Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH:28]2[CH:24]([NH:25][C:26](=[O:29])[NH:27]2)[CH2:23][S:22]1.C(N(CC)CC)C.[C:39]([O:43][C:44](=[O:53])[NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][NH2:52])([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[C:39]([O:43][C:44](=[O:53])[NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][NH:52][C:9](=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH:28]2[CH:24]([NH:25][C:26](=[O:29])[NH:27]2)[CH2:23][S:22]1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Reactant: O=C(CCCCC1SCC2NC(=O)NC21)NCCCCCC(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCCCNC(=O)CCCCCNC(=O)CCCCC1SCC2NC(=O)NC21
Temperature: 25 °C

Procedure:
6-[5-(2-Oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-pentanoylamino]-hexanoic acid 2,5-dioxo-pyrrolidin-1-yl ester (4; 0.39 g, 0.86 mmol) was completely dissolved in DMF (15 mL) with gentle warming. After cooling the solution to room temperature without reprecipitation, it was mixed with triethylamine (Et3N; 0.52 g, 5.15 mmol) followed by the addition of 5 (0.25 g, 1.14 mmol) in DMF (3 mL) dropwise while stirring. After overnight reaction at room temperature, the mixture was filtered, evaporated in vacuo, and loaded to a silica column for further purification. The products were separated by eluting with mobile phases of 5-20% MeOH in DCM to afford 6 (0.45 g; 93.8%) as a yellowish solid. 1H NMR (400 MHz) (CD3OD) δ: 4.53 (t, 1H, CHN), 4.34 (t, 1H, CHN), 3.25 (dd, 1H, CHS), 3.20 (t, 2H, CH2NH), 3.08 (t, 2H, CH2NH), 2.96 (d, 1H, CHHS), 2.73 (d, 1H, CHHS), 2.22 (t, 4H, CH2CO), 1.38-1.80 (m, 29H). 13C NMR (100.67 MHz) (DMSO) δ: 176.02, 175.97, 166.05, 158.50, 79.50, 63.39, 61.63, 57.01, 41.24, 41.04, 40.24, 36.99, 36.82, 30.90, 30.35, 30.13, 29.78, 29.49, 28.80, 27.56, 26.92, 26.74. HRMS (ESI) calculated for C27H49N5O5S, [M+Na]+ 578.3352 (calcd.), 578.3349 (found).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:22]=1[C:23](Cl)=[O:24]>C1COCC1>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:22]=1[C:23](/[N:12]=[C:6]1\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\1[CH2:4][CH2:3][O:2][CH3:1])=[O:24]
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1c(Cl)cccc1Cl
Yield: 29.1 %

Procedure:
The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.3 mL, 2.2 mmol) and 2,6-dichlorobenzoyl chloride (Aldrich, 0.2 mL, 1.4 mmol) in 25 mL THF were processed as in Example 132 to afford the title compound (0.12 g, 0.32 mmol, 30% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.28 (s, 6H), 3.27 (s, 3H), 3.74 (t, J=4.6 Hz, 2H), 4.34-4.44 (m, 2H), 7.19 (dd, J=8.8, 6.8 Hz, 1H), 7.28-7.34 (m, 2H); MS (DCI/NH3) m/z 359 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:28])[C:14]([O:16][CH2:17][CH2:18][N:19](OC(C)(C)C)[C:20](C)=O)=[O:15])[CH:7]=[CH:6]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:28])[C:14]([O:16][CH2:17][CH2:18][NH:19][CH3:20])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)OCCN(OC(C)(C)C)C(C)=O)ccc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCOC(=O)[C@@H](C)c1ccc2cc(OC)ccc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The product of the Example 45b (17.1 g, 50 mmol) was dissolved in CH2Cl2 (400 mL). The solution was cooled to 0° C. and TFA (80 mL) was added drop-wise. The ice bath was removed and the reaction mixture was stirred at room temperature overnight, then the solvent. was evaporated. The residue was treated with aqueous sodium carbonate (10%) and extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over sodium sulfate, and the solvent was evaporated. Trituration of the resulting solid with hexane gave the pure product as a white solid. Mp 64-68° C. 1HNMR (300 MHz, CDCl3) δ 7.67 (d, J=8.5 Hz, 2H), 7.66 (d, J=1.3, 1H), 7.4 (dd, J=8.5 and 1.8 Hz, 1H), 7.18-7.08 (m, 2H), 4.18 (t, J=5.4 Hz, 2H), 3.89 (s, 3H), 3.80 (q, J=7.1 Hz, 1H), 2.73 (t, J=5.4 Hz, 2H), 2.31 (s, 3H), 1.56 (d,l J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.5, 157.6, 135.6, 133.6, 129.2, 128.8, 127.1, 126.1, 125.8, 118.9, 105.5, 63.9, 55.2, 50.0, 45.3, 36.0, 18.4.
Reaction SMILES: Cl[C:2](=[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=2)[N:23]([C:33](=[O:35])[CH3:34])[C:22]1=[O:36])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[CH:5][CH:4]=1.[C:37]([O:41][C:42]([NH:44][CH2:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=1)=[O:43])([CH3:40])([CH3:39])[CH3:38].C(N(CC)CC)C>ClCCl>[C:37]([O:41][C:42]([NH:44][CH2:45][C:46]1[CH:52]=[CH:51][C:49]([NH:50]/[C:2](=[C:21]2\[C:22](=[O:36])[N:23]([C:33](=[O:35])[CH3:34])[C:24]3[C:29]\2=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)/[C:3]2[CH:8]=[CH:7][C:6]([CH2:9][N:10]3[C:14](=[O:15])[C:13]4=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]4[C:11]3=[O:20])=[CH:5][CH:4]=2)=[CH:48][CH:47]=1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1C(=O)/C(=C(\Nc2ccc(CNC(=O)OC(C)(C)C)cc2)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21

Procedure:
Prepared analogously to Example 2c from 3-[1-chloro-1-(4-phthalimidomethyl-phenyl)-methylidene]-1-acetyl-5-nitro-2-indolinone, 4-tert.butoxycarbonylaminomethyl-aniline and triethylamine in dichloromethane.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:32]3[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: CS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Yield: 38.6 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (50 mg, 0.15 mmol), 4-methanesulfonyl-piperazine hydrochloride (45 mg, 0.23 mmol) and sodium triacetoxyborohydride (40 mg, 0.19 mmol) to afford 28 mg (38%) of the desired product after purification.
Reaction SMILES: [N+:1]([O-:4])([O-])=O.[Na+].C(O)(=O)C(O)=O.[N:12]([CH2:15][CH2:16][NH:17][CH2:18][CH2:19][N:20]=[N+:21]=[N-:22])=[N+:13]=[N-:14].CCCCCC>C(Cl)Cl>[N:20]([CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:12]=[N+:13]=[N-:14])[N:1]=[O:4])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=NCCNCCN=[N+]=[N-]
Reactant: O=[N+]([O-])[O-]
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: [N-]=[N+]=NCCN(CCN=[N+]=[N-])N=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84 %

Procedure:
A suspension of sodium nitrate (13.4 g; 0.194 mol), oxalic acid (24.4 g; 0.194 mol) and N,N-bis(2-azidoethyl)amine LI (15 g; 0.097 mol) in DCM (300 mL) was stirred vigorously at r.t. for 2.5 h. Silica gel (20 g) and hexane (200 mL) was added to the reaction mixture and the resulting suspension was filtered. The solids were washed (1:1 hexane/DCM, 200 mL). The solvent was evaporated under reduced pressure to afford N,N-bis(2-azidoethyl)-N-nitrosoamine LII (15 g; 0.081 mol; 84% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.Cl.[C:29](=[NH:34])(OCC)[CH3:30].C(N(CC)CC)C>ClCCl>[C:29]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1)(=[NH:34])[CH3:30]
Reactant: CCOC(C)=N
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(C)=N)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.01 %

Procedure:
A mixture of N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide (30 mg, 81.9 μmol), ethyl acetimidate hydrochloride (12.1 mg, 98.2 μmol) and triethylamine (22.8 μL, 164 μmol) in dichloromethane was stirred at room temperature overnight. The mixture was concentrated and the crude product was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 7.01% yield. LCMS m/z (%)=408 (M+H, 100). 1H NMR (400 MHz, MeOH-d4) δ 2.2 (s, 2H) 2.7 (s, 3H) 3.0 (s, 1H) 3.6 (t, J=5.1 Hz, 2H) 3.7 (s, 3H) 3.9 (s, 3H) 4.2 (t, J=5.1 Hz, 2H) 6.3 (d, J=2.0 Hz, 1H) 7.2 (dd, J=7.3, 2.8 Hz, 1H) 7.2 (d, J=8.6 Hz, 1H) 7.4 (t, J=7.8 Hz, 1H) 7.5 (m, 2H) 7.6 (d, J=2.0 Hz, 1H) 7.7 (d, J=3.0 Hz, 1H) 7.8 (dd, J=9.1, 2.5 Hz, 1H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>P(Cl)(Cl)(Cl)=O.C(OCC)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1
Reactant: OCCCCCBr
Reactant: C1=COCCC1
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: BrCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 36 g of 5-bromopentan-1-ol were added 24.72 ml of 2,3-dihydropyran and 3 drops of phosphorus oxychloride under cooling in an ice bath, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with diethyl ether, washed with 5% aqueous potassium hydroxide, water, a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (1:19) as eluent to give 49.5 g of the subtitle compound having the following physical characteristics:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[NH:12][C:13](=[O:15])[CH3:14])[C:7]#[N:8])([O-:3])=[O:2].[N-:16]=[N+:17]=[N-:18].[Na+].[Cl-].[NH4+]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[NH:18][N:17]=[N:16][N:8]=2)[CH:9]=[CH:10][C:11]=1[NH:12][C:13](=[O:15])[CH3:14])([O-:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)Nc1ccc(C#N)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(-c2nnn[nH]2)cc1[N+](=O)[O-]

Procedure:
The sulfonylbenzimidazole compounds wherein R3 is a heterocyclic moiety such as 1,3-dithiane, 1,3-dithiolane, oxadiazole or tetrazole can be prepared by the following methods. The following embodiment illustrates in principle the preparation of the 5(6)-(1-alkyltetrazol-5-yl) sulfonylbenzimidazole compounds of the invention. The process begins by preparing the desired 2-substituted-5(6)-(1-alkyltetrazol-5-yl)benzimidazole reactant as illustrated by the following example. 4-Aminobenzonitrile is acetylated and nitrated to give 3-nitro-4-acetamidobenzonitrile. The benzonitrile is reacted with sodium azide in dimethylformamide in the presence of ammonium chloride to yield 5-(3-nitro-4-acetamidophenyl)tetrazole. The tetrazole moiety is alkylated with methyl iodide in acetone and triethylamine to provide 1(2)-methyl-5-(3-nitro-4-acetamidophenyl)tetrazole as an isomeric mixture. The tetrazole mixture is hydrolyzed with concentrated sulfuric acid at room temperature for several hours to yield 1(2)-methyl-5-(3-nitro-4-aminophenyl)tetrazole. The nitro group of the benzene moiety is hydrogenated in ethanol-ethyl acetate at 30° C. in the presence of palladium-on-carbon to give 1(2)-methyl-5-(3,4-diaminophenyl)tetrazole. The diaminophenyltetrazole is reacted with cyanogen bromide in methanol-water to yield essentially one methyl isomer, 2-amino-5(6)-(1-methyltetrazol-5-yl)benzimidazole. When the benzimidazole is reacted with dimethylsulfamoyl chloride in acetone in the presence of triethylamine, the product is 1-dimethylaminosulfonyl-2-amino-5(6)-(1-methyltetrazol-5-yl)benzimidazole. By employing the appropriate 2-substituted-5(6)-(1-alkyltetrazol-5-yl)benzimidazole reactants and sulfonyl chlorides as described above, other 5(6)-(1-alkyltetrazol-b 5-yl)sulfonylbenzimidole compounds of the invention can be prepared.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][C:14]([NH2:16])=[O:15])=[C:7]2[S:17]([C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=1)(=[O:19])=[O:18])([O-])=O.[H][H]>O1CCCC1.CO.O=[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][C:14]([NH2:16])=[O:15])=[C:7]2[S:17]([C:20]1[CH:21]=[C:22]([CH3:27])[CH:23]=[C:24]([CH3:26])[CH:25]=1)(=[O:19])=[O:18]
Reactant: [H][H]
Reactant: Cc1cc(C)cc(S(=O)(=O)c2c(CC(N)=O)[nH]c3ccc([N+](=O)[O-])cc23)c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)cc(S(=O)(=O)c2c(CC(N)=O)[nH]c3ccc(N)cc23)c1
Yield: 90.7 %

Procedure:
A solution of 5-nitro-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide (5k) (0.25 g, 0.0007 mol) in tetrahydrofuran (40 ML) and methanol (16 mL) was reduced under an atmospheric pressure of hydrogen in the presence of PtO2 (50 mg) as a catalyst for 6 hours. Catalyst was separated by filtration and the solvent evaporated to give 0.227 g (100%) of pure 5-amino-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxyamide as a brown oil. A solution of the last compound (0.227 g, 0.0007 mol), 2,5-dimethoxythetrahydrofuran (0.09 g, 0.0006 mol) in glacial acetic acid (5 mL) was refluxed for 30 minutes. After evaporation of the solvent the residue was triturated with ice water and extracted with ethyl acetate. Organic layer was washed with brine and dried. Removal of the solvent left the crude product which was purified by passing through a silica gel column chromatography (ethyl acetate as eluent) to give 0.15 g (57%) of title compound, mp 270-272° C. (from ethanol).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][N:6]([CH2:17][CH2:18][CH2:19][CH3:20])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])C.[OH-].[Na+]>CO.O>[CH2:17]([N:6]([CH2:5][C:4]([OH:21])=[O:3])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN(CC(=O)OCC)S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCN(CC(=O)O)S(=O)(=O)c1ccc(C)cc1

Procedure:
Dissolve the crude ethyl-[butyl-(toluene-4-sulfonyl)-amino]-acetate (10 mmol) in methanol (25 mL) and water (25 mL). Add sodium hydroxide (10 mmol) and stir the reaction at room temperature for 5 hours. Dilute the reaction with water (100 mL) and rinse with methylene chloride. Neutralize the aqueous with 1N hydrochloric acid and extract with methylene chloride (3×75 mL). Combine the organic extracts and rinse with water (100 mL), brine (100 mL), dry over anhydrous sodium sulfate, filter and concentrate under vacuum to provide [butyl-(toluene-4-sulfonyl)-amino]-acetic acid.
Reaction SMILES: [CH2:1]([C:5]1[C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:31]3[N:32]=[N:33][NH:34][N:35]=3)[CH:11]=2)[N:6]=1)[CH:2]([CH3:4])[CH3:3].Cl[CH2:37][C:38]([NH2:40])=[O:39].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:40][C:38](=[O:39])[CH2:37][N:33]1[N:34]=[N:35][C:31]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[C:13]3[C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[N:32]1
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(-c4nn[nH]n4)cc23)cc1
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(-c4nnn(CC(N)=O)n4)cc23)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
A mixture of tert-butyl [2-isobutyl-4-(4-methylphenyl)-6-(2H-tetrazol-5-yl)quinolin-3-yl]methylcarbamate (0.16 g, 0.33 mmol), 2-chloroacetamide (0.047 g, 0.50 mmol), potassium carbonate (0.070 g, 0.50 mmol) and N,N-dimethylformamide (5 ml) was stirred at 80° C. for 3 hrs. The reaction mixture was partitioned between ethyl acetate-tetrahydrofuran and water and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give tert-butyl [6-[2-(2-amino-2-oxoethyl)-2H-tetrazol-5-yl]-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methylcarbamate (0.12 g, yield 69%) as a pale-yellow powder.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][NH:14][C:15]1[N:23]=[C:22]2[C:18]([NH:19][C:20](=[O:32])[N:21]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:17]([C:33]([O:35]CC)=O)[N:16]=1)=O)(C)(C)C.[NH2:38]C1C(C(OCC)=O)=NC(NC[C@H]2CCCN2C(OC(C)(C)C)=O)=NC=1NC1C=CC=CC=1OC>ClCCl>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:21]1[C:20](=[O:32])[NH:19][C:18]2[C:22]1=[N:23][C:15]([NH:14][CH2:13][C@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[N:16][C:17]=2[C:33]([NH2:38])=[O:35]
Reactant: CCOC(=O)c1nc(NC[C@H]2CCCN2C(=O)OC(C)(C)C)nc(Nc2ccccc2OC)c1N
Reactant: CCOC(=O)c1nc(NC[C@H]2CCCN2C(=O)OC(C)(C)C)nc2c1[nH]c(=O)n2-c1ccccc1OC
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(NC[C@H]3CCCN3)nc21
Yield: 100 %

Procedure:
(R)-Ethyl 2-((1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methylamino)-9-(2-methoxy-phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. (R)-Ethyl 5-amino-2-((1-(tert-butoxy-carbonyl)pyrrolidin-2-yl)methylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (0.360 g, 0.740 mmol) and carbonyldiimidiazole (1.19 g, 7.40 mmol) in dichloromethane (20 mL) were reacted according to General Procedure F and purified using Biotage chromatography (0-100% ethyl acetate in hexanes) to afford the title product (0.381 g, 100%). MS (ESI) m/z 513.0 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][CH2:23]Cl>ClCCl>[CH3:21][O:22][CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: COCCl
Reactant: Cc1ccc(C(=O)O)cc1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(C(=O)O)ccc1C
Yield: 104.7 %

Procedure:
In a similar manner to Step 1 of Example 347, 3-hydroxy-4-methylbenzoic acid (2.00 g, 13.1 mmol) was suspended in dichloromethane (50 mL), and the suspension was treated with diisopropylethylamine (13.7 mL, 78.6 mmol) and chloromethyl methyl ether (5.00 mL, 65.8 mmol). The solvent was evaporated under reduced pressure. The residue was dissolved in methanol (50 mL), and the solution was treated with 2 mol/L aqueous potassium hydroxide solution (50 mL). The solvent was evaporated under reduced pressure. The residue was added with 4 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 3-methoxymethoxy-4-methylbenzoic acid (2.69 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Brc1ccc2nccc(N3CCOCC3)c2c1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
6-Bromo-4-chloroquinoline (1.0 G, 4.1 mmol), morpholine (0.468 g, 5.3 mmol) and K2CO3 (1.0 G, 7.2 mmol) in NMP (5 mL) were heated at 100° C. for 12 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and the product was extracted into EtOAc/hexanes (140 mL/60 mL). The organic layer was washed with water (75 mL) and brine (20 mL) successively, dried over MgSO4 and filtered. The filtrate was concentrated and purified by flash column chromatography (Combiflash® companion System® with RediSep® silica gel column 40 g and 30-70% EtOAC/hexanes as an eluting solvent]. The product fractions were concentrated to provide 4-(6-bromoquinolin-4-yl)morpholine (700 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.73 (d, J=5.0 Hz, 1H), 8.13 (d, J=2.2 Hz, 1H), 7.90 (d, J=8.9 Hz, 1H), 7.81 (dd, J=9.0, 2.2 Hz, 1H), 7.06 (d, J=5.0 Hz, 1H), 3.87-3.84 (m, 4H), 3.18-3.02 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=O)[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:5][C:4]=2[N:3]=1.NC1N=C(C)C2C(=[N:38][OH:39])CC(C3C=CC=CC=3C3C=CC=CC=3)CC=2N=1>>[NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:38][OH:39])[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1-c1ccccn1)C2
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccc1)C2
Product: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccn1)C2

Procedure:
The title compound was prepared from 2-amino-4-methyl-7-(2-pyridin-2-yl-phenyl)-7,8-dihydro-6H-quinazolin-5-one from stage 1, following the procedure describing the synthesis of 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (example 5/a stage 2—method A).
Reaction SMILES: Cl/[C:2](/[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[CH:3]/[CH:4]=O.[SH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[O-]CC.[Na+]>CCO.CCOC(C)=O>[NH:8]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[C:6]([C:2]2[S:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][CH:3]=2)=[CH:7]1
Reactant: O=C/C=C(/Cl)c1c[nH]c2ncccc12
Reactant: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-c2c[nH]c3ncccc23)s1
Yield: 74 %

Procedure:
(E)-3-chloro-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)acrylaldehyde (0.9 g. 4.3 mmol) was dissolved in EtOH (20 mL) and ethyl 2-mercaptoacetate (0.76 g, 6.3 mmol) and sodium ethoxide (1.0 g, 14.7 mmol) were added. The reaction mixture was heated to reflux for 90 minutes. The reaction mixture was diluted with EtOAc and the organic layer was washed with saturated sodium bicarbonate, dried over sodium sulfate, and concentrated to a solid, which was purified by column chromatography on silica (20 to 100% EtOAc/hexanes) to give the product, 890 mg, 3.3 mmol, 74% yield. 1H NMR 500 MHz (DMSO-d6) 12.19 (1H, br s), 8.32 (2H, m), 8.13 (1H, s), 7.78 (1H, d), 7.48 (1H, d), 7.23 (1H, dd), 4.31 (2H, q), 1.30 (3H, t).