[C:20]([F:26])=[CH:19][C:18]=1[Cl:27].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CN(C)C=O.O>[Cl:27][C:18]1[C:17]([OH:16])=[CH:22][C:21]([N:23]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:24]2=[O:25])=[C:20]([F:26])[CH:19]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: COC(=O)Oc1cc(N=C=O)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(O)c(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 4.67 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 15 ml of toluene is added dropwise while stirring at 0° C. during 20 minutes to a suspension of 1.11 g of a 55% sodium hydride dispersion in 30 ml of absolute dimethylformamide, and the mixture is stirred at 0° C. for 15 minutes. The reaction mixture is subsequently cooled to -40° C. and a solution of 6.24 g of 2-chloro-4-fluoro-5-isocyanatophenyl methyl carbonate in 30 ml of toluene is added dropwise during 5 minutes. The reaction mixture is stirred at room temperature for 1 hour and stirred for a further 30 minutes with a solution of 5.40 g of sodium carbonate in 100 ml of water. The aqueous phase is separated. extracted twice with 50 ml of diethyl ether each time and adjusted to pH 1 with 8 ml of 2N hydrochloric acid. The mixture is extracted twice with 100 ml of diethyl ether each time and the organic phases are washed with water. dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from diethyl ether/n-hexane. There is obtained 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 223°-225° C.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[C:9]([O:15][CH3:16])[CH:8]=3)[N:4]([CH2:17][CH:18]([N:20](C)[CH3:21])[CH3:19])[N:3]=1.ClC(OC(Cl)C)=O>>[Cl:1][C:2]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[C:9]([O:15][CH3:16])[CH:8]=3)[N:4]([CH2:17][CH:18]([NH:20][CH3:21])[CH3:19])[N:3]=1
Reactant: COc1ccc2cc3c(Cl)nn(CC(C)N(C)C)c3nc2c1
Agent: CC(Cl)OC(=O)Cl
Product: CNC(C)Cn1nc(Cl)c2cc3ccc(OC)cc3nc21

Procedure:
3-Chloro-1-[2-(methylamino)-2-methylethyl]-7-methoxy-1H-pyrazolo[3,4-b]quinoline was prepared by demethylation of 3-chloro-1-[2-(dimethylamino)-2-methylethyl]-7-methoxy-1H-pyrazolo[3,4-b]quinoline (Example 45), with α-chloroethyl chloroformate according to the procedure of Example 41, and was obtained in the form of a colorless solid, m.p. 98°-100° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:8][C:4]1[N:3]=[C:2]([NH:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O[C@H]1CC[C@H](Nc2cncc(Cl)n2)CC1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
2,6 dichloropyrazine (0.50 g, 3.4 mmol), trans-4-aminocyclohexanol (0.39 g, 3.4 mmol) and cesium carbonate (2.2 g, 6.7 mmol) were added to a round bottom flask and flushed with nitrogen. DMF (4 mL) was then added and the reaction was stirred at 100° C. for 1.5 h. The reaction mixture was cooled to room temperature then diluted with EtOAc (50 mL). The mixture was filtered through celite to remove inorganic salts and the filtrate was concentrated to a crude residue. The residue was purified by silica gel chromatography to afford trans-4-[(6-chloropyrazin-2-yl)amino]cyclohexanol as a yellow oil. LRMS (ESI) calculated for C10H14ClN3O [M+H]+, 228.1; found 228.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]2[CH2:13]COCC2)=[N:4][NH:5][C:6]=1[I:7].[CH3:14][O:15]CCC1C=CNN=1.O1CCC(C2C=CNN=2)CC1>>[Cl:1][C:2]1[C:3]([CH2:8][CH2:13][O:15][CH3:14])=[N:4][NH:5][C:6]=1[I:7]
Reactant: COCCc1cc[nH]n1
Reactant: Clc1c(C2CCOCC2)n[nH]c1I
Agent: c1cc(C2CCOCC2)n[nH]1
Product: COCCc1n[nH]c(I)c1Cl

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 294.4, except 3-(2-methoxyethyl)-1H-pyrazole (compound 307.1) was used instead of 3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole (compound 294.2).
Reaction SMILES: S([CH2:5][C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][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][CH2:32][CH2:33][CH3:34])=[O:7])(O)(=O)=O.[Na].[Cl:36]CC(O)=O>>[Cl:36][CH2:5][C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][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][CH2:32][CH2:33][CH3:34])=[O:7]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCOC(=O)CS(=O)(=O)O
Reactant: O=C(O)CCl
Agent: [Na]
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCOC(=O)CCl
Temperature: 93 °C

Procedure:
The reactor is then heated to a temperature of 93° C. and maintained at a temperature of between 90° C. and 97° C. for about 11 hours. HPLC analysis of the resulting slurry indicates that the sodium lauryl-myristyl sulfoacetate is substantially free of monochloroacetic acid and its salts.
Reaction SMILES: [O:1]([C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:36][CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.O>CN(C)C=O>[O:1]([C:13]1[CH:18]=[C:17]([O:19][CH2:36][CH2:37][O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:16]=[CH:15][C:14]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: CCc1ccc(Cc2ccc(O)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: BrCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(Cc2ccc(OCCOCc3ccccc3)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
To a suspension of 2-(4-ethylbenzyl)-5-hydroxyphenyl β-D-glucopyranoside (0.039 g) and cesium carbonate (0.098 g) in N,N-dimethylformamide (1 mL) was added (2-bromoethyl)benzyl ether (0.025 mL), and the mixture was stirred at 50° C. for 3.5 hours. The reaction mixture was cooled to ambient temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/methanol=6/1) to give 5-[2-(benzyloxy)ethyloxy]-2-(4-ethylbenzyl)phenyl β-D-glucopyranoside (0.022 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]Br)[CH:7]=1)[CH3:2].[CH3:24][C@H:25]1[C@@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][C:27](=[O:36])[NH:26]1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:26]2[C@@H:25]([CH3:24])[C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:28][C:27]2=[O:36])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(F)cc(Oc2ccc(Br)cc2CBr)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Product: CCOC(=O)Cc1cc(F)cc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-5-fluoro-phenyl]-acetic acid ethyl ester and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[C:10]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[C:19]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=3[C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[CH:18]=[CH:17]4)[NH:11]2)=[CH:7][CH:6]=1)=[O:4].Br[CH2:46][O:47][C:48](=[O:50])[CH3:49].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[C:10]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[C:19]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=3[C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=3)[CH:18]=[CH:17]4)[N:11]2[CH2:49][C:48]([O:47][CH3:46])=[O:50])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(=O)OCBr
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc4nc(-c5cc(OC)ccc5-c5ccc(Cl)cc5)ccc4c3)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.3 %

Procedure:
To a mixture of intermediate 15-2 (1.024 g, 1.7 mmol) and bromomethylacetate (388 mg, 1.5 eq) in dry DMF (30 mL) was added NaH (60% dispersion in mineral oil, 122 mg, 1.8 eq) at 0° C. After stirring for 20 min at this temperature, the reaction mixture was warmed up to room temperature. After 24 h, the reaction mixture was poured into 300 mL of ice-cold water. The formed yellow solid was filtered off, washed with petroleum ether and purified by column chromatography (CH2Cl2) to give 450 mg (39%) of 2-[2-(4′-Chloro-4-methoxy-biphenyl-2-yl)-quinolin-6-yl]-3-cyclohexyl-1-methoxycarbonylmethyl-1H-indole-6-carboxylic acid methyl ester 15-3; m/z=674 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]([CH2:20][CH:21]=C)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:27]CC1.CC(C)=O.O.S(=O)(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O.CCCCCC>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]([CH2:20][CH:21]=[O:27])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCC(C(=O)OCC)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(CC=O)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.3 %

Procedure:
A mixture of 150 g (460 mmol) of ethyl 2-(2-tert-butoxycarbonylaminothiazol-yl)-4-pentenoate (Intermediate 34), 57 g (470 mmol) of N-methyl morpholine oxide and 1.0 g of osmium tetroxide in 1250 mL of 4/1 v/v acetone/water was stirred at RT for 1.5 h. To the mixture was added 100 g of solid sodium bisulfate and continued to stir for 0.5 h. The solid was removed by filtration and washing with acetone. The filtrates were combined and evaporated. The residue was diluted with 1000 mL of water and 2000 mL of ethyl acetate. The organic phase was separated and washed with brine (3×1000 mL), dried over Na2SO4 and condensed in vacuo. The residue was redissolved in 1500 mL of methanol and 1000 mL of water. 148 g of sodium periodate was added. The mixture was stirred for one hour, The solid was discarded by filtration and washing with methanol. The filtrates were condensed in vacuo and the reside was dissolved in 1000 mL of ethyl acetate. The organic layer was washed with brine (2×1000 mL), dried over Na2SO4 and evaporated until the solid formed. 1000 mL of hexane was added and the flask was allowed to stand at RT to let crystallization proceed. The solid was collected by filtration and washing with hexane and drying in vacuo. 79 g of the title compound was obtained as white solid. The mother liquid was condensed and the residue was suspended in hexane. A second crop of solid (24 g) was obtained as a yellow solid. The mother liquid was condensed again to afford a brown solid (22 g) which contained impurity.
Reaction SMILES: Br[CH2:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([C:21]([F:24])([F:23])[F:22])[CH:10]=2)=[CH:5][CH:4]=1.[CH3:27][O:28][C:29]([CH:31]1[CH2:34][NH:33][CH2:32]1)=[O:30].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:27][O:28][C:29]([CH:31]1[CH2:34][N:33]([CH2:2][C:3]2[CH:26]=[CH:25][C:6]([CH2:7][S:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:11]([C:21]([F:24])([F:23])[F:22])[CH:10]=3)=[CH:5][CH:4]=2)[CH2:32]1)=[O:30]
Reactant: FC(F)(F)c1cc(SCc2ccc(CBr)cc2)ccc1-c1ccccc1
Reactant: COC(=O)C1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CN(Cc2ccc(CSc3ccc(-c4ccccc4)c(C(F)(F)F)c3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(4-bromomethyl-benzylsulfanyl)-2-trifluoromethyl-biphenyl (185 mg, 0.4230 mmol, 1 eq.) in anhydrous DCM (7 mL) is added azetidine-3-carboxylic acid methyl ester (HCl salt, 96 mg, 0.6345 mmol, 1.5 eq.) and DIEA (0.74 mL, 4.230 mmol, 10 eq.). The mixture is stirred at room temperature for 3 h. The reaction mixture is applied directly to silica gel chromatography (gradient from 5:1 hexanes/EtOAc to 1:2 hexanes/EtOAc) to give 1-[4-(2-trifluoromethyl-biphenyl-4-ylsulfanylmethyl)-benzyl]-azetidine-3-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[CH:12]=1)[C:6]([O:8]C)=[O:7])#[N:2].[OH-].[Na+]>CCO.Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[CH:12]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1cc(C#N)cc(OC(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1cc(C#N)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
To a solution of methyl 3-cyano-5-isopropoxybenzoate (1.19 g, 5.4 mmol) in EtOH (4 mL) was added 5N NaOH (3 mL, 15 mmol). After stirring at room temperature for 4 h, the reaction mixture was diluted with 1N HCl and extracted with EA. The combined organic layers were dried over Na2SO4 and concentrated to provide 920 mg (83%) of 3-cyano-5-isopropoxybenzoic acid as a white solid. LCMS-ESI (m/z) calculated for C11H11NO3: 205.2. found 206.1 [M+H]+, tR=2.97 min. 1H NMR (400 MHz, CDCl3) δ 7.93 (t, J=1.4 Hz, 1H), 7.80 (dd, J=2.6, 1.4 Hz, 1H), 7.35 (dd, J=2.6, 1.4 Hz, 1H), 4.71-4.56 (m, 1H), 1.38 (dd, J=6.1, 2.2 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[S:5][C:6]=1[CH2:7][N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[CH:10]=[N:9]1.[OH-].[Na+].O>C(O)C.O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=2)[S:5][C:6]=1[CH2:7][N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[N:9]1
Reactant: CCOC(=O)c1cnn(Cc2sc(-c3cccc(C(F)(F)F)c3)nc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)sc1Cn1cc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a mixed solution of the compound (70 mg, 0.18 mmol) obtained in Example 70c in ethanol/tetrahydrofuran (v/v=1/1, 4 mL) was added 2N aqueous sodium hydroxide solution (0.71 mL, 1.4 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the aqueous layer was washed with diethyl ether, neutralized with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (44 mg, 67%) as colorless crystals.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[CH:9]=[CH:10][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:16])[C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+]>>[CH2:17]([N:11]1[CH:10]=[CH:9][C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:4])=[C:14]([OH:15])[C:13]=2[C:12]1=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1ncc2ccn(Cc3ccccc3)c(=O)c2c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1ncc2ccn(Cc3ccccc3)c(=O)c2c1O
Yield: 69.9 %

Procedure:
A mixture of 6-benzyl-4-hydroxy-5-oxo-5,6-dihydro-[2,6]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.081 mmol), glycine (805 mg, 10.7 mmol) and NaOMe solution (16 mL, 8.06 mmol, 0.5 M in MeOH) was refluxed for 16 h. Solvent was evaporated in vacuo, and the residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 2 with 4 M HCl, and then extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 20 mg of the title compound as a yellow solid. MS: (+)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].O.B1(C=C)OB([CH:25]=[CH2:26])OB(C=C)O1.C1C=CN=CC=1>COCCOC.CC#N.O>[CH:25]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1)=[CH2:26]
Reactant: COC(=O)c1cc(Cl)ncn1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: c1ccncc1
Product: C=Cc1cc(C(=O)OC)ncn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.9 %

Procedure:
Tetrakis-(triphenylphosphine)palladium(0) (0.40 g, 5 mol %) was added to a solution of methyl 6-chloropyrimidine-4-carboxylate (1.24 g) in DME (35 mL) and the solution left to stir at room temperature (20 min.). K2CO3 (1.11 g, 1.2 eq.), water (10 mL) and 2,4,6-trivinylcyclotriboroxane-pyridine complex (1.93 g, 1.2 eq.) were then added to the solution and the resultant mixture heated at reflux (24 hrs). The mixture was then cooled to room temperature and extracted with diethyl ether (200 mL) and the extract washed with water (30 mL). The diethyl ether extract was dried over MgSO4 and then diluted with hexane (200 mL). The solution was filtered through aluminium oxide (6 g) and the eluent concentrated in vacuo to give a yellow oil. The oil was then subjected to silica gel chromatography (10→100% EtOAc/Pet ether) followed by reverse phase (C18) chromatography (40% MeCN/water) to yield methyl 6-vinylpyrimidine-4-carboxylate as a white solid (0.40 g, 34% yield). 1H NMR, 270 MHz (CDCl3): 9.29 (d, 1H, H-2, J=1.1 Hz), 7.99 (d, 1H, H-5, J=1.1 Hz), dd, 1H, H-A, J=10.4 and 17.3 Hz), 6.61 (dd, 1H, H—C, J=1.0 and 17.3 Hz), 5.81 (dd, 1H, H—B, J=1.0 and 10.4 Hz), 4.02 (s, 3H, —CH3). 13C NMR, 67.5 MHz (CDCl3): 164.79 (2C), 159.22 (2C), 134.71, 124.92, 117.71, 53.52. ESI-MS Expected for molecular ion C8H8N2O2=164.0586. Found M+H=165.0664.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14](O)[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([Br:18])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(Br)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 114.3 %

Procedure:
In dichloromethane (20 ml) was dissolved N-tert-butoxycarbonyl-4-(1-hydroxyethyl)piperidine (0.92 g). After addition of carbon tetrabromide, (1.62 g), triphenylphosphine (1.58 g) was slowly added under ice-cooling. The mixture was stirred at room temperature for 2 hours, at the end of which time the dichloromethane was distilled off. The residue was diluted with ethyl acetate and an aqueous solution of NaHCO3 and the insoluble matter was filtered off. The filtrate was extracted with ethyl acetate, washed with aqueous NaCl solution, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =8:1) to provide the title compound as colorless oil (1.34 g). 1H-NMR (CDCl3) δ: 1.0-1.3(3H,m), 1.4;5(9H,s), 1.6-1.9(4H,m), 2.6-2.8(2H,brm), 3.45(2H,t,J=6.8Hz), 4.0-4.2(2H,brm).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:17])=[C:12]([N:14]=[C:15]=[S:16])[CH:13]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:17])=[C:12]([NH:14][C:15](=[S:16])[NH:2][CH2:3][C:4]([NH2:6])=[O:5])[CH:13]=1
Reactant: Cc1ccc(F)cc1N=C=S
Reactant: NCC(N)=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1NC(=S)NCC(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.8 %

Procedure:
A mixture of glycinamide hydrochloride (4.42 g), 5-fluoro-2-methylphenylisothiocyanate (6.68 g), triethyl amine (4.1 g), and chloroform (150 mL) was stirred at ambient temperature for 18 hours. The precipitate was collected by filtration, washed with chloroform and air dried to give 2-[3-(5-Fluoro-2-methylphenyl)-thioureido]acetamide (7.6 g), m.p. 172°-174° C. (dec.). This compound was used without further purification in the next paragraph.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[NH:17][CH:16]=[C:15]2[C:23]1[N:31]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[CH:24]=1>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:16]=[C:15]2[C:23]1[N:31]([S:32]([C:35]2[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=2)(=[O:34])=[O:33])[C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[CH:24]=1
Reactant: COc1cc2[nH]cc(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Reactant: CC(C)(C)OC(=O)CBr
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CC(=O)OC(C)(C)C)c2cc1OC
Yield: 89.6 %

Procedure:
tert-Butyl 2-{5,6-dimethoxy-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]indol-1-yl}-acetate is prepared by following the procedure described in example 89c, but using 1.91 g of tert-butyl bromoacetate and 4 g of 2-(5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine. 4.5 g of tert-butyl 2-{5,6-dimethoxy-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]indol-1-yl}acetate are obtained, the characteristics of which are as follows: