Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)(C)C.C(O[C:9]([C:11]1[C:12]([CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[N:13][O:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[O:10])C.Cl.[CH3:32][NH:33][O:34][CH3:35]>C1COCC1>[CH3:35][O:34][N:33]([CH3:32])[C:9]([C:11]1[C:12]([CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[N:13][O:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[O:10]
Reactant: CNOC
Reactant: CCOC(=O)c1c(COC2CCCCO2)noc1-c1ccccc1Cl
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1c(COC2CCCCO2)noc1-c1ccccc1Cl
Yield: 14.8 %

Procedure:
Add 2M iso-propylmagnesium chloride (717 mL, 1.4 mol) to a −10° C. solution of 5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carboxylic acid ethyl ester (175 g, 478 mmol) and N,O-dimethylhydroxylamine hydrochloride (56 g, 574 mmol) in THF (2 L). Stir the reaction for 45 min. and then slowly quench with a 1:1 mixture of sat. NH4Cl and water (750 mL). Extract the mixture with EtOAc (3×500 mL). Wash the organic phase with brine (1000 mL), dry over Na2SO4, filter, and concentrate under reduced pressure. Purification by flash chromatography (silica gel, 7:3 hexanes/EtOAc) gives the title compound (27 g, 52%). MS (m/e): 381 (M+H)+; m.p.=51–56° C.; 1H NMR (300 MHz, CDCl3) δ7.32–7.60 (m, 4H), 5.00 (d, J=14 Hz, 1H), 4.78–4.81 (m, 1H), 4.73 (d, J=14 Hz, 1H), 3.85–3.98 (m, 1H), 3.52–3.61 (m, 1H), 3.40 (s, 3H), 3.10–3.29 (m, 3H), 1.50–1.82 (m, 6H); HPLC >99%; TLC Rf=0.41 (1:1 Hexanes/EtOAc).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([N:13]2[C:17]([SH:18])=[N:16][N:15]=[N:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29]2[C:24](=[CH:25][C:26]([N+:30]([O-:32])=[O:31])=[CH:27][CH:28]=2)[C:22](=[O:23])[O:21]1.[Cl-].[NH4+]>CN(C)C=O>[C:7]1([N:13]2[C:17]([S:18][C:20]3([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:29]4[C:24](=[CH:25][C:26]([N+:30]([O-:32])=[O:31])=[CH:27][CH:28]=4)[C:22](=[O:23])[O:21]3)=[N:16][N:15]=[N:14]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1OC(Cl)(c2ccccc2)c2ccc([N+](=O)[O-])cc21
Reactant: Sc1nnnn1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1OC(Sc2nnnn2-c2ccccc2)(c2ccccc2)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 20 ml of thionyl chloride was added 25 g of 2-benzoyl-5-nitrobenzoic acid. The mixture was heated and stirred for 3 hours on the oil bath kept at a temperature of 60° C. Excess thionyl chloride was distilled away under reduced pressure, and 27.5 g of 3-chloro-4-phenyl-6-nitrophthalide was obtained as a brown oily substance. Separately, 4.48 g (0.04 mol.) of potassium tert-butoxide and 5.34 g (0.03 mol.) of 1-phenyl-5-mercaptotetrazole were added to 200 ml of dried dimethylformamide, and stirred for 20 minutes at room temperature. The resulting mixture was cooled to 5° C. and thereto, was added dropwise gradually the previously prepared solution containing 9.0 g (0.03 mol.) of 3-chloro-3-phenyl 6-nitrophthalide in 75 ml of dried dimethylformamide as the mixture was maintained at 5° C. After the conclusion of the dropwise addition, the reaction mixture was stirred for 30 minutes at 5° C. and further, for 2 hours at room temperature. Thereto, 200 ml of a saturated aqueous solution of ammonium chloride was added. The reaction mixture was extracted with ethyl acetate repeatedly. The extract was washed with water, and the resulting organic layer was dried over anhydrous sodium sulfate. Sodium sulfate was filtered off with suction, and the filtrate was concentrated to yield 9.2 g of crude crystals. These crude crystals were separated and purified by flash column chromatography (silica gel: 400 g, eluate: hexane-ethyl acetate (3:1 by volume) mixture). Thus, the intended compound, 3-(1-phenyltetrazole-5-ylthio)-3-phenyl-6-nitrophthalide (4), was obtained. It was recrystallized from an ethyl acetate-hexane mixture. Yield 5.5 g, Melting Point 176° to 179° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.N1C=CC=CC=1.[C:28](Cl)(=[O:30])[CH3:29].O>ClCCl.C(OCC)C>[C:28]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: COc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2NC(C)=O)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3-amino-6-chloro-2-(3-methoxybenzoyl)indole (Example 18, 413 mg, 1.37 mmol) in dichloromethane (20 ml) was added pyridine (0.33 ml, 4.12 mmol) and acetyl chloride (0.14 ml, 2.06 mmol). After stirring for 0.5 h, water (1 ml) and diethyl ether (100 ml) were added, and the mixture washed consecutively with 1N aqueous HCl (50 ml×2) and saturated aqueous sodium bicarbonate (50 ml×2). The organic layer was dried (MgSO4) and solvent removed. The resultant residue was purified by flash chromatography eluting with ethyl acetate/hexane (1:2) to afford the title compound as an oil. Crystallization from ethanol/hexane to give 260 mg (55%) of title compound. m.p.: 161-162° C. 1H-NMR (CDCl3) δ: 9.92 (1H, br s), 8.32 (1H, br s), 8.22 (1H, d, J=9.2 Hz), 7.47 (1H, dd, J=7.7 and 8.1 Hz), 7.37-7.26 (3H, m), 7.18-7.08 (1H, m), 7.10 (1H, dd, J=1.6 and 9.0 Hz), 3.88 (3H, s), 2.25 (3H, s)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:15][CH:14]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH:28]1([C:31]2[NH:32][C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[N:35]=2)[CH2:30][CH2:29]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:28]1([C:31]2[N:32]([C:2]3[N:3]=[C:4]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:5]4[N:10]=[C:9]([CH2:11][N:12]5[CH2:13][CH:14]([CH:16]6[CH2:21][CH2:20][O:19][CH2:18][CH2:17]6)[CH2:15]5)[S:8][C:6]=4[N:7]=3)[C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[N:35]=2)[CH2:30][CH2:29]1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)sc2n1
Reactant: c1ccc2[nH]c(C3CC3)nc2c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: c1ccc2c(c1)nc(C1CC1)n2-c1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)sc2n1
Temperature: 145 °C

Procedure:
A mixture of 5-chloro-7-morpholin-4-yl-2-[3-(tetrahydropyran-4-yl)azetidin-1-ylmethyl]thiazolo[5,4-d]pyrimidine (90 mg, 0.22 mmol), 2-cyclopropylbenzimidazole (42 mg, 0.26 mmol), tris(dibenzylideneacetone)dipalladium (10 mg, 0.01 mmol), Xphos (21 mg, 0.04 mmol) and Cs2CO3 (143 mg, 0.44 mmol) in dioxane (2.5 mL) was purged with argon then heated at 145° C. for 30 min in a microwave reactor. The reaction mixture was filtered through a pad of celite, washing with EtOAc. The filtrate was concentrated in vacuo and purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-7%). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 484 as an orange solid (83 mg, 71%). LCMS (Method I): RT 2.89 min, [M+H]+ 532.2. 1H NMR (CDCl3, 400 MHz): δ 7.94-7.89 (m, 1 H); 7.69-7.65 (m, 1 H); 7.26-7.20 (m, 2 H); 4.43 (m, 4 H); 3.99 (m, 4 H); 3.87 (m, 4 H); 3.61 (m, 2 H); 3.38 (m, 2 H); 3.10 (m, 2 H); 2.89-2.82 (m, 1 H); 2.36 (m, 1 H); 1.71 (m, 1 H); 1.56 (m, 2 H); 1.37-1.31 (m, 2 H); 1.30-1.18 (m, 2 H) and 1.10-1.04 (m, 2 H)
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])([O-:14])=O.O>CO.C(O)(=O)C>[OH:14][N:12]=[C:15]1[CH:20]=[CH:19][C:18](=[C:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:10]#[N:11])[CH:17]=[C:16]1[CH3:21]
Reactant: Cc1ccccc1[N+](=O)[O-]
Reactant: N#CCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC1=CC(=C(C#N)c2ccccc2)C=CC1=NO
Temperature: 55 °C
Reaction time: 4 h

Procedure:
39.6 g of KOH (0.6 mol, assay 85%) are dissolved in 200 ml of methanol and heated up to 55° C. To the solution are added 23.4 g (0.20 mol) of phenylacetonitrile, followed by 25 g (0.18 mol) of o-nitrotoluene. The dark red reaction mixture is stirred at 55° C. for 4 hrs. After cooling, the mixture is poured into 500 ml of water, and acidified by addition of 60 ml of acetic acid. The resulting orange precipitate is filtered, washed with water, methanol:water 1:1 (v/v), and dried under vacuum. The crude product (16.8 g, 40%) has a melting point of 161-164° C. (dec) (Lit: 161° C. dec; J. Org. Chem. 26, 4270, 1961) and is used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][CH:13]=[CH:14][N:15]=2)[CH:8]=[CH:7][C:6]=1[C:16]1[C:17]([S:22]([NH:25][C:26]2[O:30][N:29]=[C:28]([CH3:31])[C:27]=2[CH3:32])(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C.[F:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](Cl)=[O:45]>>[CH3:31][C:28]1[C:27]([CH3:32])=[C:26]([NH:25][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[O:12][CH:13]=[CH:14][N:15]=3)=[CH:10][C:5]=2[CH2:4][N:3]([CH3:2])[C:44](=[O:45])[C:43]2[CH:47]=[CH:48][CH:49]=[C:41]([F:40])[CH:42]=2)(=[O:24])=[O:23])[O:30][N:29]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CNCc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CN(C)C(=O)c2cccc(F)c2)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2'-[(methylamino)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide, monohydrochloride (25 mg, 0.053 mmol, prepared as described in Step (A) of Example 28), triethylamine (13.3 mg, 0.13 mmol) was added and followed by 3-fluorobenzoyl chloride (8.3 mg, 0.053 mmol). The reaction was stirred at room temperature overnight and concentrated. The residue was purified by preparative HPLC on an ODS S10 column using 29% solvent A (10% MeOH, 90% H2O, 0.1% TFA) and 71% solvent B (90% MeOH, 10% H2O, 0.1% TFA) to provide the title compound of this Example (18 mg, 61%) as a white solid, m.p. 125°-135° C. (amorphous).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[CH:30])=[N:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]#[C:30][C:2]3[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[CH:4][CH:3]=3)=[N:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: Ic1ccc(C#CCN2CCCC2)cc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(C#CCN4CCCC4)cc3)nc2)cc1

Procedure:
Prepared according to general working method I from 1-[3-(4-iodo-phenyl)-prop-2-ynyl]-pyrrolidine (230 mg, 75%, 0.55 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (118 mg, 0.55 mmol).
Reaction SMILES: [N:1]([C:4]1[C:21](=[O:22])[CH2:20][CH2:19][C@@:18]2([CH3:23])[C:5]=1[CH2:6][CH2:7][C@@H:8]1[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]1[CH2:10][CH2:11][C:12]2=[O:24])=[N+]=[N-].[N-]=[N+]=[N-].[Na+]>CN(C)C=O>[NH2:1][C:4]1[C:21](=[O:22])[CH2:20][CH2:19][C@@:18]2([CH3:23])[C:5]=1[CH:6]=[CH:7][C@@H:8]1[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]1[CH2:10][CH2:11][C:12]2=[O:24]
Reactant: C[C@]12CCC(=O)C(N=[N+]=[N-])=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]12CCC(=O)C(N)=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 74.4 %

Procedure:
A mixture of 0.125 g of 4-azidoandrost-4-en-3,17-dione in 10 ml of dimethylformamide and 0.4 ml of a 1N sodium azide aqueous solution is stirred and heated at 90°-100° C. for 30 minutes, during which time the evolution of nitrogen is observed. After cooling the reaction mixture is worked up as described in the example 1. There are obtained 0.085 g of the title compound, m.p. 147°-149° C. (dec.).
Reaction SMILES: [CH2:1]([S:13]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])=[CH:21][CH:20]=1)(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([S:13]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]/[CH:26]=[C:27](\[O:32][C:40](=[O:42])[CH3:41])/[C:28]([F:29])([F:30])[F:31])=[CH:21][CH:20]=1)(=[O:14])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCS(=O)(=O)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCS(=O)(=O)CCOc1ccc(C/C=C(\OC(C)=O)C(F)(F)F)cc1
Temperature: -25 °C
Reaction time: 2.5 h
Yield: 78.5 %

Procedure:
A solution of 4-[4-[2-(dodecylsulfonyl)ethoxy]phenyl]-1,1,1-trifluoro-2-butanone (1.10 g, 2.30 mmol) in dichloromethane (15 ml) was cooled to −25° C. and treated with triethylamine (0.5 ml) and 4-dimethylaminopyridine (0.560 g, 4.58 mmol). Then acetic anhydride (0.65 ml, 6.9 mmol) was added and the resulting mixture was stirred at −25° C. for 2.5 h. The solution was then diluted with ethyl acetate, washed with saturated sodium bicarbonate, dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica gel (elution toluene-ethyl acetate, 9:1) to give 0.94 g (78%) of a solid which was recrystallized from hexane to give white crystals: mp 48-49° C.
Reaction SMILES: [C:1]([CH:6]([NH:15][CH2:16][C:17]([N:19]1[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][C:21]2([CH2:25][S:24][CH2:23][CH2:22]2)[CH2:20]1)=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:3]CC)=[O:2].[OH-].[Na+]>>[C:1]([CH:6]([NH:15][CH2:16][C:17]([N:19]1[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][C:21]2([CH2:25][S:24][CH2:23][CH2:22]2)[CH2:20]1)=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)C(CCc1ccccc1)NCC(=O)N1CC2(CCSC2)C[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(CCc1ccccc1)NCC(=O)N1CC2(CCSC2)C[C@H]1C(=O)O

Procedure:
As described in Example 48, hydrolyse 7-[N-(1-carboethoxy-3-phenylpropyl)glycyl]-2-thia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid (prepared as described in Example 58 with sodium hydroxide to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([Cl:35])=[C:30]([CH:34]=1)[C:31](Cl)=[O:32].C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([Cl:35])=[C:30]([CH:34]=1)[C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:32]
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3cc(Br)ccc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 23.7 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (20 mg, 0.063 mmol) obtained in Example 1, (3), and 5-bromo-2-chlorobenzoyl chloride (0.0945 mmol), the title compound (8 mg, yield 24%) was obtained as pale yellow crystals in the same manner as that of Example 1, (4).
Reaction SMILES: [C:1]1([CH3:48])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:13][CH:12]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([O:44]CC)=[O:43])[CH:37]=3)=[O:34])[C:11]2=[O:47])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[C:1]1([CH3:48])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:13][CH:12]([NH:32][C:33](=[O:34])[NH:35][C:36]3[CH:37]=[C:38]([CH:39]=[CH:40][CH:41]=3)[C:42]([OH:44])=[O:43])[C:11]2=[O:47])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)OCc3ccccc3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C(=O)OCc1ccccc1
Yield: 72.3 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-benzyloxycarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (435 mg) was dissolved in methanol (20 ml), aqueous lithium hydroxide monohydrate (141 mg) solution (10 ml) and tetrahydrofuran (10 ml) were added, the mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (150 ml), washed with diethyl ether (100 ml), acidified with 1N hydrochloric acid, and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, n-hexane was added to the residue for trituration, and collected by filtration, to thereby obtain 301 mg of the titled compound (Yield: 72.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23](=[N:29]O)[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[O:11][N:29]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:22]=2)=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: O=C(O)Cc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc(Cc2ccc(F)cc2C(F)(F)F)n1
Yield: 10.5 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-(4-fluoro-2-(trifluoromethyl)phenyl)acetic acid (0.420 g; 1.89 mmol) and oxalyl chloride (0.176 mL; 2.08 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.250 g; 1.89 mmol) and N,N diisopropylethylamine (0.527 mL; 3.03 mmol) in dichloromethane (10 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.063 g (10%) of ethyl 5-(4-fluoro-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.
Reaction SMILES: [C:1]([S:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[CH3:16])[C:12]([CH3:18])([CH3:17])[CH2:11][CH2:10][C:9]2([CH3:20])[CH3:19])(=[O:5])=[O:4])#[CH:2].[C:21]([O:26][CH2:27][CH3:28])(=[O:25])[C:22]#[C:23][CH3:24]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:24][C:23]([C:2]#[C:1][S:3]([C:6]1[C:15]([CH3:16])=[CH:14][C:13]2[C:12]([CH3:18])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:20])([CH3:19])[C:8]=2[CH:7]=1)(=[O:5])=[O:4])=[CH:22][C:21]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CC#CC(=O)OCC
Reactant: C#CS(=O)(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(C)C#CS(=O)(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Yield: 11.9 %

Procedure:
In a manner similar to that of Example 5(c), by reaction of 6-ethynylsulphonyl-1,1,4,4,7-pentamethyl-1,2,3,4-tetrahydronaphthalene (2.08 g, 151 mmol) in 60 ml of toluene with Pd(OAc)2 (70 mg, 0.3 mmol), TDMPP (140 mg) and ethyl 2-butynoate (2.05 g, 20.9 mmol), 1 g (27%) of the expected ester is obtained in the form of a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH:24]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][N:26]2[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[C@H:24]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:25]2)[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1c1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)C[C@H]1c1ccccc1

Procedure:
Intermediate 1 was coupled with 2-phenyl-piperazine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 465.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]2[CH2:16][C@@H:17](OS(C)(=O)=O)[CH2:18][CH2:19][C:7]=12)[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+].CCN(CC)CC.N#N>O.CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:14]2[C:9](=[C:10]([F:15])[CH:11]=[CH:12][CH:13]=2)[N:8]2[CH2:16][C@H:17]([N:26]=[N+:27]=[N-:28])[CH2:18][CH2:19][C:7]=12)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)Cc1c2n(c3c(F)cccc13)C[C@@H](OS(C)(=O)=O)CC2
Agent: N#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c2n(c3c(F)cccc13)C[C@H](N=[N+]=[N-])CC2
Temperature: 68 °C
Reaction time: 18 h

Procedure:
A reaction mixture of the mesylate of Step 7 (1.67 kg, 4.32 mol), DMF (8.35 L), NaN3 (0.457 kg, 7.03 mol) and Et3N (65 ml, 0.466 mol) under a constant stream of N2 was maintained between 66-70° C. After 18 h, the mixture was cooled to room temperature and H2O (8.45 L) was slowly added with vigorous stirring. The reaction mixture was filtered; the crystals were washed with 1:1 DMF:H2O (16 L), 3:7 DMF:H2O (8.5 L), and water (14 L). The dark brown solid was dried under vacuum and nitrogen.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)(=[O:5])=[O:4].[OH-].[Na+]>C(O)C.Cl>[F:16][C:2]([F:1])([F:17])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reaction time: 3 h

Procedure:
The 4-(trifluoromethylsulfonyloxy)-1-nitrobenzene (27.1 grams; 0.10 mole) in 300 ml of ethanol was added dropwise to 94.8 grams of stannous chloride (0.5 mol; 5 equivalents) in 525 ml of concentrated HCl, at room temperature. The rate of addition was controlled to prevent the temperature of the reaction mixture from rising. The reaction mixture was stirred for 3 hours, 10N NaOH added until the pH was ~12, and extracted into ether. The ether extract was washed with water, dried over magnesium sulfate, and the ether evaporated to yield the desired 4-(trifluoromethylsulfonyloxy)aniline as a yellowish brown oil. Its identity was confirmed by NMR, MS, and elemental analysis, the last of which showed: