Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[N:34][CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([C:2]2[C:3]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[C:12]([F:21])[CH:11]=3)=[O:8])[CH:22]=2)[CH:33]=[N:34][CH:35]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 198.1) and (5-fluoropyridin-3-yl)boronic acid to afford a yellow wax. UPLC-MS (Condition 3) tR=1.06 min, m/z=481.3 [M+H]+, m/z=479.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.80 (m, 1H) 1.80-1.91 (m, 1H) 2.89 (d, J=11.25 Hz, 1H) 3.19-3.29 (m, 2H) 3.35-3.46 (m, 1H) 4.21 (br. s, 1H) 4.86 (d, J=3.67 Hz, 1H) 7.55 (m, J=8.56 Hz, 1H) 7.61 (m, J=1.47 Hz, 1H) 7.83 (m, J=1.96 Hz, 1H) 7.98 (dd, J=13.20, 2.20 Hz, 1H) 8.07 (d, J=2.20 Hz, 1H) 8.51 (br. s, 1H) 8.60 (d, J=2.69 Hz, 1H) 8.78 (d, J=2.20 Hz, 1H) 10.30 (s, 1H).
Reaction SMILES: Cl[CH:2]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12]2)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:25][OH:26]>>[CH3:25][O:26][CH:2]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12]2)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc2cc(C(Cl)c3cccnc3)ccc2c1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1ccc2cc(C(OC)c3cccnc3)ccc2c1
Yield: 94 %

Procedure:
52 mg (0.17 mmol) of methyl 6-[1-chloro-1-(3-pyridyl) methyl]-2-naphthoate and 8 mg (0.18 mmol) of sodium hydride dispersion (55%) in 4 ml of absolute methanol are heated under reflux for 6 hours. After the reaction mixture has been evaporated, the residue is taken up in sodium bicarbonate solution, which is extracted with ethyl acetate. After the ethyl acetate phase has been dried and evaporated in vacuo, the residue is chromatographed on silica gel using ethyl acetate. 48.2 mg (94%) of methyl 6-[1-methoxy-1-(3-pyridyl)methyl]-2-naphthoate are obtained. RF (ethyl acetate/cyclohexane 1:1): 0.17.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH2:8])[CH:7]=1.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH:8][S:19]([C:13]2[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=2[F:11])(=[O:21])=[O:20])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: CSc1ccc(Cl)cc1N
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(F)cc1F
Yield: 93.9 %

Procedure:
Following General Procedure B, the title compound (358 mg, 94%) was prepared from 5-chloro-2-methylsulfanyl-phenylamine (189 mg, 1.09 mmol) and 2,4-Difluoro-benzenesulfonyl chloride (231 mg, 1.09 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]([C:27]([CH:29]2[CH2:31][CH2:30]2)=[O:28])[CH2:25][CH3:26])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2].I[CH3:34]>>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:27]([CH:29]2[CH2:30][CH2:31]2)=[O:28])[CH2:25][CH3:26])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:34])[CH3:2]
Reactant: CCOC(=O)Cc1cc(Cl)cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CC2)c1
Reactant: CI
Product: CCOC(=O)C(C)c1cc(Cl)cc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 213, Step 5, using the following starting materials: {5-chloro-2′-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid ethyl ester and iodomethane.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][C:17]([C:13]3[O:12][CH:16]=[CH:15][CH:14]=3)=[N:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccco1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: CCO
Product: O=[N+]([O-])c1ccc2oc(-c3ccco3)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.9 %

Procedure:
15.4 g of 4-nitro-2-aminophenol is dissolved in 250 ml of ethanol and to this solution 9.6 g of furaldehyde is added to room temperature. The reaction is allowed to stir at room temperature for 0.25 hr and the precipitated crystals are collected. The resulting Schiff Base is then dissolved in 250 ml of glacial acetic acid, treated with 44 g of lead tetraacetate and then refluxed for 2 hr. The mixture is then diluted with 250 ml of water and the precipitated product is collected and washed with water. Recrystallization from 150 ml of CH2Cl2 yields 10.1 g of 5-nitro-2-(2-furyl)benzoxazole, mp 175°-177°.
Reaction SMILES: C([S:4]([C:7]1[C:11]([CH:12]2[CH:17]3[CH2:18][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[N:10][S:9][N:8]=1)(=O)=O)CC.C(=O)([O-])[O-].[K+].[K+].O.[SH-].[Na+]>CN(C=O)C>[N:14]12[CH2:18][CH:17]([CH2:16][CH2:15]1)[CH:12]([C:11]1[C:7]([SH:4])=[N:8][S:9][N:10]=1)[CH2:13]2
Reactant: CCCS(=O)(=O)c1nsnc1C1CN2CCC1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Sc1nsnc1C1CN2CCC1C2
Temperature: 70 °C

Procedure:
Endo (-) 3-(3-(3-propylsulfonyl-1,2,5-thiadiazol-4-yl)-1-azabicyclo[2.2.1]heptane (W094/20496) (1.5 g, 5.2 mmol) and potassium carbonate (1.4 g, 10.4 mmol) in dry DMF(20 ml) was added sodium hydrosulfide monohydrate (1.15 g, 15.6 mmol). The reaction mixture was heated to 70° C. During this period another two portions of sodium hydrosulfide monohydrate was added to complete the reaction. DMF was evaporated and the residue added ice water followed by 4 N hydrochloric acid to pH 8-9. The product was isolated by filtration to give 862 mg (78%) of Endo (β) 4-(1-azabicyclo[2.2.1]hept-3-yl)-1,2,5-thiadiazol-3-thiol.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:27][Si](C)(C)C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH2:27])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(3,4-dichlorophenyl)-propionic acid (105 mg, 0.37 mmol) in methylene chloride (10 mL) and 1 drop of N,N-dimethylformamide was cooled to 0° C. and then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.18 mL, 0.37 mmol). The reaction was stirred for 30 min at 0° C., at which time, 1,1,1,3,3,3-hexamethyldisilazane (0.25 mL, 1.17 mmol) was added to the reaction mixture. The reaction was then allowed to slowly warm to 25° C. and stirred at 25° C. for 16 h. The reaction mixture was then washed with a 5% aqueous sulfuric acid solution (2×10 mL). The combined aqueous layers were extracted with methylene chloride (3×10 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 hexanes/ethyl acetate) afforded 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide (60 mg, 58%) as a white solid: [α]23589=−67.6° (c=0.106, chloroform); EI-HRMS m/e calcd for C14H17Cl2N1O1(M+) 285.0687, found 285.0685.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH:19]1([C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[CH:23]=[C:24]([NH:25][C:15](=[O:17])[CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)[CH:26]=[CH:27][CH:28]=2)[CH2:21][CH2:20]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc(C2CC2)c1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(C2CC2)c1
Yield: 66.3 %

Procedure:
The product is prepared according to the following procedure, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 395 mg of 3-cyclopropylaniline (prepared according to Wallace et al., in Tetrahedron Lett. 2002, 43, 6987) in place of the 2,4-difluoroaniline. 225 mg of N-(3-cyclopropylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [N:1]#[C:2]Br.[C:4]([NH:19][NH2:20])(=[O:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O1CCOCC1.O>[NH2:1][C:2]1[O:18][C:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[N:19][N:20]=1
Reactant: N#CBr
Reactant: CCCCCCCCCCCCCC(=O)NN
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCc1nnc(N)o1

Procedure:
Cyanogen bromide (2.9 g, 0.027 mol) was added to a mixture of the compound prepared in Step 1 above (6.1 g, 0.025) and KHCO3 (2.8 g, 0.028 mol) in dioxane/water (1:1, 50 mL) at room temperature. The mixture was refluxed for 1 hour, allowed to cool, filtered, washed with dioxane/water (1:1, 20 mL), then water (50 mL), and dried in vacuo. The solid was recrystallized from chloroform to yield 4.16 g, m.p. 147°-150° C.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17]O)[CH:12]=[CH:13][CH:14]=2)[CH:2]=1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12>>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][N:29]3[C:25](=[O:35])[C:26]4[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:28]3=[O:30])[CH:12]=[CH:13][CH:14]=2)[CH:2]=1
Reactant: OCCCc1cccc(C#Cc2cccc(-c3ccccc3)c2)c1
Reactant: O=C1NC(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(C#Cc2cccc(-c3ccccc3)c2)c1

Procedure:
Coupling of 3-(3-(biphenyl-3-ylethynyl)phenyl)propan-1-ol with phthalimide was conducted following the method described in Example 21. Purification by flash chromatography (6% EtOAc-hexanes) gave 2-(3-(3-(biphenyl-3-ylethynyl)phenyl)propyl)isoindoline-1,3-dione. Yield (0.320 g, 42%): 1H NMR (400 MHz, CDCl3) δ 7.84 (dd, J=5.6, 3.2 Hz, 2H), 7.77 (m, 1H), 7.71 (dd, J=5.6, 3.2 Hz, 2H), 7.61-7.63 (m, 2H), 7.32-7.57 (m, 8H), 7.18-7.25 (m, 2H), 3.77 (t, J=7.2 Hz, 2H), 2.70 (t, J=7.2 Hz, 2H), 2.02-2.09 (m, 2H).
Reaction SMILES: [CH3:1]/[C:2](/[NH2:6])=[CH:3]\[C:4]#[N:5].[NH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)N.Cl.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:5][C:4]1[N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:2]([CH3:1])[CH:3]=1
Reactant: NNc1ccccn1
Reactant: C/C(N)=C\C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(N)n(-c2ccccn2)n1
Reaction time: 0.17 h

Procedure:
3-Aminocrotonitrile (1.98 g, 24.1 mmol) was added to a stirred solution of 2-hydrazinopyridine (2.63 g, 24.1 mmol) in a mixture of concentrated hydrochloric acid (2.5 ml) and water (10 ml). After 10 minutes at room temperature, concentrated hydrochloric acid (5 ml) was added, and the mixture was heated for 30 minutes under reflux. The mixture was cooled and rendered basic by the addition of saturated aqueous potassium carbonate. The solid which precipitated was filtered off and dried to give the title compound, 2.43 g (58%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@@H:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl.N1C=CC=CC=1.C(N(C(C)C)CC)(C)C>[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@@H:18]3[CH2:22][CH2:21][N:20]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 520.1 %

Procedure:
4-(3-chloro-2-fluoroanilino)-6-[(3R)-pyrrolidin-3-yloxy]-7-methoxyquinazoline hydrochloride (0.21 g, 0.49 mmole) was dissolved in a mixture of dichloromethane (4 ml), pyridine (1 ml) and diisopropylethylamine (0.17 ml) under a nitrogen atmosphere. Methanesulfonyl chloride (0.06 ml, 0.07 mmol) was added to the stirred solution. After stirring 2 hours at room temperature, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (96/4). The fractions containing the expected product were combined and evaporated under vacuum and the residual gum was triturated with diethylether, filtered and dried under vacuum to give the title product as a white solid (0.17 g, 74%); 1H NMR Spectrum: (DMSO d6) 2.18-2.37 (m, 2H); 2.93 (s, 3H); 3.33-3.45 (m, 2H); 3.5 (d, 1H); 3.69 (dd, 1H); 3.92 (s, 3H); 5.17 (m, 1H); 7.15-7.35 (m, 2H); 7.40-7.60 (m, 2H); 7.5 (m, 2H); 7.80 (s, 1H); 8.37 (s, 1H); 9.6 (s, 1H); Mass Spectrum: (M+H)+ 467.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][CH:20]=1)[O:8][C:9]1([C:13]([O:15]CC)=[O:14])[CH2:12][CH2:11][CH2:10]1>O1CCCC1.O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][CH:20]=1)[O:8][C:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)C1(Oc2cccc(Cl)c2)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(Oc2cccc(Cl)c2)CCC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (1.7 g, 40.3 mmol) was added to a suspension of Example 15A (4.7 g, 13.4 mmol) in tetrahydrofuran (320 mL) and water (160 mL) at room temperature. The reaction mixture was stirred at 55° C. overnight. The reaction was concentrated under reduced pressure to remove tetrahydrofuran, acidified to pH˜3 by adding aqueous 1 M HCl while cooling. The precipitate was collected by filtration and dried in a dessicator containing KOH overnight. Recrystallization from heptane afforded the titled compound. MS (ESI+) m/z 227 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20](O)=[O:21])=[CH:16][C:10]=3[C:9]=2[C:26](=[O:29])[NH:27][CH3:28])=[CH:4][CH:3]=1.Cl.[C:31]1([C:37]2([NH2:40])[CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]4[CH:25]=[CH:24][CH:23]=[C:19]([C:20](=[O:21])[NH:40][C:37]5([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH2:39][CH2:38]5)[CH:18]=4)=[CH:16][C:10]=3[C:9]=2[C:26]([NH:27][CH3:28])=[O:29])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: NC1(c2ccccc2)CC1
Agent: Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12

Procedure:
2-(4-fluorophenyl)-N-methyl-5-(3-(1-phenylcyclopropylcarbamoyl)phenyl)benzo[b]thiophene-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzo[b]thiophen-5-yl)benzoic acid (0.075 g, 0.154 mmol) and 1-phenylcyclopropanamine hydrochloride (0.038 g, 0.22 mmol). 1H NMR (500 MHz, DMSO-D6) δ ppm 9.36 (s, 1H), 8.41 (d, J=4.58 Hz, 1H), 8.22 (s, 1H), 8.17 (d, J=8.24 Hz, 1H), 7.98 (d, J=1.53 Hz, 1H), 7.93 (d, J=7.63 Hz, 1H), 7.89 (d, J=7.94 Hz, 1H), 7.83 (dd, J=8.39, 1.68 Hz, 1H), 7.66-7.68 (m, 1H), 7.65 (d, J=5.19 Hz, 1H), 7.61 (t, J=7.78 Hz, 1H), 7.37 (t, J=8.70 Hz, 2H), 7.29 (t, J=7.63 Hz, 2H), 7.22-7.26 (m, 2H), 7.15-7.19 (m, 1H), 2.77 (d, J=4.58 Hz, 3H), 1.31 (d, J=11.90 Hz, 4H). LCMS: retention time: 3.250 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 521 (MH+).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][C:29]1[CH:30]=[C:31]([CH2:34][N:35]2[CH2:55][CH2:54][C:38]3([O:43][CH2:42][CH2:41][N:40]([C:44]([C:46]4[N:47]=[C:48]([CH:51]([CH3:53])[CH3:52])[S:49][CH:50]=4)=[O:45])[CH2:39]3)[CH2:37][CH2:36]2)[S:32][CH:33]=1)(C(C)(C)C)(C)C>O1CCCC1>[OH:26][CH2:27][CH2:28][C:29]1[CH:30]=[C:31]([CH2:34][N:35]2[CH2:55][CH2:54][C:38]3([O:43][CH2:42][CH2:41][N:40]([C:44]([C:46]4[N:47]=[C:48]([CH:51]([CH3:52])[CH3:53])[S:49][CH:50]=4)=[O:45])[CH2:39]3)[CH2:37][CH2:36]2)[S:32][CH:33]=1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(CCO[Si](C)(C)C(C)(C)C)cs4)CC3)C2)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(CCO)cs4)CC3)C2)cs1
Reaction time: 1 h

Procedure:
Tetrabutylammonium fluoride (1M in tetrahydrofuran, 2 mL) was added to a solution of (9-((4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 36, step a) (0.27 g) in tetrahydrofuran (4 mL). After 1 h, the solution was evaporated in vacuo. Purification by silica gel chromatography eluting with ethyl acetate:triethylamine, 20:1 gave the subtitled compound as a gum. Yield 0.18 g.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([S:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:8]2[CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[N:48]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:46][C:47]4[CH:56]=[CH:55][C:54]5[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=5)[N:48]=4)=[CH:13][CH:14]=3)[C:9]([S:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:8]2[CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methyl 3-[N-(p-chlorobenzyl)-5-hydroxy-3-(t-butylthio)indol-2-yl]-2,2-dimethylpropanoate (33.6 g) from Step C was dissolved in 500 mL of dry DMF and the solution was charged with 2.4 g of KI, 30.3 g of K2CO3, 4.77 g of Cs2CO3 and 23.5 g of 2-(chloromethyl)quinoline hydrochloride. The reaction was stirred at RT, under N2, for 72 hours then it was poured into water (1.5L), acidified with 1N HC1 and extracted (3×200 mL) with CH2C12. The organic phase was washed with H2O (3×150 mL), dried and evaporated. The residue was dissolved in hot EtOAc and upon cooling crystallized to deposit 22.0 g of the title compound, m.p. 166°-167° C.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][O:10][C:6]=2[CH:5]=[N:4][N:3]=1.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.C(N(CC)CC)C>C(O)C.C(=O)(O)[O-].[Na+]>[C:11]1([C:8]2[C:7]3[C:2]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[N:3][N:4]=[CH:5][C:6]=3[O:10][N:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Clc1nncc2onc(-c3ccccc3)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CNc2nncc3onc(-c4ccccc4)c23)CC1
Temperature: 80 °C
Yield: 88.5 %

Procedure:
The compound prepared in Example 82 (202 mg), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.266 g) and triethylamine (0.607 mL) were combined in ethanol (1.5 mL) and heated at 80° C. for 17 hours. The reaction mixture cooled to room temperature, diluted with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1 to 2:1) to obtain the title compound (316 mg) having the following physical data.
Reaction SMILES: C(=O)([O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][CH:21]=[N:20]3)=[O:16])[C:9]=1[F:27])OC(C)(C)C>Cl.O1CCOCC1>[F:27][C:9]1[C:8]([OH:7])=[CH:13][CH:12]=[C:11]([F:14])[C:10]=1[C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[N:20]2)=[O:16]
Reactant: CC(C)(C)OC(=O)Oc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1F
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1ccc2nccnc2c1)c1c(F)ccc(O)c1F
Yield: 77.6 %

Procedure:
A solution of tert-butyl (2,4-difluoro-3-(quinoxaline-6-carbonyl)phenyl) carbonate (1.06 g, 2.7 mmol, 1.0 eq.) in HCl/dioxane (2.5 N, 50 mL) was stirred at rt overnight, then concentrated. The residue was suspended in NaHCO3 solution, extracted with EA (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified via flash column chromatography (PE/EA=2/1,v/v) to afford (2,6-difluoro-3-hydroxyphenyl) (quinoxalin-6-yl)methanone as a brown solid (600 mg, 77.7%). LRMS (M−H+) m/z calculated 285.1, found 285.0. 1H NMR (DMSO-d6, 400 MHz) δ 10.34 (s, 1 H), 9.09-9.12 (dd, 2 H), 8.39 (s, 1 H), 8.31-8.31 (d, 1 H), 7.14-7.27 (m, 2 H).
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:11]([C:18]1[O:19]CC(C)(C)[N:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S(=O)(=O)(O)[O-].[Na+].CN1CCCC1=O>O.C1(C)C(C)=CC=CC=1>[Cl:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18](=[O:19])[NH:22]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC1(C)COC(Cc2ccccc2)=N1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1C
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2cc1-c1ccccc1

Procedure:
17.5 g of 2,4-dichlorobenzaldehyde, 18.9 g of 2-benzyl-4,4-dimethyl-2-oxazoline, 1 g of sodium bisulphate, 50 ml of 1-methylpyrrolidin-2-one and 30 ml of xylene are heated at a bath temperature of 170° C., using a water separator, until 2 ml of water have been separated off. 20 ml of solvent are then distilled off at a bath temperature of 220° C., the mixture is stirred under reflux at this temperature for a further 15 minutes and, after cooling, 300 ml of water are added. The precipitate which has separated out is filtered off and washed with water and methanol. Yield: 21.26 g of m. 254°-258° C.