Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([F:10])[CH:4]=1)#[N:2].CC(N=NC(C#N)(C)C)(C#N)C.[Br:23]N1C(=O)CCC1=O>ClCCCl>[Br:23][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[F:10]
Reactant: Cc1ccc(C#N)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: N#Cc1ccc(CBr)c(F)c1
Temperature: 72 °C

Procedure:
1,2-Dichloroethane (151 kg) was charged to a suitable vessel along with 4-cyano-2-fluorotoluene (24 kg) and AIBN (2 kg). The mixture was heated to 70-74° C. Once the batch temperature reached 70° C., N-bromosuccinimide (47.4 kg) was added in portions at the rate of 12 kg/h, maintaining the temperature at 70˜74° C. (it is important to control addition rate to avoid exothermic reaction). The mixture was sampled via GC detection after 24 kg of N-bromosuccinimide was added, and the reaction was heated at 70-74° C. until complete reaction was observed. The mixture was cooled to 0-5° C. and allowed to stand for 2 additional hours. The mixture was filtered, and the cake was washed with MTBE (24 kg). The filtrate was washed with water (3×65 kg). The organic layer was dried with sodium sulfate (10.3 kg) for 6 hours, filtered and the cake was washed with MTBE (24 kg). The solution was evaporated under reduced pressure, ethanol (12 kg) was added and the mixture was heated to 40-45° C., then cooled slowly to 0-5° C. while stirring to crystallize. The mixture was filtered and the cake was washed with cold ethanol (5 kg). The crude solid was recrystallized from petroleum ether, filtered and washed with petroleum ether (10 kg), giving the title compound 4-(bromomethyl)-3-fluorobenzonitrile as an off white solid (21 kg, 55% yield). 1H NMR (300 MHz, CDCl3) δ ppm 4.46-4.50 (m, 2H) 7.36 (dd, J=8.85, 1.32 Hz, 1H) 7.44 (dd, J=7.91, 1.32 Hz, 1H) 7.52 (dd, J=7.91, 7.16 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ ppm 23.65 (d, J=4.60 Hz, 1C) 113.76 (d, J=9.77 Hz, 1C) 117.09 (d, J=2.87 Hz, 1C) 119.44 (d, J=24.71 Hz, 1C) 128.44 (d, J=4.02 Hz, 1C) 130.66-130.81 (s, 1C) 130.81-131.06 (s, 1C) 132.18 (d, J=3.45 Hz, 1C) 159.86 (d, J=254.03 Hz, 1C). IR: (KBr) 3088, 3077, 3040, 2982, 2250, 1571, 1508, 1439, 1248 cm−1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][CH2:15][C:16](=O)[CH2:17][CH3:18]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:16]([CH2:17][CH3:18])[CH2:15][CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCC(=O)CC
Product: CCC(CC)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Prepared from 3-pentanone and piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C@@H:1]1([OH:7])[CH2:5][CH2:4][CH2:3][C@H:2]1[OH:6].Cl[C:9]1[N:18]=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[H-].[Na+].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN(C)C=O.O1CCOCC1.O>[OH:6][C@@H:2]1[CH2:3][CH2:4][CH2:5][C@H:1]1[O:7][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:18]=1
Reactant: C1CNCCN1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: O[C@@H]1CCC[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O[C@@H]1CCC[C@H]1Oc1nc(N2CCNCC2)nc2ccccc12
Temperature: 0 °C
Yield: 34.8 %

Procedure:
To a solution of (1R,2R)-cyclopentane-1,2-diol [manufactured by Fluka Co.] (1.16 g) and 2,4-dichloroquinazoline (2.00 g) in dimethylformamide (40 ml) is added gradually 60% sodium hydride (in oil) (0.4 g) with stirring under ice-cooling, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is poured into water and extracted with ethyl acetate twice, and the extract is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The resulting residue is briefly purified with medium pressure column chromatography (eluent, chloroform:methanol=100:1, v/v) to give an oily substance. The oily substance thus obtained is dissolved in dioxane (20 ml), and the mixture is slowly added dropwise to a solution of piperazine (1.9 g) in dioxane (20 ml) with stirring at 70° C., and the mixture is stirred at the same temperature for one hour. The reaction mixture is poured into ice-water and extracted with chloroform. The extract is wished with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The resulting residue is purified by medium pressure liquid column chromatography (eluent, chloroform:methanol=20:1, 5:1, v/v) to give 4-[(1R,2R)-(2-hydroxycyclopentan-1-yl)oxy]-2-(1-piperazinyl)-quinazoline (1.1 g).
Reaction SMILES: [ClH:1].[C:2]([NH:6][C:7](=[O:23])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[N:16]([CH:20]=[N:21][CH:22]=3)[CH2:17][CH2:18][CH:19]=2)=[CH:10][CH:9]=1)([CH3:5])([CH3:4])[CH3:3]>C(O)C.[Pd]>[ClH:1].[C:2]([NH:6][C:7](=[O:23])[C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][N:16]3[CH:20]=[N:21][CH:22]=[C:15]23)=[CH:12][CH:13]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NC(=O)c1ccc(C2=CCCn3cncc32)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)(C)NC(=O)c1ccc(C2CCCn3cncc32)cc1
Reaction time: 8 h

Procedure:
A solution of 1.79 mmol of N-tert-Butyl-4-(5,6-dihydro-imidazo[1,5-a]pyridin-8-yl)-benzamide hydrochloride in 8 ml of ethanol is mixed with 270 mg of 10% Pd/C, and the reaction mixture is then hydrogenated at 20-25° C. under atmospheric pressure for 8 hours. The reaction mixture is clarified by filtration and the filtrate is evaporated. The crude title compound is obtained as a brown solid. Rf=0.35 (toluene:methanol=85:15), Rt=5.54.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:11]2[N:12]=[C:13]([CH:16]=[CH:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[S:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[NH2:28][C:29]1[CH:34]=[C:33]([CH2:35][CH2:36][CH2:37][S:38]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)(=[O:40])=[O:39])[CH:32]=[CH:31][C:30]=1[OH:48].Cl>ClCCl.N1C=CC=CC=1>[Cl:47][C:44]1[CH:43]=[CH:42][C:41]([S:38]([CH2:37][CH2:36][CH2:35][C:33]2[CH:32]=[CH:31][C:30]([OH:48])=[C:29]([CH:34]=2)[NH:28][C:21](=[O:23])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([CH:17]=[CH:16][C:13]3[S:14][CH:15]=[C:11]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:12]=3)[CH:19]=2)(=[O:40])=[O:39])=[CH:46][CH:45]=1
Reactant: Nc1cc(CCCS(=O)(=O)c2ccc(Cl)cc2)ccc1O
Reactant: O=C(O)c1cccc(C=Cc2nc(-c3ccccc3)cs2)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1cc(CCCS(=O)(=O)c2ccc(Cl)cc2)ccc1O)c1cccc(C=Cc2nc(-c3ccccc3)cs2)c1
Yield: 92.8 %

Procedure:
Thionyl chloride (2 ml) was added to 3-[2-(4-phenyl-2-thiazolyl)vinyl]benzoic acid (0.45 g, 1.46 mmol), the mixture was stirred with heating under reflux for 30 minutes, and then the reaction solution was concentrated under reduced pressure. Toluene was added to the resulting residue, the mixture was concentrated under reduced pressure and, after repeating this step again, dried in vacuo. The resulting residue was added to a mixture of 2-amino-4-[3-(4-chlorophenylsulfonyl)propyl]phenol hydrochloride (0.50 g, 1.38 mmol), pyridine (3 ml) and dichloromethane (2 ml) with stirred under ice-cooling, followed by 12 hours of reaction at room temperature. The reaction solution was poured into ice and 1 N hydrochloric acid and the solid precipitated was collected by filtration. By washing the collected solid with ethanol, 5'-[3-(4-chlorophenylsulfonyl)propyl]-2'-hydroxy-3-[2-(4-phenyl-2-thiazolyl)vinyl]benzanilide (0.79 g, 1.28 mmol, 93%) was obtained as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[C:10]=1[C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:24][CH:23]=1)=[O:21].[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(N(CC)CC)C.S(Cl)(Cl)(=O)=O>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:20](=[O:21])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:24][CH:23]=2)=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([O:19][S:38]([CH3:37])(=[O:40])=[O:39])[CH:13]=[CH:12]2
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(F)cc2F)ccc2cc(O)ccc12
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: O=S(=O)(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Oc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)cc3F)ccc2c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 69 %

Procedure:
Dissolve [2-(2,4-difluoro-phenyl)-6-hydroxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (540 mg, 1.11 mmoles), and methane sulfonyl chloride (254 mg, 2.22 mmoles) in 10 ml acetonitrile and add triethylamine (224 mg, 2.22 mmoles). Stir the mixture for 5 days at room temp. Add equivalent amounts of the sulfonyl chloride and triethylamine and stir for 30 minutes. Evaporate the mixture to dryness, dissolve in methanol and pass through an SCX column. Wash the column with methanol and elute the product with 2 N ammonia/methanol to yield 433 mg (69%) of the title compound: mass spectrum (ion spray) m/z=566 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:7]([CH:11]=[C:12](I)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2[C:37]3[O:36]C4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C[OH:60].C(N(CC)CC)C.Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:37]([OH:36])=[O:60])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(c1)OCCn1cc(I)nc1-2
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(O)c1cn2c(n1)-c1ccc(F)cc1OCC2
Temperature: 50 °C
Reaction time: 72 h
Yield: 648 %

Procedure:
A round bottom flask containing 9-fluoro-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazapine (0.794 g, 2.40 mmol) was purged thoroughly with nitrogen. Palladium (II) acetate (27 mg, 0.12 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (139 mg, 0.24 mmol) was added sequentially with more purging. Methanol (10 mL, 200 mmol) and triethylamine (30 mL, 200 mmol) purged with nitrogen were added and the reaction mixture was purged with Carbon monoxide for 5 minutes. Two Carbon monoxide balloons were attached and the reaction mixture was heated at 50° C. for 4.5 hours. Complete formation of the methyl ester was confirmed by LCMS. Purged reaction with nitrogen and concentrated in vacuo. Purified the ester by flash chromatography on the ISCO 0 to 50% ethyl acetate in heptane and concentrated in vacuo. The ester was dissolved in tetrahydrofuran and (20 mL, 200 mmol) and 1 M Lithium hydroxide was added (7.22 mL) and the reaction was stirred for three days. Complete hydrolysis by LCMS. Adjusted to pH ˜5 with 1 M HCl and extracted off the product with dichloromethane and 5% methanol to give 9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid (0.386 g, 64.6% yield)
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[S:3]1.O[N:16]1[C:20](=O)[CH2:19][CH2:18][C:17]1=O.C[N:24](C)C=O>>[N:16]1([C:8]([CH2:7][N:6]2[C:5]3[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=3[S:3][C:2]2=[O:1])=[O:10])[CH2:20][CH2:19][NH:24][CH2:18][CH2:17]1
Reactant: O=C(O)Cn1c(=O)sc2ccccc21
Reactant: CN(C)C=O
Reactant: O=C1CCC(=O)N1O
Product: O=C(Cn1c(=O)sc2ccccc21)N1CCNCC1
Temperature: 25 °C

Procedure:
To an ice-cooled solution of 2-oxo-3-benzothiazolineacetic acid [J. Prakt. Chem. 27 (3-4), 220-4 (1965); 8.1 g] and N-hydroxysuccinimide (5.4 g) in N,N-dimethylformamide (50 ml) was gradually added N,N-dicyclohexylcarbodiimide (9.6 g), and the mixture was stirred for an hour at ambient temperature. The dicyclohexylurea that precipitated from the reaction mixture was filtered off. To a stirred solution of piperazine (16.7 g) in N,N-dimethylformamide (200 ml) was added dropwise the filtrate for a period of 40 minutes below 20° C. The final mixture was stirred for 3.5 hours at ambient temperature and then filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in 2N hydrochloric acid and the solution was washed with chloroform. The aqueous layer was adjusted to pH 9 with an aqueous solution of sodium hydrogen carbonate, and the turbid solution was extracted with chloroform (80 ml×3). The extracts were combined and dried over magnesium sulfate. After evaporation of the solvent, 3-[(1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (9.50 g) was obtained as white powders.
Reaction SMILES: [OH:1]/[CH:2]=[C:3]1/[CH:4]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[C:23]#[C:24][Si](C)(C)C)[CH:5]2[N:6](C(OC(C)(C)C)=O)[C:7]/1=[O:8].O/C=C1/C2CC3C(=CC=CC=3C#C[Si](C)(C)C)C2NC/1=O.FC(F)(F)C(O)=O.[Na]>ClCCl>[C:23]([C:20]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:21]=1[CH2:22][CH:4]1[CH:5]2[NH:6][C:7](=[O:8])/[C:3]/1=[CH:2]\[OH:1])#[CH:24]
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\O)C2Cc3c(C#C[Si](C)(C)C)cccc3C21
Agent: C[Si](C)(C)C#Cc1cccc2c1CC1/C(=C/O)C(=O)NC21
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#Cc1cccc2c1CC1/C(=C/O)C(=O)NC21
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of tert-butyl (3Z)-3-(dimethylaminomethylene)-2-oxo-5-(2-trimethylsilylethynyl)-4,8b-dihydro-3aH-indeno[1,2-b]pyrrole-1-carboxylate D2 (Example 2, Step 2, 0.13 g, 0.3 mmol) in dioxane (5 mL) was added HCl (37%, 0.321 mL). The solution was stirred 2 h at room temperature and was then diluted with water, extracted with ethyl acetate, washed with brine, dried and concentrated to give 0.130 g of a mixture of tert-butyl (3Z)-3-(hydroxymethylene)-2-oxo-5-(2-trimethylsilylethynyl)-4,8b-dihydro-3aH-indeno[1,2-b]pyrrole-1-carboxylate and (3Z)-3-(hydroxymethylene)-5-(2-trimethylsilylethynyl)-1,3a,4,8b-tetrahydroindeno[1,2-b]pyrrol-2-one. A solution of 0.13 g of a mixture of tert-butyl (3Z)-3-(hydroxymethylene)-2-oxo-5-(2-trimethylsilylethynyl)-4,8b-dihydro-3aH-indeno[1,2-b]pyrrole-1-carboxylate and (3Z)-3-(hydroxymethylene)-5-(2-trimethylsilylethynyl)-1,3a,4,8b-tetrahydroindeno[1,2-b]pyrrol-2-one in dichloromethane (18 mL) was added trifluoroacetic acid (2 mL) at 0° C. The solution was stirred for 1 h at 0° C. A saturated solution of sodium hydrogenocarbonate was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with a saturated solution of sodium hydrogenocarbonate, dried and concentrated in vacuo to give ((3Z)-5-ethynyl-3-(hydroxymethylene)-1,3a,4,8b-tetrahydroindeno[1,2-b]pyrrol-2-one C2 (70 mg, 72%). LC-MS (Method C) RT 0.67 min, ES− 224 (M−H+), ES+226 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6](=[O:31])[CH2:7][NH:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:25][C:24]2[C:26]([Cl:30])=[C:27]([Cl:29])[S:28][C:23]=2[CH:22]=1)=[O:20]>C1COCC1>[C:1]([N:8]([CH2:7][C:6]([NH2:5])=[O:31])[C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:25][C:24]2[C:26]([Cl:30])=[C:27]([Cl:29])[S:28][C:23]=2[CH:22]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: NC(=O)CN[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)N(CC(N)=O)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
Acetyl chloride (17 μL, 0.24 mmol) was added to a solution of N-{(1R,2R)-1-[(2-amino-2-oxoethyl)amino]-2,3-dihydro-1H-inden-2-yl}-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Example 28, 100 mg, 0.24 mmol) in THF (10 mL). The reaction was stirred at ambient temperature for 1 h. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (50 mL), washed with water (2×10 mL), brine (10 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure and the residue purified by column chromatography (EtOAc:isohexane 1:2) to afford the title compound (50 mg, 45%) as a white solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:9]=[C:8]2[C:10]([CH3:16])=[CH:11][C:12]([CH3:15])([CH3:14])[NH:13][C:7]2=[CH:6][CH:5]=1.[C:17]([O:20][C@@H:21]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[C@@H:24]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[O:23][C@@H:22]1Br)(=[O:19])[CH3:18]>CC(C)=O>[C:17]([O:20][C@@H:21]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[C@@H:24]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[O:23][CH:22]1[N:13]1[C:7]2[C:8](=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=2)[C:10]([CH3:16])=[CH:11][C:12]1([CH3:15])[CH3:14])(=[O:19])[CH3:18]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOc1ccc2c(c1)C(C)=CC(C)(C)N2
Solvent: CC(C)=O
Product: CCOc1ccc2c(c1)C(C)=CC(C)(C)N2C1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 0.33 h
Yield: 74.6 %

Procedure:
Ethoxyquin (240 g) and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (228 g) were stirred at 80° for 18 hours. Acetone (200 ml) was added to the hot reaction mixture and stirring continued for an additional 20 minutes. After cooling, the solid ethoxyquin hydrobromide was filtered off, washed thoroughly with acetone and the combined acetone filtrates were evaporated under reduced pressure. The resulted crude product was recrystallised (iso-propanol) to yield 226.5 g of 1-(2,3,4,6-tetra-O-acetyl-D-glucopyranosyl)-6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline. m.p.: 180°-181°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:26])[O:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][N:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH3:18])[CH2:7][O:6]1)=[O:4].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH3:1][O:2][C:3]([C:5]1([CH3:26])[O:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][N:16]=[C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:25][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:23][CH:24]=2)[CH3:18])[CH2:7][O:6]1)=[O:4]
Reactant: COC(=O)C1(C)OCC(CCCCON=C(C)c2ccc(O)cc2)CO1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1(C)OCC(CCCCON=C(C)c2ccc(OS(C)(=O)=O)cc2)CO1
Temperature: 0 °C
Yield: 82.4 %

Procedure:
To an ice cold solution of Methyl-5-{4-[1-(4-hydroxy-phenyl)-ethylideneaminooxy]-butyl}-2-methyl-[1,3]dioxane-2-carboxylate (prepared as per example 40) (200 mg) in anhydrous dichloromethane were added triethyl amine (82 mg) and methane sulfonyl chloride (75 mg) and the reaction mixture was stirred at the same temperature for about an hour. Reaction mixture was diluted with dichloromethane, washed with water, dried over sodium sulphate and evaporated under, reduced pressure on a rotavapor. Crude product was flash chromatographed over silica gel using 20% ethyl acetate in petroleum ether as eluent to obtain 200 mg of pure product.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[S-:11][C:12]#[N:13].[NH4+].[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=1>CC(C)=O>[CH3:15][N:16]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=1)[C:12]1[S:11][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:5])[N:13]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CNc1ccc(CC#N)cc1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: CN(c1ccc(CC#N)cc1)c1nc(=O)c2cccnc2s1
Yield: 54.9 %

Procedure:
The reaction procedure of Example 102 was followed except that 362 mg of 2-chloronicotinoyl chloride, 156 mg of ammonium thiocyanate, 300 mg of [4-(methylamino)phenyl]acetonitrile and 7 ml of acetone were used. The product was then recrystallized from a mixture of ethanol and chloroform to obtain 347 mg of [4-[N-methyl-N-(4-oxo-4H-pyrido[3,2-e]-1,3-thiazin-2-yl)amino]phenyl]acetonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[NH2:9][CH2:10][CH2:11][CH2:12]O.[C:14]([OH:18])(=O)[CH2:15][CH3:16]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][CH2:11][CH2:10][NH:9][C:14](=[O:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: NCCCO
Reactant: CCC(=O)O
Product: CCC(=O)NCCCSc1ccc(Br)cc1

Procedure:
The experiment of Example 1A was repeated in all essential details except that p-bromobenzenethiol, 3-aminopropanol and propionic acid are the reactants. There is obtained N-[3-(p-bromophenylthio)propyl]propionamide, m.p. 64°-65.5°. The nmr spectrum was consistent with the proposed structure. The compound, which was designated P-2172, was ineffective against eight species of bacterium and one species of fungi (Candida albicans), but the MIC for three species of fungi was 50-1000 and is thus effective for controlling their growth.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[CH:14][N:15]([CH3:27])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:18][CH:17]=2)[S:10][C:9]1=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(OC)(=O)=O)=CC=1.[NH2:41][C:42]1[CH:43]=[C:44]([C:51](=[O:53])[CH3:52])[CH:45]=[CH:46][C:47]=1[NH:48][CH2:49][CH3:50]>CN(C=O)C>[C:51]([C:44]1[CH:45]=[CH:46][C:47]([NH:48][CH2:49][CH3:50])=[C:42]([N:41]=[C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12](=[O:13])[C:11](=[CH:14][N:15]([CH3:27])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:18][CH:17]=3)[S:10]2)[CH:43]=1)(=[O:53])[CH3:52]
Reactant: CCNc1ccc(C(C)=O)cc1N
Reactant: COCCOc1ccc(N(C)C=C2SC(=S)N(Cc3ccccc3)C2=O)cc1
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CN(C)C=O
Product: CCNc1ccc(C(C)=O)cc1N=C1SC(=CN(C)c2ccc(OCCOC)cc2)C(=O)N1Cc1ccccc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 8.9 %

Procedure:
A mixture of 3-benzyl-5-({N-[4-(2-methoxy-ethoxy)-phenyl]-methylamino}-methylene)-2-thioxothiazolidin-4-one (60 mg, 0.14 mmol) and methyl p-toluenesulfonate (54 mg, 0.29 mmol) in DMF (1.0 mL, anhyd) was heated at 130° C. After 2 h the reaction mixture was allowed to cool to ambient temperature, charged with 3′-amino-4′-ethylamino-acetophenone (50 mg, 0.28 mmol) and TEA (70 μL, 0.72 mmol), and then heated at 65° C. After 20 h the reaction mixture was cooled and chromatographed (HPLC-MS conditions) to yield the title product (7 mg) as a yellow solid. 1H-NMR (CDCl3): δ 7.82 (1H, s), 7.61 (1H, dd), 7.48 (1H, d), 7.27-7.40 (5H, m), 7.08 (2H, m), 6.90 (2H, m), 6.44 (1H, d), 5.09 (2H, s), 4.20 (1H, br s), 4.07 (2H, m), 3.73 (2H, m), 3.46 (3H, s), 3.44 (3H, s), 3.00 (2H, m), 2.43 (3H, s), 1.00 (3H, t); MS (ESI): 559 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].C(OC([NH:24][CH2:25][C:26]1[CH:27]=[C:28]([CH2:34][CH:35]([O:39][CH:40]([CH3:42])[CH3:41])[C:36]([O-:38])=[O:37])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])=O)(C)(C)C>>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([NH:24][CH2:25][C:26]1[CH:27]=[C:28]([CH2:34][CH:35]([O:39][CH:40]([CH3:42])[CH3:41])[C:36]([OH:38])=[O:37])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])=[O:8])[CH3:2]
Reactant: CCOc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CNC(=O)OC(C)(C)C
Product: CCOc1cc(C(F)(F)F)ccc1C(=O)NCc1cc(CC(OC(C)C)C(=O)O)ccc1OC

Procedure:
Using 2-ethoxy-4-(trifluoromethyl)benzoic acid and 3-[3-([(tert-butoxycarbonyl)amino]methyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 3-(3-[(2-ethoxy-4-(trifluoromethyl)benzoyl]aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoic acid was obtained in the same method as in Example 38).