Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[NH:13][C:12](=[O:22])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:25][N:26]([CH2:28][CH2:29]Cl)[CH3:27]>C1(C)C=CC=CC=1>[CH3:25][N:26]([CH3:27])[CH2:28][CH2:29][N:13]1[C:14]2[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=2[C:16](=[O:17])[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11][C:12]1=[O:22]
Reactant: CN(C)CCCl
Reactant: COc1ccc(C2CCC(=O)Nc3ccccc3C2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(C2CCC(=O)N(CCN(C)C)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To azeotropically dried 4,5-Dihydro-5-(4-methoxyphenyl)-1-benzazocine-2,6(1H,3H)-dione (1.80 g) in toluene (40 ml) was added 60% sodium hydride in mineral oil (0.27 g) and the mixture stirred under nitrogen at room temperature overnight. The slurry was stirred and heated to 70° for 15 minutes, and the freshly prepared N,N-dimethylaminoethyl chloride (1.25 g) was slowly added. After a half an hour at 70°, a further 1.25 g of N,N-dimethylaminoethyl chloride was added. The temperature was then raised to 90° and maintained for 3 hours. The cooled reaction mixture was filtered through sintered glass and the filtered solid discarded. The filtrate was evaporated and the residue was triturated with ether. The resulting white solid was collected on a filter; wt. 1.58 g (72%), mp=115-116. Recrystallization from ether gave pure titled product; wt. 1.25 g, mp=116°-117°.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][N:27]3[CH:35]=[CH:36][CH:37]=[C:26]3[CH2:25]2)=[O:23])=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:35]1[N:27]2[C:26]([CH2:25][N:24]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[O:9][CH3:8])=[CH:17][CH:18]=3)=[O:23])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28]2)=[CH:37][CH:36]=1)=[O:4]
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Trichloroacetyl chloride (2.63 mL, 23.6 mmol) was added dropwise over five minutes to a solution of (2′-methoxy-biphenyl-4-yl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (3.0 g, 7.60 mmol) and N,N-diisopropylethyl amine (2.65 mL, 15.2 mmol) in dichloromethane (60 mL). The reaction was stirred under nitrogen at room temperature overnight and then quenched with water. The organic layer was washed with 0.1N hydrochloric acid and water, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was purified by flash chromatography over silica gel Merck-60 using a 0-5% gradient of ethyl acetate in dichloromethane to give the title compound (2.34 g) as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:22]([CH2:23]O)=[N:21][N:20]=[C:19]2[CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=[O:8].[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:22]([CH2:23][N:34]3[C:33](=[O:35])[C:32]4=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]4[C:30]3=[O:40])=[N:21][N:20]=[C:19]2[CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=[O:8]
Reactant: CN(C)CCc1nnc(CO)n1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)CCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F

Procedure:
In the manner given in Example 1B, 5-chloro-2',6'-difluoro-2-[3-[2-(dimethylamino)ethyl]-5-(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone in methylene chloride is treated with phthalimide, triphenylphosphine and diethyl azodicarboxylate to give 5-chloro-2',6'-difluoro-2-[3-[2-(dimethylamino)ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[CH2:25]([NH2:33])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:33][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Reactant: NCCc1ccccc1
Solvent: CCOC(C)=O
Product: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(NCCc3ccccc3)nc21
Temperature: 180 °C
Yield: 31.4 %

Procedure:
A mixture of 100 mg (0.26 mmol) of 3-(2,6-dichlorophenyl)-3,4-dihydro-7-methanesulfonyl-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 400 μl (3.4 mmol) of phenethylamine was heated at 180° C. for 4 hours and then cooled to room temperature. The mixture was dissolved in 10 ml of ethyl acetate and washed in sequence with 10 ml of 2M hydrochloric acid and 10 ml of saturated aqueous sodium bicarbonate solution. The ethyl acetate phase was separated, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash column chromatography on silica gel using 5% methanol/dichloromethane for the elution. Product-containing fractions were combined and evaporated to give 35 mg of 3-(2,6-dichlorophenyl)-3,4-dihydro-1-methyl-7-(2-phenylethylamino)pyrimido[4,5-d]pyrimidin-2(1H)-one as a pale yellow solid of melting point 148-151° C.
Reaction SMILES: [CH2:1]([SnH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH:10]([O:12][CH:13]=[CH2:14])=[O:11]>>[CH:10]([O:12][CH2:13][CH2:14][Sn:5]([CH2:14][CH2:13][O:12][CH:10]=[O:11])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])=[O:11]
Reactant: C=COC=O
Reactant: CCCC[SnH2]CCCC
Product: CCCC[Sn](CCCC)(CCOC=O)CCOC=O

Procedure:
The addition of dibutyltin dihydride to vinyl formate was carried out in a Pyrex® tube at 30°-35° C. by following the operating procedure of Example 5. The product was not isolated, because it decomposed as it was being formed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13](=[O:37])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([C:29](=[O:36])[C:30]#[C:31][C:32]([OH:35])([CH3:34])[CH3:33])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2I)[CH:15]=1>>[CH3:11][O:12][C:13](=[O:37])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)/[C:30](=[C:31](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:32]([OH:35])([CH3:34])[CH3:33])/[C:29]2=[O:36])[CH:15]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#CC(C)(C)O)c2ccccc2I)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/c3ccc(Cl)cc3)C(C)(C)O)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 84 starting from 4-chlorophenylboronic acid (commercially available) and 3-{[(4-hydroxy-4-methyl-pent-2-ynoyl)-(2-iodo-phenyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (400 MHz, DMSO-d6) δppm 1.30 (s, 6H) 3.83 (s, 3H) 5.14 (s, 2H) 5.43 (d, J=7.58 Hz, 1H) 6.68 (t, J=7.58 Hz, 1H) 7.01 (d, J=7.83 Hz, 1H) 7.12 (t, J=7.45 Hz, 1H) 7.27 (d, J=8.34 Hz, 2H) 7.51 (t, J=7.71 Hz, 1H) 7.58-7.65 (m, 4H) 7.87 (d, J=7.58 Hz, 1H) 7.97 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[N:3]=1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: COc1ccc(CN)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(Cl)nc3c2ncn3C(C)C)cc1

Procedure:
2Chloro-6-[(4-methoxybenzyl)amino]-9-(2-propyl)purine is prepared from 2,6-dichloro-9-(2-propyl)purine (see Example 19 for preparation), 4-methoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [Na].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1.[CH2:25]([O:27][C:28](=[O:31])[CH2:29]Br)[CH3:26]>C(O)C>[C:28]([CH2:29][N:22]1[N:23]=[N:24][C:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH2:12][C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:2]=3)[CH:15]=2)=[N:21]1)([O:27][CH2:25][CH3:26])=[O:31]
Reactant: CCOC(=O)CBr
Reactant: c1cc(OCc2ccc3ccccc3n2)cc(-c2nnn[nH]2)c1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)Cn1nnc(-c2cccc(OCc3ccc4ccccc4n3)c2)n1
Reaction time: 16 h

Procedure:
To a solution of 0.2 g sodium in 30 ml ethanol was first added 1.1 g of 5-[3-(2-quinolylmethyloxy)phenyl]tetrazole and then 30 minutes 0.6 g of ethylbromoacetate and stirring was continued at 80° C. for 16 hours.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[CH:2]1.CCN(CC)CC.C(OCl)(C)(C)C.[CH3:36][C:37]([CH3:49])=[CH:38][CH2:39]B1C2CCCC1CCC2>C1COCC1>[CH3:36][C:37]([C:2]1[NH:1][C:9]2[C:4]([C:3]=1[CH2:10][CH2:11][N:12]1[C:13](=[O:22])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]1=[O:21])=[CH:5][CH:6]=[CH:7][CH:8]=2)([CH3:49])[CH:38]=[CH2:39]
Reactant: CC(C)=CCB1C2CCCC1CCC2
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccccc12
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(C)(C)c1[nH]c2ccccc2c1CCN1C(=O)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[2-(1H-indol-3-yl)ethyl]-1H-isoindole-1,3(2H)-dione (3.77 g, 13.0 mmol) in dry THF (0.13 L) under argon was added NEt3 (1.84 mL, 13.0 mmol). This mixture was cooled to −78° C., and neat t-BuOCl (1.54 mL, 13.0 mmol) was added. The reaction mixture was stirred for 30 min at −78° C. A solution of 9-(3-methyl-2-butenyl)-9-bora-bicyclo[3.3.1]nonane (40 mmol) in hexanes was added. The reaction mixture was stirred for 6 h at −78° C. It was quenched with 1 M aq HCl, and permitted to warm to rt overnight. The reaction mixture was extracted with CH2Cl2. The CH2Cl2 extracts were dried, filtered, and concentrated to give an oil. The oil was purified by silica chromatography to give the title compound: TLC Rf=0.36 (CH2Cl2); MS (ESI+) m/z 381.2, 359.2; 1H NMR (300 MHz, CDCl3) δ 7.91 (1H), 7.88-7.69 (5H), 7.29 (1H), 7.10 (2H), 6.18 (1H), 5.25 (2H), 3.95 (2H), 3.16 (2H), 1.61 (6H).
Reaction SMILES: [CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]([NH2:21])=[N:18][CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.C1O[C@H]1CCl.C12[CH:37]([C:38]3C=C[C:41]([OH:44])=[CH:40][CH:39]=3)C(CCC1)CCC2.C(OCC)(=O)C#CCC>C(O)C>[CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]5=[N:21][C:41](=[O:44])[CH:40]=[C:39]([CH2:38][CH3:37])[N:18]5[CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:4][CH2:3][CH2:2]1)[CH2:6][CH2:7][CH2:8]2
Reactant: Oc1ccc(C2C3CCCC2CCC3)cc1
Reactant: NC1=NC[C@@H](COc2ccc(C3C4CCCC3CCC4)cc2)O1
Agent: CCC#CC(=O)OCC
Agent: ClC[C@H]1CO1
Solvent: CCO
Product: CCc1cc(=O)nc2n1C[C@@H](COc1ccc(C3C4CCCC3CCC4)cc1)O2
Temperature: 25 °C

Procedure:
To a solution of (S)-5-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.26 g, 0.828 mmol), prepared in accordance with the procedures as set forth in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 4-bicyclo[3.3.1]non-9-yl phenol (prepared with the same procedure as set forth in steps 1 and 2 of Example 20), in ethanol (5 mL) was added ethyl 2-pentynoate (0.157 g, 1.24 mmol). The reaction mixture was heated at reflux for 14 hrs and then cooled to room temperature. The reaction mixture was concentrated and loaded onto a silica gel column, and eluted with 4-6% methanol/methylene chloride to afford 120 mg of (S)-2-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-5-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one. [α]D25 −36.89 (c 0.501, CHCl3).
Reaction SMILES: O1CCOCC1.[C:7](O)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[N:17]1([C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29](=[O:34])[CH2:28]3)=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(Cl)Cl>[C:7]([N:20]1[CH2:21][CH2:22][N:17]([C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29](=[O:34])[CH2:28]3)=[O:24])[CH2:18][CH2:19]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C1Cc2cc(C(=O)N3CCNCC3)ccc2N1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1Cc2cc(C(=O)N3CCN(C(=O)c4ccccc4)CC3)ccc2N1
Yield: 23 %

Procedure:
To a mixed solvent of 20 ml of dioxane and 20 ml of methylene chloride were added 1.2 g of benzoic acid and 3.0 g of 5-(1-piperazinylcarbonyl)oxindol hydrochloride. To this mixture, a solution of 2.1 g of N,N-dicyclohexylcarbodiimide dissolved in 5 ml of methylene chloride was added dropwise at 10° to 20° C. under ice-cooling externally with stirring. Then, the mixture was stirred for 3.5 hours at the same temperature. Crystals which precipitated were filtered off, and the filtrate was concentrated to dryness under reduced pressure. The resultant residue was dissolved in 100 ml of methylene chloride, and the organic layer was washed, in turn, with 5% aqueous hydrochloric acid solution, 5% aqueous sodium hydrogen carbonate solution, and water, and dried over anhydrous sodium sulfate. Under reduced pressure, the solvent was distilled off and the residue was recrystallized from methanol to give 0.79 g of 5-(4-benzoyl-1-piperazinylcarbonyl)oxindol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:5]([O:7][CH3:8])=[O:6].[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([S:40](Cl)(=[O:42])=[O:41])=[CH:39][C:34]=2[O:33][CH2:32]1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[O:31]1[C:35]2[CH:36]=[CH:37][C:38]([S:40]([NH:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[C:11]=3[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[C:5]([O:7][CH3:8])=[O:6])(=[O:41])=[O:42])=[CH:39][C:34]=2[O:33][CH2:32]1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Reactant: COC(=O)c1cc(N)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc3c(c2)OCO3)c(Oc2ccccc2OC)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1.04 g of methyl 3-amino-4-(2-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in pyridine (30 ml), treated dropwise while cooling with ice with a solution of 1.1 g of benzo[1,3]-dioxol-5-sulphonyl chloride in toluene (10 ml) and subsequently stirred at RT for 20 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate. After removing the solvent there was obtained the desired methyl 3-(benzo[1,3]dioxol-5-sulphonylamino)-4-(2-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a resin.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[N:11][CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:13].[Mn]([O-])(=O)(=O)=O.[K+]>>[C:1]1([C:7]2[N:12]=[N:11][CH:10]=[N:9][C:8]=2[NH2:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cncnn2)cc1
Reactant: N
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: Nc1ncnnc1-c1ccccc1
Temperature: -37 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a mixture of 6-phenyl-[1,2,4]triazine (18 g, 115 mmol) in anhydrous liquid ammonia (1 l) under an atmosphere of nitrogen at −37° C. was added in one portion potassium permanganate (22.6 g, 143 mmol). The reaction mixture was stirred at −37° C. for 30 min and then the ammonia evaporated. To the residue was added propan-2-ol (800 ml) and the resulting mixture heated under reflux for 10 min, then filtered through hyflo. The filtrate was evaporated in vacuo. The residue was purified by flash chromatography (SiO2; 4% MeOH in CH2Cl2+0.5% NH3) to afford 9.8 g (57 mmol, 50%) of 6-phenyl-[1,2,4]triazin-5-ylamine as a yellow solid. δH (360 MHz; CDCl3) 5.58 (2H, br s, NH2), 7.51-7.57 (3H, m, aromatics), 7.68-7.72 (2H, m, aromatics), 8.80 (1H, s, triazine H3); m/z (ES+) 173 (M++H, 100%).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][NH:5][C:6](=[O:29])[CH2:7][C:8]1[N:9]=[C:10]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:15])[S:11][CH:12]=1.C(OC1C=C(C)C=CC=1NC(=O)NC1SC=C(CC(O)=O)N=1)C(C)C.Cl.COC(=O)CN>>[CH2:25]([O:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[NH:16][C:14](=[O:15])[NH:13][C:10]1[S:11][CH:12]=[C:8]([CH2:7][C:6]([NH:5][CH2:4][C:3]([OH:30])=[O:2])=[O:29])[N:9]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: COC(=O)CNC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2OCC(C)C)n1
Agent: COC(=O)CN
Agent: Cc1ccc(NC(=O)Nc2nc(CC(=O)O)cs2)c(OCC(C)C)c1
Agent: Cl
Product: Cc1ccc(NC(=O)Nc2nc(CC(=O)NCC(=O)O)cs2)c(OCC(C)C)c1
Yield: 85.6 %

Procedure:
(2-{2-[3-(2-isobutoxy-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetylamino)-acetic acid (90 mg, 86%) was prepared from (2-{2-[3-(2-isobutoxy-4-methyl-phenyl)-ureido]-thiazol-4-yl)-acetylamino)-acetic acid methyl ester (108 mg, 0.25 mmol) following the general procedure J. (2-{2-[3-(2-asobutoxy-4-methyl-phenyl)-ureido]-thiazol-4-yl)-acetylamdino)-acetic acid methyl ester (150 mg, 70%) was in turn prepared from {2-[3-(2-isobutoxy-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid (181 mg, 0.5 mmol) and glycine methyl ester hydrochloride following the general procedure K.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.[CH3:11][CH2:12][OH:13].CC(O)=O.O>[Pd]>[C:12]([O:10][CH2:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)(=[O:13])[CH3:11]
Reactant: CCO
Reactant: OCCCc1ccncc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCCCC1CCNCC1
Reaction time: 24 h

Procedure:
Commercially available 4-pyridinepropanol (6-10) (38 g, 277 mmol) was dissolved in 100 ml EtOH/HOAc/H2O (4:1:1) and treated with 2.0 g 10% Pd/C. This mixture was hydrogenated on a Parr reactor for 24 h at 55 psi. The catalyst was removed by filtration and the filtrate evaporated to give 3-(4-piperidinyl)propyl acetate.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[CH:21]=[CH:22][CH:23]=[C:13]3[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(O)C>[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[CH:21]=[CH:22][CH:23]=[C:13]3[CH2:12][CH2:11]2)=[O:9])=[CH:24][CH:25]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cccn2-c2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCc3cccn3-c3ccccc32)cc1
Reaction time: 5 h

Procedure:
A mixture of 2.0 g of 6,7-dihydro-5-(4-nitrobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepine, 20 ml of ethyl alcohol and 20 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography on silica gel to give the desired product.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH2:9][O:10][CH:11]2[CH2:20][CH2:19][C:14]3(OCC[O:15]3)[CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1.O>C(O)(=O)C>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:4]=[C:5]([CH2:9][O:10][CH:11]2[CH2:12][CH2:13][C:14](=[O:15])[CH2:19][CH2:20]2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(COC2CCC3(CC2)OCCO3)c1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCC(OCc2cccc(C(F)(F)F)c2)CC1

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 2, using 7.9 grams (0.025 mole) of 8-(3-trifluoromethylphenylmethoxy)- 1,4-dioxaspiro[4.5]decane, and 25 mL of water in 50 mL of acetic acid, yielding 4-(3-trifluoromethylphenylmethoxy)cyclohexanone.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>C(#N)C>[Br:1][C:2]1[N:3]=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: NCc1ccncc1
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: Brc1cn2ccnc2c(NCc2ccncc2)n1
Temperature: 25 °C

Procedure:
A solution of 6,8-Dibromo-imidazo[1,2-a]pyrazine 3 (1.0 equiv.), 4-aminomethylpyridine (1.0 equiv.) and potassium carbonate (3.0 equiv.) is dissolved in 20 ml 3:1 acetonitrile: dimethylacetamide and is stirred at 100° C. for 16 hours. The mixture is cooled to RT and partitioned between ethyl acetate (EtOAc) and saturated NaHCO3. The aqueous phase is extracted with EtOAc and combined extracts are dried over Na2SO4. The solvent is removed under reduced pressure and the resulting residue is purified by flash chromatography (EtOAc) to yield (6-Bromo-imidazo[1,2-a]pyrazin-8-yl)-pyridin-4-ylmethyl-amine 4.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][C:16]1[NH:17][CH:18]=[C:19]([CH3:21])[CH:20]=1>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:4]([C:18]2[NH:17][C:16]([CH3:15])=[CH:20][C:19]=2[CH3:21])=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: Cc1c[nH]c(C)c1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(C(=O)c2cccnc2Cl)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
2-Chloronicotinoyl chloride (3.4 g, 20 mmol) (Aldrich, Milwaukee, Wis.) was added to a solution of aluminum chloride (2.7 g, 20 mmol) (Aldrich, Milwaukee, Wis.) in dichloromethane (100 mL) at 0° C., followed by a solution of 2,4-dimethylpyrrole (2.9 g, 30 mmol) in dichloromethane (20 mL). The mixture was then stirred at room temperature for one hour. The reaction was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was purified on a silica gel column to give 2.9 g (62%) of (2-chloro-pyridin-3-yl)-(3,5-dimethyl-1H-pyrrol-2-yl)-methanone.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[N:4]([S:13]([CH3:12])(=[O:15])=[O:14])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: ClCc1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)n1c(CCl)nc2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.8 %

Procedure:
To a solution of 2-(chloromethyl)benzimidazole (80 g, 0.48 mol) and methanesulfonyl chloride (58.3 mL, 0.75 mol) in 0.5 L of methylene chloride, triethylamine (136 mL, 0.97 mol) was added dropwise under nitrogen. The resulting mixture was stirred at room temperature for 6 hours. The mixture was filtered and the filtrate was evaporated. The residue was triturated in methanol and filtered to afford 74.9 g of the title compound as a brown solid.