Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:4][NH:5][C:6]=1[S:7][CH3:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:4][N:5]([CH2:23][C:24]([N:26]2[CH2:27][CH2:28][N:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:30][CH2:31]2)=[O:25])[C:6]=1[S:7][CH3:8]
Reactant: CSc1[nH]nc(-c2ccc(F)cc2)c1Cl
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CSc1c(Cl)c(-c2ccc(F)cc2)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 4-Chloro-3-(4-Fluoro-phenyl)-5-methylsulfanyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 7.46-7.5 (m, 2H), 7.12-7.18 (m, 2H), 6.96-7.1 (m, 2H), 6.88-6.92 (m, 2H), 4.86 (s, 2H), 3.72-3.78 (m, 2H), 3.56-3.62 (m, 2H), 3.06-3.18 (m, 4H), 2.54 (s, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([F:28])[C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](OC)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([NH:35][CH2:34][C:33]3[CH:36]=[CH:37][C:30]([CH3:29])=[CH:31][CH:32]=3)=[O:24])[N:17]=[CH:16]4)[C:10]([CH3:27])=[C:9]([F:28])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)cc(F)c3C)ccc21
Reactant: Cc1ccc(CN)cc1
Product: Cc1ccc(CNC(=O)Cn2ncc3cc(-c4cc(C(=O)NC5CC5)cc(F)c4C)ccc32)cc1

Procedure:
Example 133 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 123) and 4-methylbenzylamine to give the title compound (0.011 g).
Reaction SMILES: C[Si](Cl)(C)C.C[O:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Na+].[I-]>C(#N)C>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C@H:12]2[CH2:13][CH2:14][C@H:9]([CH2:8][OH:7])[CH2:10][CH2:11]2)=[CH:16][CH:17]=1)#[N:22]
Reactant: COC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1ccc([C@H]2CC[C@H](CO)CC2)cc1
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
Trimethylsilyl chloride (305.6 g, 2.81 mols) was dropwise added to trans-4-methoxymethyl-1-(4-cyanophenyl)-cyclohexane (III) (322.5 g, 1.41 mol), NaI (421.6 g, 2.81 mols) and acetonitrile (2.5 l) in nitrogen atmosphere with stirring at 35° C. over 30 minutes, followed by agitating the mixture for 20 minutes, cooling down to 10° C., filtering the reaction mixture by suction, pouring the mother liquor in ice water (2 Kg), extracting with chloroform (1.5 l), subjecting the resulting chloroform solution to twice washing with a 10% by weight aqueous solution of thiosulfate (0.5 l) and separating, further three times subjecting to washing with water (1 l) and separating, distilling off chloroform and three times recrystallizing the residue from toluene (300 ml) to obtain trans-4-(4-cyanophenyl)-cyclohexylcarbinol (IV) (182.5 g, 0.848 mol) having a m.p. of 108.5°-110.8° C. On the other hand, pyridinium chlorochromate (161.7 g, 0.750 mol) was added to dichloromethane (1 l), followed by instantaneously adding to the solution a solution of trans-4-(4-cyanophenyl)cyclohexylcarbinol (IV) (107.6 g, 0.500 mol) obtained above (107.6 g, 0.500 mol) in dichloromethane (0.7 l) with stirring at room temperature, further agitating the mixture at room temperature for 1.5 hour, adding diethyl ether (1 l) to the resulting reaction solution and concentrating the supernatant according to florysil column chromatography to obtain trans-4-(4-cyanophenyl)cyclohexylcarboaldehyde (V) (101.2 g, 0.474 mol).
Reaction SMILES: [Br-].C(OC([NH:9][CH:10]([CH3:37])[CH2:11][N+:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([O:20][C:21](=[O:36])[C:22]([OH:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13]2)=O)(C)(C)C.Br.[ClH:39]>O1CCOCC1>[ClH:39].[Cl-:39].[NH2:9][CH:10]([CH3:37])[CH2:11][N+:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([O:20][C:21](=[O:36])[C:22]([OH:35])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:13]2
Reactant: CC(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2)NC(=O)OC(C)(C)C
Agent: Br
Agent: Cl
Agent: [Br-]
Solvent: C1COCCO1
Product: CC(N)C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2
Product: [Cl-]

Procedure:
This compound is prepared analogously to (R)-1-((R/S)-2-Amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide hydrobromide [Example 49ii] but by replacing (R)-1-(2-tert-butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide [Example 49i] with (R)-1-((R/S)-2-tert-Butoxycarbonylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide [Example 164] and hydrogen bromide solution in dioxane with hydrogen chloride solution in dioxane. The product is isolated on concentration of the reaction medium, without further purification.
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[C:15]([OH:17])[CH:16]=1.[C:29](=O)([O-])[O-:30].[Ca+2]>O1CCOCC1>[CH2:22]([O:21][C:19]([NH:18][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:29]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:30])=[CH:16][C:15]=1[OH:17])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccc(NC(=O)OCc2ccccc2)c(O)c1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)c1ccccc1
Agent: [Ca+2]
Solvent: C1COCCO1
Product: O=C(Cc1ccccc1)Nc1ccc(NC(=O)OCc2ccccc2)c(O)c1

Procedure:
12 g of benzoyl chloride are slowly added dropwise to 0.77 mole (20 g) of 5-amino-2-(benzyloxycarbonylamino)phenol (prepared in the 2nd stage of Example 1) and 12 g of calcium carbonate in 120 ml of dioxane brought to 80° C. The mixture is heated for a further 20 minutes after the addition is complete. The mixture is filtered while hot in order to remove the inorganic salts. The expected product is precipitated by diluting the filtrate with ice-cold water. When recrystallized from methoxyethanol, it melts at 252° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:12]([NH:16][OH:17])([CH3:15])([CH3:14])[CH3:13]>>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[N+:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[O-:17]
Reactant: CC(C)(C)NO
Reactant: COc1ccc(C=O)c(O)c1
Product: COc1ccc(C=[N+]([O-])C(C)(C)C)c(O)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 2-hydroxy-4-methoxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 72.9% yield as a pale yellow crystalline solid, m.p. 115.2-116.0° C. (Rf=0.49 on a silica gel plate using 1:1 EtOAc/hexanes as an eluant).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH2:19])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:28](=[O:29])[O:27][C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1.C(Cl)Cl.CO.C[N:38]([CH:40]=[O:41])C>>[C:28]([OH:27])(=[O:29])/[CH:23]=[CH:24]\[C:25]([OH:26])=[O:41].[F:20][C:21]1[CH:31]=[C:30]([C:40]([NH2:38])=[O:41])[C:24](=[CH:23][CH:22]=1)[C:25]([NH:19][CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][CH:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][N:7]=2)[CH2:16][CH2:15]1)=[O:26]
Reactant: CN(C)C=O
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: NCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1cc(F)ccc1C(=O)NCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Product: O=C(O)/C=C\C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-[4-(6-fluoro-1H-3-indazolyl)-1-piperidinyl]ethylamine (6.1 g, 23.3 mmol) in DMF (230 ml) was added 4-fluorophthalic anhydride (4.2 g, 25.5 mmol) at room temperature under nitrogen. The reaction mixture was warmed to 80 C. for 2.5 hours at which time it was allowed to cool to room temperature. The DMF was removed under reduced pressure to give a brown oil which was dissolved into DCM/MeOH. Purification via flash column chromatography (silica gel, 2% MeOH/DCM) afforded 3.6 g of the desired product as a white solid. The maleate salt was prepared in methanol (75 ml) using maleic acid (2.1 eq.). The precipitated salt was collected via filtration and recrystallized from acetonitrile to give a white solid, m.p. 193°-195° C.
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[F:11][C:12]([F:26])([F:25])[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:22][C:23]#[N:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[N+:1]([C:4]1[S:5][C:6](/[CH:9]=[C:22](/[S:19]([C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:26])([F:11])[F:25])=[CH:18][CH:17]=2)(=[O:21])=[O:20])\[C:23]#[N:24])=[CH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: N#CCS(=O)(=O)c1ccc(C(F)(F)F)cc1
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
Reaction of 2-nitrothiophen-5-carboxaldehyde and 4-trifluoromethylphenylsulfonylacetonitrile as in Example 1 gave (E)-3-(2-nitrothien-5-yl)-2-[4-(trifluoromethyl)phenylsulfonyl]acrylonitrile
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[C:5]([CH3:32])[CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=1.[CH3:33][O-:34].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:23][C:10]1[C:9]2[C:4](=[C:5]([CH3:32])[CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=[C:2]([O:34][CH3:33])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1cc(C(=O)c2cncn2C)cc2c(Cl)c(Cc3ccc(S(C)(=O)=O)cc3)c(Cl)nc12
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc2c(C)cc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A mixture of (2,4-dichloro-8-methyl-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (1.1 g, 2.15 mmol, Intermediate 40: step d) and dry sodium methoxide (0.58 g, 10.75 mmol) in toluene was heated in a sealed tube at 110° C. for 12 hours, cooled to room temperature, diluted with DCM, stirred for 30 minutes at room temperature and the resulting suspension filtered through Celite® rinsing several times with DCM. The solvents were removed under reduced pressure and the residue chromatographed (10% MeOH in DCM, gradient) to provide the title compound as a white solid after recrystallization from MeOH and drying under reduced pressure overnight.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O.O>[Si:22]([O:21][CH2:20][CH2:19][CH2:18][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (400 mg) in N,N-dimethylformamide (2.6 mL) was added cesium carbonate (957 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added (3-bromopropoxy)(tert-butyl)dimethylsilane (979 mg), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer washed with saturated brine (30 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=85/15→10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (630 mg) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[H][H].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.Cl.C(OC)(C)(C)C>[CH3:8][C:3]([CH3:9])([CH2:2][O:1][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C)(C)CO
Reactant: BrCc1ccccc1
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)COCc1ccccc1
Temperature: 60 °C
Yield: 33.3 %

Procedure:
Adapting procedures or variations thereof according to Eliel et al., J. Org. Chem., 1985, 50(15), 2707-2711; Roth et al., J. Agri. & Food. Chem. 1991, 39(3), 612-616; and Rega et al., Eur. J. Org. Chem. 2007, 6, 934-942, in an oven dried 500 mL round bottomed flask equipped with a magnetic stir bar and rubber septum, was added under a nitrogen atmosphere, 2.4 g of a 60 mass-% suspension of sodium hydride (NaH) in mineral oil (1.44 g of NaH, 60.0 mmol). The mineral oil was removed by washing with hexanes (Hxn) and the residue was dried under reduced pressure to yield a colorless solid (activated sodium hydride). Seven point nine (7.9) g (60 mmol) of methyl 3-hydroxy-2,2-dimethylpropanoate was added to a suspension of the activated sodium hydride in 200 mL of anhydrous N,N-dimethylformamide (DMF). The suspension was stirred until the hydrogen evolution ceased. Five-point-nine (5.9) mL (8.5 g, 50.0 mmol) of benzyl bromide (BnBr) was added and the mixture was stirred at ca. 60° C. for more than 10 hours. Upon completion and cooling, the reaction mixture was further diluted with one molar (1.0 M) hydrochloric acid (HCl) and methyl tert-butyl ether (MTBE) and the phases were separated. The aqueous phase was extracted two additional times with methyl tert-butyl ether (MTBE) and the combined organic extracts were washed with a saturated aqueous solution of sodium hydrogen carbonate (NaHCO3), water, and brine. The organic solution was dried over anhydrous magnesium sulfate (MgSO4), filtered, and the solvents were removed under reduced pressure using a rotary evaporator. The residue was further purified by silica gel column chromatography using a mixture of n-heptane (Hptn) and ethyl acetate (EtOAc) as eluent (EtOAc/Hptn=1:9) to provide 3.7 g (33% yield) of the title compound (26a) as a yellow oil. Rf=0.45 (EtOAc/Hptn=1:9). 1H NMR (400 MHz, CDCl3): δ=1.22 (s, 6H), 3.46 (s, 2H), 3.69 (s, 3H), 4.53 (s, 2H), 7.26-7.36 (m, 5H) ppm. The analytical data was consistent with the proposed structure.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[C:14]([NH:15][C:16](=[O:43])[CH:17]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]3[C:35](=[O:36])[CH2:34][O:33][C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[N:31]3)=[CH:25][CH:24]=2)[CH:18]([CH3:22])[CH2:19][CH2:20][CH3:21])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:44][CH2:45][C:46]([O:48]C(C)(C)C)=[O:47]>ClCCl>[CH3:8][C:9]1[C:14]([NH:15][C:16](=[O:43])[CH:17]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]3[C:35](=[O:36])[CH2:34][O:33][C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[N:31]3)=[CH:25][CH:24]=2)[CH:18]([CH3:22])[CH2:19][CH2:20][CH3:21])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:44][CH2:45][C:46]([OH:48])=[O:47]
Reactant: CCCC(C)C(C(=O)Nc1cccc(CCC(=O)OC(C)(C)C)c1C)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)C(C(=O)Nc1cccc(CCC(=O)O)c1C)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.74 ml (22.56 mmol) of trifluoroacetic acid were added to a solution of 460 mg (0.75 mmol) of tert-butyl 3-{2-methyl-3-[(3-methyl-2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}hexanoyl)amino]phenyl}propanoate (Example 163A) in 10 ml of dichloromethane, and the mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated to dryness under reduced pressure. This gave 410 mg (0.74 mmol, 98% of theory) of the title compound as a mixture of isomers.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=O)[C:12]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:20])(=[O:3])[NH2:2].[OH-].[Na+]>C(O)(=O)C>[Cl:20][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:12]=1[C:11]1[NH:2][C:1](=[O:3])[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: COc1cccc(Cl)c1C(=O)Nc1ccccc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cccc(Cl)c1-c1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Yield: 13.8 %

Procedure:
N-(2-carbamoylphenyl)-2-chloro-6-methoxybenzamide (13 g, 42.7 mmol) was suspended in 100 mL of a 2 N NaOH solution and heated to reflux. After refluxing for 3 hours, another 25 mL of a 2 N NaOH solution was added, and the reaction was refluxed for another hour. The mixture was cooled to room temperature and acidified with acetic acid to pH 5. The formed precipitate was collected by filtration. The product was purified over alumina using EtOAc as an eluent giving 1.7 g (5.9 mmol, 14%) of 2-(2-chloro-6-methoxy-phenyl)-3H-quinazolin-4-one.
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[O:14][CH:15]1[CH2:32][CH:31]2[N:17]([C:18](=[O:44])[N:19]([CH3:43])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]3[C:28]([C:34]([NH:36][S:37]([CH:40]4[CH2:42][CH2:41]4)(=[O:39])=[O:38])=[O:35])([NH:29][C:30]2=[O:33])[CH2:27]3)[CH2:16]1.[C:45]1(B(O)O)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CC1C=CN=CC=1C1C(OC)=CC=C2C=1C=CN=C2OC1CC2N(C(=O)N(C)CCCCC=CC3C(C(NS(C4CC4)(=O)=O)=O)(NC2=O)C3)C1>>[C:45]1([C:2]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]=[C:7]3[O:14][CH:15]2[CH2:32][CH:31]3[N:17]([C:18](=[O:44])[N:19]([CH3:43])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([NH:36][S:37]([CH:40]5[CH2:42][CH2:41]5)(=[O:38])=[O:39])=[O:35])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nccc2c1Br
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nccc2c1-c1cnccc1C
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nccc2c1-c1ccccc1

Procedure:
The title product was prepared from N-[17-(5-bromo-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl) sulfonamide (51, example 13) and benzeneboronic acid following the procedure described for N-[17-[5-(4-methyl-3-pyridyl)-6-methoxyisoquinolin-1-yloxy]-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (52, Example 14): m/z=688 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[C:4]([CH3:20])[CH:3]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>C1(C)C=CC=CC=1>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30]([NH:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:15])([CH3:16])[C:11]([O:13][CH3:14])=[O:12])=[C:4]([CH3:20])[CH:3]=1)=[O:31]
Reactant: COC(=O)C(C)(C)CCCOc1cc(C)c(N)cc1C
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)CCCOc1cc(C)c(NC(=O)Nc2ccc(F)cc2F)cc1C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
5-(4-Amino-2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, methyl ester as the free base (Example 2) (4.15 g, 15 mmol) in 50 mL of toluene, 2.33 g (15 mmol) of 2,4-difluorophenyl isocyanate is added and the solution is stirred at 50° C. for 18 hours overnight. The solid mixture is evaporated on a rotary evaporator; the precipitate is taken up in acetonitrile, treated with charcoal, filtered, evaporated, and the residual, crystalline precipitate is recrystallized from 70 mL of toluene: 50 mL of isooctane to afford 5.7 g of the title compound as a slight pink solid; mp 152°-153° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]2[CH2:11][C:12]2[O:16][C:15]([C:17](OCC)=[O:18])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:28][CH3:29].[NH3:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]2[CH2:11][C:12]2[O:16][C:15]([C:17]([NH2:30])=[O:18])=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: CCOC(=O)c1ccc(Cn2c(-c3ccccc3)cc3cc(OC)c(Cl)cc32)o1
Reactant: N
Product: COc1cc2cc(-c3ccccc3)n(Cc3ccc(C(N)=O)o3)c2cc1Cl
Temperature: 25 °C
Reaction time: 44 h

Procedure:
A suspension of ethyl 5-(6-chloro-5-methoxy-2-phenylindol-1-ylmethyl)furan-2-carboxylate (258 mg) in ammonia (Ca. 7 mol/L methanol solution, 12.4 mL) was stirred at room temperature for 44 hours. The reaction mixture was filtered, washed with methanol, and then concentrated under reduced pressure to obtain the title compound (138 mg). 1H-NMR (CDCl3) δ ppm: 3.95 (3H, s), 5.23 (2H, s), 6.10 (1H, d, J=3.5 Hz), 6.50-6.55 (1H, m), 7.03 (1H, d, J=3.5 Hz), 7.15 (1H, s), 7.35-7.55 (6H, m).
Reaction SMILES: [CH:1]([S:4]([C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:14][S:15]([O:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[N:12]=1)(=[O:17])=[O:16]
Reactant: CC(C)S(=O)(=O)c1cccc(O)n1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)c1cccc(OS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
2.2 g of 6-isopropylsulfonyl-2-pyridinol and 1.48 g of methanesulfonyl chloride were dissolved in 30 ml of methylene chloride. 1.65 g of triethylamine was added dropwise to the solution at 10° C. or below. The mixture was stirred at room temperature for 2 hours and at 50° to 60° C. for 2 hours to complete the reaction. The reaction mixture was poured into 100 ml of chilled water to separate the methylene chloride layer. The water layer was further extracted with methylene chloride. The resulting organic layer was combined with the above methylene chloride layer. The combined layer was washed with water and chilled to remove the solvent. The resulting residue was purified by silica gel column chromatography (with ethyl acetate and n-hexane) to obtain 2.4 g of objective 6-isopropylsulfonyl-2-pyridyl methanesulfonate as a colorless crystal (yield: 76.0%).