Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>N1C=CC=CC=1>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][NH:21][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(CCNS(C)(=O)=O)CC1
Reaction time: 12 h
Yield: 39.3 %

Procedure:
Methanesulfonyl chloride (0.7 mL, 9.0 mmol) was added to a cooled solution of 4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.33 g, 5.8 mmol) in pyridine (25.0 mL). The reaction was stirred for 12 h and partitioned between partitioned between aqueous sodium bicarbonate and methylene chloride. The organic phase was washed with 1 M hydrochloric acid, aqueous sodium bicarbonate, and brine, dried over anhydrous magnesium sulfate and concentrated. Purification of the crude residue by chromatography over silica gel using 0-5% methanol in methylene chloride gave 4-(2-methanesulfonylamino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.70 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10](=[O:12])(=[O:11])[N:9]([CH3:13])[C:8]([C:14]([O:16]C)=O)=[C:7]([OH:18])[C:6]=2[CH:19]=1.[NH2:20][C:21]1[CH:26]=[N:25][CH:24]=[C:23]([Cl:27])[N:22]=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10](=[O:11])(=[O:12])[N:9]([CH3:13])[C:8]([C:14]([NH:20][C:21]3[CH:26]=[N:25][CH:24]=[C:23]([Cl:27])[N:22]=3)=[O:16])=[C:7]([OH:18])[C:6]=2[CH:19]=1
Reactant: Nc1cncc(Cl)n1
Reactant: COC(=O)C1=C(O)c2cc(Cl)ccc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2cncc(Cl)n2)=C(O)c2cc(Cl)ccc2S1(=O)=O
Yield: 80 %

Procedure:
3.04 (10 mmols) of methyl 6-chloro-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 1.5 g (12 mmols) of 2-amino-6-chloro-pyrazine were reacted in 150 ml of xylene analogous to Example 2. 3.2 g (80% of theory) of 6-chloro-N-(6-chloro-pyrazin-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)=[CH:7][CH2:6]1>ClCCl>[O:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([Cl:3])=[O:20])=[CH:17][CH:16]=2)=[CH:7][CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C2=CCOc3ccccc32)cc1
Solvent: ClCCl
Product: O=C(Cl)c1ccc(C2=CCOc3ccccc32)cc1
Reaction time: 4 h
Yield: 99 %

Procedure:
Thionyl chloride (2 mL) was added to a suspension of 4-(2H-chromen-4-yl)benzoic acid from reaction 34c (0.415 g, 1.6 mmol) in dichloromethane (10 mL) at room temperature. The reaction was stirred for 4 h, concentrated in vacuo to give 4-(2H-chromen-4-yl)benzoyl chloride (0.445 g, 99%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]3[CH:22]=[CH:23][C:24]([C:26]([OH:28])=[O:27])=[CH:25][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].[BH4-].[Na+]>>[CH2:13]([C:12]([C:17]1[S:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]([OH:28])=[O:27])=[CH:25][C:19]=2[CH:18]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:30])[C:2]([CH3:31])([CH3:32])[CH3:1])=[C:7]([CH3:29])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)O)ccc2s1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)O)ccc2s1
Yield: 92.2 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-5-carboxylic acid (330 mg, 0.730 mmol) is reduced using NaBH4 (55 mg, 1.46 mmol) in a reaction analogous to Example 2 to afford the title compound (0.306 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[CH:14][CH:13]=3)=[N:8][C:7]=2[CH:22]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>COCCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:14][CH:13]=3)=[N:8][C:7]=2[CH:22]=1
Reactant: COc1ccc2sc(Nc3ccc(OCCCl)cc3)nc2c1
Reactant: C1CCNC1
Solvent: COCCO
Product: COc1ccc2sc(Nc3ccc(OCCN4CCCC4)cc3)nc2c1

Procedure:
A mixture of 5-methoxy-2-[4-(2-chloroethoxy)anilino]benzothiazole (200 g.), pyrrolidine (144 ml.) and 2-methoxyethanol (1 liter) is boiled under reflux for 16 hours. The mixture is evaporated from the steam bath at reduced pressure and the residue dissolved in approximately 2N hydrochloric acid. The solution is washed with ethyl acetate, basified with 40% sodium hydroxide solution and extracted with chloroform. The chloroform is washed with water, dried over magnesium sulphate and passed through a column of alumina. The column is washed with chloroform and the combined chloroform solutions evaporated. The residue is recrystallised from 2-methoxyethanol to give 5-methoxy-2-[4-(2-pyrrolidin-1-ylethoxy)anilino]benzothiazole, m.p. 167° - 168°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(N(CC)C(C)C)(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:26]([S:37]([CH3:36])(=[O:39])=[O:38])[S:37]([CH3:36])(=[O:39])=[O:38])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 117.8 %

Procedure:
To a solution of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in THF (2 mL) were added N,N-diisopropyl ethyl amine (0.15 mL, 0.86 mmol), 4-dimethylaminopyridine (8 mg, 0.06 mmol) and methanesulfonyl chloride (53 μL, 0.69 mmol). The resulting suspension was then stirred for 18 h at ambient temperature. Further N,N-diisopropyl ethyl amine (0.15 mL, 0.86 mmol) and methanesulfonyl chloride (54 μL, 0.689 mmol) was added and stirred was continued for 24 h at 50° C. The reaction mixture was extracted with aqueous HCl (1 M, 15 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with brine (half-saturated, 20 mL) and aqueous sodium carbonate (saturated, 20 mL). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20) afforded the title compound (205 mg, 71%) as a white solid. MS: m/e=505.0 [M+H]+.
Reaction SMILES: CC(=C[N:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1[CH:11]=CC=C[CH:7]=1)C.[C:19]1([CH3:26])[CH:24]=[CH:23][CH:22]=[C:21](C)[CH:20]=1>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:7][C:6]1([CH3:11])[CH2:26][C:19]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCN(C=C(C)C)c1ccccc1
Reactant: Cc1cccc(C)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CCCCCCCN1c2ccccc2CC1(C)C
Yield: 95.8 %

Procedure:
N-(2-methylprop-2-en-3-yl)N-n-heptyl aniline (0.38 mole), zinc chloride (0.4 mole) and m-xylene (200 cm3) were refluxed for 17 hours before cooling and dissolving in dichloromethane. The dichloromethane was filtered and washed with water, separated, dried over magnesium sulphate, filtered and evaporated to leave an oil. The oil was eluted from silica using 50:50 dichloromethane/hexane as eluent evaporated of the solvent gave 2,2-dimethyl-N-n-heptylindoline (122 g, 95.8%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](=[O:9])[N:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]=1[S-:16])#[N:2].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CCO>[CH2:23]([O:22][C:20]([C:19]1[S:16][C:4]2[N:5]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6](=[O:9])[CH:7]=[CH:8][C:3]=2[C:1]=1[NH2:2])=[O:21])[CH3:24]
Reactant: N#Cc1ccc(=O)n(-c2ccccc2)c1[S-]
Reactant: CCOC(=O)CBr
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccccc2)c1N

Procedure:
A mixture of Example 1 (0.34 g at 100%) and ethyl bromoacetate (0.197 mL) in EtOH (6 mL) was stirred at room temperature for 1 h. H2O (10 mL) was then added. The solid was filtered and washed with more H2O (2 mL). The product was dried under vacuum at 40° C. to constant weight to give the title compound as a pale pink solid (0.35 g). δH (DMSO-d6) 8.20 (1H, d, J 9.6 Hz), 7.60 (3H, m), 7.45 (2H, m), 7.15 (2H, br s), 6.55 (1H, d, J 9.6 Hz), 4.15 (2H, q, J 7.1 Hz), 1.20 (3H, t, J 7.1 Hz). LCMS (ES+) RT 3.29 minutes, 315 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1=[N:3][C:4](=[O:30])[N:5]([CH3:29])/[C:6]/1=[CH:7]\[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[C:25]([F:28])([F:27])[F:26])[CH2:10][CH2:9]1.[CH2:31](N)[C:32]#[CH:33]>C1(C)C=CC=CC=1>[F:27][C:25]([F:26])([F:28])[C:16]1[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:15]=1[CH2:14][N:11]1[CH2:12][CH2:13][CH:8](/[CH:7]=[C:6]2/[C:2]([NH:1][CH2:33][C:32]#[CH:31])=[N:3][C:4](=[O:30])[N:5]/2[CH3:29])[CH2:9][CH2:10]1
Reactant: C#CCN
Reactant: CN1C(=O)N=C(N)/C1=C/C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Solvent: Cc1ccccc1
Product: C#CCNC1=NC(=O)N(C)/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To a solution of (5Z)-4-amino-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-1-methyl-1,5-dihydro-2H-imidazol-2-one (1.50 g) in toluene (10 mL) was added propargylamine (1.90 g) at room temperature. The reaction mixture was stirred at 100° C. overnight. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (870 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][CH2:11][CH:12]([O:31][CH3:32])[CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:4]=1.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>C1(C)C=CC=CC=1>[CH2:15]([O:14][CH2:13][CH:12]([O:31][CH3:32])[CH2:11][O:10][CH2:9][C:5]1[CH:4]=[C:3]([CH2:2][N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[CH:8]=[CH:7][CH:6]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCOCC(COCc1cccc(CBr)c1)OC
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(COCc1cccc(Cn2ccnc2)c1)OC
Temperature: 80 °C
Yield: 86.3 %

Procedure:
a mixture of 2.4 g of 1-(bromomethyl)-3-[[3-(hexadecyloxy)-2-methoxypropoxy]methyl]benzene, 2.54 g of imidazole and 30 ml of toluene was heated at 80° C. under argon in a pressure bottle for 4 hours and then evaporated. The residue was purified by chromatography, giving 2.02 g of the desired product as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])[CH2:9][O:10][C:11]2[C:12](=[O:18])[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=2)[CH2:4][CH2:3]1.[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1O>>[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8](=[O:19])[CH2:9][O:10][C:11]2[C:12](=[O:18])[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=2)[CH2:6][CH2:7]1
Reactant: Oc1ccc(F)cc1Cl
Reactant: Cn1nccc(OCC(=O)N2CCC(O)CC2)c1=O
Product: Cn1nccc(OCC(=O)N2CCC(Oc3ccc(F)cc3Cl)CC2)c1=O
Yield: 18 %

Procedure:
Compound 22 is prepared from intermediate 5c and from 2-chloro-4-fluoro-phenol following synthesis method 3 (yield: 18%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CC#N>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH3:9]
Reactant: C1COCCN1
Reactant: CCOC(=O)CCCBr
Solvent: CC#N
Product: CCOC(=O)CCCN1CCOCC1
Temperature: 80 °C
Yield: 96 %

Procedure:
A solution of ethyl 4-bromobutyrate (681 mg) in MeCN (5.0 mL) was treated with morpholine (0.61 mL) at rt. The reaction mixture was heated to 80° C. for 3 h and cooled down to rt. It was concentrated under reduced pressure, diluted with EA and the org. layer was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The title compound was obtained, without additional purification, as a yellow oil (643 mg; 96% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[C:24]#[N:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>N.CCO.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][C:15]=2[CH2:24][NH2:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2C#N)CC1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2CN)CC1
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a solution 4-(2-cyano-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.42 mmol) in NH3/EtOH (2M, 10 mL) was added Raney Nickel (3 mL slurry in water). The atmosphere was exchanged with hydrogen via balloon and the mixture was allowed to stir for 30 min. After this time the mixture was filtered through celite and concentrated to yield the title compound (148 mg). m/z (M+1) 360.23.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N+:12]([O-])=[C:11]([CH3:17])[CH:10]=[CH:9]2)(=[O:4])=[O:3].C1(C)C=CC(S([Cl:27])(=O)=O)=CC=1>ClCCCl>[Cl:27][CH2:17][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:7]=2)[N:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc2cc(NS(C)(=O)=O)ccc2[n+]1[O-]
Solvent: ClCCCl
Product: CS(=O)(=O)Nc1ccc2nc(CCl)ccc2c1
Reaction time: 17 h

Procedure:
6-Methanesulphonamido-2-methylquinoline-1-oxide (1.65 g) and p-toluenesulphonyl chloride (1.72 g) were heated under reflux for 1 hour in 1,2-dichloroethane solution, and the reaction mixture was then stood at room temperature for 17 hours. The reaction mixture was then washed twice with aqueous sodium bicarbonate, dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 1%). The product-containing fractions were combined and evaporated to give a gum which solidified when triturated with ether. Recrystallisation from toluene gave the title compound, yield 0.75 g, m.p. 160°-162°.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:8]1[C:9]([C:9]2[CH:8]=[CH:7][C:3]3[C:4]([O:6][C:1](=[O:11])[C:2]=3[CH:10]=2)=[O:5])=[CH:10][C:2]2[C:1]([O:6][C:4](=[O:5])[C:3]=2[CH:7]=1)=[O:11]
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: O=C1OC(=O)c2cc(-c3ccc4c(c3)C(=O)OC4=O)ccc21

Procedure:
20 g (135 mmol) of phthalic anhydride was heated at 80° C. for 5 hours in the same manner as in Example 1 except that palladium acetate was omitted. As a result, a BPDA was not formed.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Cl[CH2:12][C:13](=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][CH:12]=[C:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)Cc1csc(-c2ccc(F)cc2)n1

Procedure:
To a stirred solution of 4-fluorothiobenzamide (8.94 g, 57.6 mmol) in ethanol (70 mL) was added ethyl 4-chloroacetoacetate (7.8 mL, 58 mmol). The reaction was heated at reflux for 4 hours, treated with an addition aliquot of ethyl 4-chloroacetoacetate (1.0 mL, 7.4 mmol) and refluxed for an additional 3.5 hours. The reaction was then concentrated and the residue was partitioned between ethyl acetate (200 mL) and aqueous NaHCO3 (200 mL). The organic layer was combined with a backextract of the aqueous layer (ethyl acetate, 1×75 mL), dried (Na2SO4) and concentrated. The resulting amber oil was purified by flash chromatography using a hexane/ethyl acetate gradient to afford ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)acetate as a low melting, nearly colorless solid (13.58 g, 89%).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:15][S:16][C:17](SC)=[N:18][C:19]#[N:20]>C(O)C>[C:19]([N:18]=[C:17]([N:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:13]=[CH:14][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:8][CH2:9]1)[S:16][CH3:15])#[N:20]
Reactant: CSC(=NC#N)SC
Reactant: Fc1ccc(CN2CCNCC2)cc1
Solvent: CCO
Product: CSC(=NC#N)N1CCN(Cc2ccc(F)cc2)CC1

Procedure:
A 28.7 g. (0.1 mole) portion of N-(p-fluorobenzyl)piperazine was dissolved in 25 ml. of ethanol and then added dropwise over 30 minutes to a stirred solution of 14.6 g. (0.1 mole) of dimethyl cyanodithioiminocarbonate in 200 ml. of ethanol. The mixture was refluxed for 6 hours, the evolved gas being led through a sodium hypochlorite trap. The mixture was then evaporated to a syrup.
Reaction SMILES: [C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:32][CH:33]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:34]O>C(O)C>[C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][CH2:34][CH:33]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH2:32])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][CH2:34][CH:33]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH2:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(CO)Cc1ccccc1
Reactant: OB(c1ccccc1)C(OC(B(O)c1ccccc1)c1ccccc1)c1ccccc1
Solvent: CCO
Product: NC(COB(c1ccccc1)C(OC(B(OCC(N)Cc1ccccc1)c1ccccc1)c1ccccc1)c1ccccc1)Cc1ccccc1

Procedure:
The entitled compound (6 mg) was obtained by allowing 34 mg of bis(3,3′-(phenylhydroxyboryl)benzyl) ether and 26 mg of 2-amino-3-phenylpropanol to act in 1 mLof ethanol.
Reaction SMILES: C([NH:6][NH:7][CH2:8][CH2:9][CH:10]1[NH:14]C(=O)N[C:11]1=[O:16])(OCC)=O.[OH2:17].O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>O>[NH2:14][CH:10]([CH2:9][CH2:8][NH:7][NH2:6])[C:11]([OH:16])=[O:17]
Reactant: CCOC(=O)NNCCC1NC(=O)NC1=O
Reactant: O
Agent: [Ba+2]
Agent: [OH-]
Product: NNCCC(N)C(=O)O

Procedure:
Mix 5-[(2-(carbethoxyhydrazino)-ethyl)]-hydantoin (2.3 g, 10 mmol), barium hydroxide octahydrate (18.15 g, 10 mmol) and water (55 mL). Reflux for 12 hours, remove the white solid by filtration, extract the filter cake with boiling water (25 ml) and finally wash with hot water (25 mL). Combine the filtrate and washings, treat with ammonium carbonate (5.7 g) and heat with stirring. Filter off the barium carbonate, wash the filter cake with hot water and evaporate the filtrate and washings in vacuo to give 2-amino-4-hydrazino-butanoic acid.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][S:12][C:11]=1[N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31])=[O:9])C.Cl>O>[O:30]=[C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:31])[N:21]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c(-c2ccccc2)csc1N1C(=O)c2ccccc2C1=O
Yield: 92 %

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) was added 2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-4-phenyl-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 1, Part C). The mixture was heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitated was collected by filtration, washed with water, and dried, affording the desired compound as a white solid in 92% yield.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:6]=1.C(O)(=O)/C=C\C(O)=O.C(N[CH:26]=[N:27][C:28]1[CH:33]=[CH:32][C:31](C2N=C(C)NC=2)=[CH:30][C:29]=1OC)CC>>[C:28]1([NH:27][CH:26]=[N:13][C:10]2[CH:11]=[CH:12][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=3)=[CH:8][CH:9]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCNC=Nc1ccc(-c2c[nH]c(C)n2)cc1OC
Reactant: Cc1nc(-c2ccc(N)cc2)c[nH]1
Agent: O=C(O)/C=C\C(=O)O
Product: Cc1nc(-c2ccc(N=CNc3ccccc3)cc2)c[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Methyl-4-(4-amino-phenyl)-1H-imidazole (5 g) was added to a solution of ethyl N-phenyl-formamidate (5 g) in acetone (25 ml). After 3 hours of stirring at room temperature, the solid which separated out was filtered off and dried. The product was treated with glacial acetic acid in acetone. The acetate salt which precipitated was filtered off and dried to give 4.6 g of the title compound.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].C(NCC)C.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=1>C(O)C>[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([OH:17])[CH2:4][N+:1]([O-:3])=[O:2])[CH:11]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccnc1
Solvent: CCO
Solvent: CCNCC
Product: O=[N+]([O-])CC(O)c1cccnc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cooled stirring solution of 15 grams (0.25 mol) nitromethane and 0.35 gram (0.005 mol) diethylamine in 26 milliliters of ethanol was added dropwise 10 grams (0.093 mol) 3-pyridine carboxaldehyde. The reaction was stirred for 3 hours at 0° C. then warmed to ambient temperature. Concentration yielded crude 1-(3-pyridyl)-2-nitroethanol.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=1[O:31][CH3:32]>>[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=3)[CH2:7][CH2:6]2)=[O:27])=[CH:24][C:23]=1[O:31][CH3:32]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Product: COc1cc(C(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)ccc1N

Procedure:
Prepared as described in Example 1 from (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1 g) and 4-amino-3-methoxybenzoic acid (0.052 g). Title compound obtained as white solid (0.053 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][NH2:37])[CH:32]=[CH:33][CH:34]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([NH:37][CH2:36][CH2:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([CH3:28])[CH:30]=2)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Cc1cccc(CCN)c1
Reactant: COc1ccc(CCC(=O)O)cc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(CCC(=O)NCCc2cccc(C)c2)cc1OC
Reaction time: 0.83 h
Yield: 87.4 %

Procedure:
A solution of 3-(3,4-dimethoxyphenyl) propionic acid (21 g, 0.10 mol) and 16.4 g (0.101 mol) of carbonyldiimidazole in dry THF was stirred for 1 h in a flask protected from moisture. To this solution was added 2-(3-methylphenyl)ethylamine (14.2 g, 0.105 mol) and stirring was continued for 50 min. The solvent was evaporated and the residue was triturated with water and collected by filtration. The crude amide was recrystallized from methanol-water to give 28.6 g (88%) of the title compound mp 100-103°.