Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:21])=[O:5])[CH3:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:47])C(=O)C1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21][Br:47])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Temperature: 0 °C

Procedure:
To a solution of 200 g of commercially available 4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester in 1.6 L of dichloromethane were added 20.5 g of benzoyl peroxide and 124 g of NBS. The resulting mixture was refluxed in the dark for 22 h. After cooling to 0° C., the mixture was filtered. The filtrate was concentrated to half volume under reduced pressure, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a white solid. The solid was recrystallized in 900 mL of diisopropyl ether 80/dichloromethane 20 to give a first crop of 101 g of 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester. The filtrate was concentrated under reduced pressure then recrystallized in 300 mL of diisopropyl ether 90/dichloromethane 10 to give a second crop of 72 g. A total of 173 g of 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester was obtained as a white solid. 4 WO02067912
Reaction SMILES: CC1(C)CCC(C)(C)C2C=C(N)C=CC1=2.[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.S(Cl)(Cl)=[O:27]>>[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:27])=[O:22])=[CH:19][CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CC1(C)CCC(C)(C)c2cc(N)ccc21
Product: O=C(O)c1ccc(F)cc1

Procedure:
In a manner analogous to Example 9, by reacting 5.9 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylamine with 4-fluorobenzoyl chloride, obtained from 4 g of 4-fluorobenzoic acid and 15 ml of thionyl chloride, there were obtained, after recrystallization from hexane/ethyl acetate, 6.3 g of p-fluoro-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)benzamide, m.p. 160° C.-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:24][CH2:23][C:18]3(OCC[O:19]3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:16][CH2:17][C:18](=[O:19])[CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccccc2CN2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCN(Cc2ccccc2-c2ccc(Cl)cc2)CC1
Temperature: 85 °C
Yield: 100.1 %

Procedure:
8-((4′-Chlorobiphenyl-2-yl)methyl)-1,4-dioxa-8-azaspiro[4.5]decane (4.73 g, 13.76 mmol) was dissolved in dioxane (50 mL) and water (30 mL). Hydrochloric acid (37%, 14.3 mL, 174 mmol) was added, and the reaction was heated to 85° C. for 26 hours. After cooling to room temperature, the volatiles are removed in vacuo. The remaining aqueous phase is basified to pH ˜9 with 2M NaOH, and then extracted with CH2Cl2. The organic layers are dried over MgSO4 and concentrated to afford the title compound (4.13 g, 100% yield). MS (ESI) m/e (M+H)+: 300.4
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:22][C:23]1[N:28]=[CH:27][C:26]2[C:29](=O)[O:30][CH:31]([CH2:32][CH3:33])[C:25]=2[CH:24]=1.Cl>C1COCC1>[Cl:22][C:23]1[N:28]=[CH:27][C:26]2[C:29](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[O:30][CH:31]([CH2:32][CH3:33])[C:25]=2[CH:24]=1
Reactant: CCC1OC(=O)c2cnc(Cl)cc21
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.5 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (4.71 g, 31.2 mmol.) in THF (30 mL) is cooled to 0° C. under an argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (60 mL of a 1 M solution in THF, 60.0 mmol) dropwise. The resulting solution is stirred at 0° C. for 10 min and warmed room temperature. A solution of 6-chloro-1-ethyl-1H-furo[3,4-c]pyridin-3-one, (4.11 g, 20.8 mmol) in THF (30 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution (350 mL). The resulting mixture is heated to 90° C. for 2 h and then stirred at room temperature for 36 h. The precipitate which forms is collected by filtration and washed with small volumes of ethyl acetate (10×3 mL) and dried to give the title compound as a yellow solid (2.37 g, 34%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[F:25][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([F:24])[CH:21]=1)[O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[N:9]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cc(F)cc(F)c4)cc3)c3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3cc(F)cc(F)c3)cc1)nn2[C@@H]1CCCNC1
Yield: 76.5 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of tert-butyl (3R)-3-[4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (340 mg, 0.65 mmol, 1.00 equiv) in dichloromethane (50 mL), followed by the addition of trifluoroacetic acid (10 mL) dropwise with stirring. The resulting solution was stirred for 12 h at room temperature and then concentrated under vacuum. The resulting solution was diluted with 20 of water. The pH value of the solution was adjusted to >7 with sodium carbonate and then extracted with dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give 210 mg (76%) of 3-[4-(3,5-difluorophenoxy)phenyl]-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a brown solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][CH:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:19]1([CH2:25][CH2:26][NH2:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH:1]1[C:10]2[C:5](=[C:6]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([NH:27][CH2:26][CH2:25][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: NCCc1ccccc1
Reactant: O=C1CCC(Nc2cccc3cnccc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1ccc(CCNC2CCC(Nc3cccc4cnccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.8 %

Procedure:
4-(5-Isoquinolylamino)-1-cyclohexanone (intermediate 4) (60 mg) and 2-phenylethylamine (61 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (24 mg) and a syn-form compound (11 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:28]O)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:15][CH:14]=2)[O:10][N:9]=1)[CH3:2].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:55]1[CH2:58][CH:57]([C:59]([O:61][CH3:62])=[O:60])[CH2:56]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:28][N:55]2[CH2:58][CH:57]([C:59]([O:61][CH3:62])=[O:60])[CH2:56]2)[S:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:17][CH:18]=2)[O:10][N:9]=1)[CH3:2]
Reactant: COC(=O)C1CNC1
Reactant: CCc1cc(CO)sc1-c1noc(-c2ccc(Oc3ccccc3OC)cc2)n1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CN2CC(C(=O)OC)C2)sc1-c1noc(-c2ccc(Oc3ccccc3OC)cc2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using (4-ethyl-5-{5-[4-(2-methoxyphenoxy)phenyl]-1,2,4-oxadiazol-3-yl}-2-thienyl)methanol (0.14 g, 0.35 mmol) that was obtained in Example 21 (21b), carbon tetrabromide (0.17 g, 0.53 mmol), triphenylphosphine (0.14 g, 0.53 mmol), methyl 3-azetidinecarboxylate hydrochloride (80 mg, 0.53 mmol), and N,N-diisopropylethylamine (0.18 mL, 1.1 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:5 to 1:2) as the eluent to afford the title compound (89 mg) in a yield of 50% as a colourless oily product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[CH2:13]([NH:20][C:21]([C:23]1[S:24][C:25]([N:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]2=[O:36])=[CH:26][C:27]=1[CH3:28])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:21]([C:23]1[S:24][C:25]([N:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=3)=[CH:31][C:30]2=[O:36])=[CH:26][C:27]=1[CH3:28])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: Cc1cc(-n2ccc(OCc3ccc(C(F)(F)F)cc3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 42 %

Procedure:
Following the procedure as described in Example 9, making variations only as required to use 1-(bromomethyl)-4-(trifluoromethyl)benzene in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-benzyl-5-(4-hydroxy-2-oxopyridin-1(2H)-yl)-3-methylthiophene-2-carboxamide, the title compound was obtained as a colorless solid in 42% yield: mp 225-227° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.56 (t, J=6.0 Hz, 1H), 8.18 (d, J=7.9 Hz, 1H), 7.80 (d, J=8.2 Hz, 2H), 7.68 (d, J=8.1 Hz, 2H), 7.37-7.20 (m, 6H), 6.32 (dd, J=7.9, 2.8 Hz, 1H), 6.14 (d, J=2.8 Hz, 1H), 5.30 (s, 2H), 4.41 (d, J=6.0 Hz, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.0, 162.4, 160.9, 140.3, 139.6, 138.7, 137.2, 135.2, 128.2 (d, JC-F=3.7 Hz), 127.4, 127.1, 126.6, 125.4 (d, JC-F=3.8 Hz), 120.7, 102.4, 97.5, 69.0, 42.5, 15.5; MS (ES+) m/z 499.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][NH:13][C:12](=[O:18])[CH:11]=2)[CH:3]=1.[H-].[Na+].Cl[CH:22]([O:28][CH2:29][CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][N:13]([CH:22]([O:28][CH2:29][CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:12](=[O:18])[CH:11]=2)[CH:3]=1
Reactant: CCOC(=O)C(Cl)OCC
Reactant: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(OCC)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon and at 0° C., 10 min apart two portions of in total 350 mg (purity 82%, 1.10 mmol) of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile were added to a suspension of 53 mg (1.32 mmol, 1.2 eq.) of sodium hydride (60% in mineral oil) in 2.1 ml of dimethylformamide. The reaction mixture was stirred at RT for 60 min and then cooled back to 0° C., 245 mg (purity 90%, 1.32 mmol, 1.2 eq.) of ethyl 2-chloro-2-ethoxyacetate were added and the mixture was stirred at RT for 2 h. This batch together with an analogous test batch was combined with 50 mg (purity 82%, 0.16 mmol) of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile. After addition of 20 ml of water and phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (IR-50Si, petroleum ether/ethyl acetate 15-50%). Yield: 277 mg (55% of theory based on in total 1.26 mmol of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile employed)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[C:9](Cl)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6].[NH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][C:8]1[C:9]([N:19]2[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6]
Reactant: O=C(Nc1cc(Cl)cnc1Cl)c1cccc(Cl)c1
Reactant: OCCC1CCNCC1
Solvent: CC#N
Product: O=C(Nc1cc(Cl)cnc1N1CCC(CCO)CC1)c1cccc(Cl)c1
Temperature: 180 °C
Yield: 99.9 %

Procedure:
A mixture of 1.06 g (5.00 mmol) of 3-chloro-N-(2,5-dichloro-pyridin-3-yl)-benzamide and 0.646 g (5.00 mmol) of 4-piperidine ethanol in acetonitrile (25 mL) is heated in a microwave reactor at 180° C. for 4 hours. Upon standing at room temperature a solid precipitates from solution. The solid is collected by filtration, washed with cold acetonitrile, and dried on the filter pad to provide 1.97 g (76%) of 3-chloro-N-[5′-chloro-4-(2-hydroxy-ethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-benzamide as a clear solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[F:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:17]2[N:16]=[C:15]3[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=4)=[N:14]3)=[CH:19][CH:18]=2)=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: Nc1ccc2ccc(Oc3ccc(F)cc3)nc2n1
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)Nc2ccc3ccc(Oc4ccc(F)cc4)nc3n2)cc1
Temperature: 4 °C
Yield: 73.3 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (14.3 g), N,N'-carbonyldiimidazole (15.2 g) and 2-amino-7-(4-fluorophenoxy)-1,8-naphthyridine (15.2 g). The product produced by precipitation in water (22.6 g; m.p. approximately 70° C.) is dissolved in boiling ethanol (130 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×15 cc) and dried at 25° C. under reduced pressure (0.067 kPa). N-[7-(4-fluorophenoxy)-1,8-naphthyridin-2-yl]-4-methoxybenzamide (17 g) is produced, m.p. 100° C.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:21]=[C:20]2[C:15]([C:16]([Cl:26])=[CH:17][N:18]=[C:19]2[NH:22][C:23]([NH2:25])=[NH:24])=[CH:14][CH:13]=1)=[O:11])(C)(C)C.C1(C)C=CC=CC=1>C(C(O)=O)(F)(F)F>[Cl:26][C:16]1[C:15]2[C:20](=[CH:21][C:12]([C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:27])=[O:5])=[O:11])=[CH:13][CH:14]=2)[C:19]([NH:22][C:23]([NH2:25])=[NH:24])=[N:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NCCC(=O)O)cc12
Reaction time: 1 h
Yield: 70.3 %

Procedure:
A solution of N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-β-alanine t-butyl ester (145 mg, 0.37 mmol) in CF3CO2H (1.5 mL) was stirred at 0° C. for 30 min, and then at room temperature for 1 h. PhMe (15 mL) was added, the mixture evaporated in vacuo, and the residue triturated with EtOAc and Et2O to give N-[(4-Chloro-1-guanidino-7-isoquinolinyl)carbonyl]-β-alanine (117 mg, 0.26 mmol) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:17][CH:16]=2)[N:7]=1.Br[CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]/[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]/[C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)=[CH:10][CH:9]=[C:8]([C:13]#[C:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:20]=2)[N:7]=1
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Reactant: COC(=O)CCc1nc(C#Cc2ccc(CC(=O)OC)cc2)ccc1O
Product: COC(=O)CCc1nc(C#Cc2ccc(CC(=O)OC)cc2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 54.8 %

Procedure:
Under the conditions of example 1 D, 600 mg of 3-{3-hydroxy-6-[2-(4-methoxycarbonylmethylphenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester is reacted with 460 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene, worked up, and the crude product is chromatographed on silica gel with hexane/0-10% ethyl acetate. 504 mg of 3-{3-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-6-[2-(4-methoxycarbonylmethylphenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester is obtained as oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][O:12][CH2:13][CH2:14][N:7]3[C@H:6]3[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][C@@H:5]23)[CH:10]=1.[F:26][C:27]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.C(O)(=O)C>[F:26][C:27]1[C:34]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:1][C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][O:12][CH2:13][CH2:14][N:7]3[C@H:6]3[CH2:15][CH2:16][NH:17][CH2:18][C@@H:5]23)[CH:10]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: Fc1c(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B (35 mg, 0.10 mmol) in 5 mL of acetonitrile was added 2-fluoro-3-(trifluoromethyl)benzaldehyde (38 mg, 0.20 mmol) and three drops of glacial acetic acid. The reaction was stirred at ambient temperature for 1 h and then there was added sodium triacetoxyborohydride (64 mg, 0.30 mmol). The reaction was stirred at ambient temperature for 3 h and then was quenched by the addition of aq ammonium hydroxide. The mixture was extracted with methylene chloride, washed with brine, dried (K2CO3) and concentrated. The residue was taken up in 10 mL of methylene chloride and then there was added 5 mL of trifluoroacetic acid. The reaction was allowed to stir at ambient temperature for 3 h and then was concentrated in vacuo. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and the product containing fractions were concentrated, free-based with aq ammonium hydroxide, extracted with chloroform, washed with brine, dried (K2CO3) and concentrated to afford the title compound of EXAMPLE 126. 1H NMR(CDCl3) δ: 7.55-7.40 (m, 2H), 7.12 (t, 1H, J=7.7 Hz), 6.31 (d, 1H, J=2.0 Hz), 6.15 (d, 1H, J=1.9 Hz), 4.48 (ABq, 2H, JAB=14.3 Hz), 4.32 (s, 2H), 4.12 (app d, 1H), 3.63 (app t, 1H), 3.30-3.20 (m, 2H), 3.18-2.98 (m, 4H), 2.56 (app t, 1H), 2.43 (app t, 1H), 2.05-1.92 (m, 2H). LRMS (ES)+: 422.3 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([OH:11])=[CH:5][C:4]=1[O:12][CH3:13])=[O:2].CC(C)([O-])C.[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O>[CH:1]([C:3]1[C:4]([O:12][CH3:13])=[CH:5][C:6]([O:11][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:7][C:8]=1[O:9][CH3:10])=[O:2]
Reactant: COc1cc(O)cc(OC)c1C=O
Reactant: CCOC(=O)CCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOc1cc(OC)c(C=O)c(OC)c1
Temperature: 0 °C

Procedure:
To a suspension of 4-formyl-3,5-dimethoxyphenol (22.6 g, 124 mmol) and potassium tert-butoxide (15.3 g, 136 mmol) in dimethylformamide (125 mL) was added ethyl 5-bromovalerate (28.5 g, 136 mmol) in dimethylformamide (125 mL) over a period of 20 min. The mixture was heated at 11 0° C. for 6 h and concentrated in vacuo. To the obtained product was added ethyl acetate (400 mL) and the mixture was filtered. The filtrate was washed with water (100 mL), 1 N sodium hydroxide (2×50 mL), and brine (3×100 mL), dried (magnesium sulfate), and concentrated in vacuo to 37 g of ethyl 5-(4-formyl-3,5-dimethoxyphenoxy)valerate.
Reaction SMILES: [O:1]=[C:2]1[CH2:25][O:24][C:5]2=[CH:6][CH:7]=[C:8]3[C:12]([N:11]([CH2:13][CH:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[N:10]=[CH:9]3)=[C:4]2[NH:3]1.[H-].[Na+].IC.[CH3:30]N(C)C=O>O1CCCC1>[CH3:30][N:3]1[C:4]2[C:5](=[CH:6][CH:7]=[C:8]3[C:12]=2[N:11]([CH2:13][C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH3:15])[N:10]=[CH:9]3)[O:24][CH2:25][C:2]1=[O:1]
Reactant: CC(Cn1ncc2ccc3c(c21)NC(=O)CO3)NC(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc3c(c21)N(C)C(=O)CO3)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To a solution of the product from Example 2, Step F (0.22 g, 0.64 mmol) in anhydrous tetrahydrofuran (30 mL) was added sodium hydride (60% dispersion, 28 mg, 0.70 mmol) and this mixture was stirred under a nitrogen atmosphere for 10 min. Iodomethane (99 mg, 44 uL, 0.70 mmol) was added and the mixture was stirred for 1 h followed by the addition of anhydrous dimethylformamide (20 mL); this mixture was stirred for 4 h, poured into ice water, and the solution was extracted with ethyl acetate (3×50 mL). The combined extracts were evaporated to a residue that was purified by chromatography (gradient, 20% to 50% ethyl acetate in hexane to give an oil (0.14 g, 57%): LC/MS (+APCI) m/z 361 (M+H).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]([S:17][Na])([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([S:17][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CC(C)(C)S[Na]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(SC(C)(C)C)cc1
Temperature: 80 °C

Procedure:
Ethyl 4-fluorobenzoate (5.00 g, 29.7 mmol) and tert-butylsulfanylsodium (6.67 g, 59.5 mmol) were combined in DMF (50 mL). The reaction mixture was heated at 80° C. for 67 hours. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield ethyl 4-tert-butylsulfanylbenzoate. The aqueous layer was acidified with hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3×100 mL), and the combined organic layer was washed with water (1×50 mL) and brine (1×50 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield 4-(tert-butylthio)benzoic acid as an off-white solid. 1H NMR (400 MHz, DMSO) δ 13.10 (s, 1H), 7.93 (d, J=8.2 Hz, 2H), 7.61 (d, J=8.2 Hz, 2H), 1.28 (s, 9H). ESI-MS m/z calc. 210.1, found 211.1 (M+1)+; Retention time: 1.64 minutes (3 min run).