Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[C:10]=2[NH:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:45][CH:46]([CH3:48])[CH3:47]>CN(C=O)C.O>[CH2:45]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][N:14]=2)[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:10]([NH:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[C:11]1=[O:19])[CH:46]([CH3:48])[CH3:47]
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)[nH]c3ncccc23)c1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CC(C)C)c3ncccc23)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.9 %

Procedure:
To a solution of N-[4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (100 mg, 0.21 mmol) in DMF (5 ml) were added potassium carbonate (1.39 g, 10.1 mmol), potassium iodide (10 mg, 0.07 mmol) and 1-bromo-2-methylpropane (58 mg, 0.43 mmol), and the mixture was stirred at room temperature for five hours. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1-3% methanol in chloroform) to give the title compound (71 mg, 0.13 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O-:10])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[C:16]1([CH:26]([NH2:28])[CH3:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:11][C:4]1[CH:5]=[C:6]([C:8]([NH:28][C@@H:26]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH3:27])=[O:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1c(Cl)cc(C(=O)[O-])cc1Cl
Reactant: CC(N)c1cccc2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)cc(C(=O)N[C@H](C)c2cccc3ccccc23)cc1Cl
Yield: 96 %

Procedure:
A solution of 2,6-dichlorobenzene-1,4-dicarboxylic acid, 1-methyl ester (Example 4; 3.00 g, 12.0 mmol), ®-(+)-1-(1-naphthyl)ethylamine (2.00 g, 11.7 mmol), HBTU (5.68 g, 15.0 mmol), HOBT (2.04 g, 15.1 mmol), and diisopropylethylamine (6.20 g, 48.0 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature over the weekend. The solvent was evaporated and ethyl acetate (150 mL) was added. The solution was washed with 1 M HCl (100 mL) and the aqueous layer was back-extracted with ethyl acetate (100 mL). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate and brine (200 mL each), then dried (MgSO4), filtered, evaporated and chromatographed (30% ethyl acetate/hexanes) to give 2,6-dichloro-4-[[[(1R)-1-(1-naphthalenyl)ethyl]amino]carbonyl]benzoic acid, methyl ester (4.52 g, 96%) as a white foam.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:32])=O)=[C:24]([F:33])[CH:23]=3)[CH:15]=2)=[C:9]([CH3:34])[CH:8]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:47]1([CH2:53][S:54]([NH2:57])(=[O:56])=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH2:53]([S:54]([NH:57][C:30](=[O:32])[CH2:29][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][CH2:20][C:16]2[CH:15]=[C:14]([C:10]3[C:9]([CH3:34])=[CH:8][C:7]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:12][C:11]=3[CH3:13])[CH:19]=[CH:18][CH:17]=2)=[CH:23][C:24]=1[F:33])(=[O:56])=[O:55])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)O)c(F)c3)c2)c(C)c1
Reactant: NS(=O)(=O)Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CCC(=O)NS(=O)(=O)Cc4ccccc4)c(F)c3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.4 %

Procedure:
To a solution of 3-[4-({[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methyl}amino)-2-fluorophenyl]propanoic acid (0.186 g, 0.400 mmol) in tetrahydrofuran (5 mL) was added 1,1′-carbonyldiimidazole (97.3 mg, 0.600 mmol), and the mixture was heated under reflux under a nitrogen atmosphere for 1 hr. After cooling the reaction mixture, 1-phenylmethanesulfonamide (91.5 mg, 0.480 mmol) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.0897 mL, 0.600 mmol) were added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 24 hr. The reaction mixture was concentrated under reduced pressure, 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane) to give the title compound (0.189 g, yield 76%) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([OH:23])=O)[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl.[NH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:28].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[F:35][C:32]1[CH:31]=[CH:30][C:29]([C:27](=[O:28])[CH2:26][NH:25][C:21]([CH:17]2[CH2:18][CH2:19][CH2:20][N:15]([C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[CH2:16]2)=[O:23])=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: NCC(=O)c1ccc(F)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)NCC(=O)c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
Triethyl amine (1.52 mL, 10.4 mmol) was added dropwise to a solution of piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (600 mg, 2.6 mmol) and 2-amino-1-(4-fluorophenyl)ethanone hydrochloride (500 mg, 2.6 mmol) in THF (12 mL), followed by T3P (propylphosphonic anhydride) (1.7 mL, 2.6 mmol, 50% in EtOAc) at 0° C. The reaction mixture was stirred 30 min, allowed to warm up to room temperature and stirred for an additional 8 h. The reaction mixture was then concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with aqueous 10% NaHCO3, water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by purified by column chromatography (silica gel 60-120 mesh, eluent 20-25% EtOAc in petroleum ether) to afford tert-butyl 3-((2-(4-fluorophenyl)-2-oxoethyl)carbamoyl)piperidine-1-carboxylate (500 mg, yield 52%). 1H NMR (400 MHz, DMSO-d6) δ 8.33-8.30 (t, J=5.6 Hz, 1H), 8.08-8.04 (dd, J=8.5 Hz, 5.8 Hz, 2H), 7.39-7.35 (t, J=8.7 Hz, 2H), 4.57-4.56 (m, 2H), 3.99-3.86 (m, 2H), 2.39-2.32 (m, 1H), 1.87-1.84 (m, 1H), 1.66-1.62 (m, 1H), 1.56-1.46 (m, 2H), 1.40 (s, 9H), 1.32-1.23 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[S:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=1>C(O)C>[Br:20][C:18]1[CH:17]=[CH:16][C:15]([S:21][C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:26][CH:27]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(Br)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(Br)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (106 mg, 0.59 mmol) was reacted in ethanol (2 mL) with the product from Example 106b (200 mg, 0.59 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (53 mg, 19%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.05 (s, 3H) 2.77 (s, 3H), 6.41 (d, J=6.99 Hz, 1H), 7.02 (d, J=8.82 Hz, 1H), 7.33 (d, J=8.46 Hz, 2H), 7.58 (d, J=8.82 Hz, 2H), 7.65 (dd, J=8.46, 2.21 Hz, 1H) 7.77 (d, J=2.21 Hz, 1H), 7.81 (d, J=8.82 Hz, 1H), 8.48 (d, J=6.99 Hz, 1H), 8.96 (d, J=8.82 Hz, 1H), 10.11 (s, 1H), 11.06 (s, 1H), 14.53 (s, 1H); MS (DCI/NH3) m/z 479 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH2:8][CH:7]=[CH:6][CH2:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12].C(N(CC)CC)C.N([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N+]=[N-]>C1COCC1>[C:27]([O:26][C:24]([NH:1][CH2:2][C:3]1[CH2:8][CH:7]=[CH:6][CH2:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: NCC1=C(CCC(=O)O)CC=CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC1=C(CCC(=O)O)CC=CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of β-(2-aminomethyl-1,4-cyclohexadienyl)propionic acid (1.40 L g., 7.7 mmoles) and triethylamine (2.02 g., 20 mmoles) in 50% aqueous THF (20 ml.) was added a solution of t-butyl azidoformate (1.43 g., 10 mmoles) in THF (5 ml.) and the reaction mixture was stirred overnight at room temperature. The mixture was washed with ether (2×20 ml) and the aqueous layer was acidified to pH 2 with dil. hydrochloric acid. The mixture was extracted with chloroform (4×30 ml.) and the combined extracts were washed with water and dried. Evaporation of the extracts under reduced pressure afforded β-(2-tert.-butoxycarbonylaminomethyl-1,4-cyclohexadienyl)propionic acid as a colorless oil. Yield, 2.10 g. (97%).
Reaction SMILES: CC[C:3]([NH:5][C:6]1[S:7][C:8]([Cl:20])=[CH:9][C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=O.Cl>C(O)C>[CH3:3][NH:5][C:6]1[S:7][C:8]([Cl:20])=[CH:9][C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18]
Reactant: CCC(=O)Nc1sc(Cl)cc1C(=O)c1ccccc1F
Agent: Cl
Solvent: CCO
Product: CNc1sc(Cl)cc1C(=O)c1ccccc1F
Temperature: 90 °C

Procedure:
To a solution of 1.5 g of 2-(N-methylacetylamino)-3-(o-fluorobenzoyl)-5-chlorothiophene in 7 ml of ethanol is added 4 ml of 6 N aqueous hydrochloric acid. The mixture is heated at 90°C for 2 hours, evaporated under reduced pressure to a residue, neutralized with aqueous ammonia, then extracted with ether. The ether extracts are washed with water, dried over sodium sulfate, when evaporated under reduced pressure to a oil, which is chromatographed on silica gel using chloroform as an eluent to give 2-(N-methylamino)-3-(o-fluorobenzoyl)-5-chlorothiophene as crystals having a melting point of 93° - 94°C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C@@H:8](O)[CH2:7][C@@H:6]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:20]([NH:23][CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]>[Pd].CO>[OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]([OH:9])=[C:5]([C@@H:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH2:8][N:23]([CH:24]([CH3:26])[CH3:25])[CH:20]([CH3:22])[CH3:21])[CH:4]=1
Reactant: CC(C)NC(C)C
Reactant: OCc1ccc2c(c1)[C@@H](c1ccccc1)C[C@H](O)O2
Agent: [Pd]
Solvent: CO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CO)ccc1O)C(C)C

Procedure:
A mixture consisting of methanol, Pd/C catalyst, (R)-6-hydroxymethyl-4-phenylchroman-2-(R)-ol, and an excess of diisopropyl amine will be hydrogenated at ambient temperature at a pressure of 4 bar. After at least 18 hours, the reaction mixture will be filtered and evaporated to dryness. Subsequently, it is treated with 1 molar equivalent of a solution of lithium aluminium hydride in tetrahydrofuran for cleaving any cyclic hemiaminal. The reaction is quenched with water, and the product will be extracted with ethyl acetate. Removal of the solvent and drying in vacuum provides (R)-4-hydroxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenol in the form of a colourless oil.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([O:10][CH3:11])[CH:4]=1)#[N:2].Cl[S:13]([OH:16])(=[O:15])=[O:14]>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][S:13](=[O:15])(=[O:14])[OH:16])=[C:5]([O:10][CH3:11])[CH:4]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1N
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(C#N)ccc1NS(=O)(=O)O

Procedure:
To a solution of 4-cyano-2-methoxyaniline (1 mmol) in chloroform (1 mL) at −78° C. is added chlorosulfonic acid. Upon reaction completion, the crude material is concentrated and may be purified by recrystalization to give N-(4-cyano-2-methoxyphenyl)-sulfamic acid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:13]2[CH:12]=[CH:11][C:10]3[CH:14]=[CH:15][CH:16]=[C:17]([I:18])[C:9]=3[CH:8]([OH:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(Cl)Cl.CN(C)C1C=CN=CC=1.O1CCCC1>[C:20]([O:1][CH2:2][C:3]1[C:13]2[CH:12]=[CH:11][C:10]3[CH:14]=[CH:15][CH:16]=[C:17]([I:18])[C:9]=3[CH:8]([OH:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1cccc2c1C=Cc1cccc(I)c1C2O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)OCc1cccc2c1C=Cc1cccc(I)c1C2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
310 mg of the mixture of 1-(hydroxymethyl)-6-iodo-5H-dibenzo[a,d]cyclohepten-5-ol with its 4-iodo form prepared in Example 6-e was dissolved in 15 ml of methylene chloride, and 100 mg of 4-(dimethylamino)pyridine and 0.8 ml of 1M solution of acetic anhydride in tetrahydrofuran were added under ice-cooling, followed by stirring at room temperature for 2 hours. The solvent was evaporated, and the residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=3:17), to give 230 mg of a mixture of the title compound with its 4-iodo form as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2OC)[C:10]1=[O:24].[CH2:25](NC1C=CC=CC=1C)C=C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:25])[C:10]1=[O:24]
Reactant: COc1ccccc1N1CCCC[C@H](N)C1=O
Reactant: C=CCNc1ccccc1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1N1CCCC[C@H](N)C1=O

Procedure:
(S)-3-Amino-1-o-tolylazepan-2-one trifluoroacetate (17 mg, 0.051 mmol) was synthesized as described for the preparation of Intermediate 62 using N-allyl-2-methylaniline in step A. Anal. Calcd. for C13H18N2O m/z 218.2. found: 219.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20](Br)[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].[OH-].[Na+].O>CN(C)C=O>[CH2:20]([O:11][C:10](=[O:12])[CH:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(C(=O)OCC(=O)c1ccccc1)c1ccc(O)cc1
Yield: 99.6 %

Procedure:
A solution of N-tert-butoxycarbonyl-2-(4-hydroxyphenyl) glycine (9.18 g.), phenacyl bromide (6.86 g.) and sodium hydroxide (1.37 g.) in N,N-dimethylformamide (100 ml.) was stirred for 4 hours at ambient temperature. The reaction mixture was poured into water (500 ml.) and extracted three times with every 50 ml. portions of ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and evaporated to dryness under reduced pressure to give an oily N-tert-butoxycarbonyl-2-(4-hydroxyphenyl)glycine phenacyl ester (13.19 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].ClC1C=CC(O[CH2:22][C:23]#[N:24])=CC=1.CC([O-])(C)C.[K+].Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([C:12]([F:13])([F:14])[F:15])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[C:7]([CH2:22][C:23]#[N:24])[CH:8]=1
Reactant: N#CCOc1ccc(Cl)cc1
Reactant: COc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CC#N)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: -10 °C
Yield: 77.7 %

Procedure:
A mixture of 1-methoxy-4-nitro-2-trifluoromethylbenzene (93 g, 0.421 mol) and 4-chlorophenoxyacetonitrile (77.55 g, 0.463 mol) in dry DMF (500 ml) was added dropwise over 0.75 h to a stirred solution of KOtBu (103.85 g, 0.927 mol) in dry DMF (400 ml) at −10° C. After complete addition the resulting purple solution was maintained at −10° C. for 1 h then poured into a mixture of ice/water (1.5 l) and 5 M aqueous HCl (1.5 l). The resulting mixture was extracted with dichloromethane (3×1 l). The combined extracts were washed with water (3 l), dried (Na2SO4) and evaporated under reduced pressure. The residue was chromatographed on silica using 10-40% ethyl acetate/petroleum ether as eluant to give the crude product which was recrystallised from ethyl acetate/petroleum ether to afford the title compound (85.13 g, 78%) as a white solid. Mp 103-104° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH3:30][O:31][C:32](Cl)=[O:33].CCN(C(C)C)C(C)C>>[CH3:30][O:31][C:32]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)=[O:33]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCNC3)cnc21
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CC[C@@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
(R)-3-{3-[5-(2-Trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid methyl ester was prepared from (R)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and methylchloroformate using DIPEA as base and following the general synthetic procedures described in the above Examples.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:5]=1)(=O)[CH3:2].Cl.[CH3:27][O:28][NH2:29].N1C=CC=CC=1>O1CCOCC1>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[S:8][C:4]([C:1](=[N:29][O:28][CH3:27])[CH3:2])=[CH:5][C:6]=2[C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)=[CH:10][CH:11]=1
Reactant: CC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Reactant: CON
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CON=C(C)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
A mixture of 5-acetyl-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (1.35 g), methoxyamine hydrochloride (0.45 g) and pyridine (0.44 ml) in dioxane (17 ml) was stirred at ambient temperature for 1 hour. The mixture was concentrated, and the residue was triturated with water, filtered, washed with water and dried. The crude crystals were recrystallized from ethyl acetate to give pure crystals of 2-(4-fluorophenyl)-5-[-1-(methoxyimino)ethyl]-3-[4-(methylsulfonyl)phenyl]thiophene (0.68 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH:8]([C:12]1[C:13]([CH:28]2[CH2:30][CH2:29]2)=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:9][CH2:10][CH3:11].[C:31]([O:35][C:36](=[O:47])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([SH:45])=[CH:41][C:40]=1[CH3:46])([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C.CCOCC>[C:31]([O:35][C:36](=[O:47])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45][CH:8]([C:12]2[C:13]([CH:28]3[CH2:30][CH2:29]3)=[N:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:16][CH:17]=2)[CH2:9][CH2:10][CH3:11])=[CH:41][C:40]=1[CH3:46])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1cc(S)ccc1OCC(=O)OC(C)(C)C
Reactant: CCCC(Cl)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCC(Sc1ccc(OCC(=O)OC(C)(C)C)c(C)c1)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
231 mg (0.7 mmol) cesium carbonate was added to a solution of 210 mg (0.59 mmol) [rac]-5-(1-chloro-butyl)-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 30D]) and 151 mg (0.59 mmol) (4-mercapto-2-methyl-phenoxy)-acetic acid tert-butyl ester (example 28C]) in 3 ml DMF. After stirring for 3 h at RT, the reaction mixture was taken up in ether and washed with 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:9 providing 257 mg of pure [rac]-(4-{1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylsulfanyl}-2-methyl-phenoxy)-acetic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([CH3:16])[C:8]3[N:9]2[CH:12]=[N:13][C:14]=3[CH3:15])=[CH:4][CH:3]=1.C1C(=O)N([Br:24])C(=O)C1>>[Br:24][C:12]1[N:9]2[C:10]3[C:5]([N:6]=[C:7]([CH3:16])[C:8]2=[C:14]([CH3:15])[N:13]=1)=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3
Reactant: Cc1ncn2c1c(C)nc1ccc(F)cc12
Reactant: O=C1CCC(=O)N1Br
Product: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
Yield: 88.3 %

Procedure:
Reaction of intermediate 4A (1.55 g, 7.2 mmol) and NBS (1.92 g, 10.8 mmol) provided the product 5A as an off-white solid (1.87 g, 89% yield). EIMS 293.9 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([CH3:39])([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:22]2[S:26][C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[N:24][C:23]=2[CH3:37])[CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[CH3:38])[CH3:6])C.[OH-].[Na+]>CCO>[CH3:39][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:22]2[S:26][C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:32]=3)=[N:24][C:23]=2[CH3:37])[CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][C:9]=1[CH3:38])([CH3:6])[C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN(Cc2ccco2)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(CN(Cc2ccco2)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OC(C)(C)C(=O)O
Temperature: 70 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a solution of example 92 (120 mg, 0.21 mmol) in EtOH (20 mL) was added 1N NaOH (0.63 mL, 3 eq.) and the reaction was stirred at 70° C. for 2 h. Another 3 eq. of 1N NaOH was added and the reaction stirred for an additional 2 h at 70° C. When all of the starting material had disappeared, the reaction cooled, evaporated to dryness, taken up with 1N HCl, the precipitate collected and washed with water. The precipitate dried under vacuum to afford the title compound as a yellow solid (110 mg, 96%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:8][C:9](=[O:10])[C:2]1=2)=[O:7].[Cl-].[Al+3].[Cl-].[Cl-].[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:6]([C:3]1[CH:4]=[CH:5][S:1][C:2]=1[C:9]([OH:8])=[O:10])(=[O:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccccc1
Reactant: O=C1OC(=O)c2sccc21
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccccc1)c1ccsc1C(=O)O

Procedure:
Employing 2,3-thiophene dicarboxylic anhydride and benzene, substantially the same reaction and work-up as in Reference Example 8 Step 1 in the presence of aluminum chloride were conducted to give 3-benzoyl-2-thiophenecarboxylic acid as colorless crystals.