Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(C2NC(C3C=CC(OC)=CC=3OCC)=NC2C2CCCCC2)=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[N:41]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)=[O:43])[C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=3[O:59][CH2:60][CH3:61])=[N:39][CH:38]2[CH2:62][CH:63]2[CH2:67][CH2:66][CH2:65][CH2:64]2)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[N:41]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)=[O:43])[C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=3[O:59][CH2:60][CH3:61])=[N:39][CH:38]2[CH:62]2[CH2:64][CH2:65][CH2:66][CH2:67][CH2:63]2)=[CH:33][CH:32]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Agent: CCOc1cc(OC)ccc1C1=NC(C2CCCCC2)C(c2ccc(Cl)cc2)N1
Product: CCOc1cc(OC)ccc1C1=NC(C2CCCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1

Procedure:
[5-(4-Chloro-phenyl)-4-cyclohexyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone was prepared from 5-(4-chloro-phenyl)-4-cyclohexyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 11) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 539.2790, calculated for C30H40N4O3Cl [(M+H)+]539.2784.
Reaction SMILES: [Br:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[C:7](Cl)(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]>>[C:7]([O:4][CH2:3][C:2]([Br:1])([F:6])[F:5])(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: OCC(F)(F)Br
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)OCC(F)(F)Br

Procedure:
One exemplary compound may be synthesized by reacting 2-bromo-2,2-difluoroethanol with pivalic chloride or anhydride to form 2-bromo-2,2-difluoroethyl pivalate, converting the bromo group into sodium sulfinate using a sulfur compound such as sodium dithionite, and converting sulfinic acid into sulfonic acid using an oxidizing agent such as hydrogen peroxide. This is followed by cation exchange with a triarylsulfonium halide or the like. The pivalic ester is then subjected to alkaline hydrolysis. Through reaction with (meth)acrylic anhydride, the alcohol resulting from hydrolysis is converted into a (meth)acrylic derivative, yielding the end compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13](=[O:30])[CH2:14][C:15]([C:21]2[CH:26]=[C:25]([Cl:27])[C:24]([F:28])=[C:23]([Cl:29])[CH:22]=2)(O)[C:16]([F:19])([F:18])[F:17])=[C:8]2[CH2:12][CH2:11][CH2:10][C:9]=12)=[O:4].O=S(Cl)Cl.N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13](=[O:30])[CH:14]=[C:15]([C:21]2[CH:26]=[C:25]([Cl:27])[C:24]([F:28])=[C:23]([Cl:29])[CH:22]=2)[C:16]([F:19])([F:18])[F:17])=[C:8]2[CH2:12][CH2:11][CH2:10][C:9]=12)=[O:4]
Reactant: COC(=O)c1sc(C(=O)CC(O)(c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)c2c1CCC2
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1sc(C(=O)C=C(c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)c2c1CCC2
Yield: 99.6 %

Procedure:
Stir a mixture of 3-[3-(3,5-Dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-hydroxyl-butyryl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid methyl ester (26 g, 53.7 mmol), SOCl2 (12.7 g, 7.8 mL, 0.107 mmol) and pyridine (42.3 g, 0.537 mmol) in anhydrous DCM (300 mL) at room temperature for 3 hours. Concentrate the mixture under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc 12:1) to afford 3-[3-(3,5-Dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carboxylic acid methyl ester as a pale yellow solid (25 g, 100%). (m/z): 467 (M+1).
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:26]([NH:28][CH2:29][CH2:30][C:31]3[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=3)=[O:27])[CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.C(O)(=O)[C:40]1[CH:48]=[C:46]([OH:47])[C:44]([OH:45])=[C:42]([OH:43])[CH:41]=1>>[OH:43][C:42]1[CH:41]=[C:40]([CH:48]=[C:46]([OH:47])[C:44]=1[OH:45])[C:16]([NH:18][C@H:19]([C:26]([NH:28][CH2:29][CH2:30][C:31]1[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=1)=[O:27])[CH2:20][O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:17]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccc(O)c(O)c1
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Product: CC(C)(C)OC[C@H](NC(=O)c1cc(O)c(O)c(O)c1)C(=O)NCCc1ccc(O)c(O)c1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-seryl]dopamine (1.16 g, 2.24 mmol, example 42, step A) as described for example 42 (step B) using gallic acid (571 mg, 3.36 mmol) instead of caffeic acid. The crude material was purified by flash chromatography using successively 30%, 40% and 70% EtOAc/CH2Cl2/1% AcOH as the eluent. The title compound was obtained as a white powder (300 mg, 30%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:9]=2)=[N:4][C:3]=1[NH2:25].[CH3:26][O:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:16]2[C:8]([C:5]2[N:6]=[N:7][C:2]([C:33]3[C:28]([O:27][CH3:26])=[N:29][CH:30]=[CH:31][CH:32]=3)=[C:3]([NH2:25])[N:4]=2)=[N:9]1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1Cl
Reactant: COc1ncccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: C1COCCO1
Product: COc1ncccc1-c1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
Under an argon atmosphere, 140 mg (purity 65%, 0.256 mmol) of 6-chloro-3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazine-5-amine were suspended in 5 ml of absolute dioxane. 117 mg (0.767 mmol) of (2-methoxypyridin-3-yl)boronic acid, 1.023 ml (1.023 mmol) of 1N aqueous potassium carbonate solution and 14 mg (0.051 mmol) of tricyclohexylphosphine were added and argon was passed through the suspension for 10 min with stirring. Then, 28 mg (0.038 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride were added and the reaction mixture was stirred for 60 min in the microwave at 140° C. After cooling, the mixture was filtered over an Extrelut cartridge and after-washed with a mixture of dichloromethane/methanol (v/v=20:1). The filtrate was concentrated and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80→100:0). 38 mg of the target compound were obtained (27% of theory).
Reaction SMILES: [O-]CC.[Na+].[CH3:5][CH2:6][CH2:7][C:8]1[C:13]([OH:14])=[C:12]([C:15]([CH3:17])=[O:16])[CH:11]=[CH:10][C:9]=1[OH:18].[CH2:19]([O:21][C:22](=[O:28])[C:23](OCC)=O)[CH3:20].Cl>C(O)C.CCOCC>[OH:18][C:9]1[CH:10]=[CH:11][C:12]2[C:15](=[O:16])[CH:17]=[C:23]([C:22]([O:21][CH2:19][CH3:20])=[O:28])[O:14][C:13]=2[C:8]=1[CH2:7][CH2:6][CH3:5]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCCc1c(O)ccc2c(=O)cc(C(=O)OCC)oc12
Temperature: 25 °C

Procedure:
To a solution of sodium ethoxide (from 19 gm. of sodium and 260 ml of absolute ethanol) under nitrogen atmosphere, add dropwise a solution of 40 gm of 2,4-dihydroxy-3-propylacetophenone and 68 gm of diethyloxalate in 55 ml of absolute ethanol and 55 ml of absolute ether. Heat under reflux for 3.5 hours. Cool to room temperature and pour the mixture into 500 ml of 5% aqueous hydrochloric acid. Extract the mixture twice with ether. Wash the combined organic fractions with water, dry over sodium sulfate and strip to a residue. Reflux the residue for 30 minutes in 150 ml absolute ethanol containing 2.5 ml of concentrated hydrochloric acid. Evaporate most of the ethanol and partition the residue between water and ethyl acetate. Wash the organic fraction with water, aqueous sodium bicarbonate solution and again with water. Dry over sodium sulfate and strip to a residue. Crystallize the residue from ethyl acetate-hexane to obtain a first crop (mp 155°-162° C.). Strip the mother liquors to dryness and chromatograph the residue over silica gel, eluting with a mixture of ethylacetate-hexane (1:1). Crystallize the resulting product from ethyl acetate to obtain a second crop. (mp 165°-167° C. lit. 166°-167° C.).
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1([C:39](Cl)=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:39]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)=[O:40])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C(Cl)c1cccc2ccccc12
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3cccc4ccccc34)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthoyl chloride: ESMS m/e: 533.7 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([CH2:22][CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH2:20]([O:19][C:17](=[O:18])/[C:22](/[CH3:23])=[CH:9]/[CH:8]=[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:21]
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCOC(=O)/C(C)=C/C=C(c1ccccc1)c1ccccc1
Yield: 95.9 %

Procedure:
As in the Example 99. a solution of 3,3-diphenyl-2-propenal (2.08 g) in ethanol (25 mL) was reacted with (carbethoxyethylidene)triphenylphosphorane (4.0 g) for 30 minutes at room temperature. The reaction was worked up in the usual manner to give 2.8 g of (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid ethyl ester as the sole product. The crude ester (2.8 g) in methanol (25 mL) was treated with 2N potassium hydroxide (10 mL) and the mixture was heated at reflux until the oil dissolved, then it was cooled and left at ambident temperature overnight. The reaction was diluted with water (20 mL) and most of the methanol was removed under reduced pressure. The solution was acidified with 2N hydrochloric acid (12 mL) and the resulting solid was recovered by filtration, washed with water and dried. The crude acid was triturated with hot hexane to furnish 2.08 g of (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid, mp 184°-186° C. A sample was crystallized from 2-propanol to afford the analytical specimen, mp 185°-186.5° C.
Reaction SMILES: [C:1]1(=[O:8])O[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(OO)(=O)C.C(OO)(=O)C.CC(C)=O.C1(=O)NCCCCC1>C(O)(=O)C.CC(C)=O>[C:1]1(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCCCCO1
Agent: CC(=O)OO
Agent: O=C1CCCCCN1
Solvent: CC(=O)O
Solvent: O=C1CCCCC1
Solvent: CC(C)=O
Product: Oc1ccccc1

Procedure:
The epsilon caprolactone employed in accordance with the invention is available commercially so that neither the compound per se nor the method by which it is obtained constitutes any portion of the invention. According to one method, epsilon caprolactone is prepared by oxidizing cyclohexanone with an anhydrous solution of peracetic acid and acetone. The product thus obtained comprises acetic acid and epsilon caprolactone. When this method is used, it is desirable to add the peracetic acid-acetone solution to an excess of the cyclohexanone, e.g., 5 to 1 molar ratio of cyclohexanone to peracetic acid, in a vessel maintained under reflux. The epsilon caprolactone is recovered from the vessel by conventional distillation. The cyclohexanone used in the preparation of epsilon caprolactone is an intermediate product in the preparation of caprolactam. Cyclohexanone can be obtained either by the hydrogenation of phenol or the oxidation of cyclohexane. If a commercially available epsilon caprolactone is used in accordance with the invention, I prefer to purify the material by vacuum distillation. According to a typical purification procedure, epsilon caprolactone is subjected to distillation in a vacuum distillation column, separately collecting that portion boiling at 56° to 57° C./0.4 torr. Epsilon caprolactone is water-white with a single gas-chromatography peak.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([NH:14][C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17]([OH:19])=[O:18])(=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:24](O)[CH3:25]>>[C:5]([NH:14][C:15]1[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:17]([O:19][CH2:24][CH3:25])=[O:18])(=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCO
Reactant: CCCCCCCC(=O)Nc1ccccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: CCCCCCCC(=O)Nc1ccccc1C(=O)OCC
Reaction time: 2 h
Yield: 89.2 %

Procedure:
Thionyl chloride was dropped to ethanol and the mixture was stirred for 2 hours. Then, N-n-octanoylanthranilic acid was added to the mixture and reaction was allowed to proceed for 3 days at the room temperature. After the reaction, the solvent was removed and ethyl N-n-octanoylanthranilate was obtained from the remaining reactant after the purification by column chromatography with the yield of 89.2%.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1.[CH:15](=[O:18])[CH2:16][CH3:17].Cl>CCCCCC.O1CCCC1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[CH:15]([OH:18])[CH2:16][CH3:17]
Reactant: CCC=O
Reactant: COc1cccc(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(O)c1c(F)cccc1OC
Reaction time: 1 h
Yield: 85.6 %

Procedure:
66.7 ml (106.8 mmol) of a 1.6N butyllithium solution in hexane were added at -78° to a solution of 12 g (95.14 mmol) of 3-fluoroanisole in 240 ml of anhydrous tetrahydrofuran and the mixture was stirred for one hour. Subsequently, 21 ml (288 mmol) of propionaldehyde were added dropwise thereto at -78°, the mixture was stirred for one hour and the solution was left to come to room temperature. The mixture was poured into 240 ml of 1 N HCl and extracted twice with 250 ml of diethyl ether each time After drying over sodium sulfate concentration was carried out in a vacuum. The crude product obtained was purified by column chromatography on silica gel (dichloromethane/hexane 1:1). There were obtained 15 g (86%) of 1-(2-fluoro-6-methoxy-phenyl)-propan-1-ol as a pale yellow oil.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:16]=2)=[CH:10][CH:9]=1.[C:26](OCC)(=[O:28])[CH3:27]>CCCCCC.O1CCCC1>[C:20]1([N:17]2[CH2:18][CH2:19][C:15]([N:14]([C:11]3[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=3)[C:26](=[O:28])[CH3:27])=[N:16]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(NC2=NN(c3ccccc3)CC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(N(C(C)=O)C2=NN(c3ccccc3)CC2)cc1
Reaction time: 2 h

Procedure:
1.7M n-butyl lithium in hexane (7.0 ml) was added dropwise to a solution of 4,5-dihydro-N-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-amine (2.67 g) in tetrahydrofuran (150 ml) at -25° under N2. After 40 minutes ethyl acetate was added and the solution was allowed to reach room temperature. After being stirred for 2 hours, the solution was evaporated to dryness and the residue chromatographed on silica gel eluting with ethyl acetate in dichloromethane to give an oil which crystallised on trituration with ether. The solid was recrystallised from ether and hexane to give the title compound (0.82 g) mp 83°-5° (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[Si](I)(C)(C)C.[S-2].[Na+].[Na+]>>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Agent: C[Si](C)(C)I
Agent: [Na+]
Agent: [S-2]
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1O
Temperature: 80 °C
Yield: 62.2 %

Procedure:
A mixture of (S)-7-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)isoindolin-1-one (10 g, 24.7 mmol) and TMSI (50 g, 250 mmol) was heated to 80° C. for 2 hours. The mixture was cooled to 0° C. in an ice-water bath. To the mixture, was added 5% aqueous sodium sulfide solution. The mixture was stirred at room temperature until all solid dissolved. The mixture was extracted with methylene chloride. The organic layer was washed with brine. The solvent was removed in vacuo to give a foam. The crude mixture was purified by column chromatography (silica gel. MeOH/CH2Cl2) to give (S)-7-amino-2-(1-(3-ethoxy-4-hydroxyphenyl)-2-(methylsulfonyl)ethyl)isoindolin-1-one (6 g), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].C(N(CC)CC)C.[CH2:36]([N:43]=[C:44]=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:44]([NH:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:45])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)NCc2ccccc2)c1
Reaction time: 2 h

Procedure:
Alternative synthesis: To (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (prepared as described in Example 1, Step 1 but using EtOH in place of MeOH; 44.9 g, 0.114 mol) in CH2Cl2 (450 mL) at room temperature was added triethylamine (24 mL, 0.17 mol), followed by benzylisocyanate (16.7 mL, 0.136 mol), and the reaction was stirred for 2 hours until no starting material was seen by analytical LCMS. The mixture was partitioned between H2O and CH2Cl2, and the aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated, and the residue was purified by silica gel chromatography (0-60% EtOAc in hexanes) to give the [2′-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester. Hydrolysis of the ethyl ester according to the procedure described in Example 1, Step 7 provided [2′-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid.
Reaction SMILES: [NH2:1][CH:2]([C:12]1[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[Br:11].C(N(CC)CC)C.[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38]>C(#N)C>[Br:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH:2]1[C:12]2[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]=2[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)[C:37](=[O:38])[NH:1]1)[C:7]#[N:8]
Reactant: N#Cc1ccc(C(N)C2=C(Nc3cccc(C(F)(F)F)c3)CCCC2=O)c(Br)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-{Amino-[6-oxo-2-(3-trifluoromethyl-phenylamino)-cyclohex-1-enyl]-methyl}-3-bromo-benzonitrile (INTERMEDIATE 21, 16.5 g, 33 mmol) is suspended in acetonitrile (150 mL) and triethylamine (3.47 mL, 24.7 mmol) and 1,1′-carbonyldiimidazole (6.7 g, 41.2 mmol) are added. The mixture is stirred at room temperature for 1 h. The solvent is evaporated under reduced pressure and water is added. The product precipitates; the precipitate is filtered off, washed with water and dried. Yield: 14 g. ESI mass spectrum: [M+H]+=490 (bromine isotope pattern); Retention time HPLC: 0.64 min (X012_S02).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]([Cl:11])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CN(C)C(=O)C>[Cl:11][C:8]1[C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:10][CH:9]=1
Reactant: O=C(O)c1cc(Cl)ncc1Cl
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Product: O=C(O)c1cc(N2CCOCC2)ncc1Cl
Yield: 34 %

Procedure:
2,5-Dichloroisonicotinic acid, prepared by the method of E. Marzi, A. Bigi, M. Schlosser, Eur. J. Org. Chem. 2001, 1371–1376, (1.6 g, 0.0083 mol) and morpholine (10.9 g, 0.125 mol) in 4 mL of N,N-dimethylacetamide were heated at 80° C. for 4 days. The volatiles were removed under vacuum and the resulting yellow solid partitioned between water and Et2O. The aqueous layer was acidified to pH=1.5 using an aqueous solution of HCl and extracted once with Et2O (25 mL) and three times with CH2Cl2 (25 mL). The organic extracts were combined and the solvents removed under vacuum. The resulting yellow solid was crystallized from MeOH to afford the title compound 1.07 g (yield: 34%). 1H NMR (300 MHz, d6-DMSO): δ 3.45 (t, 4H, J=4.8 Hz), 3.67 (t, 4H, J=4.8 Hz), 7.06 (s, 1H), 8.21 (s, 1H), 13.79 (s (broad), 1H). 13C HMR (100 MHz, d6-DMSO): δ 45.6, 66.4, 107.3, 116.1, 141.3, 148.3, 158.5, 166.8. M+1=243.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]([OH:14])=O)=[N:4][C:5]([CH:8]2[CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:15][NH:16][C:17]([C:19]1[N:20]([CH3:25])[N:21]=[CH:22][C:23]=1[NH2:24])=[O:18]>>[CH3:25][N:20]1[C:19]([C:17](=[O:18])[NH:16][CH3:15])=[C:23]([NH:24][C:12]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([CH:8]3[CH2:9][CH2:10][CH2:11]3)[N:4]=2)=[O:14])[CH:22]=[N:21]1
Reactant: CNC(=O)c1c(N)cnn1C
Reactant: O=C(O)c1nc(C2CCC2)ncc1Br
Product: CNC(=O)c1c(NC(=O)c2nc(C3CCC3)ncc2Br)cnn1C

Procedure:
The product was obtained starting from 5-bromo-2-cyclobutyl-pyrimidine-4-carboxylic acid (37 mg, 0.14 mmol) and 4-amino-2-methyl-2H-pyrazole-3-carboxylic acid methylamide (29 mg, 0.19 mmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as off-white solid (24 mg, 42%).