Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.CN.[CH3:30][N:31](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:30][NH:31][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C
Yield: 72 %

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methylamide (29 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (39 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg), and DIEA (0.2 ml). LCMS: m/z 407; and 1H NMR (DMSO-d6, 400 MHz): δ 8.52 (d, 1H), 7.93 (s, 1H), 7.85 (s, 1H), 7.70 (d, 1H), 7.54 (d, 1H), 7.30 (d, 1H), 7.22-7.16 (m, 2H), 3.57 (s, 3H), and 2.87 (d, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]([CH:9]([CH3:11])[CH3:10])[NH2:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[Cl:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([S:31](Cl)(=[O:33])=[O:32])[CH:29]=2)[C:24]([Cl:35])=[CH:23][N:22]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:12])[C@@H:7]([CH:9]([CH3:10])[CH3:11])[NH:8][S:31]([C:28]1[CH:29]=[C:30]2[C:25]([C:24]([Cl:35])=[CH:23][N:22]=[C:21]2[Cl:20])=[CH:26][CH:27]=1)(=[O:33])=[O:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@@H](NS(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1)C(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 16 h
Yield: 72.2 %

Procedure:
D-Valine t-butyl ester (354 mg, 1.69 mmol) and then NEt3 (0.59 mL, 4.2 mmol) were added to a stirred solution of 1,4-dichloro-7-isoquinolinesulphonyl chloride (500 mg, 1.69 mmol) and in CH2Cl2 (20 mL) and the mixture was stirred at 23° C. for 16 h. The mixture was diluted with CH2Cl2 (50 mL), washed with saturated aqueous NaHCO3, water, aqueous citric acid (1 M), water, brine, dried (MgSO4) and evaporated in vacuo. The residue was dissolved in i-Pr2O and hexane was added which gave a precipitate. The solvents were evaporated in vacuo and the solid was triturated with hexane to give N-[(1,4-dichloro-7-isoquinolinyl)sulphonyl]-D-valine t-butyl ester (532 mg, 1.22 mmol) as a white solid. An analytical sample was obtained by recrystallisation from hexane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[C@@H:16]([OH:17])[C:15](=[O:18])[NH:14][C:13]3[CH:19]=[CH:20][C:21]([O:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[CH:22][C:12]=3[S:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]Cl>C(C(C)=O)C>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][N:14]1[C:13]2[CH:19]=[CH:20][C:21]([O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:22][C:12]=2[S:11][C@@H:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[C@@H:16]([OH:17])[C:15]1=[O:18]
Reactant: COc1ccc([C@@H]2Sc3cc(Oc4ccc(F)cc4)ccc3NC(=O)[C@@H]2O)cc1F
Reactant: CN(C)CCCl
Agent: Cl
Solvent: CCC(C)=O
Product: COc1ccc([C@@H]2Sc3cc(Oc4ccc(F)cc4)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1F

Procedure:
Following a procedure similar to that described in Example 11(d), 865 mg of (2S, 3S)-2-(3-fluoro-4-methoxy- phenyl)-8-(4-fluorophenoxy)-2,3-dihydro-3-hydroxy-1,5-benzothiazepin-4(5H)-one [prepared as described in step (c) above] were alkylated with 2-dimethylaminoethyl chloride hydrochloride in 50 ml of methyl ethyl ketone to afford about 900 mg of the title compound as a syrup. The compound was used in the following reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClOC(C)(C)C.[S:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C[O-].[Na+]>CO.C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: C1CCSC1
Agent: CC(C)(C)OCl
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: Nc1ccccc1
Product: Nc1ccccc1C1CCCS1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a vigorously stirred solution of 10.0 grams (0.11 mole) of aniline in 200 ml. of methylene chloride cooled to -78° C. under nitrogen were added by means of a jacketed constant pressure additional funnel 11.7 grams (0.11 mole) of tert.-butyl hypochlorite also cooled to -78° C. This solution was stirred for 10 minutes. The funnel was rinsed with a few ml. of cold methylene chloride and 44 ml. (ca. 5 equivalents) of tetrahydrothiophene was cooled to -78° C., added dropwise to the reaction mixture, and stirred for 3 hours. In 50 ml. of methanol, 7.0 grams (0.13 mole, 1.2 equivalents) of sodium methoxide were placed in the funnel, cooled, and added quickly to the reaction mixture. The dry-ice/acetone cooling bath was removed and the solution stirred for 2 hours. The reaction was quenched by the addition of 100 ml. of water, the heterogeneous mixture separated, the aqueous layer was extracted two times with 100-ml. portions of methylene chloride. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The solvent was removed in vacuo to produce a dark red oil. Fractional distillation of the oil gave 5.03 grams (0.054 mole) of aniline and 6.11 grams (0.034 mole) of 2-(2-tetrahydrothienyl)aniline for a 31% yield based on starting material and a 64% yield based on unrecovered starting material: b.p. 130°-134° C. (0.19 mm), ND26.8 1.6258, IR (neat) 2.92, 3.36, 6.12, 6.70, and 13.40μ, NMR (CCl4)T 7.82 (4H, m), 6.99 (2H, m) 6.06 (2H, s), 5.52 (2H, t), 3.20 (4H, m).
Reaction SMILES: C(O[C:5]([C:13]#[CH:14])([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH2:7])(=O)C.CO.CCCCC.CC[O:24]CC.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(O)(=O)C.CN(C)C1C=CN=CC=1>[CH2:8]([C:5]1[C:6](=[O:24])[CH2:7][CH2:14][CH:13]=1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C#CC(C=C)(CCCCC)OC(C)=O
Reactant: CCOCC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCCCC
Product: CCCCCC1=CCCC1=O
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A mixture of 184 mg (0.95 mM) of 1-ethynyl-1-pentyl-2-propenyl acetate and 13 mg (0.05 mM) of PdCl2 (CH3CN)2 in 1.2 ml of acetonitrile and 60 μl of glacial acetic acid was heated at 80° during 2 h. 1 Ml of methanol and some crystals of 4-dimethylaminopyridine were added to the reaction mixture and the whole was stirred for 45 minutes at room temperature, whereupon 10 ml of a 1:1 mixture of pentane/ether were added followed by a small quantity of potassium carbonate. The reaction mixture was then stirred for 30 minutes, it was then filtered and evaporated. The obtained residue gave by bulb to bulb distillation 104 mg of a colorless distillate constituted by the desired product having a purity of 92% (yield 66%). By carrying out the reaction in toluene instead of acetonitrile at a temperature of about 80°, the desired product was obtained, though in lower yields.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[C:8]([CH:10]=1)[NH2:9])([O-:3])=[O:2].[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[C:8]([NH:9][C:19]([NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:20])[CH:10]=1)([O-:3])=[O:2]
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Product: O=C(Nc1ccccc1)Nc1cc([N+](=O)[O-])ccc1O
Yield: 30 %

Procedure:
The N-[5-nitro-2-hydroxyphenyl]-N′-phenyl urea was prepared from the 5-nitro 2-hydroxy aniline and phenyl isocyanate according to the procedure in General Method A. The product was purified by precipitation from toluene and filtering to afford the titled compound (100 mg, 30%). 1H NMR (CD3OD): d 9.48 (s, 1H, NH), 9.07 (d, J=1.56 Hz, NH), 8.55 (s, 1H), 7.80 (dd, 1H, J=6.25 Hz and J=1.56 Hz), 7.50 (d, 2H, J=6.25 Hz), 7.30 (t, 2H, J=6.25 Hz), 7.01 (m, 2H). EI-MS m/z 273 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH2:22]([CH:24]1[CH2:26][O:25]1)[CH3:23]>>[OH:25][CH:24]([CH2:22][CH3:23])[CH2:26][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: CCC1CO1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: CCC(O)CN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 168 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-ethyloxirane and conditions outlined in procedure X. M.p.=180-182° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.9 (m, 1H), 7.75 (m, 2H), 7.55 (m, 1H), 4.2 (s, 1H), 3.5 (br s, 1H), 3.05 (s, 2H), 2.7 (br s, 2H), 2.45-2.25 (m, 4H), 1.9 (m, 2H), 1.8 (m, 2H), 1.5-1.4 (m, 1H), 1.3-1.2 (m, 1H), 0.85 (m, 3H); LCMS: 374 [M+H].
Reaction SMILES: [CH2:1]([C:12]1[CH:36]=[CH:35][C:15]([C:16]([O:18][C:19]2[CH:34]=[CH:33][C:22]([C:23]([O:25]CC3C=CC=CC=3)=[O:24])=[CH:21][CH:20]=2)=[O:17])=[C:14]([C:37]([OH:39])=[O:38])[CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>[Pd]>[CH2:1]([C:12]1[CH:36]=[CH:35][C:15]([C:16]([O:18][C:19]2[CH:34]=[CH:33][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:17])=[C:14]([C:37]([OH:39])=[O:38])[CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCc1ccc(C(=O)Oc2ccc(C(=O)OCc3ccccc3)cc2)c(C(=O)O)c1
Agent: [Pd]
Product: CCCCCCCCCCCc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)c(C(=O)O)c1

Procedure:
By customary procedures, 3.5 g of benzyl 4-undecylcarboxybenzoate was prepared from 2.3 g of benzyl 4-hydroxybenzoate and 2.5 g of lauric acid chloride, and this ester was catalytically reduced under a hydrogen pressure of 2 kg/cm2 by using Pd/C as the catalyst to obtain 2.8 g of 4-undecylcarboxybenzoic acid. The acid was converted to 4-undecylcarboxybenzoic acid chloride by thionyl chloride and the acid chloride was reacted with 1.8 g of benzyl 4-hydroxybenzoate to form benzyl 4-(4-undecylcarboxybenzoyloxy)benzoate. The ester was catalytically reduced under a hydrogen pressure of 2 kg/cm2 by using Pd/C as the catalyst to isolate the benzyl group and obtain 3.0 g of 4-(4'undecylcarboxybenzoyloxy)benzoic acid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[NH2:12][C:13]1[N:14]=[C:15]([NH2:24])[C:16]2[C:21]([CH2:22]Cl)=[CH:20][O:19][C:17]=2[N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[NH2:12][C:13]1[N:14]=[C:15]([NH2:24])[C:16]2[C:21]([CH2:22][O:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[CH:20][O:19][C:17]=2[N:18]=1
Reactant: Nc1nc(N)c2c(CCl)coc2n1
Reactant: Oc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1nc(N)c2c(COc3ccc4ccccc4c3)coc2n1
Temperature: 45 °C
Reaction time: 24 h
Yield: 23.3 %

Procedure:
To a 50 mL three neck round bottom flask was added in sequence anhydrous DMSO (4 mL), 2-naphthol (0.27 g), compound 117 (0.25 g) and anhydrous potassium carbonate (0.26 g). The reaction mixture was stirred at 45° C. for 24 h under nitrogen in the dark and then quenched with distilled water (12 mL). The resultant suspension was stirred at room temperature for 4 h, cooled to 5° C. and filtered. The sold was washed with cold water (2×5 mL) and then dissolved in MeOH. The solution was mixed with silica gel (1 g) and the mixture was evaporated under reduced pressure and dried in vacuo. The residue was ground into a fine powder and poured on top of a wet column of silica gel (30 g) and eluted with 3% MeOH in CHCl3. Fractions corresponding to a single spot of the product (TLC) were pooled and evaporated to afford 0.09 g compound 425 (23%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:14])[CH3:13]>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:19][C:18]2[CH:20]=[CH:21][C:15]([CH:12]([CH3:14])[CH3:13])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Yield: 68.7 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-dimethylaminobenzaldehyde (11 g) and 4-isopropylaniline (10 g) as starting materials, [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (13.6 g) was obtained. melting point: 71–73° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([C:8]#[N:9])=O)=[CH:4][CH:3]=1.[C:12]([O:16][C:17](=[O:25])[N:18]([CH2:22][CH2:23]Cl)[CH2:19][CH2:20]Cl)([CH3:15])([CH3:14])[CH3:13].[H-].[Na+]>CN(C)C=O>[C:12]([O:16][C:17]([N:18]1[CH2:22][CH2:23][C:6]([C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)([C:8]#[N:9])[CH2:20][CH2:19]1)=[O:25])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CC(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Temperature: 60 °C
Yield: 53.6 %

Procedure:
To 1.26 g (8.37 mmol) 4-chloro-benzoylcyanide was added bis-(2-chloroethyl)-carbamic acid tert-butyl ester (2.02 g, 8.37 mmol) in 25 ml N,N-dimethylformamide. The resulting mixture was stirred and cooled in an ice bath, then sodium hydride (60% suspension in mineral oil) (1.1 g, 42 mmol) was added portionwise. The reaction was brought to room temperature and then heated in an oil bath at 60° C. for 16 hours. The reaction mixture was quenched by addition of ice water and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed twice with water, once with brine, dried with magnesium sulfate and concentrated in vacuo. The residual brown oil was purified by silica gel chromatography eluting with hexane-ethyl:acetate (9:1) to give the title compound (1.44 g, 54%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH:7][C:8]([CH3:41])([CH3:40])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:20]=2)[CH3:18])[CH2:12][CH2:11]1.Cl[C:43]1[CH:44]=[C:45]([CH3:51])[C:46](=[O:50])[N:47]([CH3:49])[N:48]=1>CN(C)C=O>[CH3:49][N:47]1[C:46](=[O:50])[C:45]([CH3:51])=[CH:44][C:43]([C:22]2[CH:21]=[CH:20][C:19]([C@@H:17]([N:13]3[CH2:12][CH2:11][C@:10]([CH2:9][C:8]([OH:7])([CH3:40])[CH3:41])([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:15][C:14]3=[O:16])[CH3:18])=[CH:24][CH:23]=2)=[N:48]1
Reactant: Cc1cc(Cl)nn(C)c1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nn(C)c1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2 M aqueous Na2CO3 solution (0.31 mL) was added to a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.15 g) and 6-chloro-2,4-dimethyl-2H-pyridazin-3-one (75 mg) in dimethylformamide (1 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (15 mg) was added. The mixture was heated to 100° C. and stirred at this temperature overnight. After cooling to ambient temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (CH2Cl2/MeOH 98:2->80:20) to afford the title compound. Yield: 0.10 g (67% of theory). Mass spectrum (ESI+): m/z=476 [M+H]+
Reaction SMILES: [ClH:1].C([O:6][C:7](=[O:27])[CH:8]([NH:19]C(OCCCC)=O)[CH2:9][S:10](=[O:18])(=[O:17])[CH2:11][CH2:12][NH:13][C:14](=[NH:16])[CH3:15])(C)(C)C.Cl.O1CCOCC1>O1CCOCC1>[ClH:1].[ClH:1].[NH2:19][CH:8]([CH2:9][S:10](=[O:18])(=[O:17])[CH2:11][CH2:12][NH:13][C:14](=[NH:16])[CH3:15])[C:7]([OH:27])=[O:6]
Reactant: CCCCOC(=O)NC(CS(=O)(=O)CCNC(C)=N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=N)NCCS(=O)(=O)CC(N)C(=O)O
Reaction time: 24 h
Yield: 159.4 %

Procedure:
To a solution of 2-(butyloxycarbonylamino)-6-(1-iminoethylamino)-4,4-dioxo-4-thiahexanoic acid tert-butyl ester hydrochloride (300 mg) in dioxane (15 ml) was added 4N HCl/dioxane (10 ml) and the mixture allowed to stand at room temperature for 24 hrs. The reaction mixture was then evaporated to dryness and the semi-solid residue treated with water (2 ml) and evaporated to give a colourless glass. The crude product was purified by flash chromatography on SiO2 using CH3CN:CH3CO2H:H2O (5:2:2) as the eluant to give 172.5 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C1(P(O[NH2:34])(C2C=CC=CC=2)=O)C=CC=CC=1>>[NH2:34][N:10]1[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:18]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(-c2n[nH]c(=O)c3ccccc23)cc1
Product: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1

Procedure:
4-(4-methylphenyl)-phthalazin-1(2H)-one was treated with O-(diphenylphosphoryl)hydroxylamine using a method similar to that described in Example 1B to give the title compound. MS (APCI+) M/Z 252 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:11]([C:12]2[S:13][C:14]([Br:17])=[N:15][N:16]=2)[N:10]=[C:9]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[S:8]1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:17][C:14]1[S:13][C:12]([N:11]2[N:10]=[C:9]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[S:8][C:7]2([CH2:6][CH2:5][CH2:4][NH2:1])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:16][N:15]=1
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nnc(Br)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nnc(Br)s1
Temperature: 23 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-bromo-1,3,4-thiadiazole (0.006 g, 0.011 mol) was dissolved in 0.25 mL THF, followed by addition of water (0.015 g, 15 μL) and triphenylphosphine (0.015 g, 0.057 mmol), and the reaction mixture was stirred at 23° C. overnight. The crude mixture was purified by directly loading onto a preparative TLC plate and eluting first with 12:1 (DCM:MeOH), followed by a second elution with 10:1 (DCM:MeOH) (both with NH4OH present), to afford the desired product (0.003 g, 53%). MS ESI (+) m/z 495/497 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.52 (m, 3H), 7.35 (t, 2H, J=7.6 Hz), 7.30 (d, 1H, J=7.2 Hz), 7.12 (m, 2H), 3.46 (m, 1H), 2.65 (m, 6H), 2.05 (m, 1H), 1.61 (m, 1H).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH2:17][CH3:18])(=O)C.NC1C=C(N)C=CC=1OCCC.C([O-])(=O)C.[Mg+2].C([O-])(=O)C.[BrH:40]>C(O)C>[BrH:40].[CH2:16]([O:15][C:6]1[C:5]([NH2:4])=[CH:10][C:9]([NH:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1)[CH2:17][CH3:18]
Reactant: CCCOc1ccc(NC(C)=O)cc1NC(C)=O
Agent: Br
Agent: CC(=O)[O-]
Agent: CCCOc1ccc(N)cc1N
Solvent: CCO
Product: CCCOc1ccc(NC(C)=O)cc1N
Temperature: 25 °C
Yield: 88.9 %

Procedure:
208 parts of dried crude 6-n-propoxy-3-acetylamino-aniline obtained according to Example 7 of European Pat. No. 0,011,048 (containing, in addition to 190.3 parts of target product, 8.8 parts of 2,4-bis-acetylamino-1-n-propoxybenzene and 3.5 parts of 2,4-diamino-1-n-propoxybenzene, as well as small amounts of magnesium acetate and oxidative decomposition products) are dissolved in 300 parts of ethanol at 50° C., with stirring, and, after the solution has been cooled to 25° C., 170 parts of 48% strength hydrobromic acid are added dropwise in the course of 1.5 hours. The precipitate which has separated out is filtered off with suction at 0°-5° C., washed with two portions of 60 parts of ethanol and dried in vacuo. 257.1 parts of 6-n-propoxy-3-acetylamino-aniline hydrobromide (no impurities detectable by HPLC, purity by diazotization: 99.4%) are obtained, which corresponds to a yield of 88.9% of theory (based on the crude feed product) or 97.2% of theory (based on the target product contained therein).
Reaction SMILES: O=[C:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][C:5]([CH:7]1[O:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8]1)=O.FC(F)(F)C([O-])=O.[NH4+:33]>O>[C:20]1([C:2]2[N:33]=[C:5]([CH:7]3[O:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:8]3)[NH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CNC(=O)C1CN(Cc2ccccc2)CCO1)c1ccccc1
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: c1ccc(CN2CCOC(c3nc(-c4ccccc4)c[nH]3)C2)cc1
Temperature: 150 °C
Reaction time: 1 h
Yield: 112.4 %

Procedure:
A mixture of N-(2-oxo-2-phenylethyl)-4-(phenylmethyl)-2-morpholinecarboxamide (850 mg, 2.51 mmol) and ammonium trifluoroacetate (1317 mg, 10.05 mmol) was heated at 150° C. under microwave condition with stirring for 1 hour. Water (150 mL) was added to the residue, and extracted with EtOAc (200 mL). The organic layer was dried (Na2SO4), filtered, and concentrated to afford the crude title compound (1.3 g) as a brown oil. This material was combined with another batch of crude title compound (250 mg) and purified by silica gel chromatography using as eluent EtOAc (1600 mL) in hexanes (400 mL) to afford the title compound (900 mg, 2.82 mmol) as a brown solid. LC-MS (ES) m/z=320 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][S:4][N:3]=1.C([Li])CCC.[I:15]I.Cl>C1COCC1>[I:15][C:5]1[S:4][N:3]=[C:2]([CH3:1])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: II
Reactant: Cc1nscc1C(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nsc(I)c1C(=O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methylisothiazole-4-carboxylic acid (C-4) (3.9 g, 27.3 mmol) in anhydrous THF (150 mL) at −78° C. under argon, n-butyl lithium solution (27.3 mL, 68.3 mmol) is added dropwise and the resulting mixture is stirred at −78° C. for 1 h. To this mixture, a solution of iodine (13.9 g, 54.6 mmol) in THF (50 mL) is added slowly and the resulting mixture is stirred at RT for 1 h. The mixture is acidified with concentrated HCl to adjust the pH to 3-4, and then extracted with ethyl acetate. The organic layer is washed with aqueous Na2SO3 solution. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the product, 5-iodo-3-methylisothiazole-4-carboxylic acid (C-5).