Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:7])=O.Cl.[CH3:13][O:14][NH2:15].N1C=CC=CC=1.Cl.P(Cl)(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCl.O>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:7])=[N:15][O:14][CH3:13]
Reactant: CON
Reactant: O=C(Cl)c1ccccc1CCl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON=C(Cl)c1ccccc1CCl
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
2-Chloromethylbenzoyl chloride (18.90 g, 0.1 mol) was dissolved in dichloromethane (50 ml). The solution was added to a mixture of methoxyamine hydrochloride (12.53 g, 0.15 mol), pyridine (19.78 g, 0.25 mol) and dry dichloromethane (150 ml) under ice-cooling over 1 hour, and -then the resulting mixture was stirred at 0° C. for 2 hours. After completion of the reaction, water (300 ml) was added, adjusted to pH<2 with conc. hydrochloric acid, and extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (200 ml), and phosphorus pentachloride (20.82 g, 0.1 mol) was added under ice-cooling over 5 minutes. The mixture was stirred at 0° C. for 1 hour. After completion of the reaction, saturated aqueous sodium bicarbonate solution (400 ml) was added, and the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-chloromethyl-α-methoxyiminobenzyl chloride (18.15 g, 83.2%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2=[N:14][C:15]3[N:16]([CH3:23])[CH2:17][N:18]([CH3:22])[C:19](=[O:21])[C:20]=3[N:12]2[C:11]([OH:24])=[CH:10][C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(C)=O>[CH2:33]([C:10]1[C:9](=[O:25])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]2[N:12]([C:11]=1[OH:24])[C:20]1[C:19](=[O:21])[N:18]([CH3:22])[CH2:17][N:16]([CH3:23])[C:15]=1[N:14]=2)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: CN1CN(C)c2nc3n(Cc4ccccc4)c(=O)cc(O)n3c2C1=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN1CN(C)c2nc3n(Cc4ccccc4)c(=O)c(Cc4ccccc4)c(O)n3c2C1=O

Procedure:
To a suspension of 7.1 g. (0.021 mole) of 9-benzyl-2,3-dihydro-1,3-dimethyl-6-(hydroxy)pyrimido[2,1-f]purine-4,8(1H,9H)-dione in 200 ml. of acetone, add 2.3 g. (0.023 mole) of triethylamine, and stir the mixture for 5 minutes at room temperature under a nitrogen atmosphere to obtain a clear solution. Add dropwise to the solution 4.7 g. (0.027 mole) of benzyl bromide, and reflux the mixture for 5 hours under a nitrogen atmosphere. Remove the acetone under reduced pressure, and triturate the gummy residue with methanol. Remove the resultant white solid by filtration, pour the filtrate into water, acidify to pH 4-5 with dilute hydrochloric acid, and decant the aqueous supernatant. Dissolve the gummy residue in the chloroform, wash the solution with water, and dry over anhydrous magnesium sulfate. Remove the drying agent by filtration, and evaporate solvent from the filtrate under reduced pressure. Chromatograph the residual oil on silica gel, eluting with chloroform(96)-methanol(4), to obtain the title compound as a solid with m.p. 176°-179° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=[O:27])[CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21].N1CCOCC1>>[OH:27][CH:26]1[CH2:25][CH:24]([C:16]2[CH:17]=[C:18]([O:22][CH3:23])[C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)[C:10]2[C:2](=[C:3]3[CH:4]=[CH:5][N:6]([CH3:11])[C:7]3=[CH:8][CH:9]=2)[O:1]1
Reactant: COc1cc(C=CC=O)cc(OC)c1OC
Reactant: Cn1ccc2c(O)cccc21
Solvent: C1COCCN1
Product: COc1cc(C2CC(O)Oc3c2ccc2c3ccn2C)cc(OC)c1OC
Yield: 48 %

Procedure:
The title compound was prepared following the procedure described in Example 18 using 4-hydroxy-N-methyl indole (15 mg; 0.1 mmol) and 3-(3,4,5-trimethoxy-phenyl)-propenal (25 mg; 0.11 mmol) with morpholine (10 μl; 0.11 mmol) as a base (yield: 48%). 1H NMR (acetone-d6) 6.96 (d, J=2.7 Hz) and 6.94 (d, J=3.1 Hz) (1H), 6.70 (d, J=8.2 Hz) and 6.68 (d, J=7.2 Hz) (1H), 6.45 (d, J=8.6 Hz), 6.43 (s) and 6.40 (d, J=9.0 Hz) (3H), 6.29 and 6.28 (d each, J=3.3 Hz, 1H), 6.01 (d, J=6.8 Hz) and 5.91 (d, J=4.3 Hz) (1H), 5.57-5.60 (m) and 5.42-5.44 (m) (1H), 4.19 (dd, J=6.2, 10.0 Hz; 1H), 3.63, 3.62 and 3.59 (s each, 12 H), 2.23-2.28 (m) and 2.00-2.11 (m) (2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:11][C:12]=2[C:13](=[NH:15])[NH2:14])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:31][C:32](=O)[CH2:33][N:34]1[C:42](=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]1=[O:44]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:11][C:12]=2[C:13]2[NH:14][CH:31]=[C:32]([CH2:33][N:34]3[C:42](=[O:43])[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:35]3=[O:44])[N:15]=2)=[CH:22][CH:23]=1
Reactant: O=C(CBr)CN1C(=O)c2ccccc2C1=O
Reactant: N=C(N)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1Cc1c[nH]c(-c2sc(-c3ccncc3)nc2Cc2ccc(Cl)cc2)n1
Yield: 30 %

Procedure:
To a mixture of 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboximidamide hydrochloride (112 mg, 0.306 mmol) in DMF (2.96 mL) was added sodium carbonate (162 mg, 1.53 mmol) and 2-(3-bromo-2-oxopropyl)isoindoline-1,3-dione (95.0 mg, 0.337 mmol) and the resulting mixture was heated at 100 degrees for 4 hours. The reaction was cooled and taken up in ethyl acetate (30 mL) and water (5 mL). The layers were separated and the organic layer was washed with water (3×5 mL). The organic layer was dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM=0/100→10/90) to give 47 mg (30% yield) of the title compound. LC/MS (FA) ES+ 512. 514. 1H NMR (300 MHz, DMSO-d6) δ: 12.67 (bs, 1H), 8.69-8.67 (m, 2H), 7.91-7.79 (m, 6H), 7.27-7.24 (m, 3H), 7.11-7.08 (m, 2H), 4.77 (s, 2H), 4.45 (s, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20](=[O:21])[N:19]3[CH2:22][CH2:23][N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]3=[N:17][CH:16]=2)=[CH:11][C:10]=1[F:31])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[F:31][C:10]1[CH:11]=[C:12]([C:15]2[C:20](=[O:21])[N:19]3[CH2:22][CH2:23][N:24]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:18]3=[N:17][CH:16]=2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: O=c1c(-c2ccc(OCc3ccccc3)c(F)c2)cnc2n1CCN2c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1c(-c2ccc(O)c(F)c2)cnc2n1CCN2c1ccccc1

Procedure:
A solution of 6-(4-(benzyloxy)-3-fluorophenyl)-1-phenyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one (0.084 g, 0.20 mmol) in TFA (2 mL) was stirred at 40° C. for 3 hours. The reaction was concentrated to dryness and then dried under vacuum to yield a crude residue that was purified by flash column chromatography, eluting with 25:1 CH2Cl2/MeOH. The product was obtained (80 mg; 94%) as a white solid as a TFA salt. 1H-NMR (400 MHz, DMSO-d6) δ 9.89 (br s, 1H), 7.98 (s, 1H), 7.82 (m, 2H), 7.52 (dd, 1H), 7.42 (m, 2H), 7.32 (m, 1H), 7.14 (m, 1H), 6.95 (m, 1H), 4.19 (m, 4H). LRMS (APCI pos) m/e 324 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[F:11][C:12]1[N:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:11][C:12]1[N:17]=[CH:16][C:15]([O:10][C:6]2[CH:5]=[C:4]([CH2:3][CH2:2][OH:1])[CH:9]=[CH:8][CH:7]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: OCCc1cccc(O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: OCCc1cccc(Oc2ccc(F)nc2)c1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of 3-(2-hydroxyethyl)phenol (142.5 mg) in chloroform (5 ml), 279 mg of (6-fluoro-3-pyridinyl)boronic acid, 0.043 ml of triethylamine, 681 mg of copper acetate, and 500 mg of 4A molecular sieve were added, and the reaction solution was stirred at room temperature for 6 days. The reaction solution was filtered through Celite, and the filtrate was diluted with water, extracted with chloroform, and dried over anhydrous magnesium sulfate. The reaction solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-50:50-75/25)) to afford the title compound as a yellow oil.
Reaction SMILES: C(C(NC(C1C=C(F)C=CC=1S[S:20][N:21]([C:30](=[O:38])[C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][CH:32]=1)[CH:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])=O)CC(C)C)(O)=O.BrBr>C(#N)C.ClCCl>[CH3:28][CH:27]([CH3:29])[CH2:26][C@H:22]([N:21]1[C:30](=[O:38])[C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[S:20]1)[C:23]([OH:25])=[O:24]
Reactant: CC(C)CC(NC(=O)c1cc(F)ccc1SSN(C(=O)c1cccc(F)c1)C(CC(C)C)C(=O)O)C(=O)O
Agent: BrBr
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)O)n1sc2ccc(F)cc2c1=O
Yield: 137.3 %

Procedure:
Following the general method of Example 3, a slurry of [s-(R*,R*)]-2-[-[2-(1-carboxy-3-methyl-butylcarbamoyl)-4-fluorophenyldisulfanyl]-5-fluorobenzoylamino]-4-methyl-pentanoic acid (2.1 g, 3.6 mmol) (from Preparation 21) in 8 mL acetonitrile and 25 mL dichloromethane was treated with bromine (0.7 g, 4.4 mmol) in 15 mL dichloromethane. The crude compound was recrystallized from methanol/water to afford 1.4 g of the title compound, mp 161°-162° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]([CH2:20][C:21](OCC)=[O:22])(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[C:13]1([C:12]2[CH2:20][C:21](=[O:22])[C:3]3[C:2](=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=3)[N:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2
Temperature: 255 °C
Reaction time: 48 h
Yield: 79.4 %

Procedure:
Methyl p-aminobenzoate (3.0 grams) and 4.1 grams of ethyl benzoylacetate are dissolved in 100 ml of chloroform and the solution is subjected to azeotropic dehydration for two days after the addition of 0.5 gram of p-toluenesulfonic acid. Chloroform is evaporated therefrom, n-hexane is added to the residue, the extract with n-hexane is evaporated, 30 ml of diphenyl ether is added to the residue, the mixture is heated at 255° C. for twenty minutes, cooled, crystals separate out therefrom are collected by filtration, washed with n-hexane and dried to give 4.4 grams of methyl 2-phenyl-4-quinolone-6-carboxylate, needles, melting at higher than 300° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:26]1([C:32]2[C:33]3[C:38]([C:39]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[C:40]4[C:45]=2[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41]4)=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[C:26]1([C:32]2[C:33]3[C:38]([C:39]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[C:40]4[C:45]=2[CH:44]=[C:43]([C:17]2[CH:16]=[CH:15][C:14]([C:12]5[N:13]=[C:8]([C:5]6[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=6)[N:9]=[C:10]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)[N:11]=5)=[CH:19][CH:18]=2)[CH:42]=[CH:41]4)=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Brc1ccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc1
Reactant: OB(O)c1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
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
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3ccc(-c4ccc5c(-c6ccccc6)c6ccccc6c(-c6ccccc6)c5c4)cc3)n2)cc1
Yield: 79.8 %

Procedure:
2-(4-Bromophenyl)-4,6-diphenyl-1,3,5-triazine 4.3 g (11 mmol), 9,10-diphenylanthracene-2-boronic acid 4.9 g (13 mmol) and tetrakis(triphenylphosphine)palladium 0.25 g (0.22 mmol) were dissolved in 60 mL of 1,2-dimethoxyethane. A 2.0M sodium carbonate aqueous solution 30 mL was added thereto, and the solution was refluxed for 8 hours under argon atmosphere by heating. After finishing the reaction, the solution was filtered, and a solid matter obtained was washed with water, methanol and toluene to obtain 5.6 g (yield: 80%) of a greenish white solid matter. Mass spectral analysis of the above solid matter resulted in confirming that m/e was 637 versus a molecular weight of 637.25 and that it was the aimed compound 6.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O)(=[O:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].O>[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1)(=[O:13])[CH3:12]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: CC(=O)c1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: CC(=O)c1ccccc1-c1cccc(C(=O)O)c1
Yield: 97 %

Procedure:
The general procedure described in Example 3 was used with 3-chlorobenzoic acid (157 mg, 1.00 mmol), 2-acetylphenylboronic acid (179 mg, 1.20 mmol), Pd(OAc)2 (2.2 mg, 0.010 mmol, 1 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (10.0 mg, 0.020 mmol, 2 mol %), K2CO3 (414 mg, 3.00 mmol), water (2.0 mL), 10 h, 100° C. The product was isolated as a light yellow solid (233 mg, 97%). Mp=143° C. 1H NMR (400 MHz, CDCl3) δ: 12.60 (br-s, 1H), 8.05 (m, 1H), 7.65 (d, 1H, J=7.2 Hz), 7.58-7.55 (m, 3H), 7.49 (d, 1H, J=7.2 Hz), 7.42 (d, 1H, J=7.6 Hz), 2.16 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 204.3, 172.2, 141.7, 140.7, 139.9, 134.7, 131.5, 131.0, 130.7, 130.3, 129.9, 129.2, 128.7, 128.4, 30.8. IR (neat, cm−1): 3419, 2517, 1686, 1018. Anal. Calcd for C15H12O3: C, 74.99; H, 5.03. Found: C, 75.04; H, 5.06.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5](=O)[CH2:6][CH2:7][CH3:8].O.[NH2:18]N>C(O)C>[C:10]1([C:4]2[CH:3]=[N:2][NH:18][C:5]=2[CH2:6][CH2:7][CH3:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCC(=O)C(=CN(C)C)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCCc1[nH]ncc1-c1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of 1-(dimethylamino)-2-phenylhex-1-en-3-one (3.51 g, 16.2 mmol) in ethanol (80.0 mL), was added hydrazine hydrate (1.57 mL, 32.4 mmol). The reaction mixture was stirred at 80° C. After 3 h, the reaction mixture was cooled to room temperature, concentrated under reduced pressure and crystallized in 20% ethanol/H2O to give the title compound as a white solid (3.01 g). LCMS m/z=187.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.92-1.00 (m, 3H), 1.64-1.76 (m, 2H), 2.75-2.84 (m, 2H), 7.36-7.41 (m, 5H), 7.65 (s, 1H).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
To a solution of 1-benzhydryl-3-hydroxyazetidine (4.78 g, 20 mmol) in dichloromethane (35 ml) was added triethylamine (2.43 g, 24 mmol) and cooled to 0° C. A solution of methanesulfonyl chloride (1.86 ml, 24 mmol) in dichloromethane (5 ml) was then introduced slowly, and the resulting suspension was stirred at room temperature for 18 h. The volatiles were evaporated, and the residue was extracted with a mixture of ether and ethyl acetate. The combined extract was filtered through Magnosol and the filtrate evaporated to give 6.01 g of a light yellow solid; MS (ES) m/z 318.0 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([C:15]([O:17]CC)=[O:16])=[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=12)=[O:5])C.[OH-].[Na+]>>[C:15]([C:8]1[S:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]2[O:11][CH2:12][CH2:13][O:14][C:9]=12)([OH:17])=[O:16]
Reactant: CCOC(=O)c1sc(C(=O)OCC)c2c1OCCO2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1sc(C(=O)O)c2c1OCCO2

Procedure:
The 2,5-diethoxycarbonyl-3,4-ethylenedioxythiophene and NaOH are mixed in the microwave reactor. The microwave reactor is heated by the 2.45 GHz microwave at a power of 500-1200 W to perform hydrolysis reaction for no more than 20 minutes to obtain 2,5-dicarboxy-3,4-ethylenedioxythiophene.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([F:8])[CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.[OH-].[Na+]>CO>[CH2:9]([N:5]1[CH2:6][C@@H:7]([F:8])[C@@H:3]([CH2:2][NH:1][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:4]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: NC[C@H]1CN(Cc2ccccc2)C[C@H]1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: F[C@@H]1CN(Cc2ccccc2)C[C@@H]1CNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3S,4S)-3-Aminomethyl-1-benzyl-4-fluoropyrrolidine (186 mg) was dissolved in methanol (4 mL). To this solution, molecular sieves 4A (80.0 mg) and then benzaldehyde (90.8 μL) were added. The mixture was stirred at room temperature for 1 hour, followed by addition of a borane/pyridine complex (90.2 μL) and further stirring at room temperature for 3 hours. Subsequently, 6 mol/L hydrochloric acid (1.5 mL) was added and the mixture was stirred for 1 hour. A 6 mol/L aqueous solution of sodium hydroxide was then added to make the mixture basic. The mixture was extracted with diethyl ether (3×10 mL). The diethyl ether layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane:ethyl acetate=4:1) to give (3S,4S)-1-benzyl-3-benzylaminomethyl-4-fluoropyrrolidine as a pale brown oil (179 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])=[CH:4][CH:3]=1.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:21])([CH3:20])[CH3:22])=[O:15])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C(=O)OCC[Si](C)(C)C)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: C[Si](C)(C)CCOC(=O)c1ccccc1-c1ccc(CBr)cc1

Procedure:
312 mg of 4-methyl-2'-(trimethylsilylethoxycarbonyl)biphenyl, 178 mg of N-bromosuccinimide, 5 mg of azoisobutyronitrile and 15 ml of carbon tetrachloride are heated to reflux for one hour. After cooling, the mixture is evaporated. Flash chromatography (ethyl acetate/hexane 95:5) yields 4-bromomethyl-2'-(trimethylsilylethoxycarbonyl)biphenyl as a slightly yellowish oil. 1H-NMR (CFCl3): 0 ppm (s, 9 H), 0.7 ppm (t, 2 H), 4.5 ppm (s, 2 H), 7.1-8 ppm aromatics.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][S:12][C:11]2([CH3:21])[CH3:20])[CH:8]=[N:7][C:6]=1N)=[O:4].N(OC(C)(C)C)=O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:9]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][S:12][C:11]2([CH3:21])[CH3:20])[CH:8]=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1c(N)ncn1C1c2ccccc2CSC1(C)C
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1c2ccccc2CSC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5.0 g of 4-amino-1-(3,3-dimethylisothiochroman-4-yl)-5-imidazolecarboxylic acid methyl ester in 10 ml of tetrahydrofuran is added dropwise to a solution of 3.1 ml of tert.-butyl nitrite in 10 ml of tetrahydrofuran. After stirring for 16 hours at room temperature, the reaction mixture is poured onto ice-water. After extraction with ether, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated by evaporation. The residue is purified by chromatography on silica gel (eluant: ethyl acetate/hexane 2:5). There are thus obtained 3.2 g of 1-(3,3-dimethylisothiochroman-4-yl)-5-imidazolecarboxylic acid methyl ester in the form of a yellow resin which is caused to crystallise with hexane. The crystalline compound has a melting point of 108°-109° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:26])=[C:11]([C:14]4[CH:19]=[C:18]([CH:20]=O)[CH:17]=[C:16]([O:22][CH3:23])[C:15]=4[O:24][CH3:25])[CH:12]=3)[C:7](=[O:27])[C:6]([C:28]([OH:30])=[O:29])=[CH:5]2)[CH2:3][CH2:2]1.[NH:31]([CH2:38][CH2:39][C:40]#[N:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC([O-])(C)C.[K+].Cl>CS(C)=O.O>[C:40]([C:39](=[CH:38][NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:20][C:18]1[CH:17]=[C:16]([O:22][CH3:23])[C:15]([O:24][CH3:25])=[C:14]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:27])[C:6]([C:28]([OH:30])=[O:29])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:26])[CH:19]=1)#[N:41]
Reactant: N#CCCNc1ccccc1
Reactant: COc1cc(C=O)cc(-c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)c1OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(CC(C#N)=CNc2ccccc2)cc(-c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A suspension of 310 mg of 1-cyclopropyl-6-fluoro-7-(5-formyl-2,3-dimethoxy-phenyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (Example 8a)) in 3 ml of dimethyl sulphoxide is treated with 110 mg of 3-anilinopropionitrile and 185 mg of potassium tert-butylate. The resulting solution is stirred at room temperature for one hr. The reaction mixture is poured into 30 ml of water, adjusted to pH 5 with 2N aqueous HCl and extracted twice with 50 ml of methylene chloride each time. The combined organic phases are washed with 50 ml of water and with 50 ml of saturated, aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. 400 mg (98%) of 7-[5-(2-cyano-3-phenylamino-allyl)-2,3-dimethoxy-phenyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid are obtained as a yellow foam.