Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-]#N.[Na+].[N:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28](=[O:43])/[CH:29]=[CH:30]/[C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[C:36](=[N:40][O:41][CH3:42])[CH2:35][CH2:34]3)[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[CH2:12]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([C:28](=[O:43])[CH2:29][CH:30]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[C:36](=[N:40][O:41][CH3:42])[CH2:35][CH2:34]3)[C:10](=[O:11])[C:7]2[CH:8]=[CH:9][N:4]=[CH:5][CH:6]=2)[CH2:26][CH2:27]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CON=C1CCc2cc(/C=C/C(=O)C3CCN(C(=O)OCc4ccccc4)CC3)ccc21
Reactant: O=Cc1ccncc1
Agent: O=C([O-])O
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON=C1CCc2cc(C(CC(=O)C3CCN(C(=O)OCc4ccccc4)CC3)C(=O)c3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.9 %

Procedure:
A solution of sodium cyanide (240 mg, 4.8 mmol) in DMF (15 ml) was treated with a solution of pyridine-4-carbaldehyde (1.71 g, 16 mmol) in DMF (25 ml). After 15 minutes a solution of the product of Step 2 (6.92 g, 16 mmol) in DMF (20 ml) was added dropwise. After stirring at room temperature for 18 hours the mixture was diluted with saturated sodium bicarbonate solution and ethyl acetate. The organic phase was washed with water and brine, dried and concentrated in vacuo and the residue purified by silica gel chromatography to give the title compound (5.6 g, 65%); MS(ES+) m/e 540 [M+H]+.
Reaction SMILES: C([CH:4]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1)[C:5]([CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1)=[O:6])C=C.[O:32]1CC[CH2:34][CH2:33]1.O.I([O-])(=O)(=O)=O.[Na+]>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[CH3:27][O:26][C:24]1[CH:25]=[C:20]([CH:4]([C:5](=[O:6])[CH2:7][C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[CH2:34][CH2:33][OH:32])[CH:21]=[C:22]([O:30][CH3:31])[C:23]=1[O:28][CH3:29]
Reactant: C=CCC(C(=O)Cc1cc(OC)c(OC)c(OC)c1)c1cc(OC)c(OC)c(OC)c1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cc(CC(=O)C(CCO)c2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To a solution of 27.5 g of the compound prepared in (d) above in 640 ml of a mixture of tetrahydrofuran and water (in a 2:1 ratio) was added 9 ml of a 2.5% solution of osmium tetraoxide in tert.-butanol. The reaction mixture was then allowed to stir at room temperature until it darkened to a black opaque mixture, after which time 82.07 g of sodium metaperiodate was added. The resultant mixture was then stirred at room temperature for 20 hours, after which time it was filtered and the solvent was removed by evaporation to yield a residue that was extracted with a mixture of ethyl acetate and water. The organic layer was evaporated and the resultant residue was chromatographed on silica gel employing a mixture of methylene chloride and ethyl acetate in a ratio of 8:1 as the eluent to yield a solid.
Reaction SMILES: C(OC(=O)[N:7]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39]4[CH:44]=[CH:43][CH:42]=[C:41]([P:45]([CH3:48])([CH3:47])=[O:46])[CH:40]=4)=[O:37])=[CH:31][C:30]=3[F:49])[CH:20]=2)=[CH:17][CH:18]=1)[CH2:8][CH2:9][O:10][CH3:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:48][P:45]([C:41]1[CH:40]=[C:39]([NH:38][C:36]([NH:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][C:25]3[CH:24]=[CH:23][N:22]=[C:21]4[CH:20]=[C:19]([C:16]5[CH:17]=[CH:18][C:13]([CH2:12][NH:7][CH2:8][CH2:9][O:10][CH3:11])=[CH:14][N:15]=5)[S:27][C:26]=34)=[C:30]([F:49])[CH:31]=2)=[O:37])[CH:44]=[CH:43][CH:42]=1)([CH3:47])=[O:46]
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5cccc(P(C)(C)=O)c5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)Nc5cccc(P(C)(C)=O)c5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.1 %

Procedure:
To a solution of compound 288 (230 mg, 0.32 mmol) in dichloromethane (7 mL) under nitrogen at room temperature was added trifluoroacetic acid (2.5 mL, 32 mmol). The reaction mixture was stirred for 16 h at room temperature. The solvent was removed under reduced pressure and a saturated aqueous solution of sodium bicarbonate was added. The aqueous phase was extracted with ethyl acetate (3×), the combined organic layers were concentrated. The residue was purified via Biotage (linear gradient 0-20%, methanol/dichloromethane; 25M column) to afford compound 289 as an off-white solid (75.3 mg, 0.122 mmol, 38.0%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.15 (s, 1H), 9.06 (s, 1H), 8.57 (d, J=1.6 Hz, 1H), 8.53 (d, J=5.6 Hz, 1H), 8.31 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.92-7.83 (m, 2H), 7.76 (dd, J=13.2, 2.4 Hz, 1H), 7.67-7.62 (m, 1H), 7.49-7.42 (m, 2H), 7.41-7.33 (m, 1H), 7.32-7.26 (m, 1H), 6.67 (d, J=5.6 Hz, 1H), 3.78 (s, 2H), 3.54-3.34 (2H, hidden under water signal), 3.24 (s, 3H), 2.65 (t, J=5.6 Hz, 2H), 1.65 (d, J=13.2 Hz, 6H). MS (m/z): 620.4 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH:12]=[CH2:13])[N:7]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:15][C:16]1[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=1[O:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH2:12][CH2:13][N:23]2[CH2:22][CH2:21][CH:20]([CH2:19][O:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[Cl:15])[CH2:25][CH2:24]2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1cncc(OC(C)(C)C)n1
Reactant: Clc1ccccc1OCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1cncc(CCN2CCC(COc3ccccc3Cl)CC2)n1
Temperature: 100 °C
Reaction time: 48 h
Yield: 10.9 %

Procedure:
After adding 1.16 g of 2-tert-butoxy-6-vinylpyrazine, 860 mg of 4-(2-chlorophenoxymethyl)piperidine hydrochloride and 0.43 g of anhydrous potassium carbonate to 10 ml of N,N-dimethylformamide, the mixture was stirred for 2 days at 100° C. Ice water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (145 mg, 11% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[O:17][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]=2[CH3:21])=[O:15])=[CH:6][CH:5]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:39]N1C(=O)CCC1=O>ClC1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[O:17][C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[C:20]=2[CH2:21][Br:39])=[O:15])=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(OCCNC(=O)c2oc3ccccc3c2C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: COC(=O)c1ccc(OCCNC(=O)c2oc3ccccc3c2CBr)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution of 4-{2-[(3-methylbenzofuran-2-carbonyl)amino]ethoxy}benzoic acid methyl ester (0.340 mol) in chlorobenzene (1000 ml) was treated with 2,2′-azobisisobutyronitrile (5.60 g, 0.017 mol) and N-bromosuccinimide (75.76 g, 0.426 mol). The resulting mixture is heated to 80° C. and stirred for one hour. After completion of reaction, the reaction mixture was cooled to ambient temperature and washed with water, 3% sodium hydrogensulfite, and again with water. Solvent was distilled under reduced pressure and after cooling to ambient temperature, dichloromethane was added and to give 4-{2-[(3-bromomethylbenzofuran-2-carbonyl)amino]ethoxy}benzoic acid methyl ester which was used in the next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH3:6].C(N(CC)CC)C.C(O[CH2:18][C:19]1[S:23][C:22]([NH:24][C:25]([C:27]2[CH:28]=[C:29]([Cl:44])[C:30]([N:33]3[CH2:38][CH2:37][CH:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:35][CH2:34]3)=[N:31][CH:32]=2)=[O:26])=[N:21][C:20]=1[C:45]1[S:46][CH:47]=[C:48]([Cl:50])[CH:49]=1)(=O)C>CN(C)C1C=CN=CC=1.CCO>[Cl:44][C:29]1[C:30]([N:33]2[CH2:34][CH2:35][CH:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:37][CH2:38]2)=[N:31][CH:32]=[C:27]([C:25](=[O:26])[NH:24][C:22]2[S:23][C:19]([CH2:18][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:6])=[C:20]([C:45]3[S:46][CH:47]=[C:48]([Cl:50])[CH:49]=3)[N:21]=2)[CH:28]=1
Reactant: CNCCOC
Reactant: CCOC(=O)C1CCN(c2ncc(C(=O)Nc3nc(-c4cc(Cl)cs4)c(COC(C)=O)s3)cc2Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1CCN(c2ncc(C(=O)Nc3nc(-c4cc(Cl)cs4)c(CN(C)CCOC)s3)cc2Cl)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
39 μl of N-(2-methoxyethyl)methylamine, 51 μl of triethylamine and 23 mg of 4-(dimethylamino)pyridine were added to a 6 ml EtOH suspension of 107 mg of ethyl 1-(5-{[5-[(acetoxy)methyl]-4-(4-chlorothiophen-2-yl)thiazol-2-yl]carbamoyl}-3-chloro-2-pyridyl)piperidine-4-carboxylate, and the mixture was stirred at 50° C. for 2 hours. After the solvent was distilled off, a saturated sodium hydrogencarbonate aqueous solution was added, and the mixture was extracted with EtOAc, and washed with water and with brine(saturated sodium chloride aqueous solution). The resulting product was dried over magnesium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography using a hexane:EtOAc (10:1 to 3.5:1) as an elution solvent to obtain 90 mg of ethyl 1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(2-methoxyethyl)(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylate.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CCOCC>[Pd].CO>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:12][NH2:13])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1ccc(CN2CCCCC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NCc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
Add 4-(piperidin-1-ylmethyl)-benzonitrile (890 mg, 4.45 mmol), 2M hydrogen chloride in ether (8.9 mL, 17.8 mmol) and 10% Pd/C (90 mg) to methanol (100 mL) in a pressure vessel. Flush the vessel three times with hydrogen and charge to 50 psi with hydrogen. Stir at room temperature for 2 h. Filter the catalyst through Celite® and concentrate the filtrate in vacuo. Purify by chromatography on silica gel (100 g) eluting with a gradient of DCM to 4:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain the title compound as a colorless oil (0.82 g, 90%). MS (ES+) m/z: 205 (M+H)+.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5](=[O:26])[CH2:6][N:7]([C:12](=[O:25])[C@H:13]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23])[NH:14][N+]([O-])=O)[CH2:8][CH2:9][O:10][CH3:11])[CH3:3].[H][H]>C(O)C.[Pd]>[ClH:1].[CH2:2]([O:4][C:5](=[O:26])[CH2:6][N:7]([C:12](=[O:25])[C@H:13]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:23])[NH2:24])[NH2:14])[CH2:8][CH2:9][O:10][CH3:11])[CH3:3]
Reactant: [H][H]
Reactant: CCOC(=O)CN(CCOC)C(=O)[C@H](CCCNC(=N)N)N[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CN(CCOC)C(=O)[C@@H](N)CCCNC(=N)N
Yield: 81 %

Procedure:
To a solution of 4.0 g of NG -nitro-L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride in 50 ml of ethanol was added 0.5 g of palladium-black and then the mixture was shaken in a hydrogen atmosphere for 150 hours at room temperature. At the end of this period, the ethanol solution was filtered to remove the catalyst and evaporated to give an oily product. Reprecipitation with ethanol-ethyl ether gave 3.0 g (81%) of L-arginyl-N-(2-methoxyethyl)glycine ethyl ester hydrochloride in the form of a powder.
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[C:33]([NH:34][C:35](=[O:39])[CH2:36][O:37][CH3:38])=[CH:32][C:31]2[C:27](=[CH:28][C:29](=[O:40])[N:30]=2)[CH:26]=1.N1CCCCC1>C(O)C>[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[NH:34][C:35](=[O:39])[CH2:36][O:37][CH3:38])[NH:30][C:29](=[O:40])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Reactant: COCC(=O)Nc1cc2c(cc1F)=CC(=O)N=2
Solvent: C1CCNCC1
Solvent: CCO
Product: COCC(=O)Nc1cc2c(cc1F)/C(=C/c1[nH]c3c(c1C)C(=O)N(C[C@@H](O)CN1CCOCC1)CC3)C(=O)N2
Temperature: 25 °C
Yield: 85.7 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f (40 mg, 0.125 mmol) was dissolved in 2 mL of ethanol under stirring at room temperature, and 5-fluoro-6-methoxyacetamido-2-oxoindole 13a (26.7 mg, 0.112 mmol) was then added to the solution. Upon completion of the addition, the reaction mixture was stirred until all dissolved, and piperidine (0.05 mL, 0.5 mmol) was then added to the solution. Upon completion of the addition, the reaction mixture was heated to reflux in an oil bath for 2 hours. The reaction was completed until TLC showed the disappearance of starting materials. The reaction mixture was naturally cooled down to room temperature, and filtered under reduced pressure to give the title compound (S,Z)-N-{5-fluoro-3-[5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide 13 (52 mg, yield 85.8%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>C(#N)C>[NH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NCCCN
Solvent: CC#N
Product: NCCCNc1ccc([N+](=O)[O-])cn1
Reaction time: 7.5 h

Procedure:
A solution of 2-chloro-5-nitropyridine (3.16 g, 20 mmol) in dry acetonitrile (40 ml) was added dropwise to a solution of 1,3-diaminopropane (5.0 ml) in acetonitrile (20 ml) at room temperature. After 7.5 hour, a yellow solid precipitated in the reaction mixture. The solvent was removed in vacuo and the residue was partitioned between 2.5 M aqueous sodium hydroxide and dichloromethane. The layers were separated and the aqueous portion was extracted 3× with dichloromethane. The combined organic layers were back-extracted with a saturated sodium chloride solution, then dried and concentrated in vacuo using a Buchi rotary evaporator Model R-124 to give (3-aminopropyl)(5-nitro (2-pyridyl))amine as a yellow solid (2.55 g). The amine (1.14 g, 6 mmol) was shaken with benzotriazole carboxamidinium 4-methylbenzenesulfonate (2.0 g, 6 mmol) and diisopropylethyl amine (DIEA) (1.05 ml, 6 mmol) in acetonitrile (10 ml) at room temperature over two days. Dilution with ether gave the amino-{3-[(5-nitro (2-pyridyl))amino]propyl}carboxamidinium 4-methylbenzenesulfonate as a solid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2].[CH3:34][S:35]([CH:38]=[CH2:39])(=[O:37])=[O:36]>>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][N:20]([CH2:39][CH2:38][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CNC3)n(C)c2n1
Reactant: C=CS(C)(=O)=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(CCS(C)(=O)=O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
To a solution of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxyazetidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.22 mmol) in IMS (2 mL) was added methanesulfonylethene (21 μL, 0.25 mmol) and the resulting mixture allowed to stir at r.t. for 18 h. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%). The resulting residue was triturated with EtOAc and cyclohexane and the resulting solid dried in vacuo affording 826 (83 mg, 67%). LCMS (method I): RT 2.65 min, [M+H]+ 555.3. 1H NMR (DMSO, 400 MHz): δ 8.05-8.05 (1 H, m), 7.64-7.63 (1 H, m), 7.26-7.25 (2 H, m), 4.27 (4 H, brd s), 4.02 (2 H, d, J=7.94 Hz), 3.79 (4 H, t, J=4.57 Hz), 3.72 (3 H, s), 3.42 (2 H, d, J=7.99 Hz), 3.28-3.25 (2 H, m), 3.17 (2 H, t, J=6.52 Hz), 3.05 (3 H, s), 2.89 (2 H, t, J=6.53 Hz), 1.40 (3 H, s), 1.35 (3 H, t, J=7.43 Hz)
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)(=[O:4])=[O:3].[CH3:13][C:14]([NH:18][CH2:19][CH:20]=[O:21])([CH3:17])[C:15]#[CH:16]>C1C=CC=CC=1>[CH3:13][C:14]([N:18]([CH2:19][CH:20]=[O:21])[C:11]([NH:10][C:8]1[S:9][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6][N:7]=1)=[O:12])([CH3:17])[C:15]#[CH:16]
Reactant: C#CC(C)(C)NCC=O
Reactant: CS(=O)(=O)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: C#CC(C)(C)N(CC=O)C(=O)Nc1nnc(S(C)(=O)=O)s1

Procedure:
A mixture of 5-methylsulfonyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the diethyl acetal of 2-(1,1-dimethylprop-2-ynylamino)acetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the diethyl acetal of 2-[1-(1,1-dimethylprop-2-ynyl)-3-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:24]([NH:26][C@@H:27]([C:29](O)=[O:30])[CH3:28])=[O:25])[CH:13](CC1C=CC=CC=1)[C:14](=[O:16])[OH:15])=O)C1C=CC=CC=1.Cl.[CH3:33][O:34][CH2:35][C@H:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH3:33][O:34][CH2:35][C@H:36]([NH:43][C:29](=[O:30])[C@@H:27]([CH3:28])[NH:26][C:24](=[O:25])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH2:11])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O)C(=O)O
Reactant: COC[C@H](N)c1ccccc1
Agent: Cl
Product: COC[C@H](NC(=O)[C@@H](C)NC(=O)[C@@H](N)CC(=O)O)c1ccccc1
Yield: 57.3 %

Procedure:
The same process as in Example 15 was repeated, except that N-benzyloxycarbonyl-β-benzyl-L-aspartyl-D-alanine was used in place of N-benzyloxycarbonyl-β-benzyl-L-aspartyl-D-valine and that (R)-α-methoxymethylbenzylamine hydrochloride was used in place of (R)-α-ethoxymethyl benzylamine hydrochloride, and α-L-aspartyl-D-alanine-(R)-α-methoxymethylbenzylamide was obtained as a solid product. The total yield was 57.3%.
Reaction SMILES: [O-]CC.[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:18]([CH:19]=[O:20])=[CH:17][C:16]([CH3:21])=[CH:15][C:14]=1[CH:22]=[O:23].[CH2:24]([SH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:24]([S:31][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:18]([CH:19]=[O:20])=[CH:17][C:16]([CH3:21])=[CH:15][C:14]=1[CH:22]=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: SCc1ccccc1
Reactant: Cc1cc(C=O)c(OCCCCCCBr)c(C=O)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C=O)c(OCCCCCCSCc2ccccc2)c(C=O)c1

Procedure:
A solution of sodium ethoxide (69 mg sodium, 3 mmol in ethanol 1 ml) was added to a stirred suspension of 2-(6-bromohexyloxy)-5-methyl-1,3-benzenedicarboxaldehyde (0.98 g, 3 mmol) and benzyl mercaptan (0.35 g, 3 mmol) in ethanol (10 ml) at room temperature under nitrogen. After 1 hour evaporated, water (10 ml) and 2M sodium hydroxide (2 ml) added and extracted with diethyl ether (10 ml). The extracts were washed with water, dried, filtered and evaporated to an oil (1.12 g). Chromatography on silica eluting with dichloromethane gave 2-(6-benzylthiohexyloxy)-5-methyl-1,3-benzenedicarboxaldehyde as a colourless oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:19]([OH:21])=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:23].[CH3:24][O:25][CH2:26][CH:27]1[CH2:32][NH:31][CH2:30][CH2:29][NH:28]1>N1C=CC=CC=1>[F:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:31]1[CH2:30][CH2:29][NH:28][CH:27]([CH2:26][O:25][CH3:24])[CH2:32]1)[N:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:8]=[C:7]([C:19]([OH:21])=[O:20])[C:6]2=[O:22]
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(Cl)c(F)cc2c1=O
Reactant: COCC1CNCCN1
Solvent: c1ccncc1
Product: COCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2)CCN1

Procedure:
A 906 mg portion of 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1.4 g of 2-(methoxymethyl)piperazine were added to 10 ml of pyridine and reacted as described in Example 81, giving 187 mg of the desired product, mp 216°-218° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH:24]([CH2:28]Br)[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[CH:24]([C:25]([NH2:27])=[O:26])[CH2:28]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C(Br)CBr
Reactant: COc1ccc(CNCCNc2cccc(Cl)c2)cc1OC
Product: COc1ccc(CN2CCN(c3cccc(Cl)c3)CC2C(N)=O)cc1OC

Procedure:
In a manner similar to Preparation 1, react N-(3-chlorophenyl)-N'-[(3,4-dimethoxyphenyl)methyl]-1,2-ethanediamine (13.3 g, 41 mmol) with 2,3-dibromopropanamide (19.1 g, 166 mmol) to obtainthe title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].C([O-])(O)=O.[Na+]>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])[CH3:12])=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Br)c1
Reactant: CNc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1O
Reaction time: 1 h
Yield: 56.3 %

Procedure:
3-Bromo-4-chloro-benzoyl chloride (Step 2A, 106.9 mmol) in acetonitrile (300 mL) was added dropwise over 30 minutes to a vigorously stirring solution of 2-methylamino-phenol (15.1 g, 122.9 mmol) and NaHCO3 (18.0 g, 213.7 mmol) in acetonitrile (200 mL) and water (200 mL). The mixture was stirred for additional 1 h and then concentrated to remove acetonitrile. The solid was filtered, washed with HCl (1N, 600 mL) and water (500 mL), and dried. The solid was dissolved in dichloromethane (500 mL) and n-butylamine (20 mL) was added. The mixture was stirred at rt for 16 hrs and concentrated. The residue was partially purified via silica gel flash chromatography (eluting with 20% to 35% ethyl acetate in hexane) and then crystallized from hexane/ethyl acetate (75/25) to give 3-bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide (20.5 g) as a white solid. MS [M+H]+: 339.7/341.8; tR=2.19 min. (method 1)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.BrC1C=CC([Cl:25])=C(Cl)C=1>>[Cl:8][C:6]1[CH:5]=[C:4]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=[CH:2][C:7]=1[Cl:25]
Reactant: O=C(Cc1ccccc1)c1cc(Cl)cc(Cl)c1
Reactant: Clc1ccc(Br)cc1Cl
Product: O=C(Cc1ccccc1)c1ccc(Cl)c(Cl)c1
Yield: 42.4 %

Procedure:
Prepared following the procedure described in Intermediate 13, starting from 4-bromo-1,2-dichlorobenzene, where the crude product was purified by column chromatography (PE:EtOAc=100:1) to afford Intermediate 19 (230 mg, yield 42.4%).