Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].[CH:41]1([B-](F)(F)F)[CH2:43][CH2:42]1.[K+].Cl[C:50]1[CH:51]=[C:52]2[C:57](=[C:58]([CH:60]=[O:61])[CH:59]=1)[O:56][C:55]([CH3:63])([CH3:62])[CH2:54][CH2:53]2>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:41]1([C:50]2[CH:51]=[C:52]3[C:57](=[C:58]([CH:60]=[O:61])[CH:59]=2)[O:56][C:55]([CH3:63])([CH3:62])[CH2:54][CH2:53]3)[CH2:43][CH2:42]1
Reactant: CC1(C)CCc2cc(Cl)cc(C=O)c2O1
Reactant: F[B-](F)(F)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Product: CC1(C)CCc2cc(C3CC3)cc(C=O)c2O1

Procedure:
Using essentially the same procedure as Example 5-22, Step 4, Pd(OAc)2 (7.04 mg, 0.03 mmol), X-Phos (29.9 mg, 0.06 mmol), potassium carbonate (434 mg, 3.14 mmol), potassium cyclopropyltrifluoroborate (170 mg, 1.15 mmol) and 6-chloro-2,2-dimethyl-3,4-dihydro-2H-chromene-8-carbaldehyde (235 mg, 1.05 mmol, Example 5-26, Step 3) afforded the desired product as a pale-yellow oil.
Reaction SMILES: [C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:19]([CH3:20])[C@@H:6]1[CH2:7][CH2:8]2)([O:3]C)=[O:2]>O1CCOCC1.O>[C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[CH2:10][C@H:9]2[N:19]([CH3:20])[C@@H:6]1[CH2:7][CH2:8]2)([OH:3])=[O:2]
Reactant: COC(=O)[C@H]1[C@@H](c2ccc(F)cc2)C[C@@H]2CC[C@H]1N2C
Solvent: O
Solvent: C1COCCO1
Product: CN1[C@H]2CC[C@@H]1[C@@H](C(=O)O)[C@@H](c1ccc(F)cc1)C2

Procedure:
2β-Carbomethoxy-3β-(4-fluorophenyl)tropane (WIN 35,428) (1), is boiled for 24 h in a 1:1 dioxane-water solution. The solvent is removed in vacuo and the residue is almost completely dissolved in CHCl3. Remaining undissolved solid can then be filtered off, toluene can then be added, and the volume of the solution is reduced in vacuo to approximately 25%. Cooling the resulting white suspension in a freezer for 2 h will provide a precipitated solid which can then be isolated by filtration and is washed with cold 1:1 CHCl3-toluene. The solid can then be pumped dry to give the product.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:24]>C(Cl)(Cl)Cl>[C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:10]=[CH:9][N+:8]=2[O-:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cccnc2-c2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cccc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.2 %

Procedure:
1 g of 2,3-diphenylpyridine was dissolved in chloroform and 1.4 g of 70% m-chloroperoxybenzoic acid was added, followed by stirring at room temperature for 15 hours. After the reaction solution was washed with an aqueous 5% potassium carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to obtain 1.3 g of a crude crystal. The crude crystal was washed with diisopropyl ether to obtain 922 mg of the desired compound as a colorless crystal having a melting point of 167 to 170° C.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@@H:2]([C:11]([OH:13])=O)[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].[NH2:24][C@H:25]([C:29]([NH:31][C@H:32]([C:45]([O:47][CH3:48])=[O:46])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:36][CH:35]=1)=[O:30])[CH:26]([CH3:28])[CH3:27].Cl.CO>CN(C)C=O>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@@H:2]([C:11]([NH:24][C@H:25]([C:29]([NH:31][C@H:32]([C:45]([O:47][CH3:48])=[O:46])[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[CH:38][CH:39]=1)=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:13])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(C)C

Procedure:
6.46 g (20 mmoles) of Z-D-Asp(OBut)-OH are subjected to a condensation reaction with 7.73 g (20 mmoles) of H-Val-Tyr(But)-OMe.HCl in 50 ml of dimethylformamide analogously to Examples 38 A. Yield 11.2 g (85%), melting point 90°-92°, [α]D27 =-3.5° (c=1, methanol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:9]([CH3:10])[CH2:8][CH2:7][CH2:6][CH:5]1[CH3:11].[C:12]([N:16]=[C:17]=[S:18])(=[O:15])[CH2:13][CH3:14]>>[C:12]([NH:16][C:17]([NH:1][CH2:2][CH2:3][N:4]1[CH:9]([CH3:10])[CH2:8][CH2:7][CH2:6][CH:5]1[CH3:11])=[S:18])(=[O:15])[CH2:13][CH3:14]
Reactant: CCC(=O)N=C=S
Reactant: CC1CCCC(C)N1CCN
Product: CCC(=O)NC(=S)NCCN1C(C)CCCC1C

Procedure:
By the general method described in Example 1, 1-(2-aminoethyl)-2,6-dimethylpiperidine is reacted with propionyl isothiocyanate to give the title compound which may be hydrolysed with 10% sodium hydroxide to give N-2[(2,6-dimethylpiperidino)-ethyl]thiourea.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:8]2[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)#[N:2].[N-:35]=[N+:36]=[N-:37].[Na+].[Cl-].[NH4+].O>CS(C)=O>[CH2:15]([C:10]1[C:9]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:8]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH2:3][C:1]3[N:35]=[N:36][NH:37][N:2]=3)[CH:6]=2)[N:11]=1)[CH:16]([CH3:17])[CH3:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCC#N)cc23)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCc4nn[nH]n4)cc23)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 93.5 %

Procedure:
To a solution of tert-butyl {[6-(cyanomethoxy)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (0.46 g, 1.0 mmol) and sodium azide (0.13 g, 2.0 mmol) in dimethyl sulfoxide (10 ml) was added ammonium chloride (0.22 g, 4.0 mmol), and the mixture was stirred at 70° C. for 24 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give tert-butyl {[2-isobutyl-4-(4-methylphenyl)-6-(2H-tetrazol-5-ylmethoxy)quinolin-3-yl]methyl}carbamate (0.47 g, yield 93%) as pale-yellow crystals.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[CH:26]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Oc1cccc(Cl)c1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 48 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3-chlorophenol: 1H-NMR (CDCl3) δ 8.55 (1H, d, J=2.7 Hz), 8.15 (1H, d, J=2.7 Hz), 8.05–7.97 (3H, m), 7.45–7.37 (3H, m), 7.33–7.28 (1H, m), 7.21–7.18 (1H, m), 7.09–7.03 (1H, m), 5.42–5.31 (1H, m), 3.90 (3H, s), 1.60 (3H, d, J=7.0 Hz); MS (ESI) m/z 445 (M+H)+, 443 (M−H)−.
Reaction SMILES: [S:1]([CH2:11][N+:12]#[C-:13])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][C:16]=1[F:23].[C-]#N.[Na+]>>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([C@H:19]2[O:20][CH:13]=[N:12][C@@H:11]2[S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])=[CH:17][C:16]=1[F:23]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [C-]#N
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)[C@H]2N=CO[C@@H]2c2ccc(Cl)c(F)c2)cc1

Procedure:
In a manner analogous to Preparation 1, tosylmethylisocyanide (0.30 g, 1.52 mmol), 4-chloro-3-fluorobenzaldehyde (0.25 g, 1.60 mmol) and NaCN (10 mg, 0.20 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 373.5 (M+Na+).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]3=[N:22][CH:23]=[C:24]([CH3:25])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[Sn](Cl)Cl.CCCC[N+](CCCC)(CCCC)CCCC.[FH:50].F.[F-]>>[F:50][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]3=[N:22][CH:23]=[C:24]([CH3:25])[N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: F
Reactant: Cc1cnc2n1N=C(c1ccc(N)cc1)c1cc3c(cc1C2)OCO3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Product: Cc1cnc2n1N=C(c1ccc(F)cc1)c1cc3c(cc1C2)OCO3
Temperature: 7.5 °C
Reaction time: 0.67 h
Yield: 52.5 %

Procedure:
First 200 mg of 5-(4-aminophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine is added to a solution of 6 ml of hydrogen fluoride-pyridine complex (1:1) under argon, and then 51 mg of sodium nitrite is added at 0-5° C. After stirring at 5-10° C. for 40 minutes, 117 mg of tin(II) chloride and 190 mg of tetrabutylammonium dihydrogen trifluoride are added to the preparation. It is then heated for 3 hours to a bath temperature of 100° C. After cooling, it is added to ice water and extracted three times with ethyl acetate and three times with methylene chloride. The collected organic phase is dried, filtered, concentrated by evaporation and chromatographed on silica gel first with methylene chloride:ethanol=10:1, then a second time with acetone:ethyl acetate=3:1 and then a third time with methylene chloride:ethanol=95:5. 106 mg of 5-(4-fluorophenyl)-8-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine with a melting point of 190° C. is obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][C@@H:9]1[O:11][CH2:10]1.CC(C)([O-])C.[K+].O1CCCC1>C(O)(C)(C)C>[O:11]1[CH2:10][CH:9]1[CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: ClC[C@H]1CO1
Reactant: C1COCCN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: C1CN(CC2CO2)CCO1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
Morpholine 53a (8.712 ml, 0.1 mol) was dissolved in tert-butanol (4.5 ml) under stirring at room temperature, and (R)-(−)-1-chloro-2,3-epoxypropane (8.05 ml, 0.1 mol) was added slowly to the solution at 0° C. in an ice-water bath. Upon completion of the addition, the ice-water bath was removed, and the reaction mixture was allowed to warm up to room temperature and stirred for 24 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added dropwise with a solution of potassium tert-butoxide in tetrahydrofuran (60 ml, 1.67 mol/L, 100 mmol) while maintaining the temperature below 10° C. in an ice-water bath, gradually turned from light yellow to white turbid solution and stirred for 30 minutes. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure, added with water (50 ml), exacted with dichloromethane (100 ml×2). The combined organic extracts were washed with saturated brine (100 ml), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the title compound 4-oxiranylmethyl-morpholine 53b (12.7 g, yield 88.8%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1.Br[CH2:20][CH:21]1[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:10]([CH2:20][CH:21]3[CH2:23][CH2:22]3)[C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Reactant: BrCC1CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1CC1CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
In a 15 mL reaction tube was added 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (300 mg, 0.983 mmol), (bromomethyl)cyclopropane (0.114 mL, 1.180 mmol) and potassium carbonate (408 mg, 2.95 mmol) in anhydrous N,N-dimethylformamide (1 mL) to give a brown suspension. This was stirred at 50° C. under a nitrogen atmosphere for 60 minutes. The reaction mixture was diluted with saturated sodium bicarbonate solution (5 mL) and extracted into ethyl acetate (3×5 mL). The combined organic phases were washed with 50:50 water:brine (3×5 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a brown solid. This was purified by Biotage chromatography (25 g silica cartridge, cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the title compound as a beige solid (160 mg, 0.445 mmol, 45.3% yield). 1H NMR (500 MHz, CDCl3): 7.58-7.37 (5H, m), 7.32 (1H, s), 4.88 (2H, s), 3.81 (2H, d), 1.14-1.01 (1H, m), 0.60-0.53 (2H, m), 0.47-0.40 (2H, m).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14]O)=[CH:8][CH:7]=1.C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N-:36]=[N+:37]=[N-:38].[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.CN(C=O)C>[N:36]([CH2:14][CH2:13][C:12]([C:9]1[CH:10]=[CH:11][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][CH:8]=1)([CH3:17])[CH3:16])=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(CCO)c1ccc(-c2ccco2)cc1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(CCN=[N+]=[N-])c1ccc(-c2ccco2)cc1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
To a cooled solution (0° C.) of 3-(4-furan-2-yl-phenyl)-3-methyl-butan-1-ol (1.2 g, 5.2 mmol) (reference example 22) in CH2Cl2 (17 mL) is added triethylamine (0.86 mL, 6.2 mmol), p-toluenesulfonyl chloride (1.18 g, 6.2 mmol) and 4-dimethylaminopyridine (305 mg, 2.5 mmol). The resulting solution is allowed to warm to 20° C. while stirring for 1.5 h then diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated. The residue is dissolved if DMF (17 mL), sodium azide (845 mg, 13 mmol) added and the mixture heated to 60° C. and stirred for 3 h. The mixture is cooled to 20° C., then diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 10% ethyl acetate in hexanes) to give 1.06 g of title compound as a colorless oil. 1H NMR (CDCl3) δ 1.36 (s, 6H), 1.95 (t, J=8 Hz, 2H), 3.03 (t, J=8 Hz, 2H), 6.46 (m, 1H), 6.62 (m, 1H), 7.34 (d, J=8 Hz, 2H), 7.46 (d, J=2 Hz, 1H), 7.62 (d, J=8 Hz, 2H). MS (ion spray) m/z 256 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:15][C:16]1([F:23])[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1.CCN(C(C)C)C(C)C>CC(O)C>[F:15][C:16]1([F:23])[CH2:21][CH2:20][CH:19]([NH:22][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Reactant: NC1CCC(F)(F)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccc2c(NC3CCC(F)(F)CC3)ncnc12
Yield: 61.2 %

Procedure:
A solution of 4-chloro-8-nitroquinazoline (Intermediate-7, step 2, 200 mg, 0.954 mmol), 4,4-difluorocyclohexanamine (491 mg, 2.86 mmol) and DIPEA (367 mg, 2.86 mmol) in iPrOH (2 mL) was heated in a sealed tube at 80° C. for 2 h. Then the reaction mixture was quenched with water at rt and was extracted with CHCl3. The organic layer was separated, dried, filtered and concentrated. The concentrate was purified by column chromatography using 3-5% EtOAc in CHCl3 to afford 180 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.59-8.55 (m, 2H), 8.43-8.40 (d, J=7.2 Hz, 1H), 8.27-8.25 (d, J=7.8 Hz, 1H), 7.69-7.63 (t, J=7.8 Hz, 1H), 4.41 (m, 1H), 2.26-2.00 (m, 6H), 1.75-1.71 (m, 2H); MS (m/z): 309.18 (M+H)+.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[C:6]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][C:9]([CH2:12][C:13](O)=[O:14])=[CH:8][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:6]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][C:9]([CH2:12][C:13]([N:3]([O:4][CH3:5])[CH3:2])=[O:14])=[CH:8][CH:7]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (550 mg, 5.6 mmol) was added to a mixture of biphenyl-4-ylacetic acid (Aldrich, Cat. #196487) (1 g, 5 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.5 g, 5.6 mmol), and N,N-diisopropylethylamine (1.6 mL, 9.4 mmol) in N,N-dimethylformamide (20 mL). The reaction was stirred for 3 h. at r.t., and was partitioned between water and ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was purified by Flash chromatography on a silica gel column (EtOAc:Hexane, 1:3 to 1:1) gave 2-biphenyl-4-yl-N-methoxy-N-methylacetamide (0.9 g, 70%) as a white solid. Analytical LCMS (M+H)+: m/z=255.9.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:49])[CH2:14][CH:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:27](=[O:48])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:45])=[O:37])=[C:31]([O:46][CH3:47])[CH:30]=1)[CH2:22][CH2:21][NH:20]2)[CH3:16])[CH3:11].C(N(CC)CC)C.O>O1CCCC1>[CH2:10]([O:12][C:13](=[O:49])[CH2:14][CH:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:27](=[O:48])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH3:45])=[O:37])=[C:31]([O:46][CH3:47])[CH:30]=1)[CH2:22][CH2:21][N:20]2[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16])[CH3:11]
Reactant: CCOC(=O)CC(C)c1ccc2c(c1)NCCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CC(C)c1ccc2c(c1)N(C(=O)c1ccccc1)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzoyl chloride (22 μl) was added to a stirred mixture of 3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-1,2,3,4-tetrahydro-quinoxalin-6-yl)-butyric acid ethyl ester (0.110 g, Reference Example 17) and triethylamine (87.8 μl) in tetrahydrofuran (10 ml) cooled to 0° C. under an argon atmosphere. The mixture was stirred for 1 hour at 0° C., then allowed to warm to 20° C., then stirred at this temperature for 2 hours and then treated with a further aliquot of benzoyl chloride (11 μl). After stirring overnight the reaction mixture was treated with water (20 ml) then extracted three times with ethyl acetate (25 ml). The combined extracts were dried over magnesium sulfate then evaporated (40° C., 40 mbar). The crude residue (147 mg) was subjected to flash chromatography on silica (20 g, 0.040-0.063 mm particle size) eluting with a mixture of dichloromethane and methanol (99:1, v/v) to give the title compound as a white foam (132 mg). TLC: RF 13/56 (cyclohexane:ethyl acetate, 9:1, v/v). 1H NMR [400 HMz, (CD3)2SO, at a temperature of 383° K.]: δ0.96 (d, J=7 Hz, 3H); 1.16 (t, J=7 Hz, 3H); 2.24 (d, J=7.5 Hz, 2H); 2.28 (s, 3H); 2.93 (m, 1H); 3.83 (s, 3H); 3.94 (m, 2H); 3.96 (s, 21H); 4.02 (m, 2H); 4.04 (q, J=7 Hz, 2H); 6.63 (broad s ,1H); 6.76 (broad d, J=8 Hz, 1H); 6.90 (broad s, 1H); 6.99 (m, 2H); from 7.10 to 7.20 (m, 4H); 7.34 (broad t, J=7.5 Hz, 2H); 7.41 (broad t, J=7.5 Hz, 1H); 7.57 (d, J=8 Hz, 1H); 7.67 (broad d, J=8 Hz, 1H); 8.02 (d, J=8.5 Hz, 1H); 8.16 (broad s, 1H); 8.24 (broad s, 1H). MS (EI): 648 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[C:13]([CH3:14])=[N:12][C:11](C)=[N:10]1.[C:16]([Cu])#[N:17].FC1C=CC(C#N)=C(N2C=CC=N2)C=1.CCOC(C)=O.C(Cl)Cl>CN(C=O)C.CCOCC>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]#[N:17])=[C:3]([N:9]2[C:13]([CH3:14])=[N:12][CH:11]=[N:10]2)[CH:4]=1
Reactant: Cc1nc(C)n(-c2cc(F)ccc2Br)n1
Reactant: N#C[Cu]
Agent: N#Cc1ccc(F)cc1-n1cccn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ncnn1-c1cc(F)ccc1C#N
Yield: 64 %

Procedure:
The title compound was prepared in 64% yield as a tan crystalline powder (HPLC: 1.31 min, AP 95% at 220 nm) from 1-(2-bromo-5-fluorophenyl)-3,5-dimethyl-1H-1,2,4-triazole and CuCN in DMF at 125-130° C. for 7 h by the method used for the preparation of 4-fluoro-2-pyrazol-1-yl-benzonitrile. An analytical sample was obtained by column purification (SiO2, 20% EtOAc/CH2Cl2), followed by trituration with Et2O. LC/MS m/z 217 (M+H). 1H NMR (CDCl3, 500 MHz) δ ppm 2.45 (3H, s, 11-Me), 2.49 (3H, s, 10-Me), 7.25 (1H, dd, J=8.5, 2.5 Hz, 3-CH), 7.31 (1H, dt, J=8.5, 2.5 Hz, 5-CH), 7.87 (1H, dd, J=8.7, 5.6 Hz, 6-CH). 13C NMR (CDCl3, 125.8 Hz) δ ppm 12.7 (10-Me), 13.8 (11-Me), 107.1 (d, J=3.8 Hz, 1-C), 114.8 (7-CN), 116.2, (d, J=25 Hz, 3-CH), 117.6 (d, J=22 Hz, 5-CH), 136.0 (d, J=10 Hz, 6-CH), 141.6 (d, J=10 Hz, 2-C), 153.9 (8-C), 161.0 (9-C), 165.0 (d, J=260 Hz, 4-CF). HRMS (ESI) calcd for C11H10FN4 (M+H) 217.0889, found 271.0879 (δ-4.8 ppm). Anal. calcd for C11H9FN4: C61.10, H4.19, N25.91; found C60.78, H3.93, N26.05.
Reaction SMILES: FC1C=C(C2C=CC=CC=2S(C)(=O)=O)C=CC=1NC(C1N([C:16]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:17]=2[C:18]([OH:20])=[O:19])N=C(C(F)(F)F)C=1)=O.COC(=O)C1C=C(OC)C=CC=1N1C(C(=O)NC2C=CC(C3C=CC=CC=3S(C)(=O)=O)=CC=2F)=CC(C(F)(F)F)=N1.[OH-].[Na+].Cl>CO.O>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][CH:16]=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19]
Reactant: COc1ccc(-n2nc(C(F)(F)F)cc2C(=O)Nc2ccc(-c3ccccc3S(C)(=O)=O)cc2F)c(C(=O)O)c1
Agent: COC(=O)c1cc(OC)ccc1-n1nc(C(F)(F)F)cc1C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1F
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc(C(=O)O)c1
Temperature: 25 °C

Procedure:
Part D: Preparation of 2-[5-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methoxy-benzoic acid. 2-[5-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methoxybenzoic acid methyl ester (1.70 g, 2.80 mmol) was dissolved in methanol (22 mL), 1N sodium hydroxide (5.8 mL) was added, and the solution refluxed for 6 hours. The reaction was cooled to ambient temperature and diluted with water (30 mL). 3N hydrochloric acid was added to adjust the pH to 2, and the resulting precipitate collected by filtration. The solid was dried under vacuum in a desiccator to give 1.45 g (86%) of (3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-3-trifluoromethyl-pyrazol-1-yl]-5-methoxy-benzoic acid. 1H NMR (CD3OD) δ 8.12 (dd, J=1.5, 8.1 Hz, 1H), 7.86 (t, J=8.4 Hz, 1H), 7.70 (dt, J=1.5, 7.7 Hz, 1H), 7.61 (dt, J=1.5, 7.7 Hz, 1H), 7.37 (m, 3H), 7.25 (dd, J=2.2, 11.7 Hz, 1H) 7.16 (m, 3H) 3.87 (s, 3H), 2.67 (s, 3H).