Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O.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:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)[CH:11]=1
Reactant: OB(O)c1ccncc1
Reactant: COC(=O)c1ccc(F)cc1Br
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: COCCOC
Solvent: O
Product: COC(=O)c1ccc(F)cc1-c1ccncc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
A mixture of methyl 2-bromo-4-fluorobenzoate (1.5 g), pyridine-4-boronic acid (0.95 g), sodium carbonate (1.0 g), tetrakis(triphenylphosphine)palladium(0) (0.22 g), water (1.5 mL) and DME (9.0 mL) was stirred at 120° C. for 1 hr under microwave irradiation. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.89 g).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]1([C:29]#[C:30][C:31]2[CH:32]=[N:33][CH:34]=[C:35]([CH:39]=2)[C:36]([NH2:38])=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:23]1([C:29]#[C:30][C:31]2[CH:32]=[N:33][CH:34]=[C:35]([CH:39]=2)[C:36]([NH2:38])=[S:10])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1cncc(C#Cc2ccccc2)c1
Solvent: Cc1ccccc1
Product: NC(=S)c1cncc(C#Cc2ccccc2)c1
Reaction time: 48 h
Yield: 40.3 %

Procedure:
Add Lawesson's Reagent, [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate -2,4-disulfide], (0.42 g, 1.03 mmol) to a suspension of 5-phenylethynyl-nicotinamide (0.12 g, 0.52 mmol) in toluene (3 mL) and stir for 48 h. Concentrate the reaction mixture and purify the residue by silica gel chromatography, eluting with 10:90 to 60:40 with ethyl acetate:hexanes, to give the title compound as a pale yellow solid (0.05 g, 40%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CC(C)=O>[O:30]1[CH2:29][CH:28]1[CH2:26][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10]
Reactant: ClCC1CO1
Reactant: O=C(Nc1ccccc1O)c1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1OCC1CO1)c1cccc2[nH]ccc12

Procedure:
Under an inert atmosphere, a solution of 3 g of N-(2-hydroxyphenyl)-1H-indol-4-carboxamide and 1.65 g of potassium carbonate in 100 ml of acetone was refluxed for 24 hours with 4.7 ml of epichlorhydrin and after purifying by chromatography over silica (eluent: ethyl acetate-triethylamine, 9-1) and evaporating to dryness, the residue was triturated in pentane, then filtered and dried under reduced pressure at 60° C. to obtain 2.8 g of N-[2-[(2-oxiranyl)methoxy]phenyl]-1H-indol-4-carboxamide melting at 122° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C@@H:6]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:24]=2)[CH2:7][C:8](N2[C@H](CC3C=CC=CC=3)COC2=O)=[O:9])=[N:2]1.[OH:37]O.[Li+].[OH-].Cl>C1COCC1.O>[O:1]1[CH:5]=[CH:4][C:3]([C@@H:6]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:24]=2)[CH2:7][C:8]([OH:9])=[O:37])=[N:2]1
Reactant: OO
Reactant: O=C(C[C@H](c1cccc(OCc2ccccc2)c1)c1ccon1)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@H](c1cccc(OCc2ccccc2)c1)c1ccon1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of (R)-4-benzyl-3-((R)-3-(3-(benzyloxy)phenyl)-3-(isoxazol-3-yl)propanoyl)oxazolidin-2-one (94.1C) (0.558 g, 1.16 mmol) in THF (12 mL) was cooled to 0° C. H2O2 (30% w/w, 0.50 mL) was added, and was followed by addition of LiOH, monohydrate (0.0643 mL, 2.31 mmol) in water (4 mL). The resulting mixture was stirred at 0° C. for 2 hours. The organic solvent was blown away by nitrogen, and the aqueous mixture was acidified with 1N HCl to pH 3-5. The mixture was extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4. After removing solvent, crude product (94.1D) (491 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>O>[NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:28][CH2:27][CH2:26][O:25][CH3:24])[CH:12]=3)[CH:7]=1
Reactant: COCCN
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Solvent: O
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NCCOC)cc21
Yield: 94 %

Procedure:
A suspension of Example A3 (1.50 g, 4.26 mmol) in 2-methoxyethylamine (3 mL, 34.51 mm) was heated at 120° C. for 12 h. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to provide 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(2-methoxyethylamino)-1,6-naphthyridin-2(1H)-one (1.56 g, 94% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.65 (s, 1H), 7.18 (d, J=11 Hz, 1H), 7.03 (m, 1H), 6.72 (d, J=9.5 Hz, 1H), 6.38 (s, 1H), 5.30 (s, 2H), 4.07 (m, 2H), 3.47 (m, 4H), 3.25 (s, 3H), 1.20 (s, 3H); MS (ESI) m/z: 391.1 [M+H]+.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[C:10]([F:20])=[C:11]([CH:15]=[C:16]([F:19])[C:17]=1[F:18])[C:12]([OH:14])=[O:13].[ClH:21]>C(#N)C>[Cl:21][C:9]1[C:10]([F:20])=[C:11]([CH:15]=[C:16]([F:19])[C:17]=1[F:18])[C:12]([OH:14])=[O:13]
Reactant: Cl
Reactant: Nc1c(F)c(F)cc(C(=O)O)c1F
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: O=C(O)c1cc(F)c(F)c(Cl)c1F
Temperature: 60 °C

Procedure:
9.3 g of anhydrous cuprous chloride and 8.8 g of tert-butyl nitrite were added to 150 ml of acetonitrile and under stirring and heating at 60° C., 11 g of 3-amino-2,4,5-trifluorobenzoic acid 26 (a commercial product) was added. The mixture was stirred for 20 minutes. After cooling, 500 ml of 15% hydrochloric acid was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was then removed under reduced pressure. Finally the residue was subjected to silica gel (100 g) column chromatography using chloroform as an eluent. The procedure gave 8.4 g of 3-chloro-2,4,5-trifluorobenzoic acid 27 as colorless needles.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[N:5]=[C:4]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:5][C:6]=1[CH3:11]
Reactant: [H][H]
Reactant: CCOC(=O)COc1nc(C)c([N+](=O)[O-])c(C)n1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COc1nc(C)c(N)c(C)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99.9 %

Procedure:
Compound 6 (75.98 g) and 5% Pd—C (7.598 g, N. E. CHEMCAT, STD Type) were suspended in ethanol (760 mL). Evacuation and replacement with hydrogen were repeated three times. Subsequently, the suspension was vigorously stirred at room temperature (20 to 30° C.) for 4.5 hours under hydrogen atmosphere. After the reaction was completed, the mixture was subjected to high precision pressure filtration (0.2 μm, PTFE) and the filtered product was washed with ethanol (474 mL). The filtrate was evaporated under reduced pressure to give 66.99 g (99.9% yield) of the desired product as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([C:12]3[CH:17]=[C:16]([S:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=3[O:27][CH2:28][CH2:29][CH3:30])[NH:11][C:5]=2[N:4]([CH2:31][CH2:32][CH3:33])[C:3]1=[O:34].[CH:35](=O)[CH2:36][CH3:37].[Na]>CO.C(O)(=O)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([C:12]3[CH:17]=[C:16]([S:18]([N:21]4[CH2:26][CH2:25][N:24]([CH2:35][CH2:36][CH3:37])[CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=3[O:27][CH2:28][CH2:29][CH3:30])[NH:11][C:5]=2[N:4]([CH2:31][CH2:32][CH3:33])[C:3]1=[O:34]
Reactant: CCCOc1ccc(S(=O)(=O)N2CCNCC2)cc1-c1cc2c(=O)n(C)c(=O)n(CCC)c2[nH]1
Reactant: CCC=O
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: CCCOc1ccc(S(=O)(=O)N2CCN(CCC)CC2)cc1-c1cc2c(=O)n(C)c(=O)n(CCC)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
A mixture of the title compound of example 87 (50 mg, 0.1 mmol), propanal (0.073 mL, 1 mmol) and 3 Å molecular sieves (300 mg) in methanol (2 mL) and acetic acid (0.1 mL), was stirred at room temperature for 4 hours. Then sodium cianoborohydride (32 mg, 0.51 mmol) was slowly added and the mixture was stirred at room temperature overnight. The reaction mixture was purified by solid phase extraction using a Varian Bond Elut SCX cartridge (methanol for washing, methanol-ammonia for elution) to yield the title compound (40 mg, 72%).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([N:26]3[CH2:27][CH2:28][O:24][C:25]3=[O:29])=[N:7][CH:6]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)nc3)CC2)c(C)c1
Yield: 62.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (749 mg) described in Preparation Example 20 and oxazolidin-2-one (174 mg), the title compound (473 mg) was obtained.
Reaction SMILES: CN(C)C=O.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=[O:18].[Br:19]N1C(=O)CCC1=O>O>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:17]=[C:16]([Br:19])[CH:15]=[CH:14][C:13]1=[O:18]
Reactant: O=c1ccccn1-c1ccccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc(Br)cn1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
Under ice-cooling, 15 ml of a dimethylformamide solution containing 1.50 g of 1-(2-pyridyl)-1,2-dihydropyridin-2-one was incorporated with 1.60 g of N-bromosuccinic acid imide. The mixture was stirred at room temperature for 2 hours, and then diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/hexane=1:3), to give 1.13 g of the title compound as a pale brown powder.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[C:11]([CH3:34])([CH3:33])[CH2:12][CH:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]2=[O:32])[CH2:14]1.O>ClCCl>[F:7][C:11]([CH3:34])([CH3:33])[CH2:12][CH:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]2=[O:32])[CH2:14]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)CC1CCN(CCc2ccccc2N2CCCCC2=O)C1
Solvent: ClCCl
Solvent: O
Product: CC(C)(F)CC1CCN(CCc2ccccc2N2CCCCC2=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Diethylaminosulfur trifluoride (31 μl, 0.235 mmol, 1.5 eq) is added to 1-(2-{2-[3-(2-hydroxy-2-methyl propyl)pyrrolidin-1-yl]ethyl}phenyl)piperidin-2-one a13-2 (54 mg, 0.157 mmol, 1 eq) in dichloromethane (5 ml) dropwise and the reaction mixture stirred at room temperature overnight. The reaction mixture is poured into water and stirring is pursued for 1 hour. After phase separation, the aqueous phase is further extracted with dichloromethane (3 times). The combined organic phases are washed with brine (1 time), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by basic reverse phase chromatography (gradient: acetonitrile/H2O/ammonium formiate from 5% to 40% of acetonitrile in 8 minutes) to afford 6 mg of 1-(2-{2-[3-(2-fluoro-2-methylpropyl)pyrrolidin-1-yl]ethyl}phenyl)piperidin-2-one 85 as a yellow oil.
Reaction SMILES: C[O-].[Na+].CO.[CH3:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH2:11][CH2:12][CH3:13].[CH:16]1[CH2:20][CH:19]=[CH:18][CH:17]=1>>[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH2:12][CH3:13])=[C:16]2[C:17]=1[CH:18]=[CH:19][CH2:20]2
Reactant: C1=CCC=C1
Reactant: CCCC(=O)CCC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCc1ccc(C)c2c1CC=C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
45 ml of a 30 percent strength solution of sodium methanolate in methanol (250 mmol) were initially introduced into the reaction vessel at 0° C., and a mixture of 14.2 g (100 mmol) of 2,5-octanedione and 9 ml (110 mmol) of cyclopentadiene was added in the course of 30 minutes. After the mixture had been stirred at room temperature for 3 hours, it was poured into 300 ml of ice-water and extracted with diethyl ether and the organic phase was dried over magnesium sulfate. The residue which remained after evaporation was chromatographed on silica gel. 6.8 g (39%) of the indene 2 could be isolated with hexane as the mobile phase.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:9][C:10]([C:12]1[C:13]([OH:21])=[C:14]2[S:20][CH:19]=[CH:18][C:15]2=[N:16][CH:17]=1)=[O:11])[CH3:8].Cl[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]>ClCCl>[CH:26]([O:25][C:23]([N:16]1[CH:17]=[C:12]([C:10]([O:9][CH2:7][CH3:8])=[O:11])[C:13](=[O:21])[C:14]2[S:20][CH:19]=[CH:18][C:15]1=2)=[O:24])([CH3:28])[CH3:27]
Reactant: CC(C)OC(=O)Cl
Reactant: CCOC(=O)c1cnc2ccsc2c1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(C(=O)OC(C)C)c2ccsc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Add pyridine (1.20 ml, 14.8 mmol) to a suspension of 7-hydroxy-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (1.10 g, 4.93 mmol) in dichloromethane (50 ml), and then add isopropyl chloroformate (1.0 N in toluene, 14.8 ml). Stir the reaction mixture at room temperature overnight. Wash the mixture with 1 N HCl (50 ml) followed by brine (3×50 ml). Separate the organic layer, dry over sodium sulfate, filter and concentrate. Purify using silica gel column chromatography (gradient eluent, 0-60% ethyl acetate in hexane) to provide 7-oxo-7H-thieno[3,2-b]pyridine-4,6-dicarboxylic acid 6-ethyl ester 4-isopropyl ester (1.37 g, 90%) as a white crystalline solid. MS (ES+): 310 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:9])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[S:10]1[C:14]2[CH:15]=[C:16]([S:19](Cl)(=[O:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1>>[I:9][C:3]1[C:2]([NH:1][S:19]([C:16]2[CH:17]=[CH:18][C:13]3[N:12]=[CH:11][S:10][C:14]=3[CH:15]=2)(=[O:20])=[O:21])=[CH:7][CH:6]=[C:5]([Cl:8])[N:4]=1
Reactant: Nc1ccc(Cl)nc1I
Reactant: O=S(=O)(Cl)c1ccc2ncsc2c1
Product: O=S(=O)(Nc1ccc(Cl)nc1I)c1ccc2ncsc2c1

Procedure:
By working in a manner similar to that of Example 50, starting with 3-amino-2-iodo-6-chloropyridine and 6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of an orange-colored solid (yield=33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1>CC(C)=O>[Cl:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:19][CH:20]=1)[O:8][C:7](=[O:9])[CH2:6][CH:5]2[C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[O:2][CH3:1]
Reactant: Oc1ccc(Cl)cc1
Reactant: COc1ccccc1C=CC(=O)O
Solvent: CC(C)=O
Product: COc1ccccc1C1CC(=O)Oc2ccc(Cl)cc21
Yield: 49 %

Procedure:
6-Chloro-4-(2-methoxyphenyl)-3,4-dihydrocoumarin (CVII) was prepared in a similar way in 49% yield from 2-methoxycinnamic acid and p-chlorophenol, the reaction temperature being 130° in this case. M.p. 172°-173° (acetone).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]2[O:9][CH2:10][C:11](=[O:13])[NH:12][C:7]=2[CH:6]=1)=[O:4].CCO.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CCOCC>[O:22]1[CH2:23][CH2:24][N:19]([CH2:2][C:3]([C:5]2[CH:15]=[CH:14][C:8]3[O:9][CH2:10][C:11](=[O:13])[NH:12][C:7]=3[CH:6]=2)=[O:4])[CH2:20][CH2:21]1
Reactant: O=C1COc2ccc(C(=O)CCl)cc2N1
Reactant: C1COCCN1
Solvent: CCOCC
Solvent: CCO
Product: O=C1COc2ccc(C(=O)CN3CCOCC3)cc2N1
Temperature: 80 °C

Procedure:
To a 20 mL scintillation vial with a magnetic stirrer was added commercially available 6-(2-chloroacetyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (113 mg, 0.5 mmol) and EtOH (2.5 mL) followed by morpholine (96 mg, 1.1 mmol). The reaction was heated at 80° C. for 1 h then cooled to room temperature. The solution was diluted with Et2O (10 mL) and the resulting solid was isolated by filtration, washed with Et2O and dried in vacuo to give a white solid: 1H NMR (DMSO-d6, 400 MHz): δ=10.91 (s, 1H), 9.31 (br. s., 1H), 7.65 (dd, J=8.3, 2.0 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 4.68 (s, 2H), 3.67-3.87 (m, 6H), 3.58 (t, J=4.3 Hz, 2H), 3.07 ppm (d, J=5.1 Hz, 2H). ESI-MS: m/z 277.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[Li][CH2:12]CCC.IC>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH3:12]
Reactant: [Li]CCCC
Reactant: COc1cccc(OC)c1
Solvent: CI
Solvent: C1CCOC1
Product: COc1cccc(OC)c1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
To a solution of 1,3-dimethoxybenzene (2.00 g, 14.5 mmol) in THF (30 mL) at 0° C. was added n-BuLi (6.40 mL, 15.9 mmol, 2.5 M in hexanes) slowly over a 2 min period. The solution was stirred at 0° C. for 15 min and then at room temperature for 1.5 h. The solution was re-cooled to 0° C., iodomethane (2.70 mL, 43.5 mmol) was added slowly (the solution warmed up) and the solution was stirred at 0° C. for 10 min and then at room temperature for 1.5 h. The reaction was quenched with water, most of the solvent was removed in vacuo, and extraction was done in EtOAc (2×75 mL) with water (50 mL). Flash chromatography with silica gel (gradient to 6% ethyl ether/hexanes) afforded the title compound as a colorless liquid (1.98 g, 90% yield): 1H NMR (300 MHz, CDCl3) δ 2.10 (s, 3H), 3.82 (s, 6H), 6.54 (d, 2H, J=8.3 Hz), 7.12 (t, 1H, J=8.3 Hz).
Reaction SMILES: [CH:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:16](O)[CH2:17][OH:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:2]([CH:1]1[O:18][CH2:17][CH2:16][O:15]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC/C=C\CCCCCCC=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC/C=C\CCCCCCC1OCCO1
Reaction time: 3 h

Procedure:
5.6 g (Z)-8-tetradecenal (6), 2.0 g ethylene glycol and 20 mg p-toluenesulphonic acid in 150 ml toluene were boiled in a water separator for 3 h. The reaction mixture was washed with sodium bisulphate solution and dried over sodium sulphate and the solvent was distilled off. Chromatography on silica gel gave 2-[(Z)-tridec-7-enyl]-1,3-dioxolane (7).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)N.N([O-])=O.[Na+].N1C=CC=CC=1.[FH:21]>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([F:21])[CH:8]=1
Reactant: Cc1cc(Br)cc(N)c1C
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cc(Br)cc(F)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4.00 g of 5-bromo-2,3-dimethylaniline (3-11) was dissolved in 50 ml of hydrogen fluoride-pyridine, to which under cooling with ice, 5.00 ml of an aqueous solution of 2.10 g of sodium nitrite was dropped. The resulting mixture was stirred at the same temperature for 30 minutes and further stirred at a room temperature for 1 hour, and thereafter, stirred at 85° C. for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate and the resulting organic layer was washed with sodium bicarbonate solution, and thereafter, the resulting organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=10:1) to obtain 2.92 g of 5-bromo-1-fluoro-2,3-dimethylbenzene (3-12).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[NH:15][C:14](=[O:18])[CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=O)[CH2:9]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.C(OCCO)C.Cl>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[NH:15][C:14](=[O:18])[CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1cc(=O)[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cl
Solvent: CCOCCO
Product: Cc1cc(=O)[nH]c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Temperature: 135 °C
Reaction time: 1 h
Yield: 157.6 %

Procedure:
To a mixture of 7-(2-chlorophenyl)-4-methyl-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.144 g) and aminoguanidine hydrochloride (61 mg) were added 2-ethoxyethanol (2.5 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was stirred at 135° C. for 1 hour and cooled. Precipitated crystals were filtered, washed with methanol and dried to give 7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-1,2,5,6,7,8-hexahydroquinolin-2-one hydrochloride (Compound 139) (0.15 g) as colorless crystals.
Reaction SMILES: [C:1]([C:4]1([CH2:14][CH3:15])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[Br:16]Br>CO>[Br:16][CH2:2][C:1]([C:4]1([CH2:14][CH3:15])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[CH2:5]1)=[O:3]
Reactant: CCC1(C(C)=O)Cc2ccc(F)cc2C1
Reactant: BrBr
Solvent: CO
Product: CCC1(C(=O)CBr)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
3.8 g of 2-acetyl-2-ethyl-5-fluoroindan and 35 ml of methanol were placed into a round-bottomed flask equipped with a thermometer, a mechanical stirrer and a dropping funnel. The reaction mixture was cooled in a cooling bath while stirring to a temperature between −5° C. and −8° C. and 0.7 ml of a Br2-solution in a small amount of methanol was added dropwise. The cooling bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to a temperature between −5° C. and −8° C. and an additional 0.175 ml of Br2-solution in a small amount of methanol was added dropwise. The cooling bath was removed and the reaction mixture was stirred at room temperature for an additional 1 to 2 hours. After chromatographic purification using methylene chloride as an eluent 2.51 g of 2-bromo-1-(2-ethyl-5-fluoro-indan-2-yl)-ethanone was obtained as a liquid (yield 69%).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>C(O)(=O)C.[Pt]=O>[CH2:7]1[CH2:6][CH2:5][CH:4]([CH2:3][C@H:2]([NH2:1])[C:10]([OH:12])=[O:11])[CH2:9][CH2:8]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: N[C@@H](CC1CCCCC1)C(=O)O
Yield: 106.1 %

Procedure:
2 g of L-phenylalanine was dissolved in 30 ml of 50% acetic acid, and high pressure hydrogenation was conducted (hydrogen pressure: 50 kg/cm2, 40°-70° C., two hours) by an addition of 200 mg of platinum oxide. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 2.2 g of L-cyclohexylalanine as colorless needles.