Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([N:7]2[CH2:12][CH:11]([CH3:13])[NH:10][CH:9]([CH3:14])[CH2:8]2)=[N:4][S:5][N:6]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1CO.C([CH:27](CCC)[O-:28])(C)(C)C.[K+].C(O)(C)(C)C>O>[CH3:14][CH:9]1[NH:10][CH:11]([CH3:13])[CH2:12][N:7]([C:3]2[C:2]([O:28][CH2:27][C:18]3[CH:17]=[CH:16][N:15]=[CH:20][CH:19]=3)=[N:6][S:5][N:4]=2)[CH2:8]1
Reactant: CCCC([O-])C(C)(C)C
Reactant: OCc1ccccn1
Reactant: CC1CN(c2nsnc2Cl)CC(C)N1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC1CN(c2nsnc2OCc2ccncc2)CC(C)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
1-(4-Chloro-[1,2,5]thiadiazol-3-yl)-3,5-dimethyl-piperazine (7.9 g, 34 mmol), pyridinyl-methanol (7.7 g, 70 mmol), potassium tert-butyl butoxide (11.4 g, 101 mmol) and tert-butyl alcohol (100 mL) were combined and stirred at room temperature overnight. The reaction mixture is diluted with H2O (3×) and extracted with EtOAc (3×). The combined EtOAc extractions are washed with sat'd NaHCO3 (3×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product is purified by column chromatography (1:1 hexanes:EtOAc, followed by 49:1 EtOAc:triethylamine, followed by 18:1:1 EtOAc:MeOH:triethylamine) to give 4.15 g (40%) of 3,5-dimethyl-1-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine. 1H NMR (CDCl3) 8.62 (d, 2H), 7.30 (d, 2H), 5.48 (s, 2H), 4.07 (m, 2H), 3.03 (m, 2H), 2.51 (m, 2H), 1.12 (d, 6H) ppm. LC-MS (MH+)=306.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:9](Cl)(Cl)=[O:10].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=2)=[CH:16][CH:15]=1>CCOCC>[CH:3]1([CH2:2][O:1][C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=3)=[CH:16][CH:15]=2)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: OCC1CCCCC1
Reactant: O=C(Cl)Cl
Solvent: CCOCC
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)OCC2CCCCC2)cc1
Reaction time: 1 h
Yield: 24.9 %

Procedure:
5.9 g (51.7 millimoles) of (hydroxymethyl)-cyclohexane are added dropwise to a stirred solution of 13.0 g (131.4 millimoles) of phosgene in 100 ml of absolute ether at 0°-10° C. The reaction solution is then stirred for 1 hour at 0°-10° C., and then for an hour at room temperature, and the excess phosgene is removed by means of a dry stream of nitrogen, after which the ether is removed under reduced pressure at room temperature. The cyclohexylmethyl chloroformate which is left (8.5 g) is reacted with 5.0 g (24.6 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone by the method described in Example 31. The reaction mixture is also worked up as described in Example 31. After recrystallizing the product first from dimethylformamide/water, then from ethyl acetate/petroleum ether and finally from acetone/water, 2.1 g (25% of theory) of 6-(p-cyclohexylmethoxycarbonylaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are obtained as colorless crystals of melting point 223°-225° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]([NH:15][C@H:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17][CH2:18][CH2:19][CH:20]=O)=[O:14].FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl.O>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]([N:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH:16]1[C:22]([O:24][CH3:25])=[O:23])=[O:14]
Reactant: COC(=O)[C@H](CCCC=O)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1CCC=CN1C(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 137 %

Procedure:
Transfer the solution of [2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-6-oxo-(S)-norleucine, methyl ester in methylene chloride (volume about 4.5 L) to a 12-liter flask and place under nitrogen atmosphere. Stir and add trifluoroacetic acid (440 mL, 5.71 mole) in one portion. Stir the resulting mixture at room temperature for one hour, then rapidly cool to about 0° C. Add a solution of sodium hydroxide (240 g, 6.0 mole) in water (3.4 L) in a slow stream to the vigorously stirred mixture at such a rate that the pot temperature stays at about 0° C. Separate the organic phase and extract the aqueous phase with methylene chloride (1 L). Combine the organic phases and dry (MgSO4). Filter and remove the solvent in vacuo to leave a residue (262 g, 137%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].[C:9](=N)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl.O>[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[N:6]=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@H](C)N
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H](C)N=C(c1ccccc1)c1ccccc1
Reaction time: 15 h

Procedure:
To a solution of alanine methyl ester hydrochloride (10.0 g, 71.6 mmol) in 100 mL CH2Cl2 was added benzophenone imine (12.0 mL, 71.6 mmol). A white ppt gradually came out of solution as the reaction was allowed to proceed at rt for 15 h. The reaction was diluted with H2O and CH2Cl2, and the layers were separated, the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to afford methyl-N-(diphenylmethylene)alaninate as a viscous oil which was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.62 (m, 2H), 7.47-7.29 (m, 6H), 7.19-7.16 (m, 2H), 4.16 (q, J=6.8 Hz, 1H), 3.7 (s, 3H, 1.40 (d, J=6.8 Hz, 3H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[N:8]=1)=[O:5].C(N(CC)C(C)C)(C)C.C1(C[C@H](N2[CH2:58][C:57]([O:59][C:60]3[C:65]([F:66])=[CH:64][CH:63]=[CH:62][C:61]=3[F:67])=[CH:56][C:55]2=[O:68])C(NC2C=CN(CC(O)(C)C)N=2)=O)CCCCC1>CO>[F:66][C:65]1[CH:64]=[CH:63][CH:62]=[C:61]([F:67])[C:60]=1[O:59][C:57]1[CH2:58][N:2]([C@@H:3]([CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]([NH:6][C:7]2[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:16])([CH3:14])[CH3:15])[N:8]=2)=[O:5])[C:55](=[O:68])[CH:56]=1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3c(F)cccc3F)=CC2=O)n1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@@H](N)CC2CCCCO2)n1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCO2)N2CC(Oc3c(F)cccc3F)=CC2=O)n1
Yield: 29 %

Procedure:
(S)-2-amino-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydropyran-2-yl)-propionamide hydrochloride (prepared as in Example 92, 300 mg, 0.78 mmol) was dissolved in methanol (5 mL) and N,N-diisopropylethylamine (0.5 mL) was added. The mixture was evaporated to dryness. The residue was dissolved acetonitrile (8 mL). To this solution was added (E)-4-bromo-3-(2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 36, 296 mg, 0.92 mmol). The mixture was refluxed for 40 h. The mixture was evaporated and the residue was treated with ethyl acetate and water. The layers were separated and the organic layer was dried and concentrated. The crude material was purified through reverse phase preparative HPLC (acetonitrile in water, 25% to 100% linear gradient) to afford (S)-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-2-yl)-propionamide (114 mg, 29%): HR-ES-MS m/z calculated for C25H30N4O5F2 [M+H]+ 505.2257, observed 505.2260; 1H NMR (300 MHz, CDCl3) δ ppm 1.16 (s, 6H), 1.24-1.70 (m, 5H), 1.74-1.97 (m, 2H), 2.17-2.30 (m, 1H), 3.29-3.52 (m, 2H), 3.92-4.05 (m, 1H), 3.95 (s, 3H), 4.25 (d, J=17.8 Hz, 1H), 4.43 (d, J=17.8 Hz, 1H), 4.95 (s, 1H), 5.10 (dd, J=8.6, 6.5 Hz, 1H), 6.69 (s, 1H), 6.97-7.10 (m, 2H), 7.14-7.25 (m, 1H), 7.30 (s, 1H), 8.77 (br. s., 1H).
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4]C[CH:2]1[CH2:11][NH2:12].N1C2C(=CC=CC=2)C(C(Cl)=[O:23])=C1>>[NH:5]1[C:10]2[C:1](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:2]([C:11]([NH2:12])=[O:23])=[CH:4]1
Reactant: O=C(Cl)c1c[nH]c2ccccc12
Reactant: NCC1CCN2CCCCC2C1
Product: NC(=O)c1c[nH]c2ccccc12
Yield: 55 %

Procedure:
eq-Quinolizidin-2-ylmethylamine (D12) was reacted with indole-3-carboxylic acid chloride using the method of Description 1b) to afford N-(eq-quinolizidin-2-ylmethyl) indole-3-carboxamide as a white solid (55%).
Reaction SMILES: I[C:2]1[CH:15]=[C:14]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:16])=[CH:10][C:11]=3[CH2:12][CH2:13]2)=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH2:24]([OH:28])[CH2:25][C:26]#[CH:27].Cl>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[OH:28][CH2:24][CH2:25][C:26]#[C:27][C:2]1[CH:15]=[C:14]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:16])=[CH:10][C:11]=3[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(c1)CCc1cc(I)ccc1-2
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: OCCC#Cc1ccc2c(c1)CCc1cc(O)ccc1-2
Reaction time: 1.5 h

Procedure:
9.0 g (24.6 mmol) of 7-iodo-9,10-dihydrophenanthren-2-ol are initially introduced in 100 ml of THF, 1.0 g (1.43 mmol) of bis(triphenylphosphine)palladium(II) chloride, 0.3 g (1.58 mmol) of copper(I) iodide and 11 ml of diisopropylamine are added, and subsequently a solution of 3.0 g (42.8 mmol) of but-3-yn-1-ol in 20 ml of THF is added dropwise at max. 30° C. with gentle cooling. The batch is left to stir at room temp. for 1.5 h, added to water and acidified using 2 N hydrochloric acid. The aqueous phase is separated off and extracted three times with ethyl acetate. The combined org. phases are washed with water, dried over sodium sulfate, and the solvent is removed in vacuo. The crude product is filtered through silica gel with dichloromethane/ethyl acetate (3:1) and recrystallised from toluene, giving 7-(4-hydroxybut-1-ynyl)-9,10-dihydrophenanthren-2-ol as colourless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[C:18]([C:29]#N)=[CH:17][N:16]=2)=[O:14])=[CH:5][CH:4]=1.[OH-:32].[Na+].Cl.C[OH:36]>>[CH3:1][N:2]([CH3:31])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[C:18]([C:29]([OH:36])=[O:32])=[CH:17][N:16]=2)=[O:14])=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: COc1cc2c(C#N)cnc(C(=O)c3ccc(N(C)C)c4ccccc34)c2cc1OC
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3ccc(N(C)C)c4ccccc34)c2cc1OC
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To the suspension of 1-(4-dimethylamino-naphthalene-1-carbonyl)-6,7-dimethoxy-isoquinoline-4-carbonitrile (31 mg, 0.082 mmol) in methanol (2 mL) was added 25% of aqueous sodium hydroxide solution (0.27 mL, 1.68 mmol). The mixture was stirred at 90° C. for 12 h. After cooling to room temperature, the reaction was adjusted to pH=2 with 2 N HCl solution. The product was extracted with chloroform (2×200 mL). The combined organic layers were washed with water (3×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified directly by HPLC (Reverse C18, 10%–90% acetonitrile in water in 10 min) afforded our desired product 1-(4-dimethylamino-naphthalene-1-carbonyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid (9 mg) as a solid. LC/MS m/e calcd for C25H22N2O5 (MH+) 431. found 431.
Reaction SMILES: [CH3:1][Si:2]([CH3:38])([CH3:37])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]=O)[CH:9]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.CC(O)=O.[BH3-]C#N.[Na+]>CCO>[O:42]1[CH2:43][CH2:44][N:39]([CH2:27][C:10]2[CH:9]=[C:8]([N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:37])[CH3:38])[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:34])[CH3:36])[N:13]3[N:14]=[CH:15][C:16]([C:17]4[CH:18]=[N:19][C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[C:12]3[N:11]=2)[CH2:40][CH2:41]1
Reactant: C1COCCN1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C=O)nc2c(-c3cnc4ccccc4c3)cnn12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(CN2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 107.4 %

Procedure:
To 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carbaldehyde (0.15 g, 0.3 mmol) in EtOH (10 mL) was added morpholine (0.12 mL, 1.4 mmol) and AcOH (0.2 mL), and the resulting mixture was stirred at room temperature for 15 minutes. NaBH3CN (0.12 g, 2.0 mmol) in EtOH (1.5 mL total) was then added and the reaction mixture was stirred at room temperature for 16 hours, at which time LC/MS analysis confirmed full consumption of starting material. Saturated NaHCO3 solution (˜20 mL) was added and the mixture was stirred for 30 minutes. The mixture was transferred to a separatory funnel with CH2Cl2 (30 mL) and H2O (10 mL) and brine (20 mL) was then added. Organics were extracted with CH2Cl2 (4×30 mL), dried (Na2SO4) and concentrated in vacuo to give crude 5-(morpholinomethyl)-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine as a brown oil (0.2 g). LCMS: 2.01 mins, m/z=621.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Product: CCN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.062 mMol) 5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.068 mMol) 4-fluorobenzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([CH3:13])=[C:10]([CH:12]=2)[NH2:11])=[CH:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26]([NH:11][C:10]2[CH:12]=[C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:7]=[CH:8][C:9]=2[CH3:13])=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: Cc1ccc(-c2ccoc2)cc1N
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: Cc1ccc(-c2ccoc2)cc1NC(=O)COCC(=O)Nc1ccc(Cl)cc1C(=O)O

Procedure:
Using the same method as in Example 15-(i), 5-(furan-3-yl)-2-methylaniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([5-(furan-3-yl)-2-methylphenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 87%).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)=[O:7])C.CO.C1COCC1.O[Li].O>O>[C:15]1([C:12]2[N:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[CH2:5][C:4]([OH:21])=[O:3])=[CH:14][CH:13]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(-c2ccccc2)nc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a stirred solution of 5-amino-2-phenyl-pyridine (4.0 g, 0.0235 mol) in dichloromethane (40 mL) was added ethyl malonyl chloride (5.307 g, 0.035 mol) dropwise. The resulting mixture was stirred for 1 hour. The mixture was diluted with water and the product was extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution, brine, dried over Na2SO4 and evaporated to afford 5.46 g (80%) of N-(6-phenyl-pyridin-3-yl)-malonamic acid ethyl ester. To a solution of N-(6-phenyl-pyridin-3-yl)-malonamic acid ethyl ester (5.46 g, 0.019 mol) in the mixture of methanol (27.5 mL), THF (55 mL) and H2O (16.5 mL) was added LiOH.H2O (1.212 g, 0.0288 mol). The resulting reaction mixture was stirred for 1 hour at ambient temperature then concentrated. The resulting residue was diluted with water, acidified with concentrated HCl and the product was extracted with ethyl acetate. The ethyl acetate was washed with brine, dried over Na2SO4 and evaporated under reduced pressure to afford 4.0 g (82%) of N-(6-phenyl-pyridin-3-yl)-malonamic acid.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[CH3:13][N:14]([CH3:29])[CH2:15][CH2:16][N:17]1C(=O)C[S:19][CH:18]1[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.CI.[Na+].[Cl-].[O:34]1[CH2:38][CH2:37][CH2:36]C1>CCCCCC>[CH3:1][C:37]1([CH3:36])[S:19][CH:18]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[N:17]([CH2:16][CH2:15][N:14]([CH3:13])[CH3:29])[C:38]1=[O:34]
Reactant: [Li]CCCC
Reactant: CN(C)CCN1C(=O)CSC1c1cccnc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CI
Solvent: CC(C)NC(C)C
Product: CN(C)CCN1C(=O)C(C)(C)SC1c1cccnc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
A n-butyllithium solution (10 ml, 16 mmol) in hexane was added to dropwise to a solution of diisopropylamine (2.84 ml, 15.9 mmol) in dry tetrahydrofuran (6 ml) at -20° to -30° C. The mixture was kept between those temperatures for 1 hour and then cooled to -78° C. Thereto was added dropwise a solution of 3-(2-dimethylaminoethyl)-2-(3-pyridyl)thiazolidin-4-one (2 g, 7.96 mmol) in dry tetrahydrofuran (10 ml). The resulting mixture was kept at -78° C. for 1 hour. After addition of methyl iodide (2.26 g, 15.9 mmol), this reaction mixture was slowly warmed up to the room temperature and allowed to stand overnight. The resulting mixture, after addition of aqueous NaCl, was extracted with ethyl acetate. The extract was washed with aqueous NaCl, dried, and the solvent was removed in vacuo. The residue was purified by column chromatography, giving 5,5-dimethyl-3-(2-dimethylaminoethyl)-2-(3-pyridyl)thiazolidin-4-one (257 mg, 12% yield).
Reaction SMILES: C([C:5](=[CH2:9])[C:6]([NH2:8])=[O:7])(C)(C)C.[C:10]1([CH3:16])[CH:15]=CC=C[CH:11]=1.N(C(C)(C)C#N)=NC(C)(C)C#N>CCCCCC>[C:10]([NH:8][C:6](=[O:7])[CH:5]=[CH2:9])([CH3:16])([CH3:15])[CH3:11]
Reactant: Cc1ccccc1
Reactant: C=C(C(N)=O)C(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCC
Product: C=CC(=O)NC(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of 50.0 g of t-butylacrylamide and 250 ml of toluene was heated at 80° C. with stirring under a nitrogen atmosphere in a 500 ml three-necked flask. 10 ml of a toluene solution containing 500 mg of azobisisobutyronitrile was added thereto as a polymerization initiator thereby polymerization was initiated. After polymerization for 3 hours, the polymerization solution was cooled and poured into 1 liter of hexane. The solids thus-deposited were collected by filtration, washed with hexane and dried with heating under a reduced pressure to obtain 47.9 g of P-17.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH:21]([NH:23][CH2:24][CH:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1)=[O:22]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][CH2:29][O:30][CH:25]([CH2:24][NH:23][CH:21]=[O:22])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=CNCC1CNCCO1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Product: O=CNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCO1

Procedure:
By the use of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(formylaminomethyl)morpholine, the reaction is similarly carried out as Example 11 to give 1-cyclopropyl-6,8-difluoro-7-[2-(formylaminomethyl)morpholino]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 210°-213° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][CH:12]([CH2:19]CS([O-])(=O)=O)[CH2:13]CS([O-])(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].[OH2:37]>CN(C)C=O>[O:30]=[C:28]1[C:27]2[C:26](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25](=[O:35])[N:29]1[CH2:19][CH:12]([O:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][N:29]1[C:25](=[O:37])[C:26]2[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28]1=[O:30]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O
Reactant: CC(C)(C)OC(=O)NCCOC(CCS(=O)(=O)[O-])CCS(=O)(=O)[O-]
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOC(CN1C(=O)c2ccccc2C1=O)CN1C(=O)c2ccccc2C1=O
Reaction time: 18 h
Yield: 78.5 %

Procedure:
A 20 L 4-neck round-bottom flask was flushed with N2. Then charged a solution of 2-(2-(tert-butoxycarbonylamino)ethoxy)propane-1,3-diyl-dimethanesulfonate (929 g, 2.37 mol, 1.0 eq) in N,N-dimethylformamide (9300 mL) and potassium phthalimide (2194 g, 11.85 mol, 5.0 eq). The resulting mixture was stirred for 18 hours at 70˜75° C. in an oil bath. The reaction progress was monitored with LCMS. The reaction mixture was cooled to 20˜30° C., then added icy water (28 L) with stirring. The mixture was stirred for 30 minutes, and then filtered. The filter cake was dried under vacuum at 60° C. to give 919 g (78.5%) tert-butyl 2-(1,3-bis(1,3-dioxoisoindolin-2-yl)propane-2-yloxy)ethylcarbamate as an off-white solid.
Reaction SMILES: Br[C:2]1[C:3]([F:13])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.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>[F:13][C:3]1[C:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][C:6]([C:7]#[N:8])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: OB(O)c1ccccc1
Reactant: N#Cc1cc(Br)c(F)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cc(-c2ccccc2)c(F)cc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 48 h

Procedure:
5-Bromo-4-fluoro-2-nitrobenzonitrile (I-240) (9.1 g, 37.14 mmol) was dissolved in tetrahydrofuran (270 ml), and at room temperature, phenylboronic acid (9.06 g, 74.28 mmol), tripotassium phosphate (15.77 g, 74.28 mmol) and tetrakis(triphenylphosphine)palladium (2.15 g, 1.86 mmol) were added. After stirred under nitrogen atmosphere at 75° C. for 48 hours, this was cooled to room temperature. The insoluble matter was separated by filtration, the filtrate was concentrated under reduced pressure. The residue was fractionated with chloroform and aqueous saturated ammonium chloride solution. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate.