Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C:10]2[CH:9]=[C:8]3[N:11](S(C4C=CC(C)=CC=4)(=O)=O)[C:12]([NH:14][CH3:15])=[N:13][C:7]3=[CH:6][C:5]=2[N:4]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:3]1=[O:31].[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:32])[C:10]2[CH:9]=[C:8]3[NH:11][C:12]([N:14]([CH3:15])[C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:13][C:7]3=[CH:6][C:5]=2[N:4]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:3]1=[O:31]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3c(cc21)nc(NC)n3S(=O)(=O)c1ccc(C)cc1
Solvent: c1ccncc1
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(N(C)C(=O)c4ccccc4)nc3cc21
Temperature: 130 °C
Yield: 35.6 %

Procedure:
To a solution of 7,7-dimethyl-2-methylamino-5-pentyl-1-(toluene-4-sulfonyl)-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (120 mg) in pyridine (5 ml) is added drop-wise benzoyl chloride (0.1 ml; 0.79 mmol) at 0° C. After addition the mixture is heated at 130° C. for 5 h. An aqueous work-up and purification by flash chromatography on silica gel eluting with CH2Cl2/MeOH (40:1) yield the desired compound (38 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11]Cl)[S:9][CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:20][NH:21][CH3:22].C(Cl)Cl>CN(C=O)C>[CH3:20][N:21]([CH2:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=1)[CH3:22]
Reactant: CNC
Reactant: CCOC(=O)c1csc(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1csc(CN(C)C)n1
Temperature: 25 °C
Yield: 34.2 %

Procedure:
2-Chloromethyl-thiazole-4-carboxylic acid ethyl ester (500 mg, 2.431 mmol) and potassium carbonate (504 mg, 3.65 mmol) were dissolved in dry DMF. Dimethylamine hydrochloride (218 mg, 2.67 mmol) in dry DMF was added slowly to the reaction mixture and stirred at RT over three nights. DCM was added and the mixture was washed with concentrated NaHCO3 and water. Organic phase was evaporated to dryness and the product was purified by Flash-chromatography. Yield 34.2%. 1H-NMR (400 MHz; CDCl3): δ 1.41 (t, 3H), 2.49 (s, 6H), 3.99 (s, 2H) 4.43 (q, 2H), 8.20 (s, 1H).
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[O:16]([CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][C:24]([CH2:23][O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][C:1](=[O:6])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(COc1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(COc2ccccc2)(c2ccccc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 0.85 mL of methyl acetoacetate, 350 mg of NaH 60% dispersion in oil, 5 mL of 1.6M n-butyl lithium in hexane, 2.0 g of 2-phenoxy-1-phenyl ethanone and 60 mL of tetrahydrofuran. After addition of the ketone, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature and stirred for 1 hour. The crude product was triturated from diethyl ether to afford a solid (m.p. 133°-135° C.). 1 H NMR (DMSO-d6) δ3.03 (d, 1H), 3.35 (d, 1H), 4.18 (dd, 2H), 4.90 (s, 1H), 6.92-6.95 (m, 3H), 7.24-7.49 (m, 7H), 11.56 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([C:11](=[O:21])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[NH2:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[CH3:32][O:31][C:29]1[CH:28]=[C:26]([N:27]2[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][C:11](=[O:21])[C:2]([CH3:1])=[C:3]2[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:25]=[C:24]([O:23][CH3:22])[CH:30]=1
Reactant: CC(C(=O)CC(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: COc1cc(N)cc(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Product: COc1cc(OC)cc(-n2c(-c3ccccc3)cc(=O)c(C)c2-c2ccccc2)c1

Procedure:
to 170 ml of chlorobenzene were added 4.2 g (0.015 mole) of 2-methyl-1,5-diphenyl-1,3,5-pentanetrione, 11.5 g (0.075 mole) of 3,5-dimethoxyaniline, 5.2 g (0.027 mole) of para-toluenesulfonic acid and 35.0 g of Molecular Sieves 5A, followed by refluxing the resulting mixture for 2 hours. After cooling the reaction mixture, solid matter was removed from the reaction mixture, followed by addition of 200 ml of chloroform thereto. The organic layer was washed first with 200 ml of 10% hydrochloric acid and then with 200 ml of a 10% aqueous solution of sodium hydroxide. The organic layer was washed further with water and was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate by filtration, the solvent was distilled off and the residue was subjected to chromatography on a silica gel column (eluent: ethyl acetate). Upon recrystallization of the resultant crystals from a 2:1 mixed solvent of acetone and hexane, 2.0 g of 1-(3,5-dimethoxyphenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinone having a melting point of 232°-236° C. was obtained.
Reaction SMILES: Br[CH:2]([C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:3].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>CN(C)C=O.O>[CH:15]1([NH:18][CH:2]([C:4]2[NH:13][C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH3:3])[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: CC(Br)c1nc2ccccc2c(=O)[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: CC(NC1CC1)c1nc2ccccc2c(=O)[nH]1
Reaction time: 18 h

Procedure:
To a suspension of 2-(1-bromoethyl)quinazolin-4(3H)-one (2.53 g) in N,N-dimethylformamide (30 mL) was added cyclopropylamine (3.46 mL), and the mixture was diluted with N,N-dimethylformamide (20 mL) and water (1 mL), and then stirred for 18 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added aqueous sodium hydrogen carbonate solution, and then the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was triturated with diisopropyl ether/ethyl acetate (20:1) to give 2-[1-(cyclopropylamino)ethyl]quinazolin-4(3H)-one [REx(33-1)] (1.71 g) as a colorless powder.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14]>C1CCN2C(=NCCC2)CC1.C1CCCCC1>[CH3:17][O:16][C:12](=[O:15])[CH2:13][CH2:14][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])([C:2](=[O:1])[CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: C=CC(=O)OC
Solvent: C1CCCCC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCC(=O)C(CCC(=O)OC)(CCC(=O)OC)C(=O)OCC
Temperature: 60 °C
Reaction time: 2 h
Yield: 115.4 %

Procedure:
41.2 g (0.26 mol) of ethyl 3-oxo-hexanoate and 1.9 g (0.012 mol) of DBU were placed in a three necked round bottom flask, equipped with dropping funnel and reflux condenser. At room temperature, 56.3 g (0.65 mol) of methyl acrylate was slowly added drop by drop. After the exothermal behavior of the reaction leveled off, the reaction mixture was stirred at 60° C. for an additional two hours. The mixture was poured into cyclohexane and was washed with diluted hydrochloric acid and was subsequently washed with distilled water until the aqueous layer showed a neutral reaction. The organic layer was dried with sodium sulfate, the solvent was removed, and the residual addition product was isolated by fractional distillation in a vacuum. 50.0 g (0.15 mol) of 4-(ethoxycarbonyl)-4-(1-oxobutyl)-heptanedioic acid 1,7-dimethyl ester was obtained (yield: 58%; boiling point: 149° C. at 0.007 mbar; colorless).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([OH:14])=O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[C:3]([C:12]([NH:15][C:16]2[NH:20][N:19]=[N:18][N:17]=2)=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(O)c1nc2ccccc2nc1Cl
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1nnn[nH]1)c1nc2ccccc2nc1Cl

Procedure:
3-Chloro-2-quinoxalinecarboxylic acid (1.5 g) and N,N'-carbonyldiimidazole (1.2 g) in tetrahydrofuran (50 ml) were heated under reflux for 15 minutes. 5-Amino-1H-tetrazole (0.7 g) in dimethylformamide (5 ml) was added and the solution heated under reflux for 1 hour. The solvent was distilled off and the residue was triturated with dilute hydrochloric acid (25 ml., 2N). The solid was collected and crystallised from aqueous dimethylformamide. It had m.p. 257°-260° (d) (38%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:6][C:7]([NH:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:8]([C:10]([OH:12])=O)[N:9]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:51][C:52]1[N:57]=[C:56]([NH2:58])[CH:55]=[CH:54][CH:53]=1>CN(C)C=O>[CH3:51][C:52]1[N:57]=[C:56]([NH:58][C:10]([C:8]2[N:9]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[S:6][C:7]=2[NH:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])[CH:55]=[CH:54][CH:53]=1
Reactant: COCCc1nc(C(=O)O)c(Nc2cccnc2)s1
Reactant: Cc1cccc(N)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCc1nc(C(=O)Nc2cccc(C)n2)c(Nc2cccnc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
A solution of 2-(2-methoxy-ethyl)-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid (0.032 g, 0.11 mmol) in dimethylformamide (1.00 ml) was treated with DIPEA (0.042 g, 0.33 mmol), TBTU (0.053 g, 0.16 mmol) and 6-methyl-pyridin-2-yl-amine (0.018 g, 0.16 mmol). The mixture was stirred at room temperature overnight, then purified by direct injection in preparative HPLC (ZORBAX Eclipse XDB-C18, 21.2×50 mm, 5 μm, gradient acetonitrile/water+0.1% formic acid). The tide compound (0.011 g, 27%) was obtained as a white solid, MS (ISP): m/e=370.1 (M+H+).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[CH3:6][C:7]1[C:12]([CH3:13])=[C:11]([N+]([O-])=O)[CH:10]=[CH:9][N:8]=1.CCOCC>C(OC(=O)C)(=O)C>[C:1]([O:4][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:6])[C:12]=1[CH3:13])(=[O:3])[CH3:2]
Reactant: Cc1nccc([N+](=O)[O-])c1C
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccnc(C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
Anhydrous potassium acetate (49 g, 0.5 mol) was added to a solution of 2,3-dimethyl-4-nitropyridine (45.6 g, 0.3 mol) prepared in Step 2 in 300 ml of acetic anhydride and then refluxed under stirring for 16 hours. The reaction mixture was cooled to room temperature and then 400 ml of anhydrous ether was added thereto. The reaction mixture was stirred for 1 hour, filtered with Celite, and then concentrated under reduced pressure to give 4-acetoxy-2,3-dimethylpyridine (45 g, 91%). The resulting residue was added to 250 ml of water, refluxed under stirring for 4 hours, and then left overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give 32.6 g of 2,3-dimethyl-4-hydroxypyridine as a liquid form. The liquid product was dissolved in 120 ml of concentrated sulfuric acid and heated to 60° C. A mixture of 90% nitric acid (40 ml) and sulfuric acid (30 ml) was slowly added to the reaction mixture for 45 minutes, while maintaining the temperature at 60-65° C. The reaction mixture was heated for 2 hours at 65° C. and then for 30 minutes at 75° C. The reaction mixture was cooled to room temperature and then added to ice water. The resulting solution was brought to pH 5˜6 with ammonium hydroxide to give a pale yellow solid. The resulting solid was filtered, washed with cold water, and then dried at 80˜90° C. to give 34.5 g of the titled compound.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)C1C=CC=CC=1.ClCCl.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCCl>[OH:8][C:9]1[C:10]([CH:16]=[CH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1
Reactant: Cc1ccc(OCc2ccccc2)c(C=Cc2ccccc2)n1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccc(O)c(C=Cc2ccccc2)n1
Temperature: 50 °C
Yield: 32.6 %

Procedure:
875 mg of 3-benzyloxy-6-methyl-2-styrylpyridine (Example 57a) was dissolved in 15 ml of 1,2-dichloroethane and 1.2 ml of a dichloromethane solution containing 1.0 mol of boron tribromide was added thereto in a nitrogen atmosphere, followed by heating under stirring at 50° C. in an oil bath over night. After cooling as it was, an aqueous saturated sodium bicarbonate solution was added thereto, and the mixture was extracted with 5% methanol/dichloromethane. The organic phase was further washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was vacuum-dried, to give 200 mg of the target compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:9]([C:15]([OH:14])=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:22]=[N:8]2)=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(C(C)(C)C)ccc2c1O
Temperature: 25 °C

Procedure:
A mixture of 3-t-butylaniline (67.6 g.) and diethyl ethoxymethylenemalonate was heated on the steam bath for 3 hours, the ethanol formed being collected by distillation. The resulting yellow oil was dissolved in diphenyl ether (200 ml.) and added during 0.5 hour to stirred diphenyl ether (800 ml.) at 250°-260°, the ethanol formed being collected by distillation. The mixture was stirred at 250°-260° for 0.5 hour, then allowed to cool to room temperature and diluted with an equal volume of petroleum ether (b.p. 60°-80°). THe precipitate was collected by filtration to give the novel compound ethyl 7-t-butyl-4-hydroxyquinoline-3-carboxylate, m.p. 279°-281°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][CH:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]2=[O:32])[CH:5]=[C:6]([F:21])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:21][C:6]1[CH:5]=[C:4]([N:22]2[CH2:26][CH:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]2=[O:32])[CH:3]=[C:2]([F:1])[C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(=O)NCC1CN(c2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCC1CN(c2cc(F)c(N3CCNCC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71.7 %

Procedure:
The N-[[3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (1.00 g, 2.20 mmol) was dissolved in CH2Cl2 (6 mL) and cooled to 0° C. with an ice bath. Trifluoroacetic acid (20 mL) was added, the cooling bath removed, and the reaction mixture allowed to warm to ambient temperature over 1 h. The reaction mixture was then concentrated in vacuo and the residue dissolved in H2O (15 mL). The resultant solution was added to Bio Rad AG-1-X8 ion exchange resin (12 mL; OH- form, washed with H2O until neutral), additional H2O (5 mL) was added, and the mixture stirred for 10 min. The mixture was then filtered and the resin washed with additional H2O (3×5 mL). The aqueous filtrate was lyophilized to give 0.559 g (72%) of the title compound as a white solid with mp 108°-112° C. (dec).
Reaction SMILES: [OH:1][C@@H:2]([CH2:32][OH:33])[CH2:3][NH:4][C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH3:23])[CH:17]=2)=O)=[CH:8][CH:7]=1.Cl.[NH2:35][OH:36].C(=O)([O-])O.[Na+]>>[OH:1][C@@H:2]([CH2:32][OH:33])[CH2:3][NH:4][C:5](=[O:31])[C:6]1[CH:7]=[CH:8][C:9]([CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH2:13]/[C:14](=[N:35]\[OH:36])/[C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH3:23])[CH:17]=2)=[CH:10][CH:11]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC[C@@H](O)CO)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC[C@@H](O)CO)cc1

Procedure:
In analogy to example 151, step 3, N—((R)-2,3-dihydroxypropyl)-4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as an off-white solid containing <10% of the corresponding Z isomer, MS (ESI+): m/z=464.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:33]=[C:32]4[C:27]([CH:28]=[C:29]([C:34]([O:36]C)=[O:35])[N:30]=[CH:31]4)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[C:14]([CH:38]([CH3:40])[CH3:39])[O:13][N:12]=1.O1CCCC1.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:33]=[C:32]4[C:27]([CH:28]=[C:29]([C:34]([OH:36])=[O:35])[N:30]=[CH:31]4)=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)=[C:14]([CH:38]([CH3:40])[CH3:39])[O:13][N:12]=1
Reactant: COC(=O)c1cc2ccc(-c3ccc(OCc4c(COc5c(C)cccc5C)noc4C(C)C)cc3)cc2cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(C)c1OCc1noc(C(C)C)c1COc1ccc(-c2ccc3cc(C(=O)O)ncc3c2)cc1
Temperature: 100 °C
Yield: 74.7 %

Procedure:
To a solution of methyl 7-[4-({[3-{[(2,6-dimethylphenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylate (44 mg, 0.082 mmol) in 2:1 tetrahydrofuran:methanol (3 mL) was added 0.123 mL of 1 N sodium hydroxide. The solution was heated in a microwave reactor at 100° C. for 500 seconds. Then 1N hydrochloric acid (0.123 mL, 0.123 mmol) was added and the solution was concentrated. The residue was taken up with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combine organic layers were washed with brine, dried over magnesium sulfate and concentrated. The resulting solid was dried under vacuum overnight and then suspended in ethyl acetate and washed three times with water. The solvent was evaporated to afford 7-[4-({[3-{[(2,6-dimethylphenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylic acid (32 mg, 75%). 1H-NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.61 (s, 1H), 8.50 (s, 1H), 8.24-8.19 (m, 2H), 7.86 (d, J=9 Hz, 2H), 7.19 (d, J=9 Hz, 2H), 7.00-6.91 (m, 3H), 5.09 (s, 2H), 4.90 (s, 2H), 3.41 (septet, J=7 Hz, 1H), 2.14 (s, 6H), 1.27 (d, J=7 Hz, 6H). HRMS (ESI) C32H30N2O5 calculated: 523.2228 (M+H)+, found: 523.2230 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:14][C:15]1[S:19][C:18]([C:20](O)=[O:21])=[CH:17][CH:16]=1>>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:20]([C:18]2[S:19][C:15]([Cl:14])=[CH:16][CH:17]=2)=[O:21])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc(Cl)s2)C1

Procedure:
6.1 Using general procedure D (R)-1-Boc-3-aminopyrrolidine was coupled with 5-chlorothiophene-2-carboxylic acid to give (R)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester. Yellow solid. MS 329.3 ([M−H]−)
Reaction SMILES: [CH2:1]([N:8]1[CH2:22][CH2:21][C:11]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:22][CH2:21][C:11]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:28](=[O:30])[CH3:29])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCC3(CCNc4ccccc43)CC2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1CCC2(CCN(Cc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-benzyl-2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline] 1ad (4.5 g, 15.4 mmol) in dry CH2Cl2 (35 mL) was added NaHCO3 (6.47 g, 77 mmol) at room temperature. Then acetyl chloride (1.2 g, 15.4 mmol) was added dropwise at ambient temperature. The mixture was stirred for 2 hours at room temperature. After filtration, the filtrate was washed with brine, dried over Na2SO4 and evaporated under reduced pressure to give a white solid, which was washed with ether and filtered to afford the pure product 1-(1-benzyl-2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline]-1′-yl)ethanone 1ae (not shown). The solid (5.2 g, 15.6 mmol) was dissolved in MeOH (50 mL), then Pd(OH)2/C (0.25 g) was added under Ar. The suspension was hydrogenated under H2 (50 psi) at 50-55° C. overnight. After cooling and filtration, the filtrate was evaporated under reduced pressure to give 1-(2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline]-1′-yl)ethanone 1ae (3.12 g, 83%, two steps). 1H NMR (CDCl3, 300 MHz) δ 7.46-7.49 (m, 2H), 7.21-7.26 (m, 3H), 3.82 (t, J=5.7 Hz, 2H), 3.38 (d, J=12.9 Hz, 2H), 3.08-3.16 (m, 2H), 2.38-2.48 (m, 2H), 2.24 (s, 3H), 1.97 (t, J=6.0 Hz, 2H), 1.77 (d, J=14.7 Hz, 2H). MS (ESI) m/z (M+H+) 245.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:2]=12.S(Cl)([Cl:15])=O>>[N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([C:10]([Cl:15])=[O:12])=[CH:9][C:2]=12
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc2nccnc2s1
Product: O=C(Cl)c1cc2nccnc2s1
Yield: 100 %

Procedure:
A solution of thieno[2,3-b]pyrazine-6-carboxylic acid (400 mg, 2.220 mmol) in thionyl chloride (1.6 mL, 22.20 mmol) was heated to 80° C. for 2 h. Concentrated to dryness and coevaporated with toluene to give thieno[2,3-b]pyrazine-6-carbonyl chloride 63 (441 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[O:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:27][CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: NC1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(Cl)nc1NC1CCOCC1
Temperature: -64 °C
Reaction time: 5 h
Yield: 78.1 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (1.03 g, 5.15 mmol) in THF (40 mL) at −78° C., DIPEA (2.0 mL, 11.86 mmol) and tetrahydro-2H-pyran-4-amine (0.54 mL, 5.15 mmol) were added. The reaction mixture was stirred from −78 to −50° C. for 5 h. The crude mixture was quenched with H2O (50 mL), extracted with EtOAc (3×40 mL) and the combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using EtOAc/hexanes mixtures of increasing polarity as eluent, to afford 1.04 g of the desired compound (78% yield).
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3]=[CH2:4].N1C=CC=CC=1.P(Br)(Br)[Br:22]>CCCCCC>[Br:22][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: C=CC(C)(O)CCC=C(C)CC(C)C
Reactant: BrP(Br)Br
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(=CCBr)CCC=C(C)CC(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
19.8 g. of 3,7,9-trimethyl-1,6-decadien-3-ol, 100 ml. of hexane and 1 ml. of pyridine and cooled to -15° C. and treated dropwise over a period of 1.5 hours with a solution of 4 ml. of phosphorus tribromide in 50 ml. of hexane while maintaining the temperature between -15° and -10° C. The mixture is stirred for a further 90 minutes while slowly warming to room temperature. For the working-up, the mixture is poured on to 50 ml. of ice-water, the organic phase is separated and washed once with 20 ml. of 10% soda solution, once with 50 ml. of semi-saturated aqueous sodium chloride solution and once with 50 ml. saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. There is obtained 1-bromo-3,7,9-trimethyl-2,6-decadiene.