Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([O:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17]([C@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:18])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(#N)C>[C:25]1([S:31]([N:21]2[CH2:22][CH2:23][CH2:24][C@H:19]([C:17]([NH:16][C@H:13]3[CH2:12][CH2:11][C@H:10]([O:9][C:6]4[CH:5]=[CH:4][N:3]=[CH:8][CH:7]=4)[CH2:15][CH2:14]3)=[O:18])[CH2:20]2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(N[C@H]1CC[C@H](Oc2ccncc2)CC1)[C@H]1CCCNC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@H](Oc2ccncc2)CC1)[C@H]1CCCN(S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3S)—N-[trans-4-(pyridin-4-yloxy)cyclohexyl]piperidine-3-carboxamide dihydrochloride (28 mg, purity: 40%, 0.03 mmol), benzenesulfonyl chloride (6.3 mg, 0.036 mmol), triethylamine (16 μL, 0.12 mmol) in acetonitrile (1 mL) was stirred at r.t. overnight. the mixture was purified with prep. HPLC. 5.9 mg (45%) of final product was obtained. LCMS: m/z 444.1 (M+H)+; 466.1 (M+Na)+.
Reaction SMILES: [CH3:1][N:2]1[C:12](=[O:13])[C:6]2[S:7][CH2:8][CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=[N:3]1.N1C=CC=CC=1.[N+:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>O>[CH3:1][N:2]1[C:12](=[O:13])[C:6]2[S:7][CH2:8][CH2:9][NH:10][CH:11]([C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:31][CH:30]=3)[C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2c(c1=O)SCCNC2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: O
Product: Cn1ncc2c(c1=O)SCCNC2C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 57.5 °C
Reaction time: 19 h
Yield: 77 %

Procedure:
To a suspension of 0.8 g (4.06 mmol) of 8-methyl-2,3,4,5-tetrahydro-9(8H)-pyridazino[4,5-b][1,5]thiazepinone in 8 ml of anhydrous pyridine 0.99 g (5.33 mmol) of 4-nitrobenzoyl chloride is added, whereafter the suspension is stirred for 18-20 hours at 55-60° C., while adding every 4 hours 0.5 g (2.54 mmol) of 4-nitrobenzoyl chloride. The reaction mixture is poured on 60 ml of icy water and extracted with 3×50 ml of dichloromethane. The organic phase is washed with 2×50 ml of 2 M hydrochloric acid solution, then with 30 ml of saturated sodium hydrogen carbonate solution and 2×60 ml of water. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography. In this way 1.08 g (77%) of the title compound is obtained with a melting point of 230-232° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[C:5]([NH:8][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(Br)cnc(N)c1-c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ncc(Br)c(C)c2-c2cccc(C(F)(F)F)c2)cc1
Temperature: 80 °C
Yield: 86.1 %

Procedure:
To a solution of 5-bromo-4-methyl-3-(3-trifluoromethyl-phenyl)-pyridin-2-ylamine (Int. 1, 1.91 g, 5.77 mmol) in pyridine (25 mL) was added p-toluenesulfonyl chloride (1.75 g, 9.18 mmol) and then the reaction mixture was heated at 80° C. for 23 hrs. The solvent was removed by evaporation in vacuo and then the residue was purified by flash chromatography, eluting with a gradient of 0-30% EtOAc in cyclohexane, to give the title compound as an off-white solid (2.41 g).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:26]=[CH:25][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=O)[CH2:18][CH2:17]3)=[CH:13][CH:12]=2)[CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][CH2:52][C:53]([CH3:56])([OH:55])[CH3:54].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[OH:55][C:53]([CH3:56])([CH3:54])[CH2:52][NH:51][C:22]([CH:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:14]2[CH:25]=[CH:26][C:11]([C@@H:3]3[O:4][C:5]4=[N:6][CH:7]=[CH:8][CH:9]=[C:10]4[O:1][CH2:2]3)=[CH:12][CH:13]=2)[CH2:17][CH2:18]1)=[O:24]
Reactant: CC(C)(O)CN
Reactant: O=C(O)C1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(O)CNC(=O)C1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1

Procedure:
To a solution of Intermediate K (50 mg, 0.14 mmol) in DMA (1 mL) is added HATU (59 mg, 0.16 mmol) followed by 1-amino-2-methyl-propan-2-ol (14 mg, 0.16 mmol) as a solution in DMA (1 mL) and DIEA (0.10 mL, 0.56 mmol) and the mixture stirred at rt overnight. Add water (0.1 mL) and purify by reversed phase HPLC eluting with 10-90% MeCN in water (+0.1% TFA). The concentrated pooled fractions are dissolved in 1:1 methanol/DCE and passed through a carbonate resin cartridge to provide the title compound 255 as a free base. (LC/MS method 16: ES+ m/z 426.5 [M+H]+, Rt=1.48 min)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH:10]([N+:15]([O-:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=1)[CH3:2].[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:20].S(=O)(=O)(O)O.O>C(Cl)Cl>[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH:10]([N+:15]([O-:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:24][CH:23]=1)[CH3:20]
Reactant: CCOc1ccccc1
Reactant: CCCCC(C(O)c1ccc(CC)cc1)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CCCCC(C(c1ccc(CC)cc1)c1ccc(OCC)cc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
25.1 g of 1-p-ethylphenyl-2-nitro-1-hexanol and 14.6 g of ethoxybenzene are dissolved in 80 ml of methylene chloride, and the solution is added dropwise at 0° C, with vigorous stirring, to 90 g of conc. sulphuric acid and 10 ml of water. After 2 hours' stirring at room temperature, the mixture is poured on to 400 ml of ice water. The product is taken up in methylene chloride and washed with saturated sodium bicarbonate solution. After the solvent has been removed by evaporation, the oil remaining behind is dried in high vacuum at 60° C for 2 hours. There is obtained the compound of the formula ##STR7## as viscous, dark yellow oil having a refractive index of nD22 = 1.5452.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:18]2)[CH2:13][CH2:14][NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[O-:33][C:34]#[N:35].[K+]>O>[NH2:35][C:34]([N:15]([CH2:14][CH2:13][C@@H:12]([N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:18]1)[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[OH:16])=[O:33]
Reactant: N#C[O-]
Reactant: CCOc1cc([C@@H](CCNO)N2Cc3cccc(NC(=O)C(C)C)c3C2=O)ccc1OC
Agent: [K+]
Solvent: O
Product: CCOc1cc([C@@H](CCN(O)C(N)=O)N2Cc3cccc(NC(=O)C(C)C)c3C2=O)ccc1OC
Reaction time: 1 h
Yield: 55.6 %

Procedure:
To a solution of (1R)—N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide (1.3 g, 2.6 mmol) in water (30 mL) was added a solution of potassium cyanate (442 mg, 5.5 g) in water (10 mL) at room temperature. After 1 h, the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with HCl (1N, 25 mL), brine (25 mL) and dried over MgSO4. The solvent was removed in vacuo and the residue was purified by prep HPLC to give (1R)—N-{2-[3-(N-aminocarbonyl-N-hydroxy-amino)-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide as a white solid (0.70 g, 55% yield): mp: 137-139° C. 1H NMR (DMSO-d6) δ 1.18 (d, J=7 Hz, 6H, 2CH3), 1.31 (t, J=7 Hz, 3H, CH3), 2.25-2.34 (m, 2H, CH2), 2.51-2.66 (m, 1H, CH), 3.22-3.40 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.95-4.06 (m, 2H, CH2), 4.10 (d, J=18 Hz, 1H, NCHH), 4.55 (d, J=18 Hz, 1H, NCHH), 5.26 (t, J=8 Hz, 1H, NCH), 6.34 (s, 2H, NH2), 6.92-6.98 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.50 (t, J=8 Hz, 1H, Ar), 8.29 (d, J=8 Hz, 1H, Ar), 9.34 (s, 1H, CH), 10.48 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.70, 19.18, 28.73, 35.94, 46.25, 47.22, 52.04, 55.43, 63.76, 111.94, 112.40, 116.55, 117.52, 117.60, 119.58, 131.99, 132.73, 137.12, 142.20, 147.89, 148.43, 161.57, 168.34, 174.93; Anal Calcd for C25H32N4O6+0.9 H2O: C, 59.96; H, 6.80; N, 11.19; H2O, 3.24. Found: C, 60.16; H, 6.58; N, 10.81; H2O, 3.24.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH3:11][C@@H:12]1[NH:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1>>[NH2:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[N:17]1[CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C@@H:12]1[CH3:11]
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1c(N)cnn1C

Procedure:
Following the procedure for Intermediate 10 starting from 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 and (S)-tert-butyl 3-methylpiperazine-1-carboxylate gave (S)-tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate as an orange gum (134 mg, 73% over two steps). LCMS (ES+) m/z 296 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].Cl.[CH2:14]([O:16][C:17](=[O:24])[CH2:18][C:19](OCC)=N)[CH3:15]>CCO>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[N:12]=[C:19]([CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:24])[NH:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: CCOC(=N)CC(=O)OCC
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1nc2ccc(C(=O)OC)cc2[nH]1
Temperature: 25 °C

Procedure:
Methyl 3,4-diaminobenzoate (1 equivalent), was stirred with ethyl-3-ethoxy-3-iminopropanoate hydrochloride (2 equivalents) in EtOH at 70° C. overnight. The reaction mixture was cooled to room temperature, and the EtOH was removed under reduced pressure. The residue was taken up in water and extracted with CH2Cl2 (3×). The organic extracts were dried over Na2SO4, and the solvent was removed. The solid was triturated with Et2O to yield the desired ethyl 2-[5-(methoxycarbonyl)-benzimidazol-2-yl]acetate as an off-white solid. LC/MS m/z: 263.2 (MH+), Rt 1.80 minutes.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1.[Na].CCCCCCC.[C:17]([C:19]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([OH:24])[C:20](OC)=[O:21])#[CH:18]>CO>[C:17]([C:19]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([OH:24])[C:20]([O:8][CH:4]1[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]1)=[O:21])#[CH:18]
Reactant: CN1CCCC(O)C1
Reactant: C#CC(O)(C(=O)OC)c1ccccc1
Agent: [Na]
Solvent: CCCCCCC
Solvent: CO
Product: C#CC(O)(C(=O)OC1CCCN(C)C1)c1ccccc1

Procedure:
1-Methyl-3-piperidinol (3.5 g., 0.03 mole) and a small piece of sodium (~0.05 g.) were refluxed in 150 ml. of n-heptane for about 1 hour in a flask equipped with a small distilling head. Methyl α-ethynyl-α-phenylglycolate (4.0 g., 0.02 mole) was then added intermittently over a one hour period with the temperature of the reaction mixture maintained at 90°. The reaction mixture was heated at 90°-95° for three hours during which time very little methanol was collected. The reaction mixture was subsequently refluxed for 11 hours and the azeotrope collected periodically. During this time sodium methoxide (0.075 g.) was added and 50 ml. of fresh n-heptane was added as an equal volume of distillate was collected simultaneously. These operations were carried out twice. Heating was stopped and a total of 0.3 ml. (38% of theory) of methanol was obtained. As the reaction mixture cooled, an oil settled out. The n-heptane was decanted and the residue was washed with ice water (3×10 ml.). Ether and ice were added to the oil and the mixture worked up as described in Example 12, to yield 1.9 g. (35%) of the product as a yellow oil. Crystallization was effected by dissolving the material in ether, adding 30°-60° petroleum ether to produce turbidity and refrigerating the solution for several days. The product melted at 92°-95° after recrystallization from hexane.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[S:9][CH:10]=[CH:11][C:4]=2[S:3]1(=[O:13])=[O:12].CS(C)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(N(CC)CC)C>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:6]2[C:5]3[S:9][CH:10]=[CH:11][C:4]=3[S:3](=[O:13])(=[O:12])[N:2]([CH3:1])[C:7]=2[OH:8])=[O:27])=[CH:21][CH:20]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: CN1C(=O)Cc2sccc2S1(=O)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1C(O)=C(C(=O)Nc2ccc(Br)cc2)c2sccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.1 G. of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[ 2,3-e] 1,2-thiazine 1,1-dioxide are dissolved in 31 ml. of absolute dimethylsulfoxide under an atmosphere of nitrogen. 1.44 G. of freshly distilled triethylamine and 2.83 g. of 4-bromophenyl isocyanate are added to the solution and the mixture is then stirred for 24 hours at room temperature. This mixture is then poured into 225 ml. of 3-N hydrochloric acid and the precipitate which separates out is filtered on a sinter filter, washed three times with 20 ml. of distilled water each time and dried as much as possible. The precipitate is dissolved in 250 ml. of methylene chloride, dried over sodium sulfate, stirred with activated charcoal and filtered. The organic phase is shaken out four times with 250 ml. of saturated sodium bicarbonate solution each time and the aqueous phase is shaken again each time with a little methylene chloride. The combined aqueous phases are rendered strongly acid with concentrated hydrochloric acid. The product which separates out is extracted three times with 250 ml. of methylene chloride each time. The combined organic phases are dried over sodium sulfate, stirred with activated charcoal, filtered and the solvent is removed by distillation. The crystalline residue is dissolved in 50 ml. of chloroform. While boiling, activated charcoal is added and the mixture is filtered hot. The product is made to crystallize by scratching. The crystals are removed by filtration, digested with a little cold chloroform, and 4'-bromo-3-hydroxy-2-methyl-2N-thieno[[2,3-e] 1,2-thiazine-4-carboxanilide 1,1-dioxide, melting point 178° C. to 179° C. (decomposition), is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][OH:14])=[NH:12])=[CH:6][CH:5]=1)([OH:3])=[O:2].[F:15][C:16]([F:21])([F:20])[C:17](O)=O>O1CCCC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:12]=[C:17]([C:16]([F:21])([F:20])[F:15])[O:14][N:13]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)C(F)(F)F
Reactant: N=C(NO)Nc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Nc2noc(C(F)(F)F)n2)cc1
Temperature: 0 °C
Yield: 62.5 %

Procedure:
In 100 ml of tetrahydrofuran was dissolved 4.0 g of N-(4-carboxyphenyl)-N'-hydroxyguanidine produced in Reference Example 27. To the solution was added, while stirring at 0° C., 6.75 g of anhydrous trifluoroacetic acid. The mixture was stirred for 1.5 hour under the same conditions, followed by concentration under reduced pressure. To the concentrate was added water. The resulting crystalline product was collected by filtration, which was recrystallized from ethyl acetate--hexane to afford 3.5 g of the title compound as a colorless crystalline product.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH3:10]>CO.[Ni]>[NH2:10][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: N
Reactant: O=Cc1ccc(O)cc1
Agent: [Ni]
Solvent: CO
Product: NCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of 4-hydroxybenzaldehyde (10 g, 81.9 mmol) in methanol (45 mL) was added Raney nickel (3 g) and 7N aqueous ammonia solution (45 mL), and the solution was stirred under hydrogen atmosphere (1 atm) at room temperature for 21 hours. The reaction solution was filtered through Celite pad to remove the catalyst, the filtrate was concentrated, and 4-aminomethyl-phenol (10 g, quantitatively) was obtained as a pale green solid.
Reaction SMILES: [C:1]([C:6]1[CH:40]=[C:39]([C:41]([CH2:44][CH3:45])([CH3:43])[CH3:42])[CH:38]=[CH:37][C:7]=1[O:8][CH:9]([CH2:35][CH3:36])[C:10]([NH:12][C:13]1[CH:14]=[C:15]([CH:32]=[CH:33][CH:34]=1)[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:22]2[C:23]([C:30]=1[OH:31])=[CH:24][CH:25]=[CH:26][C:27](=[O:29])[N:28]=2)=[O:17])=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].S(Cl)([Cl:49])(=O)=O.C(OCC)(=O)C.[Cl-].[Na+]>C(Cl)Cl>[Cl:49][C:21]1[C:22]2[C:23](=[CH:24][CH:25]=[CH:26][C:27](=[O:29])[N:28]=2)[C:30]([OH:31])=[C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:32]=[CH:33][CH:34]=[C:13]([NH:12][C:10](=[O:11])[CH:9]([O:8][C:7]3[CH:37]=[CH:38][C:39]([C:41]([CH2:44][CH3:45])([CH3:42])[CH3:43])=[CH:40][C:6]=3[C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])[CH2:35][CH3:36])[CH:14]=2)[CH:20]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cccc(C(=O)Nc2ccc3nc(=O)cccc3c2O)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cccc(C(=O)Nc2cc(Cl)c3nc(=O)cccc3c2O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 30 ml of methylene chloride was dispersed 6 g of the 7-{3-[2-(2,4-di-t-amylphenoxy)butanoylamino]benzoylamino}-6-hydroxybenzazepin-2-one prepared in (6) above, and 0.84 ml of sulfuryl chloride was added drop-wise to the dispersion at room temperature. After stirring at room temperature for 2 hours, ethyl acetate and a saturated aqueous solution of sodium chloride were added thereto to effect extraction. The extract was concentrated under reduced pressure, and the residue was dispersed in 30 ml of acetonitrile and 15 ml of ethyl acetate. The dispersion was heat-refluxed, followed by cooling. The precipitated crystals were collected by filtration and dried to obtain 5.8 g of the desired coupler having a melting point of 234° to 236° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:6]([OH:16])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:36])C=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][S:2]([C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:6]([OH:16])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1)=[O:36]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCCCC1(O)C=C(SC)C(=O)C1=CCCCCCC(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCC1(O)C=C(S(C)=O)C(=O)C1=CCCCCCC(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 12 mg of 2-methylthio-4-hydroxy-5-(6-methoxycarbonylhexylidene)-4-octyl-2-cyclopentenone obtained in Example 101 dissolved in 2 ml of dichloromethane was added 6.5 mg of 3-chloroperbenzoic acid. After the mixture was stirred at 0° C. for 1 hour, saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. After washing with saturated aqueous sodium chloride, the product was subjected to silica gel chromatography to obtain 7.3 mg (yield 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47][C:48]#[N:49]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47][C:48]#[N:49]
Reactant: N#CCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Solvent: CCO
Product: N#CCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Yield: 50.6 %

Procedure:
The preceding Intermediate 1 (compound 6, mixture of α,β-anomer in about 1:2 ratio, 105 g, 156 mmol) was slurried in ethanol (1 L) and heated to reflux with stirring. The reaction mixture was held at reflux for 1 h to ensure that all of solution had homogenized; it was then cooled evenly at 15 t/h to ambient temperature and stirred overnight at this temperature. The resulting solid was isolated by filtration and dried in vacuo to yield the title compound (53 g, 79 mmol, 51%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[O:11][C:12]([CH:15]=O)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:17]([NH:21][OH:22])([CH3:20])([CH3:19])[CH3:18]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9][C:10]2[O:11][C:12]([CH:15]=[N+:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[O-:22])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)NO
Reactant: COc1ccc(Sc2ccc(C=O)o2)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Sc2ccc(C=[N+]([O-])C(C)(C)C)o2)cc1
Yield: 86.2 %

Procedure:
2-(4-Methoxyphenylthio)-5-furaldehyde (24.50 g) was mixed with N-tert-butylhydroxylamine (15.0 g, 168.16 mmol), molecular sieves (100 g) and silica gel (20 g) in CHCl3 (500 mL). The mixture was refluxed overnight under argon gas, and then filtered and concentrated on a rotary evaporator. The residue was recrystallized from hexanes (435 mL) to afford the title compound as yellowish crystals (27.52 g, yield 78.8%), m.p. 91.7° C. (Rf =0.15 on a silica gel plate using hexanes/EtOAc, 2:1, v:v, as the eluant).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][C:21]([OH:25])([C:23]#[CH:24])[CH3:22]>>[F:19][C:3]1[C:2]([C:24]#[C:23][C:21]([OH:25])([CH3:22])[CH3:20])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(C)O
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Yield: 83 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a brown solid (140 mg, 83%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:48](OC(=O)C)(=[O:50])[CH3:49]>CN(C=O)C>[C:48]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)(=[O:50])[CH3:49]
Reactant: NC(=O)c1nnc(N2CCC[C@@H](NC(=O)N3CCCCC3)C2)nc1Nc1ccc(C2CCNCC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(c2ccc(Nc3nc(N4CCC[C@@H](NC(=O)N5CCCCC5)C4)nnc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-5-(4-(Piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide hydrochloride (494) (70 mg, 0.13 mmol) was dissolved in 4 mL DMF. To it were added DIEA (230 μL, 1.30 mmol) and then acetic anhydride (37 μL, 0.39 mmol). The mixture was stirred at RT for 1 hour, quenched with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC to isolate the title compound, (R)-5-(4-(1-acetylpiperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide (497), as HCl salt (47 mg). LC-MS (ESI): m/z (M+1) 550.3. UV: λ=261, 329, 337 nm.