Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=1)[C:5]([OH:7])=O)=[N+]=[N-].[NH2:23][C:24]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=1[CH2:26][CH2:27][C@H:28]1[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])[N:30](C(OC(C)(C)C)=O)[CH2:29]1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C@@H:8]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=2)[C@@H:4]([C:5]([NH:23][C:24]2[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=2[CH2:26][CH2:27][C@H:28]2[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:40])([F:42])[F:41])[NH:30][CH2:29]2)=[O:7])[NH:1][C:36]([O:35][CH3:34])=[O:43])=[CH:17][CH:18]=1
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(Cl)cc1)c1cncc(F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Product: COC(=O)N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(Cl)cc1)c1cncc(F)c1

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 of Example 99 using the procedures given in steps 2 and 3 of Example 93 and steps 1 and 2 of Example 91. MS (ES) m/z=714 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Product: CCOC(=O)c1c(N2CCCCC2)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 12 step A from 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 11 step B) and piperidine.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH:23]([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][C:18](B5OC(C)(C)C(C)(C)O5)=[CH:19][CH:20]=4)[CH2:15]3)[N:11]=[C:10]([NH2:34])[N:9]=2)[CH2:4][CH2:3]1.Br[C:36]1[CH:40]=[CH:39][N:38]([CH2:41][CH2:42][OH:43])[N:37]=1>>[NH2:34][C:10]1[N:11]=[C:12]([N:14]2[CH:23]([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][C:18]([C:36]4[CH:40]=[CH:39][N:38]([CH2:41][CH2:42][OH:43])[N:37]=4)=[CH:19][CH:20]=3)[CH2:15]2)[CH:13]=[C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[N:9]=1
Reactant: CC1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: OCCn1ccc(Br)n1
Product: CC1Cc2ccc(-c3ccn(CCO)n3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
The compound was prepared by using procedure analogous to those described for the synthesis of Example 82B, Step 3 starting from 4-(4-methylpiperazin-1-yl)-6-[3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine and 2-(3-bromo-1H-pyrazol-1-yl)ethanol. LCMS (M+H)+: m/z=449.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12]([CH2:14][CH2:15][N:16]2[C:20]([CH3:21])=[C:19]([C:22](OCC)=[O:23])[N:18]=[CH:17]2)=O)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.B.C1COCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][CH2:12][CH2:14][CH2:15][N:16]2[C:20]([CH3:21])=[C:19]([CH2:22][OH:23])[N:18]=[CH:17]2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn(CCC(=O)NC(C)(C)c2ccc(Cl)cc2)c1C
Agent: B
Solvent: C1CCOC1
Product: Cc1c(CO)ncn1CCCNC(C)(C)c1ccc(Cl)cc1

Procedure:
In a similar manner to Example 64b, a mixture of ethyl 1-{N-[1-(4-chlorophenyl)-1-methylethyl]-2carbamoylethyl}-5-methylimidazole-4-carboxylate (28.8 g, from Example 78) and borane/THF (303.4 ml, 400 ml THF, 1.0M solution) gave 1-{3-[1-(4-chlorophenyl)-1-methylethylamino]propyl}-5-methylimidazol-4-yl-methanol, m.p. 97°-99° C.
Reaction SMILES: [Cl-].[Na+].[Cl:3][C:4]1[CH:30]=[CH:29][C:7]([NH:8][C:9]2[CH:17]=[C:16]([C:18]([OH:20])=O)[C:15]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[CH:14][C:10]=2[C:11]([OH:13])=O)=[CH:6][CH:5]=1.P(=O)(O)(O)O.CO>O>[CH:5]1[C:4]([Cl:3])=[CH:30][C:29]2[C:11]([C:10]3[C:9]([NH:8][C:7]=2[CH:6]=1)=[CH:17][C:16]1[C:18]([C:23]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=2[NH:21][C:15]=1[CH:14]=3)=[O:20])=[O:13]
Reactant: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=c1c2cc(Cl)ccc2[nH]c2cc3c(=O)c4cc(Cl)ccc4[nH]c3cc12
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
To 300 g of polyphosphoric acid (116% phosphoric acid) heated at 80°-95° C. was added 1.0 g (17.1 mmole) of sodium chloride followed by 50 g (0.12 mole) of 2,5-di(4-chloroanilino)terephthalic acid. The mixture was heated at 110°-115° C. for five hours. After the viscous solution was cooled to 90°-95° C., the acid strength was adjusted to 110.5% by the dropwise addition of 75% phosphoric acid. The resultant melt was stirred for 20 minutes and then slowly poured into a mixture of 324 g of methanol and 36 g of water (i.e., 90% aqueous methanol) at 35° C. The temperature of the resultant slurry was allowed to rise during the addition to about 64° C., with the temperature being controlled during addition by external cooling and adjustment of melt addition rate. The slurry was heated at reflux for one hour and diluted with 280 g of water. After the resultant slurry was stirred for 30 minutes, the solid component was collected by filtration and washed with water until acid-free. The press-cake was reslurried in water, the pH was adjusted to 8.5 using aqueous sodium hydroxide, and methanol was added. The resultant slurry was heated at about 120° C. in a closed system (e.g., a pressure reactor). After the slurry was cooled to ambient temperature, the solid component was collected by filtration and washed with water until neutral. The wet cake can be oven dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give about 43 g of 2,9-dichloroquinacridone as a brilliant magenta solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)CC4=O)[CH2:20][CH2:19]3)=[O:17])=[CH:8][N:9]2[CH2:12][CH2:13][NH:14][CH3:15])=[CH:5][CH:4]=1.Cl.N1CCC([N:41]2C3C=CC=CC=3N=[N:42]2)CC1.C(N(CC)C(C)C)(C)C>>[ClH:2].[N:24]1([CH:21]2[CH2:22][CH2:23][N:18]([C:16]([C:7]3[C:6]4[C:5](=[CH:4][C:3]([Cl:2])=[CH:11][CH:10]=4)[N:9]([CH2:12][CH2:13][NH:14][CH3:15])[CH:8]=3)=[O:17])[CH2:19][CH2:20]2)[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:42]=[N:41]1
Reactant: c1ccc2c(c1)nnn2C1CCNCC1
Reactant: CNCCn1cc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c2ccc(Cl)cc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CNCCn1cc(C(=O)N2CCC(n3nnc4ccccc43)CC2)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedures described for the preparation of 1-{1-[6-chloro-1-(2-methylamino-ethyl)-1H-indole-3-carbonyl]-piperidin-4-yl}-1,3-dihydro-indol-2-one hydrochloride using 1-(4-piperidyl)-1H-1,2,3-benzotriazole hydrochloride instead of 1,3-dihydro-1-(piperidin-4-yl)-(2H)-indol-2-one and a total of 3.2 molar equivalents of N,N-diisopropylethylamine instead of 2.2 molar equivalents in step a).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[NH2:23][C@@H:24]1[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>>[OH:30][C@@H:27]1[CH2:28][CH2:29][C@H:24]([NH:23][C:2]2[C:3]([CH3:22])=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:25][CH2:26]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: N[C@H]1CC[C@@H](O)CC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H]1CC[C@@H](O)CC1
Temperature: 100 °C

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 41 mg, 0.138 mmol), cis-4-aminocyclohexanol (42.0 mg, 0.277 mmol, J&W Pharmlab, Levittown, Pa.), and DIPEA (121 μl, 0.692 mmol), heating at 100° C. for 1 h. Purification by silica gel (100% DCM to 10% MeOH/DCM) provided 2-(3-((cis-4-hydroxycyclohexyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (26% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61-1.71 (m, 2H) 1.72-1.83 (m, 4H) 1.83-1.96 (m, 2H) 2.56 (s, 3H) 2.89 (t, J=6.85 Hz, 2H) 3.41-3.48 (m, 2H) 3.88 (br. s., 1H) 3.97-4.07 (m, 1H) 4.42 (br. s., 1H) 6.77 (d, J=7.04 Hz, 1H) 6.91 (br. s., 1H) 7.18 (d, J=1.76 Hz, 1H) 7.31 (t, J=7.82 Hz, 1H) 7.55 (d, J=7.82 Hz, 1H) 7.87 (d, J=7.63 Hz, 1H) 11.94 (br. s., 1H). MS (ESI, pos. ion) m/z: 392.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([OH:9])=[N:6][C:7]=1[CH3:8].[CH3:11]I>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([O:9][CH3:11])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)nc(C)c1Br
Reactant: CI
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: COc1cc(C)c(Br)c(C)n1

Procedure:
A mixture of 5-bromo-4,6-dimethylpyridin-2-ol (7 g), methyl iodide (21.6 mL) and silver carbonate (19.1 g) was stirred in a chloroform solvent (140 mL) at room temperature for 36 hours. The reaction mixture was subjected to silica gel pad and eluted with a mixed solvent of (ethyl acetate:n-heptane=2:8). The resulting solution was concentrated under reduced pressure to give the title compound (6.98 g).
Reaction SMILES: [CH2:1]1[CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=2[O:2]1.[CH:13]([NH:16][OH:17])([CH3:15])[CH3:14]>>[CH2:1]1[CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=[N+:16]([CH:13]([CH3:15])[CH3:14])[O-:17])=[CH:4][C:3]=2[O:2]1
Reactant: CC(C)NO
Reactant: O=Cc1ccc2c(c1)OCCO2
Product: CC(C)[N+]([O-])=Cc1ccc2c(c1)OCCO2

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 3,4-ethylenedioxybenzaldehyde and N-isopropylhydroxylamine. The crude produce was purified by column chromatography over silica gel using ethyl acetate as the eluant. The title compound was isolated in 53% yield as a solid, m.p. 108.8° C. (Rf =0.31 on a silica gel plate using EtOAc as the eluant).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](I)[CH2:11][CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:13][CH:12]([CH3:14])[CH2:11][CH2:10][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)CCI
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.5 %

Procedure:
A mixture of 1.00 g of p-hydroxybenzaldehyde, 1.46 g of isoamyl iodide and 1.80 g of potassium carbonate in 15 ml of N,N-dimethylformamide was stirred at room temperature for 2 days. Water was added to the reaction mixture, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed in sequence with 1N sodium hydroxide, water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.34 g of p-(3-methylbutoxy)benzaldehyde.
Reaction SMILES: [I-:1].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:14]=[C:13]([CH2:24]OS(C)(=O)=O)[CH:12]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]>C1COCC1.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:14]=[C:13]([CH2:24][I:1])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: [I-]
Reactant: COc1ccc(-n2nc(COS(C)(=O)=O)cc2-c2ccc(Cl)c(Cl)c2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(CI)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 40 °C

Procedure:
Sodium iodide (4.06 kg, 27.1 mol) was added to the THF/toluene solution of methanesulfonic acid 5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-ylmethyl ester (Example 517, 6.32 kg, 14.8 mol). The resulting reaction mixture was heated at 40° C. for 6 h and then allowed to cool to rt overnight. When HPLC analysis indicated the disappearance of the starting material, the reaction was quenched with 28% aq. sodium thiosulfate (6.3 L). The organic layer was washed with sat. aq. NaHCO3 (6.3 L), brine (6.3 L), then dried (MgSO4). After filtration to remove the drying agent, the desired product was obtained in a solution, which was used in the next synthetic step without isolation. Chemical characterization data obtained herein for the title compound is not duplicated in this Example in light of the same data given in Example 1, Step E.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)([OH:3])=[O:2].O=S(Cl)Cl.N1C=CC=CC=1.[CH2:31]([CH:34]1[CH2:39][CH2:38][CH:37](O)[CH2:36][CH2:35]1)[CH2:32][CH3:33]>C1(C)C=CC=CC=1.O>[CH2:31]([C@H:34]1[CH2:39][CH2:38][C@H:37]([O:2][C:1]([C@H:4]2[CH2:5][CH2:6][C@H:7]([N:10]3[CH2:11][CH2:12][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][CH2:15]3)[CH2:8][CH2:9]2)=[O:3])[CH2:36][CH2:35]1)[CH2:32][CH3:33]
Reactant: CCCC1CCC(O)CC1
Reactant: CCCCCC1CCN(C2CCC(C(=O)O)CC2)CC1
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1CCN([C@H]2CC[C@H](C(=O)O[C@H]3CC[C@H](CCC)CC3)CC2)CC1
Reaction time: 2 h

Procedure:
2.49 g of 1-(4-carboxycyclohexyl)-4-pentylpiperidine (m.p. 208°) is boiled for 1 hour together with 2.4 g of SOCl2 ; the mixture is evaporated to dryness; the crude acid chloride obtained is dissolved in 15 ml of toluene; 1 ml of pyridine and 1.42 g of 4-propylcyclohexanol are added; and the mixture is boiled for 2 hours. Water is then added. The phases are separated, and the organic phase is washed with water, dried over Na2SO4 and evaporated to dryness, to give 1-[trans-4-(trans-4-propylcyclohexyloxycarbonyl)-cyclohexyl]-4-pentylpiperidine.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([O:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[C:22]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][C:41]([CH2:44][C:45]([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])=[CH:40][CH:39]=3)=[CH:34][CH:33]=2)[C:18]=1[C:19]([OH:21])=[O:20])[CH:14]=[CH2:15].[CH3:51][CH:52](O)[CH3:53].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:13]([O:16][C:17]1[C:25]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:23]=[C:22]([CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[CH:39]=[CH:40][C:41]([CH2:44][C:45]([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])=[CH:42][CH:43]=3)=[CH:34][CH:33]=2)[C:18]=1[C:19]([O:21][CH:52]([CH3:53])[CH3:51])=[O:20])[CH:14]=[CH2:15]
Reactant: CC(C)O
Reactant: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C(=O)O)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OCC=C)c3C(=O)OC(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Diethyl azodicarboxylate (108 μl, 0.68 mmol) was added to a solution of 2-(allyloxy)-6-{[(4′-{[(allyloxy)carbonyl]methyl}-1,1′-biphenyl-4-yl)oxy]methyl}-3-(trifluoromethyl)benzoic acid (150 mg, 0.29 mmol), 2-propanol (26 μl, 0.34 mmol) and triphenylphosphine (180 mg, 0.68 mmol) in tetrahydrofuran (3 ml) at room temperature. After the mixture was stirred at room temperature for 1 hour, the solvent of the reaction mixture was removed under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography (developing solvent: n-hexane/ethyl acetate=4/1) to give isopropyl 2-(allyloxy)-6-{[(4′-{[(allyloxy)carbonyl]methyl}-1,1′-biphenyl-4-yl)oxy]methyl}-3-(trifluoromethyl)benzoate (141 mg, yield: 87%).
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=1)[N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:16]=[CH:15]2)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=1)[N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[N:16]=[CH:15]2
Reactant: COC(=O)c1cc(NC(=O)OCc2ccccc2)cc2cnn(COCC[Si](C)(C)C)c12
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)cc2cnn(COCC[Si](C)(C)C)c12
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a solution of methyl 5-{[(benzyloxy)carbonyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-7-carboxylate (364 mg) in MeOH (10 mL) was added 5% palladium on carbon (55 mg), and the reaction mixture was stirred overnight under hydrogen atmosphere at an ordinary pressure. The reaction mixture was filtered off on celite and washed with MeOH. The mother liquor was concentrated under reduced pressure to obtain the titled compound (234 mg) as green powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1cccc(OCCCCl)c1
Temperature: 25 °C

Procedure:
A mixture of 3′-hydroxyacetophenone (5 g) and 1-bromo-3-chloropropane (5.0 mL) in acetone (40 mL) was treated with potassium carbonate (8.1 g). The mixture was stirred at reflux temperature for 17 hours. The reaction was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo. The residue was partitioned between dichloromethane (50 mL) and H2O (50 mL). The aqueous phase was washed with two fresh portions of dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated to yield the title compound (8.6 g) which was used without further purification.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[CH:8][C:7]([CH:11]2[CH2:14][C:13]([O:17][CH3:18])([O:15][CH3:16])[CH2:12]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26](O)([C:28]([F:31])([F:30])[F:29])=[O:27].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O>[C:1]([N:5]1[C:9]([NH:10][C:26](=[O:27])[C:28]([F:31])([F:30])[F:29])=[CH:8][C:7]([CH:11]2[CH2:12][C:13]([O:15][CH3:16])([O:17][CH3:18])[CH2:14]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC1(OC)CC(c2cc(N)n(C(C)(C)C)n2)C1
Reactant: O=C(O)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC1(OC)CC(c2cc(NC(=O)C(F)(F)F)n(C(C)(C)C)n2)C1
Reaction time: 72 h
Yield: 59.6 %

Procedure:
To a stirring solution of 2-tert-butyl-5-(3,3-dimethoxy-cyclobutyl)-2H-pyrazol-3-ylamine (5.0 g, 19.7 mmol) in EtOAc (40 mL) was added triethylamine (27 mL, 197 mmol), TFA (2.3 mL, 29.6 mmol), followed by a solution of 1-propanephosphonic acid cyclic anhydride (25 mL, 50 wt % sol. in EtOAc, 39.4 mmol). After 72 hr, the reaction was diluted with EtOAc and washed with aqueous NaOH (1 N). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of this material was accomplished by MPLC, using a Biotage® column (35 L), eluting with 25% EtOAc/hexanes. The product-containing fractions were collected and concentrated to yield the title compound (4.1 g, 60% yield) as a colorless oil. 400 MHz 1H NMR (CDCl3) d 8.00 (bs, 1H), 6.26 (s, 1H), 3.22 (dddd, J=8.7, 8.7, 8.7, 8.7, Hz, 1H), 3.18 (s, 3H), 3.15 (s, 3H), 2.61-2.55 (m, 2H), 2.25-2.19 (m, 2H), 1.59 (s, 9H). LRMS m/z (APCI+) 350 (M+1).
Reaction SMILES: [OH-].[K+].C([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1)(=O)C>CO.O.[Cl-].[Na+]>[C:14]([C:10]1[N:9]=[C:8]([CH2:7][OH:6])[CH:13]=[CH:12][CH:11]=1)(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)OCc1cccc(C(=O)c2ccccc2)n1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(c1ccccc1)c1cccc(CO)n1
Reaction time: 8 h

Procedure:
Potassium hydroxide (1.1 g, 18 mmol) is dissolved in 25 ml methanol, after which is added 2-(acetoxymethyl)-6-benzoylpyridine (2.3 g, 9 mmol) in 20 ml methanol and the mixture is then stirred overnight. The mixture is diluted with water and saturated sodium chloride, then extracted with ether (2×), washed with sat. sodium chloride, dried over magnesium sulfate and stripped to yield (6-benzoyl-2-pyridyl)methanol.
Reaction SMILES: C(S([NH:7][CH:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]([CH3:17])([CH3:16])[C:11](OCC)=[O:12])=O)(C)(C)C.Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1.C[OH:40]>>[CH3:16][C:10]1([CH3:17])[C:9](=[O:40])[CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:7][C:11]1=[O:12]
Reactant: CCOC(=O)C(C)(C)CC(NS(=O)C(C)(C)C)c1ccccc1
Reactant: CO
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)NC(c2ccccc2)C1=O
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of Ethyl 4-[(tert-butylsulfinyl)amino]-2,2-dimethyl-4-phenylbutanoate from Step B (0.19 g, 0.55 mmol) in MeOH (10 mL) was added anhydrous HCl (gas, bubbled in for about 1 minute). After 20 minutes, nitrogen was bubbled though the reaction mixture for about 20 minutes. The initial solvent was removed in vacuo, and then more MeOH was added and removed in vacuo. The residue was then dissolved in MeOH (20 mL) and treated with triethylamine (0.22 g, 2.2 mmol). The solvent was once again removed in vacuo. This residue was then treated with toluene (10 mL) and triethylamine (0.22 g, 2.2 mmol) before being heated to 100° C. for 15 hours. After cooling to ambient temperature the solvent was removed in vacuo and the residue was partitioned between diethyl ether (50 mL) and 1 M HCl (50 mL). The organics were then successively washed with another volume of 1 M HCl, water and lastly saturated brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound which was used without further purification. MS: m/z=190 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[CH:15][N:14](/[CH:17]=[CH:18]\[C:19]([O:21]C(C)C)=[O:20])[N:13]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Li+].[OH-]>C1COCC1.O>[OH:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[CH:15][N:14](/[CH:17]=[CH:18]\[C:19]([OH:21])=[O:20])[N:13]=2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CC(C)OC(=O)/C=C\n1cnc(-c2cc(O)cc(C(F)(F)F)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)/C=C\n1cnc(-c2cc(O)cc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.5 %

Procedure:
A solution of (Z)-isopropyl 3-(3-(3-hydroxy-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylate (4 g, 1.0 eq.) in THF (40 mL) and water (40 mL) was treated with LiOH (1.92 g, 4 eq.). The reaction mixture was stirred at RT for 2-3 hrs then quenched with acidic ice-water slurry (300 mL) and extracted with EtOAc (3×250 mL). The combined organic layers were washed with dil HCl solution (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 3 g of crude compound. The resulting crude off-white compound was used as such in the following step. Yield: 85.5%. Mass: (ES+) 299.92 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH:6]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:5])[O:3]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)C(Cc2ccccc2)C(=O)O1

Procedure:
Meldrum's acid (73) is treated with benzaldehyde in the presence of borane-triethylamine complex in toluene. The product is isolated by flash chromatography over silica gel to give (74).