Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:5][N:6]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13][N:12]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10][N:9]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:8][CH2:7]1)([O:3][CH3:4])=[O:2].C[O-].[Na+].[O:31]1[CH2:44][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42]>CO>[C:1]([CH2:5][N:6]1[CH2:17][CH2:16][N:15]([CH2:44][CH:32]([OH:31])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])[CH2:14][CH2:13][N:12]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10][N:9]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:8][CH2:7]1)([O:3][CH3:4])=[O:2]
Reactant: O=C(O)CCCCCCCCC1CO1
Reactant: COC(=O)CN1CCNCCN(CC(=O)OC)CCN(CC(=O)OC)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CN1CCN(CC(=O)OC)CCN(CC(O)CCCCCCCCC(=O)O)CCN(CC(=O)OC)CC1

Procedure:
To a methanol solution of 1,4,7-tris-(carbomethoxymethyl)-1,4,7,10-tetraazacyclododecane (DO3A methyl ester) is added 1.0 equivalent of freshly prepared anhydrous sodium methoxide and the solution is allowed to stir for several hours. To this solution is added one equivalent of 10,11-epoxyundecanoic acid and the solution is brought to reflux overnight. The solvent is removed in vacuo to give a crude hydroxyethylated product, 1,4,7-tris-(carbomethoxymethyl)-10-[2′-hydroxy-10′-carboxy(decyl)]-1,4,7,10-tetraazacyclododecane. Two to five equivalents of this product are dissolved in dimethylformamide (DMF) and corresponding equivalents of dicyclohexylcarbodiimide (DCC) and N-hydroxysuccinimide are added with stirring overnight. To this solution is added one equivalent of generation 2 PAMAM and stirring is continued another 24 hours. The corresponding DO3A methyl ester conjugate is selectively hydrolyzed by treatment with aqueous sodium hydroxide in methanol. Treatment of the DO3A conjugate with excess Gadolinium(III) acetate (Gd(OAc)3) (buffered to pH=6) followed by incubation with excess diethylenetriaminepentaacetic acid (DTPA) and purification of the conjugate using preparative reverse phase HPLC gives a hydroxyethyl DO3A PAMAM starburst conjugate product which contains two to five equivalents of gadolinium which can not be removed by further challenges with excess DTPA.
Reaction SMILES: [Si]([O:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([NH:21][C:22]([CH3:30])([CH2:24][CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH3:23])[C:17]([CH3:31])=[N:16]2)=[CH2:10])(C(C)(C)C)(C)C.[Br:32]N1C(=O)CCC1=O.O>C1COCC1.C(Cl)Cl>[Br:32][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([NH:21][C:22]([CH3:30])([CH2:24][CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH3:23])[C:17]([CH3:31])=[N:16]2)=[O:10]
Reactant: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2nc(C)c(NC(C)(C)CCS(C)(=O)=O)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2cccc(C(=O)CBr)c2nc1NC(C)(C)CCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
A solution of 8-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-methyl-N-(2-methyl-4-(methylsulfonyl)butan-2-yl)quinoxalin-2-amine (338d), 1-bromopyrrolidine-2,5-dione (0.26 g, 1.46 mmol), and water (0.42 mL, 23.49 mmol) in THF (14.68 mL) was stirred at 0° C. for 15 min before it was warmed to RT and stir for 2 h when product was observed via lcms. The reaction mixture was diluted with DCM (150 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (75 mL) before the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% DCM followed by 3% 2 M NH3 in MeOH/DCM to give 2-bromo-1-(2-methyl-3-((2-methyl-4-(methylsulfonyl)butan-2-yl)amino)quinoxalin-5-yl)ethanone (338e, 306 mg, 0.71 mmol, 49% yield) as a red oil. MS (ESI, pos. ion) m/z: 428.2/430.2 (M+1).
Reaction SMILES: [I:1][C:2](=[CH:4][CH2:5][C@H:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)O)[CH3:3].C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:32]([C@H:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)[CH2:5][CH:4]=[C:2]([I:1])[CH3:3])=[N+:33]=[N-:34]
Reactant: CC(I)=CC[C@@H](O)c1ccc2ncccc2c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(I)=CC[C@H](N=[N+]=[N-])c1ccc2ncccc2c1
Temperature: 25 °C

Procedure:
A solution of (5R)-2-iodo-5-(6-quinolyl)-5-hydroxy-2-pentene (1.74 g) in 30 mL of toluene is cooled to 0° C. and treated with diphenylphosphoryl azide (1.65 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.91 g) for 2 hours. The mix is warmed to ambient temperature and diluted with ethyl acetate. The solution is washed sequentially with water, sat. NaHCO3, and brine, then dried over MgSO4, filtered, and evaporated. The product is purified by SiO2 chromatography.
Reaction SMILES: [CH3:1][N:2]([C@@H:9]([CH3:22])[CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)C(=O)C(F)(F)F.C([O-])([O-])=O.[K+].[K+]>CO.O.O>[CH3:1][NH:2][C@@H:9]([CH3:22])[CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(OC[C@H](C)N(C)C(=O)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN[C@@H](C)COc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a stirred solution of methyl (S)-4-[2-[(N-methyl)trifluoroacetamido]-1-propoxy]benzoate (710 mg, 2.22 mmol) in MeOH—H2O (10 ml, 1:1, v/v) was added K2CO3 (460 mg, 3.33 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with H2O and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated to give methyl (S)-4-[2-(N-methylamino)-1-propoxy]benzoate (430 mg, 87%) as a colorless oil. 1H-NMR (CDCl3) δ1.17 (d, J=6.6 Hz, 3 H), 2.48 (s, 3 H), 2.98-3.06 (m, 1 H), 3.86-3.96 (series of s and m, total 5 H), 6.92 (d, J=9.0 Hz, 2 H), 7.98 (d, J=9.0 Hz, 2 H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH2:14]Cl.[C:16]([O-:19])(=[O:18])[CH3:17].[K+].CN(C=O)C>O>[C:16]([O:19][CH2:14][C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:6]2[C:7](=[O:8])[C:2]=1[Br:1])(=[O:18])[CH3:17]
Reactant: O=c1c(Br)c(CCl)nc2ccc(F)cn12
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc2ccc(F)cn2c(=O)c1Br
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A mixture of 3-bromo-2-(chloromethyl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one (10.60 g, 36.36 mmol), potassium acetate (4.283 g, 43.64 mmol), and DMF (138.5 mL) was stirred at 40° C. After 3 h, the mixture was concd under reduced pressure. To the residue was added water (200 mL) and the resulting precipitate was collected by filtration, washed with water (300 mL), and dried to give (3-bromo-7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.98 (1H, dd, J=4.9, 2.7 Hz), 8.18 (1 H, ddd, J=9.8, 7.1, 2.8 Hz), 7.86 (1 H, dd, J=9.7, 5.4 Hz), 5.21 (2 H, s), 2.16 (3 H, s); Mass Spectrum (ESI) m/e=315.0 [M+1 (79Br)] and 316.9 [M+1 (81Br)].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.[CH:21](=O)[CH3:22].[C:24](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:25].[Na+]>>[CH2:21]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1)[CH3:22].[CH2:24]([N:1]([CH2:21][CH3:22])[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1)[CH3:25]
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC=O
Agent: [Na+]
Product: CCN(CC)c1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Product: CCNc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %
Yield: 5 %

Procedure:
A mixture of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (581 mg, 2.20 mmol), acetaldehyde (116 mg, 2.64 mmol), and sodium triacetoxyborohydride (606 mg, 2.86 mmol) was stirred at room temperature for 3 h. The reaction was then partitioned between ethyl acetate and H2O. The organic phase was washed with dilute aqueous NaHCO3 solution, H2O, brine and then dried with Na2SO4. The solvent was removed in vacuo and the residue was dissolved in CHCl3/MeOH and purified by chromatography (silica gel, hexanes/EtOAc, 7:3) to give 3-(6-Ethylamino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (395.1 mg, 61%) as a yellow solid and 3-(6-Diethylamino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (32.9 mg, 5%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([F:9])[C:7]=1[OH:8]
Reactant: CCOC(=O)/C=C/c1cc(F)c(O)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-ethyl 3-(3,5-difluoro-4-hydroxyphenyl)acrylate (10) (0.751 g, 3.29 mmol) in ethanol (20 mL) was added Pd/C (81 mg, 10% Degussa type). A balloon of hydrogen gas was added and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred under a hydrogen balloon overnight at room temperature, filtered through a pad of celite and concentrated in vacuo to give ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (11).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([N+:14]([O-])=O)=[C:10]([CH:13]=2)[C:11]#[N:12])[CH:5]=[CH:4][N:3]=[CH:2]1.O.NN.C([OH:22])C>[Ni].CC(N(C)C)=O>[NH2:14][C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:13][C:10]=1[C:11]([NH2:12])=[O:22]
Reactant: CCO
Reactant: N#Cc1cc(-n2ccnc2)ccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CC(=O)N(C)C
Product: NC(=O)c1cc(-n2ccnc2)ccc1N
Temperature: 40 °C

Procedure:
A mixture of 5-(1-imidazolyl)-2-nitrobenzonitrile (2.14 g), hydrazine hydrate (2 ml), ethanol (25 ml) and DMA (10 ml) was stirred and heated to 40° C. Raney nickel (0.6 g) was added in portions whilst maintaining the temperature at 40-50° C. The mixture was stirred at 40-50° C. for 2 hours. The Raney nickel was filtered off, the mixture was evaporated and the residue was triturated with ethyl acetate (10 ml) to give 2-amino-5-(1-imidazolyl)benzamide (2.03 g); NMR Spectrum: (CD3SOCD3) 6.70 (s, 2H), 6.79 (d, 1H), 7.03 (s, 1H), 7.2 (s, 1H), 7.37 (s, 1H), 7.55 (s, 1H), 7.71 (d, 1H), 7.73 (s, 1H), 8.02 (s, 1H);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9](O)[CH3:10])[CH:5]=[N:6][C:7]=1[Cl:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>ClC1C=CC=CC=1>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([CH:9]=[CH2:10])=[CH:5][N:6]=1
Reactant: CC(O)c1cnc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Solvent: O
Product: C=Cc1cnc(Cl)c(Cl)c1
Temperature: 4 °C
Yield: 63 %

Procedure:
To a solution of the 1-(5,6-dichloro-pyridin-3-yl)-ethanol 15 (311 g. 1.62 mole) in chlorobenzene (3 L) was added p-toluene sulfonic acid (431 g, 2.5 mole) and the reaction mixture was heated at reflux with concomitant removal of water. When the reaction was complete the mixture was concentrated to about 500 mL, diluted with 2 L water, and extracted with 3×1 L ethyl acetate. The organic layer was dried (Na2SO4), concentrated under reduced pressure with low heat, dissolved in 500 mL methylene chloride, and applied to the top of 2 Kg silica column. The purified vinyl pyridine was eluted with a slight gradient of ethyl acetate in hexane, 0% to 10%. 178.55 g, 100% pure 2,3-dichloro-5-vinylpyridine was collected as a clear oil which solidified upon cooling to 4° C. 63% yield. 1H NMR (400 MHz, CDCl3) δ 8.27 (m, 1H), 7.80 (dd, J=12, 18 Hz, 1H), 6.62 (d, J=18 Hz, 1H), 5.46 (d, J=12 Hz, 1H).
Reaction SMILES: [CH:1]([C:4]1[N:5]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]=2[N+:20]([O-])=O)[CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2].CO>[H][H].[C].[Pd]>[NH2:20][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:9]=1[N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[CH:1]([CH3:2])[CH3:3])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1ccc(-n2ccnc2C(C)C)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1ccc(-n2ccnc2C(C)C)c(N)c1

Procedure:
A mixture of ethyl 4-(2-isopropyl-1H-imidazol-1-yl)-3-nitrobenzoate as synthesized in above Production Example 9, 4.94 g, methanol 150 mL and 10% palladium carbon 500 mg was stirred for 16 hours in hydrogen atmosphere. After removing the insoluble matter by filtration, the solvent was distilled off to provide 4.12 g of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].Cl[C:9]1[CH:14]=[CH:13][N:12]=[N:11][C:10]=1[Cl:15].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[Cl:15][C:10]1[N:11]=[N:12][C:13]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])=[CH:14][CH:9]=1
Reactant: NCCCCCO
Reactant: Clc1ccnnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: OCCCCCNc1ccc(Cl)nn1

Procedure:
A mixture of 5-amino-1-pentanol (433 mg, 4.2 mmol), dichloropyridazine (1.25 g, 8.39 mmol) and sodium carbonate (890 mg, 8.39 mmol) was stirred in 1,4-dioxane (40 ml) and heated at 70-80° for 3 days under an atmosphere of argon. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (300 ml) and water (38 ml). The organic layer was separated, dried and concentrated to give an orange solid which was chromatographed on silica, using hexane/ethyl acetate (1:1). The product, 5-(6chloro-3-pyridazinyl)amino-1-pentanol was isolated as a pale yellow solid (202 mg, 22%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]([F:31])([F:30])[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].CO>C(OCC)(=O)C>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:27]3[CH2:28][CH2:29][CH:24]([C:21]4[CH:22]=[CH:23][C:18]([O:17][C:16]([F:15])([F:30])[F:31])=[CH:19][CH:20]=4)[CH2:25][CH2:26]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: FC(F)(F)Oc1ccc(C2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccc(OC(F)(F)F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-trifluoromethoxyphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 76% overall yield. FDMS m/e=434 (M+ of free base). α[D]589 =-13.45 (c=1.04, methanol).
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[C:19]([NH2:28])[C:18]=2[N:17]=[CH:16]1>N1C=CC=CC=1>[NH2:28][C:19]1[C:18]2[N:17]=[CH:16][N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)N1CCOCC1
Solvent: c1ccncc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)N1CCOCC1
Temperature: 25 °C
Yield: 194.5 %

Procedure:
4-Morpholinecarbonyl chloride (0.15 ml, 1.3 mmol) was added to a stirring solution of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.3 g, 1.2 mmol) and pyridine (70 ml). The reaction was maintained at room temperature overnight. The solvent was removed in vacuo and the residue was purified by flash column chromatography (silica gel, 9:1 dichloromethane\methanol). The fractions containing product were combined, washed with saturated aqueous sodium bicarbonate, dried (MgSO4), filtered, and concentrated to provide 0.86 g of N4-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]morpholinecarboxamide as a tan powder, m.p. 177.0-179.5° C. 1H NMR (300 MHz, DMSO-d6) δ 5 8.22 (s, 1H), 8.04 (d, J=7.1 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.47 (t, J=7.1 Hz, 1H), 7.28 (t, J=7.1 Hz, 1H), 6.72 (broad s, 2H), 6.52 (t, J=5.4 Hz, 1H), 4.61 (t, J=6.9 Hz, 2H), 3.48 (t J=4.6 Hz, 4H), 3.18 (t, J=4.6 Hz, 4H), 3.05 (m, 2H), 1.84 (m, 2H), 1.44 (m, 2H); MS (EI) m/e 368.1966 (368.1961 calcd for C19H24N6O2).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[S:23][CH:22]=[CH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=3)[N:13]=2)[CH:5]=[CH:4][N:3]=1.[C-]#N.[Na+].[CH3:27][N:28]1C(=O)CCC1>O.[Ni](Br)Br>[OH:20][C:16]1[CH:15]=[C:14]([C:12]2[N:13]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]#[N:28])[CH:7]=3)[C:9]3[S:23][CH:22]=[CH:21][C:10]=3[N:11]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CN1CCCC1=O
Reactant: Oc1cccc(-c2nc(-c3ccnc(Cl)c3)c3sccc3n2)c1
Agent: Br[Ni]Br
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#Cc1cc(-c2nc(-c3cccc(O)c3)nc3ccsc23)ccn1
Temperature: 200 °C

Procedure:
A mixture of 3-[4-(2-chloro-pyridin-4-yl)-thieno[3,2-d]pyrimidin-2-yl]-phenol (90 mg), sodium cyanide (26 mg), nickel (II) bromide (58 mg) and NMP was heated under microwave irradiation at 200° C. for 30 minutes. The mixture was cooled, diluted with water and the precipitate collected by filtration. The title compound was isolated following flash column chromatography (31 mg).
Reaction SMILES: BrBr.[CH3:3][O:4][C:5]([N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]1)=[O:6].C([NH:20][C:21]([NH2:23])=[NH:22])(OC(C)(C)C)=O.[ClH:24]>CN(C=O)C.CO.CC#N>[ClH:24].[CH3:3][O:4][C:5]([N:7]1[CH2:8][CH:9]=[CH:10][C@H:11]2[NH:22][C:21]([NH2:23])=[N:20][C@@H:12]12)=[O:6]
Reactant: COC(=O)N1C=CC=CC1
Reactant: CC(C)(C)OC(=O)NC(=N)N
Agent: BrBr
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)N1CC=C[C@H]2NC(N)=N[C@H]21
Yield: 71 %

Procedure:
A solution of Br2 (0.73 ml, 14.3 mmol, 1 equiv.) in DMF (5 ml) is added over 15 min to a solution of N-methoxycarbonyl-1,2-dihydropyridine 1 (2 g, 14.3 mmol, 1 equiv.) and of Boc-guanidine (9.15 g, 57.5 mmol, 4 equiv.) in a mixture of DMF (10 ml) and of CH3CN (5 ml) under cold conditions (0-5° C.) and under argon. The reaction being complete from the end of the addition of bromine, the reaction mixture is poured onto ice-cold water (600 ml). The aqueous phase is subsequently extracted with DCM (3×200 ml). The crude product obtained (3.5 g) is dissolved in the minimum amount of methanol, followed by addition of a 2N hydrochloric acid solution (10 ml). The solution is brought to reflux in [illegible] for 5 min. After cooling, the reaction mixture is washed with ether and then evaporated to dryness to give 2.4 g of the deprotected compound 4 with a yield of 71% over the two stages.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3C=CC([CH:4]2[CH:3]=[CH:2]1)C3.C[SiH:12]([Cl:14])[Cl:13].CCCCCCCCCCCCCCCC>C1(C)C=CC=CC=1>[CH:5]1([CH2:6][SiH:12]([Cl:14])[Cl:13])[CH2:4][CH2:3][CH:2]=[CH:1]1
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C[SiH](Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCCCCCCCCCCCCCCC
Product: Cl[SiH](Cl)CC1C=CCC1
Reaction time: 1 h
Yield: 781.2 %

Procedure:
As described in Example 2, 1.49 g (0.0113 mol) of dicyclopentadiene, 10.79 g (0.0902 mol) of methyldichlorosilane, 5 mL of toluene and 2 mL of hexadecane were placed in a reactor. The reactor was sealed and the reaction was performed at 250° C. for 1 hour. Products were subject to simple vacuum distillation, thereby providing a mixture (15.99 g) of (2-cyclopentenyl)methyldichlorosilane (1.2 g, 29%), unreacted methyldichlorosilane, toluene and hexadecane.
Reaction SMILES: CN(C)C=O.[O:6]=[C:7]1[NH:12][C:11](=[O:13])[CH:10]=[CH:9][NH:8]1.Br[CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:19]([O:18][C:16]([CH2:15][N:8]1[CH:9]=[CH:10][C:11](=[O:13])[NH:12][C:7]1=[O:6])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1ccc(=O)[nH]c1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.3 %

Procedure:
To anhydrous dimethylformamide solution (10 ml) containing 2,4-dioxopyrimidine (1.0 g) are added benzyl bromoacetate (2.5 g) and potassium carbonate (2.5 g), and the mixture is stirred at room temperature for 15 hours. The reaction solution is poured into water, and the mixture is extracted with ethyl acetate. The extract is washed with a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure, and the precipitated crystals are washed with diethyl ether to give the desired 1-benzyloxycarbonylmethyl-2,4-dioxopyrimidine (1.4 g) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:8].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:29]([O:28][C:26]([CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:8])=[O:27])[CH3:30]
Reactant: O=C(NCc1ccccn1)c1cc(O)ccc1OCC(F)(F)F
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc(OCC(F)(F)F)c(C(=O)NCc2ccccn2)c1

Procedure:
Using the general method of Example I Part A, 10.4 g (0.032 mole) of 5-hydroxy-N-(2-pyridylmethyl)-2-(2,2,2- trifluoroethoxy)benzamide was reacted with 7.45 g (0.045 mole) of ethyl bromoacetate to give 5.0 g of ivory powdery 5-(ethoxycarbonylmethoxy)-N-(2-pyridylmethyl)-2-(2,2,2- trifluoroethoxy)benzamide, m.p. 73°-76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[N:10](C(=O)[C@@H]3CCCN3S(C3C=CC5C(=CC=CC=5)C=3)(=O)=O)[CH2:9]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[NH:10][CH2:9]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:6][CH:7]=1
Reactant: O=C([C@@H]1CCCN1S(=O)(=O)c1ccc2ccccc2c1)N1C[C@@H](c2ccc(Cl)cc2)Sc2ccc3ccccc3c21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Clc1ccc([C@@H]2CNc3c(ccc4ccccc34)S2)cc1
Temperature: 0 °C
Yield: 63.1 %

Procedure:
A mixture of (R)-3-(4-chlorophenyl)-1-[(S)-N-(2-naphthalenesulfonyl)prolyl]-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine (11.50 g, 0.019 mole), 86% potassium hydroxide (15.0 g, 0.227 mole) and ethanol-water (10:1, 230 ml) is refluxed under argon for one hour. The reaction mixture is poured into ice water and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water and saline, dried over sodium sulfate and distilled to remove the solvent. The residue is purified by silica gel column chromatography (CHCl3) and thereafter recrystallized from ethyl acetate-hexane to give (R)-(+)-3-(4-chlorophenyl)-2,3-dihydro-1H-naphtho[2,1-b][1,4]thiazine (3.74 g, 63%). M.p. 205°-206° C.