Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[O:13][C:12]([CH:14]=O)=[CH:11][CH:10]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:8][C:9]1[O:13][C:12]([CH2:14][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:11][CH:10]=1
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc(Br)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(Br)o2)CC1
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
A round-bottomed flask was charged with 1-methylpiperazine (2.02 mL, 18.2 mmol), 5-bromofuran-2-carbaldehyde (3.03 g, 17.3 mmol), and CH2Cl2 (30 mL). The reaction mixture was stirred for 30 minutes, and then sodium triacetoxy borohydride (4.77 g, 22.5 mmol) was added slowly over five minutes. The reaction mixture was stirred at room temperature for 4 hours, then poured into Na2CO3 (100 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to provide the product (2.35 g, 50%) as an orange solid. LRMS (esi pos) m/e 260 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=[CH:6][N:5]2[C:17]=1[CH3:18].C([Li])(C)(C)C.[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]>C(OCC)C.CCCCC>[CH2:33]([Sn:28]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:29][CH2:30][CH2:31][CH3:32])[C:8]1[CH:7]=[CH:6][N:5]2[C:17]([CH3:18])=[C:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[NH:10][C:11](=[O:16])[C:12]([CH3:14])([CH3:15])[CH3:13])[CH2:34][CH2:35][CH3:36]
Reactant: Cc1nc2c(NC(=O)C(C)(C)C)cccn2c1C
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccn2c(C)c(C)nc2c1NC(=O)C(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of 1 g of 2,3-dimethyl-8-pivaloylaminoimidazo[1,2-a]pyridine in 40 ml of diethyl ether is treated dropwise at −78° C. with 8 ml of a 1.5 molar solution of t-butyllithium in n-pentane. The mixture is stirred for 15 min and then treated with 3.3 ml of tri-n-butyltin chloride. The internal temperature is then allowed to rise to room temperature, the mixture is poured onto ice water and extracted three times with ethyl acetate, the combined extracts are washed with a little water and dried over potassium carbonate, the solvent is stripped off in vacuo and the oil obtained is chromatographed on silica gel using ethyl acetate/petroleum ether (1:3) as an eluent. 1.3 g of 7-tributylstannyl-2,3-dimethyl-8-pivaloylaminoimidazo[1,2-a]pyridine are obtained as a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH:24](OCC)[C:23]3[CH:22]=[C:21]4[CH:28]=[CH:29][CH:30]=[CH:31][C:20]4=[CH:19][C:18]=3[C:17]2=[O:32])=[O:8])=[CH:5][CH:4]=1.[CH2:35]([O:37][C:38]([O:40][Si](C)(C)C)=[CH2:39])[CH3:36].B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH:24]([CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:40])[C:23]3[CH:22]=[C:21]4[CH:28]=[CH:29][CH:30]=[CH:31][C:20]4=[CH:19][C:18]=3[C:17]2=[O:32])=[O:8])=[CH:33][CH:34]=1
Reactant: CCOC1c2cc3ccccc3cc2C(=O)N1c1ccccc1NC(=O)c1ccc(OC)cc1
Reactant: C=C(OCC)O[Si](C)(C)C
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CC1c2cc3ccccc3cc2C(=O)N1c1ccccc1NC(=O)c1ccc(OC)cc1
Yield: 50.9 %

Procedure:
A solution of N-(4-methoxybenzoyl)-2-(1-ethoxy-1,3-dihydro-3-oxo-2H-benz[f]isoindol-2-yl)benzeneamine (0.75 g, 1.7 mmol) and 1-ethoxy-1-trimethylsilyloxyethylene (0.80 g, 5.0 mmol) in methylene chloride at −78° C. was treated dropwise with boron triflouride etherate (0.23 mL, 1.8 mmol). Upon complete addition, the cooling bath was removed and the mixture was allowed to warm for 0.5 h. The mixture was poured into a mixture of ethyl acetate and aqueous saturated sodium bicarbonate solution. The organic layer was washed with water, saturated sodium chloride solution, dried (potassium carbonate), and filtered. Concentration and purification of the residue by radial chromatography (silica gel, hexanes/ethyl acetate) yielded 428 mg (44%) of the title compound. An analytical sample was obtained by recrystallization from ethyl acetate/hexanes.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:38])[CH2:11][O:12][C:13]2[CH:14]=[C:15]([C@@H:19]([NH:26][C:27](=[O:37])[O:28][C@@H:29]3[CH:34]4[CH2:35][CH2:36][N:31]([CH2:32][CH2:33]4)[CH2:30]3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=[CH:17][CH:18]=2)=[CH:5][CH:4]=1>O1CCOCC1.[O-2].[Mn+4].[O-2]>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:38])[CH2:11][O:12][C:13]2[CH:14]=[C:15]([C@@H:19]([NH:26][C:27](=[O:37])[O:28][C@@H:29]3[CH:34]4[CH2:33][CH2:32][N:31]([CH2:36][CH2:35]4)[CH2:30]3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:8]=1)=[O:1]
Reactant: O=C(COc1cccc([C@@H](NC(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1)Nc1ccc(CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: O=Cc1ccc(NC(=O)COc2cccc([C@@H](NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a stirred solution of (R)-quinuclidin-3-yl ((S)-(3-(2-((4-(hydroxymethyl)-phenyl)amino)-2-oxoethoxy)phenyl)(phenyl)methyl)carbamate (0.68 g, 1.31 mmol) in 1,4-dioxane (10 mL) was added manganese (IV) oxide (0.57 g, 6.58 mmol). The reaction mixture was stirred at room temperature for 60 hours. The suspension was filtered and the filter cake was washed with ethyl acetate. The filtrate was evaporated at reduced pressure to afford the crude title compound. This material was used without further purification.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=O)[CH3:5].[NH2:8][C:9]1[N:13]=[C:12]([S:14][CH3:15])[NH:11][N:10]=1>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:5])[N:10]2[N:11]=[C:12]([S:14][CH3:15])[N:13]=[C:9]2[N:8]=1
Reactant: CSc1nc(N)n[nH]1
Reactant: CC(=O)CC(C)=O
Solvent: CC(=O)O
Product: CSc1nc2nc(C)cc(C)n2n1
Temperature: 135 °C
Reaction time: 0.33 h
Yield: 71.2 %

Procedure:
A mixture of 2,4-pentanedione (11.54 g, 115 mmol), 3-amino-5-methylthio-1H-1,2,4-triazole (15.0 g, 115 mmol), and glacial acetic acid (115 mL) was added to a 1 L RBF with a magnetic stirring bar. The flask was fitted with a condenser, and warmed in an oil bath to a gentle reflux at 135° C. The mixture was heated for 15 hours. Progress of the reaction was monitored by analytical HPLC with UV detection at 215 and 254 nm. The starting material 3-amino-5-methylthio-1H-1,2,4-triazole elutes rapidly with retention time of 0.7 min, and the product elutes with retention time of 5.0 min. The mixture was cooled to room temperature, then slowly poured into stirring ice/water (750 mL) to precipitate product and stirred ˜20 minutes. Solids were isolated by filtration, rinsed with 250 mL of water, and then dried under reduced pressure to afford the title compound as a powder (15.9 g, 71% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH:5]=[C:6]([CH3:23])[C:7]=1[C:8]1[C:9](=[O:22])[N:10]([CH3:21])[C:11]2([CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]2)[C:12]=1[OH:13].C(=O)([O-])O.[Na+].S(Cl)([Cl:39])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Cl:39][C:8]1([C:7]2[C:6]([CH3:23])=[CH:5][C:4]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[CH:3][C:2]=2[Cl:1])[C:12](=[O:13])[C:11]2([CH2:14][CH2:15][N:16]([O:19][CH3:20])[CH2:17][CH2:18]2)[N:10]([CH3:21])[C:9]1=[O:22]
Reactant: O=S(=O)(Cl)Cl
Reactant: CON1CCC2(CC1)C(O)=C(c1c(C)cc(-c3ccc(Cl)cc3)cc1Cl)C(=O)N2C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CON1CCC2(CC1)C(=O)C(Cl)(c1c(C)cc(-c3ccc(Cl)cc3)cc1Cl)C(=O)N2C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(3,4′-dichloro-5-methyl-biphenyl-4-yl)-4-hydroxy-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]dec-3-en-2-one (100 mg, 0.224 mmol) and sodium hydrogen carbonate (47 mg, 0.560 mmol) in dichloromethane (5 ml) at −5° C. was added sulfuryl chloride (0.017 ml, 28.3 mg, 0.210 mmol) in dichloromethane (0.5 ml) dropwise. The reaction mixture was stirred at 0° C. for 30 minutes and at room temperature overnight, poured on saturated aqueous sodium carbonate, the layers were separated, the water phase extracted with ethyl acetate (3×20 ml), the combined organic phases washed with saturated aqueous sodium carbonate and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/cyclohexane 2:1). Yield: 65 mg of 3-chloro-3-(3,4′-dichloro-5-methyl-biphenyl-4-yl)-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]decane-2,4-dione (title compound P1.9) as a gum.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.CN(C)CCN(C)C.C([Li])CCC.CN([CH:32]=[O:33])C.Cl>C(OCC)(=O)C.C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:5]([CH:32]=[O:33])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cl)n1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(Cl)ccc1C=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
The reaction takes place under argon, the apparatus is heat-dried and operated with a KPG stirrer. 15 g (65.6 mmol) of tert-butyl (6-chloropyridin-2-yl)carbamate (Example 25A) and 19 g (164 mmol) of 1,2-bis(dimethylamino)ethane are introduced into 270 ml of THF and cooled to −78° C. 102.5 ml (164 mmol) of butyllithium (1.6N) are added dropwise. After the dropwise addition is complete, the reaction is slowly warmed to −10° C. and kept at −10° C. for 2 h and then cooled again to −78° C., and 10 ml (131 mmol) of DMF are added. The reaction is slowly warmed to RT, and the reaction mixture is added to 1 l of ethyl acetate and 350 ml of 1N hydrochloric acid and stirred for 15 min, and the organic phase is separated off. It is washed with water and saturated sodium bicarbonate solution, dried over magnesium sulphate and concentrated in a rotary evaporator. The residue is mixed with diethyl ether and the solid is filtered off with suction and dried. 12.3 g (73% of theory) of the product are obtained as a solid.
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.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[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]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:21])[CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][C:7]=2[N:8]=1
Reactant: CSc1ncc2c(n1)CCN(c1cccc(C(=O)O)n1)C2
Reactant: Nc1ccccc1
Product: CSc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3ccccc3)n1)C2

Procedure:
In a manner similar to that described in Example 108, a mixture of 6-[2-(methylthio)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]pyridine-2-carboxylic acid and aniline were converted to the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:20]([O:22][CH3:23])=[O:21])=[CH:13]3)[CH:10]([CH2:24][OH:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:26]([O-])([OH:28])=[O:27].O>C[N+]([O-])=O>[C:1]([O:5][C:6]([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[C:17]([N+:26]([O-:28])=[O:27])[CH:18]=2)[NH:15][C:14]([C:20]([O:22][CH3:23])=[O:21])=[CH:13]3)[CH:10]([CH2:24][OH:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1cc2c3c(ccc2[nH]1)N(C(=O)OC(C)(C)C)CC3CO
Solvent: O
Solvent: C[N+](=O)[O-]
Product: COC(=O)c1cc2c3c(cc([N+](=O)[O-])c2[nH]1)N(C(=O)OC(C)(C)C)CC3CO
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 45.4 %

Procedure:
A warm solution of 55 (447 mg, 1.29 mmol) in CH3NO2 (50 mL) was cooled in an ice bath. As the starting material began to precipitate (internal temperature ca. 5° C.) c.HNO3 (0.16 mL, 2.6 mmol) was added dropwise, giving an orange-red mixture. The suspension was stirred at 0° C. for 40 min, then poured into cold H2O and extracted with CH2Cl2 (×3). The extracts were washed with aq. NaHCO3, dried (Na2SO4), and evaporated. The residue was recrystallized from MeOH to give methyl 3-(t-butyloxycarbonyl)-1-hydroxymethyl-5-nitro-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate (29) as an orange powder (229 mg, 45%), mp 200° C. (dec.). The mother liquor was purified by chromatography (40% EtOAc-petroleum ether) to give more 29 (70 mg, 14%). 1NMR [(CD3)2SO] δ 11.22 (d, J=1.5 Hz, 1 H, NH), 8.72 (br, s, ca. 0.8 H, H-4 major rotamer), 8.42 (br s, ca. 0.2 H, H-4 minor rotamer), 7.47 (d, J=2.0 Hz, 1 H, H-8), 5.02 (t, J=5.2 Hz, 1 H, OH), 4.14 (t, J=10.5 Hz, 1 H), 3.95 (dd, J=11.2, 4.7 Hz, 1 H), 3.92 (s, 3 H, CO2Me), 3.89-3.80 (m, 1 H), 3.73 (t, J=5.2 Hz, 2 H), 1.54 (s, 9 H, t-Bu). Anal. Calculated for C18H21N3O7 : C, 55.2; H, 5.4; N, 10.7. Found: C, 55.4; H, 5.4; N, 10.7%.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.F[C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1>CN(C=O)C.O>[N:7]1[CH:8]=[CH:9][C:4]([S:3][C:11]2[CH:20]=[C:19]3[C:14]([C:15](=[O:21])[NH:16][CH:17]=[N:18]3)=[CH:13][CH:12]=2)=[CH:5][CH:6]=1
Reactant: Sc1ccncc1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]cnc2cc(Sc3ccncc3)ccc12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
Sodium hydride (3.3 g of a 50% suspension in mineral oil, 69 mmol) was added to a solution of 4-mercaptopyridine (8.12 g, 73 mmol) in DMF (100 ml) and the mixture stirred for 30 minutes. 7-Fluoro-3,4-dihydroquinazolin-4-one (1.5 g, 9 mmol) was added and the reaction heated at 100° C. for 4 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (97/3) to give 7-(4-pyridylthio)-3,4-dihydroquinazolin-4-one (500 mg, 6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl.[NH2:35][OH:36]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([NH:35][OH:36])=[NH:28])=[CH:25][CH:26]=2)[CH:12]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]2=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 77.2 %

Procedure:
4-Chloro-N-(4-cyano-benzyl)-N-(2-oxo-azepan-3-yl)-benzenesulfonamide (2.09 g, 5.00 mmol), sodium bicarbonate (0.52 g, 6.15 mmol) and hydroxylamine hydrochloride (0.43 g, 6.15 mmol) in a mixture of 20 ml ethanol and 4 ml water were refluxed for 11 hours. The solvents were removed by distillation and the residue was recrystalized from water. The solid was then suspended in dichloromethane, refluxed, cooled to room temperature and filtered to yield 1.74 g (77%) 4-{[(4-chloro-benzenesulfonyl)-(2-oxo-azepan-3-yl)-amino]-methyl}-N-hydroxy-benzamidine as white solid, MS: m/e (%)=451.0 (MH+, 100).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[CH:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([CH3:28])[CH3:27]>>[CH:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:2][C:3]([NH:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([NH:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH3:23])[O:12][CH2:13][C:8]=3[CH:7]=2)=[O:4])[CH2:31][CH2:30]1)([CH3:28])[CH3:27]
Reactant: COc1ccccc1CNC1=Nc2ccc(NC(=O)CCl)cc2CO1
Reactant: CC(C)N1CCNCC1
Product: COc1ccccc1CNC1=Nc2ccc(NC(=O)CN3CCN(C(C)C)CC3)cc2CO1
Yield: 257.5 %

Procedure:
Prepared from 2-chloro-N-[2-(2-methoxy-benzylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 26 step A) (50 mg, 0.129 mmol, HPLC 0.889 min 81%) and N-isopropylpiperazine (1 ml, 8 mmol) according to the procedure described for Example 3 step B. Obtained the title compound as a white foam (150 mg, 72%, HPLC 0.492 min 87%), MS (ISP) m/e=452.3 [(M+H)+].
Reaction SMILES: C(O/[CH:4]=[CH:5]/[C:6]1[C:7]([C:14]([O:16]C)=O)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)C.[NH3:18]>CO.C1(C)C=CC=CC=1>[CH3:13][S:12][C:9]1[N:10]=[CH:11][C:6]2[CH:5]=[CH:4][NH:18][C:14](=[O:16])[C:7]=2[N:8]=1
Reactant: CCO/C=C/c1cnc(SC)nc1C(=O)OC
Reactant: N
Solvent: Cc1ccccc1
Solvent: CO
Product: CSc1ncc2cc[nH]c(=O)c2n1
Temperature: 85 °C
Yield: 84 %

Procedure:
(E)-Methyl 5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylate (Preparation 31, 2.30 g, 9.04 mmol) was treated with ammonia in methanol 7M (45 mL) and heated to 85° C. for 18 hours in a capped vial. The solvent was removed under reduced pressure, and the resulting solid was treated with TsOH monohydrate (175 mg, 0.92 mmol), suspended in toluene (50 mL) and heated to 90° C. for 2 hours. The mixture was concentrated and the residue was purified by silica gel column chromatography eluting with 0 to 5% MeOH in DCM to give the title compound (1.47 g, 84%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[C:8]2[CH:15]=O.[CH3:17][C:18](=[O:22])[O:19][CH2:20][CH3:21]>C1COCC1.O>[CH2:20]([O:19][C:18](=[O:22])/[CH:17]=[CH:15]/[C:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH3:3])[N:6]=2)[N:11]=[CH:10][CH:9]=1)[CH3:21]
Reactant: CCOC(C)=O
Reactant: COc1ccc2nccc(C=O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1ccnc2ccc(OC)nc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 56 %

Procedure:
Triethylphosphonoacetate (7.3 g, 32.6 mmol) was added to a suspension of a NaH dispersion (1.4 g, 32.5 mmol, 55% in paraffin) in THF (40 mL) at 0° C. The mixture was stirred at 0° C. for 20 min before the dropwise addition of 6-methoxy-[1,5]naphthyridine-4-carbaldehyde (4.0 g, 21.3 mmol; prepared as in WO 2006/032466) in THF. The mixture was stirred at rt for 5 h, diluted with water and EA. The phases were separated and the aq. phase extracted with EA (2 times 50 mL). The combined org. phases were washed with brine, dried over MgSO4 and concentrated. The residue was purified by chromatography on SiO2 (Hex/EA 1:1) to give the desired alkene as a colourless solid (3.0 g, 56% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:20])=[C:7]([C:11]([I:19])=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[C:13]=1[I:14])[C:8](Cl)=[O:9])(=[O:3])[CH3:2].Cl.[CH2:22]([O:24][C:25](=[O:34])[C@H:26]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[NH2:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:34])[C@H:26]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[NH:27][C:8](=[O:9])[C:7]1[C:6]([I:20])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:13]([I:14])=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[C:11]=1[I:19])[CH3:23]
Reactant: CCOC(=O)C[C@H](N)C(=O)OCC
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)Cl)c1I
Agent: Cl
Product: CCOC(=O)C[C@H](NC(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I)C(=O)OCC

Procedure:
Following the procedure of example 13, 112 g (65%) of the product is synthesized from 140 g (0.22 Mol) 3,5-diacetamido-2,4,6-triiodobenzoyl chloride and 75 g (0.33 Mol) L-aspartic acid diethyl ester hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4].[C:24](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:10]([CH3:24])[C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4]
Reactant: COC(=O)C1CC(NC(=O)C(F)(F)F)CN1C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1CC(N(C)C(=O)C(F)(F)F)CN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2,2,2-Trifluoro-acetylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.26 g, 0.76 mmol) in DMF (2 mL) was added potassium carbonate (0.139 g, 1 mmol) followed by methyl iodide (0.14 g, 1 mmol). The reaction mixture was stirred at 80° C. for 16 hours and partitioned between water and ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (50% ethyl acetate in Hexanes) to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([CH3:22])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:22])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1N
Yield: 90.7 %

Procedure:
The 3-(3-Methyl-4-nitro-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (12.0 g, 43 mmol) was dissolved in 50 mL methanol and 50 mL ethyl acetate. An amount of 1.0 g of 10% wet Pd—C (50% w/w) was added. The reaction mixture was subjected to hydrogenation under 40 PSI of hydrogen for 3 hours. The solution was then filtered through Celite to remove catalyst. The filtrate was concentrated under reduced pressure to give the desired product (10.8 g, 39 mmol). 1H-NMR (400 MHz, CDCl3): δ=6.60 (m, 1H), 6.02 (m, 1H), 5.95 (m, 1H), 4.78 (m, 1H), 4.24 (m, 2H), 3.95 (m, 2H), 3.45 (br, 1H), 2.15 (s, 3H), 1.45 (s, 9H). MS: 301 (M++23).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13](I)[C:12]=3[N:11]=[C:10]([CH3:20])[C:9]=2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2].[C:21]1([CH3:33])[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].COCCOC>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.O>[CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([C:22]4[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=4[CH3:33])[C:12]=3[N:11]=[C:10]([CH3:20])[C:9]=2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1cc(C)c(OB(O)O)c(C)c1
Reactant: CCC(CC)n1ccc2c(C)nc3c(I)cccc3c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CCC(CC)n1ccc2c(C)nc3c(-c4c(C)cc(C)cc4C)cccc3c21
Temperature: 80 °C
Reaction time: 8 h
Yield: 6.7 %

Procedure:
1-(1-Ethylpropyl)-6-iodo-4-methyl-1H-pyrrolo[3,2-c]quinoline (170 mg, 0.45 mmol), mesitylboric acid (82 mg, 0.50 mmol), barium hydroxide octahydrate (213 mg, 0.68 mmol) and tetrakistriphenylphosphinepalladium (26 mg, 0.02 mmol) were suspended into a mixture of 1,2-dimethoxyethane (6 mL) and water (1 mL), followed by stirring at 80° C. overnight in nitrogen atmosphere. Water was added to the reaction mixture, followed by extracting with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then evaporated. The residue was purified by silica gel column chromatography (5% ethyl acetate/hexane), to give the title compound (11 mg, 0.03 mmol) as a pale yellow oil.