Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:21]1C(C=O)=CC2OCOC=2[CH:22]=1.NC1C=CC(C(OCC)=O)=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[N:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([O:18][CH2:21][CH3:22])=[O:17])=[CH:14][CH:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: O=C(O)c1ccc(NCc2ccc3c(c2)OCO3)cc1
Agent: CCOC(=O)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2ccc3c(c2)OCO3)cc1

Procedure:
Commercial quantities of 4-(((1,3-benzodioxol-5-yl)methyl)amino)benzoic acid are generally prepared by reacting piperonal with ethyl 4-aminobenzoate in absolute ethanol in the presence of a catalytic amount of 4-toluenesulfonic acid monohydrate to give the intermediate ethyl 4-(((1,3-benzodioxol-5-yl)mehylene)amino)benzoate. The intermediate is isolated and reduced in absolute ethanol using sodium borohydrate. The resulting ethyl 4-(((1,3-benzodioxol-5-yl)methyl)amino)benzoate is not isolated, but immediately hydrolyzed with aqueous sodium hydroxide to give sodium 4-(((1,3-benzodioxol-5-yl)methyl)amino)benzoate. The salt is converted to 4-(((1,3-benzodioxol-5-yl)methyl)amino)benzoic acid with aqueous acetic acid. The above process has been used to give satisfactory yields and was used to produce a batch containing 33 kg of pharmaceutically-acceptable product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[N:11]=[CH:12][C:13]2[CH:19]=[C:18]([C:20]3[C:25]([Cl:26])=[C:24]([O:27][CH3:28])[CH:23]=[C:22]([O:29][CH3:30])[C:21]=3[Cl:31])[C:17](=[O:32])[N:16]([CH3:33])[C:14]=2[N:15]=1.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>C(Cl)Cl>[Cl:26][C:25]1[C:24]([O:27][CH3:28])=[CH:23][C:22]([O:29][CH3:30])=[C:21]([Cl:31])[C:20]=1[C:18]1[C:17](=[O:32])[N:16]([CH3:33])[C:14]2[N:15]=[C:10]([NH:9][C:3]3[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:34](=[O:37])[CH:35]=[CH2:36])[N:11]=[CH:12][C:13]=2[CH:19]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3cnc(Nc4c(C)cccc4N)nc3n(C)c2=O)c1Cl
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(C)c1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)c(=O)n(C)c2n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-(2-amino-6-methylphenylamino)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methylpyrido[2,3-d]pyrimidin-7(8H)-one (11) was taken up in DCM (2 ml) and cooled to 0° C., followed by addition of acryloyl chloride (0.010 mL, 0.13 mmol). The reaction was allowed to warm to room temperature and stirred overnight. The mixture was loaded directly onto silica gel and purified by flash chromatography using 0-100% EtOAc/Hexanes gradient to provide the product, N-(2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenyl)acrylamide (Compound E). The product was obtained as an off-white solid (10 mg; 19% yield). MS (ES+) C26H23Cl2N5O4, 540 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C@H:11]([NH2:13])[CH3:12].ClC1N=C(Cl)C(F)=CN=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([NH2:13])[CH3:12]
Reactant: C[C@@H](N)c1ccc2ccccc2c1
Agent: Fc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(N)c1ccc2ccccc2c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of (R)-(+)-1-(2-napthyl)ethylamine (102.6 mg, 0.599 mmol), 2,4-dichloro-5-fluoro pyrimidine (100 mg, 0.599 mmol) and cesium carbonate (390 mg, 1.2 mmol) was dissolved in 1,4-dioxane (3 ml) and H2O (3 ml) in a 10 ml microwave vial. The mixture was stirred in the microwave reactor at 80° C. for 10 minutes. The residue was dissolved in CH2Cl2 (50 ml), washed with water (20 ml), brine (20 ml) dried (Na2SO4) and concentrated to get the crude intermediate 2-chloro-5-fluoro-pyrimidin-4-yl)-(1-naphthalen-2-yl-ethyl)-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[S:10][C:11]=2[C:12]2[N:16](S(N(C)C)(=O)=O)[CH:15]=[N:14][CH:13]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>Br.O.C(Cl)Cl>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN(C)S(=O)(=O)n1cncc1-c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(Cc2nc(-c3ccncc3)sc2-c2cnc[nH]2)cc1
Yield: 88.4 %

Procedure:
A solution of 5-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (50 mg, 0.109 mmol) in 48% HBr in water (3.0 mL) was heated to 90° C. for 2.5 hours. The cooled solution was taken up in DCM (20 mL) and saturated sodium bicarbonate (20 mL). The layers were separated and the aqueous extracted with DCM (20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. To this crude material was added the 19 mg of deprotected material obtained in the previous step. The combined material was purified by silica gel chromatography (methanol/DCM=0/100→315/85) to give 34 mg of the title compound as a white solid (27% yield). LC/MS (FA) ES+ 353. 1H NMR (300 MHz, d4-MeOH) δ: 8.63-8.61 (m, 2H), 7.93-7.91 (m, 2H), 7.80 (d, 1H, J=1.1 Hz), 7.30-7.19 (m, 5H), 4.35 (s, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])[N:3]=[CH:2]1.[H][H]>CO.[Pd]>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:3]=[CH:2]1
Reactant: COC(=O)C=Cc1c[nH]cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1c[nH]cn1
Reaction time: 1 h

Procedure:
To a solution of ester 2 (5.3 g) in methanol at room temperature was added 10% palladium on carbon (20 mg) under a blanket of argon. A balloon of hydrogen was applied, and the reaction was stirred for one hour. The solution was filtered, and then concentrated in vacuo to dryness to provide the crude product 3 which was sufficiently pure for use in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CS(O[CH:20]([CH:22]1[CH2:26][C:25](=[O:27])[N:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=2[O:37][CH3:38])[CH2:23]1)[CH3:21])(=O)=O.[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:38][O:37][C:30]1[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:29]=1[CH2:28][N:24]1[CH2:23][CH:22]([CH:20]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH3:21])[CH2:26][C:25]1=[O:27]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COc1ccc(CN2CC(C(C)OS(C)(=O)=O)CC2=O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2CC(C(C)n3cc(B4OC(C)(C)C(C)(C)O4)cn3)CC2=O)c(OC)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
The mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 5.0 mmol), 1-[1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-3-yl]ethyl methanesulfonate (1.5 g, 4.2 mmol), NaI (64.0 mg, 0.04 mmol) and K2CO3 (1.2 g, 8.4 mmol) in DMF (15 mL) was stirred at 80° C. for 8 hours. The mixture was then diluted with water and extracted with EtOAc. The EtOAc layer was dried over sodium sulfate and concentrated under reduced pressure to afford racemic 1-(2,4-dimethoxybenzyl)-4-{1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl}pyrrolidin-2-one which was used in next step without purification. MS ESI calc'd. for C24H35BN3O5 [M+H]+ 456. found 456.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[OH-].[Na+].Cl[S:22]([C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][CH:29]=[C:30]2[NH:35][C:36](=[O:38])[CH3:37])(=[O:24])=[O:23].Cl>O1CCOCC1.O.CO>[C:36]([NH:35][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:31]=1[CH:32]=[CH:33][CH:34]=[C:25]2[S:22]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)(=[O:24])=[O:23])(=[O:38])[CH3:37]
Reactant: CC(=O)Nc1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: NCc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1cccc2c(S(=O)(=O)NCc3ccc(C(=O)O)cc3)cccc12
Yield: 85397.2 %

Procedure:
4-(Aminomethyl)benzoic acid (726 mg, 4.8 mmol) and triethylamine (0.67 ml, 4.8 mmol) were dissolved in a mixed solution of 2N sodium hydroxide solution (2.4 ml, 4.8 mmol), dioxane (4.8 ml) and water (12 ml). A suspension of N-[5-(chlorosulfonyl)-1-naphthalenyl]acetamide (1.135 g, 4 mmol) in dioxane (4 ml) and methanol (12 ml) was added to the mixture under ice cooling and stirring, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid, and the precipitated solid was washed with water and dried under reduced pressure to give the title compound as a light brown crystal (1,361 g, 85.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[C:12]2[C:13]([CH3:21])=[CH:14][C:15]([C:18](O)=[O:19])=[N:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:30].[NH2:31][CH2:32][CH2:33][OH:34].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[C:12]2[C:13]([CH3:21])=[CH:14][C:15]([C:18]([NH:31][CH2:32][CH2:33][OH:34])=[O:19])=[N:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:30]
Reactant: NCCO
Reactant: Cc1cc(S(=O)(=O)C(c2cnc(C(=O)O)cc2C)c2cc(F)ccc2F)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(S(=O)(=O)C(c2cnc(C(=O)NCCO)cc2C)c2cc(F)ccc2F)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
5-[[(4-Chloro-3-methylphenyl)sulfonyl](2,5-difluorophenyl) methyl]-4-methylpyridine-2-carboxylic acid (300 mg, 0.66 mmol), 2-aminoethanol (60 μl, 0.99 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (191 mg, 0.99 mmol), 1-hydroxybenzotriazole (89 mg, 0.66 mmol), and triethylamine (275 μl, 1.98 mmol) were dissolved in methylene chloride (60 ml), and the resulting mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with methylene chloride. The combined organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (developed with 5% methanol/methylene chloride, eluted with 30% methanol/methylene chloride), to obtain the title compound (190 mg, 0.38 mmol, 58%) as a white amorphous substance.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)=[CH:8][C:7]=1[C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)=[O:4].C([O-])(=O)C.[NH4+:36]>CS(C)=O>[Cl:28][C:24]1[CH:23]=[C:22]([C:21]2[C:7]3[C:6](=[CH:11][CH:10]=[C:9]([C:12](=[O:20])[C:13]4[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=4)[CH:8]=3)[NH:5][C:3](=[O:4])[N:36]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(c1ccc(I)cc1)c1ccc(NC(=O)C(Cl)(Cl)Cl)c(C(=O)c2cccc(Cl)c2)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: O=C(c1ccc(I)cc1)c1ccc2[nH]c(=O)nc(-c3cccc(Cl)c3)c2c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 74.3 %

Procedure:
A mixture of intermediate (37) (0.0285 mol) and ammonium acetate (0.057 mol) in DMSO (180 ml) was stirred at 120 ° C. for 2 hours. The mixture was poured out into ice water. The precipitate was filtered, washed with water (several times) then with CH3CN/diethyl ether and dried at 60° C. under vacuum, yielding 10.3 g (74%) of 4-(3-chlorophenyl)-6-(4-iodobenzoyl)-2(1H)-quinazolinone (intermediate 38).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@H:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][C:23](Cl)=[O:24]>CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C@H:10]([N:13]([CH2:14][CH2:15][CH3:16])[C:23](=[O:24])[CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)[CH2:9][CH2:8]2
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCCN[C@@H]1CCc2cccc(OC)c2C1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCN(C(=O)Cc1cccs1)[C@@H]1CCc2cccc(OC)c2C1

Procedure:
Synthesis worked according to the preparation of A4-1 when using 39 mg (0.18 mmol) enantiomerical pure (R)—N-(8-methoxytetralin-2-yl)-N-propylamine ((R)-A2-1: R═OMe) and 0.05 mL (0.41 mmol) 2-thienyl acetic acid chloride. Flash chromatography was done with hexane/ethyl acetate 20/1.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]([C:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]2)=[CH2:9])=[N:6][CH:7]=1.[F:20][CH:21]([F:45])[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]2[CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=[C:31]([CH3:44])[CH:30]=2)[N:23]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.[Cl-].[Na+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:45][CH:21]([F:20])[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]2[CH:34]=[C:33]([C:2]3[CH:3]=[N:4][C:5]([C:8]([C@H:10]4[CH2:15][CH2:14][C@H:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]4)=[CH2:9])=[N:6][CH:7]=3)[CH:32]=[C:31]([CH3:44])[CH:30]=2)[N:23]=1
Reactant: C=C(c1ncc(Cl)cn1)[C@H]1CC[C@H](C(=O)OC)CC1
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: C=C(c1ncc(-c2cc(C)cc(Nc3nccc(C(F)F)n3)c2)cn1)[C@H]1CC[C@H](C(=O)OC)CC1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of methyl trans-4-[1-(5-chloropyrimidin-2-yl)ethenyl]cyclohexanecarboxylate (8 mg, 0.028 mmol), 4-(difluoromethyl)-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (10.3 mg, 0.028 mmol), tris(dibenzylideneacetone)-dipalladium(0) (1.3 mg, 1.42 μmol), XPhos (1.36 mg, 2.85 μmol) and potassium phosphate tribasic (18 mg, 0.085 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was stirred at 110° C. under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the mixture was diluted with brine and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to afford methyl trans-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethenyl}cyclohexanecarboxylate. MS ESI calc'd for C26H28F2N5O2 [M+H]+ 480. found 480. 1H NMR: (400 MHz, CDCl3) δ 8.94 (s, 2H), 8.72 (d, J=4.8 Hz, 1H), 8.62 (d, J=5.2 Hz, 1H), 7.88 (s, 1H), 7.37 (s, 1H), 7.13-7.11 (m, 1H), 7.04-7.03 (m, 1H), 6.43 (s, 1H), 5.48 (s, 1H), 3.69 (s, 3H), 3.09-3.06 (m, 1H), 2.46 (s, 3H), 2.05-2.02 (m, 3H), 1.69-1.62 (m, 3H), 1.39-1.33 (m, 3H).
Reaction SMILES: [CH:1]([N:4]1[CH2:8][C:7]2([CH2:14][O:13][C:12]3[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:11]=3[O:10][CH2:9]2)[O:6]C1=O)([CH3:3])[CH3:2].[OH-].[Na+].O>C(O)C>[OH:6][C:7]1([CH2:8][NH:4][CH:1]([CH3:3])[CH3:2])[CH2:14][O:13][C:12]2[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:11]=2[O:10][CH2:9]1
Reactant: CC(C)N1CC2(COc3ccc([N+](=O)[O-])cc3OC2)OC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)NCC1(O)COc2ccc([N+](=O)[O-])cc2OC1

Procedure:
A mixture of 0.15 mole of the oxazolidinone from Step B above and 15 g. (0.38 mole) of sodium hydroxide in 100 ml. of water and 200 ml. of 95% ethanol is refluxed, the solution evaporated to a small volume and the product extracted with diethyl ether. Evaporation of the solvent gives 3-hydroxy-3-isopropylaminomethyl-7-nitro-3,4-dihydro-2H-1,5-benzodioxepin.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([Sn:13]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:20]([N:22]=[N+]=[N-])[CH3:21])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C(OCC)C>[CH:25]1([Sn:13]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)([CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:20]([NH2:22])[CH3:21])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC(N=[N+]=[N-])c1ccccc1[Sn](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(N)c1ccccc1[Sn](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Yield: 76.5 %

Procedure:
To the mixture of 486 mg of lithium aluminum hydride (12.3 mmol) and 20 ml of diethylether in a 100 ml two-neck flask, 20 ml of a diethylether solution containing 643 mg of tricyclohexyl[o-(1-azidoethyl)phenyl]tin (1.25 mmol) was added dropwise, followed by a heat-refluxing for 11.5 hours. Upon completion of the reaction, the organic layer was separated using 10 ml of water. After the ether layer was washed with 30 ml of a saturated brine and dried over sodium sulfate, the solvent was removed under reduced pressure to yield a crude product. The resultant crude product was purified by column chromatography on silica gel (for which, 25 g of silica gel, and hexane as a development solvent were employed) to yield 467 mg of the final product (yield=76.5%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:16]=3[N:17]=[C:18]([CH3:20])[N:19]=2)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:32][CH2:33]4)=[O:26])[C:16]=3[N:17]=[C:18]([CH3:20])[N:19]=2)[CH2:3][CH2:4]1
Reactant: COCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)nc(C)nc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f57) and commercially available available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:29][CH:26]4[CH2:27][CH2:28][S:23][CH2:24][CH2:25]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCSCC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCSCC1
Yield: 84.4 %

Procedure:
A mixture 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.50 g, 1.50 mmol) and tetrahydro-thiopyran-4-ylamine (0.19 g, 1.60 mmol) and DIEA (0.52 mL, 3.00 mmol) in IPA (4 mL) was heated in a microwave reactor at 120° C. for 10 minutes. The mixture was diluted with EtOAc, washed with water, brine, dried over sodium sulfate and then purified by column chromatography on silica gel (gradient: 0 to 30% ethyl acetate/heptane) to afford (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(tetrahydro-thiopyran-4-yl)-amine (0.53 g, 86%). 1H NMR (400 MHz, CDCl3) δ 9.18-9.03 (m, 2H), 8.26-8.12 (m, 2H), 7.70-7.46 (m, 4H), 6.65 (d, J=4.2 Hz, 1H), 4.07-3.91 (m, 1H), 2.88-2.70 (m, 4H), 2.49-2.34 (m, 2H), 2.05-1.76 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])[C:11]([CH3:13])=O>>[CH2:16]([O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCOC(=O)C(C)=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: CCCCOC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure AA above and using 3,4-dichloroaniline (Aldrich) and n-butyl pyruvate (prepared by following General Procedure AO above using n-butanol in place of iso-butanol), the title compound was prepared. The reaction was monitored by tlc on silica gel (Rf=0.7 in 25% EtOAc/hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:21][OH:22])([CH2:19][OH:20])[C:7](=[O:18])[N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:19][O:20][S:31]([CH3:30])(=[O:33])=[O:32])([CH2:21][O:22][S:31]([CH3:30])(=[O:33])=[O:32])[C:7](=[O:18])[N:8]2[C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C(CO)(CO)c2ccc(Br)cc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C(=O)C(COS(C)(=O)=O)(COS(C)(=O)=O)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of tert-butyl 6-bromo-3,3-bis(hydroxymethyl)-2-oxoindoline-1-carboxylate (5.27 g, 14.16 mmol) in DCM (94 mL) was added triethylamine (7.89 mL, 56.6 mmol) followed by methanesulfonyl chloride (2.21 mL, 28.3 mmol). The solution was stirred for 1 h and then it was concentrated under reduced pressure. Purification by column chromatography (eluting with a gradient of 10-60% EtOAc in hexanes) gave tert-butyl 6-bromo-3,3-bis((methylsulfonyloxy)methyl)-2-oxoindoline-1-carboxylate as a white foam. Mass Spectrum (ESI) m/e=550.0 [(M+Na+) (79Br)] and 552.0 [(M+Na+) (81Br)].
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH2:7]([O:9][CH:10]([O:15][CH2:16][CH3:17])[CH2:11][CH2:12][CH2:13][NH2:14])[CH3:8].N1C=CC=CC=1.O>ClCCl>[CH2:16]([O:15][CH:10]([O:9][CH2:7][CH3:8])[CH2:11][CH2:12][CH2:13][NH:14][C:2](=[O:3])[O:4][CH2:5][CH3:6])[CH3:17]
Reactant: CCOC(=O)Cl
Reactant: CCOC(CCCN)OCC
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)NCCCC(OCC)OCC
Reaction time: 0.5 h

Procedure:
Ethyl chloroformate (0.3 ml, 3.1 mmol) was added dropwise to a solution of 4-aminobutanal diethyl acetal (0.5 ml, 2.9 mmol) and pyridine (0.28 ml, 3.5 mmol) in dichloromethane (10 ml) at 5° C. The mixture was stirred for 30 min. Water was added and the mixture was extracted with ether. The ether was dried (sodium sulphate) and evaporated to give the product as a yellow oil, MS (+EI) 232 ([M-H]+), 1H NMR (CDCl3) 4.69 (1H, s), 4.4 (1H, t), 4.00 (2H, q), 3.5-3.65 (2H, m), 3.35-3.5 (2H, m), 3.05-3.15 (2H, m), 1.5-1.6 (4H, m), 1.1-1.2 (9H, m).