Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[C@H:10]([C:15]([F:18])([F:17])[F:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-]S([O-])(=O)=O.[Na+].[Na+].[O:26]=[C:27]1[NH:32][C:31]2[CH:33]=[C:34]([CH:37]=O)[CH:35]=[CH:36][C:30]=2[S:29][CH2:28]1.[BH4-].[Na+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][CH2:37][C:34]2[CH:35]=[CH:36][C:30]3[S:29][CH2:28][C:27](=[O:26])[NH:32][C:31]=3[CH:33]=2)[C@H:10]([C:15]([F:18])([F:16])[F:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](C(F)(F)F)C1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccc3c(c2)NC(=O)CS3)[C@H](C(F)(F)F)C1
Reaction time: 12 h

Procedure:
To a solution of (3R,4S)-4-amino-3-(trifluoromethyl)piperidine-1-carboxylic acid tert-butyl ester (2d) (1 equiv.) in acetonitrile is added Na2SO4 and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxaldehyde (in) (1 equiv.). After 12 hr at RT, the reaction is filtered through a sintered-glass funnel and the filtrate is concentrated under vacuum. The remaining residue is dissolved in EtOH and NaBH4 (1 equiv.) is added. After 12 h, the reaction is concentrated and the residue is dissolved in 1 N HCl. The solution is neutralized with 6 N NaOH and extracted with EtOAc. The organic fraction is dried over Na2SO4 and concentrated under vacuum. The crude product is purified by flash chromatography on silica gel to afford the title compound.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:16](=[O:33])[CH:17]=[CH:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O>C(O)C.ClCCl>[C:1]([NH:4][CH:5]([CH:16]([OH:33])[CH:17]=[CH:18][C:19]1[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:20]=1)[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(Cc1csc2ccccc12)C(=O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC(Cc1csc2ccccc12)C(O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
A solution of the product of Example 1 (2.0 g) was dissolved in ethanol/dichloromethane (5:1, 100 ml) and treated with sodium borohydride (0.156 g). The reaction was stirred for 1 hour and then poured into water (500 ml), extracted with ethyl acetate, dried (MgSO4), filtered, and evaporated to yield an oil which was purified by chromatography on silica using ethyl acetate/petroleum ether (bp 60°-80° C.) to yield the title compound isomer A as a pale yellow solid (0.25 g) mp=190°-191° C.; found: C, 56.19; H, 3.93; N, 2.91; C23H19F6NO2S.0.25H2O requires C, 56.15; H, 4.00; N, 2.85%.
Reaction SMILES: N=C=N.[CH:4]([C:7]1[N:8]=[N:9][S:10][C:11]=1[C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=2)[CH:20]=1)[C:15](O)=[O:16])([CH3:6])[CH3:5].[CH3:28][C:29]1[N:30]=[CH:31][C:32]([CH2:35][NH2:36])=[N:33][CH:34]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CCN(CC)CC>[CH:4]([C:7]1[N:8]=[N:9][S:10][C:11]=1[C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=2)[CH:20]=1)[C:15]([NH:36][CH2:35][C:32]1[CH:31]=[N:30][C:29]([CH3:28])=[CH:34][N:33]=1)=[O:16])([CH3:6])[CH3:5]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3snnc3C(C)C)c2)nc1
Reactant: Cc1cnc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)cn3)cc(-c3snnc3C(C)C)c2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-(4-Isopropyl-[1,2,3]thiadiazol-5-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide was prepared using the carbodiimide-based amide synthesis procedure of example 7 in published patent application US2008004442. Briefly, 3-(4-isopropyl-[1,2,3]thiadiazol-5-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid, C-(5-methyl-pyrazin-2-yl)-methylamine, EDCI, HOBt and Et3N were added to methylene chloride, and the mixture was stirred at room temperature for 16 hours, then was partitioned between water and methylene chloride. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified via flash chromatography to give3-(4-isopropyl-[1,2,3]thiadiazol-5-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=445.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.[N:29]1([C@@H:35]2[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]2O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:36]4[CH2:37][CH2:38][CH2:39][CH2:40][CH:35]4[N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: O[C@@H]1CCCC[C@H]1N1CCCCC1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC3CCCCC3N3CCCCC3)cc2)cc1
Yield: 64.8 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)benzo[b]thiophene (1.17 g, 3.00 mmol), trans-2-piperidinylcyclohexanol (1.10 g, 6.00 mmol), triphenylphosphine (1.57 g, 6.00 mmol), and DEAD (6.0 mmol) were converted to product by the procedure of Example 11 to give 1.08 g of the title compound. Yield: 65%. MS(FD) 555(M+). IR (CHCl3) ν max 3014, 2938, 2860, 1644, 1595, 1476, 1254, 1165.
Reaction SMILES: CO[C:3]([C@H:5]([C@@H:17]([CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])[CH2:6][N:7]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]([CH3:15])[C:8]1=[O:16])=[O:4].Cl.[CH2:33]([O:40][NH2:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cl-].[NH4+]>C1COCC1>[CH2:33]([O:40][NH:41][C:3]([C@H:5]([C@@H:17]([CH2:26][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31]1)[C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])[CH2:6][N:7]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]([CH3:15])[C:8]1=[O:16])=[O:4])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)[C@@H](CN1C(=O)N(C)C(C)(C)C1=O)[C@@H](CC1CCCC1)C(=O)N1CCCCC1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1C(=O)N(C[C@H](C(=O)NOCc2ccccc2)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C

Procedure:
A solution of 1.10 g of methyl ester from Example 10 and 568 mg of O-benzylhydroxylamine hydrochloride in 7 ml of THF was treated at −20° with 3.5 ml of a 2M i-PrMgCI solution in THF and, after 1 hr. at −20°, treated with a further 1.7 ml of the Grignard reagent. After a further 2½ hrs. at −20° the mixture was treated with ammonium chloride solution and extracted with methylene chloride. The extracts were dried and concentrated. The residue was crystallized from t-butyl methyl ether/hexane and the crystallizate was dried, there being obtained 1-[2(R)-[1(R)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl)piperidine VII, m.p. 135-137°.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:19]=[C:18]2[C:10]([C:11]3C[C:13]4C=C[C:23]([O:26]C)=[CH:22][C:14]=4[C:15]([CH3:21])([CH3:20])[C:16]=3[NH:17]2)=[CH:9][CH:8]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+]>C(OCC)C.O>[F:6][C:7]1[CH:19]=[C:18]2[C:10]([C:11]3[C:23](=[O:26])[C:22]4[CH:2]=[CH:1][C:5]([O:4][CH3:3])=[CH:13][C:14]=4[C:15]([CH3:20])([CH3:21])[C:16]=3[NH:17]2)=[CH:9][CH:8]=1
Reactant: C1CCOC1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(F)ccc3c1C2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(F)ccc3c1C2=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Under nitrogen atmosphere, to the THF (1.8 mL)-water (0.18 mL) solution of 3-fluoro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole (Compound V2, 72.4 mg, 0.245 mmol), DDQ (122.4 mg, 0.539 mmol) was added and the mixture was stirred at room temperature for 5 hr. The reaction mixture was added with diethyl ether and 0.5 N aqueous solution of sodium hydroxide (2 mL), and the resulting mixture was extracted twice with diethyl ether. The organic layer was washed twice with 0.5 N aqueous solution of sodium hydroxide (2 mL) and subsequently twice with brine (2 mL), and dried over sodium sulfate. After concentration under reduced pressure, hexane/ethyl acetate (5:1) and diethyl ether were added to the obtained crude product, and the solid was triturated. After removing the supernatant and drying under reduced pressure, the title compound was obtained (yellow solid, 57.0 mg, 75%).
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][N:32]=[C:33]=[O:34]>ClCCl>[C:31]1([NH:32][C:33]([N:13]2[CH2:12][CH2:11][N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:30])([F:28])[F:29])=[CH:17][CH:16]=3)[CH2:9][CH:8]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:34])[CH:9]=[CH:8][CH:1]=[CH:2][CH:3]=1
Reactant: CN=C=O
Reactant: FC(F)(F)c1ccccc1-c1ccc(CN2CCNC(Cc3ccccc3)C2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CCN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)CC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above compound was made in the following manner: 100 mg of 3-benzyl-1-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-piperazine dissolved in dichloromethane, 1.1 equiv. methylisocyanate added. The reaction was shaken at room temperature overnight. The reaction was concentrated in vacuo. The residue was diluted with DCM, washed with 1M aqueous sodium hydroxide solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was identified by ES MS(+) (m/z 530).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([C:14]([S:17]([C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)(=[O:19])=[O:18])([CH3:16])[CH3:15])[N:11]=[C:10]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[N:9]=1.C(=O)(O)[O-].[Na+].Cl[C:39]([O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:40]>O1CCOCC1.C(OCC)C>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([C:14]([S:17]([C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)(=[O:19])=[O:18])([CH3:16])[CH3:15])[N:11]=[C:10]([C:26]2[CH:27]=[CH:28][C:29]([NH:30][C:39](=[O:40])[O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:31][CH:32]=2)[N:9]=1
Reactant: Cc1csc(S(=O)(=O)C(C)(C)c2cc(N3CCOC[C@@H]3C)nc(-c3ccc(N)cc3)n2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1csc(S(=O)(=O)C(C)(C)c2cc(N3CCOC[C@@H]3C)nc(-c3ccc(NC(=O)Oc4ccccc4)cc3)n2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.1 %

Procedure:
To a solution of 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-[2-[(4-methyl-1,3-thiazol-2-yl)sulfonyl]propan-2-yl]pyrimidin-2-yl]aniline (340 mg, 0.72 mmol) in 1,4-dioxane (4 mL) was added sodium bicarbonate (90 mg, 1.08 mmol). Phenyl chloroformate (0.104 mL, 0.83 mmol) was then added dropwise and the resulting mixture was stirred at RT for 6 hours. Reaction mixture was then evaporated and the residue was partitioned between DCM (5 mL) and water (5 mL). The organic layer was separated and aqueous re-extracted with more DCM (5 mL). The combined organic layers were combined and evaporated to dryness to afford an amber gum, which was taken up in diethyl ether (5 mL) and triturated with sonication. The resultant solid was collected by suction filtration and dried to afford the desired material (334 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[ClH:1].[OH:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[NH:18][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: Nc1cccc(O)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Product: Cl
Product: Oc1cccc(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192 mmol) and 3-aminophenol (31 mg, 0.288 mmol) similar to Example 97 and isolated as a tan solid (28 mg,). 1H NMR (DMSO-d6): 10.26 (s, 1H), 9.62 (s, 1H), 9.51-9.50 (m, 1H), 8.87-8.83 (m, 2H), 7.30 (s, 1H), 7.23-7.21 (m, 3H), 6.57-6.54 (m, 1H).
Reaction SMILES: C(O[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(C)(C)C.[NH2:13][C:14]1[S:15][C:16]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:21]=2)=[CH:17][N:18]=1>C1COCC1>[CH3:29][O:28][C:26](=[O:27])[C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([S:19][C:16]2[S:15][C:14]([NH:13][C:6]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:12])=[N:18][CH:17]=2)[CH:21]=1
Reactant: COC(=O)c1cccc(Sc2cnc(N)s2)c1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cccc(Sc2cnc(NC(=O)OC(C)(C)C)s2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Di-t-butylcarbonate (4.36 g, 20 mmol) was added to a stirred solution of 2-amino-5-[(3-carbomethoxyphenyl)thio]thiazole(1.33 g, 5 mmol) and 4-N,N-dimethylaminopyridine (62 mg, 0.5 mmol) in THF (120 mL). The solution was stirred at rt. for 6 h and concentrated. The residue was purified using flash column chromatography on silica gel. Elution with 10% EtOAc in hexanes followed by 25% EtOAc in hexanes afforded a mixture of the titled compound and the corresponding bis(tert-butoxycarbonyl)amino adduct (1.8 g) as an oil.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([N:8]=[C:9]=[O:10])(=[O:7])[C:4]([CH3:6])=[CH2:5]>C(Cl)(Cl)Cl.ClCCCl>[C:3]([NH:8][C:9]([NH:2][CH3:1])=[O:10])(=[O:7])[C:4]([CH3:6])=[CH2:5]
Reactant: C=C(C)C(=O)N=C=O
Reactant: CN
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)NC(=O)NC
Yield: 99.9 %

Procedure:
To a solution of methylamine (0.35 g; 11.29 mmol) in chloroform (30 ml), a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (2 ml) was dropwise added under nitrogen stream while cooling with ice. After completion of the addition, chloroform, 1,2-dichloroethane and methylamine were evaporated under reduced pressure to give 1-methacryloyl-3-methylurea (1.42 g), which was recrystallized from a mixture of benzene and hexane to give colorless plates. M.P., 112°-113.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([C:6](=O)[CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[C:18]([NH2:22])=[N:19][O:20][N:21]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl.[NH2:32][OH:33]>C(O)C>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([C:6](=[N:32][OH:33])[CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[C:17]2[C:18]([NH2:22])=[N:19][O:20][N:21]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: Nc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1nonc1-c1nc2ccccc2n1CC(=NO)c1ccc(Br)cc1

Procedure:
A mixture of 4-[1-(4-bromophenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine (0.083 g, 0.21 mmol, prepared according to Example 1), sodium bicarbonate (0.021 g, 0.25 mmol) and hydroxylamine hydrochloride (0.014 g, 0.21 mmol) in ethanol (5 ml) is refluxed for 20 hours. Partitioning of the reaction mixture between ethyl acetate and water, separation of the organic phase followed by drying and evaporation of the solvent gives the crude product. Purification by chromatography on silicagel yields the title compound as an E/Z-mixture, m.p. 198-201° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: CC(C)N
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CC(=O)O)cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccc(CC(=O)NC(C)C)cc2)=C(C)C1=O
Yield: 22.2 %

Procedure:
4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetic acid (21 mg, 0.063 mmol) obtained in Example 52 and isopropylamine (0.008 ml, 0.095 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (5.1 mg, 0.014 mmol, yield 22%).
Reaction SMILES: [CH:1]([NH:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])([CH3:23])[CH3:22])[C:15]2=[O:31])[CH:8]=1)(CC)[CH3:2].[C:33](=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][Cl:42]>C(#N)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][CH:1]2[CH2:2][CH2:33]2)=[O:32])=[CH:8][C:9]=1[N:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:40][CH2:41][Cl:42])([CH3:22])[CH3:23])[C:15]1=[O:31]
Reactant: CCC(C)NC(=O)c1ccc(Cl)c(-n2ccnc(NC(C)(C)c3ccccc3O)c2=O)c1
Reactant: ClCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2Cl)c1=O)c1ccccc1OCCCl
Temperature: 75 °C
Reaction time: 10 h

Procedure:
A solution of N-(sec-butyl)-4-chloro-3-[3-{[1-(2-hydroxyphenyl)-1-methylethyl]amino}-2-oxopyrazin-1(2H)-yl]benzamide (Example 330h, 1 g) dissolved in acetonitrile (10 mL) was treated with potassium carbonate (3.15 g) and 1-bromo-2-chloroethane (1.896 mL) under nitrogen. The resulting suspension was stirred at 75° C. for 10 h. The reaction mixture was evaporated to dryness, diluted with water (300 mL), and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and evaporated to afford the crude product. The crude product was triturated with 50% ether in isohexane to afford the subtitle compound (1.100 g).
Reaction SMILES: Br[CH2:2][C:3]#[C:4][OH:5].[CH:6]#[C:7][CH2:8][CH2:9][C:10]#[CH:11]>>[CH2:4]([OH:5])[C:3]#[C:2][C:6]#[C:7][CH2:8][CH2:9][C:10]#[CH:11].[CH2:4]([OH:5])[C:3]#[C:2][C:6]#[C:7][CH2:8][CH2:9][C:10]#[C:11][C:2]#[C:3][CH2:4][OH:5]
Reactant: OC#CCBr
Reactant: C#CCCC#C
Product: C#CCCC#CC#CCO
Product: OCC#CC#CCCC#CC#CCO

Procedure:
Employing a Cadiot-Chodkiewicz-type reaction, 3-bromopropyne-1-ol was reacted with 1,5-hexadiyne to give two products, 2,4,8-nonatriyne-1-ol (I) and 2,4,8,10-dodecatetrayne-1,12-diol (II), which were separated by use of appropriate solvents. Oxidative coupling of (I) gave 2,4,8,10,14,16-octadecahexayne-1,18-diol (III).
Reaction SMILES: C([O:3][C:4](=[O:26])[C@@:5]([CH3:25])([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH:27]1([C:33]2[O:34][C:35]([CH3:51])=[C:36]([CH2:38][CH2:39]OS(C3C=CC(C)=CC=3)(=O)=O)[N:37]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([C:33]2[O:34][C:35]([CH3:51])=[C:36]([CH2:38][CH2:39][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C@:5]([CH3:25])([O:14][C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[C:4]([OH:3])=[O:26])=[CH:8][CH:9]=3)[N:37]=2)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CCOC(=O)[C@](C)(Cc1ccc(O)cc1)Oc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(C[C@](C)(Oc2ccc(C(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from (S)-3-(4-hydroxyphenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester (95% ee; Chiralpak AD separation, 8×27 cm, 10% IPA/heptane, 275 nm) and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester by the procedure described in Example 1.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5](C(O)=O)[CH2:4][CH2:3]1.C1C=CC(OP([O:24][C:25]2C=CC=CC=2)(N=[N+]=[N-])=O)=CC=1.C([N:33](CC)CC)C>C1(C)C=CC=CC=1>[F:11][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([N:33]=[C:25]=[O:24])[CH2:6][CH2:7]1
Reactant: O=C(O)C1CCC(F)(F)CC1
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Product: O=C=NC1CCC(F)(F)CC1

Procedure:
A mixture of 4,4-difluorocyclohexanecarboxylic acid (0.20 g, 1.2 mmol) (Matrix Scientific, Cat. #018320), diphenylphosphonic azide (0.67 g, 2.4 mmol) (Aldrich, Cat. #178756) and triethylamine (0.51 mL, 3.6 mmol) in toluene (10 mL) was refluxed overnight. The volatiles were removed under reduced pressure to afford the product which was directly used for next step reaction without further purification.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].P([O-])([O-])([O-])=O.[NH2:15][C:16]1[CH:17]=[C:18]([S:22]([N:25]2[CH2:30][CH:29]([C:31]([NH2:33])=[O:32])[CH2:28][CH:27]([C:34]([NH2:36])=[O:35])[CH2:26]2)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1.[OH-:37].[Na+]>O1CCOCC1.CN(C)C=O.O>[Cl:3][C:2]1[N:1]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([N:25]3[CH2:30][CH:29]([C:31](=[O:32])[NH2:33])[CH2:28][CH:27]([C:34](=[O:35])[NH2:36])[CH2:26]3)(=[O:24])=[O:23])[CH:17]=2)[N:7]=[C:5]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([N:25]3[CH2:30][CH:29]([C:31](=[O:32])[NH2:33])[CH2:28][CH:27]([C:34](=[O:35])[NH2:36])[CH2:26]3)(=[O:23])=[O:37])[CH:17]=2)[N:4]=1
Reactant: NC(=O)C1CC(C(N)=O)CN(S(=O)(=O)c2cccc(N)c2)C1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: [OH-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: NC(=O)C1CC(C(N)=O)CN(S(=O)(=O)c2cccc(Nc3nc(Cl)nc(Nc4cccc(S(=O)(=O)N5CC(C(N)=O)CC(C(N)=O)C5)c4)n3)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
A solution of cyanuric chloride (280 mg, 1.5 mmol) in dioxane (5 ml) was added with stirring to phosphate buffer (10 ml, 0.3M, pH 7) at 0°-2° C. To the resulting suspension was added dropwise a solution of 1-(3-amino-benzenesulfonyl)piperidine-3,5-dicarboxylic acid diamide (Example 49, 1.0 g, 3.1 mmol) in N,N-dimethylformamide (5 ml) and the pH maintained at 6.5-7.2 by addition of 1N NaOH. After completion of the addition, the reaction mixture was warmed up to 50°-55° C. and stirred at that temperature for 2 h (until HPLC showed the completion of the reaction), then cooled to the room temperature, diluted with water, the product precipitate filtered, washed with cold water (10 ml), acetone (5 ml) and dried under vacuum at 20° C. to give 845 mg (74.2%) of the desired product; m.p.>250° C. dec; MS (ES) m/z 765.0 (M+H), MW 764.2.
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][N:16]4C(=O)C5=CC=CC=C5C4=O)[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.C(O)C>O.NN>[NH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:7]2[S:6][C:5]3[N:4]=[CH:3][CH:2]=[N:1][C:10]=3[NH:9][C:8]=2[CH:11]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc2c(c1)Nc1nccnc1S2
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1ccc2c(c1)Nc1nccnc1S2
Temperature: 80 °C
Yield: 99 %

Procedure:
7.9 g of N-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)phthalimide was suspended in hydrazine monohydrate (10 ml)/ethanol (50 ml) and the reaction mixture was heated to 80° C. for 20 minutes. Then the reaction mixture was brought back to room temperature. After distilling off the solvent under reduced pressure, the residue was distributed into an aqueous solution of potassium carbonate and ethyl acetate. The organic layer was extracted and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue thus obtained was purified by silica gel column chromatography (eluted with dichloromethane/methanol/aqueous ammonia) to thereby give 5.0 g of the title compound as yellow orthorhombic crystals.