Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](OB(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[N:20]=[N:21][C:22]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[CH:23][CH:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(Cl)nn2)cs1
Reactant: OB(O)Oc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)nn2)cs1
Yield: 70 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(6-chloropyridazin-3-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (500 mg) synthesized in Example 123-1 and 4-fluorophenylboric acid (292 mg) were dissolved in dioxane (6 mL) and aqueous sodium carbonate solution (2 mol/L, 3 mL), tetrakis(triphenylphosphine)palladium (80 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1) to give the title compound (400 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([C:7]([N:9]=[C:10]=[O:11])=[O:8])=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C(OCC)C.C(#N)C>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:13]=[CH:12][C:6]([C:7]([NH:9][C:10]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:11])=[O:8])=[CH:5][CH:4]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C=NC(=O)c1ccc(C(F)(F)F)cc1
Solvent: CCOCC
Solvent: CC#N
Product: O=C(NC(=O)c1ccc(C(F)(F)F)cc1)Nc1ccc(Cl)cc1

Procedure:
To a stirred solution of 1.08 g of 4-trifluoromethylbenzoylisocyanate in 5 ml of dry diethylether is added a solution of 0.64 g of 4-chloroaniline in 50 ml of acetonitrile. A precipitate is immediately formed. The precipitate is sucked off and washed with acetonitrile. The title compound is obtained a yield of 1.1 g; melting point 260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[C:19]([C:29]#[N:30])[CH:18]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:32][CH2:33][CH2:34][OH:35].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][CH2:25][N:26]([CH2:32][CH2:33][CH2:34][OH:35])[CH2:27][CH2:28]4)=[C:19]([C:29]#[N:30])[CH:18]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Nc2ccc(N3CCNCC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(N3CCN(CCCO)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 54.9 %

Procedure:
1-(4-Chlorophenyl)-N-[3-cyano-4-(piperazin-1-yl)phenyl]-5-methylpyrazole-4-carboxamide (4.0 g), 3-bromopropanol (1.6 g) and potassium carbonate (1.6 g) were added to dimethylformamide (25 ml) and the mixture was stirred at 60° C. for 3 h. The reaction mixture was added into water, and the obtained crystals were recrystallized from hydrous dimethylformamide to give the title compound (2.5 g), melting point: 213° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21]>C(OCC)C>[CH3:29][O:28][C:24]1[CH:23]=[C:19]([C:20]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:21])[CH:18]=[C:17]([O:16][CH3:15])[C:25]=1[O:26][CH3:27]
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: CCOCC
Product: COc1cc(C(=O)Nc2ccccc2Nc2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-phenyl-o-phenylenediamine (1.84 g, 10 mmol) in diethyl ether (90 ml) was stirred at room temperature as 3,4,5-trimethoxybenzoyl chloride (2.31 g, 10 mmol) in diethyl ether (40 ml) was added dropwise. The reaction mixture was then stirred overnight at room temperature. The solvents were then removed in vacuo leaving N-[(3,4,5-trimethoxyphenyl)carbonyl)-N'-phenyl-phenylenediamine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]3[CH2:16][N:15]([C:17]([N:19]4[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([CH3:27])[CH2:21][C@@H:20]4[CH3:28])=[O:18])[C:14]([CH3:30])([CH3:29])[C:11]=3[NH:12][N:13]=2)[C:5]([F:31])=[CH:4][N:3]=1.[CH2:32](B1OC(C)(C)C(C)(C)O1)[CH:33]=[CH2:34].C(=O)([O-])[O-].[Cs+].[Cs+].O>[Pd].C1COCC1>[F:31][C:5]1[C:6]([NH:8][C:9]2[C:10]3[CH2:16][N:15]([C:17]([N:19]4[CH2:24][C:23]([CH3:26])([CH3:25])[N:22]([CH3:27])[CH2:21][C@@H:20]4[CH3:28])=[O:18])[C:14]([CH3:30])([CH3:29])[C:11]=3[NH:12][N:13]=2)=[N:7][C:2]([CH2:32][CH2:33][CH3:34])=[N:3][CH:4]=1
Reactant: C[C@H]1CN(C)C(C)(C)CN1C(=O)N1Cc2c(Nc3nc(Cl)ncc3F)n[nH]c2C1(C)C
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1ncc(F)c(Nc2n[nH]c3c2CN(C(=O)N2CC(C)(C)N(C)C[C@@H]2C)C3(C)C)n1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a pressure vessel was added [3-(2-Chloro-5-fluoro-pyrimidin-4-ylamino)-6,6-dimethyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-5-yl]-((S)-2,4,5,5-tetramethyl-piperazin-1-yl)-methanone (0.150 g, 0.330 mmol), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.12 g, 6.66 mmol), cesium carbonate (0.543 g, 1.66 mmol), dichloro[1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.0408 g, 0.0498 mmol), H2O (0.3 mL), and THF (3 mL). The suspension was purged with argon for 2 min, then stirred at 100° C. for 15 h. The cooled solution was filtered to remove undissolved solids and the volatiles removed in vacuo. The residue was redissolved in MeOH (5 mL) and 10% palladium on carbon (0.0400 g, 0.380 mmol) was added. The suspension was evacuated and backfilled with hydrogen for 3 times and allowed to stir for 15 h under hydrogen. The suspension was filtered through Celite, the filter cake washed with CH2Cl2, and the filtrate concentrated. Preparative HPLC provided the desired product I1 as a white solid (0.025 g, 14%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[CH:11]=[CH:10][C:9]=1[NH:17][C:18](=[O:34])[CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:22]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]2[NH:17][C:18](=[O:34])[CH2:19][C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:22]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1ccc(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)c(NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc2c(c1)N=C(c1cccc(-c3cccnc3)c1)CC(=O)N2

Procedure:
The title compound was prepared from {5-ethoxy-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M144) (170 mg, 0.36 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a brown solid (84 mg, 65%).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=O)=[N:14][CH:15]=1>O.CO>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[N:7][OH:8])=[N:14][CH:15]=1
Reactant: NO
Reactant: O=C(Cc1ccc(Cl)cn1)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=C(Cc1ccc(Cl)cn1)c1ccc(F)cc1
Yield: 98.9 %

Procedure:
Sodium acetate (6.47 g) and hydroxylamine hydrochloride (5.74 g) were dissolved in water (45 ml) and added to a solution of 2-(5-chloropyridin-2-yl)-1-(4-fluorophenyl)ethanone (3.39 g, 13.6 mmol) in methanol (200 ml). After heating at reflux for 2 h, the cooled reaction mixture was partitioned between water and ethyl acetate and the organic phase dried and concentrated to give the title compound as a yellow solid (3.56 g, 98%). NMR (CDCl3) δ 4.35 (2H, s, CH2); 7.02 (2H, t, 8 Hz, arom); 7.25 (1H, d, J 9 Hz, arom); 7.53 (1H, dd, J 9 & 2 Hz, arom); 7.71 (2H, m, arom); 8.12 (1 H, br s, OH); 8.48 (1H, s, 2 Hz, arom); Tlc SiO2 cyclohexane:ethyl acetate (3:1) Rf 0.42 detection uv254.
Reaction SMILES: [NH2:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=1[Cl:21].C(N(CC)CC)C.ClC(OCC)=O.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:10])=[CH:18][C:19]=1[Cl:20]
Reactant: Nc1c(Cl)cc(C(=CC(=O)O)c2ccc(Cl)cc2)cc1Cl
Reactant: C1COCCN1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Nc1c(Cl)cc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)cc2)cc1Cl
Temperature: -10 °C

Procedure:
20 g (0.058 mol) of 4-amino-β-(4-chlorophenyl)-3,5-dichloro-cinnamic acid (mixture of isomers A and B in the ratio 1:1.5) were dissolved in 700 ml of dry chloroform. 5.93 g (0.058 mol) of triethylamine were added while cooling with ice and stirring, and the mixture was cooled to -10° C. and combined with 6.35 g (0.058 mol) of ethyl chloroformate. After the addition had ended, 25.5 g (0.29 mol) of morpholine were added while further stirring and cooling. The resulting mixture was stirred for 4 hours more at room temperature and then extracted three times with water, and the organic phase was dried over sodium sulfate and concentrated to dryness in vacuo. The residue was chromatographed on a silica gel column (silica gel: substance=10:1, eluant: chloroform/ethyl acetate=1:1). The eluates containing substance were combined and evaporated to dryness in vacuo. Colorless crystals were obtained, melting point 140°-144° C., which contained the cis/trans isomer mixture in a proportion of 3:2.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[Br:44][C:45]1[CH:46]=[C:47]([OH:51])[CH:48]=[CH:49][CH:50]=1>>[Br:44][C:45]1[CH:50]=[CH:49][C:48]([C:4]2([OH:17])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=3)[N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[O:16])=[C:47]([OH:51])[CH:46]=1
Reactant: Oc1cccc(Br)c1
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2ccc(Br)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 3-bromophenol, the title compound was obtained (48%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 9.66 (br, 1H), 7.50-7.38 (m, 2H), 7.24-7.16 (m, 2H), 6.98-6.86 (m, 2H), 6.64 (d, 1H), 4.15 (br, 1H), 3.80-3.55 (m, 2H), 1.75-1.62 (m, 2H), 1.40-1.34 (m, 4H), 0.89 (t, 3H); MS (ES+) m/z 391.4 (M+1), 393.4 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=[O:6].[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[C:22]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)=[CH:8][CH:9]=1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCl)c1ccc(Cl)cc1
Product: CCC(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-chlorophenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 413.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O1CCCC1>[Cl:27][CH2:28][C:29]([N:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[CH:4][C:3]([C:14]3[N:15]=[CH:16][CH:17]=[CH:18][N:19]=3)=[C:2]([F:1])[CH:7]=2)[CH2:9][CH2:10]1)=[O:30]
Reactant: Fc1cc(N2CCNCC2)ccc1-c1ncccn1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCN(c2ccc(-c3ncccn3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(2-Fluoro-4-piperazin-1-yl-phenyl)-pyrimidine (5AB) (889 mg, 3.442 mmol, 1 equiv) was dissolved in anhydrous tetrahydrofuran (5 mL) and triethylamine (697 mg, 959 uL, 6.884 mmol, 2 equiv) was added, followed by slow addition of a solution of chloroacetyl chloride (6AB) (466.5 mg, 330 uL, 4.13 mmol, 1.2 equiv) in tetrahydrofuran at room temperature. The mixture was then stirred for about 1 hour at room temperature.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[N:29]1[C:38]2[C:33](=[C:34]([NH:39][NH2:40])[CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>>[N:23]1([S:20]([C:16]2[CH:15]=[C:14]([N:9]3[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]4[N:39]([C:34]5[CH:35]=[CH:36][CH:37]=[C:38]6[C:33]=5[CH:32]=[CH:31][CH:30]=[N:29]6)[N:40]=[CH:3][CH:4]=4)=[N:8]3)[CH:19]=[CH:18][CH:17]=2)(=[O:22])=[O:21])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)N3CCCC3)c2)ccc1=O
Reactant: NNc1cccc2ncccc12
Product: O=c1ccn(-c2cccc(S(=O)(=O)N3CCCC3)c2)nc1-c1ccnn1-c1cccc2ncccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[3-(pyrrolidine-1-sulfonyl)-phenyl]-1H-pyridazin-4-one (A-29) and quinolin-5-yl-hydrazine according to the method described for example 91. MS: M=499.2 (M+H)+
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.S(=O)(=O)(O)O.[C:19](=O)(O)[O-].[Na+]>CO>[OH:9][C:8]1[CH:10]=[CH:11][C:3]([CH2:2][C:1]([O:13][CH3:19])=[O:12])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: O=C([O-])O
Reactant: COc1cc(CC(=O)O)ccc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(O)c(OC)c1
Yield: 94 %

Procedure:
A solution of homovanillic acid 10 (2 g, 11 mmol) and sulfuric acid (500 ml, 9.4 mmol) in methanol (100 ml) was refluxed for 3 hours. After cooling, a sodium bicarbonate solution was added to the reaction mixture. The product was extracted with CH2Cl2 (2×50 ml). The combined organic phases were dried over MgSO4 and concentrated under reduced pressure to give methyl 4-hydroxy-3-methoxyphenylacetate 9 (2 g, 94%) in the form of a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 7.00-6.70 (m, 3H), 5.82 (br s, OH), 3.87 (s, 3H), 3.70 (s, 3H), 3.56 (s, 2H). 13C NMR (CDCl3, 75 MHz) δ 172.6, 146.6, 144.8, 125.7, 122.1, 114.5, 111.8, 55.9, 52.1, 40.8.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[N:31]=[C:30]([C:32]([OH:34])=O)[CH:29]=[CH:28][CH:27]=1.FC(F)(F)C(O)=O.[CH3:42][O:43][C:44]1[CH:64]=[CH:63][C:47]([O:48][C:49]2[CH:62]=[CH:61][C:52]([CH2:53][NH:54][C:55]([C:57]3([NH2:60])[CH2:59][CH2:58]3)=[O:56])=[CH:51][CH:50]=2)=[C:46]([C:65]([F:68])([F:67])[F:66])[CH:45]=1>CN(C=O)C>[CH3:42][O:43][C:44]1[CH:64]=[CH:63][C:47]([O:48][C:49]2[CH:62]=[CH:61][C:52]([CH2:53][NH:54][C:55]([C:57]3([NH:60][C:32]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:25])[N:31]=4)=[O:34])[CH2:58][CH2:59]3)=[O:56])=[CH:51][CH:50]=2)=[C:46]([C:65]([F:66])([F:67])[F:68])[CH:45]=1
Reactant: Cc1cccc(C(=O)O)n1
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cccc(C)n4)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
28 μL (0.20 mmol) of TEA and 118.8 mg (0.30 mmol) of HATU were added to a solution of 27.7 mg (0.20 mmol) of 6-methylpicolinic acid in 5 mL DMF and the mixture was stirred for 5 min at RT. Then 112 μL (0.81 mmol) of TEA and 100 mg (0.20 mmol) of 1-amino-cyclopropanecarboxylic acid 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamide-trifluoroacetic acid salt (from 85a) were added and the mixture was stirred overnight at RT. The reaction mixture was purified by chromatography (reversed phase).
Reaction SMILES: [CH:1]12[CH2:10]C3CC(CC(C3)[CH:2]1OCC1C(Cl)=CC(C(NS(C)(=O)=O)=O)=C(F)C=1)C2.[C:28]12([O:38][CH2:39][C:40]3[C:55](Cl)=[CH:54][C:43]([C:44]([NH:46][S:47]([N:50]4[CH2:53][CH2:52][CH2:51]4)(=[O:49])=[O:48])=[O:45])=[C:42]([F:57])[CH:41]=3)[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2>>[C:28]12([O:38][CH2:39][C:40]3[C:55]([CH:10]4[CH2:1][CH2:2]4)=[CH:54][C:43]([C:44]([NH:46][S:47]([N:50]4[CH2:53][CH2:52][CH2:51]4)(=[O:49])=[O:48])=[O:45])=[C:42]([F:57])[CH:41]=3)[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(COC2C3CC4CC(C3)CC2C4)cc1F
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(COC23CC4CC(CC(C4)C2)C3)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(COC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 49 and making variations as required to replace 4-((adamantan-2-yloxy)methyl)-5-chloro-2-fluoro-N-(methylsulfonyl)benzamide with 4-((adamantan-1-yloxy)methyl)-N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluorobenzamide, the title compound was obtained as a colorless solid (0.135 g, 83%): 1H NMR (300 MHz, CDCl3) δ8.82-8.68 (m, 1H), 7.76-7.68 (m, 1H), 7.44-7.34 (m, 1H), 4.72 (s, 2H), 4.33-4.18 (m, 4H), 2.35-2.15 (m, 5H), 1.90-1.60 (m, 13H), 1.02-0.89 (m, 2H), 0.73-0.62 (m, 2H); MS (ES+) m/z 463.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:5]=[CH:6][C:7]=1[F:8].[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=2[CH3:37])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=4)[NH:13][C:12]3=[O:18])[NH:31][C:30]=2[CH3:37])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)c(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(F)c(Cl)c4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42 %

Procedure:
To a solution of 4-(3-chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (65.4 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (53 mg, 45%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=C=O)=[CH:15][CH:14]=1.O>[O-]CC.[Na+].CC(N(C)C)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(NC(=O)c2ccc(O)cc2)cc1
Temperature: 30 °C
Reaction time: 0.42 h
Yield: 81.2 %

Procedure:
p-Hydroxybenzoic acid (69.06 grams, 0.50 mole), sodium ethoxide catalyst (0.155 gram, 0.225% wt. of the p-hydroxybenzoic acid used) and dimethylacetamide solvent (400 grams) are added to a reactor equipped with a reflux condenser and stirred under a nitrogen atmosphere at 80° C. p-Methoxyphenylisocyanate (78.30 grams, 0.525 mole) is added dropwise over a ten minute period with cooling of the reactor exterior to maintain the 80° C. reaction temperature. After an additional ten minutes at 80620 C., heating of the reactor commenced and a 160° C. temperature is achieved 25 minutes later. After three hours at the 160° C. reaction temperature, the reactor is cooled to 30° C. then the contents poured into two liters of deionized water. A precipitated white powder is recovered via filtration of the aqueous slurry then dissolved into one liter of boiling methanol. After cooling the methanol solution to 5° C., a first crop of white crystalline product is filtered off and dried at 90° C. under vacuum to a constant weight of 67.9 grams. The methanol solution is concentrated by rotary evaporation to a 300 milliliter volume then cooled to 5° C. until a second crop of white crystalline product appeared. After filtration, drying of the product to constant weight provided an additional 30.8 grams to give a total isolated yield of 81.2% of 4-hydroxy-4'-methoxybenzanilide.
Reaction SMILES: C(O)(=O)C.C([O:7][C:8](=[O:23])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=O)=O)=[CH:13][C:12]=1[CH2:21][CH3:22])C.Cl[Si](Cl)(C)C.[CH3:29][C:30]1[O:31][C:32]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)=[CH:33][C:34]=1[CH2:35]O>C(OCC)(=O)C.[Zn]>[CH2:21]([C:12]1[CH:13]=[C:14]([S:17][CH2:35][C:34]2[CH:33]=[C:32]([C:37]3[CH:38]=[CH:39][C:40]([C:43]([F:46])([F:44])[F:45])=[CH:41][CH:42]=3)[O:31][C:30]=2[CH3:29])[CH:15]=[CH:16][C:11]=1[O:10][CH2:9][C:8]([OH:7])=[O:23])[CH3:22]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)cc1CO
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1CC
Agent: C[Si](C)(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCc1cc(SCc2cc(-c3ccc(C(F)(F)F)cc3)oc2C)ccc1OCC(=O)O
Temperature: 60 °C

Procedure:
To a mixture of zinc (407 mg) in ethyl acetate (10 ml) stirred at 60° C. was added acetic acid (0.203 ml) followed by a solution of ethyl[4-(chlorosulfonyl)-2-ethylphenoxy]acetate (intermediate 111, 546 mg) in ethyl acetate. The reaction mixture was stirred 60° C. for 2 hours and then dichlorodimethylsilane (0.431 ml) was added drop-wise. After a further 90 minutes {2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol (472 mg) was added and the reaction mixture stirred at reflux for 17 hours. The reaction mixture was diluted with ethyl acetate; extracted with water, saturated aqueous sodium bicarbonate, water and dried with brine and over sodium sulfate. An attempt was purify the crude material by Biotage® chromatography using 3:2 petroleum ether: ethyl acetate as eluent. The partially purified material (223 mg) was hydrolyzed in 1,4-dioxan (6 ml) using 0.5 M aqueous sodium hydroxide (1.86 ml) for 16 hours. The reaction mixture was neutralized with 50W×2-200 Dowex; evaporated and the residue purified by mass-directed autopreparative HPLC to give the title compound as a solid.