Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3=[N:26][CH:27]=[N:28][C:29]([O:30][C:31]4[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=4)=[C:24]3[CH:23]=[N:22]2)[CH2:17][CH2:16]1)=[O:14])(C)(C)C.ClC(O[CH2:42][CH:43]([CH3:45])[CH3:44])=O.C(N(CC)CC)C>ClCCl.O>[CH2:42]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3=[N:26][CH:27]=[N:28][C:29]([O:30][C:31]4[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=4)=[C:24]3[CH:23]=[N:22]2)[CH2:17][CH2:16]1)=[O:14])[CH:43]([CH3:45])[CH3:44]
Reactant: CC(C)COC(=O)Cl
Reactant: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OCC(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of 4-[4-(2-methyl-pyridin-3-yloxy)pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 92; 50 mg, 0.12 mmol) in dichloromethane (2 mL). The solution was stirred at room temperature for 30 min and then the solvents were evaporated using high vacuum. Dichloromethane (4 mL) was added to the residue, and then isobutyl chloroformate (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 25 mg, 0.18 mmol) was added at room temperature, followed by triethylamine (80 mg, 0.79 mmol). The mixture was stirred overnight at room temperature and then water was added. The layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water to give 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isobutyl ester (31 mg, 63%) as a powder. 1H NMR (300 MHz, CDCl3) δ 0.97 (d, 6H, J=6.5 Hz), 1.90-2.06 (m, 3H), 2.20-2.35 (m, 2H), 2.45 (s, 3H), 2.95-3.10 (m, 2H), 3.90 (d, 2H, J=6.3 Hz), 4.32-4.48 (m, 2H), 4.95-5.10 (m, 1H), 7.26-7.72 (m, 1H), 7.50-7.54 (m, 1H), 8.07 (s, 1H), 8.45-8.60 (m, 2H). Mass spectrum MH+=411. HRMS Calcd. For C21H27N6O3 (MH+): 411.2139. Found: 411.2138.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[C:5]([CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4][N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:30][C:31]3[CH:41]=[C:40]([N:42]([CH3:47])[S:43]([CH3:46])(=[O:45])=[O:44])[C:39](B4OC(C)(C)C(C)(C)O4)=[CH:38][C:32]=3[C:33]=2[C:34]([NH:36][CH3:37])=[O:35])=[CH:25][CH:24]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:17][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[C:8]([C:6]1[C:5]([CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4][N:3]=[C:2]([C:39]3[C:40]([N:42]([CH3:47])[S:43]([CH3:46])(=[O:45])=[O:44])=[CH:41][C:31]4[O:30][C:29]([C:26]5[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=5)=[C:33]([C:34]([NH:36][CH3:37])=[O:35])[C:32]=4[CH:38]=3)[CH:7]=1)[NH:9]2
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CC(C)=Cc1cnc(Cl)cc1-c1cc2c(F)cccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cc(-c4cc5c(F)cccc5[nH]4)c(C=C(C)C)cn3)cc12
Temperature: 90 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To a degassed solution of 2-(2-chloro-5-(2-methylprop-1-en-1-yl)pyridin-4-yl)-4-fluoro-1H-indole (230 mg, 0.767 mmol) and 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (322 mg, 0.767 mmol) in 1,4-dioxane/H2O (4 mL/1 mL), Pd2(dba)3 (30 mg, 0.038 mmol), X-Phos (36 mg, 0.076 mmol) and K3PO4 (612 mg, 2.301 mmol) were added under N2 atmosphere. The mixture was stirred at 90° C. for 3 hours under N2 atmosphere. The reaction mixture was then diluted with water (100 mL) and extracted with EA (50 mL×3). The organic layer was washed with brine (10 mL), dried over Na2SO4. After concentrated, the residue was purified by column chromatography (PE:EA=2:1) to give the product of 5-(4-(4-fluoro-1H-indol-2-yl)-5-(2-methylprop-1-en-1-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (400 mg, yield: 81.5%). 1H-NMR (CDCl3, 400 MHz) δ 9.67 (br s, 1H), 8.61 (s, 1H), 8.20 (s, 1H), 8.09 (s, 1H), 8.00˜8.06 (m, 2H), 7.54 (s, 1H), 7.11˜7.24 (m, 4H), 6.99 (s, 1H), 6.75˜6.83 (m, 1H), 6.39 (br s, 1H), 6.01 (br s, 1H), 3.22 (s, 3H), 2.99˜3.06 (m, 6H), 2.07 (s, 3H), 1.93 (s, 3H). MS (M+H)+: 641.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.[Cl-].[NH4+]>O1CCCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: BrCCOC1CCCCO1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.2 %

Procedure:
20 g of a 55-60% dispersion of sodium hydride in oil are suspended in 200 ml of dry tetrahydrofuran. A solution of 85 g of 3,4-dichlorophenylacetonitrile in 500 ml of tetrahydrofuran is added dropwise at 20° C. over 30 minutes and the reaction mixture is then stirred at room temperature for 2 hours. A solution of 98 g of 2-bromoethoxytetrahydropyran in 100 ml of tetrahydrofuran is added to the resulting mixture cooled to -20° C., the mixture is allowed to warm up to room temperature and, after 2 hours, a solution of 50 g of ammonium chloride in 3 liters of water is added. Extraction is carried out with 1.5 liters of ethyl ether and the extract is washed with a saturated solution of sodium chloride, decanted, dried over MgSO4 and concentrated under vacuum. The residue is chromatographed on silica gel using dichloromethane as the eluent. The pure product fractions are concentrated under vacuum to give 83.6 g of an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1)#[N:2].[H][H]>C(O)C.N.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1
Reactant: COc1ccc(C#N)cn1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COc1ccc(CN)cn1

Procedure:
A 1.00 g portion of 5-cyano-2-methoxypyridine was dissolved in 30 ml of ethanol and 10 ml of 28% aqueous ammonia, mixed with 1 g of Raney nickel and then stirred at room temperature for 4 hours at atmospheric pressure in a stream of hydrogen. After filtration through celite, the solvent was evaporated to obtain 962 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][C@H:16]1[CH3:21].Br[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:21][C@H:16]1[N:15]([C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][N:10]=3)[N:4]=2)[CH2:20][CH2:19][N:18]([C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[C:25]#[N:26])[CH2:17]1
Reactant: C[C@@H]1CNCCN1c1nc(-c2ccncn2)cc(=O)n1C
Reactant: N#Cc1ccccc1Br
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: C[C@@H]1CN(c2ccccc2C#N)CCN1c1nc(-c2ccncn2)cc(=O)n1C
Temperature: 80 °C
Reaction time: 12 h
Yield: 59.2 %

Procedure:
To a stirred solution of 1-methyl-2-((2R)-2-methyl-piperazin-1-yl)-1H-[4,4′]bipyrimidinyl-6-one (150 mg, 0.524 mmol) in ethylene glycol dimethyl ether (2.0 ml) was added 2-bromobenzonitrile (143 mg, 0.786 mmol), tris(dibenzylideneacetone)dipalladium (24 mg, 0.026 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (25 mg, 0.052 mmol) and tripotassium phosphate (167 mg, 0.786 mmol), and the reaction mixture was stirred for 12 hours at 80° C. The reaction was quenched with water, the aqueous layer was extracted with ether. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was purified with HPLC to afford 2-[(3R)-3-methyl-4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yl)-piperazin-1-yl]-benzonitrile (120 mg, 0.310 mmol, 59%) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>C(COC)OC>[Cl:10][CH2:11][C:12]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]2[CH:14]=1
Reactant: COc1ccc(N)nc1
Reactant: O=C(CCl)CCl
Solvent: COCCOC
Product: COc1ccc2nc(CCl)cn2c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-amino-5-methoxypyridine (0.5036 g; prepared by the method of Lombardino, J. Med. Chem. 1981, 24, 39-42), 1,3-dichloroacetone (Aldrich; 0.3935 g), and dimethoxyethane (2.5 mL) is stirred overnight at room temperature. The mixture is concentrated under reduced pressure and ethanol (7.9 mL) is added. After the mixture has stirred for 30 min at 80° C., it is cooled and concentrated under reduced pressure. The residue is partitioned between dichloromethane and saturated aq. sodium bicarbonate and the combined organic layers are dried with MgSO4 and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (4/96) to give 0.1392 g of 2-(chloromethyl)-6-methoxyimidazo[1,2-α]pyridine; 1H NMR (CDCl3) δ3.82, 4.75, 6.99, 7.48, 7.56, 7.59.
Reaction SMILES: [S:1]([N:11]1[CH2:13][CH:12]1[CH2:14][C:15]1([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:22][NH2:23]>CO>[CH3:22][NH:23][CH2:13][CH:12]([NH:11][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH2:14][C:15]1([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1ccc(S(=O)(=O)N2CC2CC2(O)CCCCC2)cc1
Reactant: CN
Solvent: CO
Product: CNCC(CC1(O)CCCCC1)NS(=O)(=O)c1ccc(C)cc1

Procedure:
A solution of 1-((1-tosylaziridin-2-yl)methyl)cyclohexanol (270 mg, 0.87 mmol) and methylamine in MeOH was stirred at rt for 4 h and concentrated to give 1-(3-(methylamino)-2-(tosylamino)propyl)cyclohexanol. The crude product was used in the next step without purification. MS m/z 341 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[C:32]([NH2:33])=[CH:31][C:30]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[C:32]([NH:33][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[C:3]=3[CH3:20])=[CH:31][C:30]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1
Reactant: Cc1c(N2CCCCC2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCCCC2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(piperidin-1-yl)quinoline (110 mg, 0.37 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(piperidin-1-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 7.62 (1H, br. s.), 7.53 (1H, d), 7.37 (1H, br. s.), 6.69-6.84 (1H, m), 6.29 (1H, d, J=2.3 Hz), 3.90 (4H, t, J=4.3 Hz), 3.72-3.84 (4H, m), 3.36 (4H, br. s.), 3.18 (2H, br. s.), 2.91-3.06 (4H, m), 2.09 (3H, s), 1.47-1.90 (8H, m). Mass Spectrum (ESI) m/e=525.3 (M+1).
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[C:11]([F:19])[CH:10]=2)C=CC=CC=1.Cl>C1COCC1.C([O-])(O)=O.[Na+]>[F:19][C:11]1[CH:10]=[C:9]([NH2:8])[CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2
Reactant: Fc1cc(N=C(c2ccccc2)c2ccccc2)cc2ncccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cc(F)c2cccnc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
A mixture of N-(diphenylmethylene)-5-fluoroquinolin-7-amine (185 mg, 0.566 mmol) and hydrochloric acid (1.132 mL, 1.132 mmol) in THF (5 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with saturated NaHCO3 (5 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude product was purified by silica gel chromatography eluting with 80% EtOAc/hexanes to give 5-fluoroquinolin-7-amine (82 mg, 0.506 mmol, 89% yield). 1H NMR (300 MHz, CDCl3) δ 4.02 (s, 2H) 7.11 (dd, J=9.65, 8.18 Hz, 1H) 7.29-7.40 (m, 1H) 7.45 (d, J=2.48 Hz, 1H) 7.76 (d, J=8.48 Hz, 1H) 8.53 (d, J=2.78 Hz, 1H). m/z (ESI, +ve ion) 163.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([O-:13])=[O:12])[C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Na+].[Na+]>[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C([O-])c1cc(Cl)c(C(=O)[O-])cc1Cl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1cc(Cl)c(C(=O)O)cc1Cl

Procedure:
The di-silver salt of 2,5-dichloroterephthalic acid was prepared in quantitative yield from an aqueous solution of 1 mole di-sodium 2,5-dichloroterephthalate added to an aqueous solution of 2 moles of silver nitrate, by filtering, washing, and drying. The salt decomposes at 298° C.
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:23][CH:22]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([O:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:27][CH2:26]3)[O:21][C:20]2=[O:40])=[CH:15][CH:14]=1)=O)C1C=CC=CC=1.C(OC(NCC1C=CC(N2CC(CCl)OC2=O)=CC=1)=O)C1C=CC=CC=1.N1CCC(OCC(OC(C)(C)C)=O)CC1.O>CO.[Pd].[C].C(O)(=O)C>[NH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:23][CH:22]([CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([O:31][CH2:32][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:29][CH2:30]3)[O:21][C:20]2=[O:40])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)COC1CCN(CC2CN(c3ccc(CNC(=O)OCc4ccccc4)cc3)C(=O)O2)CC1
Agent: [Pd]
Agent: CC(C)(C)OC(=O)COC1CCNCC1
Agent: O=C(NCc1ccc(N2CC(CCl)OC2=O)cc1)OCc1ccccc1
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)COC1CCN(CC2CN(c3ccc(CN)cc3)C(=O)O2)CC1

Procedure:
A solution of 1 g of tert-butyl 1-(3-(4-benzyloxycarbonylaminomethylphenyl)-2-oxo-5-oxazolidinylmethyl)piperidine-4-oxyacetate (obtainable from 3-(4-benzyloxycarbonylaminomethylphenyl)-5-chloromethyl-2-oxazolidinone and tert-butyl piperidine-4-oxyacetate in accordance with the method described in Example 3) in a mixture of 38 ml of methanol, 6 ml of water and 6 ml of acetic acid is hydrogenated on 0.6 g of 5% Pd-carbon at 20° and 1 bar until H2 uptake has ceased. The mixture is filtered and the filtrate is concentrated by evaporation, and tert-butyl 1-(3-(4-aminomethylphenyl)-2-oxo-5-oxazolidinylmethyl)piperidine-4-oxyacetate is obtained, m.p. 95°-96°, FAB 420.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]3([C:29]4[C:20](=[CH:21][C:22]5[O:27][CH2:26][CH2:25][O:24][C:23]=5[CH:28]=4)[O:19][CH2:18]3)[C:9]2=[O:30])C=CC=CC=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]1([C:29]3[C:20](=[CH:21][C:22]4[O:27][CH2:26][CH2:25][O:24][C:23]=4[CH:28]=3)[O:19][CH2:18]1)[C:9](=[O:30])[NH:8]2
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(F)c2C12COc1cc3c(cc12)OCCO3
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2cccc(F)c2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A solution of 1′-(diphenylmethyl)-4′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (1.18 g, 2.45 mmol) and triethylsilane (1.21 g, 9.84 mmol) in trifluoroacetic acid (20 mL) was heated at 65° C. for 16 h. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo. The residue was recrystallized from N,N′-dimethylformamide/water to afford 4′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.65 g, 84%) as a colourless solid: mp 282-285° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.30 (ddd, J=8.2, 8.2, 5.9 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 6.75 (d, J=9.2 Hz, 1H), 6.47 (s, 1H), 6.27 (s, 1H), 4.71 (dd, J=9.4 Hz, 2H), 4.14 (dd, J=5.3, 3.2 Hz, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.3, 160.9 (d, 1JC-F=244 Hz), 147.0, 143.3 (d, 2JC-F=96.3 Hz), 135.5, 131.9, 131.2 (d, 4JC-F=2.9 Hz), 128.6, 128.5, 123.2 (d, 2JC-F=120 Hz), 116.4 (d, 3JC-F=22.8 Hz), 115.1, 108.2, 103.3, 74.3, 64.2, 63.7; MS (ES+) m/z 313.1 (M+1).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41])(OCC)=O>O.C(#N)C>[C:32]1(=[O:41])[N:2]([CH:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=2)[CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]12
Reactant: CCOc1cc(C(N)CC(=O)OC)ccc1OC
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOc1cc(C(CC(=O)OC)N2C(=O)c3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a stirred solution of methyl 3-amino-3-(3-ethoxy-4-methoxyphenyl)propionate hydrochloride (0.87 g, 3.0 mmol) and sodium carbonate (0.32 g, 3.0 mmol) in a mixture of water (10 mL) and acetonitrile (10 mL) was added N-carbethoxyphthalimide (0.68 g, 3.0 mmol). The resulting solution was stirred for 3 hours at room temperature. The acetonitrile was removed in vacuo. To the resulting mixture was added ether (5 mL) and the mixture was stirred at room temperature overnight allowing the ether to evaporate. The resulting white solid was filtered. The solid was washed with water, air dried, and dried in vacuo (60° C., <1 mm) to afford 1.0 g (87%) of methyl 3-phthalimido-3-(3-ethoxy-4-methoxyphenyl)propionate as a white solid: mp 86°-87° C.; 1H NMR (CDCl3) δ7.86-7.63 (m, 4H), 7.16-7.05 (m, 2H), 6.88-6.76 (m, 1H), 5.77 (dd, J=5.9, 10 Hz, 1H), 4.11 (q, J=7 Hz, 2H), 3.84 (s, 3H), 3.77 (dd, J=10, 6.7 Hz, 1H), 3.63 (s, 3,25 (dd, J=5.9, 165.5 Hz, 1H), 1.45 (t, J=7 Hz, 3H); 13C NMR (CDCl3) δ171.0, 168.0, 149.0, 148.2, 133.9, 131.7, 130.9, 123.2, 120.2, 112.5, 111.1, 64.3, 55.8, 51.8, 50.7, 35.8, 14.6; HPLC (Waters Nova-Pak C18 column, 3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 45/55, acetonitrile/0.1% aqueous phosphoric acid 6 min, 100%, Anal. Calcd. for C21H21NO6. Theoretical: C, 65.79; H, 5.52; N, 3.65. Found: C, 65.71; H, 5.70; N, 3.63.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:9]([O:23][CH3:24])=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([C:28]([OH:30])=[O:29])=[CH:6][N:7]2[CH:25]1[CH2:27][CH2:26]1.OS(O)(=O)=O.C([O-])(O)=O.[Na+].[CH3:42][CH2:43]O>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:13][CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:9]([O:23][CH3:24])=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([C:28]([O:30][CH2:42][CH3:43])=[O:29])=[CH:6][N:7]2[CH:25]1[CH2:27][CH2:26]1
Reactant: CCO
Reactant: COc1c(NCCNc2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cn(C2CC2)c2c(OC)c(NCCNc3ccccn3)c(F)c(N)c2c1=O
Temperature: 0 °C
Yield: 44 %

Procedure:
A mixture of 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (428 mg, 1.00 mmol) and concentrated H2SO4 (1.0 mL) in EtOH (15 mL) was refluxed for 8 h. After cooling, the mixture was poured into ice water (100 mL). Saturated aq. NaHCO3 (50 mL) was added and the crude product was extracted with CH2Cl2 (2×50 mL). The extraction mixture washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (Chromatorex NH-DM2035 (Fuji Sylysia Chemical Co., Ltd.), EtOAc) to give ethyl 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylate (311 mg, 44%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[C:16]([N+:22]([O-])=O)[CH:17]=[C:18]([Cl:21])[CH:19]=2)[NH:14][C:13](=[O:25])[C@@H:12]1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Ni]>[NH2:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[C:20]2[C:15]=1[NH:14][C:13](=[O:25])[C@H:12]([CH3:26])[N:11]2[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: C[C@H]1C(=O)Nc2c(cc(Cl)cc2[N+](=O)[O-])N1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: C[C@H]1C(=O)Nc2c(N)cc(Cl)cc2N1C(=O)OCc1ccccc1

Procedure:
The compound of Example IV (1.5 g, 4.0 mmol) was dissolved in 150 ml of methanol and hydrogenated at room temperature with Raney nickel catalysis, using 1 atm hydrogen. When the calculated amount of hydrogen had been taken up, the catalyst was removed by filtration with suction, and the filtrate was concentrated in vacuo. The product was purified by silica gel chromatography using ethyl acetate/heptane=2:1 as eluent. The yield was 0.68 g (49%) of brownish solid of melting point 152-154° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:10])[NH:5][C:6](=O)[NH:7][CH:8]=1)[CH3:2].[Cl:11]C1NC(=O)C(C)=C(C)N=1>>[Cl:11][C:6]1[NH:5][C:4](=[O:10])[C:3]([CH2:1][CH3:2])=[CH:8][N:7]=1
Reactant: Cc1nc(Cl)[nH]c(=O)c1C
Reactant: CCc1c[nH]c(=O)[nH]c1=O
Product: CCc1cnc(Cl)[nH]c1=O
Yield: 67 %

Procedure:
The title compound was prepared in 67% yield from 5-Ethyl-1H-pyrimidine-2,4-dione utilizing a method analogous to the preparation of 2-chloro-5,6-dimethyl-3H-pyrimidin-4-one (see Lee, et al., WO 9605177). 1H NMR (400 MHz, DMSO-d6): δ 13.21 (br s, 1H), 7.90 (br s, 1H), 2.39 (q, 2H, J=7.6 Hz), 1.08 (t, 3H, J=7.6 Hz). MS (ES) [m+H] calc'd for C6H7N2OCl, 159, 161; found 159, 161.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[S:5][CH:6]=1.[NH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24]>CN(C=O)C>[Br:1][C:2]1[C:3]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:13])=[CH:14][CH:15]=2)[S:5][CH:6]=1
Reactant: CCC(N)CC
Reactant: COC(=O)Cc1c(Br)csc1-c1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Product: CCC(CC)NC(=O)c1ccc(-c2scc(Br)c2CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
4-(4-Bromo-3-methoxycarbonylmethyl-thiophen-2-yl)-benzoic acid (0.303 g, 0.85 mmol) was dissolved in DMF (2 mL) and carbonyldiimidizole (0.172 g, 1.06 mmol) was added. The solution was stirred at RT for thirty minutes and 3-aminopentane (0.222 g, 2.55 mmol) was added. Stirring was continued for 3 h and the solvent was removed. The mixture was partitioned between EtOAc and H2O. The EtOAc was dried (MgSO4) and the solvent was removed to yield methyl [4-bromo-2-(4-{[(1-ethylpropyl)amino]carbonyl}phenyl)thien-3-yl]acetate (0.248 g) as a white solid. mp 97-98° C.; 1H NMR (500 MHz, DMSO-d6) δ: 0.87 (t, 6H, J=7.3 Hz), 1.49 (m, 2H), 1.54 (m, 2H), 3.65 (s, 3H), 3.71 (s, 2H), 3.80 (m, 1H), 7.51 (d, 1H, J=8.5 Hz), 7.85 (s, 1H), 7.95 (d, 2H, J=8.5 Hz), 8.12 (d, 1H, J=8.7 Hz). MS (ES) m/z 424.0 ([M+H]+). MS (ES) m/z 456.0 ([M+CH3OH+H]+). MS (ES) m/z 847.0 ([2M+H]+). Anal. Calcd for C19H22BrNO3S: C, 53.78; H, 5.23; N, 3.30. Found: C, 53.65; H, 4.77; N, 3.52.