Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([NH2:32])(=[O:31])=[O:30]>C1C=CC=CC=1>[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29](=[O:31])(=[O:30])[NH2:32])=[O:15])=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(C#Cc2ccccc2)cc1
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.7 %

Procedure:
A benzene (30 ml) solution containing 3.00 g (13.5 mmol) of 4-phenylethynylbenzoic acid and 2 ml of thionyl chloride was heated under reflux for 2 hours and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in methylene chloride (30 ml), this solution was added dropwise under ice-cooling to a pyridine (50 ml) solution containing 2.32 g (13.50 mmol) of 2-aminobenzenesulfonamide, the mixture was stirred at room temperature for 18 hours and then methylene chloride was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with a 1 N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was recrystallized from ethyl acetate-hexane to obtain 4.00 g (yield: 78.7%) of the title compound.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].C[O:18][C:19]([CH2:21][CH:22]1[NH:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1)=[O:20].CS(C)=O>O.Cl>[C:31]([O:30][C:28]([N:24]1[CH2:25][CH2:26][N:27]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH:22]([CH2:21][C:19]([OH:20])=[O:18])[CH2:23]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2[N+](=O)[O-])C(CC(=O)O)C1
Temperature: 100 °C
Reaction time: 22 h

Procedure:
Solid K2CO3 (1070 mg, 7.74 mmol) was added to a mixture of 1-fluoro-2-nitrobenzene (655 mg, 4.65 mmol) and the product of Example 22B (1000 mg, 3.87 mmol). Dimethyl sulfoxide (40 mL) was added, and the mixture was heated at 100° C. with stirring under nitrogen. After 22 hours, additional 1-fluoro-2-nitrobenzene (350 mg) was added and heating was continued for 14 hours longer. The mixture was cooled to 40° C., diluted with water (400 mL), and aqueous 10% HCl (25 mL) was added to bring the pH˜3-4. The mixture was extracted with CHCl3 (4×200 mL). The combined extract was concentrated under vacuum to a residue that was purified by chromatography (SiO2, eluted with hexanes-ethyl acetate, 100:0-50:50-0:100) to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.48 (s, 9H), 2.34-2.55 (m, 1H), 2.73-2.90 (m, 1H), 3.20-3.42 (m, 2H), 3.55-3.82 (m, 4H), 3.93-4.12 (m, 1H), 7.13-7.23 (m, 2H), 7.45-7.55 (m, 1H), 7.74 (dd, J=7.9, 1.6 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][C@H:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1.[CH:41]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH2:42].CCO>CC(O)C>[CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][C@H:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:30][CH2:31][N:32]([CH2:42][CH2:41][S:43]([CH3:46])(=[O:45])=[O:44])[CH2:33][CH2:34]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1
Reactant: C=CS(C)(=O)=O
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCNCC2)C4)c(C)c1
Solvent: CC(C)O
Solvent: CCO
Product: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(CCS(C)(=O)=O)CC2)C4)c(C)c1
Temperature: 100 °C
Yield: 77.6 %

Procedure:
A mixture of 2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (3.04 g, 5.6 mmol) and methyl vinyl sulfone (5.94 g, 56 mmol) in a mixed solvent of EtOH (70.0 mL) and 2-propanol (70.0 mL) was heated at 100° C. for 22 h and then evaporated. Chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (190:10:1) afforded title compound (2.82 g, 78%). 1H NMR (DMSO-d6) δ 1.68-1.85 (4H), 2.15 (m, 2H), 2.18 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.75 (m, 2H), 3.05 (m, 2H), 3.08 (s, 3H, CH3), 3.54 (m, 1H), 3.70 (m, 1H), 3.93-4.19 (4H), 4.43 (s, 1H), 4.47 (s, 1H), 5.48 (d, J=6 Hz, 0.5H, NH), 5.53 (d, J=6 Hz, 0.5H, NH), 6.20 (m, 1H), 6.81 (m, 1H), 6.90-6.99 (2H), 7.31-7.37 (1.5H), 7.67 (s, 0.5H), 7.80 (s, 0.5H), 7.94 (s, 0.5H), 11.14 (br d, J=6 Hz, 1H, NH), 11.22 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 649.5 (MH+); Anal. Calcd for C33H40N6O6S: C, 61.09; H, 6.21; N, 12.95; S, 4.94. Found: C, 60.85; H, 6.17; N, 12.87; S, 4.85.
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]([CH2:24][CH2:25][NH:26]C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:17][CH:24]=[CH:25][N:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(NCCNc2ccccc2)cc1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: Cc1ccccc1C
Product: c1ccc(-c2nccnc2-c2ccccc2)cc1
Temperature: 130 °C
Yield: 160.8 %

Procedure:
Bis-phenyl pyrazine was prepared by heating at 130° C. for 12 hrs a suspension of benzoin (Aldrich, 1.25 g) and 1,2 dianilinoethane (Aldrich, 2.13 g) in xylene (20 ml). The mixture was cooled to room temperature and was purified by column chromatography (silicagel, hexane:ethyl acetate, 95:5) to give 2.2 grams of pure bis-phenyl pyrazine as pale yellow solid. NMR: (CDCl3) 7.2-6.8 (20H, m) and 3.6 (4H, s).
Reaction SMILES: F[C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7]C)=[O:5].C(N(C(C)C)CC)(C)C.[CH:22]12[O:29][CH:26]([CH2:27][CH2:28]1)[CH2:25][NH:24][CH2:23]2>CN1C(=O)CCC1>[CH:26]12[O:29][CH:22]([CH2:28][CH2:27]1)[CH2:23][N:24]([C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH2:25]2
Reactant: CCOC(=O)c1cccnc1F
Reactant: C1CC2CNCC1O2
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccnc1N1CC2CCC(C1)O2
Yield: 55.9 %

Procedure:
To a solution of ethyl 2-fluoronicotinate (0.15 g, 0.97 mmol) in NMP (0.5 mL) was added diisopropylethyl amine (0.50 mL, 2.9 mmol), and 8-oxa-3-azabicyclo[3.2.1]octane (0.17 g, 0.72 mmol). The resulting mixture was irradiated with microwaves (100° C.) for 1 h and loaded directly onto a silica column. Eluting the column with EtOAc/hexanes (0-100%) provided methyl 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)nicotinate as a clear oil (0.100 g, 42% yield). MS (ES) for C13H16N2O3: 249 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23]([OH:25])=O)[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH2:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[CH3:35][O:36][CH2:37][CH2:38][NH2:39].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:25])[NH:39][CH2:38][CH2:37][O:36][CH3:35])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH2:33][CH3:34])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCO[C@@H]1CN(c2nc(C(=O)O)c(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Reactant: COCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCCO[C@@H]1CN(c2nc(C(=O)NCCOC)c(C(=O)OCC)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 63 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained in Example (74c) (222 mg, 0.43 mmol), methoxyethylamine (0.1 mL, 1.15 mmol), WSC hydrochloride (260 mg, 1.36 mmol) and HOBT (55 mg, 0.41 mmol), to obtain 154.6 mg of the title compound as a white solid (63%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.[CH3:25][Si:26]([CH3:31])([CH3:30])[CH2:27][C:28]#C>C(NC(C)C)(C)C.ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:11][C:9]1[CH:10]=[C:2]([C:28]#[C:27][Si:26]([CH3:31])([CH3:30])[CH3:25])[CH:3]=[C:4]2[C:8]=1[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: C#CC[Si](C)(C)C
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.7 %

Procedure:
A mixture of 5-bromo-7-chloro-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.210 g, 0.5 mmol), PdCl2(PPh3)2 (0.019 g, 0.05 mmol), and CuI (0.010 g, 0.05 mmol) in diisopropyl amine (4 mL) was treated with trimethyl-prop-2-ynyl-silane (0.141 mL, 1 mmol) and stirred at ambient temperature for 16 h. The reaction mixture diluted with dichloromethane (20 mL) filtered and concentrated. Silica gel column chromatography using 3:1 hexane-ethyl acetate afforded 7-chloro-2-(4-trifluoromethoxy-benzyl)-5-trimethylsilanylethynyl-2,3-dihydro-isoindol-1-one (0.100 g, 46%). GC-MS: 437 (M)+, 356 (M-81)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(COc1cccc(Br)c1)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Into a 3-L three neck round-bottom flask, was placed a solution of 3-bromophenol (50.00 g, 289.0 mmol) in N,N-dimethylformamide (1 L). The system was purged with nitrogen and the solution was cooled to 0° C., then sodium hydride (60%, 12.8 g, 320 mmol) was added portion-wise. To the resulting mixture was added 2-bromo-1,1-diethoxyethane (53.1 mL, 345 mmol) drop-wise at 0° C. The resulting mixture was stirred overnight at 120° C., behind a blast shield (CAUTION: NaH and DMF can become a runaway reaction. All necessary safety precautions were performed). The mixture was cooled to room temperature, then diluted with ethyl acetate (3 L). The mixture was washed with brine (4×500 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/50-1/30) as the eluent to yield the title compound as a light yellow oil (78.9 g, 94%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11](C3N(CC4C=CC(CCC(O)=O)=CC=4)C4C=C(F)C(F)=CC=4N=3)=[CH:10][CH:9]=CN=2)CC1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:46](CC3CCCCC3)[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=2)=[C:38]([O:60][CH2:61]C2C=CC=CC=2Cl)[CH:37]=1.BrCC1CCOCC1>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:46]([CH2:9][CH:10]3[CH2:1][CH2:4][O:5][CH2:6][CH2:11]3)[C:45]3[CH:54]=[C:55]([F:59])[C:56]([F:58])=[CH:57][C:44]=3[N:43]=2)=[C:38]([O:60][CH3:61])[CH:37]=1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3cccnc3OCC3CC3)nc3cc(F)c(F)cc32)cc1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3OCc3ccccc3Cl)n(CC3CCCCC3)c2cc1F
Agent: BrCC1CCOCC1
Product: COc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCOCC1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and 4-bromomethyl-tetrahydro-pyran (CAS Reg. No. 125552-89-8). Light brown solid (29%). MS (Turbo Spray): m/z=393.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7](=[O:16])[C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[N:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[N:3]=1.CC(C)([O-])C.[K+].Cl[C:35](=[O:43])[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>C1COCC1>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][CH2:36][C:35]([NH:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:4]2[N:3]=[C:2]([NH2:1])[N:6]([C:7](=[O:16])[C:8]3[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=3[F:15])[N:5]=2)=[CH:19][CH:20]=1)(=[O:25])=[O:26])=[O:43])[CH3:42]
Reactant: Nc1nc(Nc2ccc(S(N)(=O)=O)cc2)nn1C(=O)c1c(F)cccc1F
Reactant: CCOC(=O)CCC(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)NS(=O)(=O)c1ccc(Nc2nc(N)n(C(=O)c3c(F)cccc3F)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
To a nitrogen purged flask was added 4-[5-amino-1-(2,6-difluorobenzoyl)-1H-[1,2,4]triazol-3-ylamino]-benzenesulfonamide Compound 1a (1.0 g, 2.5 mmol) and THF (100 mL). The mixture was cooled to 0° C. and potassium tert-butoxide (2.8 mL, 1.0 M solu THF) was added dropwise. After addition the mixture was stirred at 0° C. for 1 hr, then ethyl 4-chloro-4-oxobutyrate (0.46 g in 10 mL THF, 2.8 mmol) was added dropwise. The stirring was continued for 30 min, then the mixture was warmed to rt and stirred overnight. After being concentrated, the residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH/9:1) to afford the desired product (200 mg, 15%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.72 (d, 2H), 7.70 (m, 1H), 7.50 (d, 2H), 7.15 (t, 2 H), 4.20 (q, 2H), 3.32 (s, 2H), 2.71 (s, 2H), 1.25 (t, 2H); MS (ESI) m/z: 523 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])/[C:12](=[N:15]\[NH:16][C:17]3[C:18]([OH:32])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29](Cl)=[O:30])[CH:24]=4)[CH:20]=[CH:21][CH:22]=3)/[C:11]([CH3:33])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].N.C[N:36]1C(=O)CCC1.Cl>CCO>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[N:15][NH:16][C:17]3[C:18]([OH:32])=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH2:36])=[O:30])[CH:24]=4)[CH:20]=[CH:21][CH:22]=3)[C:11]([CH3:33])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CN1CCCC1=O
Reactant: CC1=NN(c2ccc(C)c(C)c2)C(=O)/C1=N\Nc1cccc(-c2cccc(C(=O)Cl)c2)c1O
Agent: Cl
Agent: N
Solvent: CCO
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=NNc1cccc(-c2cccc(C(N)=O)c2)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
(Z)-3′-(2-(1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)hydrazinyl)-2′-hydroxybiphenyl-3-carbonyl chloride (5 g, 10.9 mmol) was added portion wise (over one hour) to an NH3/NMP solution (120 mL) and the resulting reaction mixture was cooled to 0° C. The cooled reaction mixture was stirred for one hour, then warmed to room temperature and EtOH (50 mL) was added followed by drop wise addition of 4 M HCl (100 mL). The resulting orange suspension was stirred for half an hour, filtered, washed with 2×50 mL EtOH. The filtered orange crystals were suspended in EtOAc (50 mL) and refluxed for 4 hours, then cooled to room temperature and 20 mL of MeOH/H2O (1/1) were added. the resulting orange suspension was filtrated, washed with MeOH/H2O=1/1 (30 mL) and dried in vacuum oven (0 bar/50° C.) for four hours giving 2.54 g of fluorescent orange crystals of Z)-3′-(2-(1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1H-pyrazol-4(5H)-ylidene)hydrazinyl)-2′-hydroxybiphenyl-3-carboxamide (Yield: 50.9%; HPLC purity: 98%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[O:21])=[CH:14][C:13]=3[N+:35]([O-:37])=[O:36])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[C:38]([OH:44])([C:40](F)(F)F)=[O:39].BrCC(OC(C)(C)C)=O>C(Cl)Cl.C(#N)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH2:40][C:38]([OH:44])=[O:39])[CH2:24][CH2:23]4)=[O:21])=[CH:14][C:13]=3[N+:35]([O-:37])=[O:36])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c([N+](=O)[O-])c2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: CC(C)(C)OC(=O)CBr
Solvent: ClCCl
Solvent: CC#N
Product: O=C(O)CN1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c([N+](=O)[O-])c2)CC1

Procedure:
The title compound was prepared by deprotection of the compound of Example 205 with TFA in CH2Cl2. The resultant free amine was treated with tert-butyl bromoacetate and TEA in acetonitrile at room temperature, and followed by deprotection with TFA in CH2Cl2, giving a light solid, mp 120° C. (dec.). 1H NMR (DMSO-d6, 300 MHz) δ 3.20-3.45 (m, 4H), 4.20 (s, 2H), 3.50-3.80 (m, 4H), 4.28-4.46 (m, 4H), 6.86 (d, J=8.5 Hz, 1H), 7.04 (m, J=8.0 Hz, 1H), 7.09 (dd, J=2.0 8.0 Hz, 1H), 7.15 (d, J=2.0 Hz, 1H), 7.40 (d, J=15.5 Hz, 1H), 7.56 (d, J=15.0 Hz, 1H), 7.90 (dd, J=2.0, 8.5 Hz, 1H), 8.63 (m, 1H). MS (ESI) m/z 484 (M−H)+, 486 (M+H)+. Calcd. Anal for C23H21N3O7S.1.19CF3COOH.1.34H2O: 47.63; H, 4.11; N, 6.89. Found: C, 47.93; H, 4.51; N, 6.49.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C@@H:5]([NH2:7])[CH3:6].[N+:11]([C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[S:23](Cl)(=[O:25])=[O:24])([O-:13])=[O:12].C(N(CC)C(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:5]([NH:7][S:23]([C:15]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:14]=2[N+:11]([O-:13])=[O:12])(=[O:24])=[O:25])[CH3:6])[CH:8]=[CH:9][CH:10]=1
Reactant: C[C@H](N)c1cccc(Br)c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 94.4 %

Procedure:
To a stirred ice-cooled solution of (S)-(−)-3-bromo-α-methylbenzylamine (832 mg, 4.16 mmol, from Chiragene) in 15.6 mL of THF was added 1.33 g (4.99 mmol, 1.20 eq.) of 2,4-dinitrobenzenesulfonyl chloride, followed by 1.08 mL (6.20 mmol, 1.49 eq.) of N,N-diisopropylethylamine. The ice bath was removed, and the mixture was stirred at room temperature for 19 h and then concentrated. The residue was taken up in EtOAc, washed with 2×H2O, dried over Na2SO4, filtered, and concentrated. The residue was sonicated in ca. 5 mL of EtOAc until a precipitate was formed. The mixture was diluted to ca. 25 mL with hexanes. Filtration afforded product as a tan solid (1.69 g, 94.4% yield).
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[CH2:20][O:21][C@H:22]([CH3:31])[C:23](N3CCOCC3)=[O:24])=[CH:14][CH:13]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:32]([C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1)=[O:33].C1C[O:44]CC1.[OH-].[Li+]>CO.O>[CH3:1][C:2]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[CH2:20][O:21][C@H:22]([CH3:31])[C:23]([OH:44])=[O:24])=[CH:16][CH:17]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:32](=[O:33])[C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1
Reactant: Cc1ccc(C(=O)c2c(C)n(Cc3ccc(/C=C/CO[C@H](C)C(=O)N4CCOCC4)cc3)c3ncccc23)cc1
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)c2c(C)n(Cc3ccc(/C=C/CO[C@H](C)C(=O)O)cc3)c3ncccc23)cc1
Yield: 96 %

Procedure:
The compound of Example 74-1 (33 mg, 0.06 mmol) was dissolved in methanol (1 ml) and THF (1 ml) and thereto was added 2N aqueous lithium hydroxide solution (1 ml), followed by stirring under reflux for 8 hours. The mixture was diluted with water and washed with ethyl ether. The aqueous layer was adjusted to around pH 4 with 5% aqueous potassium hydrogen sulfate solution and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to give the subject compound (28 mg, 96%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH:29][CH3:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(N(CC)CC)C>O1CCCC1>[CH2:11]([N:29]([CH3:30])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCCCNC
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCN(C)c1ccc([N+](=O)[O-])cc1

Procedure:
Dissolve 28.2 g (0.2 mol) p-fluoronitrobenzene into 300 ml tetrahydrofuran. Add a solution of which 56.4 g (0.2 mol) N, N-octadecylmethylamine and 20.3 g (0.2 mol) triethylamine are dissolved in 300 ml tetrahydrofuran into the above solution, while stirring. After the completion of the adding heat and reflux it for four days. 60.6 g (0.15 mol) N, N-octadecylmethyl-p-nitroaniline is obtained by recrystalization of the solution using ethyl alcohol and water after concentrating the above solution.
Reaction SMILES: [OH:1][N:2]1[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[NH:10][C:9](=[O:17])[C:3]21[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N12CCN(CC1)CC2>C1C=CC=CC=1>[OH:1][N:2]1[C:11]2([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[N:10]([C:25](=[O:26])[NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9](=[O:17])[C:3]21[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2
Reactant: O=C=Nc1ccccc1
Reactant: O=C1NC2(CCCCC2)N(O)C12CCCCC2
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1)N1C(=O)C2(CCCCC2)N(O)C12CCCCC2
Reaction time: 18 h

Procedure:
3.6 Parts of 7-oxyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one (prepared from 7,14-diazadispiro[5.1.5.2]pentadecan-15-one by oxidation with hydrogen peroxide and sodium tungstate), 2.1 parts of phenyl isocyanate and a trace of 1,4-diazabicyclo[2.2.2]octane in 75 parts of dry benzene were heated at reflux for 18 hours. The solvent was evaporated in vacuo and the residue allowed to stand in 100 parts of water for 18 hours. The mixture was extracted thoroughly with chloroform and the extract washed with brine and dried over magnesium sulphate. Evaporation in vacuo afforded a solid material which was chromatographed on an alumina column to yield 7-oxyl-14-phenylcarbamoyl-7,14-diazadispiro[5.1.5.2]-pentadecan-15-one as pale red crystals of melting point 125° to 128°C. This material had the following elemental analysis by weight:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][N:17]=[C:16]4[C:19]5[C:24]([CH2:25][CH2:26][C:15]=34)=[CH:23][C:22]([CH2:27][OH:28])=[CH:21][CH:20]=5)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:28][CH2:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[C:16]1=[N:17][O:18][C:14]([CH:11]3[CH2:12][CH2:13][CH:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)=[C:15]1[CH2:26][CH2:25]2)(=[O:39])=[O:38]
Reactant: OCc1ccc2c(c1)CCc1c-2noc1C1CCC(c2ccc(Cl)cc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc2c(c1)CCc1c-2noc1C1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of the (3-(4-(4-chlorophenyl)cyclohexyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methanol (Preparation 27D, 0.046 g, 0.118 mmol) in dichloromethane (2.0 mL) at room temperature was added triethylamine (0.049 mL, 0.354 mmol) followed by methanesulfonyl chloride (0.014 mL, 0.177 mmol). The reaction mixture was stirred for 1 h at room temperature, concentrated under reduced pressure to yield (3-(4-(4-chlorophenyl)cyclohexyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl methanesulfonate.