Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[CH:19][C:10]=1[C:11]([NH:13][CH2:14][C:15]([O:17]C)=[O:16])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:20]=[CH:19][C:10]=1[C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CNC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CNC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
A solution of methyl N-(2,4-dibenzyloxybenzoyl)glycinate (900 mg) in methanol (20 mL) is treated with 1 M NaOH (20 mL) and stirred at 25° C. for 2 hours. The solution is evaporated, the residue diluted with water, brought to pH 1 and extracted with ethyl acetate. The extract is dried and evaporated. The residue is recrystallized from methanol to yield N-(2,4-dibenzyloxybenzoyl)glycine as a colourless solid (300 mg), m.p. 183° C. H NMR (CDCl3) 4.15(2H,d), 5.05 (2H,s), 5.2(2H,s), 6.6(1H,s), 6.7(1H,d), 7.3-7.5(10H,m), 8.2(1H,d), 8.4(1H,t).
Reaction SMILES: [C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)[NH2:2].[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:24]([O:22][C:7]1[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=[C:11]2[C:6]=1[CH:5]([CH2:4][O:3][C:1](=[O:23])[NH2:2])[C:17]1([OH:19])[O:18][N:12]2[CH2:13][CH:14]2[CH:16]1[N:15]2[C:4](=[O:3])[CH2:5][CH3:6])(=[O:27])[CH2:25][CH3:26]
Reactant: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCC(=O)Oc1cc(C=O)cc2c1C(COC(N)=O)C1(O)ON2CC2C1N2C(=O)CC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (50 mg) and 4-dimethylaminopyridine (150 mg) in dimethylformamide (2 ml) was added propionyl chloride (0.1 ml) in an ice-water bath. The mixture was stirred for 20 hours at ambient temperature and evaporated in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and mthanol (10:1, v/v) to afford 8-carbamoyloxymethyl-4-formyl-9-hydroxy-11-propionyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6-yl propionate (30 mg).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1O)[CH:2]=[CH2:3].N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[O:30][C:29](=[O:31])[O:28][N:27]=1)=[O:19]>O1CCOCC1.C(Cl)(Cl)Cl>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:21]([O:20][CH:18]=[O:19])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[O:30][C:29](=[O:31])[O:28][N:27]=1)[CH:2]=[CH2:3]
Reactant: O=C(Cl)OCCCCCc1noc(=O)o1
Reactant: C=CCc1ccccc1O
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: C=CCc1ccccc1C(CCCCc1noc(=O)o1)OC=O
Yield: 69.4 %

Procedure:
2-Allylphenol (4.70g = 0.035 moles) and 2.76g (0.035 moles) pyridine dissolved in 11 ml 1,4-dioxane are added over a 1 hour period to a well stirred solution of 8.25g (0.035 moles) 5-(chloroformyloxypentyl)-1,3,4-dioxazol-2-one in 25 ml 1,4-dioxane at 40° C. Stirring is continued at 53° C for 11/2 hours. The product is then dissolved in 150 ml chloroform, washed 3 times with ice water, dried over Drierite and evaporated under vacuum. The residue, 11.67g of yellow liquid is analyzed by IR and NMR spectroscopy and found to contain 69.4 wt. % of 5-[(o-allylphenyl)-formyloxypentyl]-1,3,4-dioxazol-2-one (yield = 69.4%), having the following structural formula: ##STR15##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[CH2:11][CH2:12][C:13]([OH:15])=O>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:11][CH2:12][C:13](=[O:15])[NH:8]2
Reactant: O=C(O)CCc1c(F)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: O=C1CCc2c(F)cccc2N1
Reaction time: 3 h
Yield: 99.5 %

Procedure:
The suspension of 3-(2-fluoro-6-nitrophenyl)propanoic acid (6.0 g, 28 mmol) and 10% Pd-C (300 mg) in MeOH was hydrogenated under H2 (4 atm) for 3 h. After filtration, the filtrate was concentrated in vacuo to afford 5-Fluoro-3,4-dihydroquinolin-2(1H)-one (4.6 g) as a slightly brown solid. This crude product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[N+:13]([O-])([OH:15])=[O:14]>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:13]([O-:15])=[O:14])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Cc1cccc(C(F)(F)F)c1Cl
Reactant: O=[N+]([O-])O
Product: Cc1cc([N+](=O)[O-])cc(C(F)(F)F)c1Cl
Reaction time: 0.33 h
Yield: 98.1 %

Procedure:
72 gms of the crude mixture of 2, 4, and 6 mono chloro 3-methyl benzotrifluoride (0.37 moles) from Example I was added dropwise to 200 gms of 98% HNO3 at about -5° C. to 0° C. over a period of about 1 hour. After addition, solution was stirred for an additional 20 minutes. The solution was then washed with ice water and solvent extracted with CH2Cl2 to give 87 gms of an amber colored liquid. The liquid was distilled at 100°-110° C./(<0.1 mm) to give 84.5 gms of a yellow colored liquid (96% yield)
Reaction SMILES: CCOCC.C[C:7]1[C:12]([OH:13])=[CH:11][C:10]2[CH2:14][CH2:15][C@:16]([CH2:19][CH2:20]/[CH:21]=[C:22](/[CH2:24][CH2:25]/[CH:26]=[C:27](/[CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])\[CH3:28])\[CH3:23])([CH3:18])[O:17][C:9]=2[C:8]=1C>>[CH3:33][C:32]([CH3:34])=[CH:31][CH2:30][CH2:29]/[C:27](/[CH3:28])=[CH:26]/[CH2:25][CH2:24]/[C:22](/[CH3:23])=[CH:21]/[CH2:20][CH2:19][C:16]1([CH3:18])[O:17][C:9]2[CH:8]=[CH:7][C:12]([OH:13])=[CH:11][C:10]=2[CH2:14][CH2:15]1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC[C@]1(C)CCc2cc(O)c(C)c(C)c2O1
Solvent: CCOCC
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC1(C)CCc2cc(O)ccc2O1
Yield: 70 %

Procedure:
The procedure for the preparation of tocotrienol from the MEM-ether [17b] (700 mg, 1.49 mmole) follows that described for gamma-tocotrienol. Tocotrienol (400 mg, 1.05 mmole, 70%) was isolated as a colorless oil:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[CH3:31][O:32][CH2:33][CH2:34][O:35][CH2:36]Cl>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COCCOCCl
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(O)cc1
Product: COCCOCOc1ccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1

Procedure:
The present compound was synthesized by a method similar to that in Example 260 and using 6-bromo-2-(4-hydroxybenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (200 mg) and methoxyethoxymethylchloride. Colorless crystals (28 mg).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:6]2=[N:7][S:8][N:9]=[C:5]2[CH:4]=1.Br>>[N:7]1[S:8][N:9]=[C:5]2[CH:4]=[C:3]([OH:2])[CH:11]=[CH:10][C:6]=12
Reactant: COc1ccc2nsnc2c1
Agent: Br
Product: Oc1ccc2nsnc2c1
Temperature: 10 °C
Yield: 26.7 %

Procedure:
5-Methoxybenzo-2,1,3-thiadiazole (4.09 g, 24.6 mmol) was stirred with hydrobromic acid (60 mL, 165 mmol, 30% in acetic acid) at 80° C. 5 days. The mixture was cooled to 10° C. and filtered. The solids were purified by short column chromatography (50% ethyl acetate/hexane). Solvents were stripped in vacuo to afford 1.0 g of a yellow solid (27% yield).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:7]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:6][CH:5]=1.O1CCCC1.[OH-].[Li+].Cl>O>[O:13]1[CH2:14][CH2:15][CH:10]([C:8]2[C:7]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[N:6][CH:5]=[C:4]([CH:9]=2)[C:3]([OH:22])=[O:2])[CH2:11][CH2:12]1
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(C2CCOCC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCOCC2)c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
In a 25 mL round-bottomed flask, the above prepared 5-(tetrahydro-pyran-4-yl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid methyl ester (538 mg, 1.69 mmol, Eq: 1.00) was combined with tetrahydrofuran (4 ml) and water (2 ml) to give a colorless solution. Lithium hydroxide (80.7 mg, 3.37 mmol, Eq: 2) was added and the reaction mixture was stirred at 40° C. TLC after 3 h showed that the reaction was complete. 6 ml H2O and 4.5 ml 1N HCl were added and the white suspension was stirred for 10 min at 0° C. The solid was filtered off, washed with H2O and dried on hv to yield 489 mg of the title compound as white solid; MS (EI) 304.2 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)=[CH:5][CH:4]=1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23]>CN(C)C=O.O>[CH:22]([N:13]1[C:14]2[C:10](=[CH:9][C:8]([O:7][C:6]3[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:16][CH:15]=2)[CH:11]=[N:12]1)([CH3:24])[CH3:23]
Reactant: COc1ccc(Oc2ccc3[nH]ncc3c2)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc3c(cnn3C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(4-methoxy-phenoxy)-1H-indazole (0.20 grams, 0.83 mmol) in 1 mL of dimethylformamide was added sodium hydride (0.040 grams of a 60% dispersion in mineral oil, 1.0 mmol). After shaking at room temperature for 10 minutes, the mixture was treated with 2-iodopropane (0.090 mL, 0.15 grams, 0.9 mmol). The mixture was heated to 50° C. for 6 hours. After cooling to room temperature, the mixture was diluted with water and was extracted 3 times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-30% ethyl acetate in hexanes, affording 1-isopropyl-5-(4-methoxy-phenoxy)-1H-indazole (90 miligrams) MS: 283.4 [M+H]+ and 2-isopropyl-5-(4-methoxy-phenoxy)-2H-indazole MS: 283.4 [M+H]+ (75 miligrams) as colorless syrup.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9](COCC[Si](C)(C)C)[CH:8]=[CH:7]2.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)[N:21]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:24]1[CH:25]=[CH:20][N:21]=[C:22]([NH:26][CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)[N:23]=1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: Cc1cccc2ccn(COCC[Si](C)(C)C)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Cc1cccc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c12

Procedure:
The title compound was prepared as described in Example 215, starting from 7-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole (prepared by SEM protection of 7-methyl-1H-indole using standard procedures) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by cleavage of the SEM protecting group with TBAF. Yield: 190 mg (51%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][S:5][CH:6]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)[CH2:7][N+:8]([O-])=O>[Zn].C(O)(=O)C>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH:6]2[CH2:7][NH:8][C:3](=[O:2])[CH2:4][S:5]2)=[CH:12][CH:13]=1
Reactant: COC(=O)CSC(C[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(C2CNC(=O)CS2)cc1
Yield: 10.8 %

Procedure:
Acetic acid (240 mL) was heated to 72° C., then Zn (25.38 g, 388 mmol) and [2-nitro-1-(4-nitrophenyl)-ethylsulfanyl]-acetic acid methyl ester (3.00 g, 10.00 mmol) were added in one portion. The well-stirred suspension was heated at reflux for 0.5 h, filtered through activated charcoal and evaporated. Dichloromethane (50 mL), water (30 mL) and 10% aqueous NaOH (50 mL) were added. The suspension was filtered through Perlite, the layers were separated and the aqueous layer was extracted with dichloromethane (2×20 mL). the combined organic layers were washed with water (10 mL), dried over sodium sulfate and evaporated. The residue was triturated with chloroform (10 mL) and the solid was collected and washed with chloroform (2 mL) to obtain the title product (0.225 g, 1.08 mmol, 11%). ESMS m/z 209 (M+H)+.
Reaction SMILES: O.[Br:2][C:3]1[CH:4]=[C:5]([C:9]([CH:11]=O)=[O:10])[CH:6]=[CH:7][CH:8]=1.Cl.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:25][OH:26])[CH3:24])=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+]>CO>[Br:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([CH:11]=[N+:25]([CH:23]([CH3:24])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)[O-:26])=[O:10]
Reactant: O=CC(=O)c1cccc(Br)c1
Reactant: COc1ccc(CC(C)NO)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(CC(C)[N+]([O-])=CC(=O)c2cccc(Br)c2)cc1

Procedure:
2.31 g (10 mmol) of 3-bromophenylglyoxal hydrate, 2.175 g (20 mmol) of N-(2-(4-methoxyphenyl)-1-methylethyl)hydroxylamine hydrochloride and 820 mg (10 mmol) of sodium acetate were stirred in 50 ml of absolute methanol at room temperature for 4 hours. After filtration, the fitrate was evaporated, 50 ml of water were added to the residue and the mixture was extracted with methylene chloride (3×25 ml).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:34]#[N:35])=[C:13]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][N:18]([CH:23]([CH2:31][CH3:32])[C:24]([O:26]C(C)(C)C)=[O:25])[C:17](=[O:33])[CH:16]=2)[CH:14]=1>ClCCl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:34]#[N:35])=[C:13]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][N:18]([CH:23]([CH2:31][CH3:32])[C:24]([OH:26])=[O:25])[C:17](=[O:33])[CH:16]=2)[CH:14]=1
Reactant: CCC(C(=O)OC(C)(C)C)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon and at RT, 7.8 ml (101.8 mmol, 10 eq.) of trifluoroacetic acid were added to a solution of 4.1 g (10.2 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoate (racemate) in 40 ml of dichloromethane, the mixture was stirred at RT for 1 h, a further 7.8 ml (101.8 mmol, 10 eq.) of trifluoroacetic acid were added, the mixture was stirred at RT for 1 h, a further 7.8 ml (101.8 mmol, 10 eq.) of trifluoroacetic acid were added and the mixture was stirred at RT for 1 h. Once the reaction had gone to completion, the reaction mixture was concentrated under reduced pressure and the residue was co-evaporated in each case three times with dichloromethane and once with toluene and dried under reduced pressure. The residue was taken up in 100 ml of ethyl acetate and washed repeatedly with a strongly diluted aqueous sodium bicarbonate solution (where the pH of the washing water should not exceed pH 3-4 since otherwise the product is well soluble in water). The organic phase was subsequently dried (sodium sulphate), filtered and concentrated under reduced pressure. The residue was triturated with methyl tert-butyl ether, filtered, washed twice with methyl tert-butyl ether and dried under reduced pressure. Yield: 2.9 g (83% of theory)
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[Br:15][C:16]1[CH:17]=[C:18]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C)C(=O)C>[C:19]([C:18]1[CH:27]=[CH:28][C:29]([NH:30][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[C:16]([Br:15])[CH:17]=1)(=[O:20])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1Br
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2ccccc2)cc1Br)C(F)(F)F
Temperature: -17.5 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.75 g) in N,N-dimethylacetamide (10 mL) was rapidly added thionyl chloride (0.56 g) and the mixture stirred at -15 to -20° C. for 1 hour. 3-Bromo-4-aminobenzophenone (0.75 g) was then added in one portion and the mixture was allowed to stir at room temperature overnight. The solution was poured into ice water and the aqueous phase decanted from the resulting oily solid. Chromatography (eluent methylene chloride) gave the title compound (0.43 g) as a white solid; mp 138-40° C. Analysis for C17H13BrF3NO3 : Calculated: C, 49.06; H, 3.15; N, 3.37; Found: C, 49.06; H, 3.10; N, 3.35.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([CH3:7])[CH2:5][CH2:4][S:3]1.[C:8]1([N:14]=[C:15]=[S:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCOCC>C1C=CC=CC=1>[CH3:7][N:6]1[CH2:5][CH2:4][S:3][C:2]1=[N:1][C:15]([NH:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[S:16]
Reactant: CN1CCSC1=N
Reactant: S=C=Nc1ccccc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CN1CCSC1=NC(=S)Nc1ccccc1
Yield: 75 %

Procedure:
A solution of 0.043 mole of 2-imino-3-methylthiazolidine and an equimolar amount of phenylisothiocyanate in 70 ml of dry benzene is refluxed under nitrogen for 2.5 hours. Some ether is added to the cooled reaction mixture and solids are filtered off, 9.8 g (90%). Recrystallization from acetonitrile-ether (1:1) gives 8.0 g (75%) of pure N-(3-methyl-2-thiazolidinylidene)-N'-phenylthiourea; m.p. 168.5°-170.5° C.
Reaction SMILES: [C@@H:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C@@H:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)[C@H]1CCCc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)[C@H]2CCCc3ccccc32)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a solution of (S)-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid (300 mg, 1.7 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (349 mg, 1.7 mmol), HATU (760 mg, 2 mmol) in anhydrous DMF (8 mL) is added DIPEA (330 μL, 2 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5%-50% EtOAc in heptane) to give a pure product (69) as white solid (615 mg, 100%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[NH:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17]>>[NH2:19][CH2:18][C:15]1[C:16]([NH2:17])=[N:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[N:8][C:14]=1[C:13]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:12]=1[Cl:11]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)c1ccc(F)cc1
Product: NCc1c(N)nc(-c2ccc(F)cc2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=362.9 (M+H+), was prepared from 4-fluoro-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: Cl[S:2]([N:5]1[CH2:10][CH2:9][O:8][C:7]2[N:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:6]1=2)(=[O:4])=[O:3].Cl.[F:20][C:21]([F:29])([F:28])[CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(Cl)Cl>[F:20][C:21]([F:29])([F:28])[CH:22]1[CH2:27][CH2:26][N:25]([S:2]([N:5]2[CH2:10][CH2:9][O:8][C:7]3[N:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:6]2=3)(=[O:4])=[O:3])[CH2:24][CH2:23]1
Reactant: COC(=O)c1cnc2c(c1)N(S(=O)(=O)Cl)CCO2
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cnc2c(c1)N(S(=O)(=O)N1CCC(C(F)(F)F)CC1)CCO2
Temperature: -10 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
To a solution of methyl 1-(chlorosulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (250 mg, 0.854 mmol) in DCM (10 mL) at −10° C. was added TEA (0.595 mL, 4.27 mmol) and 4-(trifluoromethyl)piperidine hydrochloride (324 mg, 1.708 mmol). The reaction was allowed to stir for 3 h at −10° C. and slowly warmed to room temperature over 2 h. The reaction was allowed to stir at room temperature for 16 h. The reaction mixture was diluted with DCM (10 mL) and washed with H2O (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting solid was purified by flash column chromatography using a gradient elution of DCM with 0-25% acetonitrile to provide methyl 1-(4-(trifluoromethyl)piperidin-1-ylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (280 mg, 0.684 mmol, 80% yield) as a white solid. LCMS (+ESI) m/z=410.1 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:24]1CCOCC1.C(OC(Cl)=O)C(C)C>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:20]([NH2:24])=[O:22])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN1CCOCC1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 0.02 h

Procedure:
An 18 g portion of Nα -[(phenylmethoxy)carbonyl]-L-phenylalanine and 6.6 ml of N-methylmorpholine were dissolved in 150 ml of tetrahydrofuran and stirred at 31 10° C. as 8.04 ml of isobutylchloroformate was added. After 1 minute, ammonia gas was bubbled through the mixture until it was saturated. The mixture was stirred an additional 30 minutes and then poured into ice-water. The white solid was collected, giving 16.76 g of the desired compound, mp 164°-165° C.