Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C@H:8]1[CH2:13][N:12]([CH3:14])[C@@H:11]2[CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[C:10]2=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[O-]CC.[Na+]>[C:1]([NH:5][C:6]([C@H:8]1[CH2:13][N:12]([CH3:14])[C@H:11]2[CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[C:10]2=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)C1=C[C@@H](C(=O)NC(C)(C)C)CN(C)[C@@H]1CO2
Agent: CC[O-]
Agent: [Na+]
Product: COc1ccc2c(c1)C1=C[C@@H](C(=O)NC(C)(C)C)CN(C)[C@H]1CO2

Procedure:
A solution of 950 mg of cis-2-(N-t-butylcarbamoyl)-9-methoxy-4-methyl-2,3,4a,5-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridine in 50 ml of 0.1M ethanolic sodium ethoxide is heated at 70° for 15 minutes. After removal of the solvent in vacuo, the residue is chromatographed over 20 g silica gel with ether/hexane 1:1 as the eluent to give trans-2-(N-t-butylcarbamoyl)-9-methoxy-4-methyl-2,3,4a,5-tetrahydro-4H-[1]-benzopyrano[3,4-b]pyridine crystallized as the hydrochloride salt, m.p. 238°-240°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][CH:27]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:28][CH:27]=1)=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.9 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (62.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (82 mg, 63%).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C@@:14]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:15]([OH:17])=O)[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.O.ON1C2C=CC=CC=2N=N1.[O:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH:44]1[O:49][NH2:50].Cl.CN(CCCN=C=NCC)C>ClCCl>[CH:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C@@:14]([CH3:22])([S:18]([CH3:21])(=[O:20])=[O:19])[C:15]([NH:50][O:49][CH:44]3[CH2:45][CH2:46][CH2:47][CH2:48][O:43]3)=[O:17])[CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@@](CCn1cc(C2CCCCC2)cn1)(C(=O)O)S(C)(=O)=O
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: C[C@@](CCn1cc(C2CCCCC2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 22.6 %

Procedure:
To a solution of ((2R)-4-(4-cyclohexyl-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (30 mg, 0.091 mmol, 1 eq) in dichloromethane (5 mL) under nitrogen, was added DIPEA (24.9 mg, 0.193 mmol, 0.0340 mL, 2.12 eq) followed by 1-hydroxybenzotriazole monohydrate (27.0 mg, 0.176 mmol, 1.93 eq). The solution was allowed to stir for 30 minutes before being treated with O-tetrahydro-2H-pyran-2-yl-hydroxylamine (14.3 mg, 0.122 mmol, 1.34 eq) and then dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (24.9 mg, 0.130 mmol, 1.43 eq). The mixture was then allowed to stir for 3 hours at RT. The reaction mixture was then adsorbed onto silica gel and purified by flash chromatography eluting with 5-100% EtOAc/Hpt to give (2R)-4-(4-cyclohexyl-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (8.8 mg, 23% yield). LC-MS M+H+428.1.
Reaction SMILES: C12BC(CCC1)CCC2.[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13]([CH3:20])[C:12]=1[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[CH2:28])[C:22]1=[O:29].[OH-].[Na+].OO.S(=O)(O)[O-:35].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[C:13]([CH3:20])[C:12]=1[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][OH:35])[C:22]1=[O:29]
Reactant: O=S([O-])O
Reactant: C=Cc1cccn(-c2c(C)cc([N+](=O)[O-])cc2C)c1=O
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CCO)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
With ice-cooling, a solution of 902 mg (7.40 mmol) of 9-borabicyclo[3.3.1]nonane in 14.8 ml tetrahydrofuran is added to 800 mg (2.96 mmol) of the compound from Example 52A. The mixture is stirred at room temperature for 3 h and then cooled to 0° C., and an aqueous solution of 591 mg (14.8 mmol) of sodium hydroxide is added over a period of 15 min. 2.60 ml of a 30% strength hydrogen peroxide solution are added such that the temperature does not exceed 30° C. After the addition has ended, the mixture is stirred at 0° C. for 30 min. With ice-cooling, a solution of 8.73 g (32.6 mol) of sodium bisulphite in 12 ml of water is added to the reaction mixture. The mixture is diluted with 50 ml of ethyl acetate, the organic phase is removed and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated to dryness under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:2). This gives 765 mg (89% of theory) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:24])=[C:21]([CH:23]=1)[NH2:22]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:22][C:21]1[CH:23]=[C:17]([O:16][CH3:15])[CH:18]=[CH:19][C:20]=1[CH3:24])=[O:11]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: COc1ccc(C)c(N)c1
Product: COc1ccc(C)c(NC(=O)c2cc(C(N)=O)ccc2OC)c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 5-methoxy-2-methylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][CH:9]([CH:12]([OH:17])[CH:13]([CH3:16])[CH:14]=[CH2:15])[CH:10]=[CH2:11].[N+]([C:21]1[CH:28]=[CH:27][CH:26]=[C:23]([C:24]#[N:25])[C:22]=1[C:29]#[N:30])([O-])=O>C1(C)C=CC=CC=1.O>[CH3:8][CH:9]([CH:12]([O:17][C:21]1[CH:28]=[CH:27][CH:26]=[C:23]([C:24]#[N:25])[C:22]=1[C:29]#[N:30])[CH:13]([CH3:16])[CH:14]=[CH2:15])[CH:10]=[CH2:11]
Reactant: C=CC(C)C(O)C(C)C=C
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=CC(C)C(Oc1cccc(C#N)c1C#N)C(C)C=C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
9.6 g (0.24 mol) of 60% sodium hydride and 150 ml of N,N-dimethylformamide were placed in a container equipped with a stirrer, a reflux condenser and a nitrogen-introducing tube, and the solution was then stirred under the feed of nitrogen. Afterward, 35 g (0.25 mol) of 3,5-dimethyl-1,6-heptadiene-4-ol was added dropwise thereto at 20°-30° C. over 1 hour, and the solution was then stirred at the same temperature for 3 hours to prepare a sodium alcoholate solution. Next, 34.6 g (0.2 mol) of 3-nitrophthalonitrile and 150 ml of N,N-dimethylformamide were placed in a container equipped with a stirrer, and the above-mentioned sodium alcoholate solution was added dropwise thereto at 0° C. or less over 5 hours. After completion of the addition, the temperature of the solution was raised up to a level of 20°-30° C., and the solution was then stirred for 3 hours to bring reaction to an end. The thus obtained reaction solution was poured into 3 l of water and then stirred for 30 minutes, and 500 ml of toluene were added. After stirring for 30 minutes, the resulting toluene layer was separated. After toluene was distilled off under reduced pressure, recrystallization was carried out from 600 ml of n-hexane to obtain 44.7 g of 3-(3,5-dimethyl-1,6-heptadiene-4-oxy)phthalonitrile (yield=84.0%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[C:13]([O:20][CH3:21])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][C:13]=2[O:20][CH3:21])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: Fc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Temperature: 90 °C
Reaction time: 16 h
Yield: 34.2 %

Procedure:
A batch with 2,4-dichloro-5-fluoropyrimidine (200 mg; 1.20 mmol; Aldrich Chemical Company Inc.), (4-fluoro-2-methoxyphenyl)boronic acid (224 mg; 1.31 mmol; Aldrich Chemical Company Inc.) and tetrakis(triphenylphosphin)palladium(0) (138 mg; 0.12 mmol) in 1,2-dimethoxyethane (3.6 mL) and 2 M solution of potassium carbonate (1.8 mL) was degassed using argon. The batch was stirred under argon for 16 hours at 90° C. After cooling the batch was diluted with ethyl acetate and washed with brine. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by column chromatography (hexane/ethyl acetate 1:1) to give the desired product (106 mg; 0.41 mmol).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:11]1[O:12][C:13](=[O:23])[C:14]2[C:19]([C:20]=1[CH:21]=O)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.[O-]S([O-])(=O)=O.[Na+].[Na+]>[Si:1]([O:8][CH:9]([C:11]1[O:12][C:13](=[O:23])[C:14]2[C:19]([C:20]=1[CH2:21][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1oc(=O)c2ccccc2c1C=O
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(O[Si](C)(C)C(C)(C)C)c1oc(=O)c2ccccc2c1CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.3 %

Procedure:
To a solution of 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-1-oxo-1H-isochromene-4-carbaldehyde (Intermediate B59.2, 0.5 g, 1.5 mmol) and morpholine (0.12 ml, 1.35 mmol) in DCM (20 ml), dry Na2SO4 was added and the mixture stirred RT for 10 min. Sodium triacetoxyborohydride (0.286 g, 2.25 mmol) and acetic acid (0.09 ml, 1.5 mmol) were added and the reaction mixture was stirred for 24 h at RT. The reaction was quenched by the addition of 2M HCl (3 ml), the heterogeneous mixture was filtered and the filtrate was purified by flash chromatography on silica NH cartridge (cyclohexane:EtOAc=90:10 to 80:20) affording 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-(morpholinomethyl)-1H-isochromen-1-one (Intermediate B59.3, 0.183 g, 0.45 mmol, 30%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([CH3:28])=[CH2:27])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:10][C@H:9]1[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH:26]([CH3:28])[CH3:27])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:10][C@H:9]1[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)c1ccc2c(c1)N(C(=O)CN1CCN(C(=O)OC(C)(C)C)[C@H](C)C1)CC2
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc2c(c1)N(C(=O)CN1CCN(C(=O)OC(C)(C)C)[C@H](C)C1)CC2
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
Pd(PPh3)4 (32 mg, 0.03 mmol), (R)-4-[2-(6-bromo-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (246 mg, 0.56 mmol) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (113 mg, 0.67 mmol) were dissolved in DMF (1.87 mL). Cs2CO3 (549 mg, 1.7 mmol) dissolved in water (0.37 mL) was added to the DMF solution. The reaction was degassed and heated to 85° C. for 18 h then was filtered and concentrated. Column chromatography on silica gel (gradient elution, 0-100% EtOAc/petrol), gave (R)-4-[2-(6-isopropenyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.18 g) as a yellow oil. 10% Pd/C (48 mg, 0.05 mmol) and (R)-4-[2-(6-isopropenyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.18 g) were mixed with MeOH (4.5 mL). The reaction was hydrogenated at 1 bar for 30 min at ambient temperature then filtered under vacuum and concentrated, to give the title compound (157 mg, 86%) as a colourless oil. 1H NMR (Me-d3-OD): 8.08 (1H, s), 7.15 (1H, d), 6.95 (1H, d), 4.35-4.18 (3H, m), 3.83 (1H, d), 3.30 (2H, s), 3.25-3.12 (3H, m), 2.97-2.76 (3H, m), 2.33 (1H, dd), 2.20-2.08 (1H, m), 1.48 (9H, s), 1.31 (3H, d), 1.25 (6H, d).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[NH:22][C:21](=[O:23])[C@H:20]([CH:24]([CH3:26])[CH3:25])[NH:19][C:18](=[O:27])[C@@H:17]([NH2:28])[CH2:16][C:15]2=[CH:29][CH:30]=[C:12]([CH:13]=[CH:14]2)[O:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[CH3:31][S:32](Cl)(=[O:34])=[O:33].CCN(C(C)C)C(C)C.CCOC(C)=O>CN(C=O)C>[CH3:2][O:3][C:4]([C@H:6]1[NH:22][C:21](=[O:23])[C@H:20]([CH:24]([CH3:26])[CH3:25])[NH:19][C:18](=[O:27])[C@@H:17]([NH:28][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:16][C:15]2=[CH:29][CH:30]=[C:12]([CH:13]=[CH:14]2)[O:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1CCCCOc2ccc(cc2)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCCOc2ccc(cc2)C[C@H](NS(C)(=O)=O)C(=O)N[C@@H](C(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Amine 47 (200 mg) was dissolved in anhydrous DMF (5 mL). Methane-sulfonyl chloride (39 μL) and DIPEA (0.175 mL) were added and the reaction mixture was stirred at rt for 18 h before being partitioned between chloroform and 1M hydrochloric acid. The aqueous phase was extracted three more times with chloroform and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification was achieved using flash chromatography, eluting with a gradient of 1/1 EtOAc/(50/70) petroleum ether to EtOAc to yield a light brown solid, 40 mg, 17%. Rf=0.12 (1/1 EtOAc/(50/70) petroleum ether).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=O)[C:7]2=[O:16])=[CH:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1>CC(O)=O.CO>[CH3:24][C:21]1[CH:22]=[CH:23][C:18](/[N:17]=[C:8]2/[C:7](=[O:16])[N:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[C:14]3[C:9]/2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:19][CH:20]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C1C(=O)N(c2ccsc2)c2ccccc21
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(/N=C2/C(=O)N(c3ccsc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.5 %

Procedure:
A solution of 1-(3-Thienyl)-1H-indole-2,3-dione (20 mg, 0.087 mmol) in 1% HOAc/MeOH (8 mL) was added to a solution of p-toluidine (19 mg, 0.18 mmol) in 1% HOAc/MeOH (8 mL). The reaction mixture was stirred for 12 h at room temperature, heated at 50° C. for 1 h, and concentrated in vacuo. The residue was purified by preparative TLC on silica using EtOAc/hexanes (3:7, 0.1% TEA) giving the desired product (14 mg, 50%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:21].[C:22]([NH:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)(=[O:24])[CH3:23].C(=O)(O)[O-].[Na+]>C(#N)C>[C:22]([NH:25][CH:26]1[CH2:30][CH2:29][N:28]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:20])[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:8][N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:21])[CH2:27]1)(=[O:24])[CH3:23]
Reactant: CC(=O)NC1CCNC1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3CCC(NC(C)=O)C3)c(F)cc2c1=O
Yield: 93.4 %

Procedure:
A mixture of ethyl 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (1.24 g), 3-acetylaminopyrrolidine (563 mg), sodium bicarbonate (437 mg) and acetonitrile (40 ml) was refluxed for 30 minutes. After evaporation to dryness under reduced pressure, water was added to the residue. The resulting crystals were filtered and recrystallized from ethanolisopropyl ether to give ethyl 7-(3-acetylamino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (1.50 g), m.p. 246°-248° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[N:11][OH:12])[NH2:7])=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=NO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
To a solution of 4-fluorobenzonitrile (0.500 g, 4.13 mmol) in ethanol (3 mL) was added hydroxylamine HCl (0.427 g, 6.19 mmol) and potassium carbonate (1.14 g, 8.26 mmol). The reaction mass was stirred at RT for 15-17 h. Excess of solvent was removed under vacuum. The obtained residue was diluted with water, acidified with dilute HCl and extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 0.450 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 5.84 (br s, 2H), 7.17-7.27 (m, 2H), 7.68-7.73 (m, 2H), 9.64 (br s, 1H); MS (m/z): 155.13 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[Cl:5][C:6]1[N:11]=[C:10](Cl)[N:9]=[C:8]([CH2:13][CH2:14][CH3:15])[N:7]=1>O1CCOCC1>[Cl:5][C:6]1[N:7]=[C:8]([CH2:13][CH2:14][CH3:15])[N:9]=[C:10]([NH:1][CH2:2][CH2:3][OH:4])[N:11]=1
Reactant: NCCO
Reactant: CCCc1nc(Cl)nc(Cl)n1
Solvent: C1COCCO1
Product: CCCc1nc(Cl)nc(NCCO)n1
Reaction time: 8 h
Yield: 95.8 %

Procedure:
24.4 g (0.4 mole) of 2-aminoethanol, dissolved in 100 ml of dioxane, are added dropwise into a solution of 38.4 g (0.2 mole) of 2,4-dichloro-6-propyl-1,3,5-triazine in 100 ml of dioxane at room temperature. After the addition, stirring is continued overnight. The 2-aminoethanol hydrochloride is filtered off and the filtrate is evaporated under reduced pressure. The residue obtained is recrystallized from a mixture of ethyl acetate-hexane 50:50 (v/v). 41.5 g of 2-[(4-chloro-6-propyl-1,3,5-triazin-2-yl)amino]-ethanol are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]#[N:15])=[CH:9][C:3]=1[C:4]([O:6]CC)=O.[CH3:16][NH2:17].C[O-].[Na+]>>[NH2:1][C:2]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]#[N:15])=[CH:9][C:3]=1[C:4]([NH:17][CH3:16])=[O:6]
Reactant: CN
Reactant: CCOC(=O)c1cc(C#N)cc(C)c1N
Agent: C[O-]
Agent: [Na+]
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Yield: 96.9 %

Procedure:
The above-described method (Example 3) was repeated to stir ethyl 2-amino-5-cyano-3-methylbenzoate (0.50 g, 2.40 mmol) with methylamine (3.73 g, 48 mmol, 40% in methanol) and sodium methoxide (22 mg, 30% in methanol) at room temperature for 18 hours. The entire reaction batch was vacuum distilled and 2-amino-5-cyano-N,3-dimethylbenzamide (0.44 g, 95.9% of theory, 99.0 area % LC) was obtained as a pale brown solid.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:20])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[CH2:1]([O:5][C:6](=[O:20])[CH:7]([NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:21][CH:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1c[nH]c2ccccc12

Procedure:
A solution of 20.2 g. (0.070 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester and 8.8 g. (0.075 mol.) of indole in 300 ml. of toluene was slowly distilled over a 30 minutes interval with periodic replacement of the toluene with fresh solvent. After an additional 45 minutes the reaction mixture was cooled and the solvent was evaporated in vacuo. The residue was triturated with hexane to give α-(N-t-butoxycarbonylamino)indole-3-acetic acid n-butyl ester, m.p. 127°-128° (ether-hexane).
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8](F)[C:5]=1[C:6]#[N:7].CN(C)C=O.[CH2:19]([SH:22])[CH2:20][CH3:21].[OH-].[K+]>O>[F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([S:22][CH2:19][CH2:20][CH3:21])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c(F)cccc1OC(F)F
Reactant: CCCS
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCSc1cccc(OC(F)F)c1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
180 g (0.96 mol) 2-difluoromethoxy-6-fluorobenzonitrile were introduced into 1.5 l of dimethylformamide at room temperature. 73.2 g (0.96 mol) of propanethiol were added dropwise and, after cooling to 0° C., 70 g (1.25 mol) of potassium hydroxide pellets, dissolved in 600 ml of water, were added dropwise at 0° C. The mixture was stirred for one hour and then warmed to room temperature. The reaction mixture was stirred into 3.5 l of ice-water and extracted three times with 500 ml of methyl tert.-butyl ether. The combined organic phases were washed twice with 500 ml of 1N hydrochloric acid and dried over sodium sulfate. Then, the solvent was distilled off in vacuo. The oil obtained was distilled in vacuo (b.p.: 180-185° C./0.5 mbar). Yield: 76% of theory.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][CH2:37][C:38]([N:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1)=[O:39]>C(Cl)Cl>[CH2:8]([NH:26][C:27](=[O:28])[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][CH2:37][C:38]([N:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1)=[O:39])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CN1CCN(C(=O)CCc2ccccc2O)CC1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)Oc1ccccc1CCC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triethylamine (0.62 ml) and octadecyl isocyanate (1.40 ml) were added to a solution containing 3-(2-hydroxyphenyl)-1-(4-methylpiperazino)-1-propanone (1.00 g) in methylene chloride (10 ml) and stirred for 4 hours at room temperature. The insoluble matters were filtrated out and washed with chloroform. The filtrate and washings were combined and the mixture was washed with saturated sodium hydrogencarbonate aqueous solution and brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=50:1), thereby yielding the entitled compound (2.05 g) as white solid.