Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:8]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[CH:7][CH:6]=[C:5]([O:20][CH3:21])[N:4]=1.[BrH:22].CCOCC>C(O)(=O)C>[BrH:22].[O:19]=[C:10]1[C:11]2[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:14])[N:9]1[C:8]1[C:3]([OH:2])=[N:4][C:5]([O:20][CH3:21])=[CH:6][CH:7]=1
Reactant: COc1ccc(N2C(=O)c3ccccc3C2=O)c(OC)n1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1ccc(N2C(=O)c3ccccc3C2=O)c(O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
1,3-Dioxo-2-(2-hydroxy-6-methoxypyridin-3-yl)-isoindoline hydrobromide (6) was prepared and isolated as follows. To a flask were added 2,6-dimethoxy-3-phthalimidopyridine (155 mg, 0.546 mmol) and hydrogen bromide solution in acetic acid (30%, 6 ml). The mixture was stirred at room temperature under N2 for 18 h. Dry ether was added slowly until the solution became cloudy. White crystals were precipitated, filtered and washed with ether and ethyl acetate to afford 6 (127 mg, 67%) as white powdery crystals: mp 250° C.; 1H NMR (DMSO-d6) δ 7.97-7.94 (m, 2H), 7.91-7.88 (m, 2H), 7.64 (d, J=8.2 Hz, 1H), 6.25 (d, J=8.2 Hz, 1H), 3.86 (s, 3H); 13C NMR (DMSO-d6) δ 167.5, 162.1, 159.1, 142.8, 135.4, 132.1, 123.7, 108.2, 96.4, 54.8; MS (CI/CH4) 270 [M]+.
Reaction SMILES: [K+].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[O:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([O-:14])=O)=[CH:5][CH:4]=1.Cl.[NH2:25][CH2:26][C:27]#[N:28]>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[O:10][CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH:28][CH2:27][C:26]#[N:25])=[O:14])=[CH:7][CH:8]=1
Reactant: CC(C)CC(OC(c1ccc(Br)cc1)c1nccs1)C(=O)[O-]
Reactant: N#CCN
Agent: Cl
Agent: [K+]
Product: CC(C)CC(OC(c1ccc(Br)cc1)c1nccs1)C(=O)NCC#N

Procedure:
Using the same protocol as described in example 17, step 3, 2-[(4-bromophenyl)(1,3-thiazol-2-yl)methoxy]-4-methylpentanoic acid potassium salt from step 3 (427 mg, 1.11 mmol) was coupled with aminoacetonitrile HCl Salt. The crude residue obtained was chromatographed on silica gel using 50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([C:22]([O:24][CH3:25])=[O:23])=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:27][C:28]1[C:29]([C:36]2[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:43])=[N:30][O:31][C:32]=1[CH:33]([CH3:35])[CH3:34].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:42][C:41]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:43])[C:36]=1[C:29]1[C:28]([CH2:27][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:17]=[C:16]4[C:11]([C:12]([C:22]([O:24][CH3:25])=[O:23])=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[N:15]4)=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[C:32]([CH:33]([CH3:35])[CH3:34])[O:31][N:30]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Reactant: COC(=O)c1cc(C(=O)OC)c2ccc(-c3ccc(O)cc3)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)OC)c2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc2n1
Yield: 46.5 %

Procedure:
A solution of 75 mg (0.22 mmol) of dimethyl 7-(4-hydroxyphenyl)-2,4-quinolinedicarboxylate, 135 mg (0.44 mmol) of 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole and 125 mg (0.89 mmol) of K2CO3 in 2 mL DMF was stirred at ambient temperature for 60 hr. EtOAc was added and the mixture washed with three portions of H2O then brine. The solution was concentrated and the residue purified by silica gel chromatography (12 g of silica gel eluting with 0-50% EtOAc in hexanes over 45 minutes) to give 62 mg (46%) of dimethyl 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2,4-quinolinedicarboxylate as a clear glass. 1H NMR (400 MHz, CDCl3): δ 8.88 (d, J=9.0 Hz, 1H), 8.65 (s, 1H), 8.50 (s, 1H), 7.98 (d, J=9 Hz, 1H), 7.65 (d, J=9 Hz, 2H), 7.41 (d, J=8 Hz, 2H), 7.35-7.31 (m, 1H), 6.91 (d, J=9 Hz, 2H), 4.79 (s, 2H), 4.11 (s, 3H), 4.07 (s, 3H), 3.36 (septet, J=7 Hz, 1H), 1.44 (d, J=7 Hz, 6H). ESI-LCMS m/z 606 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9](=O)[CH3:10])[CH:6]=[CH:5][N:4]=1.[C:12]([OH:21])(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:15].CC1C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH:9]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[C:12]([OH:21])=[O:20])[CH3:10])[CH:6]=[CH:5][N:4]=1
Reactant: CNc1nccc(C(C)=O)n1
Reactant: Nc1ccccc1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CNc1nccc(C(C)Nc2ccccc2C(=O)O)n1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(2-methylamino-pyrimidin-4-yl)-ethanone (Step A, 1.0 g, 6.61 mmol) in dry toluene (40 mL) was added anthranilic acid (635 mg, 4.63 mmol) and TsOH (25 mg, 0.132 mmol). The resulting mixture was heated at 90° C. for 20 h, then cooled to RT. NaBH4 (500 mg, 13.23 mmol) was added and the reaction was stirred for 5 h. The reaction was quenched with MeOH and evaporated in vacuo. The crude solid was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH mixture (95:5) gave final compound. MS m/z: 273.3 (M+H). Calc'd. for C14H17N4O2-273.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9]O)[CH:5]=[CH:4][N:3]=1.CN(C=O)C.O=P(Cl)(Cl)[Cl:18]>N#N>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][Cl:18])[CH:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCc1ccnc(Cl)c1Cl
Agent: N#N
Solvent: CN(C)C=O
Product: ClCc1ccnc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2,3-Dichloro-pyridin-4-yl)-methanol (0.256 g, 1.44 mmol) was dissolved in 5 mL anhydrous under N2. Anhydrous DMF (o. 111 mL, 1.44 mmol) was added followed by dropwise addition of POCl3 (0.134 mL, 1.44 mmol). The reaction was stirred at RT overnight. After 16 h the reaction was quenched by the addition of sat aq NaHCO3. The mixture was extracted 3× with DCM. The organic phases were dried over Na2SO4, filtered, and concentrated to provide the pure titled compound. 1H NMR (CDCl3) δ 8.33 (d, 1H, J=4.9 Hz), 7.44 (d, 1H, J=4.9 Hz), 4.68 (s, 2H).
Reaction SMILES: [OH2:1].[CH2:2]([OH:16])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15]>OS(O)(=O)=O.CC(O)=O>[C:2]([OH:1])(=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15]
Reactant: O
Reactant: CCOCCCCCOCCCCCO
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOCCCCCOCCCCC(=O)O
Temperature: 25 °C
Reaction time: 7 h
Yield: 54.8 %

Procedure:
Kiliani reagent [Chem. Ber. 34, 3562 (1901)]was prepared in situ by dissolving Na2Cr2O7 2H2O(3 g) in a cold solution of H2SO4 (4 g) and water (13.5 g). To a solution of compound 6 (1.2 g, 5.5 mmol ) in AcOH (28 mL ) was added Kiliani reagent (20 g) at 0° C. The reaction mixture was stirred for 7 h at room temperature. Water (120 mL) was added to the mixture and then extracted with EtOAc (2×100 mL). The organic phase was washed with water (2×30 mL) and dried (Na2SO4). The residual oil was purified by column chromatography on silica gel with CHCl3 : MeOH (7:1) and subsequent Kugelrohr distillation to give the title product (1) (0.7 g, 52%); bp 128°-132° C. / 0.1 torr); IR(neat): 3000 (broad) and 1730 cm-1 ; 1H NMR: 1.23 (t, 3H, J=7.4 Hz), 1.3-1.8 (m, 10H), 2.38 (t, 2H, J=5.4 Hz), 3.3-3.6 (m 8H), and 9.98 ppm (b s, 1H); Anal. Calcd for C12H24O4 : C, 62.04; H, 10.41%. Found: C, 61.95; H, 10.43%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li]CCCC.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>C1COCC1>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])[C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[CH2:25][CH2:26][CH3:27]
Reactant: c1ccc2ocnc2c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2o1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
20 ml of freshly distilled THF was flushed for 30 min with a stream of nitrogen after which benzoxazole (1.0 g, 8.3 mmol) was added. After being flushed for another 30 min, the solution was cooled to −78° C. and placed under inert nitrogen atmosphere. 0.9 equivalents of n-BuLi (2 M solution in hexane, 3.0 ml, 7.6 mmol) was added dropwise over a period of 1 h, during which the solution turned to pink. The solution was kept at −78° C. for 30 min and then tri-n-butyltin chloride (2.3 ml, 8.3 mmol) was added dropwise over a period of 1 h. During this addition, the solution shifted from pink to brown. After yet another hour at −78° C., the solution was allowed to reach room temperature, at which it turned to deep red. The THF was removed on a rotary evaporator and the product, an orange oil, was isolated by distillation in vacuo. Yield: 1.37 g, 40%. 1H NMR (CDCl3): δ 0.90 (t, J=7, 9H, Bu3Sn), 1.30 (m, 6H, Bu3Sn), 1.35 (m, 6H, Bu3Sn), 1.62 (t, J=7, 6H, Bu3Sn), 7.29 (t, 2H, ArH), 7.55 (d, 1H, ArH), 7.77 (d, 1H, ArH).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[C:5]([C:15]#[N:16])=[C:4]([SH:17])[N:3]=1.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[S:23][CH:24]=1.C(=O)(O)[O-].[Na+].O>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1cc[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cc[nH]n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
50 mg (0.21 mmol) of the compound from Example 6A and 156 mg (0.64 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole were dissolved in 1 ml of dimethylformamide, 52 mg (0.62 mmol) of sodium bicarbonate were added and the mixture was stirred at RT for 2.5 h. About 10 ml of water were added to the mixture, and the solid formed was purified by preparative HPLC (acetonitrile/water 10:90→95:5, 0.1% TFA added).
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([Br:23])=[CH:13][N:12]=1)=[O:10])([C:6]#[N:7])[CH:3]1[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl.[NH2:32][OH:33]>C(O)C>[CH:3]1([C:2]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])[C:14]([Br:23])=[CH:13][N:12]=2)=[O:10])([C:6](=[NH:7])[NH:32][OH:33])[CH3:1])[CH2:5][CH2:4]1
Reactant: NO
Reactant: CC(C#N)(NC(=O)c1cc(OCC(F)(F)F)c(Br)cn1)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(NC(=O)c1cc(OCC(F)(F)F)c(Br)cn1)(C(=N)NO)C1CC1
Temperature: 65 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
To a solution of 5-Bromo-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (methyl-cyano-cyclopropyl-methyl)-amide (Example 78e, 900 mg, 2.29 mmol) in ethanol (15 ml) were added triethylamine (244 mg, 336 μl, 2.41 mmol) and hydroxylamine hydrochloride (167 mg, 2.41 mmol). The reaction mixture was then stirred at 65° C. for 18 hours. Volatiles were removed in vacuo and the residue was dissolved in ethylacetate which was extracted with an 1.0M aqueous solution of sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethylacetate gradient to yield the title compound (576 mg, 59%) as a white solid. MS (ESI, m/z): 425.3 (M+H+).
Reaction SMILES: [Br-].[Br-].[Br-].[Al+3].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1>ClCCl>[C:5]([C:14]1[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][C:13]=1[CH2:17][C:18]([OH:20])=[O:19])(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: COc1cccc(CC(=O)O)c1
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Product: COc1ccc(C(C)=O)c(CC(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a solution of aluminum tribromide (57.6 g, 216 mmol) in dichloromethane (90 mL) at 0° C. was slowly added acetyl chloride (11.5 mL, 162 mmol). To the reaction mixture was added (3-methoxy-phenyl)-acetic acid (17.9 g, 108 mmol) in dichloromethane (20.0 mL). The reaction mixture was stirred for one hour and then poured over ice (100 mL). The organic layer was separated and 1N aqueous sodium hydroxide was added (100 mL). The biphasic mixture was stirred vigorously for 90 minutes and the layers were separated. The organic layer was discarded and concentrated hydrochloric acid was added to the aqueous layer until the pH reached 1. A solid precipitated and was filtered and air-dried to afford (2-acetyl-5-methoxy-phenyl)-acetic acid (16.8 g, 75%). M.p. 153-155° C. 1H NMR (300 MHz, CDCl3) δ2.68 (s, 3), 3.91 (s, 3), 3.92 (s, 2), 6.92-6.95 (m, 2), 7.88 (d, 1, J=9.5). 13C NMR (100 MHz, CDCl3) δ28.33, 41.43, 55.46, 112.54, 118.26, 129.17, 133.08, 136.94, 162.65, 174.80, 200.96. IR 3435, 1704, 1663, 1609, 1568, 1258 cm−1. Analysis calculated for C11H12O4: C, 63.45; H, 5.81. Found: C, 63.35; H, 5.46.
Reaction SMILES: C1COCC1.[C:6]1([C:12]2[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:22](=O)[C:23]5[CH:34]=[C:33]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:26]6=[CH:27][CH:28]=[CH:29][C:30]7[C:31](=O)[C:14](=[C:15]([C:24]=5[C:25]=76)[C:16]=34)[CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[C:6]1([C:12]2[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[CH:22]=[C:23]5[CH:34]=[C:33]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[C:26]6=[CH:27][CH:28]=[CH:29][C:30]7[CH:31]=[C:14]([C:15]([C:16]=34)=[C:24]5[C:25]=76)[CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=c1c2cc(-c3ccccc3)c3cccc4c(=O)c5cc(-c6ccccc6)c6cccc1c6c5-c2c34
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc(-c2cc3cc4cccc5c(-c6ccccc6)cc6cc7cccc2c7c3c6c45)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a 1 L of three neck flask with nitrogen protected condenser were charged with 500 mL of anhydrous tetrahydrfuran (THF) containing 9.2 g (0.02 mol.) of 4,10-Diphenyl-dibenzo[def,mno]chrysene-6,12-dione. Then 20 mL of 1.0 M of boran etherate was added by syringe slowly to above solution. The reaction mixture was slowly warm to 70° C. while stirring until the reaction mixture change to a completely pale yellow solution and then another 5 mL of 0.1.0 M of boran etherate was added by syringe. The reaction was continued for another 1 hour at 70° C. The reaction mixture was cooled to room temperature and 15 mL of methanol was slowly added to quench the excess boran agent. After the bubbles were ceased, the solvents were removed with a rotary evaporator. The residue was added to 20 mL of ethanol and the precipitates were filtered and dried. The 6.4 g of pure 4,10-Diphenyl-dibenzo[def,mno]chrysene was obtained by nitrogen flow sublimation at 275˜285° C. under 2 torr vacuum. Yield is in 74.8%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[CH3:10][N:11]=[C:12]=[O:13]>C(OC(=O)C)C>[Cl:9][C:4]1[CH:3]=[C:2]([NH:1][C:12]([NH:11][CH3:10])=[O:13])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: CN=C=O
Reactant: Nc1ccc(O)c(Cl)c1
Solvent: CCOC(C)=O
Product: CNC(=O)Nc1ccc(O)c(Cl)c1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A solution of 4-amino-2-chlorophenol (21.5 g; 0.15 mol) in ethylacetate (400 ml) is cooled to 0° C. and then methyl isocyanate (18.6 g; 0.15 mol) added slowly. The solution is stirred for one hour and then evaporated under vacuum to afford 30 g of title product, m.p. 188°-189° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([NH2:8])[CH2:6][OH:7])=[O:4].Cl.[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:1][O:2][C:3](=[O:4])[CH:5]([NH:8][S:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:18])=[O:17])[CH2:6][OH:7]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)C(N)CO
Agent: Cl
Product: COC(=O)C(CO)NS(=O)(=O)c1ccccc1

Procedure:
In analogy to example 1, DL-serinemethylester hydrochloride was reacted with benzenesulfonyl chloride to give 2-benzenesulfonylamino-3-hydroxy-propionic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=O.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([C:13]([F:12])([F:21])[F:22])[CH:15]=1)=[O:7]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1cc(Br)cc(C(=O)O)c1
Product: Cc1cc(Br)cc(C(=O)Nc2cccc(C(F)(F)F)c2)c1
Yield: 58 %

Procedure:
In a manner similar to that described in Preparation 41, 3-bromo-5-methylbenzoic acid (400 mg) and 3-(trifluoromethyl)aniline were converted to the title compound (388 mg, 58%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:30][C:31]1[CH:32]=[C:33]([N:37]=[C:38]=[O:39])[CH:34]=[CH:35][CH:36]=1>O1CCCC1>[F:30][C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:39])[NH:1][C:2]2[CH:3]=[C:4]([CH:8]3[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=4)[NH:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Reactant: O=C=Nc1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)Nc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
To a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (220 mg, 0.74 mmol) in tetrahydrofuran (5 mL) and triethyl-amine (0.2 mL, 1.48 mmol) was added 3-fluorophenyl isocyanate (0.1 mL, 0.89 mmol) dropwise. The reaction mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×30 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-{3-[3-(3-fluoro-phenyl)-ureido]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (67 mg, 20%) as a white solid: LC/MS m/e calcd for C25H24FN3O3 (M+H)+: 434.49, observed: 434.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[F:31])[CH2:23]1)[CH3:21])=[O:19])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][N:11]=[CH:10]2)[CH3:2].FC(F)(F)S(O[CH2:39][CH:40]([F:42])[F:41])(=O)=O>>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][N:6]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]([CH2:39][CH:40]([F:42])[F:41])[N:11]=[CH:10]2)[CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[F:31])[CH2:23]1)[CH3:21])=[O:19])[CH3:2]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CCOC(=O)CN(CC(=O)N(C)N1Cc2cccc(F)c2C1)c1cc2cn[nH]c2cc1C
Product: CCOC(=O)CN(CC(=O)N(C)N1Cc2cccc(F)c2C1)c1cc2cnn(CC(F)F)c2cc1C
Yield: 70.2 %

Procedure:
Using the compound (909 mg, 2.07 mmol) of step A and 2,2-difluoroethyl trifluoromethanesulfonate (612 mg, 2.86 mmol), and according to the method of Example 241, step C, the title compound (732 mg, yield 70%) was obtained as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:14](=[O:16])[CH3:15])[CH2:6][CH2:7][C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH3:2].[H-].[Na+].Cl([F:24])(=O)(=O)=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:14](=[O:16])[CH3:15])([F:24])[CH2:6][CH2:7][C:8]#[C:9][Si:10]([CH3:11])([CH3:13])[CH3:12])[CH3:2]
Reactant: CCOC(=O)C(CCC#C[Si](C)(C)C)C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(F)(CCC#C[Si](C)(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-acetyl-6-(trimethylsilyl)-5-hexynoic acid ethyl ester (7.1 g) was added to a suspension of sodium hydride (1.0 g) in toluene under a postive argon atmosphere. After stirring for 1 hour, the reaction mixture was cooled to -10° and a mixture of perchloryl fluoride and argon gases was bubbled through the reaction mixture at such a rate that the internal temperature never exceeded 0° C. The perchloryl fluoride addition was discontinued when it ceased to be exothermic. Argon was bubbled through the mixture as it was allowed to warm to room temperature. The reaction mixture was partitioned between hexane and water and the organic phase was dried (MgSO4) and condensed by rotary evaporation to give an oil. The components of the oil were separated by silica gel chromatography using 30% ethyl acetate/hexane as the eluant to give 5.9 g of 2-acetyl-2-fluoro-6-(trimethylsilyl)-5-hexynoic acid ethyl ester. There was also obtained 0.25 g of 2-fluoro-6-(trimethylsilyl)-5-hexynoic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[CH:13]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:9]([C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([C:13]#[C:12][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)([O-:11])=[O:10]
Reactant: C#Cc1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Nc1ccc([N+](=O)[O-])cc1C#Cc1ccccc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 14271.2 %

Procedure:
To a deoxygenated solution of 2-bromo-4-nitroaniline (2.17 g, 0.01 mmol), ethynylbenzene (1.53 g, 0.015 mol) and CuI (10 mg, 0.05 mmol) in triethylamine (20 mL) was added Pd(PPh3)2Cl2 (210 mg, 0.2 mmol) under N2. The mixture was heated at 70° C. and stirred for 24 hours. The solid was filtered off and washed with EtOAc (50 mL×3). The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to give 4-nitro-2-(phenylethynyl)aniline (340 mg, 14%). 1H NMR (300 MHz, CDCl3) δ 8.37-8.29 (m, 1H), 8.08-8.00 (m, 1H), 7.56-7.51 (m, 2H), 7.41-7.37 (m, 3H), 6.72 (m, 4.95 (brs, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][OH:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.Br[CH:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:32]>>[CH3:26][C:23]1[C:22]([CH2:27][CH2:28][O:29][CH:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:32])=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:6]4([C:4]([OH:3])=[O:5])[CH2:8][CH2:7]4)=[CH:10][CH:11]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CC(Br)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCO)cc3)cc2)CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CCOC(C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-{4′-[4-(2-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and (1-bromoethyl)benzene.