Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][O:19][NH:20][CH3:21].O.N1(O)C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[N:20]([O:19][CH3:18])[CH3:21])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N,N-dimethylformamide. O,N-dimethyl-hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylanine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0° C., N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 1.0 minutes and the mixture was stirred vigorously at 0° C. for 1 h and at r.t. for 18 h.
Reaction SMILES: CCOCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([Mg]Br)=[CH:9][CH:8]=1.[F:15][C:16]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:17]=1[C:18](N(OC)C)=[O:19]>C1COCC1>[F:15][C:16]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:17]=1[C:18]([C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=1)=[O:19]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1F
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(c1ccc(F)cc1)c1cccc(C(F)(F)F)c1F
Temperature: 50 °C
Yield: 0.7 %

Procedure:
2M Et2O solution of 4-fluorophenylmagnesium bromide (32.5 ml; 65 mmol) was added to a solution of 12.8 g (65 mmol) of 2-fluoro-N-methoxy-N-methyl-3-trifluoromethyl-benzamide in 150 ml of THF at 0° C. The reaction mixture was heated overnight at 50° C. The reaction mixture was partitioned with EtOAc and H2O. The organic phases were washed with brine and dried over Na2SO4. The resulting ketone (135 mg) was obtained after flash chromatographic purification using hexane/CH2Cl2 (3:1, v/v) as an eluent.
Reaction SMILES: [CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[CH2:12][CH:11]([CH3:16])[CH2:10][CH2:9][C:8]=2[N:7]([C:17]2[C:18]([CH3:32])=[C:19](C([O-])=O)[C:20](C3C=CC=CC=3)=[CH:21][CH:22]=2)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:33]([OH:36])(=[O:35])[CH3:34]>[OH-].[Na+]>[CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[CH2:12][CH:11]([CH3:16])[CH2:10][CH2:9][C:8]=2[N:7]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:6]3[C:34]([C:33]([OH:36])=[O:35])=[CH:3][CH:2]=[CH:1][CH:5]=3)=[CH:22][CH:32]=2)[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCc1cn(-c2ccc(-c3ccccc3)c(C(=O)[O-])c2C)c2c(c1=O)CC(C)CC2
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1cn(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2c(c1=O)CC(C)CC2
Temperature: 60 °C

Procedure:
Using the procedure of Example 31, 0.4 g of product A of Example 32 in 10 ml of 2N sodium hydroxide were reacted. The mixture was stirred over-night at about 60° C. and the medium was cooled to ambient temperature, acidified with glacial acetic acid, decanted, impasted in a solution of 2N hydrochloric acid, separated, dried and crystallized from 50 ml of an ethanol-water 49-1 mixture to obtain 0.220 g of the expected product melting at 255° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:24]([CH3:26])[CH3:25])[C:7]([N:9]1[C@H:13]([C:14]([O:16]CC)=[O:15])[CH2:12][C:11]2([CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:10]1)=[O:8])=[O:4].C1COCC1.[Li+].[OH-]>C(O)(C)(C)C>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:24]([CH3:26])[CH3:25])[C:7]([N:9]1[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][C:11]2([CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[CH2:10]1)=[O:8])=[O:4]
Reactant: CCOC(=O)[C@@H]1CC2(CCOCC2)CN1C(=O)[C@@H](NC(=O)OC)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: COC(=O)N[C@H](C(=O)N1CC2(CCOCC2)CC1C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
In a 10 mL round-bottomed flask, (S)-ethyl 2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-8-oxa-2-azaspiro[4.5]decane-3-carboxylate (300 mg, 810 μmol) was combined with THF 6(ml) and tert-butanol (1 ml) to give a colorless solution. LiOH (1.0M, 1.62 ml, 1.62 mmol, Eq: 2) was added and stirred at room temperature for 2 hr. Then more LiOH (1.0M, 1 ml, 1 mmol) was added and stirred for an another 2 hr. THF was removed and the aqueous was acidified with 1N HCl to pH=3 and diluted with EtOAc (100 ml). It was washed with brine (10 ml), dried with MgSO4, filtered and concentrated to afford 2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-8-oxa-2-azaspiro[4.5]decane-3-carboxylic acid as a white solid (270 mg, 97.4%). ESI-LRMS m/e calcd for C16H26N2O6 [M+] 342. found 341 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:18]=[O:19])[CH:14]=2)[N:9]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:8]1=[O:26].[BH4-].[Na+]>CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][OH:19])[CH:14]=2)[N:9]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:8]1=[O:26]
Reactant: COc1ccc(Cn2c(=O)c3cc(C=O)ccc3n(C3CCOCC3)c2=O)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c3cc(CO)ccc3n(C3CCOCC3)c2=O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
A mixture of 0.575 g of the compound obtained in Step 14.2 and 0.077 g of NaBH4 in a mixture of 20 ml of MeOH and 10 ml of THF is stirred for 30 minutes at room temperature. The reaction medium is evaporated under reduced pressure. The residue is taken up in DCM. This solution is washed with saturated NH4Cl solution. The organic phase is dried over Na2SO4, filtered and evaporated under reduced pressure to give 0.554 g of the expected product.
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=1)[CH:7]=[CH:6][CH:5]=2.[CH:25]1([Mg]Br)[CH2:27][CH2:26]1.O1CCCC1.Cl>C1(C)C=CC=CC=1>[CH:25]1([C:2]2[CH2:3][C:4]3[C:9]([CH:10]=2)=[C:8]([C:11]2[CH:12]=[C:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:16]=2)[CH:7]=[CH:6][CH:5]=3)[CH2:27][CH2:26]1
Reactant: CC(C)(C)c1cc(-c2cccc3c2C=C(Br)C3)cc(C(C)(C)C)c1
Reactant: Br[Mg]C1CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(-c2cccc3c2C=C(C2CC2)C3)cc(C(C)(C)C)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
A solution of compound 6 (16.1 g, 42.0 mmol, 1 equiv) and anhydrous toluene (200 mL) was treated with [1,1′-bis(diphenylphos-phino)ferrocene]dichlopalladium(II) DCM adduct (3.43 g, 4.2 mmol, 0.1 equiv). After stirring for 10 minutes, 0.5 M cyclopropylmagnesium bromide in tetrahydrofuran (420 mL, 210 mmol, 5 equiv) was added dropwise. The reaction was heated at 60° C. overnight. The reaction was cooled with an ice bath, acidified with 1N HCl to pH 3 and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with saturated brine (800 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified on an AnaLogix (65-200 g) column with dry-loading, eluting with heptanes to give compound 7 (7.0 g, 48% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH:7]=1.[Na].[CH3:20][OH:21]>>[CH3:20][O:21][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH:7]=1
Reactant: Cc1ccccc1Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CO
Agent: [Na]
Product: COc1ccc([N+](=O)[O-])c(Nc2ccccc2C)c1
Temperature: 0 °C

Procedure:
1 g of 5-chloro-2-nitrophenyl-o-tolylamine was added to a solution of 1 g of sodium in 20 ml of methanol, and it was refluxed for 72 hours. Then, it is cooled to 0° C., and the crystalline product is suctioned off.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14](S(C)=O)=[N:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[NH2:27]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:27][C:26]4[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:24]([O:23][CH3:22])[CH:25]=4)=[N:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: COc1ccc(Cl)cc1-c1ccc2cnc(S(C)=O)nn12
Solvent: CN1CCCC1=O
Product: COc1ccc(Cl)cc1-c1ccc2cnc(Nc3cc(OC)c(OC)c(OC)c3)nn12
Temperature: 140 °C
Yield: 28.4 %

Procedure:
7-(5-Chloro-2-methoxy-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (75.0 mg, 0.000233 mol) and 3,4,5-Trimethoxyaniline (51 mg, 0.00028 mol) were dissolved in N-Methylpyrrolidinone (5.00 mL) and the reaction was heated at 140° C. until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 29.22 mg of [7-(5-Chloro-2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)-amine as a lyophilated powder. (M+H)=441.09. 1H NMR (400 MHz, DMSO, d6) δ 9.29 (s, 1H), 8.97 (s, 1H), 7.73 (s, 1H), 7.45 (m, 1H), 7.22 (d, 1H, J=8.84 Hz), 7.02 (s, 2H), 6.92 (m, 2H), 3.76 (s, 3H), 3.57 (s, 3H), 3.49 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].[Br:16]Br.O>C(O)(=O)C>[NH2:1][C:2]1[C:3]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:9][C:10]=1[Br:16]
Reactant: Nc1ccc(C(=O)O)cc1OC(F)(F)F
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(Br)cc(C(=O)O)cc1OC(F)(F)F
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a solution of 4-amino-3-trifluoromethoxybenzoic acid (5 g, 22.6 mmoles) in acetic acid (50 mL), bromine (3.98 g, 24.9 mmoles) in acetic acid (10 mL) was added dropwise at room temperature. After the reaction mixture was kept stirring for one hour, water was added into the mixture. The solid was filtered and washed with water to give 4-amino-3-bromo-5-trifluoromethoxybenzoic acid (3.9 g, 54.9%).
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([N:27](CC3C=CC(OC)=CC=3OC)[C:28]3[S:32][N:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:21][CH:22]=2)[N:17]([CH3:44])[CH:16]=1>>[CH3:44][N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([S:24]([NH:27][C:28]3[S:32][N:31]=[CH:30][N:29]=3)(=[O:25])=[O:26])[CH:19]=2)[C:15]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:16]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Reactant: OB(O)c1cccc2ccccc12
Product: Cn1cc(-c2cccc3ccccc23)c2ccc(S(=O)(=O)Nc3ncns3)cc21

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using naphthalen-1-ylboronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 1-methyl-3-(naphthalen-1-yl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.98 (s, 3 H) 7.37 (d, J=8.36 Hz, 1 H) 7.44-7.48 (m, 2 H) 7.51-7.62 (m, 3 H) 7.80 (s, 1 H) 7.93 (dd, J=8.19, 4.64 Hz, 2 H) 7.97-8.03 (m, 2 H) 8.08 (s, 1 H). m/z (ESI) 420.1 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:22][CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=2)[OH:23])=[O:30])=[CH:27][CH:26]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (200 mg, 0.57 mmol) in ethyl acetate (5 ml) were added 4-fluorobenzoyl chloride (136 mg, 0.86 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization from ethyl acetate-hexane gave the title compound (182 mg, 73%).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[F:15][C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[CH:20][CH:21]=1>[N+](C1C=CC=CC=1)([O-])=O>[F:15][C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[CH:20][C:21]=1[C:10]([C:9]1[CH:13]=[CH:14][C:6]([F:5])=[CH:7][CH:8]=1)=[O:11]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2ccc(F)cc2)c(F)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 24.5 %

Procedure:
To a cold (5° C.) mixture of aluminium trichloride (144 g, 1.08 mol, 1.13 eq.) in nitrobenzene (450 mL) was slowly added a solution of 4-fluorobenzoyl chloride (120 mL, 1 mol, 1.05 eq.) in nitrobenzene (200 mL). 3-fluoroanisole (108.5 mL, 0.95 mol) was slowly added to the reaction mixture. The cooling bath was removed and the reaction mixture was stirred 3 h at 20° C., and poured into ice-water. The aqueous layer was extracted with dichloromethane (2 times). The combined organic layers were dried over sodium sulfate, filtered and the volatiles were removed in vacuo. The crude mixture was crystallized in cyclohexane, filtered and the solid was washed with cyclohexane. The solid was dried in vacuo, affording the title compound (57.78 g, 25%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].CS(O)(=O)=O.O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:14][C:13]2[CH:15]=[CH:16][C:10]([CH3:9])=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(Nc2ncc(Br)cn2)cc1[N+](=O)[O-]

Procedure:
5-Bromo-2-chloropyrimidine 4 (50 mmol), 4-methyl-3-nitroaniline (60 mmol) and methylsulphonic acid (15 mmol) are heated at reflux in 1,4-dioxane (100 mL) for 16 h. The mixture is poured into water, filtered and dried under vacuum to give 5-bromo-N-(4-methyl-3-nitrophenyl)pyrimidin-2-amine 27 as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 10.25 (s, 1H), 8.68 (s, 2H), 8.49 (d, J=2.0 Hz, 1H), 7.86 (dd, J=2.4, 8.4 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 2.46 (s, 3H). MS (m/z) (M+1)+: 309.0, 311.0.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Br:10])=[CH:5][CH:4]=1.[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>C1(C)C=CC=CC=1>[Br:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][P:14]([O:15][CH2:16][CH3:17])([O:13][CH2:11][CH3:12])=[O:18])=[CH:4][CH:5]=1
Reactant: BrCc1ccc(CBr)cc1
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc(CBr)cc1)OCC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
α,α'-Dibromo-p-xylene (22.9 gm) was combined with toluene (70 mL) and heated to reflux. Once the dibromide had completely dissolved, triethylphosphite (5.9 mL) was added all at once and heating continued for 6 hours. The reaction mixture was allowed to cool to room temperature and the excess solid dibromide was removed by suction filtration and washed with a small amount of methylene chloride. The organic solutions were combined and concentrated, on a rotatory evaporator, to a white solid. The solid was taken up in methylene chloride (50 mL) and chromatographed on silica (350 gm). The column was eluted with methylene chloride and fractions of about 25 mL were collected The first peak eluted in fractions 14-24 (excess dibromide), then the solvent was changed to 5% ethanol/methylene chloride. The second major peak, fractions 37-53, was the desired product obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:7][CH:8]=[CH2:9])[C:3](OC)=[O:4].O.[NH2:12][NH2:13]>CO>[CH3:1][C:2]([CH3:10])([CH2:7][CH:8]=[CH2:9])[C:3]([NH:12][NH2:13])=[O:4]
Reactant: NN
Reactant: C=CCC(C)(C)C(=O)OC
Solvent: CO
Solvent: O
Product: C=CCC(C)(C)C(=O)NN
Temperature: 60 °C

Procedure:
To a solution of methyl 2,2-dimethyl-4-pentenoate (1 g) in MeOH (2 ml) was added hydrazine monohydrate (2.7 ml). The solution was heated in a close microwave vial at 60° C. for 12 h. Volatiles were evaporated in vacuo to give 1 g of the title compound as a yellow pale foam, which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[N:12]=1)([CH3:10])([CH3:9])[CH3:8]>CCO>[C:7]([C:11]1[N:12]=[C:13]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[CH:14]=[C:15]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[N:16]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: C1CNCCN1
Reactant: CC(C)(C)c1nc(Cl)cc(C2CCC2)n1
Solvent: CCO
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Yield: 87.4 %

Procedure:
piperazine (7.54 g, 87.57 mmol) was dissolved in EtOH, 2-tert-butyl-4-chloro-6-cyclobutyl-pyrimidine (3.28 g, 14.60 mmol) was added dropwise at 80° C. over 10 min The solution was refluxed overnight and then concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (3.5 g, 87%).
Reaction SMILES: CCN=C=NCCCN(C)C.OC(C(F)(F)F)=O.[NH2:19][CH2:20][C:21]([NH:23][CH:24]1[CH2:27][N:26]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25]1)=[O:22].[Br:40][C:41]1[CH:42]=[C:43]([C:50]([F:53])([F:52])[F:51])[CH:44]=[C:45]([CH:49]=1)[C:46](O)=[O:47]>>[Br:40][C:41]1[CH:49]=[C:45]([CH:44]=[C:43]([C:50]([F:51])([F:52])[F:53])[CH:42]=1)[C:46]([NH:19][CH2:20][C:21](=[O:22])[NH:23][CH:24]1[CH2:27][N:26]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25]1)=[O:47]
Reactant: NCC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1cc(Br)cc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from the EDCI coupling of 2-amino-N-[1-(4-phenyl-cyclohexyl)-azetidin-3-yl]-acetamide TFA salt (as prepared in Step D of Example 66) and 5-bromo-3-trifluoromethyl-benzoic acid (Aldrich) using the procedure described in Step F of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[F:20][C:21]([F:32])([C:28]([F:31])([F:30])[F:29])[C:22]([F:27])([F:26])[C:23](Cl)=[O:24]>ClCCl>[F:26][C:22]([F:27])([C:21]([F:20])([F:32])[C:28]([F:29])([F:30])[F:31])[C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1)=[O:24]
Reactant: Nc1ccc(CCO)cc1
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(CCO)cc1)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a 0° C. solution of 2-[(4-amino)phenyl]ethanol (25 g), diisopropylethylamine (23.9 g) and dichloromethane (400 mL) was added heptafluorobutyryl chloride (41.8 g) dropwise over 0.5 hour. The mixture was allowed to warm gradually to room temperature and stirred for 2 hours. The precipitate was filtered off and the filtrate was diluted with ethylacetate (100 mL), washed with water (3×500 mL), dried over sodium sulfate, filtered and concentrated with a rotary evaporator. The residue was triturated with dichloromethane and collected by filtration. The combined solids were dissolved in diethyl ether and washed with water and saturated aqueous sodium chloride solutions, dried over sodium sulfate, filtered and concentrated to give 2,2,3,3,4,4,4-heptafluoro-N-[4-(2-hydroxyethyl)phenyl]butanamide as a white solid (39.2 g).
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)=O.O.O.[NH2:25]N>CO>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:4]2[C:5]([C:7]3[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=3)=[N:25][NH:2][CH:3]=2)=[CH:16][CH:17]=1
Reactant: NN
Reactant: CSc1ccc(C(=O)C(=CN(C)C)c2ccc(F)cc2)cc1
Solvent: CO
Solvent: O
Product: CSc1ccc(-c2n[nH]cc2-c2ccc(F)cc2)cc1
Yield: 90.1 %

Procedure:
The crude ketone from step 1 (23.9 g) was stirred in 500 mL methanol and 100 mL water with 8 mL hydrazine hydrate at reflux under nitrogen for 24 hour. The mixture was cooled, concentrated, diluted with ethyl acetate, washed successively with 1N HCl and brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from ethyl acetate-hexane gave 4-(4-fluorophenyl)-3-[4-(methylthio)phenyl]-1H-pyrazole as a pale yellow solid (16.9 g, 90.1%). Elemental analysis Calc'd for C16H13 N2FS: C, 67.58, H, 4.61, N, 9.85, S, 11.28. Found: C, 67.44, H, 4.76, N, 9.69, S, 11.27.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:47]=[CH:46][C:27]4[C:28]([NH:31][C:32]([C@@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5C(OC(C)(C)C)=O)=[O:33])=[N:29][O:30][C:26]=4[CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49]>C(Cl)Cl>[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:47]=[CH:46][C:27]4[C:28]([NH:31][C:32]([C@@H:34]5[CH2:38][CH2:37][CH2:36][NH:35]5)=[O:33])=[N:29][O:30][C:26]=4[CH:25]=3)=[CH:22][CH:23]=2)=[CH:16][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1noc2cc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1noc2cc(-c3ccc(-c4cnc([C@@H]5CCCN5)[nH]4)cc3)ccc12)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
A solution of (S)-tert-butyl 2-(6-(4-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)benzo[d]isoxazol-3-ylcarbamoyl)pyrrolidine-1-carboxylate (0.115 mg, 0.178 mmol) in CH2Cl2 (3 mL) was treated with TFA (1 mL) and the solution was allowed to stir at rt for 2 h. The solvents were removed in vacuo and the residue was purified by prep HPLC (CH3CN—H2O-TFA) to give the TFA salt of the title compound (74.8 mg, 53%) as a colorless glass. 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 9.53-9.58 (m, 1H), 9.30-9.36 (m, 1H), 8.97-9.04 (m, 1H), 8.79-8.84 (m, 1H), 8.10 (d, J=8.6 Hz, 1H), 8.06 (s, 1H), 7.93 (AB doublet of AB quartet 2H), 7.86 (AB doublet of AB quartet 2H), 7.78-7.83 (m, 1H), 4.73-4.78 (m, 2H), 4.51-4.54 (m, 2H), 3.28-3.38 (m, 4H), 1.95-2.22 (m, 6H). LCMS: Anal. Calcd. for C25H26N6O2: 442; found: 443 (M+H)+.