Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[Si:16]([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:17][Si:16]([CH3:19])([CH3:18])[O:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][N:11]([Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]2=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][Si:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C1NCCN1c1ccc(O)c(O)c1
Reactant: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)Oc1ccc(N2CCN([Si](C)(C)C)C2=O)cc1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3.4 g (17.5 mmol) of 1-(3,4-dihydroxyphenyl)-2-imidazolidinone in 10 ml of ethyl acetate was added 7.6 g (70 mmol) of chlorotrimethylsilane, and subsequently 7.0 g (70 mmol) of triethylamine. After stirring overnight at room temperature, the precipitate was filtered off under nitrogen and the filtrate evaporated to dryness in vacuo; yield: 7.14 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=2[O:22][CH3:21])[N:14]=1)=[O:8]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CI)cs1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: C1CCOC1
Product: COc1ccc(CNCc2csc(NC(=O)NCc3ccc(Cl)c(Cl)c3)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3,4-dichlorobenzyl)-3-(4-(iodomethyl)thiazol-2-yl)urea (Intermediate 6) was taken up in tetrahydrofuran and an excess of the 2,4-dimethoxy-benzylamine (20 eq.) was added. The reaction was allowed to stir overnight at room temperature. The volatiles were removed in vacuo. Resulting oil triturated with water to give a gooey solid. Water was decanted off and resulting residue was purified by column chromatography using 0-8% gradient of 7 N ammonia/MeOH and DCM to give 1-(3,4-Dichloro-benzyl)-3-{4-[(2,4-dimethoxy-benzylamino)-methyl]-thiazol-2-yl}-urea.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[CH:23]=[CH:24][C:9]2=3)=[CH:4][CH:3]=1.[N+:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35])([O-:27])=[O:26]>N1C=CC=CC=1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=3[CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N+:25]([O-:27])=[O:26])(=[O:35])=[O:36])=[CH:7][CH:6]=2)[C:14](=[O:15])[CH2:13]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)cc1
Solvent: c1ccncc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])cc2)c2ccc3c(c2N1)CCCC3
Temperature: 80 °C
Reaction time: 17 h
Yield: 78 %

Procedure:
5-(4-Aminophenyl)-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione (190 mg, 0.59 mmol) obtained in Example 10, o-nitrobenzenesulfonyl chloride (197 mg, 0.89 mmol), and dry pyridine (5 mL) were mixed. The mixture was stirred at 80° C. for 17 hours. Pyridine was removed by evaporation under reduced pressure. To the residue was added water. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give the titled compound as pale yellow crystal (233 mg, yield 78%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].[CH:19](OCC)=[O:20].[H-].[Na+].O>CCOCC>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH:19]=[O:20])[C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccccc1-c1ccccc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(C=O)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 24 g biphenylacetic acid ethyl ester and 8.2 g ethyl formate is added dropwise while stirring to a suspension of 2.4 g sodium hydride in 250 ml ether. The reaction mixture is stirred for 2 hours at room temperature and cold water is carefully added. The aqueous phase is acidified to pH 2 and the product is extracted with ether. The extract is dried and concentrated by evaporation.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]1.N1C2C(=CC=CC=2)C=[C:15]1C(OCC)=O>>[CH3:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]1
Reactant: COC(=O)c1cccc2cc[nH]c12
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: COC(=O)c1cccc2ccn(C)c12
Yield: 90 %

Procedure:
According to the procedure of Preparation 9 (a), except substituting methyl indole-7-carboxylate for the ethyl indole-2-carboxylate, the title compound (2.4 g, 90%) was obtained as an oil: MS (ES) m/e 190.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][CH:33]=[C:34]([CH:37]=2)[C:35]#[N:36])O1.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:35]([C:34]1[CH:37]=[C:30]([C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])[CH:31]=[N:32][CH:33]=1)#[N:36]
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cncc(-c2cccc(C(=O)Nc3ccc(OC(F)(F)F)cc3)c2)c1

Procedure:
3-bromo-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 3.1, 50 mg, 0.139 mmol), 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (0.180 mmol), 2 M Na2CO3 (0.104 mL, 0.208 mmol), (Ph3P)4Pd (8 mg, 6.94 μmol), water (0.8 mL) and DME (2.4 mL) were added to a vial, which was sealed and subjected to MW irradiation at 150° C. for 10 min. The RM was filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL) and the cartridge was washed with MeOH (10 mL). The combined filtrates were evaporated to dryness under reduced pressure and the crude product was purified by preparative HPLC to afford the title compound. LC-MS (Condition 5) tR=1.24 min, m/z=384.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[N:18]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([Sn](CCCC)(CCCC)[C:82]1[CH:87]=[CH:86][CH:85]=[CH:84][N:83]=1)CCC>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]>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:24]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:19]2[N:20]=[C:21]([CH3:23])[N:22]=[C:17]([C:4]3[CH:3]=[C:2]([C:82]4[CH:87]=[CH:86][CH:85]=[CH:84][N:83]=4)[CH:7]=[N:6][C:5]=3[NH:8][C:9]3[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[N:18]=2)=[CH:27][CH:28]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
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
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(-c4ccccn4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 110 °C

Procedure:
A mixture of 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.100 g, 0.171 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (4.08 mg, 8.56 μmol), tris(dibenzylideneacetone)dipalladium(0) (7.84 mg, 8.56 μmol) and 2-(tributylstannyl)pyridine (0.082 g, 0.223 mmol) (Alfa Aesar) was purged with argon and toluene (0.9 mL) was added. The tube was sealed and the mixture was heated at 110° C. The reaction mixture was cooled to room temperature, treated with water, extracted with DCM (2×15 mL), dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography using an ISCO Combiflash Companion (12 g column, 20-50% EtOAc in hexanes over 30 min; product eluted with about 30-35% EtOAc). 1H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H); 9.41 (d, J=2.5 Hz, 1H); 8.93 (d, J=2.3 Hz, 1H); 8.66 (d, J=4.9 Hz, 1H); 8.30 (d, J=2.7 Hz, 1H); 7.93 (dd, J=8.9, 2.6 Hz, 1H); 7.67-7.75 (m, 1H); 7.59-7.65 (m, 1H); 7.15-7.24 (m, 5H); 6.85 (dd, J=20.0, 8.6 Hz, 4H); 6.72 (d, J=8.8 Hz, 1H); 4.87 (d, J=17.2 Hz, 4H); 3.94 (s, 3H); 3.81 (s, 3H); 3.76 (s, 3H); 2.59 (s, 3H). m/z (ESI, +ve ion) 627.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][Br:15])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)C(F)(F)Oc1cccc(CBr)c1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
EX-628A) To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (50 g, 0.24 mol) and N-bromosuccinimide (42.75 g, 0.24 mol) in 100 mL of carbon tetrachloride under nitrogen was added 2,2′-azobisisobutyronitrile (0.71 g, 0.004 mol). The resultant mixture was refluxed for 2 h then cooled to room temperature and quenched with 300 mL of water. The organic layer was collected, washed with water and brine, dried over MgSO4, and concentrated in vacuo to give 66.0 g (96%) of the desired crude 3-(1,1,2,2-tetrafluoroethoxy)bromomethylbenzene product as a yellow oil. 1H NMR indicates that this oil is a mixture of products: 7% dibrominated, 67% monobrominated, and 20% starting material. The crude product was used without further purification. ESMS m/z=287 [M+H]+.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(O[CH:12]=[C:13]([C:19]#[N:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.O>C(O)(=O)C>[NH2:20][C:19]1[N:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=[CH:12][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1ccccn1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cnn(-c2ccccn2)c1N
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A solution of 21.83 g of 2-hydrazinopyridine and 38.2 g of ethyl (ethoxymethylene)cyanoacetate dissolved in 150 ml of acetic acid and 50 ml of water was heated on a steam bath for approximately 16 hours. The reaction mixture was allowed to cool to room temperature and placed in a refrigerator whereupon crystals slowly formed. The precipitated solid was collected by filtration and washed with cold 50% aqueous ethanol to provide 23.6 g of 5-amino-1-(2-pyridinyl)-1H-pyrazole-4-carboxylic acid, ethyl ester. Yield 50.9%. mp=89°-91° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=[CH:4][CH:3]=1.[OH:25]O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=[O:25])=[CH:4][CH:3]=1
Reactant: OO
Reactant: O=c1ccc2cc(OCCCCSc3ccc(Br)cc3)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCS(=O)c3ccc(Br)cc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 123 from 6-[4-(4-bromophenyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:16])[N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][N:38]([C:41](=[O:43])[CH3:42])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1>CN(C=O)C.CCOC(C)=O>[C:41]([N:38]1[CH2:37][CH2:36][N:35]([C:32]2[CH:33]=[CH:34][C:29]([NH:28][C:2]3[N:10]=[C:9]4[C:5]([NH:6][C:7](=[O:16])[N:8]4[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][N:3]=3)=[CH:30][CH:31]=2)[CH2:40][CH2:39]1)(=[O:43])[CH3:42]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CCC(CC)n1c(=O)[nH]c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)n1c(=O)[nH]c2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Temperature: 140 °C
Yield: 30.7 %

Procedure:
To a mixture of 2-chloro-9-(1-ethyl-propyl)-7,9-dihydro-purin-8-one (95 mg, 0.4 mmol) and TsOH (1.6 mL, 0.2 M in 1,4-dioxane) in DMF (0.25 mL) is added 1-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanone (105 mg, 0.5 mmol). The reaction mixture is sealed in a microwave reactor and heated at 140° C. for 30 min. The mixture is diluted with EtOAc and washed with NaHCO3 aqueous solution and brine. The organic layer is dried over Na2SO4, filtered and concentrated. The crude product is purified by preparative HPLC to give 52 mg of 2-[4-(4-acetyl-piperazin-1-yl)-phenylamino]-9-(1-ethyl-propyl)-7,9-dihydro-purin-8-one as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[C:24]([O:28][C:29]([N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:39]=2)[NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O1CCCC1.CN(C)C1C=CN=CC=1>[C:24]([O:28][C:29]([N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:39]=2)[N:34]([C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)CCc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of 3-methoxy-4-[3-o-tolyl-ureido]phenylacetic acid (0.282 g, prepared as described in Example 52B of International Patent Application Publication No. WO 96/22966) in anhydrous tetrahydrofuran (5 ml), under an atmosphere of argon and at 25° C., was treated with powdered molecular sieves 4 Å (0.5 g), 7-(2-ethoxycarbonyl-ethyl)-1,2,3,4-tetrahydro-quinoxaline-1-carboxylic acid tert-butyl ester (0.2 g, Reference Example 3), triethylamine (0,336 ml), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.273 g) and 4-dimethylaminopyridine (7 mg). After stirring at 25° C. for 3 hours the reaction mixture was filtered through a pad of celite and the filter pad was washed three times with ethyl acetate (10 ml). The combined filtrate and washings were washed twice with an aqueous saturated solution of ammonium chloride (20 ml), then with water (20 ml), then dried over magnesium sulphate and then evaporated under reduced pressure (2.7 kPa) at 40° C. The resulting white foamy solid (0.483 g) was subjected to flash chromatography on silica (0,040-0,063 mm) eluting with a mixture of cyclohexane and ethyl acetate (1:1, v/v) to give the title compound (0.3 g) as a white foamy solid. 1H NMR, 400 Hz, (CD3)2SO: δ1.2 (t, 3H); 1.5 (s, 9H); 2.3 (s, 3H); 2.65 (t, 2H); 2.9 (t, 2H); 3.65 (t, 2H); 3.85 (m, 7H); 4.1 (q, 2H); 6.7 (very broad s, 2H); 7.2 (m, 2H); 7.5 (very broad s, 1H); 7.65 (broad s, 1H); 7.8 (d, J=8 Hz, 1H); 8.05 (broad d, J=8 Hz, 1H); 8.5 (s, 1H); 8.6 (broad s, 1H). MS (CI, NH3): MNH4+ 648, MH+ 631.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][O:9][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1
Reactant: CC(C)(CO)CCCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(CCCCCBr)COC1CCCCO1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
To a solution of 7-bromo-2,2-dimethylheptan-1-ol (36.0 g, 133.0 mmol) in dichloromethane (60 mL) was added p-toluenesulfonic acid (0.28 g, 1.3 mmol) and 3,4-dihydro-2H-pyran (18.54 g, 213 mmol) at 5-10° C. under cooling with an ice-water bath. The mixture was stirred and allowed to warm to room temperature overnight. The reaction solution was filtered through neutral alumina (200 g), which was rinsed with dichloromethane (500 mL). Concentration of the solvent gave the crude product as a brown oil, which was subjected to column chromatography on silica gel (240 g) using hexanes:ethyl acetate (50:1) as eluent to yield 2-(7-bromo-2,2-dimethylheptyloxy)-tetrahydropyran as a colorless oil (23.0 g, 48%). 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.54 (t, 1 H, J=3.0 Hz), 3.84 (m, 1 H), 3.51-3.39 (m, 4 H), 2.98 (d, 1 H, J=9.3 Hz), 1.89-1.80 (m, 3 H), 1.70-1.40 (m, 7 H), 1.29-1.22 (m, 4 H), 0.89 (s, 6 H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 99.3, 76.6, 62.1, 39.3, 34.3, 34.2, 33.0, 30.8, 29.2, 25.7, 24.7, 23.2, 19.6. HRMS (LSIMS, nba): Calcd. for C14H27BrO2: 307.1272, found: 307.1245.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[CH2:10]([O:9][C:7]([C:6]1[CH:5]=[C:4]([CH3:12])[S:3][C:2]=1[NH:1][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:8])[CH3:11]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCOC(=O)c1cc(C)sc1N
Solvent: CCO
Product: CCOC(=O)C(=CNc1sc(C)cc1C(=O)OCC)C(=O)OCC
Temperature: 110 °C

Procedure:
A mixture of 3.7 parts of ethyl 2-amino-5-methylthiophene-3-carboxylate and 4.4 parts of diethyl ethoxymethylenemalonate is heated at 110° C for 1.5 hour. After cooling ethanol is added and the crystals are collected by filtration, whereby diethyl (3-ethoxycarbonyl-5-methylthienyl)aminomethylenemalonate is obtained as crystals. Recrystallization from ethanol give pale yellow needles melting at 67°-68° C
Reaction SMILES: [C:1]1(=[O:8])O[C:5](=[O:6])[CH2:4][C:2]1=[CH2:3].[CH2:9]([NH2:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>N1C=CC=CC=1>[CH2:3]=[C:2]1[CH2:4][C:5](=[O:6])[N:18]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:1]1=[O:8]
Reactant: CCCCCCCCCN
Reactant: C=C1CC(=O)OC1=O
Solvent: c1ccncc1
Product: C=C1CC(=O)N(CCCCCCCCC)C1=O
Temperature: 90 °C

Procedure:
A solution of itaconic anhydride (0.1 M) in pyridine (20 ml)was treated with nonylamine (0.1 M). The reaction mixture was heated to 90° C. for six hours. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: CO[C:3]([C:5]12[CH2:12][CH2:11][CH2:10][N:9]1[CH2:8][CH2:7][CH2:6]2)=[O:4].[CH3:13][C:14](=[N:16]O)[CH3:15].C([Li])CCC>>[CH3:15][C:14]1[CH:13]=[C:3]([C:5]23[CH2:12][CH2:11][CH2:10][N:9]2[CH2:8][CH2:7][CH2:6]3)[O:4][N:16]=1
Reactant: COC(=O)C12CCCN1CCC2
Reactant: CC(C)=NO
Agent: [Li]CCCC
Product: Cc1cc(C23CCCN2CCC3)on1
Yield: 11.2 %

Procedure:
8-(Methoxycarbonyl)-hexahydro-1H-pyrrolizine (from step 1d, 1.56 g, 9.22 mmol), acetone oxime (1.45 g, 19.8 mmol) and n-butyllithium (2.5M in hexane, 16 mL, 39.6 mmol) were combined in a similar fashion as that outlined by J. Saunders et at., J. Med. Chem. 1990, 33: 1128. The crude material was chromatographed (silica gel; CHCl3 /MeOH, 99:1) to afford a yellow oil (199 mg, 11%). MS (CI/NH3) m/e: 193 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.76-1.92 (m, 6H), 2.14-2.29 (m, 2H), 2.24 (s, 3H), 2.61-2.69 (m, 2H), 3.13-3.32 (m, 2H), 5.95 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][C:5]2=[N:4][N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[N:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)nnc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1nnc2n1CCNC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
To a solution of tert-butyl 3-bromo-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (52 mg, 0.172 mmol) in DCM (6 mL) at 0° C. was added TFA (0.26 mL). The reaction was stirred at room temperature for 16 hours before concentrating in vacuo. The residue was purified by elution through an SCX-2 column using 2M NH3/MeOH to give the title compound as yellow solid (29 mg, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N+:10]([CH2:13][CH3:14])([O-:12])=[O:11].C([O-])(=O)C.[NH4+].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:13]([N+:10]([O-:12])=[O:11])[CH3:14])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CC(=Cc1ccc(Br)cc1)[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
A solution of 30.0 g (162 mmol) of 4-bromobenzaldehyde, 116 mL (1.6 mole) of nitroethane, and 37.5 g (486 mmol) of ammonium acetate in 200 mL of toluene was heated under a Dean and Stark trap for 18 hours. The mixture was then cooled to 80° C., 1 mL of concentrated sulfuric acid was added, and the mixture was stirred at 80° C. for 2 hours. The mixture was then cooled to ambient temperature and washed with 200 mL of brine. The organic layer was separated and the aqueous layer was extracted three times with 60 mL of diethyl ether. The combined organics were dried (MgSO4), filtered and coincentrated in vacuo. The residue was recrystallised from methanol to afford 18.7 g (47%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[Cl:1][C:2]1[N:11]=[C:10]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccccc1N
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: COc1ccccc1Nc1nc(Cl)nc2ccccc12

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline and 2-methoxyaniline by a procedure similar to Example 28 (35% yield). 1H NMR (CDCl3): 8.76-8.79 (m, 1H), 8.50 (s, broad, 1H), 7.77-7.88 (m, 3H), 7.54-7.59 (m, 1H), 7.09-7.13 (m, 2H), 6.95-6.99 (m, 2H), 4.00 (s, 3H).