Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:18][CH2:19][O:20]S(C1C=CC(C)=CC=1)(=O)=O.C([O:33][C:34](=[O:55])[C:35]([CH3:54])([O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:36][C:37]1[CH:42]=[CH:41][C:40](O)=[C:39]([CH2:44][CH2:45][CH3:46])[CH:38]=1)C>C(O)C>[CH3:54][C:35]([O:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:20][CH2:19][CH2:18][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[C:39]([CH2:44][CH2:45][CH3:46])[CH:38]=1)[C:34]([OH:55])=[O:33]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1
Reactant: CCCc1cc(CC(C)(Oc2ccccc2)C(=O)OCC)ccc1O
Solvent: CCO
Product: CCCc1cc(CC(C)(Oc2ccccc2)C(=O)O)ccc1OCCc1nc(-c2ccc(-c3cccs3)cc2)oc1C
Temperature: 55 °C

Procedure:
Toluene-4-sulfonic acid 2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (see Ex. 3, Part B) (0.132 mmol) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxy-3-propylphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) (see Ex. 10, Part C) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55 ° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by mass-directed HPLC to provide analytically pure material. MS (EI) 582.1 (M+H)+; LC RT=3.56 min (>99% pure).
Reaction SMILES: O1CCCC1.[C:6]1([C:12]2[N:13]=[C:14]([C:23]3[CH:24]([CH2:28][C:29]4[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=4)[C:32]([OH:34])=O)[CH2:25][CH2:26][CH:27]=3)[O:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.ClC(OCC)=O.[NH3:44]>C(N(CC)CC)C>[C:6]1([C:12]2[N:13]=[C:14]([C:23]3[CH:24]([CH2:28][C:29]4[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=4)[C:32]([NH2:44])=[O:34])[CH2:25][CH2:26][CH:27]=3)[O:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)c1cccc(CC2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: N
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc(CC2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.5 h

Procedure:
To a tetrahydrofuran solution (10 ml) of 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl}benzoic acid (0.30 g) and triethylamine (0.15 ml) was added ethyl chloroformate (0.15 ml) at 0° C. The solution was stirred for 30 minutes at the same temperature. Then aqueous ammonia (10 ml) was added to the solution. After stirred for 6 hours at 0° C., the solution was partitioned between ethyl acetate and water. The organic layer was washed with water, 1N hydrochloric acid, water and brine. After dried over MgSO4, the solvent was evaporated in vacuo to afford 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl}benzamide (0.24 g).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:16])[CH:10]=2)=[CH:5][CH:4]=1.P(CCCC)(CCCC)CCCC.O[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:35]([CH3:46])[CH:34]=1>C1COCC1>[CH3:46][C:35]1[CH:34]=[C:33]([O:16][CH2:15][C:11]2[CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:18])[F:1])=[CH:8][CH:7]=3)[CH:14]=[CH:13][CH:12]=2)[CH:38]=[CH:37][C:36]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]
Reactant: CCOC(=O)CCc1ccc(O)cc1C
Reactant: OCc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
To a solution of [4′-(trifluoromethyl)-3-biphenylyl]methanol (121 mg, 0.48 mmol) in dry THF (5 mL) under nitrogen at 0° C. (ice/water bath) was added nBu3P (240 μL, 0.96 mmol) followed by ethyl 3-(4-hydroxy-2-methylphenyl)propanoate (100 mg, 0.48 mmol) and then ADDM (246 mg, 0.96 mmol) portion-wise. The mixture was stirred at 0° C. for 1 hour, allowed to warm to rt over 21 hours and then partitioned between water and EtOAc, and the layers separated. The aqueous layer was then extracted with EtOAc and the combined organic extract washed with water and then brine, dried (Na2SO4) and the solvent removed under vacuum. Purification by flash chromatography (silica) eluting with cyclohexane:EtOAc (15:1) afforded the title compound as a clear oil (141 mg).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH:18]([N:13]1[C:12]([C:33]2[CH:34]=[CH:35][C:30]([CH3:29])=[CH:31][CH:32]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: Cc1ccc(-c2c3c(nn2C(C)C)CCNCC3)cc1
Yield: 100.3 %

Procedure:
The title compound (129 mg) was prepared as in Example 177, Steps C and D, using 204 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 194 mg of 4-methylphenylboronic acid. MS (ESI): exact mass calculated for C17H23N3, 269.19; found, m/z 270.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.28 (d, J=7.7 Hz, 2H), 7.12 (d, J=7.7 Hz, 2H), 4.32 (m, 1H), 3.34-3.33 (m, 2H), 3.12-3.10 (m, 2H), 2.70-2.68 (m, 2H), 2.33 (s, 3H), 1.30 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[C:9](O)=O.C12(C(O)=O)CC(CC1)C(=C)C2(C)C>>[CH:7]12[CH2:8][CH:4]([CH2:5][CH2:6]1)[C:3](=[CH2:9])[C:2]2([CH3:12])[CH3:1]
Reactant: CC1(C)C2CCC(C2)C1C(=O)O
Agent: C=C1C2CCC(C(=O)O)(C2)C1(C)C
Product: C=C1C2CCC(C2)C1(C)C

Procedure:
3.3-Dimethylbicyclo-[2.2.1]-heptane-2-carboxylic acid, further to be called camphenic acid, has been described in Bull. Soc. Chim. France 1972 (no. 12) pages 4770-4777, as an intermediate in the synthesis of the corresponding alcohol. Further the synthesis of this compound has been described in Monatshefte fur Chemie 107, page 945 (1976), wherein is stated that it is an important starting material for the preparation of e.g. bicyclic fragrances. In Nippon Kagaku Zasshi 85, pages 593-597 (1964) it is stated that e.g. camphenic acid can be obtained by oxidation of camphene by peracids; see Chem. Abstr. 62, 11858c (1965).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[NH:16][NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[N:21][C:19]=3[N:20]=2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:25]([Cl:33])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>>[ClH:33].[C:25]([N:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[N:21][C:19]=2[N:20]=[C:15]([N:12]2[CH2:11][CH2:10][N:9]([CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:14][CH2:13]2)[NH:16]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1
Reactant: c1ccc(CN2CCN(C3=Nc4ncccc4NN3)CC2)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: O=C(c1cccnc1)N1NC(N2CCN(Cc3ccccc3)CC2)=Nc2ncccc21
Yield: 83 %

Procedure:
3-(N-Benzylpiperazino)-1,2-dihydro-pyrido[2,3-e]-as-triazine hydrochloride is reacted with nicotinoyl chloride as described in Example 6. The title compound, melting at 218°-219° C., is obtained with a yield of 83%.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][C:24]=3[F:26])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: OB(O)c1ccc(F)cc1F
Product: CCCNC(=O)c1nnc2c(-c3ccc(F)cc3F)cccc2c1N
Yield: 89.4 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 2,4-difluorophenyl boronic acid (202 mg, 1.28 mmol) were reacted to afford the title compound (101 mg, 92.3% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.55 (br, 1H), 7.92 (dd, J=8.0 Hz, J′=1.7 Hz, 1H), 7.70-7.80 (m, 2H), 7.49 (m, 1H), 6.90-7.05 (m, 2H), 3.46 (q, J=6.7 Hz, 2H), 1.66 (m, J=7.3 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H) MS APCI, m/z=343 (M+H) HPLC 1.84 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:16]O>>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c(Cl)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)cc1Cl
Reaction time: 8 h

Procedure:
2-chloro-4-methylbenzoic acid (500 mg, 2.93 mmol) was dissolved in Methanol (7 mL) and SOCl2 (0.215 mL, 2.93 mmol) was slowly added to the mixture and the reaction was left at room temperature overnight. Next morning HPLC showed completion. Volatiles were removed under vacuum to afford 526 mg of the title compound as brown oil.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([C:15]([OH:17])=O)=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([CH3:14])[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.[CH3:18][C:19]([NH2:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:19]([NH:22][C:15]([C:5]1[C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH3:14])=[N:12]2)=[CH:7][CH:6]=1)=[O:17])([CH3:21])([CH3:20])[CH3:18]
Reactant: Cc1ccc2ccc(C(=O)O)c(C3CC3)c2n1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc2ccc(C(=O)NC(C)(C)C)c(C3CC3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a solution of 8-cyclopropyl-2-methylquinoline-7-carboxylic acid (0.050 g, 0.220 mmol) and 2-methylpropan-2-amine (0.116 mL, 1.10 mmol) in DMF (1 mL) was added HATU (0.125 g, 0.33 mmol) at ambient temperature and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was purified directly by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 0-90% CH3CN/water gradient; 25 column volumes) to give N-tert-butyl-8-cyclopropyl-2-methylquinoline-7-carboxamide (0.033 g, 53.1%) as a solid.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[N:41][CH:40]=[CH:39][N:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[N:41][CH:40]=[CH:39][N:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Brc1cnccn1
Product: C[C@@H](c1ccc(-c2cnccn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromopyrazine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.249, m/z=374; 1H NMR (CDCl3) 1.12 (s, 3H), 1.28 (s, 3H), 1.58 (m, 3H), 2.19-2.20 (m, 4H), 2.39 (m, 1H), 2.89 (m, 1H), 5.74 (m, 1H), 7.09 (m, 2H), 7.28-7.40 (m, 5H), 7.78 (m, 2H), 8.48 (m, 1H), 8.59 (m, 1H), 8.94 (m, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CCN(CC)CC.[C:27](Cl)([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>CO>[C:14]([O:13][C:12]([NH:11][C@@H:3]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C@@H:2]([NH:1][C:27](=[O:28])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:19])=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H](N)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@H](NC(=O)OCc1ccccc1)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.7 %

Procedure:
To a mixture of tert-butyl (2S,3S)-3-amino-1-cyclohexylbutan-2-ylcarbamate (0.153 g, 0.57 mmol) and Et3N (0.19 mL, 1.42 mmol) in methanol (5 mL) at 0° C. was added dropwise a solution of CBZCl (0.116 g, 0.68 mmol) in methanol (3 mL). The mixture was warmed to rt, stirred 2 h, evaporated to remove methanol, diluted with water (15 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (15 mL), dried and evaporated to give benzyl (2S,3S)-3-(tert-butoxycarbonyl)amino-4-cyclohexylbutan-2-ylcarbamate (0.117 g, 51%) that was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): 7.32 (m, 5H), 5.37 (brs, 1H), 5.09 (s, 2H), 4.36 (brs (1H), 3.76 (m, 2H), 1.82 (m, 1H), 1.66 (m, 4H), 1.44 (s, 9H), 1.35-1.10 (m, 6H), 1.07 (d, J=6.4 Hz, 3H), 1.00-0.78 (m, 2H); MS (E/Z): 405 (M+H+).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=1)[CH:3]([CH3:5])[CH3:4].[CH3:25][O:26][CH:27]([O:30][CH3:31])[CH2:28]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:16]([N:15]1[C:14](=[O:23])[C:13]2[C:8](=[CH:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[N:7]=[C:6]1[CH:2]([NH:1][CH2:28][CH:27]([O:30][CH3:31])[O:26][CH3:25])[CH:3]([CH3:5])[CH3:4])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(CBr)OC
Reactant: CC(C)C(N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CNC(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)C(C)C)OC
Temperature: 135 °C
Yield: 58.6 %

Procedure:
To a solution of 2-(1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3H-quinazolin-4-one (1.87 g, 5.48 mmol) in DMF (30 mL) was added bromoacetaldehyde dimethylacetal (2.78 g, 16.44 mmol) and potassium carbonate (2.27 g, 16.44 mmol) and the resulting suspension was heated at 135° C. for 18 h. The cooled reaction was concentrated in vacuo, triturated with methylene chloride to remove any solids, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica gel; 2:1 hexanes:ethyl acetate) to give the title compound as a pale yellow oil (1.38 g, 59%). MS(ES+) m/e 430 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[F:10][C:11]([F:18])([F:17])[C:12]1[CH:13]=[N:14][NH:15][CH:16]=1.O[C@H]1CN[C@H](C(O)=O)C1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O.[Cu]I>[F:10][C:11]([F:18])([F:17])[C:12]1[CH:13]=[N:14][N:15]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: OCc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: OCc1ccc(-n2cc(C(F)(F)F)cn2)cc1
Temperature: 85 °C

Procedure:
A mixture of (4-iodophenyl)methanol (1030 mg, 4.41 mmol), 4-(trifluoromethyl)-1H-pyrazole (600 mg, 4.41 mmol), copper (I) iodide (168 mg, 0.882 mmol), trans-4-hydroxy-L-proline (231 mg, 1.76 mmol) and cesium carbonate (2900 mg, 8.82 mmol) in dimethylsulfoxide (7.5 mL) was heated to 85° C. for 20 hours. The mixture was diluted with water and extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-45% ethyl acetate in heptane), gave (4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol. 1H NMR (400 MHz, CDCl3, δ): 8.16 (s, 1H), 7.89 (s, 1H), 7.65 (d, J=8.39 Hz, 2H), 7.47 (d, J=8.39 Hz, 2H), 4.74 (d, J=5.66 Hz, 2H), 1.85 (t, J=5.86 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.[F-].[Cs+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2ccc(OC)cc2)cc1
Temperature: 85 °C

Procedure:
A stirred mixture of 4-bromobenzoic acid, ethyl ester (23.6 g, 103 mmol), 4-methoxyphenylboronic acid (15.6 g, 103 mmol), tetrakis(triphenylphosphine)palladium (0) (2.0 g, 1.73 mmol) and powdered caesium fluoride (30.0 g, 200 mmol) in 1,2-dimethoxyethane (300 mL) is heated at 85° C. for 3 h. The mixture is then treated with water (500 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts are washed (saturated NaCl), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, 5% ethyl acetate/95% cyclohexane) to 4′-methoxy-[1,1′-biphenyl]-4-carboxylic acid, ethyl ester as a colourless crystalline solid. m.p. 103-104° C.
Reaction SMILES: CC(C)([O-])C.[Na+].Cl[C:8]1[N:9]([CH2:16][CH2:17][CH:18]([OH:48])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][CH:30]([CH2:33][C:34]4[O:35][C:36]5[CH:42]=[CH:41][C:40]([O:43][C:44]([F:47])([F:46])[F:45])=[CH:39][C:37]=5[CH:38]=4)[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[N:12]=1.[Cl-].[NH4+]>CN1CCCC1=O>[N+:13]([C:11]1[N:12]=[C:8]2[N:9]([CH:10]=1)[CH2:16][CH2:17][CH:18]([CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][CH:30]([CH2:33][C:34]4[O:35][C:36]5[CH:42]=[CH:41][C:40]([O:43][C:44]([F:47])([F:46])[F:45])=[CH:39][C:37]=5[CH:38]=4)[CH2:29][CH2:28]3)=[CH:23][CH:22]=1)[O:48]2)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1cn(CCC(O)COc2ccc(N3CCC(Cc4cc5cc(OC(F)(F)F)ccc5o4)CC3)cc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cn2c(n1)OC(COc1ccc(N3CCC(Cc4cc5cc(OC(F)(F)F)ccc5o4)CC3)cc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
Sodium tert-butoxide (81 mg) was added to an N-methylpyrrolidone solution (5 ml) of 4-(2-chloro-4-nitroimidazol-1-yl)-1-{4-[4-(5-trifluoromethoxybenzofuran-2-ylmethyl)piperidin-1-yl]phenoxy}butan-2-ol (469 mg), and the mixture was stirred at room temperature for 1 hour. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and precipitated solid was sequentially washed with water and diisopropyl ether. The crude product formed was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1→3:1) to afford the title compound as a white powder (181 mg).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:9]1[O:10][C:11]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)=[N:12][N:13]=1)(=O)[NH2:7].O>N1C=CC=CC=1>[C:6]([C:9]1[O:10][C:11]([C:14]2[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[CH:19]=2)=[N:12][N:13]=1)#[N:7]
Reactant: Cc1cc(C)cc(-c2nnc(C(N)=O)o2)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(C)cc(-c2nnc(C#N)o2)c1
Reaction time: 4 h

Procedure:
200 g of phosphorus oxychloride are added to a suspension of 189.5 g of 2-carbamoyl-5-(3,5-dimethylphenyl)-1,3,4-oxadiazole in 873 cm3 of anhydrous pyridine, in the course of one hour and whilst stirring. During this addition, the temperature of the reaction medium rises from 20° to 42° C. The stirring is continued for 4 hours, whilst allowing the temperature of the medium to return to 20° C. The reaction mixture is then poured into 8.7 liters of water and the precipitate which forms is filtered off, washed twice with 500 cm3 of water and then dried in the air. After recrystallization from isopropanol, 163 g of solid 2-cyano-5-(3,5-dimethylphenyl)-1,3,4-oxadiazole, which melts at 127° C., are obtained.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[N:28][CH:29]=3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:32]1COCC1.[H-].[Na+].CI>ClCCl.CO>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:22]([CH3:32])[CH2:23][C:24]3[CH:29]=[N:28][CH:27]=[N:26][CH:25]=3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:30])([F:1])[F:31])[CH:8]=1
Reactant: C1CCOC1
Reactant: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NCc1cncnc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CI
Solvent: CO
Product: CN(Cc1cncnc1)C(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
In a 50 mL, 3N round-bottomed flask equipped with nitrogen inlet, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(pyrimidin-5-ylmethyl)acrylamide (0.05 g, 1.0 eq.) was charged along with THF (5 mL, 5V). The reaction mixture was cooled to −20° C. and sodium hydride (60% in mineral oil) was added (0.051 g, 1.1 eq.). Reaction mixture was allowed to stir for 1 h. Methyl Iodide (0.018 g, 1.1) was added into the reaction mixture and stirred at −20° C. for 1 h. The progress of the reaction was followed by TLC analysis on silica gel with 5% Methanol in dichloromethane as mobile phase and visualization with UV. Reaction mixture was quenched in water (50 mL) and extracted with EtOAc (50×2). The organic layer was washed with brine solution, dried over Na2SO4 and concentrated by rotary evaporation (25° C., 20 mm Hg) to afford 0.060 g of Crude compound. The crude reaction mixture was purified by column chromatography using 60/120 mesh silica and Methanol: dichloromethane as mobile phase. The column was packed in dichloromethane and started eluting in MeOH in gradient manner starting with fraction collection (500 mL fractions). The compound started eluting from 4% Methanol in dichloromethane. Fractions containing such TLC profile were collected together to obtain pure compound 0.015 g Yield (30%).