Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=O.[CH3:13][N:14]1[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[C:15]1[C:22]([OH:24])=[O:23].[CH2:25](O)[C:26]1[CH:34]=[CH:33][C:32]2[O:31][CH2:30][O:29][C:28]=2[CH:27]=1.Cl>CN(C)C=O.O>[O:31]1[C:32]2[CH:33]=[CH:34][C:26]([CH:25]([O:23][C:22]([C:15]3[N:14]([CH3:13])[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=3)=[O:24])[C:12]3[CH:11]=[CH:27][C:28]4[O:29][CH2:30][O:31][C:32]=4[CH:33]=3)=[CH:27][C:28]=2[O:29][CH2:30]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: Cn1cc(C(=O)O)cc1C(=O)O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)O)cc1C(=O)OC(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
1,1′-Carbonyldiimidazole (1.3 g, 8.0 mmol) was added to a stirred solution of N-methyl-2,4-pyrrole-dicarboxylic acid (0.6 g, 3.5 mmol) in dimethylformamide (6 mL) under an inert atmosphere and heated to 40° C. After 30 minutes the mixture was allowed to cool, and piperonyl alcohol (1.1 g, 7.1 mmol) was added. The mixture was heated to 60° C. for 3 hours, then poured into water (100 mL), stirred, and acidified with 4N HCl. The resulting mixture was extracted twice with ethyl acetate (60 mL), and the combined extracts were washed successively with water, 0.5 M aqueous sodium bicarbonate, and saturated brine, then dried over MgSO4. The solvent was removed under reduced pressure, and the residue was dissolved in a minimum of hot acetonitrile, cooled, and filtered. The filtrate was taken to dryness under reduced pressure, and the residual product (0.9 g) was chromatographed on a column of silica gel under nitrogen pressure, eluting with ethyl acetate/petroleum ether 2:3. Evaporation of the appropriate fractions and drying afforded 1-methyl-1H-pyrrole-2,4-dicarboxylic acid di-1,3-benzodioxol-5-ylmethyl ester; mp 103-110° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC1C([P+]([O:32][C:33]([CH3:35])=[O:34])(C2C=CC=CC=2)C2C=CC=CC=2)=CC=CC=1.[C:36]1(C)C=CC=CC=1>>[CH3:36][O:32][C:33](=[O:34])[CH:35]=[C:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: CC(=O)O[P+](c1ccccc1)(c1ccccc1)c1ccccc1C
Reactant: Cc1ccccc1
Reactant: O=C1CCC2(CC1)OCCO2
Product: COC(=O)C=C1CCC2(CC1)OCCO2
Yield: 81 %

Procedure:
A solution of 1,4-dioxa-spiro[4.5]decan-8-one (5.00 g, 32.0 mmol) in 65 mL of anhydrous toluene was treated with methyl(triphenylphosphoranylidene) acetate (13.9 g, 41.6 mmol). The mixture was stirred at reflux for 18 h under nitrogen. Solvent was removed and the crude was purified by silica gel column chromatography using a 20% EtOAc:hexanes mixture as eluent to afford (1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid methyl ester (5.51 g, 81%) as a colorless oil.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[C:15]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[S:30][C:29](N)=[N:28][C:27]=3[C:32]([F:35])([F:34])[F:33])[CH:23]=[CH:22][N:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:12])[CH3:9].O.[ClH:37]>C(#N)C.C(Cl)(Cl)Cl>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[C:15]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[S:30][C:29]([Cl:37])=[N:28][C:27]=3[C:32]([F:35])([F:34])[F:33])[CH:23]=[CH:22][N:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:12])[CH3:9]
Reactant: Cl
Reactant: CCOC(=O)c1cccc(Nc2nccc(-c3sc(N)nc3C(F)(F)F)n2)c1
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cccc(Nc2nccc(-c3sc(Cl)nc3C(F)(F)F)n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
t-Butyl nitrite (0.87 mL, 6.54 mmol) is added drop-wise to a suspension of N-[3-ethoxycarbonyl-phenyl]-4-(2-amino-4-trifluoromethyl-5-thiazolyl)-2-pyrimidineamine (1.34g, 3.27 mmol) and anhydrous cupric chloride (925 mg, 6.55 mmol) in acetonitrile (15 mL) over 0.5 hours. After stirring at room temperature for 3 hours, water and chloroform are added and the mixture is made acidic with 12N hydrochloric acid. The layers are separated and the aqueous layer is extracted with chloroform. The combined organic extracts are dried over MgSO4, filtered and concentrated. The residue is purified by chromatography on silica gel to give N-[3-ethoxycarbonyl-phenyl]-4-[2-chloro-4-trifluoromethyl-5-thiazolyl]-2-pyrimidineamine (1.1 g); ESI-MS (m/z): 429 (M++H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13]3[N:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][C:7]=2[N:8]=1.[CH:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)([CH3:24])[CH3:23].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:22]([C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:19]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([N:11]3[CH2:10][CH2:9][C:7]4[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[CH2:12]3)[N:18]=2)=[O:21])=[CH:27][CH:26]=1)([CH3:24])[CH3:23]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CSc1ncc2c(n1)CCN(c1cccc(C(=O)O)n1)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3ccc(C(C)C)cc3)n1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-[2-(Methylthio)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]pyridine-2-carboxylic acid (600 mg, 1.98 mmol), 4-isopropylaniline (0.28 ml, 1.98 mmol) and DIEA (1.64 ml, 9.90 mmol) in DMF (10 ml) was treated with HATU (828 mg, 2.18 mmol) and the reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water, dried (MgSO4), filtered and concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 1:1 hexanes:EtOAc) gave the title compound as an oil which crystallized on standing (804 mg, 97%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:7]=[C:6]([CH3:19])[C:5]=1[C:20]([OH:22])=O.[N:23]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][CH2:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[N:7]=[C:6]([CH3:19])[C:5]=1[C:20]([N:31]1[CH2:32][CH2:33][CH:28]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:29][CH2:30]1)=[O:22]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COCc1c(C(=O)O)c(C)nn1-c1cccc(C(F)(F)F)c1
Product: COCc1c(C(=O)N2CCC(N3CCCC3)CC2)c(C)nn1-c1cccc(C(F)(F)F)c1
Yield: 95 %

Procedure:
In analogy to the procedure described in Example 18], 5-methoxymethyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave the title compound in 95% yield as light brown viscous oil. MS: 451.2 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:49])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]2[C:25]3[C:17](=[CH:18][C:19]4[CH2:20][O:21][CH2:22][C:23]=4[C:24]=3[CH3:26])[C@@H:16]([N:27]([CH2:34][C:35]3[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([C:45]([F:48])([F:47])[F:46])[CH:36]=3)[C:28]3[N:29]=[N:30][N:31]([CH3:33])[N:32]=3)[CH2:15][CH2:14][CH2:13]2)[CH2:7][CH2:6]1.[OH-].[Na+].Cl>CO.O>[F:48][C:45]([F:46])([F:47])[C:37]1[CH:36]=[C:35]([CH:40]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:38]=1)[CH2:34][N:27]([C:28]1[N:29]=[N:30][N:31]([CH3:33])[N:32]=1)[CH:16]1[C:17]2=[CH:18][C:19]3[CH2:20][O:21][CH2:22][C:23]=3[C:24]([CH3:26])=[C:25]2[N:12]([CH2:11][CH:8]2[CH2:9][CH2:10][CH:5]([CH2:4][C:3]([OH:49])=[O:2])[CH2:6][CH2:7]2)[CH2:13][CH2:14][CH2:15]1
Reactant: COC(=O)CC1CCC(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc4c(c(C)c32)COC4)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c2c(cc3c1N(CC1CCC(CC(=O)O)CC1)CCCC3N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)COC2
Temperature: 60 °C

Procedure:
To a solution of (S)-(4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-4-methyl-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}-cyclohexyl)-acetic acid methyl ester (0.15 mmol) in methanol (5 mL), add 5 N sodium hydroxide (3 mL). Heat the mixture to 60° C. for 2 h, then cool to room temperature and dilute with water (20 mL). Neutralize the reaction with 5M HCl and extract the organics with ethyl acetate (3×10 mL). Dry the combined organics over sodium sulfate, filter, and remove the solvent under vacuum. Chromatograph the product over silica gel, eluting with ethyl acetate/hexane (10-70%) to obtain the title compound as a colorless foam. MS (ES+): 681 (M+H).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1[Cl:12])=[O:5])C.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Mg]Br>C1COCC1>[Cl:12][C:11]1[CH:10]=[C:9]([Cl:13])[N:8]=[N:7][C:6]=1[C:4]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH3:14])=[O:5]
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: COc1ccccc1[Mg]Br
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)c1nnc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
4,6-Dichloro-pyridazine-3-carboxylic acid ethyl ester (1.032 g, 4.67 mmol, prepared as described by Xie et al., WO 2004031174) was dissolved in 25 ml dry THF, and the reaction mixture was cooled in a dry ice/acetone bath for 15 minutes. 2-Methoxyphenyl magnesium bromide (7 mL of 1 M solution in THF, 7.00 mmol) was added, and the reaction mixture was stirred for 8 hours under nitrogen at −78° C. Silica gel (11.0 g) was added, and the reaction mixture was allowed to warm to room temperature. Solvent was removed under reduced pressure, and the residue was purified by flash chromatography (0% to 20% EtOAc/Hexanes) to yield 1.029 g (3.65 mmol, 78%) of (4,6-dichloro-pyridazin-3-yl)-(2-methoxy-phenyl)-methanone as a yellow solid. Mass Spec. M+H=283.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:18]([O:20][C:21](=[O:26])/[CH:22]=[CH:23]/[CH2:24]Br)[CH3:19]>CO>[CH2:18]([O:20][C:21](=[O:26])/[CH:22]=[CH:23]/[CH2:24][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)=[CH:16][CH:15]=1)[CH3:19]
Reactant: CCOC(=O)/C=C/CBr
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Solvent: CO
Product: CCOC(=O)/C=C/COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
Analogously to the procedure described in Example 5, the use of 11.4 g of 4-(1-adamantyl)-phenol and 14.5 g of 4-bromocrotonic acid ethyl ester as starting materials gives 4-[4-(1-adamantyl)-phenoxy]-crotonic acid ethyl ester of melting point 91°-93° C (from methanol).
Reaction SMILES: C(O[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[CH2:11][NH:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([C:19](Br)=[CH:20][N:21]=2)[N:18]=1)=[O:5])=C.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CC#N.O.CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:19]1[N:17]2[N:18]=[C:13]([N:12]3[CH2:11][C@@H:7]4[CH2:8][CH2:9][CH2:10][N:6]4[C:4]3=[O:5])[CH:14]=[CH:15][C:16]2=[N:21][CH:20]=1
Reactant: C=COC(=O)N1CCC[C@H]1CNc1ccc2ncc(Br)n2n1
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1-c1cnc2ccc(N3C[C@@H]4CCCN4C3=O)nn12
Temperature: 150 °C
Yield: 64.4 %

Procedure:
A mixture of (S)-2-[(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-methyl]-pyrrolidine-1-carboxylic acid vinyl ester (125 mg, 0.34 mmol), (2-methoxyphenyl)boronic acid (67.2 mg, 0.44 mmol), K2CO3 (141 mg, 1.02 mmol) and dichlorobis(triphenylphosphine)palladium(II) (12 mg, 0.017 mmol) in MeCN/water (3.2 ml/0.8 ml) was heated in a microwave at 150° C. for 15 min. The reaction was repeated at 140° C. After removal of the water the reaction mixtures was combined and diluted with MeCN and filtered. The filtrate was subjected to preparative HPLC to give the titled compound (S)-2-[3-(2-Methoxy-phenyl)-imidazo[1,2-b]pyridazin-6-yl]-hexahydro-pyrrolo[1,2-c]imidazol-3-one (76.5 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39-1.51 (m, 1H) 1.89-2.02 (m, 1H) 2.05-2.18 (m, 2H) 3.18-3.26 (m, 1H) 3.72-3.96 (m, 6H) 4.09-4.16 (m, 1H) 7.04-7.13 (m, 2H) 7.35-7.42 (m, 1H) 7.90-7.96 (m, 1H) 8.03-8.10 (m, 2H) 8.40 (dd, J=9.85, 2.78 Hz, 1H). LRMS (ESI) m/z 350.2 [(M+H)]+, calc'd for C19H19N5O2: 349.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:5][NH:6][NH2:7].C([O:14][C:15](=O)[CH:16]([CH:18]=O)[CH3:17])C>C(O)C>[CH3:18][C:16]1[C:15](=[O:14])[N:6]([CH2:5][C:4]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)[NH:7][CH:17]=1
Reactant: CCOC(=O)C(C)C=O
Reactant: NNCc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: Cc1c[nH]n(Cc2ccc(Cl)c(Cl)c2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.9 g of 3,4-dichlorobenzylhydrazine were added dropwise to a solution of 7.5 g of a α-formylpropionic acid ethyl ester in 50 ml of ethanol. After stirring overnight at room temperature, the solvent was distilled off in vacuo and the solid residue was recrystallized from ethanol.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][OH:13])(=[O:3])[CH3:2].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.C(=O)(O)[O-].[Na+]>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][O:13][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][O:16]1)(=[O:3])[CH3:2]
Reactant: C1=COCCC1
Reactant: CC(=O)OCC=C(C)CCC=C(C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCC=C(C)CCC=C(C)COC1CCCCO1
Yield: 95.8 %

Procedure:
A mixture of 8-acetoxy-2,6-dimethyl-2,6-octadien-1-ol (1.81 g, 8.52 mmol) and dihydropyran (1.17 ml, 12.8 mmol) in dichloromethane (6 ml) was stirred, and p-toluenesulfonic acid (40 mg) was added thereto, and the mixture was stirred at room temperature for 30 minutes. After addition of saturated aqueous sodium bicarbonate (30 ml), the product was extracted with hexane/ether (5:1.2) (30 ml). The extract was dried over Na2SO4 and evaporated in vacuo to remove the solvent to give a residue, which was purified with silica gel column chromatography to give 1-acetoxy-8-(2-tetrahydropyranyl)oxy-3,7-dimethyl-2,6-octadiene (2.42 g, 96%).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:21])[C:13]=1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.C(=O)(O)[O-].[Na+]>>[Cl:3][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:21])[C:13]=1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cn1c(-c2cccnc2)c(CCCCCCO)c2ccccc21
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1c(-c2cccnc2)c(CCCCCCCl)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.36 ml) is combined with 3-(6-hydroxyhexyl)-1methyl-2-(3-pyridyl)indole (1.37 g) at 0°. The mixture is then stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate is added and the mixture is extracted with dichloromethane. The extract is washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield the crude chloride, 3-(6-chlorohexyl)-1-methyl-2-(3-pyridyl)indole. 3-(6-Chlorohexyl)-1-methyl-2-(3-pyridyl)indole (0.5 g) is combined with dimethyl malonate (792 mg), potassium carbonate (790 mg) and dimethylformamide (11.6 ml) and the mixture is heated at 80°-90° for 18 hours under nitrogen. The mixture is poured into ice water (80 ml), and acidified with 1N NCl and washed with ether. The aqueous layer is adjusted to pH 6 and extracted with ether which is then dried over anhydrous magnesium sulfate and concentrated to yield 3-[7,7-(bis-methoxycarbonyl)heptyl]-1-methyl-2 -(3-pyridyl)indole.
Reaction SMILES: C([NH:4][C:5]1[N:14]=[C:13](C2N=CNN=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:11]=2)[N:6]=1)(=O)C.[CH3:27][O:28][CH2:29][CH2:30][OH:31]>>[NH2:4][C:5]1[N:14]=[C:13]([O:31][CH2:30][CH2:29][O:28][CH3:27])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:11]=2)[N:6]=1
Reactant: CC(=O)Nc1nc(-c2nc[nH]n2)c2cc(-c3ccc(F)cc3)ccc2n1
Reactant: COCCO
Product: COCCOc1nc(N)nc2ccc(-c3ccc(F)cc3)cc12
Yield: 84 %

Procedure:
This compound, synthesized from 2-acetamido-6-(4-fluorophenyl)-4-(1,2,4-triazolyl)-quinazoline and 2-methoxyethanol in 84% yield using the same procedure as in example 18, was characterized by its mass spectrum as follows: MS (m/z): 299 ([M+H]+, 100).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)O1>>[N+:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[CH:11]=1)([O-:14])=[O:13]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=[N+]([O-])c1cc(Br)nc2ccccc12
Product: Nc1ccc(-c2cc([N+](=O)[O-])c3ccccc3n2)cc1

Procedure:
4-(4-Nitroquinolin-2-yl)aniline T492P was prepared by using general procedure A from 2-Bromo-4-nitroquinoline (50 mg, 0.2 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (44 mg, 0.2 mmol). The product was obtained as a dark brown solid (31 mg, 58%). NMR (400 MHz, CDCl3): δ 8.36 (m, 1H), 8.32 (s, 1H), 8.20 (m, 1H), 8.06 (m, 2H), 7.80 (m, 1H), 7.65 (m, 1H), 6.81 (m, 2H), 3.99 (br s, 2H); MS (ESI): 266 (M+H+).
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[CH2:9][NH:8][CH:7]([C:14]([OH:16])=[O:15])[CH2:6]2.[CH3:17]O>>[ClH:1].[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[CH2:9][NH:8][CH:7]([C:14]([O:16][CH3:17])=[O:15])[CH2:6]2
Reactant: O=C(O)C1Cc2cc(O)c(O)cc2CN1
Reactant: CO
Agent: Cl
Product: COC(=O)C1Cc2cc(O)c(O)cc2CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 40° C., a steam of gaseous hydrogen chloride was bubbled through a solution of 1,2,3,4-tetrahydro-6,7-dihydroxy-3-isoquinolinecarboxylic acid (32.4 g, 155.0 mmol) in 1.5 l of methanol for 2 hours. After stirring overnight at room temperature, the solvent was distilled off in vacuo and the residue triturated with ether to furnish 38.95 g of the product. Melting point 204.8° C.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[N:6]([CH3:19])[CH:7]=[C:8]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:9]=1)=[O:4].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([C:8]2[CH:9]=[C:5]([C:3](=[O:4])[CH2:2][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:6]([CH3:19])[CH:7]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: Cn1cc(C(=O)c2ccc(Cl)cc2)cc1C(=O)CCl
Reactant: C1CCNCC1
Product: Cn1cc(C(=O)c2ccc(Cl)cc2)cc1C(=O)CN1CCCCC1
Yield: 81.4 %

Procedure:
A solution of 4 g (0.013 mole) of 2-chloro-1-[4-(4-chlorobenzoyl)-1-methyl-1H -pyrrol-2-yl]-ethanone (11) and 4.08 mL (0.039 mole) of piperidine in 60 mL 2-PrOH was heated under reflux for 1 h. The solvent was evaporated in vacuo and the residue was taken up in diethyl ether/THF, washed with water, brine, and dried (MgSO4). Evaporation of the solvent gave a tan solid which was recrystallized from 2-PrOH to give 3.65 g of product: mp 129-130° C.; mass spectrum (Cl—CH4) m/z=345 (M+1); NMR 300 MHz (CDCl3) d 7.8 (m, 2H); 7.6 (s, 1H); 7.45 (d, 2H); 7.35 (s, 1H); 4.0 (s, 3H); 3.6 (s, 2H); 2.5 (br s, 4H); 1.6 (m, 4H); 1.4 (m, 2H). Anal Calcd for C19H21Cl2N2O2: C, 66.18; H, 6.14; N, 8.12. Found: C, 66.25; H, 6.16; N, 8.08.
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[F:13])=[O:4].[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C@@H:16]([O:22][C:23]([C:25]1([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[CH2:15]2>CC#N>[Br-:1].[F:13][C:7]1[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=1[NH:5][C:3]([CH2:2][N+:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C@@H:16]([O:22][C:23]([C:25]1([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24])[CH2:15]2)=[O:4]
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Reactant: O=C(CBr)Nc1cc(F)ccc1F
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)Nc1cc(F)ccc1F
Product: [Br-]
Temperature: 25 °C
Reaction time: 30 h
Yield: 65.8 %

Procedure:
A mixture of 2-bromo-N-(2,5-difluoro-phenyl)-acetamide (Example 41a) (47 mg) and 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (56 mg) in MeCN (1 mL) was stirred at room temperature for 30 h. The resulting precipitate was filtered off, washed with ether and dried at 50° C. under vacuum overnight to afford the title compound (65 mg) as a colourless solid.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:18][O:19][CH3:20])[CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:6][CH:5]=1.Cl>C1COCC1.O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:18][O:19][CH3:20])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCC(=NOC)c1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(CCC(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.3 %

Procedure:
Lithium hydroxide (0.632 g, 26.40 mmol) was added in one portion at 20° C. to a solution of ethyl 4-(4-chlorophenyl)-4-(methoxyimino)butanoate (Intermediate 14) (1.78 g, 6.60 mmol) in THF (30 ml) and water (20 ml). The resulting solution was stirred at room temperature for 6 hours then acidified with dilute HCl and extracted with TBME (2×). The combined extracts were washed with brine, dried over MgSO4 and evaporated to give 4-(4-chlorophenyl)-4-(methoxyimino)butanoic acid (1.520 g, 95%) as a colourless solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:5]1=[O:15].[C:16](OC(=O)C)(=[O:18])[CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.N1CCNC1=O>>[C:16]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:6][C:5]1=[O:15])(=[O:18])[CH3:17]
Reactant: O=C1NC(c2ccccc2)CN1CCO
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1NCCN1
Product: CC(=O)OCCN1CC(c2ccccc2)NC1=O

Procedure:
Approximately 9.2 g of 1-(2-hydroxyethyl-4-phenyl-2-imidazolidone is stirred with acetic anhydride (25 ml.) and p-toluenesulfonic acid (200 mg.) for four hours, during which time the imidazolidone completely dissolves. The solution (100 ml.) from which a white solid precipitates. The solid is extracted with methylene chloride (3×100 ml.). The organic layer is separated, dried and the solvent removed to give a pale yellow solid. Recrystallization from either gives the title compound as a white crystalline solid; m.p. 88°-90° C.