Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]([CH3:41])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:27][CH2:28][N:29]([CH3:40])[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH3:19])[C:12]1=[O:42].F[B-](F)(F)F.[N:48]1(OC(N(C)C)=[N+](C)C)[C:52]2C=CC=C[C:51]=2N=N1.C(N(C(C)C)C(C)C)C.C(N)C>CN(C=O)C.O>[C:34]1([CH2:33][O:32][C:30](=[O:31])[N:29]([CH2:28][CH2:27][O:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:18]([NH:17][C:13]2[C:12](=[O:42])[N:11]([C:3]3[CH:4]=[C:5]([C:6]([NH:48][CH2:52][CH3:51])=[O:8])[CH:9]=[CH:10][C:2]=3[CH3:1])[CH:16]=[CH:15][N:14]=2)([CH3:19])[CH3:41])[CH3:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1ccc(C(=O)O)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCN(C)C(=O)OCc2ccccc2)c1=O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CCN
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(C)c(-n2ccnc(NC(C)(C)c3ccccc3OCCN(C)C(=O)OCc3ccccc3)c2=O)c1
Reaction time: 3 h
Yield: 750.1 %

Procedure:
To 4-methyl-3-[3-[[1-methyl-1-[2-[2-[methyl[(phenylmethoxy)carbonyl]amino]ethoxy]phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-benzoic acid (Example 220d, 0.14 g) in DMF (3 mL) were added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.158 g) followed by N-ethyldiisopropylamine (0.212 mL) and the reaction stirred for 15 min before ethylamine (0.032 mL) was added and the reaction stirred for 3 h. The reaction was diluted with water and the aqueous layer extracted with ethyl acetate. The combined organics were dried (Na2SO4) and solvents removed in vacuo to give the subtitle product (1.10 g).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].O1CCCC1.[Cl:14][CH2:15][CH2:16][N:17]([N:23]=[O:24])[C:18](N=[N+]=[N-])=[O:19]>C(=O)([O-])[O-].[K+].[K+]>[Cl:14][CH2:15][CH2:16][N:17]([N:23]=[O:24])[C:18]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:19]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: [N-]=[N+]=NC(=O)N(CCCl)N=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)N(CCCl)N=O)C(=O)O
Reaction time: 2 h
Yield: 64.3 %

Procedure:
Dissolved in a 5% aqueous potassium carbonate solution was 2.1 g of L-valine, and a tetrahydrofuran solution containing 3.2 g of (2-chloroethyl)-nitrosocarbamoyl azide was added at 0° C. The mixture was stirred for two hours. The reaction solution was washed with ether, neutralized with hydrochloric acid, and extracted with ether to obtain 2.9 g (Yield 64%) of N-{(2-chloroethyl)-nitrosocarbamoyl}-L-valine as a slightly yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH3:6][O:7][C:8]1[CH:41]=[CH:40][C:11]([CH2:12][N:13]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH3:36])=[CH:26][CH:25]=4)=[CH:23][C:18]=3[CH:17]=[C:16]([C:37](O)=[O:38])[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.S(Cl)(Cl)=O>O1CCCC1>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][N:13]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH3:36])=[CH:28][CH:29]=4)=[CH:23][C:18]=3[CH:17]=[C:16]([C:37]([NH:13][C:19]3[CH:20]=[CH:21][C:22]([CH2:4][N:2]([CH3:1])[CH:3]4[CH2:32][CH2:31][O:30][CH2:27][CH2:26]4)=[CH:23][CH:18]=3)=[O:38])[CH2:15][CH2:14]2)=[CH:40][CH:41]=1
Reactant: CN(C)C=O
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccc(OC)cc2)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccc(OC)cc2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 1-(4-methoxybenzyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (110 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (96 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (30 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (71 mg) and triethylamine (328 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 1-(4-methoxybenzyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 55) (86 mg) as yellow crystals.
Reaction SMILES: [SH:1][C:2]1[NH:6][N:5]=[N:4][CH:3]=1.I[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]I>C(O)C>[N:4]1[CH:3]=[C:2]([S:1][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:1][C:2]2[NH:6][N:5]=[N:4][CH:3]=2)[NH:6][N:5]=1
Reactant: ICCCCCCCCI
Reactant: Sc1cnn[nH]1
Solvent: CCO
Product: c1nn[nH]c1SCCCCCCCCSc1cnn[nH]1
Yield: 41.6 %

Procedure:
20 mmole of 5-mercapto-1H-1,2,3-triazole (sodium salt) was dissolved in 20 ml of ethanol in stirring. 10 mmole of 1,8-diiodooctane was added dropwise to the solution of 5-mercapto-1H-1,2,3-triazole (sodium salt), and stirred overnight. After the solvent was evaporated in vacuum, the residual was washed with 50 ml pure H2O for three times, and then with 50 ml hexane for 3 times. At last, the residual was dried in oven at 60° C. for 24 hours. 1.30 g product was obtained as white solid. Yield: 42%. 1H NMR (DMSO): δ (ppm) 7.88 (2H, s), 2.86 (4H, t, JH-H=7.14), 1.50 (4H, m), and 1.20-1.31 (8H, m).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:25][NH:26][CH3:27]>C1COCC1>[C:15]([C:7]1[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:26]([CH3:27])[CH3:25])([CH3:18])([CH3:17])[CH3:16]
Reactant: CNC
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CC(=O)Nc1cc([N+](=O)[O-])ccc1C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-Bromo-N-(2-tert-butyl-5-nitro-phenyl)-acetamide (Step B, 80 g, 253 mmol) and K2CO3 (70 g, 506 mmol) were combined in a 3 L 3-neck round bottom flask fitted with a mechanical stirrer, N2(g) inlet, and pressure equalizing addition funnel. THF (1.75 L) was added and the mixture cooled to 0° C. under N2(g). N,N-Dimethylamine (400 mL of a 2 M solution in THF, 800 mmol) was added to the mixture through the pressure equalizing addition funnel over 30 min. The mixture was gradually warmed to RT with stirring overnight. The reaction was quenched by filtering under vacuum and concentrating the filtrate under reduced pressure. The recovered material was eluted through a 36×7 cm column of silica gel with 50% EtOAc:Hexanes giving a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:17])[CH2:14][CH2:15]2)=[CH:3][C:2]=1[NH:1][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1N
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1Nc1ccccc1
Reaction time: 12 h
Yield: 80.7 %

Procedure:
To a stirred solution of (4-(3-amino-4-methoxyphenyl)piperazin-1-yl) (phenyl)methanone (2 g, 6.4 mmol) and phenylboronic acid (2.34 g, 19.2 mmol) in DCM (100 mL) was added triethylamine (2.7 mL, 19.2 mmol) and Cu(OAc)2 (1.74 g, 9.6 mmol). The mixture was stirred for 12 h. It was then filtered through celite, evaporated under vacuum. Flash column chromatography gave (4-(4-methoxy-3-(phenylamino) phenyl)piperazin-1-yl)(phenyl)methanone (2.0 g), 80% yield. 1H NMR (500 MHz, CDCl3): δ 3.0 (bs, 2H), 3.15 (bs, 2H), 3.59 (bs, 2H), 3.89 (s, 3H), 3.95 (bs, 2H), 6.18 (s, 1H), 6.46 (dd, J=2.5, 3 Hz 1H), 6.85 (d, J=9 Hz, 1H), 7.01 (m, 2H), 7.19 (d, J=7.5 Hz, 2H), 7.34 (m, 2H), 7.49 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[C:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]=[CH:18]3)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(C1C=C2C(=CC=1)NC=C2)#CCCCCCC>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10])[CH2:13][CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[CH:18]2
Reactant: COc1cc(C#Cc2ccc3[nH]ccc3c2)cc(OC)c1OC
Agent: CCCCCCC#Cc1ccc2[nH]ccc2c1
Product: COc1cc(CCc2ccc3[nH]ccc3c2)cc(OC)c1OC
Yield: 86 %

Procedure:
When the product of Step A was substituted for 5-(oct-1-ynyl)-1H-indole in Example 3, Step B, the identical process afforded the title compound in 86% yield., as a colourless syrup. 1H-NMR (CDCl3) 2.79-3.03 (m, 4H); 3.8 (s, 3H); 3.82 (s, 6H); 6.4 (s, 2H); 6.47 (m, 1H); 7.03 (dd, 1H, J=1.3; 8.3 Hz); 7.18 (m, 1H); 7.31 (d, 1H, J=8.3 Hz); 7.45 (s, 1H); 8.09 (broad s, 1H);
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Na+].[I-:12].[OH-].[Na+].Cl[O-].[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+].Cl>CO.O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[I:12]
Reactant: [I-]
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(O)c(I)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
4-Hydroxybenzoic acid (34.5 g, 250 mmol) is suspended in MeOH (500 mL), treated with NaI (34.5 g, 250 mmol) and NaOH (20 g, 500 mmol) and cooled to 0° C. Sodium hypochlorite (Clorox bleach) (423 mL, 250 mmol) is added slowly drop-wise at 0-5° C. and the mixture is stirred for 1 h. The mixture is treated with saturated Na2S2O3 (135 mL) and water (135 mL) and stirred overnight as the cooling bath expired. The mixture is acidified to pH 3.5 with concentrated HCl and the resulting precipitate filtered off. The solid contained a mixture of the desired mono-iodo product and the iodo-chloro and the bis-iodo byproducts; it is discarded. The filtrate is concentrated to dryness, partitioned between H2O (300 mL) and EtOAc (1×500 mL, then 3×300 mL), dried (Na2SO4) and concentrated to afford 59.6 g (90%) of 4-hydroxy-3-iodobenzoic acid as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 6.95, 7.80, 8.22 ppm.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:23])[C@H:10]2[NH:14][C:15]2[S:16][C:17]([C:20](=[O:22])[CH3:21])=[CH:18][N:19]=2)[C:7]=1[C:24]([O:26]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:25])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.CCOCC>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:23])[C@H:10]2[NH:14][C:15]2[S:16][C:17]([C:20](=[O:22])[CH3:21])=[CH:18][N:19]=2)[C:7]=1[C:24]([OH:26])=[O:25])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3ncc(C(C)=O)s3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CCOCC
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](Nc3ncc(C(C)=O)s3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
A mixture of 255 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[(5-acetyl-2-thiazolyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester was reacted with anisole and trifluoroacetic acid in dichloromethane with stirring at 0° C. for 30 minutes, then at room temperature for 30 minutes. The addition of ether and petroleum ether gave a precipitate which was washed with ether, giving 135 mg of the desired product as a pale yellow powder.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5](C)[CH:4]=[C:3]([CH3:8])C=1[Mg]Br.Cl[C:13]1[CH:18]=CC=[CH:15][CH:14]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[CH3:18][CH2:13][CH2:14][CH2:15][CH2:11][CH2:1][CH2:6][CH2:5][CH2:4][CH2:3][CH3:8]
Reactant: Clc1ccccc1
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCC
Reaction time: 10 h
Yield: 20 %

Procedure:
THF (0.10 mL) was added to rinse the internal wall of the reaction vessel. After 10 hours, a THF solution of mesitylmagnesium bromide (1.02 mL, 1.18 M, 1.2 mmol) was added to the mixture at 0° C., and the solvent was removed under reduced pressure. The obtained viscous liquid was dissolved in toluene (1.0 ml), and chlorobenzene (112.6 mg, 1.0 mmol) was added at 0° C. The reaction was performed at 120° C. for 24 hours. After cooled to the ambient temperature, 2.0 mL of saturated sodium potassium tartrate aqueous solution was added to the reaction mixture. The water layer was extracted five times using Et2O. The total organic extract was filtrated by Florisil pad (100-200 mesh, Nacalai Tesque, Inc.). As the internal standard, gas chromatographic analysis was performed using undecane (42.2 μL, 0.2 mmol) (yield=93%). After removing the solvent under reduced pressure, the crude product was purified by GPC, thereby obtaining the above compound, which was a colorless liquid (0.174 g, yield=89%, purity=>99% (GC analysis)).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[CH:13][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:21]=1
Reactant: CCOC(=O)c1cccc(Br)c1
Reactant: Cc1ccc(B(O)O)c(C)c1
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: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(-c2ccc(C)cc2C)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 104.6 %

Procedure:
(2,4-Dimethylphenyl)boronic acid (3.0 g, 20.0 mmol), ethyl 3-bromobenzoate (4.3 g, 18.8 mmol) and cesium carbonate (9.8 g, 30.0 mmol) were added to a mixed solvent of ethanol (20 mL) and toluene (80 mL). After argon substitution, tetrakis(triphenylphosphine)palladium(0) (0.30 g, 0.26 mmol) was added, and the reaction mixture was stirred under an argon atmosphere at 70° C. for 18 hr. The reaction mixture was cooled, and the insoluble material was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:10) to give the title compound (5.0 g, yield 100%) as a colorless oil.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[OH-].[Na+].[O-:22][CH2:23][CH3:24].[Na+]>>[CH2:23]([O:22][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1)[CH3:24]
Reactant: CC[O-]
Reactant: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccc2c(=O)c(-c3nnnn3C)cn(C)c2c1

Procedure:
A mixture of 7-fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone (5.0 g), aqueous sodium hydroxide (5N, 80 ml) and industrial methylated spirit (10 ml) was boiled under reflux for 160 hours. Reaction was incomplete. The hot reaction mixture was filtered and the residue extracted with hot dimethylformamide (40 ml). The extract was evaporated to give a crude product. A mixture of this crude product and ethanolic sodium ethoxide (0.13 g sodium in 110 ml absolute ethanol) was boiled under reflux for 50 hours. The hot reaction mixture was filtered and the filtrate cooled in ice. The precipitate was collected and purified by flash chromatography on Kieselgel 60 using dichloromethane:industrial methylated spirit 9:1 as the eluent. The purified product was recrystallised from industrial methylated spirit to give the novel compound 7-ethoxy-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone, m.p. 214°-217°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:21][CH2:20][C:14]2([C:18](=[O:19])[NH:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)(=[O:10])=[O:9].I[C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][CH:24]=1>>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([N:17]2[CH2:16][CH2:15][C:14]3([CH2:20][CH2:21][N:11]([S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])(=[O:9])=[O:10])[CH2:12][CH2:13]3)[C:18]2=[O:19])=[CH:24][CH:25]=1)(=[O:31])[CH3:30]
Reactant: O=C1NCCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2
Reactant: CC(=O)c1ccc(I)cc1
Product: CC(=O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 148 step F) from 8-(2-chloro-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one and 1-(4-iodo-phenyl)-ethanone. White solid. MS (ESI): 447.1 MH+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][C:19](=[O:21])[N:18]([CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[S:17]2(=[O:29])=[O:28])=[C:12]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:11]=1)(C)(C)C.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[OH:45][C:39]([C:41]([F:44])([F:43])[F:42])=[O:40].[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[S:17](=[O:29])(=[O:28])[N:18]([CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])[C:19](=[O:21])[CH2:20]2)=[C:12]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCN)cc2OCc2ccccc2)S1(=O)=O
Reaction time: 0.5 h

Procedure:
To a solution of (2-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-ethyl)-carbamic acid tert-butyl ester (1.5 g, 2.67 mmol) (from Example 59, step B) in 10 mL of CH2Cl2 is added TFA (4.0 mL). The mixture stirred for 30 min and then evaporated and azeotroped with toluene to afford the title compound as an orange foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:21])[NH:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:21][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[CH:10][N:9]=1
Reactant: COC(=O)CCCCC(=O)NCC(=O)c1ccccc1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCCc1ncc(-c2ccccc2OC)o1
Reaction time: 12 h
Yield: 57.4 %

Procedure:
Dissolve 5-[2-(2-methoxy-phenyl)-2-oxo-ethylcarbamoyl]-pentanoic acid methyl ester (4.57 g, 14.87 mmol) and 4-(dimethylamino)pryidine (3.56 g, 29.14 mmol) in 150 mL CH2Cl2 and cool the reaction mixture in an ice bath. Add triphenylphosphinedibromide (12.32 g, 1.96 mmol) to the reaction portionwise over 15 minutes. Raise the reaction to ambient temperature and allow it to stir for 12 hours. Wash the reaction with water and brine (2×). Dry the organic layers with MgSO4. Filter off the drying agent and concentrate in vacuo to afford a crude residue. Purify the residue using silica gel chromatography eluting with hexanes/ethyl acetate mixtures to afford 2.47 g of the titled product (57%): mass spectrum: m/z=290.1 (M+H).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:20]#[CH:21])[CH:19]=1)[C:15]#[N:16].N>>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:20]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:21]=2)[CH:19]=1)[C:15]#[N:16]
Reactant: C#Cc1cc(Cl)cc(C#N)c1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: N#Cc1cc(Cl)cc(-c2cc(-c3cccnc3)no2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and the product of Example 66A (82 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.62 (ddd, J=8.0, 4.9, 0.7 Hz, 1H), 7.97 (s, 1H), 8.24 (dd, J=2.0, 1.4 Hz, 1H), 8.28 (dt, J=8.1, 1.9 Hz, 1H), 8.34 (t, J=1.7 Hz, 1H), 8.41 (t, J=1.4 Hz, 1H), 8.75 (dd, J=4.7, 1.7 Hz, 1H), 9.09 (d, J=1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 282 (M+H)+, 284 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Br:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(N1CCO[C@H](CC2C=CC=C(C=CC3C=NC=CC=3)C=2)C1)(O[C:26](C)([CH3:28])[CH3:27])=O.BrC(C)C.C(O)(C(F)(F)F)=O>>[Br:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH:26]([CH3:28])[CH3:27])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Br)c2)C1
Solvent: CC(C)Br
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(C[C@@H]2CNCCO2)cc1Br

Procedure:
Example 62 was prepared using the same procedure as described for example 4, starting from N-BOC-(R)-2-(3-bromo-4-hydroxybenzyl)morpholine, example 4, intermediate (a), and 2-bromopropane. The resulting intermediate was deprotected with TFA as described for example 4 to yield the desired morpholine example 62 as a colorless oil (22 mg, 52% over 2 steps) after purification by HPLC.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]2[C:9](=[O:19])[C:10]3[C:15]([C:16](=[O:17])[C:6]=2[CH:5]=1)=[C:14]([OH:18])[CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2].[BH4-].[Na+]>C(Cl)(Cl)Cl.C(O)C>[OH:3][CH:1]([C:4]1[O:8][C:7]2[C:9](=[O:19])[C:10]3[C:15]([C:16](=[O:17])[C:6]=2[CH:5]=1)=[C:14]([OH:18])[CH:13]=[CH:12][CH:11]=3)[CH3:2]
Reactant: CC(=O)c1cc2c(o1)C(=O)c1cccc(O)c1C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(O)c1cc2c(o1)C(=O)c1cccc(O)c1C2=O
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
To a solution of 2-acetyl-5-hydroxynaphtho[2,3-b]furan-4,9-dione (694 mg, 2.73 mmol) obtained in Example 5 in chloroform (100 mL) and ethanol (25 mL) is added sodium borohydride (515 mg, 13.7 mmol) at 0° C. The mixture is stirred for 30 minutes, and then the reaction is quenched by adding 10% hydrochloric acid to the mixture. The aqueous layer is extracted with chloroform twice, and the extract is continuously washed with water and brine. The mixture is evaporated in vacuo and purified by silica gel column chromatography (eluent: chloroform) to give 2-(1-hydroxyethyl)-5-hydroxynaphtho[2,3-b]furan-4,9-dione (516 mg, 74%) as a racemic mixture of a yellow crystal.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.[F:14][C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[F:14][C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[N:7]=[CH:6]3)[CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccc(N2CCNCC2)c1
Reactant: ClCCCn1cnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Fc1cccc(N2CCN(CCCn3cnc4ccccc43)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
1-(3-chloropropyl)-1H-benzimidazole (6.98 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-fluorophenyl piperazine (6.91 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 10-15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.4 g compound (I-8) with a yield of 63.1%. ESI-MS [M+H]+: m/z 339.2.