Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:22][CH2:23][Cl:24].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Cl:24][CH2:23][CH2:22][C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: ClCCBr
Reactant: CCOC(=O)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(C)(C)CCCl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 22.2 ml of diisopropylamine in 150 ml of tetrahydrofuran being stirred, 93.6 ml of a 1.6 M solution of n-butyl lithium in hexane was added at -5° to 0° C., followed by stirring for 30 minutes. After the reaction mixture was cooled to -78° C. and 19.0 ml of ethyl isobutyrate was added dropwise to the mixture and stirred for 45 minutes. A solution of 11.9 ml of 1-bromo-2-chloroethane in 10 ml of tetrahydrofuran was added dropwise to the reaction mixture. After the reaction mixture was stirred at -78° C. for 1 hour and then at roomtemperature (15° to 20° C.) for 2 hours, an excess amount of an aqueous solution of ammonium chloride was added, followed by extractionwith ethyl acetate. After the extract was washed with water and dried over MgSO4, the solvent was distilled off; the residue was then distilled under reduced pressure, to yield 24.7 g of the title compound in the form of a colorless oily substance.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11]CC)=[O:10])=[C:7]([CH2:16][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[N:25]=[C:26]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]([N:41]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)=[O:40])=[CH:35][CH:34]=4)[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=3)[C:19]=2[CH3:47])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.CCO.O>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH2:16][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[N:25]=[C:26]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]([N:41]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)=[O:40])=[CH:35][CH:34]=4)[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=3)[C:19]=2[CH3:47])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(C(C)(C)C)cc1CNc1cccc(-c2cn(C)c(=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(NCc2cc(C(C)(C)C)ccc2C(=O)O)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(=O)N3CCOCC3)cc2)n1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 25 mL round bottom flask charged with ester 101h (100 mg, 0.16 mmol) and LiOH (20 mg, 0.47 mmol) in THF (2 mL), EtOH (2 mL) and H2O (2 mL). After the mixture was stirred at 60° C. for 16 h, the pH was adjusted to 7 with aqueous 1M HCl. The aqueous phase was extracted with EtOAc (2×10 mL), and the combined organic extracts were washed with brine (10 mL), dried with Na2SO4 and concentrated. The crude 101i (97 mg, 99%) was used without further purification.
Reaction SMILES: O=[C:2]1[CH2:16][CH:5]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH:4]2[CH2:3]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:17]([NH:24][CH:2]1[CH2:16][CH:5]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH:4]2[CH2:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC2CC(=O)CC2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC2CC(NCc3ccccc3)CC2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a solution of tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (9.57 g, 42.5 mmol) in DCM (170 mL) were added BnNH2 (4.56 g, 42.5 mmol) and AcOH (2.55 g, 42.5 mmol) at 0° C. and the reaction mixture was stirred at 0° C. for 0.5 h. Then NaBH(OAc)3 (18.00 g, 85.0 mmol) was added to the above mixture and the resulting mixture was stirred at rt for another 20 h, then quenched with saturated NaHCO3 solution (142 mL), and extracted with DCM (250 mL×3). The combined organic phases were washed with brine (250 mL×3), dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc) to give the title compound as a yellow solid (7.44 g, 55.3%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:38][S:39]([C:42]1[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][CH:43]=1)(=[O:41])=[O:40]>>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:46](=[O:47])[C:45]3[CH:44]=[CH:43][C:42]([S:39]([CH3:38])(=[O:41])=[O:40])=[CH:50][CH:49]=3)=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Product: CCCCc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccc(S(C)(=O)=O)cc2)cc1
Yield: 60 %

Procedure:
The title compound was prepared from 5-n-butyl-2,4-dihydro-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Example 16, Step C), according to the procedure of Example 43 except that p-(methylsulfonyl)benzoic acid was used as the acid. The crude product was purified by flash chromatography (gradient elution using 0.5-10% MeOH/CH2Cl2) to afford a 60% yield of the desired compound as a white solid, homogeneous by TLC in 5% MeOH/CH2Cl2 ; mass spectrum (FAB) m/e 735 (M+Na)+, 751 (M+K)+ ; mp 131°-133° C.
Reaction SMILES: [NH2:1][CH:2]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][O:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>ClCCl>[Cl:24][CH2:25][C:26]([NH:1][CH:2]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][O:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2)=[O:27]
Reactant: NC1c2ccccc2OCc2ncccc21
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)NC1c2ccccc2OCc2ncccc21
Reaction time: 2 h
Yield: 90 %

Procedure:
In this example, 1.9 g of 5-amino-5,11-dihydro[1]benzoxepino[3,4-b]pyridine prepared in a similar manner to that in Example 24 and 0.9 g of triethylamine were dissolved in 30 ml of dichloromethane. A solution of 1.0 g of chloroacetyl chloride in 5 ml of dichloromethane was added dropwise thereto under ice cooling. The mixture was stirred under ice cooling for 2 hours, and concentrated under reduced pressure to distill away about two thirds of the dichloromethane. Then, 40 ml of diisopropyl ether and 10 ml of water were added thereto, and the mixture was stirred and filtered. Drying the residue gave 2.3 g of 5-(chloroacetyl)amino-5,11-dihydro[1]benzoxepino[3,4-b]pyridine as crude crystals.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([O:22][C:20]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:15])[CH:21]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: Clc1cc(Cl)nc(-c2ccc(Cl)s2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Clc1cc(Oc2cc(Cl)nc(-c3ccc(Cl)s3)n2)ccn1

Procedure:
0.4 g 2-(5-Chloro-2-thienyl)-4,6-dichloropyrimidine, 0.2 g 2-Chloro-4-hydroxypyridine, and 0.3 g potassium carbonate are refluxed in 30 mL dry acetonitril for 16 hours. The mixture is poured into water, and the product is extracted with toluene and purified by flash chromatography (0.38 g, m.p. 154°-156° C.).
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:31]=[C:32]([S:36][CH3:37])[CH:33]=[CH:34][CH:35]=1.[Cl:38][C:39]1[C:40]2[C:50]([F:51])=[CH:49][CH:48]=[C:47]([F:52])[C:41]=2[S:42][C:43]=1[C:44](Cl)=[O:45]>>[Cl:38][C:39]1[C:40]2[C:50]([F:51])=[CH:49][CH:48]=[C:47]([F:52])[C:41]=2[S:42][C:43]=1[C:44]([N:15]([CH2:16][C:17]1[CH:18]=[C:19]([C:34]2[CH:35]=[CH:30][CH:31]=[C:32]([S:36][CH3:37])[CH:33]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]1)=[O:45]
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: CSc1cccc(Br)c1
Product: COc1ccc(-c2cccc(SC)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (300 mg, 0.77 mmol) is coupled to 3-bromothioanisole (156 mg, 0.77 mmol) using Method A. On filtration of the cooled reaction mixture through celite and removal of the solvents in vacuo, the crude biaryl amine is treated with acid chloride 8 (246 mg, 0.92 mmol) using Method D to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].CS[C:7](SC)=[CH:8][N+:9]([O-:11])=[O:10]>C1(C)C=CC=CC=1>[OH:4][CH2:3][CH2:2][NH:1][C:7]([NH:1][CH2:2][CH2:3][OH:4])=[CH:8][N+:9]([O-:11])=[O:10]
Reactant: NCCO
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: Cc1ccccc1
Product: O=[N+]([O-])C=C(NCCO)NCCO
Temperature: 25 °C
Yield: 98.2 %

Procedure:
78 ml of 2-aminoethanol (1.3 moles) were added slowly over half an hour to a solution of 95 g of 1,1-bis(methylthio)-2-nitroethene (0.57 mole) in 500 ml of toluene at 80° C. After the addition, the mixture was held at 80° C. for half an hour, was cooled to room temperature and the solid formed was filtered off, washed with chloroform (2×100 ml portions) and was dried to give 107 g N,N'-bis(2-hydroxyethyl)-2-nitro-1,1-ethenediamine (97-98% yield) in yellowish crystal form. m.p. 145°-146° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:23][CH:24]([CH3:27])[CH2:25][NH2:26].Cl>CN(C)C=O>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:26][CH2:25][CH:24]([CH3:27])[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: CC(C)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 0 °C
Yield: 90 %

Procedure:
A mixture of 2,4-dichloro-3-nitroquinoline (100 g) and N,N-dimethylformamide (180 mL) was stirred, and triethylamine (42 g, 4 eq) was added dropwise, followed by dropwise addition of 2-methylpropylamine (21.5 g, 0.7 eq). The mixture was stirred at room temperature until the reaction was completed as determined by gas chromatography. Aqueous hydrochloric acid (250 mL, 4N) was added with stirring. The resulting mixture was stirred and cooled to about 0° C. to precipitate the product. The precipitate was filtered, washed with water, and dried at reduced pressure to afford the product 2-chloro-N-(2-methylpropyl)-3-nitro-4-quinolinamine in about 90% yield.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.[NH2:26][CH2:27][CH2:28][CH2:29][OH:30]>C1COCC1>[NH:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C@H:9]([C:11]([NH:13][C@H:14]([C:16]([NH:26][CH2:27][CH2:28][CH2:29][OH:30])=[O:18])[CH3:15])=[O:12])[CH3:10]
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCCCO
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NCCCO
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 84 %

Procedure:
To a vigorously stirring solution of Boc-(Ala)2-OH (1.55 gm, 5.96 mmol) and NMM (0.98 mL, 8.9 mmol) in THF (15 mL) cooled to −15° C. was added under an atmosphere of N2 ethyl chloroformate (ECF) (587 μL, 6.14 mmol). After stirring for 2 min, a solution of H2N(CH2)3OH (546 uL, 7.2 mmol) in THF (5 mL) was added to the mixture followed by NMM (1.64 mL, 14.9 mmol) and the mixture was warmed to r.t. and stirred until silica gel TLC indicated complete consumption of the starting acid (eluting solvent-MeOH:DCM—1:10, Rf—0.5) (˜8 h). The solvent was evaporated, and the residue was diluted with EtOAc and washed with brine, water, saturated solutions of citric acid and NaHCO3, and the organic layer was dried using NaHSO4, and the solvent was removed under vacuum to yield a residue which was purified using silica gel flash column chromatography—Hexanes:EtOAc—1:4; to give the desired product in 84% yield (1.59 g) as a solid, m.p.—142° C.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].Cl.Cl[CH2:20][C:21]1[C:22]([NH:36][CH2:37][CH2:38][NH:39][C:40](=[O:42])[CH3:41])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH2:32][CH:33]1[CH2:35][CH2:34]1)=[CH:26][CH:25]=2.[Li+].[OH-]>C1COCC1>[CH:33]1([CH2:32][O:31][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([NH:36][CH2:37][CH2:38][NH:39][C:40](=[O:42])[CH3:41])[C:21]([CH2:20][C:6]2[C:7]4[C:12](=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=4)[C:3]([CH2:1][CH3:2])=[N:4][C:5]=2[OH:17])=[CH:30]3)[CH2:34][CH2:35]1
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CC(=O)NCCNc1nc2ccc(OCC3CC3)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc(O)c(Cc2cc3cc(OCC4CC4)ccc3nc2NCCNC(C)=O)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 47022 (128 mg, 0.55 mmol) in THF (13 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added N-(2-(3-(chloromethyl)-6-(cyclopropylmethoxy)quinolin-2-ylamino)ethyl)acetamide hydrochloride SLA 47096B (211 mg, 0.55 mmol) and 2 N aq. LiOH solution (0.55 mL, 1.10 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, THF was then removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 93:7) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) gave 27 mg of N-(2-(6-(cyclopropylmethoxy)-3-((1-ethyl-3-hydroxy-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-2-ylamino)ethyl)acetamide. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.149 M HCl solution in MeOH (2.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to give N-(2-(6-(cyclopropylmethoxy)-3-((1-ethyl-3-hydroxy-6,7-dimethoxyisoquinolin-4-yl)methyl)quinolin-2-ylamino)ethyl)acetamide dihydrochloride 87 as a brown solid (28.9 mg, 8% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31]([OH:33])=[O:32])[CH:26]=[CH:27][C:28]=1[OH:29]>>[F:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31]([OH:33])=[O:32])[CH:26]=[CH:27][C:28]=1[O:29][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Product: COCCOc1cc2ncnc(Oc3ccc(CC(=O)O)cc3F)c2cc1OCCOC
Yield: 41 %

Procedure:
Using an analogous procedure to that described in the portion of Note [1] below Table III in Example 8 that is concerned with the preparation of starting materials, 4-chloro-6,7-di-(2-methoxyethoxy) quinazoline was reacted with 2-(3-fluoro-4-hydroxyphenyl)acetic acid to give 2-{3-fluoro-4-[6,7-di-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}acetic acid in 41% yield; Mass Spectrum: M+H+ 447.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2[OH:17].[C:18](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:18])[CH:7]=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]2=[O:17]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cnc2ccc(Cl)nc2c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCOC(=O)c1cn(C)c2ccc(Cl)nc2c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.6 %

Procedure:
A mixture of ethyl 6-chloro-4-hydroxy[1,5]naphthyridine-3-carboxylate (Preparation 58, 694 mg), potassium carbonate (588 mg), and iodomethane (264 μL) in DMF (15 mL) is stirred at room temperature for 5 hours. The mixture is poured into water (50 mL), and the solution is extracted with CH2Cl2 (3×50 mL). The organic layers are dried (MgSO4) and concentrated. Trituration with ether (50 mL) affords 473 mg (65%) of the title compound as an off-white solid. Physical Characteristics. 1H NMR (DMSO-d6) δ8.70, 8.31, 7.90, 4.24, 3.92, 1.29; HRMS (FAB) m/z 267.0535 (C12H11ClN2O3+H). Anal. Found: C, 54.14; H, 4.24; N, 10.58.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][N:21](C(=O)C(F)(F)F)[CH2:22]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][NH:21][CH2:22]3)=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(-c2ccc3c(c2)CNCC3)cc1
Yield: 44.4 %

Procedure:
4.63 g 4-(Trifluormethyl)phenylboronic acid was dissolved in 15 ml ethanol and added to a mixture of 5.0 g 1-(7-bromo-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone in 150 ml toluene and 54 ml of a 2 molar sodium carbonate solution. The reaction mixture was degassed then 940 mg tetrakis(triphenylphosphine)palladium(0) was added and the mixture heated under reflux for two hours. The cooled reaction mixture was evaporated, the resulting residue was dissolved in 150 ml ethyl acetate and washed with 50 ml water and brine. The organic layer was dried over MgSO4 and the solvent removed in vacuo. The resulting crude material was purified by reversed phase HPLC to obtain 2.0 g 7-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-isoquinoline as its trifluoroacetate salt.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:12]=[C:11]([CH3:13])[C:9]([NH2:10])=[C:8]([CH3:14])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[Br:15][CH:16]([CH3:20])[C:17](Br)=[O:18].O.O.O.C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[Br:15][CH:16]([CH3:20])[C:17]([NH:10][C:9]1[C:11]([CH3:13])=[CH:12][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][C:8]=1[CH3:14])=[O:18]
Reactant: CCCCOc1cc(C)c(N)c(C)c1
Reactant: CC(Br)C(=O)Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCOc1cc(C)c(NC(=O)C(C)Br)c(C)c1
Reaction time: 0.5 h

Procedure:
To a chilled (ca 10° ) solution of 50.7 g (0.263 mole) of 4-butoxy-2,6-dimethylaniline [Buchi et al., Helv. Chim. Acta, 34, 278 (1951)] in 224 ml glacial acetic acid was added rapidly 62.4 g (.289 mole) of 2-bromo-propionyl bromide and immediately thereafter a chilled (ca 5° ) solution of 87.2 g sodium acetate trihydrate in 362 ml water. This mixture was shaken for 1/2 hour, filtered, washed with water until the washes were neutral, and dried in vacuo over silica gel and KOH; yield 68.9 g (71.6%); m.p. 132.5° - 133.5°. The product was recrystallized from 95% ethanol; m.p. 135.5° - 136°.
Reaction SMILES: [NH:1]([C:8]1[CH2:17][C:16]([C:18]([O:20]C)=O)=[C:15]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:14][C:9]=1[C:10]([O:12]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[CH:26]1[CH:27]=[C:28]2[C:18]([C:16]3[C:15]([NH:22][C:23]2=[CH:24][CH:25]=1)=[CH:14][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:17]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:12])=[O:20]
Reactant: COC(=O)C1=C(Nc2ccccc2)CC(C(=O)OC)=C(Nc2ccccc2)C1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
(b.1) A suspension of 37.8 parts of dimethyl 3,6-dihydro-2,5-dianilinoterephthalate in 200 parts of ®Dowtherm A is added dropwise to 150 parts of boiling ®Dowtherm A. The mixture is then kept at the boil for a further 90 minutes. After approx. 100 parts of the solvent have been distilled off, the mixture is cooled to approx. 140° C., after which 25.4 parts of iodine are added and the mixture is kept at the boil for a further 4 hours. Working up is effected as described earlier in the text under "Method A". 27.8 parts of quinacridone in the β-crystal phase are obtained, which corresponds to a yield of 89% of theory (relative to dimethyl 3,6-dihydro-2,5-dianilinoterephthalate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][C@@H:11]([O:14][CH3:15])[C@H:10]([NH:16]C(=O)OC(C)(C)C)[CH2:9][CH2:8]1.C(OC([NH:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])=[N:35][C:34]=1[C:45](O)=[O:46])=O)(C)(C)C>>[NH2:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])=[N:35][C:34]=1[C:45]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH:10]([NH2:16])[CH2:9][CH2:8]1)=[O:46]
Reactant: CO[C@@H]1CCN(c2c(N)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Product: COC1CCN(c2c(NC(=O)c3nc(-c4ccccc4F)sc3N)cnn2C)CCC1N
Yield: 63 %

Procedure:
Following the procedure Example 101, reacting tert-butyl ((4R,5R)-1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-methoxyazepan-4-yl)carbamate and 5-((tert-butoxycarbonyl)amino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid gave 324 (118 mg, 63% over two steps). 1H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 8.30 (t, J=8.2 Hz, 1H), 7.51 (s, 1H), 7.48-7.39 (m, 3H), 7.39-7.27 (m, 2H), 3.64 (s, 3H), 3.27 (s, 4H), 3.24-2.90 (m, 7H), 2.14-2.01 (m, 1H), 1.91-1.81 (m, 1H), 1.77-1.54 (m, 2H). LCMS (ES+) m/z 460 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[C:25]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27][CH:26]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:30]([C:25]5[CH2:29][CH2:28][CH2:27][CH:26]=5)=[O:31])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: O=C(O)C1=CCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)C1=CCCC1
Yield: 26.7 %

Procedure:
Using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol), N,N-dimethylacetamide (4.0 mL), 1-cyclopentenecarboxylic acid (139 mg, 1.24 mmol), O-(benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (704 mg, 1.86 mmol), 1-hydroxybenzotriazole (251 mg, 1.86 mmol) and N,N-diisopropylethylamine (323 μL, 1.86 mmol), and in the same manner as in Example 219, the title compound (69 mg, 21%) was obtained as a white powder.