Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1Cl.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=1
Reactant: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1nc(-c2cccc(F)c2)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Yield: 41.6 %

Procedure:
A microwave vial was charged with 1-(5,6-dichloro-2-methoxypyridin-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.100 g, 0.214 mmol), (3-fluorophenyl)boronic acid (0.045 g, 0.321 mmol), potassium carbonate (0.089 g, 0.642 mmol), and Pd(Ph3P)4 (0.025 g, 0.021 mmol). The vial was flushed with Ar (g), then dioxane (0.803 ml) and water (0.268 ml) were added. The reaction was microwaved at 90° C. for 30 minutes. The organic layer was pipetted off of the aqueous layer and concentrated. The resulting film was dissolved in DMSO and filtered through a syringe filter. The resulting solution was purified via reverse phase HPLC (Xbridge 19×100 mm, 10 um, 40 ml/min, 25-85% 0.1% TFA in Acetonitrile) to afford 1-(5-chloro-6-(3-fluorophenyl)-2-methoxypyridin-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.047 g, 0.089 mmol, 41.7% yield) as a tan solid. 1H NMR (500 MHz, DMSO-d6) δ=11.67 (br. s., 1 H), 8.73 (d, J=1.6 Hz, 1 H), 8.40 (d, J=1.9 Hz, 1 H), 8.30 (s, 1 H), 8.27 (d, J=9.7 Hz, 1 H), 7.87 (dd, J=2.1, 9.0 Hz, 1 H), 7.73 (d, J=7.7 Hz, 1 H), 7.67 (d, J=9.7 Hz, 1 H), 7.64-7.58 (m, 1 H), 7.42-7.33 (m, 1 H), 7.04 (d, J=9.0 Hz, 1 H), 6.84 (d, J=9.7 Hz, 1 H), 6.46 (d, J=1.6 Hz, 1H), 3.83 (s, 3H). m/z (ESI) 527.1 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:19]3[NH:23][C:22](=[O:24])[NH:21][N:20]=3)[N:9]=[C:10]2[NH:13][C@H:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)=[CH:5][CH:4]=1.CC1C=CC=C(C)N=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C(Cl)Cl>[C:33]([N:16]1[CH2:17][CH2:18][C@H:14]([NH:13][C:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([Cl:2])[CH:12]=3)[CH:7]=[C:8]([C:19]3[NH:23][C:22](=[O:24])[NH:21][N:20]=3)[N:9]=2)[CH2:15]1)(=[O:36])[CH:34]=[CH2:35]
Reactant: C=CC(=O)Cl
Reactant: O=c1[nH]nc(-c2cc3ccc(Cl)cc3c(N[C@H]3CCNC3)n2)[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3ccc(Cl)cc23)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
To a mixture of (S)-3-(7-chloro-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride (120 mg) in DCM (8 mL) was added 2,6-dimethylpyridine (105 mg, 0.978 mmol). The resulting mixture was cooled to −78° C. and acryloyl chloride (48 mg, 0.530 mmol, 10 mg/mL in dry DCM) was added dropwise. The reaction mixture was stirred at −78° C. for 30 minutes. The reaction was quenched with MeOH (5 mL) and the mixture was concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (22 mg, 18% over 2 steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.87 (s, 1H), 11.72 (s, 1H), 8.51 (S, 1H), 7.88 (m, 1H), 7.60-7.70 (m, 2H), 7.56 (d, 1H, J=4.0 Hz), 6.55-6.57 (m, 1H), 6.13-6.19 (m, 1H), 5.63-5.70 (m, 1H), 5.17-5.18 (m, 1H), 3.65-4.17 (m, 4H), 2.01-2.37 (m, 2H); ESI-MS m/z [M+H]+ 385.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:27][C:28](=O)[CH3:29].CCO>O>[Br:1][C:2]1[CH:3]=[C:4]([S:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:5]([NH:8][C:9]2[S:10][CH:27]=[C:28]([CH3:29])[N:11]=2)=[N:6][CH:7]=1
Reactant: NC(=S)Nc1ncc(Br)cc1Sc1ccccc1
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: Cc1csc(Nc2ncc(Br)cc2Sc2ccccc2)n1
Yield: 100.8 %

Procedure:
mL 1-(5-Bromo-3-(phenylthio)pyridin-2-yl)thiourea (5.0 g, 14.69 mmol), triethylamine (6.0 mL, 44 mmol), 1-chloropropan-2-one (2.3 mL, 29.4 mmol), and EtOH (100 mL) were heated to 70° C. for 6 hours. The ethanol was reduced to ˜½ volume and water (150 mL) added and the precipitate was filtered to afford the title compound (5.6 g, 100% yield) as a tan solid after drying. 1H NMR (CDCl3) δ 9.01 (s, 1H), 8.42 (m, 1H), 7.92 (m, 1H), 7.32-7.15 (m, 5H), 6.44 (m, 1H0, 2.32 (m, 3H). Mass spectrum (apci) m/z=379.8 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:39])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[CH:25][CH:24]=3)[C@@H:14]([CH3:40])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[C:41](Cl)(=[O:43])[CH3:42].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:41]([N:36]1[CH2:35][CH2:34][N:33]([CH2:32][CH2:31][CH2:30][O:29][C:26]2[CH:27]=[CH:28][C:23]([C:22]([N:15]3[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C@H:12]([N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:9](=[O:11])[CH3:10])[CH2:13][C@@H:14]3[CH3:40])=[O:39])=[CH:24][CH:25]=2)[CH2:38][CH2:37]1)(=[O:43])[CH3:42]
Reactant: CC(=O)Cl
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN3CCNCC3)cc2)c2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(CCCOc2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-{2-methyl-1-[4-(3-piperazin-1-yl-propoxy)-benzoyl]-1,2,3,4-tetrahydro-quinolin-4-yl}-acetamide (168 mg) was dissolved in CH2Cl2 (2 mL). Acetic chloride (47 mg) and DIEA (52 uL) were added. The reaction mixture was stirred at room temperature overnight. The organic phase was washed with sat. NaHCO3 (2×5 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (EtOAc) to afford pure (2S,4R)-N-(1-{4-[3-(4-acetyl-piperazin-1-yl)-propoxy]-benzoyl}-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-N-(4-chloro-phenyl)-acetamide (100 mg, 57%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][CH:16]3[CH2:25][CH2:24][C:19]4(OCC[O:20]4)[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl>O1CCCC1.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][CH:16]3[CH2:25][CH2:24][C:19](=[O:20])[CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2ccc(C#CC3CCC4(CC3)OCCO4)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1CCC(C#Cc2ccc(-c3ccc(F)cc3)cc2)CC1
Yield: 98.3 %

Procedure:
A solution of 1.30 g of 8-[(4'-fluoro-4-biphenylyl)ethynyl]-1,4-dioxaspiro[4.5]decane in 30 ml of tetrahydrofuran was stirred with 3.5 ml of 3N hydrochloric acid for 2.4 hours. The reaction mixture was diluted with diethyl ether, washed with saturated sodium hydrogen carbonate solution and with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated. 1.11 g of 4-[(4'-fluoro-4-biphenylyl)ethynyl]cyclohexanone were obtained.
Reaction SMILES: COC1C=CC(N2C=CN=C2C=N[S@@](C(C)(C)C)=O)=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][CH:32]=[N:31][C:30]=2/[CH:34]=[N:35]/[S:36]([C:38]([CH3:41])([CH3:40])[CH3:39])=[O:37])=[CH:25][CH:24]=1.[F:42][C:43]1[CH:44]=[C:45]([CH:49]=[C:50]([F:52])[CH:51]=1)[CH2:46][Mg]Br>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:33][CH:32]=[N:31][C:30]=2[CH:34]([NH:35][S:36]([C:38]([CH3:41])([CH3:40])[CH3:39])=[O:37])[CH2:46][C:45]2[CH:44]=[C:43]([F:42])[CH:51]=[C:50]([F:52])[CH:49]=2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)S(=O)/N=C/c1ncoc1-c1ccc(Cl)cc1
Reactant: Fc1cc(F)cc(C[Mg]Br)c1
Agent: COc1ccc(-n2ccnc2C=N[S@](=O)C(C)(C)C)cc1
Product: CC(C)(C)S(=O)NC(Cc1cc(F)cc(F)c1)c1ncoc1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared as a mixture of diastereomers according to the method presented for the synthesis of compound 5C and 5D of Example 5 utilizing 33E and (3,5-difluorobenzyl)magnesium bromide. MS (m/z) 438.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([CH2:13][C:14]#[N:15])(=[O:12])=[O:11])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24]Br.Cl>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:24][CH2:23][CH:13]([C:14]#[N:15])[S:10]2(=[O:12])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(NS(=O)(=O)CC#N)cc1
Reactant: BrCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCC(C#N)S2(=O)=O)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a solution of the compound obtained in Step A (0.59 g) in dimethylformamide (40 ml) was added potassium carbonate (1.1 g). Then, a solution of 1,2-dibromoethane (0.59 g) in dimethylformamide (25 ml) was added dropwise at 55° C. The reaction mixture was then stirred at 55° C. for 2 hours, cooled to room temperature, poured into 15 ml water, and aqueous 2N hydrochloric acid was added to acidic pH. The aqueous layer was then extracted with dichloromethane, the combined organic layers washed two times with 2% aqueous hydrochloric acid, dried over sodium sulfate and concentrated in vacuo. Column chromatography (ethyl acetate/cyclohexane 7:3) afforded the title product as a beige solid (310 mg). 1HNMR (CDCl3, 400 MHz): 7.30 (d, 2H), 6.90 (d, 2H), 4.25 (m, 1H), (m, 1H), 3.70-3.90 (m, 5H), 2.95 (m, 1H), 2.80 (m, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.[C:11]([NH:14][C:15]1[S:16][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:18][N:19]=1)(=[O:13])[CH3:12].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O>[CH3:2][O:3][C:4]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[S:20]([C:17]1[S:16][C:15]([NH:14][C:11](=[O:13])[CH3:12])=[N:19][CH:18]=1)(=[O:21])=[O:22])=[O:10]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CC(=O)Nc1ncc(S(=O)(=O)Cl)s1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc(NC(C)=O)s1
Temperature: 25 °C

Procedure:
A mixture of L-proline methylester hydrochloride (15 mmol), 2-acetylamino-thiazole-5-sulfonyl chloride (12 mmol) (prepared as described in J. Am. Chem. Soc 69, 2063, 1947), DIPEA (35 mmol) in DCM (50 mL) was stirred at room temperature over night. Addition of water and 1N HCl to pH 2. Isolation of the organic phase which was washed with water and brine, dried and concentrated to give (S)-1-(2-acetylamino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as brown crystals. These were suspended in EtOH (15 mL) and added 4N HCl in dioxane (15 mL) and heated for 3H at 80° C. and then cooled to room temperature. Addition of aqueous NaHCO3 to neutral pH. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo to give (S)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as colourless crystals.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]2)=[CH:8][CH:7]=[CH:6][C:5]=1[OH:25].[CH3:26][O:27][CH2:28]Cl>C1COCC1.O>[F:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]2[CH2:17][CH2:18][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:20][CH2:21]2)=[CH:8][CH:7]=[CH:6][C:5]=1[O:25][CH2:26][O:27][CH3:28]
Reactant: COCCl
Reactant: CCCC1CCC(c2ccccc2-c2cccc(O)c2F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC1CCC(c2ccccc2-c2cccc(OCOC)c2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.6 %

Procedure:
Under a nitrogen atmosphere, 1.52 g of sodium hydride was added to 9.45 g of 2-fluoro-3-((4-propylcyclohexyl)phenyl)phenol (5) dissolved in 60 mL of THF cooling with iced water, and the mixture was stirred at ambient temperature for 30 minutes. 3.07 g of chloromethyl methyl ether was added to the solution under cooling with iced water, followed by stirring at ambient temperature for 4 hours. After terminating the reaction by pouring water into the reaction solution, the aqueous layer was extracted with toluene, which was added to the organic layer, and the organic layer was washed with a saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 11.6 g of 2-fluoro-3-((4-propylcyclohexyl)phenyl)-1-methoxymethoxybenzene (6).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:37]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:33][CH2:34][CH2:35][CH3:36])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CCCCNCCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) and 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hrs. The di-n-butylamine (2.59 g, 0.02 mole) was added and the reaction mixture was heated at 60° C. for 3 hrs.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:12]=[O:13])=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[C:14]1([CH3:22])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Mg]Br>O1CCCC1.C(OCC)C>[F:1][C:2]1[C:3]([CH:12]([OH:13])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH3:22])=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cccc(F)c1C=O
Reactant: Cc1ccccc1[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(F)c1C(O)c1ccccc1C
Temperature: -78 °C
Reaction time: 8 h

Procedure:
100 mg (0.83 mmol) N-(3-fluoro-2-formyl-phenyl)-acetamide are dissolved in 4 ml of tetrahydrofuran and cooled to −78° C. Then at this temperature 1.66 ml (3.3 mmol) of a 2 M solution of o-tolylmagnesium bromide in diethyl ether are added. This reaction mixture is thawed to ambient temperature overnight with stirring. Then the reaction mixture is stirred into 30 ml dist. water and extracted three times with 10 ml of ethyl acetate. The organic phase is dried with MgSO4, the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier material used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (80:20).
Reaction SMILES: CN(C=[N:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[N:10][CH:11]=1)C.S(=O)(=O)(O)O>CO>[NH2:5][C:6]1[CH:11]=[N:10][C:9]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])=[N:8][CH:7]=1
Reactant: COC(=O)c1cccc(-c2ncc(N=CN(C)C)cn2)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cccc(-c2ncc(N)cn2)c1
Temperature: 7.5 °C
Reaction time: 0.5 h

Procedure:
10.2 g (35.9 mmol) of methyl 3-[5-(dimethylaminomethyleneamino)pyrimidin-2-yl]benzoate are suspended in 1 l of methanol. 5.3 ml (107.3 mmol) of fuming sulfuric acid are added dropwise with gentle cooling (about 5-10° C.) (note, strongly exothermic reaction). When the addition is complete, the mixture is stirred firstly at room temperature for 30 min and subsequently at an oil-bath temperature of 88°. The reaction is monitored by means of HPLC. After 20 h, the clear, dark-yellow solution is evaporated to dryness. The residue is dissolved in 600 ml of ethyl acetate and washed with 2×150 ml of 1 N NaOH and 2×1 N HCl, dried over sodium sulfate and evaporated; yield: 3 g; HPLC: Rt=2.17 min (method B); LC-MS: 300 (M+H).
Reaction SMILES: [C:1]([C:4]1([CH2:14][S:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([OH:3])=O.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:33]([O:40][C:41](=[O:47])[C@H:42]([CH:44]([CH3:46])[CH3:45])[NH2:43])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)CC)C>O1CCCC1>[C:16]([S:15][CH2:14][C:4]1([C:1]([NH:43][C@H:42]([C:41]([O:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:47])[CH:44]([CH3:46])[CH3:45])=[O:3])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)SCC1(C(=O)O)CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)C1(CSC(C)(C)C)CCc2ccccc2C1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
Dissolve 2-carboxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (278 mg, 1.0 mmol) in anhydrous tetrahydrofuran (10 mL). Add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (230 mg, 1.2 mmol), L-valine benzyl ester hydrochloride (244 mg, 1.00 mmol) and triethylamine (0.132 mL, 1.00 mmol). Stir at room temperature under an argon atmosphere overnight. Partition between ethyl ether and 5% sulfuric acid. Separate the organic phase and wash with water, saturated sodium hydrogen carbonate and brine. Dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (20% ethyl acetate/hexane) to give the title compound as a clear yellow oil (256 mg, 55%).
Reaction SMILES: BrC1C=C2C(=CC=1OC)OC(C)(C)C=C2OS(C(F)(F)F)(=O)=O.ClC1C(OCC)=C(OC(=O)/C=C(\C)/C=C/C(/F)=C\C)C=C2C=1OC(C)(C)C=C2C(C)C.[Cl:55][C:56]1[C:57]([O:85][CH2:86][CH3:87])=[C:58](/[C:71](/[CH3:84])=[C:72](/[F:83])\[CH:73]=[CH:74]\[C:75](\[CH3:82])=[CH:76]\[C:77]([O:79]CC)=[O:78])[CH:59]=[C:60]2[C:65]=1[O:64][C:63]([CH3:67])([CH3:66])[CH:62]=[C:61]2[CH:68]([CH3:70])[CH3:69].[OH-].[Na+]>C(O)C.C1COCC1>[Cl:55][C:56]1[C:57]([O:85][CH2:86][CH3:87])=[C:58](/[C:71](/[CH3:84])=[C:72](/[F:83])\[CH:73]=[CH:74]\[C:75](\[CH3:82])=[CH:76]\[C:77]([OH:79])=[O:78])[CH:59]=[C:60]2[C:65]=1[O:64][C:63]([CH3:66])([CH3:67])[CH:62]=[C:61]2[CH:68]([CH3:69])[CH3:70]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(c(Cl)c1OCC)OC(C)(C)C=C2C(C)C
Agent: C/C=C(F)\C=C\C(C)=C\C(=O)Oc1cc2c(c(Cl)c1OCC)OC(C)(C)C=C2C(C)C
Agent: COc1cc2c(cc1Br)C(OS(=O)(=O)C(F)(F)F)=CC(C)(C)O2
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1c(/C(C)=C(F)\C=C\C(C)=C\C(=O)O)cc2c(c1Cl)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure G, a solution of ethyl 7L(8-chloro-4-isopropyl-7-ethoxy-2,2-dimethyl-2H-chromen-6-yl)-6-fluoro-3-methyl-octa-2E,4E,6E-trienoate (Compound 166, 874 mg, 1.95 mmol) in ethanol and THF was hydrolyzed with 1M NaOH to give rise to the title compound as a light yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([OH:40])[CH:38]=2)[NH:33][CH:32]=1>CC(N(C)C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:40][C:37]1[CH:38]=[C:39]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[CH3:30]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: Cc1c[nH]c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCCCN1CCCCC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (168 mg, 0.5 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (207 mg, 1.5 mmol), 3-methyl-5-hydroxyindole (88 mg, 0.6 mmol), (Can. J. Chem. 1964, 42, 514), and DMA (2.0 ml) was purged with nitrogen for 5 minutes at 25° C. This mixture was then stirred at 100° C. for 3 hours then allowed to cool to ambient temperature, was filtered and the filtrate evaporated under vacuum. The residue was purified by silica column chromatography eluting with dichloromethane/methanolic ammonia (7M) (90/10) to give 6-methoxy-4-(3-methylindol-5-yloxy)-7-(3-piperidinopropoxy)quinazoline (155 mg, 69%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@H:7]([N:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([NH2:31])[CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH:33](OC)(OC)OC>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:32])[C@H:7]([N:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]2[N:30]=[CH:33][NH:31][C:26]=2[CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccc(N)c(N)c2)[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Reactant: COC(OC)OC
Solvent: Cc1ccccc1
Product: COc1ccc(S(=O)(=O)N(Cc2ccc3nc[nH]c3c2)[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 25 °C

Procedure:
To a mixture of 2(R)-{[(3,4-diamino)benzyl]-(4-methoxybenzenesulfonyl)amino}-3-methylbutyric acid tert-butyl ester (90 mg, 0.194 mmol) and trimethyl orthoformate (0.022 mL, 1.05 equiv.) in dry toluene (10 mL) was added KSF montmorillonite clay (25 mg). The reaction mixture was heated at reflux for 6.5 h and then cooled to room temperature. After reaching room temperature, the mixture was condensed in vacuo and the residue was loaded onto a preparatory thin layer chromatography plate. Elution with methanol/methylene chloride (10%) provided 2(R)-[(benzimidazol-5-ylmethyl)-(4-methoxy-benzenesulfonyl)amino]-3-methylbutyric acid tert-butyl ester (79 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]3)[O:11][C:12]=2[CH2:13][CH2:14][C:15](O)=[O:16])=[CH:4][CH:3]=1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH3:46][N:47]1[CH2:52][CH2:51][CH:50]([CH2:53][N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:49][CH2:48]1>O.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]3)[O:11][C:12]=2[CH2:13][CH2:14][C:15]([N:57]2[CH2:56][CH2:55][N:54]([CH2:53][CH:50]3[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]3)[CH2:59][CH2:58]2)=[O:16])=[CH:4][CH:3]=1
Reactant: CN1CCC(CN2CCNCC2)CC1
Reactant: Cc1cc(C)n(-c2nc(-c3ccc(Cl)cc3)c(CCC(=O)O)o2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)n(-c2nc(-c3ccc(Cl)cc3)c(CCC(=O)N3CCN(CC4CCN(C)CC4)CC3)o2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A mixture of 3-[4-(4-chlorophenyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-oxazolyl]propionic acid (51.5 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (41 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (46 mg), 4-[(1-methyl-4-piperidinyl)methyl]piperazine (60 mg) and N,N-dimethylformamide (0.5 ml) was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was concentrated, introduced into preparative HPLC and purified. Ethyl acetate was added to the obtained oil and the mixture was washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated to give 1-{3-[4-(4-chlorophenyl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-oxazolyl]propanoyl}-4-[(1-methyl-4-piperidinyl)methyl]piperazine (54.5 mg, yield 72%). Recrystallization from ethanol-isopropyl ether gave colorless prism crystals. melting point: 126–127° c.