Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH:18][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1cc(F)ccc1[N+](=O)[O-]

Procedure:
To a mixture of 2,4-difluoronitrobenzene (VII, 19.20 g), glycine ethyl ester hydrochloride (XII, 16.52 g), and acetonitrile (50 ml) is added diisopropylethylamine (42 ml). A mild exotherm ensues. The reaction is stirred (without cooling) for two hours. The acetonitrile is removed under reduced pressure and the residue is partitioned between dichloromethane and water. The organic layers are dried over sodium sulfate and concentrated to give the produce as a solid (single spot by TLC), mp 194°-195°; NMR (CDCl3) 1.33, 4.05, 4.30, 6.35, 6.45, 8.26 and 8.56 δ.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C([N:26]1[CH2:31][CH2:30][NH:29][C@H:28]([CH3:32])[CH2:27]1)(OC(C)(C)C)=O.[ClH:33]>O1CCOCC1>[ClH:33].[CH3:32][C@@H:28]1[CH2:27][NH:26][CH2:31][CH2:30][N:29]1[C:16]([C:14]1[S:15][C:11]([C:3]2[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=2)=[CH:12][CH:13]=1)=[O:18]
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(C(=O)N3CCNC[C@H]3C)s2)noc1C(F)(F)F
Reaction time: 2 h
Yield: 86 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-N-Boc-2-(R)-methyl-piperazine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford intermediate N-Boc protected product as a colorless solid (106 mg, 92%). The Boc-protected intermediate was dissolved in a 4 N solution of hydrogen chloride in 1,4-dioxane (2 mL) and stirred for 2 hr, after which time the reaction mixture was evaporated to approximately ¼ volume and diluted with ethyl ether (4 mL). The resulting solids were filtered and air dried to afford product as a colorless solid (85 mg, 86% overall). 1H NMR (D2O) 1.27 (d, J=7.5, 3 H), 2.02 (s, 3 H), 3.04 (dt, J=12.7, 3.1, 1 H), 3.12-3.18 (m, 2 H), 3.30-3.50m (m, 2 H), 4.21 (d, J=14.5, 1 H), 7.23 (s, 2 H). 19F NMR −64.1. LC/MS 4.50 min, [M+1]+ 360.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:8][OH:9].[C:10]([C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:21]=1)[C:19]#[N:20])([CH3:13])([CH3:12])[CH3:11].O>C(O)C>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:21]=1)[C:19](=[N:8][OH:9])[NH2:20])([CH3:13])([CH3:11])[CH3:12]
Reactant: COc1ccc(C(C)(C)C)cc1C#N
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(C)(C)C)cc1C(N)=NO
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.7 %

Procedure:
Sodium carbonate (57 g.) was added with stirring to a mixture of hydroxylamine hydrochloride (75 g.), 5-tert-butyl-2-methoxybenzonitrile (50 g.) and water (400 ml.) Ethanol (400 ml.) was added, and the mixture was stirred at room temperature for 45 minutes and then heated under reflux for 18 hours. The ethanol was evaporated in vacuo, and the cooled aqueous suspension was extracted three times with diethyl ether. The combined extracts were dried over magnesium sulphate, filtered, and evaporated. The residual glass was triturated with warm diethyl ether, and the solid obtained was filtered off, washed with diethyl ether, and recrystallised from benzene to give 5-tert-butyl-2-methoxybenzamidoxime (48 g.), m.p. 132°-133° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.Cl.Cl.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=4)[CH2:27][CH2:26]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Br)ccc2n1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: OCCO
Solvent: CCN(CC)CC
Product: Clc1ccc(N2CCN(Cc3cn4cc(Br)ccc4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 6-bromo-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 15, Step 1; 0.3042 g), 1-(4-chlorophenyl)piperazine dihydrochloride (Aldrich; 0.3708 g), triethylamine (Aldrich; 0.55 mL), and ethylene glycol (5.6 mL) is stirred for 1 h at 80° C. After cooling, the mixture is partitioned between water and dichloromethane. The combined organic layers are washed with brine, dried with MgSO4, and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (4/96) to give, after crystallization from ethyl acetate/methanol/dichlormetane, 0.1756 g of the title compound; mp 154-155° C.; MS m/z 404, 406, 408; IR (mineral oil) 1495, 1500, 1224, 823, 812 cm-1 ; 1H NMR (CDCl3) δ2.72, 3.19, 3.76, 6.83, 7.20, 7.22, 7.47, 7.52, 8.24.
Reaction SMILES: S(=O)(=O)(O)O.[N+]([O-])(O)=O.[CH:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH:11]1[NH2:20])[CH2:17]2.[OH-:21].[Na+]>O>[NH2:20][CH:11]1[CH:12]2[CH2:18][C:16]3([OH:21])[CH2:15][CH:14]([CH2:19][CH:10]1[CH2:17]3)[CH2:13]2
Reactant: [OH-]
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: NC1C2CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
Concentrated sulfuric acid (35 mL) was mixed with concentrated nitric acid (4.5 mL) and 2-adamantylamine (5.10 g, 4.57 mmol) under cooling with ice, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was added to ice water and adjusted to pH 10 with 7.5 M aqueous sodium hydroxide. After addition of water, the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound as a yellow solid (2.79 g, yield 61%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:3]=1[Cl:20].[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[Cl:20][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:5][C:6]2[C:11]([C:2]=1[C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=1)=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2
Reactant: OB(O)c1ccc(F)cc1
Reactant: Oc1ccc(-c2nc3ccc(O)cc3c(Br)c2Cl)cc1
Product: Oc1ccc(-c2nc3ccc(O)cc3c(-c3ccc(F)cc3)c2Cl)cc1
Yield: 95 %

Procedure:
This compound was prepared from 35a and 4-fluorophenylboronic acid according to method P. White solid; Yield: 95%; mp 295–296° C.; 1H-NMR (300 MHz, DMSO-d6) δ 6.55 (d, J=2.6 Hz, 1H), 6.87 (d, J=8.6 Hz, 2H), 7.31 (dd, J=9.1, 2.6 Hz, 1H), 7.45 (m, 4H), 7.57 (d, J=8.6 Hz, 2H), 7.92 (d, J=9.1 Hz, 1H), 9.73 (s, 1H), 10.07 (s, 1H); MS (ESI) m/z 364/366 ([M−H]−), 366/368 ([M+H]+); Anal. Calcd for C21H13ClFNO2: C: 68.96, H: 3.58, N: 3.83. Found: C: 68.19, H: 3.56, N: 3.74.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)=[O:6])[CH3:2].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1.Cl>C(O)C.O1CCOCC1>[CH2:1]([O:3][C:4](=[O:14])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:9][CH:8]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(N)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)c1ccc(Nc2ncccc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A mixture of (4-amino-phenyl)-oxo-acetic acid ethyl ester (347 mg, 1.8 mmol), 2-chloro-3-nitropyridine (294 mg, 1.8 mmol) and 4M HCl in dioxane (0.45 mL, 1.8 mmol) in ethanol (4 mL) is refluxed for 14 h. An additional 0.45 mL of 4M HCl in dioxane is added and the mixture refluxed for 5 h. The reaction mixture is cooled down to room temperature and the resulting precipitate is filtered off. [4-(3-Nitro-pyridin-2-ylamino)-phenyl]oxo-acetic acid ethyl ester is obtained as an orange solid. Title compound: ES-MS: 315.99 [M+H]+; tR=1.7 min (System 2).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](I)[CH:7]=[C:6]([Cl:11])[C:3]=1[C:4]#[N:5].O1CCCCC1[N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1.Cl>>[ClH:1].[Cl:1][C:2]1[CH:9]=[C:8]([C:20]2[NH:19][N:18]=[CH:22][CH:21]=2)[CH:7]=[C:6]([Cl:11])[C:3]=1[C:4]#[N:5]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: N#Cc1c(Cl)cc(I)cc1Cl
Agent: Cl
Product: N#Cc1c(Cl)cc(-c2ccn[nH]2)cc1Cl

Procedure:
The title compound was prepared from 2,6-dichloro-4-iodobenzonitrile (1.09 g, 3.66 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (1.32 g, 4.76 mmol) as described in Example 34 (a) and (b) until the isolation of the hydrochloride. Yield 0.824 g. 1H NMR (400 MHz; d6-DMSO): δ 7.07 (d, 1H), 7.88 (d, 1H), 8.14 (s, 2H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][C:14]([OH:16])=[O:15].[CH3:17]I.O>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:17])[CH:8]=[C:7]2[CH2:13][C:14]([OH:16])=[O:15]
Reactant: CI
Reactant: O=C(O)Cc1c[nH]c2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(CC(=O)O)c2cc(Br)ccc21
Reaction time: 1 h

Procedure:
500 mg of a 60% dispersion of sodium hydride in mineral oil were added to solution of 1 g of 5-bromoindole-3-acetic acid in 50 ml of tetrahydrofuran and the mixture was stirred under a nitrogen atmosphere for 1 hour. Thereafter, 820 mg (5.8 mmol) of methyl iodide were added and the mixture was stirred under a nitrogen atmosphere for 24 hours. Then, 5 ml of water were added and the solvent was removed under reduced pressure. The residue was treated with 2M hydrochloric acid and the precipitate formed was filtered off, washed with n-hexane and dried. The obtained solid was recrystallized from diethyl ether to give 5-bromo-1-methyl-3-indolylacetic acid of melting point 192°-194° C.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[C:9]([CH:11]2[CH2:13][CH2:12]2)[N:8]=[CH:7][N:6]=1.[F:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[C:34]1[CH:35]=[N:36][C:37]([NH2:40])=[N:38][CH:39]=1>>[CH:11]1([C:9]2[N:8]=[CH:7][N:6]=[C:5]([O:4][C:3]3[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=3[C:23]3[CH:22]=[CH:21][C:20]([C:34]4[CH:39]=[N:38][C:37]([NH2:40])=[N:36][CH:35]=4)=[C:19]([F:18])[CH:24]=3)[CH:10]=2)[CH2:13][CH2:12]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: Brc1ccccc1Oc1cc(C2CC2)ncn1
Product: Nc1ncc(-c2ccc(-c3ccccc3Oc3cc(C4CC4)ncn3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-(2-bromophenoxy)-6-cyclopropylpyrimidine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C23H18FN5O, 399.15; m/z found, 399.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.42 (s, 2H), 7.56-7.50 (m, 2H), 7.48-7.43 (m, 1H), 7.41-7.36 (m, 1H), 7.33-7.23 (m, 3H), 6.99 (s, 1H), 6.86 (s, 2H), 2.09-2.01 (m, 1H), 1.02-0.92 (m, 4H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1O[CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].NC(N)=[S:13]>O.C(O)C>[C:1]([O:6][CH2:7][CH:8]1[S:13][CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: NC(N)=S
Solvent: O
Solvent: CCO
Product: C=C(C)C(=O)OCC1CS1

Procedure:
Glycidyl methacrylate corresponding to the formula: ##STR10## is reacted with thiourea corresponding to the formula: ##STR11## at ambient temperature in a mixture of water and ethanol. The reaction gives 2,3-epithiopropyl methacrylate corresponding to the formula: ##STR12##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][CH:18]([CH2:23][O:24][CH3:25])[C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1.[C:28](OCC)(OCC)(OCC)[CH3:29]>>[CH3:28][C:29]1[N:12]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH2:23][O:24][CH3:25])[C:19]([O:21][CH3:22])=[O:20])=[CH:26][CH:27]=2)[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[N:1]=1
Reactant: COCC(Oc1ccc(Nc2ccc(C(F)(F)F)cc2N)cc1)C(=O)OC
Reactant: CCOC(C)(OCC)OCC
Product: COCC(Oc1ccc(-n2c(C)nc3cc(C(F)(F)F)ccc32)cc1)C(=O)OC

Procedure:
A solution of 7 g of 10C in 25 ml of triethyl orthoacetate was refluxed for 4 hours. The resulting mixture was concentrated in a rotary evaporator and chromatographed over silica gel to give 10, as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[C:5]([O:13][CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)(C)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]2[C:4](=[C:5]([O:13][CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccccc1
Reactant: COc1cccc2c(Cl)nc(Cl)nc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c(Nc3ccccc3)nc(Cl)nc12

Procedure:
A solution of 2,4-dichloro-8-methoxy-quinazoline (prepared as described in J. Chem. Soc. 1948, 1759) (0.6 g), N,N-diisopropyl-ethylamine (0.87 ml), and aniline (0.26 ml) in isopropanol (10 ml) is heated to reflux for 45 min. The cold reaction mixture is filtered and residue is crystallized from dichloromethane and hexanes to give 2-chloro-8-methoxy-4-phenylamino-quinazoline, m.p. 245-246° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:17]2[C:12](=[CH:13][C:14](/[CH:18]=[CH:19]/[C:20](O)=[O:21])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]([F:38])([F:37])[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)[NH2:26].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CN(C=O)C.C(OCC)(=O)C>[O:21]=[C:20]([NH:26][CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=1)[C:24]([F:38])([F:37])[F:23])/[CH:19]=[CH:18]/[C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11]2
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(/C=C/C(=O)O)ccc21
Reactant: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCc2cc(/C=C/C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)ccc21
Temperature: 50 °C
Yield: 89.9 %

Procedure:
1.5 g (4.95 mmol) of (2E)-3-{1-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl}acrylic acid and 1.2 g (4.95 mmol) of 2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethanamine were dissolved in 100 ml of DMF, 1.5 g (5.44 mmol) of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride were added, and the reaction mixture was heated to 50° C. overnight. The reaction solution was diluted with ethyl acetate, washed with sal. NaHCO3 solution, 1N hydrochloric acid and sat, sodium chloride solution, dried over sodium sulphate, filtered and concentrated. Chromatographic purification gave 2.3 g (4.45 mmol) of tert-butyl {5-[(1E)-3-oxo-3-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}amino)prop-1-en-1-yl]-2,3-dihydro-1H-inden-1-yl}carbamate (87%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[N:20]=3)[CH2:15][CH2:14]2)=[O:12])=[N:2]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:52]([O:56][C:57]([NH:59][CH2:60][C:61](O)=[O:62])=[O:58])([CH3:55])([CH3:54])[CH3:53]>CN(C)C=O.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:25][CH2:26][N:27]([C:61](=[O:62])[CH2:60][NH:59][C:57](=[O:58])[O:56][C:52]([CH3:53])([CH3:54])[CH3:55])[CH2:28][CH2:29]4)[N:20]=3)[CH2:17][CH2:18]2)=[O:12])=[N:2]1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=C(Nc1noc2ccccc12)N1CCN(c2nc(N3CCNCC3)ns2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Yield: 74 %

Procedure:
A solution of N-1,2-benzisoxazol-3-yl-4-(3-piperazin-1-yl-1,2,4-thiadiazol-5-yl)piperazine-1-carboxamide (100 mg, 0.241 mmol), 1-hydroxybenzotriazole (32.5 mg, 0.241 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (92.5 mg, 0.482 mmol) and N-(tert-butoxycarbonyl)glycine (42.3 mg, 0.241 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 12 hours. The reaction mixture was poured to water, and a solid was separated by filtration, which was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to give 102 mg (73.9%) of the desired product as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[C:15]([CH2:18][C:19]([O:21]C)=[O:20])[CH:16]=[CH:17][C:3]1=2.[Br:23]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C(Cl)(Cl)Cl>[Br:23][C:17]1[C:3]2[N:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[C:5](=[O:13])[C:4]=2[CH:14]=[C:15]([CH2:18][C:19]([OH:21])=[O:20])[CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CN2C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CN1Cc2ccccc2C(=O)c2cc(CC(=O)O)cc(Br)c21
Yield: 10.9 %

Procedure:
Methyl 5,6-dihydro-5-methyl-11-oxodibenz[b,e]azepine-2-acetate (0.750 g) was dissolved in chloroform (10 ml), and N-bromosuccinimide (0.550 g) was added to the solution. The mixture was refluxed overnight, and cooled. The mixture was then washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give an oily material. A 10% sodium carbonate aqueous solution (15 ml) and ethanol (10 ml) were added to the oily material, and the mixture was refluxed overnight. The contents were concentrated to 1/3 the original volume under reduced pressure with heating. The concentrate was treated with activated carbon powder, and acidified with 10% HCl with ice cooling. The precipitated crystals were collected by filtration and recrystallized from acetone to afford 5,6-dihydro-4-bromo-5-methyl-11-oxodibenz[b,e]azepine-2-acetic acid (prismatic crystals, 0.100 g) having a melting point of 164°-167° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[N:19])[CH:6]=[CH:5]2.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[N:19])[CH:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2cc(-c3ccccc3C#N)ccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccccc1-c1ccc2cc(CBr)ccc2c1

Procedure:
A mixture of 6.30 g of 6-methyl-2-(2'-cyanophenyl)-naphthalene, 4.60 g of N-bromosuccinimide and 0.085 g of azoisobutyronitrile in 70 ml of carbon tetrachloride is heated at 110° for 4 hours. The cooled reaction mixture is extracted twice with 45 ml of 2N sodium hydroxide solution each time. The aqueous phases are then extracted with 50 ml of CH2Cl2 in each case. The combined organic phases are dried over MgSO4. After removing the solvent in vacuo, the crude product is recrystallised from toluene/hexane and yields 6-bromomethyl-2-(2'-cyanophenyl)-naphthalene, m.p. 171°-172°.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=O.[N+:14]1([O-:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24]>>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:2]([CH2:3][CH2:4][C:5]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:7])=[O:1].[N+:14]1([O-:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(O)CCC(=O)c1ccccn1
Agent: [O-][n+]1ccccc1
Product: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1ccccn1

Procedure:
As for Example 11, γ-oxo-2-pyridinebutyric acid, pyridine-1-oxide is coupled to L-proline to give 1-[3-(2-pyridylcarbonyl)propionyl]-L-proline, pyridine-1-oxide. Reaction of the preceding compound with bromine in acetic acid and reaction of the brominated compound with sodium thioacetate in acetonitrile gives the product of the Example as a glass.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:26])=[C:5]([C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[CH3:27][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH3:26])=[C:5]([C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([CH:15]=1)[C:12]([O:14][CH3:27])=[O:13]
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)O)c2)c(OC)c(OC)c1OC
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1O
Yield: 96.4 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoic acid (0.800 g, 2.21 mmol) was dissolved in a mixed solvent of methanol (4 ml) and benzene (28 ml) and after adding thereto trimethylsilyldiazomethane (10% hexane solution) (0.303 g, 2.65 mmol), the solution was stirred at room temperature for 3 hours. The reaction solution was concentrated and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=3:1) to obtain the titled compound (0.800 g, 2.13 mmol, 96%).
Reaction SMILES: [Cl:1][C:2](=[C:6]([Cl:8])[Cl:7])[C:3](Cl)=[O:4].Cl.[NH2:10][CH2:11][C:12]#[N:13].C(Cl)(Cl)Cl>CCCCCC>[C:11]([CH2:12][NH:13][C:3](=[O:4])[C:2]([Cl:1])=[C:6]([Cl:8])[Cl:7])#[N:10]
Reactant: O=C(Cl)C(Cl)=C(Cl)Cl
Reactant: N#CCN
Agent: Cl
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: N#CCNC(=O)C(Cl)=C(Cl)Cl
Yield: 84.6 %

Procedure:
A stirred mixture of 38.8 g (0.2 moles) trichloroacryloyl chloride, 18.5 g. (0.2 moles) aminoacetonitrile hydrochloride and.150 ml chloroform was refluxed for thirty hours, with evolution of gas and dissolution of most of the aminoacetonitrile hydrochloride. The mixture was filtered hot to remove unreacted aminoacetonitrile hydrochloride. The filtrate was stripped to give an oil. The oil was rubbed with hexane and soon solidified to give 36.1 g of the above-identified product as an off-white solid, which liquified at about 56°-59° C. A small portion of product was recrystallized from a benzene-hexane mixture to give a white solid, melting point 58°-60° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([C:6]1[S:10][C:9]([C:11](OC)=[O:12])=[CH:8][CH:7]=1)=[O:5])[CH3:2].O.[NH2:18][NH2:19].O>C(O)C>[CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([C:6]1[S:10][C:9]([C:11]([NH:18][NH2:19])=[O:12])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(C(=O)OC)s1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(C(=O)NN)s1
Yield: 89 %

Procedure:
Methyl 5-(diethylcarbamoyl)thiophene-2-carboxylate (247 mg, 1.02 mmol) in ethanol (9 mL) was stirred with hydrazine monohydrate (495 mg, 10.2 mol) at 90° C. for 6 hours. After addition of water, the reaction solution was extracted with ethyl acetate and chloroform, and the extract was dried over anhydrous magnesium sulfate and concentrated to give the desired product (yield 89%).