Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.C(O[CH2:17][C:18]1[CH:23]([C:24]([OH:26])=[O:25])[N:22]2[C:27](=[O:39])[CH:28]([NH:29][C:30](=[O:38])[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:21]2[S:20][CH:19]=1)(=O)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:17][C:18]2[CH:23]([C:24]([OH:26])=[O:25])[N:22]3[C:27](=[O:39])[CH:28]([NH:29][C:30](=[O:38])[CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C@H:21]3[S:20][CH:19]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Reactant: COc1cccc2ccccc12
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC2=CS[C@@H]3C(NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)O)c2ccccc12
Reaction time: 0.25 h

Procedure:
A solution of 0.8 g of freshly distilled 1-methoxynaphthalene in 2.2 ml of trifluoroacetic acid is mixed with 0.4 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid and the resulting solution is left to stand for 15 minutes at room temperature. It is then diluted with an equal amount of toluene and evaporated to dryness under reduced pressure. The residue is taken up in 50 ml of acetic acid ethyl ester and 30 ml of a 10% strength aqueous dipotassium hydrogen phosphate solution. The whole is thoroughly shaken, the organic layer is separated off and the aqueous phase is extracted with two 50 ml portions of acetic acid ethyl ester. The aqueous phase is covered with 50 ml of acetic acid ethyl ester and the pH value is adjusted to 2 by adding 2% strength aqueous phosphoric acid. After vigorous shaking, the organic solution is separated off, and the aqueous phase is twice extracted with 50 ml portions of acetic acid ethyl ester. The combined organic extracts are washed three times with 50 ml portions of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure. 3-(4-Methoxy-1-naphthylmethyl)-7-(N-phenylacetylamino)-ceph-2-em-4ξ-carboxylic acid is obtained as an oily residue, which on trituration with acetic acid ethyl ester crystallises and after recrystallisation from methanol melts at 196°C; thin layer chromatogram (silica gel): Rf = 0.71 (system n-butanol/acetic acid/water, 75:7.5:21), Rf = 0.76 (system n-butanol/acetic acid/water, 67:10:23) and Rf = 0.52 (system n-butanol/ethanol/water, 40:10:50); ultraviolet absorption spectrum (in methanol): λmax = 225 mμ (ε = 17,600) and 298 mμ (ε = 8300) and shoulder at 308 mμ (ε = 6400) and 322 mμ (ε = 3950); infrared absorption spectrum (in mineral oil): characteristic bands at 3.02μ, 5.69μ, 5.77μ, 6.06μ and 6.59μ.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[OH:9][C:10]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]([CH3:19])[N:11]=1.O>CN(C)C=O>[CH3:1][O:9][C:10]1[CH:14]=[C:13]([C:15]([F:16])([F:18])[F:17])[N:12]([CH3:19])[N:11]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(O)cc1C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(C(F)(F)F)n(C)n1
Reaction time: 15 h
Yield: 90.4 %

Procedure:
10.0 g (72.3 mmoles) of anhydrous potassium carbonate and 12.8 g (90.3 mmoles) of methyl iodide were added, at room temperature, to a solution of 10.0 g (60.2 mmoles) of 3-hydroxy-1-methyl-5-trifluoromethyl-1H-pyrazole dissolved in 50 ml of N,N-dimethylformamide. The mixture was stirred for 15 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 9.8 g (yield: 90.7%) of 3-methoxy-1-methyl-5-trifluoromethyl-1H-pyrazole.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH:34]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35]1>>[CH:34]1([C:38]([N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:19]4=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]5[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=5)=[C:18]4[CH:25]=[N:24]3)[CH2:31][CH2:30]2)=[O:39])[CH2:37][CH2:36][CH2:35]1
Reactant: O=C(Cl)C1CCC1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)C3CCC3)CC2)cc1

Procedure:
Cyclobutyl-{4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-methanone was prepared according to General Procedure I by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with cyclobutanecarbonyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.74-2.21 (m, 10H), 2.82-2.87 (m, 1H), 3.30 (methyl sulfonyl and water peak), 3.84-3.87 (m, 1H), 4.49-4.52 (m, 1H), 5.06-5.08 (m, 1H), 7.62-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.38 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=456, M+Na=478.
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[CH3:15])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C=O)C>[Cl:19][C:9]([C:8]1[CH:12]=[C:13]([CH3:14])[C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]([CH3:15])[CH:7]=1)=[O:10]
Reactant: CC(=O)Oc1c(C)cc(C(=O)O)cc1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1c(C)cc(C(=O)Cl)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound 3,5-dimethyl-4-hydroxybenzoic acid (5.04 g, 30.33 mmol) was mixed with pyridine (20 mL). Acetic anhydride (3.72 g, 36.4 mmol) was added and the mixture was stirred at room temperature for 4 h. The solvent was evaporated in vacuo to obtain 4-acetoxy-3,5-dimethyl-benzoic acid in quantitative yield (6.33 g). The compound 4-acetoxy-3,5-dimethyl-benzoic acid (0.36 g, 1.73 mmol)) was dissolved in dichloromethane (5 mL) and oxalyl chloride (0.3 mL, 3.46 mmol) was added dropwise, followed by 1 drop of DMF. The reaction mixture was stirred at room temperature under nitrogen for 2 h. The solvent was evaporated in vacuo to obtain acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester in quantitative yield (0.392 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][N:8]2[C:12](=[O:13])C3=CC=CC=C3C2=O)=[CH:2]1.O.NN.[OH-].[Na+].[C:24]([O:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C(O)C.ClCCl>[C:27]([O:26][C:12]([NH:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[O:13])([CH3:30])([CH3:29])[CH3:28].[C:32]([O:31][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33]
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccoc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: NN
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1ccoc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 19.020 g (78.839 mmol) of N-[2-(3-furyl)ethyl]phthalimide and 5.74 ml (118 mmol) of hydrazine monohydrate in 200 ml of ethanol was refluxed for 1 hour. After cooling to room temperature, the reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude 2-(3-furyl)ethylamine was dissolved in 150 ml of dichloromethane; a solution of 22.4 g (102 mmol) of di-tert-butyl dicarbonate in 50 ml of dichloromethane was added dropwise at room temperature, followed by stirring for 0.5 hours. The solvent was distilled off under reduced pressure; the resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=15/1 to 6/1) to yield N-tert-butoxycarbonyl-2-(3-furyl)ethylamine as a mixture with di-tert-butyl dicarbonate.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:18]([OH:26])=[CH:19][C:20]4[O:24][CH2:23][CH2:22][C:21]=4[CH:25]=3)[C:9]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:35][CH2:36]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[C:28]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4[C:18](=[CH:19][C:20]5[O:24][CH2:23][CH2:22][C:21]=5[CH:25]=4)[O:26][CH2:36][CH2:35]3)[C:9]2=[O:27])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12CCOc1cc3c(cc12)CCO3
Temperature: 50 °C
Reaction time: 7 h
Yield: 38.9 %

Procedure:
A suspension of 1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one (5.1 g, 11.8 mmol), 1,2-dibromoethane (4.7 g, 25.0 mmol) and cesium carbonate (24.4 g, 75.0 mmol) in tetrahydrofuran (200 mL) was stirred under argon at ambient temperature for 16 h and at 50° C. for 7 h. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography with dichlromethane/methanol (100/1-20/1) to afford 1′-(diphenylmethyl)-2,3,6,7-tetrahydrospiro[furo[3,2-g]chromene-5,3′-indol]-2′(1′H)-one (2.11 g, 39%) as a colorless solid: MS (ES+) m/z 459.8 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]([O:15][C:16]([NH:18][C@@H:19]1[CH2:24][NH:23][CH2:22][CH2:21][CH2:20]1)=[O:17])([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C>>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:23]1[CH2:22][CH2:21][CH2:20][C@H:19]([NH:18][C:16](=[O:17])[O:15][C:12]([CH3:13])([CH3:11])[CH3:14])[CH2:24]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2[N+](=O)[O-])C1
Yield: 99 %

Procedure:
Method 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, (S)-3-N-Boc-amino piperidine and diisopropylethylamine yielding (S)-tert-butyl 1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (99%). LCMS (m/z): 323.1 (MH+); LC Rt=2.13 min.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30]Br>CN(C=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[O:17][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH3:24]
Reactant: COCCOCCBr
Reactant: CCNC(=O)Nc1nc2ccc(Br)c(O)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(Br)c(OCCOCCOC)c2s1
Yield: 39 %

Procedure:
A mixture of 1-(6-bromo-7-hydroxy-2-benzothiazolyl)-3-ethyl-urea 6, potassium carbonate and 2-(2-methoxyethoxy)ethyl bromide in DMF was reacted to give 0.026 g (39%) of the desired compound 12. 1H NMR (DMSO) δ 10.65 (br s, 1H, NH), 7.54 (d, 1H, J=8.5 Hz, ArH), 7.32 (d, 1H, J=8.6 Hz, ArH), 6.73 (br s, 1H, NH), 4.24 (d, 2H, J=4.4 Hz, CH2), 3.76 (d, 2H, J=4.8 Hz, CH2), 3.61 (dd, 2H, J=6.0, 5.2 Hz, CH2), 3.48 (dd, 2H, J=6.0, 5.2 Hz, CH2), 3.26 (s, 3H CH3), 3.19 (m, 2H, CH2), 1.09 (t, 3H, J=7.1 Hz, CH3); LC/MS 418 (MH+); RP-HPLC RT 2.95 minutes.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[NH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C1C=CC=CC=1>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH:23]1[CH2:24][CH2:25][N:20]([CH2:2][CH2:3][CH:4]=[C:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][CH2:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]2=3)[CH2:21][CH2:22]1)[CH3:33]
Reactant: CCOC(=O)CCCC1CCNCC1
Reactant: BrCCC=C1c2ccccc2CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCOC(=O)CCCC1CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Temperature: 120 °C
Yield: 80.7 %

Procedure:
A mixture of 5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (5.8 g, 19.8 mmol), ethyl 4(piperidin-4-yl)butyrate (6.1 g, 29 mmol), potassium carbonate (2.9 g, 21 mmol) and N,N-dimethylformamide (10 ml) was heated at 120° C. for 5 h. After cooling, benzene (50 ml) and water (50 ml) were added and the phases were separated. The organic phase was dried and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel (50 g) using mixtures of benzene and chloroform as eluents to give 6.9 g (83%) of 4-(1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)piperidin-4-yl)butyric acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])O.[Na+].O.[Br:15][CH:16]([CH:20]([CH3:22])[CH3:21])[C:17](Cl)=[O:18]>C(OCC)(=O)C>[Br:15][CH:16]([CH:20]([CH3:22])[CH3:21])[C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])=[O:18]
Reactant: Nc1ccccc1O
Reactant: CC(C)C(Br)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C(Br)C(=O)Nc1ccccc1O

Procedure:
To a mixture of 2-aminophenol (27 25 g), sodium hydrogencarbonate (31.5 g), ethyl acetate (250 ml), and water (200 ml), a solution of 2-bromo-3-methylbutyryl chloride (49.8 g) in ethyl acetate (100 ml) was added dropwise with ice-cooling and with stirring. After stirring with ice-cooling for further 1 hour, the ethyl acetate layer was separated, washed with water, and dried (MgSO4), and the solvent was evaporated off. The residue was crystallized from hexane, to give 2-(2-bromo-3-methylbutyryl)aminophenol. Yield was 59.7 g (87.9%). Recrystallization from isopropyl ether gave colorless prisms, mp 110°-111° C.
Reaction SMILES: Cl.I[C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([NH2:10])=[C:5]([CH3:11])[CH:4]=1.[CH2:12]([O:19][C:20]([C:22](=[CH2:27])[C:23]([O:25][CH3:26])=[O:24])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1>[NH2:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3](/[CH:27]=[C:22](\[C:20]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:21])/[C:23]([O:25][CH3:26])=[O:24])=[CH:4][C:5]=1[CH3:11]
Reactant: Cc1cc(I)cc(C)c1N
Reactant: C=C(C(=O)OC)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)/C(=C/c1cc(C)c(N)c(C)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2 L round bottom flask was charged 4-iodo-2,6-dimethylbenzenamine hydrochloride salt (55 g, 194 mmoles), methyl 2-(benzyloxycarbonyl)acrylate (59.2 g, 252 mmoles), tetrabutylammonium chloride (59.2 g, 213 mmoles), palladium (II) acetate (4.34 g, 19.4 mmoles), and tetrahydrofuran (1.2 L, degassed by a flow of nitrogen for 30 min). The mixture was stirred so that a suspension was formed and then degassed by a flow of nitrogen for 30 min. Triethylamine (110 mL, 789 mmoles) was added and the resulting mixture was heated at reflux for 3 h. After cooling to room temperature, the reaction mixture was filtered through a pad of celite, washed with tetrahydrofuran (2×100 mL), and concentrated. The residue was dissolved in dichloromethane, washed with water (3×) and brine (2×), dried over sodium sulfate, and concentrated. Flash chromatography (silica gel, using 1:9 ethyl acetate/dichloromethane) gave a tan solid. The solid was recrystallized from warm methanol (210 mL) and water (100 mL). The mixture was held at room temperature overnight, then at 0° C. for 2 h, and finally at −15° C. for 2 h. The resulting solid was filtered, washed with ice cold 1:1 methanol/water, and dried under high vacuum overnight to give 44.7 g (65%) as a light tan solid which was a mixture of Z/E isomers (73:27). 1H-NMR (DMSO-d6) 6, 2.05 (s, 6H), 3.61 (s, 0.8H), 3.68 (s, 2.2H), 5.00 (s, 0.54H), 5.13 (s, 1.46H), 5.24 (s, 2H), 7.40-7.21 (m, 8H), 8.51 (s, 0.27 H), 8.79 (s, 0.73H); 13C-NMR (DMSO-d6) δ 17.8, 51.7, 65.3, 119.4, 120.0, 120.3, 127.3, 127.7, 128.3, 130.9, 135.8, 137.2, 146.9, 154.7, 166.0.
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:19]([OH:20])=[C:18]([C:21]([CH3:23])=[O:22])[CH2:17][S:16]2)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6].S(Cl)(Cl)(=O)=O>O>[C:5]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[S:16][CH:17]=[C:18]([C:21]([CH3:23])=[O:22])[C:19]=2[OH:20])=[CH:13][CH:14]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(=O)C1=C(O)C(c2ccc(C(C)(C)C)cc2)SC1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Product: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: -23 °C
Reaction time: 0.55 h
Yield: 87.4 %

Procedure:
A chloroform (250 mL) solution of 2-(4-t-butylphenyl)-3-hydroxy-4-methylcarbonyl-2,5-dihydrothiophene (24.94 g, 64.6 mmol, purity: 78%) was cooled to −23° C., and to this solution, a chloroform (50 mL) solution of sulfuryl chloride (5.45 mL, 1.05 equivalent amounts) was dropwise added over a period of 27 minutes, followed by stirring at from −22 to −24° C. for 33 minutes. The temperature of the solution was raised to −3° C., and water (50 mL) was dropwise added over a period of 2.5 minutes, followed by liquid separation. The obtained chloroform solution was sequentially washed with water, a saturated salt solution, a sodium hydroxide aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to obtain a crude product. The obtained crude product was distilled in chloroform (80 mL) at 45° C., the solution was cooled to 0° C., and isopropanol (375 mL) was dropwise added, followed by stirring at 0° C. for 40 minutes. The formed crystals were subjected to filtration to give the desired product as a yellow solid (15.5 g, yield: 63%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][C:21]=3[O:35][CH3:36])[N:10]=2)=[C:4]([C:37](=[O:40])[NH:38][CH3:39])[CH:3]=1.ClC1C(C(F)(F)[F:49])=CN=C(NC2C=CC(CP(=O)(OCC)OCC)=CC=2OC)N=1.NC1C=CC=C(F)C=1C(NC)=O>>[F:49][C:3]1[C:4]([C:37](=[O:40])[NH:38][CH3:39])=[C:5]([NH:8][C:9]2[C:14]([C:15]([F:16])([F:18])[F:17])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])=[CH:22][C:21]=3[O:35][CH3:36])[N:10]=2)[CH:6]=[CH:7][CH:2]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(F)cc3C(=O)NC)n2)c(OC)c1)OCC
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Agent: CNC(=O)c1c(N)cccc1F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3cccc(F)c3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure from Example 102 (Diethyl (4-{[4-{[4-fluoro-2-(methylcarbamoyl)-phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate) using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 2-amino-6-fluoro-N-methylbenzamide (Compound 155A). 1H NMR (DMSO-d6, 400 MHz): δ=1.19 (t, J=7.07 Hz, 6 H), 2.76 (d, J=4.80 Hz, 3 H), 3.19-3.27 (m, 2 H), 3.76 (s, 3 H), 3.93-4.02 (m, 4 H), 6.78-6.83 (m, 1 H), 6.97-7.03 (m, 2 H), 7.38 (d, J=7.07 Hz, 1 H), 7.49 (d, J=6.82 Hz, 1 H), 8.00 (br. s., 1 H), 8.38 (s, 1 H), 8.62 (d, J=3.79 Hz, 1 H), 8.80 (br. s., 1 H), 9.78 (s, 1 H). MS (ES+): m/z 586.14 [MH+] (TOF, polar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:15])[C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:15])[C:12]([O:14][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(O)C(=O)O)cc1OC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(O)C(=O)OCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
To 137C (830 mg, 3.9 mmol) in DMF (15 mL) was added cesium carbonate (2.6 g, 8.0 mmol) followed by benzyl bromide (0.6 mL, 5 mmol). After stirring at rt overnight, the reaction was diluted with water, and was extracted with ethyl acetate (2×30 mL). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The resulting residue was purified via silica gel chromatography (0-40% ethyl acetate/hexanes) to provide 137D (520 mg, 44%). LC-MS: 445.31 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[CH:24]=[C:23]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:11][C:10]=1[F:33])[C:2]1C=CC=CC=1.ICC>>[CH2:1]([O:8][C:9]1[C:10]([F:33])=[CH:11][C:12]([C:16]2[O:17][C:18]3[CH:24]=[C:23]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:13][C:14]=1[F:15])[CH3:2]
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cc(F)c(OCc4ccccc4)c(F)c3)oc2c1
Solvent: CCI
Product: CCOc1c(F)cc(-c2nc3ccc(OC[C@H](C)NC(C)=O)cc3o2)cc1F

Procedure:
Using N-((2S)-1-((2-(4-(benzyloxy)-3,5-difluorophenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide and iodoethane, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:25]=[C:26]([CH3:29])[S:27][CH:28]=3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[NH3:31]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:31])=[O:15])=[CH:11][CH:12]=2)[CH:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:25]=[C:26]([CH3:29])[S:27][CH:28]=3)=[CH:20][CH:19]=2)[CH2:6][CH:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2ccc(-c3csc(C)n3)cc2)C[C@@H]1C
Reactant: N
Product: CC(=O)N1c2ccc(C(N)=O)cc2C(Nc2ccc(-c3csc(C)n3)cc2)CC1C

Procedure:
Reactions and treatments were carried out in the same manner as in Example 118, using 105.4 mg of (2S,4R)-1-acetyl-2-methyl-4-{[4-(2-methylthiazol-4-yl)phenyl]amino}-1,2,3,4-tetrahydroquinoline-6-carboxylic acid instead of (2S,4R)-1-acetyl-2-methyl-4-(4-morpholinophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, and using aqueous ammonia instead of monomethylamine. Thus, 74.9 mg (75.5%, cis:trans=10:1) of the title compound was obtained as a pale yellow crystalline powder.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCNc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCNc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(n-pentylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.