Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[O:17][N:16]=[C:15]([CH3:18])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1.[OH-].[OH:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34].O>CO>[OH:30][CH2:31][CH2:32][N+:33]([CH3:36])([CH3:35])[CH3:34].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O-:19])=[C:7]([C:13]3[O:17][N:16]=[C:15]([CH3:18])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:27])[CH3:28])=[CH:22][CH:21]=1
Reactant: Cc1cc(-c2c(O)c3cc(-c4ccc(N(C)C)cc4)c(Cl)cc3[nH]c2=O)on1
Agent: C[N+](C)(C)CCO
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(-c2c([O-])c3cc(-c4ccc(N(C)C)cc4)c(Cl)cc3[nH]c2=O)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
To a suspension of 7-chloro-6-(4-(dimethylamino)phenyl)-4-hydroxy-3-(3-methylisoxazol-5-yl) quinolin-2(1H)-one (Example 42) (1.5 g, 3.79 mmol) in methanol (8 mL) was added choline hydroxide 46% wt in water (1.997 g, 7.58 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered, washed with methanol and dried. The resulting solid was recrystallized with acetonitrile to give the title compound 7-chloro-6-(4-(dimethylamino)phenyl)-3-(3-methylisoxazol-5-yl)-2-oxo-1,2-dihydroquinolin-4-olate, N-2-hydroxyethyl-N,N-dimethylmethanaminium salt (1.2 g, 2.40 mmol, 63.5% yield) as off-white solid. LCMS: (M+H)+=396; Rt=2.39 min. HRMS: calculated for C21H19ClN3O3 (M+H)+: 396.1115. found: 396.1092.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH2:11]([OH:15])[CH2:12][CH2:13][OH:14]>>[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=1[O:14][CH2:13][CH2:12][CH2:11][OH:15]
Reactant: OCCCO
Reactant: N#Cc1ccc(Cl)cc1F
Product: NCc1ccc(Cl)cc1OCCCO

Procedure:
The title compound is synthesized by coupling followed by reduction of 4-chloro-2-fluoro-benzonitrile and 1,3-propane-diol analogously to the preparation of Intermediate 113.1 as a colorless solid; ES-MS: M+=216.1; HPLC: AtRet=2.23 min.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13](OS(C)(=O)=O)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br-:22].[Na+].O>CN(C)C=O>[Br:22][CH:13]([C:5]1[CH:4]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[CH3:14]
Reactant: C[C@@H](OS(C)(=O)=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
With reference to Japanese Patent No. 3938651, a solution of (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (optical purity, >99.5% ee; 1.6 g; 6.20 mmol) in dichloromethane (20 mL) was added with methanesulfonyl chloride (0.58 mL, 7.44 mmol), triethylamine (1.30 mL, 9.3 mmol), and dimethylaminopyridine (76 mg, 0.62 mmol) with stirring under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added with 1 N hydrochloric acid and chloroform at the same temperature, and the organic layer was separated. The aqueous layer was extracted with chloroform (20 mL×3), and the organic layers were combined, washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (R)-methanesulfonic acid 1-[3,5-bis(trifluoromethyl)phenyl]ethyl ester (2.23 g) as colorless oil. Then, a solution of the resulting (R)-methanesulfonic acid 1-[3,5-bis(trifluoromethyl)phenyl]ethyl ester (2.23 g) in N,N-dimethylformamide (20 mL) was added with sodium bromide (1.26 g, 12.25 mmol), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was added with water (30 mL) at room temperature, and the mixture was extracted with hexane (30 mL×3). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 1.85 g of 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane as colorless oil. On the basis of the specific rotation, it was confirmed that the resulting 1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane was obtained after racemization.
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:40][CH2:41][CH2:42][CH3:43])[C:14]([N:16]1[C@H:20]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:22])[CH2:19][CH2:18][N:17]1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].C(N)(N)=[O:45].OO.C1(=O)C2C=CC=CC=2C(=O)O1>CCOC(C)=O>[CH:1]([N:3]([CH2:12][C@@H:13]([CH2:40][CH2:41][CH2:42][CH3:43])[C:14]([N:16]1[C@H:20]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N+:25]=2[O-:45])=[O:22])[CH2:19][CH2:18][N:17]1[C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2]
Reactant: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2ccccn2)CCN1C(=O)OCc1ccccc1
Reactant: NC(N)=O
Agent: O=C1OC(=O)c2ccccc21
Agent: OO
Solvent: CCOC(C)=O
Product: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2cccc[n+]2[O-])CCN1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 118.7 %

Procedure:
To a solution of phenylmethyl (3S)-2-[(2R)-2-({formyl [(phenylmethyl)oxy]amino}methyl)hexanoyl]-3-[(2-pyridinylamino)carbonyl]-1-pyrazolidinecarboxylate (70 mg, 0.12 mmol) in EtOAc (6 mL) was added per carbamide (45 mg, 0.48 mmol) and 2-benzofuran-1,3-dione (71 mg, 0.48 mmol). The mixture was stirred overnight until TLC showed the completion of the reaction. The mixture was washed with aq. Na2CO3 and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography to provide the titled compound (86 mg, 85%)
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[O:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.C([Li])CCC.[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].[Cl-].[NH4+]>CCOCC.O1CCCC1>[Cl:1][C:2]1[S:3][C:4]([C:21]2([N+:18]([O-:20])=[O:19])[CH:22]=[CH:23][C:24]([CH2:25][OH:26])=[CH:27][CH2:28]2)=[CH:5][C:6]=1[O:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Clc1sccc1OC1CCCC1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=[N+]([O-])C1(c2cc(OC3CCCC3)c(Cl)s2)C=CC(CO)=CC1
Temperature: -78 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
To a solution of 2-chloro-3-cyclopentyloxythiophene (2.15 g, 10.6 mmol) in ether (27 mL) was added n-butyllithium (2.5 N in hexanes, 4.4 mL, 11 mmol) dropwise at −78° C. under argon. The mixture was allowed to reach 20-25° C. and stirred for 4 hours. After cooling back to −78° C., a solution of p-nitrobenzaldehyde (1.56 g, 10.3 mmol) in tetrahydrofuran (27 mL) was added dropwise. The mixture was stirred at −78° C. for 1 hour. Saturated ammonium chloride was added at −78° C. and the mixture was allowed to reach about 10° C. The crude product was extracted with ethyl acetate, washed with water, brine, dried (Na2SO4), and concentrated to dryness to give 4-(5-chloro-4-cyclopentyloxythien-2-yl)-(4-nitrophenyl)methanol (3.6 g), and was directly used in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (4.4 g) obtained in Example 2 was suspended in dimethyl sulfoxide (250 ml), and to the suspension was added potassium carbonate (4.5 g). The mixture was stirred at room temperature for 30 minutes, and t-butyl bromoacetate (2.1 ml) was added. The mixture was stirred at room temperature for 12 hours, and the reaction mixture was poured into ice water (300 ml) and extracted with methylene chloride. The methylene chloride layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride containing 3% methanol) to produce the title compound (3.4 g, 63%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[CH:3]=1.O.[NH2:17][NH2:18]>C(O)C>[NH:17]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[CH:3]=1)[NH2:18]
Reactant: CCCn1c(=O)cc(Cl)c2ccccc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCCn1c(=O)cc(NN)c2ccccc21
Yield: 94 %

Procedure:
In 140 ml of ethanol was dissolved 6.02 g (27 mmol) of 4-chloro-1-propylquinolin-2(1H)-one, and 140 ml of hydrazine monohydrate was added thereto, followed by refluxing for 3 hours. The reaction mixture was concentrated to an about half of its original volume and then allowed to cool to obtain 5.53 g (94%) of the titled compound as a pale yellow crystal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26]I.[H-].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][C@@H:9]1[CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CCCCO)C1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCC[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Into a room temperature, stirred solution of (S)-2-(4-hydroxybutyl)-piperazine-1,4-dicarboxylic acid di-tert-butyl ester (0.344 g, 0.95 mmol), and MeI (0.179 mL, 2.87 mmol) in DMF (5 mL) add NaH (0.042 g, 1.05 mmol, 20% in mineral oil). Stir overnight. Dilute the mixture with 75% brine (50 mL) and extract with EtOAc (3×100 mL). Concentrate the organic layers under reduced pressure, dilute with EtOAc (40 mL) and wash with 75% brine (5×25 mL). Dry the organic layer over Na2SO4, and filter. Concentrate the mixture under reduced pressure and purify by silica gel chromatography eluting with 20% to 98% EtOAc in hexanes. Combine the purified fractions, concentrate under reduced pressure and place under vacuum to give the title compound: yellow tar (0.209 g), mass spectrum (m/e):373.13 (M+H).
Reaction SMILES: [CH2:1]=[CH:2][C:3]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])([CH3:5])O.C[Si](C)(C)[Cl:14]>[Bi+]=O>[Cl:14][CH2:1][CH:2]=[C:3]([CH3:5])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: C=CC(C)(O)CCC=C(C)C
Reactant: C[Si](C)(C)Cl
Agent: O=[Bi+]
Product: CC(C)=CCCC(C)=CCCl
Temperature: 60 °C
Yield: 83.2 %

Procedure:
To a mixture of 170 g linalool and 20 mg bismuth(III)-oxide heated to 60° C., 130.5 g trimethylchlorosilane were added. Then, the mixture was cooled to room temperature and the organic layer was separated. The resulting oil was purified by distillation to yield 158.35 g of a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1(C)[CH:27]=CC=C[CH:23]=1.COC(C)=C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@@H:10]([C:11]([O:13][CH3:14])=[O:12])[O:15][C:22]1([CH3:27])[CH3:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Reactant: Cc1ccccc1
Agent: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: 120 °C
Yield: 36 %

Procedure:
147.5 mg (0.50 mmol) of methyl (2S,3S)-3-t-butoxycarbonylamino-3-phenyl-2-hydroxypropionate and 2.5 cm3 of anhydrous toluene are introduced, under an argon atmosphere, into a 10 cm3 round-bottomed flask equipped with a magnetic stirrer system. 10 grains of 4 Å molecular sieve, 188.5 μl (144.2 mg, 2.0 mmol) of 2-methoxypropene and 12.5 mg (0.05 mmol) of pyridinium p-toluenesulphonate are then added to the suspension obtained. The mixture is allowed to react for 1 hour at a temperature in the region of 20° C. and is then heated to 120° C. and allowed to react at this temperature for 2 hours. The resulting dark-brown reaction mixture is cooled to a temperature in the region of 20° C. 60 cm3 of dichloromethane are added. The organic phase is washed with 5 cm3 of a saturated aqueous sodium hydrogen-carbonate solution, 3 times with 5 cm3 of water and then once with 5 cm3 of a saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous sodium sulphate. After filtration and concentration to dryness under reduced pressure, a residue is obtained which is chromatographed on a column of silica gel, eluting with an ethyl ether/hexane (15/85 by volume) mixture. There are obtained, with a yield of 36%, 60 mg (0.18 mmol) of (4S,5S)-3-t-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-methoxycarbonyl-1,3-oxazolidine, the characteristics of which are the following:
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C:5]1[O:6][CH:7]=[CH:8][C:9](=[O:12])[C:10]=1[OH:11].I[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C.O>[OH:3][CH2:4][C:5]1[O:6][CH:7]=[CH:8][C:9](=[O:12])[C:10]=1[O:11][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CCCCCI
Reactant: O=c1ccoc(CO)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCCCOc1c(CO)occc1=O
Yield: 54 %

Procedure:
To a solution of 2.75 g (0.042 mole) of potassium hydroxide in 38 ml of ethanol and 10 ml of water was added 5.93 g (0.042 mole) of 2-hydroxymethyl-3-hydroxy-4-pyrone, and the resulting mixture heated to 50°. A 12.4 g (0.046 mole) portion of ethyl 6-iodohexanoate was then added and the resulting clear solution heated at reflux for 7 hr under a nitrogen atomsphere. Removal of the ethanol under reduced pressure left a residue which was dissolved in methylene chloride. The organic solution was washed successively with aqueous NaHCO3 and saturated brine, was dried over magnesium sulfate, and was evaporated to afford a viscous oil. This material was chromatographed on silica gel eluting with ethyl acetate to give 6.34 g (54%) of oily product, 2-hydroxymethyl-3-(5-carboethoxypentyloxy)-4-pyrone: NMR (CDCl3): δ1.22 (3H, t, J = 7Hz), 2.30 (2H, t, J = 5.5 Hz), 4.63 (2H, s), 6.35 (1H, d, J = 6 Hz), 7.73 (1H, d, J = 6 Hz).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.S(Cl)(Cl)=O.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:1][C:2]1[S:3][C:4]([S:13]([Cl:12])(=[O:15])=[O:14])=[C:5]([CH3:7])[N:6]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1csc(Cl)n1
Solvent: O=S(Cl)Cl
Product: Cc1nc(Cl)sc1S(=O)(=O)Cl
Temperature: 0 °C
Yield: 89.9 %

Procedure:
At room temperature, 150 g (1.12 mol) of 2-chloro-4-methyl-1,3-thiazole are added dropwise to a solution of 331 g (2.81 mol) of thionyl chloride in 653 g (5.61 mol) of chlorosulphonic acid. The solution is heated at reflux for 48 h. The mixture is then poured into 3 l of ice-water and extracted with 4×400 ml of dichloromethane. The combined organic phases are washed with 2.5 l of water, dried over sodium sulphate and concentrated. Distillation of the crude product gives 233.7 g of product in the form of an oil. (Bp 87-96° C., 0.7 mbar, GC 98.1%, yield 89.6%).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[C:11](Cl)=[O:12].[CH3:14][CH:15]([CH3:26])[CH2:16][CH:17]([C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[C:11]([NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=1[CH:17]([CH2:16][CH:15]([CH3:26])[CH3:14])[CH3:18])=[O:12]
Reactant: Cn1nc(C(F)F)c(C(=O)Cl)c1Cl
Reactant: CC(C)CC(C)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CC(C)c1ccccc1NC(=O)c1c(C(F)F)nn(C)c1Cl
Temperature: 20 °C
Reaction time: 8 h

Procedure:
0.458 g (2.00 mmol) of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride is added to a mixture of 0.322 g (1.81 mmol) of 2-(4-methylpentan-2-yl)aniline and 0.377 g (2.72 mmol) of potassium carbonate in 30 mL of acetonitrile, and the mixture is stirred at 20° C. overnight. After the reaction has ended, the mixture is extracted with water/ethyl acetate. The organic phase is dried with sodium sulfate and concentrated under reduced pressure. The crude product is purified by column chromatography (mobile phase: cyclohexane/ethyl acetate gradient). This gives 0.580 g (78% of theory) of 5-chloro-3-(difluoromethyl)-1-methyl-N-[2-(4-methylpentan-2-yl)phenyl]-1H-pyrazole-4-carboxamide having a content of 94% according to LC-MS and a logP (acidic) of 4.01.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17](=[O:20])[NH:16][C:15]=1[CH3:21])=[O:13])[CH3:10].O>C(#N)C>[CH2:9]([O:11][C:12]([C:14]1[CH:19]=[C:18]([I:1])[C:17](=[O:20])[NH:16][C:15]=1[CH3:21])=[O:13])[CH3:10]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1ccc(=O)[nH]c1C
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cc(I)c(=O)[nH]c1C
Temperature: 95 °C

Procedure:
N-Iodosuccinimide (40 g, 180 mmol) was added to a suspension of intermediate (5b), 2-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (18.1 g, 100 mmol) in acetonitrile (400 mL), under a nitrogen atmosphere. The resulting suspension was heated at 95° C. for 5 hours to give an initial orange solution. An off-white precipitate slowly formed. The resulting suspension was allowed to cool and was poured into water (1200 mL) to give an off-white precipitate. The separated by filtration and the solids washed with water (500 mL) to give an off-white powder. The solids were dried in vacuo (60° C.) to give the product as an off-white powder, 28.3 g (92%)
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][NH:6][C:7](=[O:27])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:20]2[CH:21]=[N:22][C:23](Cl)=[CH:24][CH:25]=2)[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34]([C:23]2[N:22]=[CH:21][C:20]([O:19][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:28])=[O:27])=[CH:9][CH:10]=3)[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:25][CH:24]=2)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCCCC(Oc1ccc(Cl)nc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Product: CCCCC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compounds are prepared in a manner substantially similar to Example 62 starting from 3-{4-[1-(6-chloro-pyridin-3-yloxy)-pentyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. Isomer 1 MS: 499.2 [M−H]−; Isomer 2 MS: 499.2 [M−H]−.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH:16]([F:18])[F:17])[C:5]=2[CH2:19][O:20][CH:21]2[CH2:27][CH:26]3[N:28]([C:29]4[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=4[F:37])[CH:23]([CH2:24][CH2:25]3)[CH2:22]2)[CH2:3][CH2:2]1.[N-:38]=[N+:39]=[N-:40].[Na+].[Cl-].[NH4+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH:16]([F:17])[F:18])[C:5]=2[CH2:19][O:20][CH:21]2[CH2:22][CH:23]3[N:28]([C:29]4[CH:36]=[CH:35][C:32]([C:33]5[N:38]=[N:39][NH:40][N:34]=5)=[CH:31][C:30]=4[F:37])[CH:26]([CH2:25][CH2:24]3)[CH2:27]2)[CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(N2C3CCC2CC(OCc2c(-c4ccccc4OC(F)F)noc2C2CC2)C3)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Fc1cc(-c2nn[nH]n2)ccc1N1C2CCC1CC(OCc1c(-c3ccccc3OC(F)F)noc1C1CC1)C2
Temperature: 120 °C
Reaction time: 8 h

Procedure:
4-(3-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorobenzonitrile (70 mg, 0.14 mmol) was dissolved in N,N-dimethylacetamide (2 ml), sodium azide (91 mg, 10 eq, 1.40 mmol) and ammonium chloride (75 mg, 10 eq, 1.40 mmol) were added, and the mixture was stirred at 120° C. overnight. Upon cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL) and washed with brine (2×20 mL). The combined organics were separated, dried (MgSO4), and evaporated in vacuo. The product was purified by mass directed reverse phase HPLC to give a white solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11](Cl)=[O:12])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[C:28]([CH:30]([OH:33])[C:31]#[N:32])[CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:33][CH:30]([C:31]#[N:32])[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([O:23][C:20]3[CH:19]=[CH:18][CH:17]=[CH:22][CH:21]=3)[CH:29]=2)=[O:12])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: CC(C)C(C(=O)Cl)c1ccc(N=[N+]=[N-])cc1
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(N=[N+]=[N-])cc1

Procedure:
2-(4-Azidophenyl)-3-methylbutanoyl chloride, prepared in Example 7, was dissolved in 10 ml of methylene chloride. A solution of 3.79 g of m-phenoxybenzaldehyde cyanohydrin in 10 ml of methylene chloride was added, with cooling by an ice bath, followed by 2.4 ml of triethylamine, causing an exothermic reaction and precipitating white solid. After an hour without cooling, the mixture was evaporated to a residue, which was extracted with diethyl ether, the extract filtered, and the filtrate washed with water and saturated sodium bicarbonate solution, dried (MgSO4), and evaporated to 7.4 g of residual oil, 2-(4-azidophenyl)-3-methylbutanoic acid, α-cyano-3-phenoxybenzyl ester. The infrared spectrum shows absorption peaks at 2130 cm-1 (azide) and 1760 cm-1 (ester carbonyl). Mass spectral analysis showed a molecular ion, m/e 426, corresponding to the product.
Reaction SMILES: [N:1]12[CH2:11][CH2:10][CH2:9]N=[C:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.Cl[C:13]1[N:18]=[C:17]([O:19][CH3:20])[C:16]([N+:21]([O-:23])=[O:22])=[C:15]([O:24][CH3:25])[N:14]=1.C1C2C(=CC=CC=2)CCN1>CN(C=O)C>[CH3:25][O:24][C:15]1[C:16]([N+:21]([O-:23])=[O:22])=[C:17]([O:19][CH3:20])[N:18]=[C:13]([N:1]2[CH2:11][CH2:10][C:9]3[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:7]2)[N:14]=1
Reactant: COc1nc(Cl)nc(OC)c1[N+](=O)[O-]
Reactant: C1CCC2=NCCCN2CC1
Agent: c1ccc2c(c1)CCNC2
Solvent: CN(C)C=O
Product: COc1nc(N2CCc3ccccc3C2)nc(OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.5 %

Procedure:
1,8-diazabicyclo[5.4.0]undec-7-ene (0.304 g, 2 mmol) was added to a mixture of 4a (0.438 g, 2 mmol) and 1,2,3,4-tetrahydroisoquinoline (0.293 g, 2.2 mmol) in DMF (3 ml) at 0° C. over 5 minutes. The mixture was stirred for an additional 5 minutes at room temperature. The mixture was washed with brine, extracted with ethyl acetate and chromatographed to yield 4b (0.592 g, 1.87 mmol, 94%).