Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:17][CH2:16][CH:10]3[N:11]([CH3:15])[CH2:12][CH2:13][CH:14]=[C:9]3[C:7]=2[CH:8]=1.C([Li])CCC.[C:23]([N:27]=[C:28]=[O:29])([CH3:26])([CH3:25])[CH3:24]>C1COCC1.CCCCCC.O>[C:23]([NH:27][C:28]([C@H:13]1[CH2:12][N:11]([CH3:15])[C@@H:10]2[CH2:16][O:17][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=3[C:9]2=[CH:14]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N=C=O
Reactant: COc1ccc2c(c1)C1=CCCN(C)C1CO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1ccc2c(c1)C1=C[C@@H](C(=O)NC(C)(C)C)CN(C)[C@@H]1CO2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a well stirred solution of 1.16 g of 9-methoxy-4-methyl-2,3,4a,5-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridine in 15 ml of THF is added 3.4 ml of 1.5M butyl lithium in hexane at 0°. After 5 minutes at 0°, the reaction mixture is cooled to -70° and 0.6 ml of t-butyl isocyanate is added. After warming to room temperature the reaction mixture is diluted with water and the products extracted with ether. After drying over magnesium sulfate, the solvent is removed in vacuo and the residue is crystallized from ether/hexane to yield cis-2-(N-t-butylcarbamoyl)-9-methoxy-4-methyl-2,3,4a,5,-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridine, which is converted wiht ethanolic hydrogen chloride to cis-2-(N-t-butylcarbamoyl)-9-methoxy-4-methyl-2,3,4a,5-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridine hydrochloride, melting point 188°-189° (from ethanol/ether).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:37])=[C:11]([N:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:34])[C@H:24]([CH3:33])[NH:25]C(OC(C)(C)C)=O)[C:18]([CH3:36])([CH3:35])[CH2:17]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:38])[C:6]([C:39]([OH:41])=[O:40])=[CH:5]2)[CH2:3][CH2:2]1.[ClH:42]>>[ClH:42].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:37])=[C:11]([N:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:34])[C@H:24]([CH3:33])[NH2:25])[C:18]([CH3:36])([CH3:35])[CH2:17]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:38])[C:6]([C:39]([OH:41])=[O:40])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COc1c(N2CCC(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: Cl
Product: COc1c(N2CCC(NC(=O)[C@H](C)N)C(C)(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 75 %

Procedure:
1-Cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-7-{4′-(N-t-butoxycarbonyl-L-alanyl)amino-3′,3′-dimethylpiperidin-1-yl}-4-oxo-quinoline-3-carboxylic acid (0.9 gm) is hydrolysed with 6N HCl (20 ml) at room temperature for 1 hr. The mixture concentrated to furnish the titled product. Yield 75%, m.p 245–50° C., C24H31FN4O5.HCl m/z 475 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>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.C1(C)C=CC=CC=1>[C:14]1([NH:13][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:22]4[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=4)=[CH:7][N:6]3[CH:8]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccccc1)c1cn2cc(Br)ccc2n1
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: Cc1ccccc1
Solvent: CC#N
Product: O=C(Nc1ccccc1)c1cn2cc(-c3cccnc3)ccc2n1
Yield: 48.9 %

Procedure:
150 mg of 6-bromo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 1), 0.237 g of pyridine-3-boronic acid, 45 mg of tetrakis(triphenylphosphine)palladium, 2 mL of aqueous 2M sodium carbonate solution, 4 mL of acetonitrile and 4 mL of toluene are placed in a microwave tube. The mixture is heated for 20 minutes in a microwave machine set at 150° C., and then cooled and filtered, the insoluble matter being washed with a mixture of methanol and dichloromethane. The combined filtrates are concentrated to dryness under reduced pressure. The residue is concreted with aqueous methanol to give 73 mg of N-phenyl-6-(pyrid-3-yl)imidazo[1,2-a]pyridine-2-carboxamide in the form of an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12]O.[BrH:14].S(=O)(=O)(O)O>O>[Br:14][CH2:12][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1]
Reactant: Br
Reactant: O=[N+]([O-])c1ccc(CCO)c(F)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(CCBr)c(F)c1
Temperature: 100 °C
Yield: 84 %

Procedure:
2-(2-Fluoro-4-nitrophenyl)ethanol (0.89 g, 4.8 mmol) was added to a stirred solution of 48% aqueous hydrobromic acid (0.77 g, 9.62 mmol) and concentrated sulfuric acid (0.25 mL) under cooling. The reaction mixture was heated to 100° C. for 3 h. The reaction mixture was diluted with water (25 mL) and was extracted with ethyl acetate (3×25 mL). The combined organic layer was washed with brine (25 mL) and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the crude compound. The crude product was purified by CC (eluent: 5% ethyl acetate in n-hexane) to afford 1-(2-bromoethyl)-2-fluoro-4-nitrobenzene (1 g, 85%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.O>CN(C=O)C>[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1nccc2ccccc12
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: c1ccc(CN2CCN(c3nccc4ccccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 40.6 %

Procedure:
A solution of 1-chloroisoquinoline (1.64 g 10 mmol) in dry DMF (5 ml) was added to a stirred solution of 1-benzylpiperazine (1.85 g, 10.5 mmol) and N,N-diisopropylethylamine (2 ml, 1.5 g, 11.5 mmol) in dry DMF (5 ml) under Ar at room temperature. The solution was stirred at room temperature for 17 h. The yellow solution was heated at 110° C. for 7 h, treated with water (100 ml) and extracted with ether (2×50 ml). The extracts were dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed (SiO2 ; ethyl acetate) to give the product (1.233 g).
Reaction SMILES: C([O:5][C:6]([CH:8]([N:16]1[C:20]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=2[N:18](C(OC(C)(C)C)=O)[C:17]1=[O:33])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]2[NH:18][C:17](=[O:33])[N:16]([CH:8]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:6]([OH:7])=[O:5])[C:20]=2[CH:21]=1
Reactant: CC(C)(C)OC(=O)C(Cc1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C(Cc1ccccc1)n1c(=O)[nH]c2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
950 mg (2.01 mmol) of tert-butyl 3-(1-tert-butoxycarbonyl-2-phenylethyl)-5-chloro-2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (VIIh) were dissolved in dichloromethane (10 ml) and, while stirring at room temperature, trifluoroacetic acid (10 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. Yield: 609 mg (96%) of white solid
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[NH:16][NH:17]C(OC(C)(C)C)=O.[F:25][C:26]([F:39])([F:38])[C:27]1[CH:37]=[CH:36][C:30]([C:31]([N:33]=[C:34]=[O:35])=O)=[CH:29][CH:28]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[N:16]1[C:34](=[O:35])[NH:33][C:31]([C:30]2[CH:36]=[CH:37][C:27]([C:26]([F:39])([F:38])[F:25])=[CH:28][CH:29]=2)=[N:17]1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Reactant: O=C=NC(=O)c1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C(F)(F)F)cc3)[nH]c2=O)c1
Yield: 36.8 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using tert-butyl 2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-94, 0.150 g, 0.420 mmol), 4-(trifluoromethyl)benzoyl isocyanate (Intermediate-59, 0.181 g, 0.84 mmol), DCM (15 mL), and trifluoro acetic acid (3.0 mL) to afford 0.070 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.13 (s, 9H), 4.29 (d, J=5.4 Hz, 2H), 7.36 (d, J=8.7 Hz, 1H), 7.45 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 8.06 (d, J=8.4 Hz, 2H), 8.19 (m, 1H), 12.79 (s, 1H); MS (m/z): 456.59 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[Br:13]Br>O1CCOCC1>[Br:13][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[O:11][CH3:12])=[O:10]
Reactant: BrBr
Reactant: COc1cc(Br)ccc1C(C)=O
Solvent: C1COCCO1
Product: COc1cc(Br)ccc1C(=O)CBr
Reaction time: 3 h
Yield: 76.6 %

Procedure:
To a stirred solution of 1-(4-bromo-2-methoxyphenyl)-1-ethanone (31.5 g, 138 mmol) in dioxane (32 ml) was added a solution of bromine (21.8 g, 136 mmol) in dioxane (123 ml), and the mixture was stirred for 3 hours. Then the volatile was evaporated in vacuo. The residue was recystallized with hexane-dichloromethane to give title compound (32.1 g, 76% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C=O.[OH-].[K+].Cl>O.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6]
Reactant: O=Cc1cccc(Br)c1
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: OCc1cccc(Br)c1
Temperature: 25 °C

Procedure:
Into a solution of 370 g. of 3-bromo benzaldehyde, 900 cm3. of methanol and 300 g. of 40% formaldehyde the solution of 380 g. of potassium hydroxide in 300 cm3. of water are dropped at a temperature of from 48° to 52° C. during 10 minutes while stirring. The reaction mixture is stirred for 3.5 hours at a temperature of from 50° to 55° C. Into this reaction mixture the solution of 60 g. of potassium hydroxide in 40 cm3. of water are dropped at 55° C. then the reaction mixture is stirred at 60° C. for 1.5 hours. After cooling to ambient temperature the pH-value of the reaction mixture is adjusted with 250 cm3. of an aqueous hydrochloric acid solution /1:1/ to 9. From this reaction mixture the methanol is distilled off, 2 l. of water are added to the residue and twice extracted with 400 cm3. of 1,2-dichloro ethane. After distilling the dichloro ethane off the residue is fractionated in vacuo. 333 g. of 3-bromobenzyl alcohol are obtained. Boiling point 120°-122° C./266-399 Pa.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([C:14]1[CH:23]=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:24])[CH:20]=2)[N:15]=1)[CH2:11][C:12]#[CH:13]>>[F:24][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1)[CH:23]=[N:22]2
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCc1cnc2cc(F)ccc2n1
Product: FCc1cccc(C#CCCc2cnc3cc(F)ccc3n2)n1
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 2-bromo-6-(fluoromethyl)-pyridine (43 mg, 0.22 mmol) and 2-but-3-ynyl-6-fluoro-quinoxaline (45 mg, 0.22 mmol). Microwave conditions: 120° C. for 15 minutes. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 45 mg (0.15 mmol, 65%) of 6-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)quinoxaline as an orange solid with a purity of 85%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:7]2[C:12]([C:13](=[O:26])[C:14]=1[CH2:15][C:16]1[CH:17]=[N:18][C:19]([C:22]([O:24]C)=[O:23])=[CH:20][CH:21]=1)=[CH:11][CH:10]=[C:9]([CH3:27])[N:8]=2)=[O:4].O[Li].O.O>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:7]2[C:12]([C:13](=[O:26])[C:14]=1[CH2:15][C:16]1[CH:17]=[N:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][CH:21]=1)=[CH:11][CH:10]=[C:9]([CH3:27])[N:8]=2)=[O:4]
Reactant: COC(=O)c1ccc(Cc2c(C(=O)OC)n(-c3ccccc3)c3nc(C)ccc3c2=O)cn1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Cc2ccc(C(=O)O)nc2)c(=O)c2ccc(C)nc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
To 3-(6-methoxycarbonyl-pyridin-3-ylmethyl)-7-methyl-4-oxo-1-phenyl-1,4-dihydro[1,8]naphthyridine-2-carboxylic acid methyl ester (compound 100) (0.2 g) in THF (10 mL) was added LiOH.H2O (0.06 g) and H2O (2 mL), and the mixture stirred at RT for 1 h. The product was taken up in EtOAc, washed with H2O and HCl (2M, 2 mL), filtered, and worked up with EtOAc and H2O. The organic layer was dried over MgSO4, and concentrated to a yellow oil. The oil was taken up in EtOAc, washed with H2O, dried over MgSO4, and concentrated to a yellow solid to provide 3-(6-carboxy-pyridin-3-ylmethyl)-7-methyl-4-oxo-1-phenyl-1,4-dihydro[1,8]naphthyridine-2-carboxylic acid methyl ester (0.11 g). M+H=430.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[NH:19]1[C:27]2[C:22](=[CH:23][C:24](B(O)O)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:23]=[C:22]4[C:27](=[CH:26][CH:25]=3)[NH:19][CH:20]=[CH:21]4)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc4[nH]ccc4c3)cccc2c1N
Yield: 92.1 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 5-indolyl boronic acid (156 mg, 0.97 mmol) were reacted to afford the title compound (105 mg, 95.1% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.60 (br, 1H), 8.34 (s, 1H), 7.94 (s, 1H), 7.86 (d, J=7.1 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.69 (t, J=7,7 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 7.22 (s, 1H), 6.61 (s, 1H), 3.46 (q, J=6.7 Hz, 2H), 1.66 (m, J=7.2 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H) MS APCI, m/z=346 (M+H) HPLC 1.88 min.
Reaction SMILES: C([C@@H:3]1[C@@H:7]([CH2:8][O:9]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:6][C@@H:5]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:4]1)=O.CC(O)=[O:40].Cl.CON>C(Cl)Cl.CO>[C@@H:5]1([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[O:6][C@H:7]([CH2:8][OH:9])[C@@H:3]([OH:40])[CH2:4]1
Reactant: CC(=O)O
Reactant: Cc1cn([C@H]2C[C@H](C=O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O
Agent: CON
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3′-deoxy-3′-C-formyl-5′-O-tritylthymidine (0.59, 1 mmol, prepared as per Example 4 in CH2Cl2:MeOH (2:1, 30 vol.) was added AcOH (0.5 ml) and methoxyamine hydrochloride (0.189, 2.2 mml) at room temperature. The mixture was stirred for 30 min., concentrated under vacuum and the residue dissolved in MeOH (20 ml). To this solution, concentrated HCl (0.1 ml) was added and stirred for 1 h. The solution was neutralized with NH4OH (≈2 ml) and concentrated under a vacuum to furnish the 3′-C-[(methoxyimido)methyl] derivative of thymidine. 1H NMR (CDCl3) δ 9.67 (s, 1, NH); 7.67 (s, 1, H-6); 7.33 (d, 0.70, H-3″ E isomer), 6.65 (d, 0.30, H-3′ Z isomer); 6.15 (m, 1, H-1′); 3.60-4.12 (m, 3.3, H-4′, H-5′5″, H-3′ Z isomer); 3.91 (s, 0.9, OCH3 Z isomer); 3.82 (s, 2.1, OCH3 oxime E isomer); 3.26 (m, 0.7, H-3′ E isomer); 2.27-2.60 (m, 2, H-2′,2″); 1.91 (2s, 3, C6CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[OH-].[K+].[I:13]I>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([I:13])[C:3]=12
Reactant: Clc1ccnc2[nH]ccc12
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1ccnc2[nH]cc(I)c12
Temperature: 0 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
250 g (1.64 mol) of 4-chloro-1H-pyrrolo[2,3-b]pyridine were initially charged together with 328 g (5.85 mol) of pulverulent KOH in 3000 ml of DMF and cooled to 0° C. A solution of 416 g (1.64 mol) of iodine in 3000 ml of DMF was added dropwise with cooling to this suspension and, on completion of addition, the suspension was stirred at 0° C. for a further 4 h. On completion of the reaction, the mixture was added to ice-water with stirring, and the solid formed was filtered off with suction and subsequently dried under high vacuum. A total of 403 g (1.45 mol, 88%) of 4-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine were isolated as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)N)=[CH:4][CH:3]=1.CO[CH:19](OC)[CH2:20][CH2:21][CH2:22][NH:23][CH3:24]>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]([CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:19]=[C:20]2[CH2:21][CH2:22][NH:23][CH3:24]
Reactant: CNCCCC(OC)OC
Reactant: NN(CCC1CCCC1)c1ccc(Cl)cc1
Product: CNCCc1cn(CCC2CCCC2)c2ccc(Cl)cc12

Procedure:
The title compound is prepared by General Method 10 using 1-(4-chlorophenyl)-1-(2-cyclopentylethyl)hydrazine (Example 4) and 4,4-dimethoxy-N-methylbutan-1-amine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13](O)=O)[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH4+:16].[OH-]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]3[NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=4[N:16]=3)[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cn(-c2cccc(Br)c2)cn1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Brc1cccc(-n2cnc(-c3nc4ccccc4[nH]3)c2)c1
Temperature: 200 °C
Yield: 38 %

Procedure:
1-(3-Bromo-phenyl)-1H-imidazole-4-carboxylic acid 5 (150 mg, 0.56 mmol) was added to PPA (preheated to 140° C.) and the mixture was stirred until a thick homogeneous solution was obtained. 1,2-Phenyldiamine (67 mg, 0.62 mmol) was added and the mixture was heated for 6 h at 200° C. After cooling to room temperature it was carefully diluted with 6% NH4OH aqueous solution until the pH=8. The precipitate formed was isolated by filtration, dissolved in little ethyl acetate and filtrated again. Concentration of the organic layer afforded 72 mg (38%) of the title compound as a purple solid. HRMS (ESI+): m/z=339.1949 [M+H]
Reaction SMILES: C[O:2][C:3]([C:5]1([N:14]([C:18](=[O:29])[CH2:19][C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[N:15]([CH3:17])[CH3:16])[CH2:10][CH2:9][N:8]([N:11]([CH3:13])[CH3:12])[CH2:7][CH2:6]1)=O.CC(C)([O-])C.[K+].[OH-].[NH4+].Cl>CN(C)C=O>[CH3:17][N:15]([CH3:16])[N:14]1[C:5]2([CH2:10][CH2:9][N:8]([N:11]([CH3:12])[CH3:13])[CH2:7][CH2:6]2)[C:3](=[O:2])[CH:19]([C:20]2[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])[C:18]1=[O:29]
Reactant: COC(=O)C1(N(C(=O)Cc2c(C)cc(C)cc2C)N(C)C)CCN(N(C)C)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C2C(=O)N(N(C)C)C3(CCN(N(C)C)CC3)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.8 %

Procedure:
Under an atmosphere of argon, a solution of 1.25 g 1-Dimethylamino-4-{N′,N′-dimethyl-N-[2-(2,4,6-trimethyl-phenyl)-acetyl]-hydrazino}-piperidine-4-carboxylic acid methyl ester in 10 ml dry N,N-dimethylformamide is cooled to 5° C., and treated with 1.04 g potassium t-butoxide. The mixture is stirred at ambient temperature for 18 hours, then poured into aqueous ammonium hydroxide, and the pH of the solution adjusted to 4.5 by the addition of aqueous hydrochloric acid. It is extracted three times with ethyl acetate, the organic layer separated, dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel with cyclohexane/ethyl acetate (1:3) as a solvent, to yield 377 mg 1,8-Bis-dimethylamino-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]decane-2,4-dione as a solid, mp 80-85° C. 1H-NMR (methanol-d4): 6.91 ppm (s, 2H), 3.18 ppm (m, 2H), 3.08 ppm (m, 2H), 2.93 ppm (s, 6H), 2.48 ppm (s, 6H), 2.35 ppm (m, 2H), 2.29 ppm (s, 3H), 2.14 ppm (s, 6H), 1.40 ppm (m, 2H).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)=[O:22])=[O:10])[CH2:5][CH2:4]1.[C:31]([O:35][C:36]([NH:38][CH2:39][CH2:40][CH:41]=O)=[O:37])([CH3:34])([CH3:33])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[C:31]([O:35][C:36]([NH:38][CH2:39][CH2:40][CH2:41][N:2]([C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)=[O:22])=[O:10])[CH2:7][CH2:8]1)[CH3:1])=[O:37])([CH3:32])([CH3:33])[CH3:34]
Reactant: CN[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Reactant: CC(C)(C)OC(=O)NCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCCNC(=O)OC(C)(C)C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1

Procedure:
Trans-3-[4-(methylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (250 mg) obtained in Example 221 is suspended in dichloromethane (8 ml), and thereto are added 3-t-butoxycarbonylaminopropanal (198 mg) and triethylamine (160 μl) under ice-cooling, and the mixture is stirred for several minutes. Then, sodium triacetoxy borohydride (243 mg) and the reaction solution is warmed to room temperature, and stirred for 4 hours. To the reaction solution is poured a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture is extracted with chloroform. The organic layer is washed successively with water and a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1, then 1/1) to give the title compound (312 mg).
Reaction SMILES: [N+]1([O-])C2CCCC(C(OC)=O)C=2C=CC=1.C(N)(C)(C)C.C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1.C([NH:46][C:47]1[CH:56]=[CH:55][C:54]2[CH:53]([C:57]([O:59][CH3:60])=[O:58])[CH2:52][CH2:51][CH2:50][C:49]=2[N:48]=1)(C)(C)C.FC(F)(F)C(O)=O>C1(C(F)(F)F)C=CC=CC=1>[NH2:46][C:47]1[CH:56]=[CH:55][C:54]2[CH:53]([C:57]([O:59][CH3:60])=[O:58])[CH2:52][CH2:51][CH2:50][C:49]=2[N:48]=1
Reactant: COC(=O)C1CCCc2nc(NC(C)(C)C)ccc21
Agent: COC(=O)C1CCCc2c1ccc[n+]2[O-]
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: FC(F)(F)c1ccccc1
Solvent: CC(C)(C)N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CCCc2nc(N)ccc21
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
Methyl 5,6,7,8-tetrahydroquinoline-5-carboxylate-1-oxide (2.05 g, 9.89 mmol) and t-butyl amine (5.22 ml, 49.5 mmol) were dissolved in benzotrifluoride (50 ml) and cooled with an ice bath. The p-toluenesulfonic anhydride (6.46 g, 19.79 mmol) was added portionwise keeping the reaction's internal temperature below 5° C. The reaction was monitored and after 10 mins. when the LC-MS showed M+1=263 and 207 (M-56) at 1.20 indicating formation of intermediate methyl 2-(tert-butylamino)-5,6,7,8-tetrahydroquinoline-5-carboxylate. Trifluoroacetic acid (10 ml) was then added to the reaction mixture and heated at 70° C. for 5 hrs. The reaction was cooled and evaporated to dryness. The residue was taken up with water and the pH was adjusted to pH ˜8 with 5N NaOH. The reaction was extraction with DCM 2×. The combined DCM layers were washed with brine and dried over Na2SO4, filtered and evaporated to dryness. The residue was chromatographed through a 80 g ISCO Redi-sep column and eluted with solvent system of 5%(10% NH4OH in MeOH)/DCM to yield methyl 2-amino-5,6,7,8-tetrahydroquinoline-5-carboxylate. 1H-NMR (600 MHz, CDCl3): δ ppm 7.27 (d, J=8.3 Hz, 1H), 6.35 (d, J=8.3 Hz, 1H), 4.40 (b, 2H), 3.73 (s, 3H), 3.70 (t, J=6.9 Hz, 1H), 2.68-2.82 (m, 2H) 2.12-2.17 (m, 1H), 1.93-2.12 (m, 2H), 1.81-1.86 (m, 1H); LC-MS: M+1=207;