Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][SH:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:18](Br)[CH3:19].[OH-].[K+]>CO>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][S:15][CH2:18][CH3:19])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCBr
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CS)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCSCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
4-chloro-4'-mercaptomethylbenzophenone (16.0 g), ethyl bromide (7.4 g) and potassium hydroxide (4.3 g) were added to methanol (250 ml), and the mixture was stirred for 30 minutes under reflux. The reaction mixture was cooled to room temperature and then concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1) to obtain the desired product 14.0 g, melting point: 33° to 34° C., yield: 79%).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([OH:13])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:30]=[C:29]([Cl:31])[C:28]([I:32])=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24].C(N(CC)CC)C>ClCCl.CN(C=O)C>[Cl:31][C:29]1[C:28]([I:32])=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([NH:20][C:11](=[O:13])[CH2:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])[CH:30]=1
Reactant: COC(=O)c1cc(I)c(Cl)cc1N
Reactant: O=C(O)CS(=O)(=O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)c(Cl)cc1NC(=O)CS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of 2-(phenylsulfonyl) acetic acid (Lancaster Synthesis Ltd., 0.771 mg, 3.85 mmol) in dichloromethane (50 mL) was added oxalyl chloride (4.17 mL, 4.17 mmol) and few drops of DMF. The reaction mixture was stirred 2 hours at room temperature. To a solution of methyl 2-amino-4-chloro-5-iodobenzoate (Intermediate 2) (1 g, 3.21 mmol) and triethylamine (1.074 mL, 7.70 mmol) in dichloromethane (50 mL) at RT was added dropwise the acid chloride prepared above. The reaction mixture was stirred at room temperature overnight then quenched with aqueous solution of NaHCO3. The organic layer was and washed with saturated NaHCO3, water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound methyl 4-chloro-5-iodo-2-(2-(phenylsulfonyl)acetamido)benzoate (1.1 g, 2.228 mmol, 69.4% yield) as pale yellow powder. LCMS: (M+H)+=494; Rt=3.58 min.
Reaction SMILES: CO.[CH2:3]([N:10]([CH2:29][CH2:30][C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:11][CH2:12][C:13]1[CH:28]=[CH:27][C:16]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=2)=[CH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BH4-].[Na+]>[Cl-].[Na+].O>[CH2:3]([N:10]([CH2:29][CH2:30][CH:31]([OH:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:11][CH2:12][C:13]1[CH:28]=[CH:27][C:16]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=2)=[CH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NC(=O)c1ccc(Oc2ccc(CCN(CCC(=O)c3ccccc3)Cc3ccccc3)cc2)nc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(CCN(CCC(O)c3ccccc3)Cc3ccccc3)cc2)nc1
Temperature: 0 °C
Yield: 12.7 %

Procedure:
Add methanol (10 mL) to 6-(4-{2-[benzyl-(3-oxo-3-phenyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide (0.1871 g, 0.3901 mmol) and cool to 0° C. Add sodium borohydride (0.0664 g, 1.756 mmol) and stir for 1.5 h at (0° C. under nitrogen. Pour the reaction into brine (50 mL) and extract with diethyl ether (3×50 mL). Dry the diethyl ether extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 100% ethyl acetate to yield 0.0239 g (13%) of 6-(4-{2-[benzyl-(3-hydroxy-3-phenyl-propyl)-amino]-ethyl}-phenoxy)-nicotinamide: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 8.07 minutes, Purity: 99.9%; mass spectrum (ion spray): m/z=482.3 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=[O:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:13][Mg+].[Br-].[NH4+].[Cl-]>CCOCC>[C:4]([O:3][C:1]([N:8]1[CH2:11][C:10]([OH:12])([CH3:13])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84 %

Procedure:
A solution of 1-Boc-azetidin-3-one (3.5 g, 20 mmol) in 50 mL and Et2O was cooled to 0° C. and 3M MeMgBr in Et2O (10 mL, 30 mmol) was added dropwise over 1 h. After 45 min, the reaction was allowed to warm to rt and stir an additional for 18 h. Then ½ sat'd NH4Cl (aq.) was added and the mixture extracted with EtOAc (2×). The combined organic layers were dried and the resulting semisolid was purified by RP HPLC (Agilent) to give the title compound as a white solid (3.2 g, 84%). 1H NMR (CDCl3): 3.84 (q, J=9.2 Hz, 4H), 1.97 (bs, 1H), 1.52 (s, 3H), 1.44 (m, 9H).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[CH2:18]([S:22](Cl)(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21]>C1C=CC=CC=1>[CH2:18]([S:22]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21]
Reactant: On1nnc2ccccc21
Reactant: CCCCS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)On1nnc2ccccc21
Reaction time: 4 h
Yield: 96.7 %

Procedure:
In benzene (50 ml) are dissolved 1-hydroxy-1,2,3-benzotriazole (6.8 g) and triethylamine (7.0 ml) and thereto is added dropwise a solution of n-butanesulfonyl chloride (7.8 g) in benzene (10 ml) at room temperature and the mixture is stirred for 4 hours. After the reaction, the benzene layer is separated, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give 1-(n-butanesulfonyloxy)-1,2,3-benzotriazole (12.3 g) as an oily substance. Infrared spectrum (film): 1395, 1175 cm-1.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:11][C:10]2[CH2:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[CH2:14][C:9]=2[CH2:8]1)=[O:6].[C:30]1([CH2:36][CH2:37][NH2:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:37]([NH:38][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([N:13]2[CH2:12][C:10]3[CH2:11][N:7]([C:5](=[O:6])[C:4]4[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=4[C:2]([F:29])([F:1])[F:28])[CH2:8][C:9]=3[CH2:14]2)=[N:16][CH:17]=1)[CH2:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Reactant: NCCc1ccccc1
Product: O=C(NCCc1ccccc1)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Yield: 45 %

Procedure:
6-[5-(2-Trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]nicotinic acid (50 mg, 0.124 mmol) was reacted with 2-phenylethylamine analogously to example 3d. Yield: 45%, M+H+: 507.28.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C(N(C(C)C)CC)(C)C.[CH2:23]([O:25][C@@H:26]([CH2:31][C:32]1[CH:33]=[N:34][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([NH:44][CH3:45])[CH:39]=2)=[CH:36][CH:37]=1)[C:27]([O:29][CH3:30])=[O:28])[CH3:24].O>ClCCl>[CH2:23]([O:25][C@@H:26]([CH2:31][C:32]1[CH:33]=[N:34][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([N:44]([CH3:45])[C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[CH:39]=2)=[CH:36][CH:37]=1)[C:27]([O:29][CH3:30])=[O:28])[CH3:24]
Reactant: CCO[C@@H](Cc1ccc(-c2cccc(NC)c2)nc1)C(=O)OC
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCO[C@@H](Cc1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)nc1)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
70 mg (0.3 mmol) of 4-nitrophenyl chloroformate and then 60 μl (0.3 mmol) of diisopropylethylamine are added to a solution of 70 mg (0.25 mmol) of methyl 2(S)-ethoxy-3-[6-(3-methylaminophenyl)pyrid-3-yl]propanoate in 3 ml of dichloromethane. The reaction medium is stirred at room temperature for 2 hours. After addition of water, the reaction medium is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated. 110 mg (100%) of methyl 2(S)-ethoxy-3-(6-{3-[methyl(4-nitrophenoxycarbonyl)amino]phenyl}pyrid-3-yl)propanoate are obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:7]1[CH:12]=[CH:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]1=[O:15])[CH:4]([CH3:6])[CH3:5].C1(C)C=CC(S([CH2:25][N+:26]#[C-:27])(=O)=O)=CC=1>C1COCC1>[CH2:3]([N:7]1[C:12]2=[CH:25][NH:26][CH:27]=[C:11]2[C:10](=[O:13])[N:9]([CH3:14])[C:8]1=[O:15])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)Cn1ccc(=O)n(C)c1=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c[nH]cc21
Temperature: 25 °C

Procedure:
Sodium hydride (95%, 1.74 g, 69 mmol) is suspended in 20 mL of anhydrous THF, and then a mixture of 1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione (approx. 23 mmol) and p-toluenesulfonylmethyl isocyanide (97%, 7.0 g, 35 mmol) in 20 mL of anhydrous THF is added dropwise over 80 minutes at 0° C. The mixture is stirred at room temperature for an hour after the completion of the addition, and then carefully quenched with water. The mixture is diluted with 50 mL of saturated NaHCO3, and then extracted with CH2Cl2 five times. The combined organic phase is washed with brine, and then dried with anhydrous Na2SO4. After filtration, the filtrate is evaporated to dryness under reduced pressure to give product as light brown solids, which is used for the next reaction without further purification. MS (ESI) m/z 222.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:22]([CH2:24][CH3:25])=[O:23])=[C:4]([C:8]2[N:20]([CH3:21])[C:11]3=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(=[O:28])C.OO>O>[Cl:1][C:2]1[C:3]([S:22]([CH2:24][CH3:25])(=[O:28])=[O:23])=[C:4]([C:8]2[N:20]([CH3:21])[C:11]3=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCS(=O)c1c(Cl)cccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Reactant: CC(=O)O
Agent: OO
Solvent: O
Product: CCS(=O)(=O)c1c(Cl)cccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 80 °C

Procedure:
A mixture of 2-(3-chloro-2-ethylsulfinylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.48 g) and acetic acid (12 ml) was stirred with heating at 80° C., and then 30% of an aqueous solution of hydrogen peroxide (6 ml) was added dropwise. The mixture was heated to 100° C., and stirred with heating for 3 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.21 g of 2-(3-chloro-2-ethylsulfonylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 90).
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[S:4].[C:6]([CH2:14][C:15](OCC)=[O:16])(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[SH:4][C:3]1[N:5]=[C:15]([OH:16])[CH:14]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:2]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: [Na]
Solvent: CCO
Product: Oc1cc(-c2ccccc2)nc(S)n1
Yield: 559.5 %

Procedure:
To ethanol (100 mL) was added sodium (3.3 g, 14 mmol). After dissolution, thiourea (10.7 g, 14 mmol) and ethyl benzoylacetate (24 mL, 14 mmol) were added. The reaction was heated for 16 hours and the solvent was removed in vacuo. Water was added to dissolve the residue and hydrochloric acid was added and a precipitate formed. The solid was collected and dried in a vacuum oven to give 16 g (56%) of 2-mercapto-4-hydroxy-6-phenylpyrimidine.
Reaction SMILES: [N:1]1[NH:2][N:3]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:5]=1.[F:11][C:12]([F:24])([F:23])[O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.N1C=CC=CC=1.O>CC(N(C)C)=O.C(O[Cu]OC(=O)C)(=O)C.C(OCC)(=O)C>[F:11][C:12]([F:23])([F:24])[O:13][C:14]1[CH:19]=[CH:18][C:17]([N:2]2[N:3]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:5]=[N:1]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cn[nH]n1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cnn(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 24.2 %

Procedure:
Ethyl 2H-1,2,3-triazole-4-carboxylate (CAS 1084802-21-0) (250 mg, 1.77 mmol, Eq: 1.00), 4-(trifluoromethoxy)phenylboronic acid (730 mg, 3.54 mmol, Eq: 2) and diacetoxy copper (644 mg, 3.54 mmol, Eq: 2) were dissolved in DMA (8.86 ml). Then pyridine (560 mg, 572 μl, 7.09 mmol, Eq: 4) was added and the reaction mixture was stirred at rt for 48 hours. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with brine, dried over MgSO4 and evaporated. The crude material was purified by silica gel flash chromatography to yield a white solid (129 mg, 24%). MS (ISP): 302.1 ([M+H]+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11](O)[CH3:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:15].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:15][CH:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)[CH3:12]
Reactant: BrP(Br)Br
Reactant: CC(O)c1ccc2ncccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(Br)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
To a solution of 1-quinolin-6-yl-ethanol (0.4 g, 2.3 mmol) in dry CH2Cl2 (20 mL) was added PBr3 (0.22 mL, 2.3 mmol). The reaction mixture was allowed to stir at room temperature for 12 h, and then was treated slowly with a saturated solution of NaHCO3 (100 mL) until basic. The CH2Cl2 layer was removed, product was extracted from the aqueous layer with ethyl acetate (100 mL), and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford 0.4 g (72%) of a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ ppm 8.89-8.96 (m, 1H), 8.11-8.20 (m, 2H), 7.82-7.89 (m, 2H), 7.41-7.49 (m, 1H), 5.39 (dt, 1H), 2.15 (d, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([CH3:13])([OH:12])[CH3:11].CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[CH3:11][C:10]1([CH3:13])[CH2:9][CH2:8][C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=2)[O:12]1
Reactant: CC(C)(O)CCc1ccccc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC1(C)CCc2ccccc2O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
A 4 mL vial was charged with 4-(2-bromophenyl)-2-methyl-2-butanol (97 mg, 0.40 mmol), Pd(dba)2 (11.5 mg, 0.02 mmol), Ph5FcP(t-Bu)2 (14.2 mg, 0.02 mmol) and sodium t-butoxide (46 mg, 0.48 mmol). Anhydrous toluene (2 mL) was added into the vial, and the vial was sealed with a cap containing a PTFE septum and removed from the drybox. The reaction mixture was stirred at room temperature for 10 min. The reaction solution was adsorbed onto silica gel and isolated by eluting with 5% ethyl acetate in hexanes to give 60 mg (93%) of 2,2-dimethylchroman as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=1)=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing 2-nitrobenzoyl chloride (Fluka, Buchs, Switzerland) (1.97 mL, 15 mmol) and 4-dimethylaminopyridine (Fluka, Buchs, Switzerland) (10 mg) in dichloromethane (10 mL) is added to a stirred mixture of 4-aminobenzotrifluoride (Ruka, Buchs, Switzerland) (2.66 g, 16.5 mmol) and triethylamine (1.90 g, 18.8 mmol) in dichloromethane (100 mL) under an argon atmosphere and the mixture is stirred for 16 hours at 25° C. The stirred mixture is then treated with a saturated aqueous solution of sodium hydrogen carbonate (50 mL) and then extracted with dichoromethane (2×50 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 10-50% ethyl acetate in hexane, to give the title compound as a colourless crystalline solid.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[Br:6][CH:7]([CH2:11][CH2:12][Cl:13])[C:8](Cl)=[O:9].[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[Br:6][CH:7]([CH2:11][CH2:12][Cl:13])[C:8]([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9]
Reactant: O=C(Cl)C(Br)CCCl
Reactant: OCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)C(Br)CCCl
Temperature: 24 °C
Yield: 72 %

Procedure:
Heptanes (1.5 L) and calcium carbonate (150 g; 1.50 mol) were added to the distillation residue from step (a) above and benzyl alcohol (236.8 g; 2.19 mol) was added with stirring at 23-25° C. After stirring for 3.5 hours at 23-25° C., GC analysis indicated approximately 20% of unreacted acyl chloride. After additional stirring for 20 hours, approximately 10% of unreacted acyl chloride was estimated to be present by GC. The resultant mixture was filtered, and the filter cake was washed with heptanes (600 mL). Tetrahydrofuran (200 mL) and a 6% aqueous sodium hydrogen carbonate solution (400 mL) were added to the combined filtrates, and the mixture was stirred for 1 hour at room temperature. The aqueous phase (pH approximately 1) was separated and discarded. The organic phase was washed with water (400 mL) and concentrated at 60° C. under vacuum (down to 25 mmHg). GC analysis on the residue (497.7 g; 85% yield), indicated approximately 7% of unreacted acyl chloride. The hydrolysis of unreacted starting material was forced to completion by addition of further heptanes (1.52 L), tetrahydrofuran (150 mL) and 6% aqueous sodium hydrogen carbonate (600 mL). After stirring for 1 hour at room temperature, less than 1% unreacted acyl chloride was estimated to be present by GC. The aqueous phase (pH approximately 8) was separated and discarded. The organic phase was washed with water (200 mL) and concentrated at 65° C. under vacuum (down to 25 mmHg). This resulted in 418.1 g (72%) of crude title compound as a tea coloured residual oil.
Reaction SMILES: C(N([C:15]1[N:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:17]=[C:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)C(NC1CCCCC1)=O)CCC.[Cl:31][C:32]1[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=1>CN1CCCC1=O>[Cl:31][C:32]1[CH:33]=[C:34]([NH:38][C:15]2[N:16]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:17]=[C:18]3[C:23]=2[CH:22]=[CH:21][CH:20]=[CH:19]3)[CH:35]=[CH:36][CH:37]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCCCN(C(=O)NC1CCCCC1)c1c2ccccc2nn1-c1ccc(Cl)cc1
Solvent: CN1CCCC1=O
Product: Clc1ccc(-n2nc3ccccc3c2Nc2cccc(Cl)c2)cc1

Procedure:
In analogy to the procedure described in example 4.1, 3-chloro-2-(4-chloro-phenyl)-2H-indazole (Ardakani, Manouchehr; Smalley, Robert K.; Smith, Richard H., Synthesis (1979), (4), 308-9) was reacted with 3-chloro-phenylamine ([108-42-9]) in N-methyl 2-pyrrolidone for 48 h at 175° C. in a sealed tube to give the title compound as off-white crystals. MS: m/e=354.2 [M+H+].
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=1)(=[O:27])=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[CH2:1]([C:5]1[N:6]([CH2:40][C:37]2[CH:38]=[CH:39][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:25](=[O:27])(=[O:26])[NH:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:35][CH:36]=2)[C:7](=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cccc([N+](=O)[O-])c2)c(=O)[nH]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Product: CCCCc1nn(-c2cccc([N+](=O)[O-])c2)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Yield: 74 %

Procedure:
By the procedure of Example 13, Step A, 5-n-butyl-2,4-dihydro-2-(3-nitrophenyl)-3H-1,2,4-triazol-3-one (from Step A) was alkylated with [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (from Example 12, Step D). Flash chromatography of the crude product on silica gel (gradient elution with 0.5-1.0% MeOH in CH2Cl2) gave a 74% yield of the title compound as an off-white solid, mp 164°-165° C., homogeneous by TLC (19:1 CH2Cl2 --MeOH), mass spectrum (FAB) m/e 564 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])([CH3:5])[CH3:4].[NH2:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20](F)[C:17]=1[C:18]#[N:19]>>[NH2:15][C:16]1[C:17]([C:18]#[N:19])=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:1][CH2:2][C:3]([NH:6][C:7]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])([CH3:5])[CH3:4]
Reactant: N#Cc1c(N)cccc1F
Reactant: CC(C)(CO)NC(=O)C1CCCCC1
Product: CC(C)(COc1cccc(N)c1C#N)NC(=O)C1CCCCC1

Procedure:
Prepared as in Example 22b from N-(1-hydroxy-2-methylpropan-2-yl)cyclohexanecarboxamide (Example 37c) and 2-amino-6-fluorobenzonitrile as an off-white solid (29%). MS 316 (MH+).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C@@H:7]1[C@@H:13]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:18][CH:19]=2)[CH2:12][C@H:11]2[N:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@@H:8]1[CH2:9][CH2:10]2)=[O:6]>CCO>[C:37]([O:36][C:34]([N:33]1[C@H:11]2[CH2:10][CH2:9][C@@H:8]1[C@H:7]([C:5]([OH:6])=[O:4])[C@@H:13]([C:14]1[CH:15]=[N:16][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:18][CH:19]=1)[CH2:12]2)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: COC(=O)[C@@H]1[C@@H](c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)nc2)C[C@@H]2CC[C@H]1N2C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Cl)c(OCCOc2ccc([C@H]3C[C@@H]4CC[C@H]([C@@H]3C(=O)O)N4C(=O)OC(C)(C)C)cn2)c(Cl)c1
Temperature: 70 °C
Yield: 92.4 %

Procedure:
Aq. 1M NaOH (6.50 mL) was added to a sol. of compound D8 (1.19 g, 2.10 mmol) in EtOH (12 mL). The mixture was heated to 70° C. for 2 h. The mixture was allowed to cool to rt, and the solvents were partially removed under reduced pressure. The resulting mixture was partitioned between EtOAc and aq. 2M HCl. The phases were separated, and the aq. phase was extracted with EtOAc (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (1.07 g, 92%) that was used further without purification. LC-MS: tR=1.08 min, ES+: 551.33.