Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:27])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[O:15][C:16]1[C:17]([F:26])=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH3:25])=[CH:19]2)=O)C.CC(C[AlH]CC(C)C)C.C(O)C>C(Cl)Cl>[F:26][C:17]1[C:16]([O:15][C:9]2[C:8]3=[C:7]([CH3:27])[C:6]([CH2:4][OH:3])=[CH:14][N:13]3[N:12]=[CH:11][N:10]=2)=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[C:20]([CH3:25])[NH:21]2
Reactant: CCOC(=O)c1cn2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2c1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc2c(F)c(Oc3ncnn4cc(CO)c(C)c34)ccc2[nH]1
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 62.9 %

Procedure:
To a solution of 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester (68 mg 0.19 mmol) in anhydrous methylene chloride (2.0 mL) at −78° C. under argon was added DIBAL (0.48 mmol, 0.48 mL, 1.0M, 2.5 eq.) dropwise. After 5 minutes, the mixture was warmed to −15° C. and allowed to stir for an additional 15 minutes. A drop of ethanol was added to quench the reaction followed by IN sodium hydroxide (0.2 mL) and 1.0 mL of ethyl acetate and 1.0 mL of THF. After 30 minutes, the mixture was filtered to remove the resulting solid. The filtrate was dried, concentrated in vacuo, and chromatographed using silica gel eluting with 40-75% ethyl acetate in hexanes (gradient). Concentration of the desired fractions afforded the title compound (39 mg, 63%) as a clear oil. LC/MS; (M+H)+=327.3
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][C@H:31]1[O:36][CH2:35][C@@H:34]([CH2:37][NH:38][S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(=[O:41])=[O:40])[N:33](C(OC(C)(C)C)=O)[CH2:32]1)=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].C(Cl)Cl.[C:58]([OH:64])([C:60]([F:63])([F:62])[F:61])=[O:59]>>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][C@H:31]1[O:36][CH2:35][C@@H:34]([CH2:37][NH:38][S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(=[O:40])=[O:41])[NH:33][CH2:32]1)=[O:21])[CH:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[C:58]([OH:64])([C:60]([F:63])([F:62])[F:61])=[O:59]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CNS(=O)(=O)c2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN[C@H](CNS(=O)(=O)c2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl (2R,5R)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]-5-{[(phenylsulfonyl)amino]methyl}morpholine-4-carboxylate in a 1:1 mixture of CH2Cl2/TFA (0.1 M) was stirred at rt for 1 hr. The reaction mixture was concentrated under reduced pressure and the residue was co-evaporated twice with heptane and triturated in Et2O to afford the desired product as a TFA salt. Alternatively, the TFA salt, after concentration, could be neutralized with aqueous saturated NaHCO3, extracted with EtOAc, dried over Na2SO4, filtered and concentrated and then purified by automated SiO2 flash chromatography system using solvent gradient of 0% to 10% MeOH/CH2Cl2 to afford the desired compound. Alternatively, the free base could be purified by filtration on SCX SPE cartridge made of pTSA-SiO2 eluted first with MeOH to remove non basic impurities and eluted then with 10% NH4OH/MeOH to elute the free base and afford the desired compound after concentration under reduced pressure.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:14][NH2:15].C[O-].[Na+].[C:19](=[O:26])(OCC)OCC>>[NH2:14][N:15]1[CH2:12][C@@H:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:11][C:19]1=[O:26]
Reactant: NN
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Reactant: CCOC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: NN1C[C@@H](COCc2ccccc2)OC1=O
Temperature: 90 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
(S)-2-(Benzyloxymethyl)oxirane (2.5 g, 15.23 mmol) was added dropwise to hydrazine mono-hydrate (5.44 g, 107 mmol), previously heated at 90° C. The mixture was refluxed for 30 min, under stirring. The excess of hydrazine hydrate was evaporated under vacuum (8 mbar), at 60° C., for 6 h and then at room temperature, under vigorous magnetic stirring, for 18 h. The obtained sticky colourless oil was dissolved in dry methanol (5 mL) and a solution of sodium methoxide (0.5M in MeOH, 4.57 mL, 2.28 mmol) and then diethyl carbonate (2.16 g, 18.27 mmol) were added dropwise. The mixture was refluxed for 4 h 30 min. Solvent was evaporated and the crude purified by flash silica-gel chromatography (DCM/MeOH=75:1) affording the title compound as a yellow oil that solidified (white solid) on standing (2.074 g, 9.33 mmol). Yield=61%.
Reaction SMILES: C([N:11]1[CH2:18][C@H:17]([O:19][C:20]([NH:22][CH3:23])=[O:21])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.[H][H]>[C].[Pd].CO.O>[CH3:23][NH:22][C:20]([O:19][C@H:17]1[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1)=[O:21]
Reactant: [H][H]
Reactant: CNC(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CNC(=O)O[C@H]1CN[C@H](C(=O)O)C1

Procedure:
A solution of 2.7 g. (0.0084 mole) of trans-N-carbobenzyloxy-4-[[(methylamino)carbonyl]oxy]-L-proline in 100 ml. of methanol-water (2:1) is treated with 1 g. of 5% palladium-carbon and 45 lb. of hydrogen and shaken on a Parr hydrogenator for 6 hours. The catalyst is filtered off under nitrogen, washed with methanol and the combined filtrates are evaporated, finally at 0.1-0.2 mm, to give 1.5 g. (96%) of a residue which gradually crystallizes to give trans-4-[[(methylamino)carbonyl]oxy]-L-proline as a greyish solid; m.p. 213°-215° (dec.), preceded by gradual darkening and sintering. [α]D26 -12° (c, 0.25% in 1:3 ethanol-methanol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[C:30](=[O:31])[C:29]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([NH2:32])[CH:27]=5)[NH:22][C:21]=4[C:20]([CH3:34])([CH3:33])[C:19]=3[CH:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:36](Cl)([CH3:39])(=[O:38])=[O:37]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[C:30](=[O:31])[C:29]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([NH:32][S:36]([CH3:39])(=[O:38])=[O:37])[CH:27]=5)[NH:22][C:21]=4[C:20]([CH3:34])([CH3:33])[C:19]=3[CH:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)C(C)(C)c2[nH]c4ccc(N)cc4c2C3=O)CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)C(C)(C)c2[nH]c4ccc(NS(C)(=O)=O)cc4c2C3=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the pyridine (2 ml) solution of 4-(2-amino-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yl oxy)-piperidine-1-carboxylic acid tert-butyl ester (Compound P6, 50 mg, 0.105 mmol), mesyl chloride (9 μl, 1.2 eq.) was added and stirred at room temperature for 30 min. Upon the completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain the title compound as an unpurified product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[F:21][C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=[CH:18][CH:19]=1
Reactant: C#CCCc1nc2cccc(F)c2o1
Reactant: Brc1ccccn1
Product: Fc1cccc2nc(CCC#Cc3ccccn3)oc12
Yield: 51.5 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (107 mg, 0.68 mmol) and 2-(but-3-ynyl)-7-fluorobenzo[d]oxazole (128 mg, 0.68 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 94 mg (0.35 mmol, 52%) of 7-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4](=[NH:16])[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1Br)[CH3:2].[NH2:19]N>C(O)CCC>[CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[C:5]2[C:6](=[CH:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=2)[NH:19][N:16]=1)[CH3:2]
Reactant: CCN(CC)C(=N)c1cc(C(F)(F)F)ccc1Br
Reactant: NN
Solvent: CCCCO
Product: CCN(CC)c1n[nH]c2ccc(C(F)(F)F)cc12

Procedure:
A mixture of 5.0 g. of N,N-diethyl-2-bromo-5-trifluoromethylbenzamidine and 2.0 ml. of 95% hydrazine are refluxed in butanol for 12 hours. Evaporating the solution, treating the residue with ether and filtering gives 3-diethylamino-5-trifluoromethylindazole.
Reaction SMILES: [OH-:1].[Na+].[NH2:3][C:4]1[N:11]=[C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[C:9]([C:17]2[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH2:24][CH3:25])[CH:18]=2)=[CH:8]C=1C#N.Cl.[CH2:27]([OH:29])[CH3:28]>>[NH2:3][C:4]1[N:11]=[C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[C:9]([C:17]2[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH2:24][CH3:25])[CH:18]=2)=[CH:8][C:28]=1[C:27]([OH:1])=[O:29]
Reactant: [OH-]
Reactant: CCn1cc(-c2cc(C#N)c(N)nc2-c2ccco2)ccc1=O
Reactant: CCO
Agent: Cl
Agent: [Na+]
Product: CCn1cc(-c2cc(C(=O)O)c(N)nc2-c2ccco2)ccc1=O
Yield: 98 %

Procedure:
Ethanol (5 mL) and 5 N aqueous sodium hydroxide (10 mL) were added to 2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinonitrile (308 mg, 1.01 mmol), followed by heating under reflux for 4 hours. After cooling as it was, the reaction solution was neutralized with 5 N hydrochloric acid. The resulting solid was collected by filtration and then washed with water, to give the title compound (320 mg, 98%) as a yellow solid.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl>C(O)CCCCC>[ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH2:38][CH2:3][CH2:4][CH2:5][CH3:6])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CCCCCCO
Product: CCCCCCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Temperature: 25 °C
Reaction time: 19 h
Yield: 53 %

Procedure:
0.60 g (1.1 mmol) of 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride were added to about 30 mL of n-hexanol saturated with hydrogen chloride and the mixture was stirred for 19 hours at room temperature. Then the hexanol was distilled off in vacuo, the residue was mixed with about 5 mL of 1N ammonia solution with stirring, and evaporated down once more. The crude product thus obtained was purified by column chromatography (silica gel, dichloromethane/methanol=5:1). Yield: 53% of theory, C31H37N7O3 (555.7); Rf value: 0.36 (silica gel; dichloromethane/methanol=5:1); EKA mass spectrum: (M+H)+=556.
Reaction SMILES: O.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][S:12]2(=[O:17])=[O:16])=[CH:7][CH:6]=1)([O-])=O>O1CCCC1>[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][S:12]2(=[O:17])=[O:16])=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc(N2CCCS2(=O)=O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(N2CCCS2(=O)=O)cc1

Procedure:
1.0 g of water-moist Raney nickel is added to a solution of 2.60 g (10.7 mmol) of 2-(4-nitrophenyl)isothiazolidine 1,1-dioxide in 50 ml of tetrahydrofuran, and the mixture is hydrogenated at room temperature. The catalyst is filtered off, and the filtrate is evaporated, giving 2-(4-aminophenyl)isothiazolidine 1,1-dioxide as a brownish solid; ESI 213.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:17]([CH3:19])[CH3:18]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:17]([CH3:19])[CH3:18])[C:3]=1[F:9]
Reactant: Oc1cccc(Br)c1F
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)Oc1cccc(Br)c1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
To a mixture of 3-bromo-2-fluoro-phenol (2 g, 10 mmol) and cesium carbonate (10 g, 40 mmol) in acetonitrile (20 mL) was added 2-bromopropane (4 mL, 50 mmol). The reaction mixture was stirred at 80° C. for 4 h. The mixture was filtered through a plug of Celite and eluted with ethyl acetate. The resulting solution was evaporated. The residue was purified by flash chromatography on silica gel and eluting with hexanes:EtOAc (1:1) to afford the title product (1.7 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>C(Cl)(Cl)Cl.C(#N)C>[NH:11]1[CH:15]=[N:14][C:13]([CH2:2][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)=[N:12]1.[N:11]1[N:12]=[CH:13][N:14]([CH2:2][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)[CH:15]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: c1nc[nH]n1
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(Cc2nc[nH]n2)cc1
Product: N#Cc1ccc(Cn2cnnc2)cc1

Procedure:
In the process described in '672, the reaction of refluxing 4-bromomethyl benzonitrile with 1,2,4-triazole in the presence of potassium carbonate and potassium iodide in acetone solvent (according to example 24) gives 4-[1-(1,2,4-triazolyl)methyl]benzonitrile of the formula II in an amount of 87 wt %, and 4-[4-(1,2,4-triazol-4-yl)methyl]benzonitrile of the formula III in an amount of 11 wt %, along with 2% of other impurities. The reaction of 4-bromomethyl benzonitrile with 1,2,4-triazole in a mixture of chloroform and acetonitrile (example 9) gives 4-[1-(1,2,4-triazolyl)methyl]benzonitrile of the formula II in an amount of 30 wt %, and 4-[(1,2,4-triazol-4-yl)methyl]benzonitrile of the formula III in an amount of 40 wt %, along with 20 wt % other impurities. The ratios of intended product to impurity for the prior art processes have been determined by experiment.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][N:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)C.[OH-].[Na+].Cl>CCO.CCOC(C)=O>[CH2:17]([O:16][C:14]([N:6]([CH2:5][C:4]([OH:19])=[O:3])[CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)CN(CCc1cccs1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)N(CCc1cccs1)CC(=O)O
Reaction time: 8 h

Procedure:
The crude material from step (a) (165 mmol, ˜47 g) was dissolved in EtOH (700 mL) and treated with 600 mL of 1M NaOH. After stirring overnight, the reaction was acidified with concentrated HCl to pH˜1. The crude reaction was diluted with EtOAc (400 mL) and washed with water. The water was back-extracted with EtOAc. The combined organic extracts were washed with water (2×) and dried over MgSO4. Concentration and evaporation from toluene (2×) gave the sub-title product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]2[N:17]([CH2:18][CH2:19][CH2:20]I)[C:16](=[O:22])[C:15]3[C:10](=[C:11]([O:23][CH3:24])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:33][N:34]([CH:36]=O)[CH3:35]>CCOC(C)=O>[ClH:1].[ClH:1].[N:34]1([CH:35]2[CH2:11][CH2:10][N:9]([CH2:20][CH2:19][CH2:18][N:17]3[C:16](=[O:22])[C:15]4[C:10](=[C:11]([O:23][CH3:24])[CH:12]=[CH:13][CH:14]=4)[N:9]=[C:8]3[CH2:7][O:6][C:5]3[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:8][CH2:7]2)[CH2:36][CH2:26][CH2:2][CH2:3][CH2:33]1
Reactant: CN(C)C=O
Reactant: COc1cccc2c(=O)n(CCCI)c(COc3ccc(Cl)cc3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1cccc2c(=O)n(CCCN3CCC(N4CCCCC4)CC3)c(COc3ccc(Cl)cc3)nc12
Product: Cl
Temperature: 70 °C
Yield: 74 %

Procedure:
A mixture of the product from Step B (90 mg, 0.186 mmol), 4-piperidine-piperidine (125 mg, 0.743 mmol) and K2CO3 (102 mg, 0.743 mmol) in DMF (5 mL) was heated at 70° C. for 17 h. The reaction mixture was diluted with EtOAc and the organic solution was washed with H2O, dried and concentrated. The crude residue was purified by SiO2-gel chromatography (10% NEt3/EtOAc). This product was dissolved in 4.0 M HCl in 1,4-dioxane (1 mL) and concentrated to give the desired compound (72 mg, 74%). API-MS: 526 (M+1). 1H NMR (300 MHz, d4-MeOH): d 7.8 (d, 1 H), 7.5 (t, 1 H), 7.45 (d, 1 H), 7.3 (d, 2 H), 7.15 (d, 2 H), 5.35 (s, 2 H), 4.3 (t,2 H), 4.0 (s, 3 H), 3.8 (d, 1 H), 3.45 (d, 1 H), 3.1 (m, 2 H), 2.5-1.8 (m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[C:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[CH2:30][N:31]2[C@H:35]([CH3:36])[C@H:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:33][C:32]2=[O:43])[CH:6]=1.[CH3:45][N:46]1[CH:50]=[C:49](B2OC(C)(C)C(C)(C)O2)[CH:48]=[N:47]1>>[CH3:1][O:2][C:3](=[O:44])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:49]2[CH:48]=[N:47][N:46]([CH3:45])[CH:50]=2)=[C:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][C:21]=2[CH2:30][N:31]2[C@H:35]([CH3:36])[C@H:34]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[O:33][C:32]2=[O:43])[CH:6]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1
Product: COC(=O)Cc1ccc(-c2cnn(C)c2)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[2-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-trifluoromethyl-phenoxy]-4-trifluoromethanesulfonyloxy-phenyl}-acetic acid methyl ester and 1-methylpyrazole-4-boronic acid pinacol ester.
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[CH3:7][CH:8]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][C:10](O)=[O:11]>C(CC(C)(C)C)(C)C>[CH3:7][CH:8]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][C:10]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11]
Reactant: CC(C)(C)OO
Reactant: CC(CC(=O)O)CC(C)(C)C
Solvent: CC(C)CC(C)(C)C
Product: CC(CC(=O)OOC(C)(C)C)CC(C)(C)C

Procedure:
To a reaction vial with a TEFLON fluoropolymer magnetic stirring rod, 3 ml containing 0.2 M tert-butyl hydroperoxide and 0.2 M 3,5,5-trimethylhexanoic acid in isooctane was added. The reaction was started by addition of 200 mg of Candida antartica enzyme and about 10 mg of molsieves (3 grains). After twenty-fourand one-half hours, 11.2% conversion to tert-butyl peroxy-3,5,5-trimethylhexanoate was obtained as measured with GC.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][C:11]=1[C:26](=[O:28])[CH3:27]>C(O)(C)C>[CH3:6][N:4]([CH3:5])/[CH:3]=[CH:27]/[C:26]([C:11]1[CH:12]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=2)[CH:14]=[CH:15][C:10]=1[OH:9])=[O:28]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Solvent: CC(C)O
Product: CN(C)/C=C/C(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
N,N-Dimethylformamide dimethyl acetal (0.76 mL, 5.701 mmol) was added to a solution of 1-[4-hydroxy-4′-(trifluoromethyl)biphenyl-3-yl]ethanone (Preparation 37, 795 mg, 2.84 mmol) in isopropyl alcohol (4.7 mL). The reaction mixture was heated for 18 hours at 45° C. under an atmosphere of nitrogen. After 1 hour, crystallization was observed therefore the stirring was stopped. After 18 hours at 45° C., a yellow precipitate had formed. The reaction mixture was allowed to cool, the yellow precipitate was collected by filtration and washed with cold isopropyl alcohol to afford the title compound as fine yellow needle crystals (669 mg, 70%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.[Cl-:17].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][CH:41]=[C:40]2[CH2:46][C:47](O)=[O:48]>CO>[ClH:17].[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH:9][C:47](=[O:48])[CH2:46][C:40]2[C:39]3[C:43](=[CH:44][CH:45]=[C:37]([O:36][CH3:35])[CH:38]=3)[NH:42][CH:41]=2)[CH2:5][CH2:4]1
Reactant: COc1ccc2[nH]cc(CC(=O)O)c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(N)CC1
Reactant: [Cl-]
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CO
Product: COc1ccc2[nH]cc(CC(=O)NC3CCC(c4ccccc4)(N(C)C)CC3)c2c1
Product: Cl
Reaction time: 24 h

Procedure:
The nonpolar diastereomer of N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine (387 mg) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (267 mg, 2.0 mmol.) were added to a solution of (5-methoxy-1H-indol-3-yl)acetic acid (364 mg) in abs. methanol (20 ml). Stirring was then carried out for 24 hours at RT. For working up, the mixture was concentrated, the batch was diluted with water (10 ml), and the mixture was adjusted to pH 11 with 5M NaOH and extracted with ethyl acetate (3×20 ml). The combined organic extracts were dried over Na2SO4 and concentrated by evaporation. After column chromatography with MeOH, the nonpolar amide (154 mg; colorless oil) was dissolved in 2-butanone (5 ml) and converted with chlorotrimethylsilane (72 μl) into the corresponding hydrochloride (white solid; 168 mg; m.p. 143-145° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[N:8]([CH:13]1[CH2:15][CH2:14]1)[C:7]2=[O:16].O=P(Cl)(Cl)[Cl:19].CCN(C(C)C)C(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:19])[N:8]([CH:13]1[CH2:15][CH2:14]1)[C:7]2=[O:16]
Reactant: O=c1[nH]c2c(Br)cccc2c(=O)n1C1CC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c2cccc(Br)c2nc(Cl)n1C1CC1
Yield: 85.2 %

Procedure:
A mixture of 8-bromo-3-cyclopropylquinazoline-2,4(1H,3H)-dione (723b; 5.00 g, 17.79 mmol), POCl3 (8.29 mL, 89.0 mmol) and DIPEA (12.38 mL, 71.1 mmol) was stirred at reflux overnight. The reaction was then cooled and concentrated. The brown syrup was cooled in an ice bath and then ice was added to the reaction mixture. The brown sludge was added to 100 mL of 10 M NaOH (aq.) and ice and stirred for 20 min. The mixture was filtered and the brown solid was washed with water and then put into solution with CH2Cl2 and filtered. The filtrate was collected and dried over Na2SO4, filtered and concentrated to afford 8-bromo-2-chloro-3-cyclopropylquinazolin-4(3H)-one (723) (4.54 g, 15.16 mmol, 85% yield) as a brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.17 (dd, J=8.02, 1.56 Hz, 1H), 7.99 (dd, J=7.82, 1.56 Hz, 1H), 7.32 (t, J=7.92 Hz, 1H), 3.02 (tt, J=7.12, 4.03 Hz, 1H), 1.33-1.43 (m, 2H), 0.94-1.04 (m, 2H). m/z (ES, +ve) 298.9, 301.0 (M+H)+.