Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16](C(OCC)=O)[CH3:17])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)CO>[C:23]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][CH3:17])[CH2:12][CH2:13]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)N(C)CCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: CNCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 140 °C
Reaction time: 20 h
Yield: 87.8 %

Procedure:
A solution of 1.6 g of 4-diphenylmethyl-1-[2-(N-ethoxycarbonyl-N-methylamino)ethyl]piperazine (prepared as described in Preparation 35') in 20 ml of a 10% w/v aqueous solution of potassium hydroxide and 20 ml of ethylene glycol was stirred at 140° C. for 20 hours. At the end of this time, the mixture was cooled to room temperature, poured into ice-water and extracted with methylene chloride. The extracts were combined, washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave 1.14 g (yield 88%) of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([OH:48])[CH:36]=[CH:37][C:38]=1B1OC(C)(C)C(C)(C)O1.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.CCOC(C)=O.CCCCCCC>[OH:48][C:35]1[CH:36]=[CH:37][C:38]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)(=[O:14])=[O:13])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[C:33]([O:32][CH3:31])[CH:34]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Reactant: COc1cc(O)ccc1B1OC(C)(C)C(C)(C)O1
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+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(-c4ccc(O)cc4OC)nccc3c2)cc1
Temperature: 80 °C
Yield: 63.9 %

Procedure:
A vial was charged with 1-chloro-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (INTERMEDIATE ZZZZ, 122 mg, 0.277 mmol), 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (138 mg, 0.553 mmol), potassium carbonate (191 mg, 1.384 mmol), and Pd(PPh3)4 (32.0 mg, 0.028 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (1038 μl) and water (346 μl) were added. The vial was sealed and heated to 80° C. for 2 h in a Biotage Initiator microwave reactor. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (25-g Interchim column, 35-85% EtOAc/Heptane, then with 85-100% EtOAc/Heptane) to give 1-(4-hydroxy-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (93.6 mg, 0.177 mmol, 64.0% yield) as an off-white solid. m/z (ESI) 529.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([F:16])=[C:11]([F:17])[CH:10]=2)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:21])=O>O>[Cl:21][C:7]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:15][C:14]2[C:9](=[CH:10][C:11]([F:17])=[C:12]([F:16])[CH:13]=2)[N:8]=1
Reactant: CCOC(=O)c1cc2cc(F)c(F)cc2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cc2cc(F)c(F)cc2nc1Cl
Temperature: 70 °C

Procedure:
50 g of 3-ethoxycarbonyl-6,7-difluorocarbostyril are added in the course of 10 minutes with stirring at 20° C. to 200 cm3 of phosphoryl chloride. The suspension is heated to a temperature in the region of 70° C. and maintained at this temperature for 3 hours. After cooling to approximately 10° C., the solution obtained is poured with stirring into a mixture of 1,000 cm3 of water and 1,000 g of crushed ice. The temperature is allowed to rise to approximately 20° C. and the mixture is extracted with twice 500 cm3 of dichloromethane. The combined organic extracts are washed with 1,000 cm3 of water, and 1,000 cm3 of water to which sodium bicarbonate has been added to pH 7, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (20 kPa) at approximately 40° C. 45.6 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline are obtained in the form of a beige solid, melting point 108° C. which is used without further purification for the subsequent steps.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][C:28](/[C:32](/[CH3:37])=[CH:33]/[C:34](O)=[O:35])=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)=[CH:20][CH:19]=1>>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][C:28](/[C:32](/[CH3:37])=[CH:33]/[C:34]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:35])=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)=[CH:38][CH:39]=1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2Cc2ccc(C)cc2)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2Cc2ccc(C)cc2)c1

Procedure:
425 mg of compound 33 was obtained in a similar manner to those described in the Examples 1 and 2 using 777 mg of ethyl 4-(2-aminophenoxy)butyrate and 531 mg of 3-[1-(4-methylbenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=[C:5]([NH2:17])[N:4]=1.[C:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([N:31]=[C:32]=[O:33])(=[O:30])=[O:29])([O:20][CH3:21])=[O:19].CCOCC>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:6]=[C:5]([NH:17][C:32]([NH:31][S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:18]([O:20][CH3:21])=[O:19])(=[O:30])=[O:29])=[O:33])[N:4]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1cc(COc2ccccc2)nc(N)n1
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(COc2ccccc2)cc(OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a mixture of 0.23 g (1.0 mmol) of 4-methoxy-6-(phenoxymethyl)-2-pyrimidinamine in 15 ml dry acetonitrile was added 0.48 g (2.0 mmol) o-carbomethoxybenzenesulfonyl isocyanate and stirred at ambient temperature overnight. Ether was added to the suspension of white solids which were then collected by filtration to afford 0.37 g of the title compound, m.p. 178°-180°. NMR (90 MHz, CDCl3 +DMSO-d6): δ 3.91 (s, 3H); 4.02 (s, 3H); 5.20 (s, 2H); 6.69 (s, 1H); 7.0-7.9 (m, 8H); 8.5 (m, 1H); 9.20 (s, NH); 12.9 (s, NH) ppm; IR (nujol) 1725, 1700 cm-1.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3([C:26]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)O)CCCC3)cc2)cc1
Reactant: COC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)C1(c2ccc(-c3ccc(CCN4CCC[C@H]4C)cc3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (15 mg, 0.040 mmol), methyl 3-aminopropanoate hydrochloride (6.10 mg, 0.044 mmol), HATU (16.62 mg, 0.044 mmol), and TEA (0.017 mL, 0.119 mmol) in DMF (0.4 mL) was stirred at room temperature overnight. The mixture was acidified with 1M HCl and purified by HPLC. LCMS m/z=463.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[CH:14][S:15][C:3]=12.Cl>C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[CH:14][S:15][C:3]=12
Reactant: CCOC(=O)c1cnc2ccsc2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc2ccsc2c1Cl
Temperature: 0 °C
Yield: 94 %

Procedure:
A mixture of ethyl 7-chlorothieno[3,2-b]pyridine-6-carboxylate (2.98 g, 12.3 mmol) [Thompson, M.; Forbes, I. F. EP 126970] in 40 mL of ethanol and 15 mL of 2.5 N sodium hydroxide is heated at reflux for 1 hour. The mixture is cooled to 0° C. and the pH is adjusted to 4 by the addition of 4 N hydrochloric acid. The mixture is stirred at room temperature and the resulting precipitate is collected by filtration washing with water to provide 2.47 g of 7-chlorothieno[3,2-b]pyridine-6-carboxylic acid as a white solid, 1H NMR (DMSO-d6) δ 7.73 (d, J=6 Hz, 1H), 8.44 (d, J=6 Hz, 1H), 9.07 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28]C)=[O:27])=[C:24]([CH:30]([OH:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[C:22]2[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([OH:28])=[O:27])=[C:24]([CH:30]([OH:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[C:22]2[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nc(C(O)C(C)(C)C)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCCc1nc(C(O)C(C)(C)C)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 86.2 %

Procedure:
Following a procedure similar to that described in Example 4, 0.87 g of methyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxy-2,2-dimethylpropyl)imidazole-5-carboxylate [prepared as described in step (b) above] was hydrolyzed, using 342 mg of lithium hydroxide monohydrate, to afford 0.73 g of the title compound as crystals, melting at 199°-201° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:45])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[CH:37]=[C:36]([C:41]([O:43]C)=[O:42])[CH:35]=[CH:34]3)=[O:29])[CH:5]=[CH:6][CH:7]=1.[Br-].[Al+3].[Br-].[Br-].CSC>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:45])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[CH:37]=[C:36]([C:41]([OH:43])=[O:42])[CH:35]=[CH:34]3)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2c1
Agent: [Al+3]
Agent: [Br-]
Solvent: CSC
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc3cc(C(=O)O)ccc3c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 6-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-naphthoate (120 mg, 0.184 mmol) in methylene chloride 10 ml), aluminum bromide (295 mg, 1.11 mmol) and dimethyl sulfide (150 ul, 2.03 mmol) were added and the mixture was stirred at rt for overnight. LC/mass indicates complete reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:32])=[C:10]2[C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][C@@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])=[N:15][N:14]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[F:42][C:43]([F:58])([S:54](F)(=[O:56])=[O:55])[C:44]([F:53])([F:52])[C:45]([F:51])([F:50])[C:46]([F:49])([F:48])[F:47]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([O:32][S:54]([C:43]([F:42])([F:58])[C:44]([F:52])([F:53])[C:45]([F:50])([F:51])[C:46]([F:49])([F:48])[F:47])(=[O:56])=[O:55])=[C:10]2[C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][C@@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])=[N:15][N:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(O)c(-c3nnc(O[C@H](C)c4ccccc4)c4ccccc34)c2c1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2ccc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(-c3nnc(O[C@H](C)c4ccccc4)c4ccccc34)c2c1
Temperature: 23 °C
Reaction time: 19 h
Yield: 83.3 %

Procedure:
A solution of 7-methoxy-1-[4-((R)-1-phenyl-ethoxy)-phthalazin-1-yl]-naphthalen-2-ol (1.0 g, 2.4 mmol) in diisopropylethylamine (0.94 ml, 7.1 mmol) and dichloromethane (35 ml) was treated with N,N-dimethylaminopyridine (DMAP, 50 mg, 0.41 mmol) at 0° C. Then perfluoro-1-butanesulfonyl fluoride (0.51 ml, 2.8 mmol) was added dropwise and the resulting solution was stirred for 19 hrs at 23° C. The resulting solution was quenched with sat. aqueous ammonium chloride solution. The organic layer was separated and the water layer was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane/EtOAc 3:1) to give 1.4 g (2.0 mmol) of the title compound as an oil.
Reaction SMILES: CC[O-].[Na+].[CH3:5][C:6]1[CH:7]=[C:8]([CH:11]=O)[S:9][CH:10]=1.[C:13]([O:22]CC)(=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([C:15](=[CH:11][C:8]1[S:9][CH:10]=[C:6]([CH3:5])[CH:7]=1)[CH2:14][C:13]([OH:22])=[O:21])=[O:17])[CH3:20]
Reactant: Cc1csc(C=O)c1
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1cc(C)cs1)CC(=O)O
Yield: 42.9 %

Procedure:
Sodium ethylate (71 g, 1.05 mol) was added under vigorous stirring to a solution of 4-methylthiopene-2-carbaldehyde (88 g, 80% purity, 0.56 mol) and diethyl succinate (183 g, 1.05 mol) in ethanol (1 L). The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 50° C. until the solvent distillation ceased. The obtained residue was diluted with 500 mL of 10% HCl and 500 mL of ethyl acetate. The mixture was shaken. The organic layer was separated, diluted with 1 L of a saturated aqueous solution of NaHCO3, and shaken. The aqueous layer was separated, neutralized by 10% HCl to pH 2, and subjected to extraction by 1 L of ethyl acetate. The organic layer was evaporated in vacuum (˜20 mmHg) at 60° C. and chromatographed on a layer of silica gel (300×150 mm) with hexane/ethyl acetate mixture, 1:1 as eluent. Fractions with the target product were collected and evaporated in vacuum to give the desired product 61 g (0.24 mol, 43%) as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([S:13]([N:16]([C:34]2[CH:50]=[C:49]([Cl:51])[C:48]([Cl:52])=[CH:47][C:35]=2[O:36][C:37]2[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=2[C:39]([O:41]C)=[O:40])S(C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)(=O)=O)(=[O:15])=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Na+]>CO>[F:54][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([S:13]([NH:16][C:34]2[CH:50]=[C:49]([Cl:51])[C:48]([Cl:52])=[CH:47][C:35]=2[O:36][C:37]2[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=2[C:39]([OH:41])=[O:40])(=[O:15])=[O:14])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COC(=O)c1ccccc1Oc1cc(Cl)c(Cl)cc1N(S(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)S(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1Oc1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 2-[2-[N,N-bis-[3-,5-bis(trifluoromethyl)phenylsulfonyl]amino]-4,5-dichlorophenoxy]benzoate (0.4 g, 0.46 mmol) was dissolved in methanol (5 mL), a 1N solution of sodium hydroxide (3 mL, 3 mmol) was added and the mixture was stirred for 16 h at room temperature. The solvents were evaporated and the residue was acidified with dilute HCl, extracted with EtOAc, dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (silica gel, ethyl acetate/hexane/formic acid), and then recrystallized from EtOAc/hexane to give the title compound; mp 139°-140° C.
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])[O:4]1.[Na+].[I-].[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22].C([O-])(O)=O.[Na+]>CS(C)=O>[CH2:21]([N:23]([CH2:2][C@H:3]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])[O:4]1)[CH2:24][CH3:25])[CH3:22]
Reactant: CCNCC
Reactant: COc1ccc(F)cc1CC[C@H]1CC[C@H](CBr)O1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCN(CC)C[C@H]1CC[C@H](CCc2cc(F)ccc2OC)O1
Temperature: 50 °C
Yield: 28.3 %

Procedure:
To a vial under Ar was added trans-2-(bromomethyl)-5-(2′-methoxy-5′-fluorophenethyl)tetrahydrofuran (50 mg, 0.16 mmol), NaI (30 mg), diethylamine (55 mg, 0.75 mmol), NaHCO3 (120 mg), and dry DMSO (4 mL). The mixture thus obtained was heated to 50° C. under Ar for 72 h. After it was cooled to room temperature, the reaction mixture was poured into a separatory funnel containing sodium bicarbonate aqueous solution (sat. NaHCO3:H2O=1:1, 30 mL). The organic function was extracted with ethyl acetate (3×30 mL) and the combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. The solvent then was removed in vacuo and crude product thus obtained was purified by flash column chromatography (15% EtOAc in hexane, Rf=0.09) to give the product (14 mg, 28%) as an oil.
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[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[CH:29][NH:30]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[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[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[CH:29][NH:30]2)=[CH:26][CH:25]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: Oc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4cc[nH]c4c3)ncnc2cc1OCCCN1CCCC1
Temperature: 95 °C
Yield: 69.4 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 m g, 0.31 mmol), (prepared as described for the starting material in Example 9), 6-hydroxyindole (50 mg, 0.37 mmol) and potassium carbonate (64 mg, 0.466 mmol) in DMF (1 ml) was heated at 95° C. for 4 hours. After cooling, the mixture was diluted with methylene chloride and poured onto a silica column. The product was eluted with methylene chloride, followed by methylene chloride/methanol (80/20 followed by 70/30 and 50/50). After removal of the solvent by evaporation, the precipitate was triturated with ether, filtered and dried under vacuum to give 6-methoxy-4-(indol-6-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (90 mg, 69%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][C:13]#[CH:14])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:15]([N:17]([CH3:21])[C:18](Cl)=[O:19])[CH3:16]>>[CH3:21][N:17]([CH2:15][CH3:16])[C:18]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][C:13]#[CH:14])[CH2:9]2)=[CH:4][CH:3]=1)=[O:19]
Reactant: C#CCN1CCc2ccc(O)cc2C1
Reactant: CCN(C)C(=O)Cl
Product: C#CCN1CCc2ccc(OC(=O)N(C)CC)cc2C1
Yield: 50 %

Procedure:
7-Hydroxy-N-propargyl-1,2,3,4-tetrahydroisoquinoline (8) was mixed homogeneously with N-ethyl-N-methyl-carbamoyl chloride (10a) and then carried out step (f-1). Purified on a silica gel column (EtOAc/n-hexane=2:1) gave propargyl- and N-Ethyl-N-methyl amino-containing 7-(N-Methyl-N-ethylcarbamoyloxy)-N-propargyl-1,2,3,4-tetrahydroisoquinoline (11a) (Yield 50%). 1H NMR (300 MHz, CDCl3) (NMR, Varian Gemini): δ 7.08 (d, J=8 Hz, 1H, Aryl H), 6.88 (d, J=7 Hz, 1H, Aryl H); 6.80 (s, 1H, Aryl H), 3.76 (s, 2H, Ph-CH2—N), 3.50 (d, J=2 Hz, 2H, N—CH2—CCH), 3.42 (q, J=7 Hz, 2H, N—CH2—CH3), 3.04-2.81 (m, 7H, N—CH3, Ph-CH2—CH2—N), 2.28-2.26 (m, 1H, C≡CH), 1.25-1.15 (m, 3H, N—CH2—CH3); IR (KBr): ν cm−1=3300, 2923, 1715. Fast Atom Bombardment Mass Spectrometry (FABMS) m/z: 273 (M+1) (C16H20N2O2).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=O)[CH:13]([CH3:18])[CH2:14][C:15](O)=[O:16])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:21][NH2:22]>O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]([CH3:18])[CH2:14][C:15](=[O:16])[NH:21][N:22]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(CC(=O)O)C(=O)c1ccc(-n2ccnc2)cc1
Reactant: NN
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(-n2ccnc2)cc1

Procedure:
4-[4-(1-Imidazolyl)phenyl]-3-methyl-4-oxobutyric acid (75.7 g) was suspended in 145 m of water. After the addition of 17 ml of hydrazine hydrate, the reaction mixture was stirred at reflux temperature for 2 hours. After cooling, the precipitated solid was collected by filtration, washed with water, and dried.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9](Cl)[CH:8]=1)[CH3:2].CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[S:32][CH:33]=[CH:34][C:35]=3[NH:36][S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+].Cl>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:25]2[CH:26]=[CH:27][C:28]([C:31]3[S:32][CH:33]=[CH:34][C:35]=3[NH:36][S:37]([CH:40]([CH3:42])[CH3:41])(=[O:38])=[O:39])=[CH:29][CH:30]=2)[C:10]([C:13]#[N:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCOC(=O)COc1ccc(C#N)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)COc1ccc(C#N)c(-c2ccc(-c3sccc3NS(=O)(=O)C(C)C)cc2)c1
Yield: 84 %

Procedure:
Heat (3-chloro-4-cyano-phenoxy)-acetic acid ethyl ester (120 mg, 0.50 mmol), propane-2-sulfonic acid {2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-thiophen-3-yl}-amide (204 mg, 0.50 mmol), 2 M aqueous Na2CO3 solution (0.75 mL) and Pd(PCy3)2Cl2(55.4 mg, 0.075 mmol) in 1,4-dioxane (3.0 mL) to 80° C. under nitrogen atmosphere for 20 h. Pour into 0.1 M HCl solution and adjust pH to 7, then extract with diethyl ether (3×50 mL) and dry the combined organic phases (MgSO4) and concentrate to furnish a crude mixture as a yellowish solid. Purification by flash chromatography (Silica gel-Hexane /diethyl ether 1:1) yields 201 mg, 0.42 mmol (83%) of {6-Cyano-4′-[3-(propane-2-sulfonylamino)-thiophen-2-yl]-biphenyl-3-yloxy}-acetic acid ethyl ester as a pale yellow solid.