Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17]Cl)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(=O)(O)[O-:21].[Na+]>O1CCCC1.O>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17][OH:21])[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CO)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.5 %

Procedure:
To a suspension of 2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (20.0 g, 73 mmol) in a mixture of tetrahydrofuran and water (180 g, 5:1) sodium bicarbonate (9.2 g, 110 mmol) is added. The reaction mixture is stirred at room temperature for 5 hours and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:4) to yield 9.6 g of 2-(2H-Benzotriazol-2-yl)-6-hydroxymethyl-4-methyl-phenol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]([C:8]1[C:9]([C:15]([F:18])([F:17])[F:16])=[N+:10]([O-:14])[CH:11]=[CH:12][CH:13]=1)=[O:7])[CH3:2].Br[CH2:21][C:22]([C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[C:27]([O:33][CH3:34])=[C:26]([O:35][CH3:36])[CH:25]=1)=O.Cl>N1C=CC=CC=1>[CH3:36][O:35][C:26]1[CH:25]=[C:24]([C:22]2[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:19])=[C:6]([C:8]3[C:9]([C:15]([F:17])([F:16])[F:18])=[N+:10]([O-:14])[CH:11]=[CH:12][CH:13]=3)[O:7][CH:21]=2)[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[C:27]=1[O:33][CH3:34]
Reactant: COc1cc(C(=O)CBr)cc([N+](=O)[O-])c1OC
Reactant: CCOC(=O)CC(=O)c1ccc[n+]([O-])c1C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(-c2cc(OC)c(OC)c([N+](=O)[O-])c2)coc1-c1ccc[n+]([O-])c1C(F)(F)F
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 3-(3-ethoxy-3-oxopropanoyl)-2-(trifluoromethyl)pyridine-1-oxide (1.39 g, 5 mmol) in pyridine (25 mL) was added 2-bromo-1-(3,4-dimethoxy-5-nitrophenyl)ethanone (1.67 g, 5.5 mmol). The reaction mixture was heated to 70° C. and stirred for 5 hours, then cooled to room temperature and poured onto 6 N aqueous HCl (100 mL). The precipitate was filtered off, washed with water and dried over P2O5 under vacuum. The solid was recrystallised from dichloromethane/ispropanol to give crude 3-(4-(3,4-dimethoxy-5-nitrophenyl)-3-(ethoxycarbonyl)furan-2-yl)-2-(trifluoromethyl)pyridine 1-oxide, 1.05 g (43%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([Br:19])=[CH:14][N:13]=2)=[CH:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C.O1CCCC1>[Br:19][C:15]1[CH:16]=[C:17]([CH3:18])[C:12]([C:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH:8]=2)=[N:13][CH:14]=1
Reactant: CCOC(=O)C1CC=C(c2ncc(Br)cc2C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(Br)cnc1C1=CCC(C(=O)O)CC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
To a solution of [4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]carboxylic acid ethyl ester (8.57 g) in ethanol (26 ml) and tetrahydrofuran (26 ml) was added 2N aqueous solution of sodium hydroxide (52 ml) at room temperature, and stirred at 70° C. for 1 hour. After completion of the reaction, the mixture was cooled to room temperature, and extracted with diethyl ether. To the obtained aqueous layer was added 1 N hydrochloric acid aqueous solution under ice-cooling, and the precipitated solid was collected by filtration to give [4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]carboxylic acid (5.37 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([CH:16]=O)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[BH4-].[Na+]>C(O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([CH2:16][NH:2][CH3:1])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)(c2ccc(Cl)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CNCC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A mixture of methylamine in ethanol (18 ml, 33% in ethanol) and 4-(4-chlorophenyl)-4-formyl-piperidine-1-carboxylic acid tert-butyl ester (206 mg, 0.62 mmol) was stirred at room temperature overnight. The solvents were concentrated. The crude material was redissolved in methanol (18 ml) followed by addition of sodium borohydride (49 mg, 1.29 mmol). After stirring for 40 minutes at room temperature, the mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogen carbonate (100 ml). After separation of the two phases the aqueous phase was re-extracted with ethyl acetate (100 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated. Flash column chromatography on silica, eluting with 10% methanol in dichloromethane gave 4-(4-chloro-phenyl)-4-methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester (142 mg, 0.42 mmol, 68%). GC-MS m/z 239 [(M-Boc)+], Rt 5.18 min. 1H NMR (250 MHz, CDCl3): 1.43 (9H, s), 1.80-1.88 (2, m), 2.15-2.24 (2, m), 2.31 (3H, s), 2.81 (2H, s), 2.98-3.09 (2H, m), 3.72-3.78 (2H, m), 7.32 (2H, d, 9 Hz), 7.38 (2H, d, 9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C@@H:14]3[CH2:18][S:17](=[O:20])(=[O:19])[CH2:16][C@H:15]3[NH2:21])[CH2:8]2)=[CH:4][CH:3]=1.[ClH:24].[N+](C1C=CC([O:34][C:35](=O)[NH:36][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=CC=1)([O-])=O.C(N(CC)CC)C>CN(C)C=O>[ClH:24].[ClH:24].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][C@@H:14]3[CH2:18][S:17](=[O:19])(=[O:20])[CH2:16][C@H:15]3[NH:21][C:35]([NH:36][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:34])[CH2:8]2)=[CH:22][CH:23]=1
Reactant: N[C@@H]1CS(=O)(=O)C[C@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1
Reactant: O=C(NCCN1CCOCC1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCN1CCOCC1)N[C@@H]1CS(=O)(=O)C[C@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 67 h
Yield: 149.9 %

Procedure:
(3S,4S)-4-[(S)-3-(4-fluorobenzyl)-piperidin-1-ylmethyl]-1,1-dioxo-tetrahydrothiophen-3-ylamine (47 mg, 137 μmol) and (2-morpholin-4-yl-ethyl)-carbamic acid 4-nitro-phenyl ester hydrochloride (55 mg, 164 μmol) were dissolved in N,N-dimethylformamide (1 mL) and treated with triethylamine (23 μL, 164 μmol). The mixture was stirred at room temperature for 67 h, and then concentrated. The residue was purified by flash column chromatography (3% methanol/dichloromethane containing 0.3% aqueous ammonium hydroxide). After isolation, the product was dissolved in 1N hydrochloric acid and water and lyophilized to provide a fluffy white solid (70 mg, 90%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:16]4=[O:23])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1.CC1(C)C(C)(C)OB([C:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH:34]=2)O1>>[CH3:20][C:19]1([CH3:21])[N:15]([C:13]2[S:14][C:10]3[CH2:9][CH2:8][O:7][C:6]4[CH:24]=[C:2]([C:33]5[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH:34]=5)[CH:3]=[CH:4][C:5]=4[C:11]=3[N:12]=2)[C:16](=[O:23])[NH:17][C:18]1=[O:22]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)OCCc2sc(N4C(=O)NC(=O)C4(C)C)nc2-3)CC1
Yield: 19 %

Procedure:
1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dione was coupled with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate to give tert-butyl 4-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-8-yl)-5,6-dihydropyridine-1(2H)-carboxylate. Yield 19%. MS(ESI+): 511.3
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[F:31][C:32]1[CH:33]=[C:34]([NH:38][CH3:39])[CH:35]=[CH:36][CH:37]=1>>[F:31][C:32]1[CH:33]=[C:34]([N:38]([CH3:39])[C:26]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)=[O:25])[CH:35]=[CH:36][CH:37]=1
Reactant: CNc1cccc(F)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: CN(C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O)c1cccc(F)c1

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and (3-Fluoro-phenyl)-methyl-amine. MS (ESI): 466.4 (MH+).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[O:17]=[C:18]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH:19]=[CH:20][CH3:21]>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH:20]([CH3:21])[CH2:19][C:18]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:17])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC=CC(=O)N1CCCC1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CO
Product: CC(CC(=O)N1CCCC1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
Following the procedure of Example 4, 2,6-bis(1,1-dimethylethyl)4-mercaptophenol (2.0 g. 0.008 mole) and 1(1-oxo-2-butenyl)pyrrolidine (1.11 g, 0.008 mole) were dissolved in methanol (20 ml) under an argon atmosphere and refluxed for 24 hours. The solvent was removed and the product isolated by chromatography on silica, and recrystallized from hexane to yield the product as a white solid, m.p. about 95°-99° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[F:20][C:21]1[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[CH:24][C:22]=1[NH2:23]>CC(O)CCC>[ClH:2].[F:20][C:21]1[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[CH:24][C:22]=1[NH:23][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COCCOc1cc2nccc(Cl)c2cc1OC
Agent: Cl
Solvent: CCCC(C)O
Product: COCCOc1cc2nccc(Nc3cc(O)c(C)cc3F)c2cc1OC
Yield: 50.1 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinoline hydrochloride (304 mg, 1 mmol), (prepared as described for the starting material in Example 5), 2-fluoro-5-hydroxy-4-methylaniline (155 mg, 1.1 mmol), (prepared as described for the starting material in Example 1), in 2-pentanol (15 ml) was heated at reflux for 15 hours. The precipitate was collected by filtration, washed with isopropanol and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)quinoline hydrochloride (205 mg, 50%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[OH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]2[C@H:19]3[C@H:29]([CH2:30][CH2:31][C@:14]12[CH3:15])[C@:27]1([CH3:28])[C:22]([C:23]([CH3:34])([CH3:33])[C:24](=[O:32])[CH2:25][CH2:26]1)=[CH:21][CH2:20]3.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:9]1[C@H:21]2[CH2:20][C@@H:19]3[C@@H:29]([C@@:27]4([CH3:28])[CH2:26][CH2:25][C:24](=[O:32])[C:23]([CH3:34])([CH3:33])[C@:22]124)[CH2:30][CH2:31][C@@:14]1([CH3:15])[C@H:16]3[CH2:17][CH2:18][C@@H:13]1[OH:12]
Reactant: CC1(C)C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3C[C@@H]3O[C@]312
Reaction time: 8 h
Yield: 21.9 %

Procedure:
mCPBA (1.17 g) was added to a stirred solution of 17β-hydroxy-4,4-dimethylandrost-5-en-3-one (1.00 g) in DCM (30 ml). After 8 h at RT, a 10% Na2SO3 aqueous solution was added. The mixture was neutralized by addition of 5% aqueous NaHCO3 solution and was extracted with DCM (3×100 ml). The combined organic extracts were washed with H2O, dried over Na2SO4, and evaporated to dryness. The mixture was purified by flash chromatography (SiO2, n-hexane/EtOAc 70/30) to give 5α,6α-epoxy-4,4-dimethyl-17β-hydroxyandrostan-3-one (230 mg, 23%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[OH-:15].[K+].[Mn]([O-])(=O)(=O)=[O:18].[K+]>O>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[C:8]([OH:18])=[O:15]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccc(C(=O)C(C)(C)C)cc1F
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)C(=O)c1ccc(C(=O)O)c(F)c1

Procedure:
A mixture of 16.5 g. (0.085 mole) of 3'-fluoro-2,2,4'-trimethyl propiophenone, 30.0 g. (0.532 mole) potassium hydroxide and 150 ml. H2O is treated with 26.7 g. (0.170 mole) of potassium permanganate in 150 ml. of water. The resulting mixture is refluxed for 4 1/2 hours. The cooled mixture is then treated with 5 ml. ethanol and filtered. The aqueous solution is extracted with ether and then acidified with concentrated hydrochloric acid. The resulting solid is washed with water and suspended in methylene chloride and then filtered. The methylene chloride filtrate is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give o-fluoro-4-pivaloyl benzoic acid.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([CH:16]=[CH:17][CH:18]=O)=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[O:22]1[CH2:26][C:25](=[O:27])[NH:24][C:23]1=[O:28].N1CCCCC1.C(O)C>O1CCCC1>[CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([CH2:16][CH2:17][CH2:18][CH:26]2[O:22][C:23](=[O:28])[NH:24][C:25]2=[O:27])=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C1COC(=O)N1
Reactant: CN(CCOc1ccc(C=CC=O)cc1)c1ccccn1
Solvent: C1CCOC1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(CCOc1ccc(CCCC2OC(=O)NC2=O)cc1)c1ccccn1
Yield: 21 %

Procedure:
A mixture of 4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]cinnamaldehyde (4.00 g), 2,4-oxazolidinedione (2.86 g), piperidine (0.60 g) and ethanol (50 ml) was heated for 2 hours under reflux. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography. Fractions eluted with ethyl acetate-chloroform (1:4) gave crystals. The crystals were dissolved in tetrahydrofuran (100 ml). To the solution was added palldium-carbon (5%, 1.40 g). The mixture was subjected to catalytic hydrogenation at room temperature under atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. From the fractions eluted with chloroform-methanol (100:2), 5-[3-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]phenyl]propyl]-2,4-oxazolidinedione (1.10 g, 21%) was obtained. Recrystallization from dichloromethane-isopropylether gave colorless prisms. Melting point: 126-127° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([N:14](CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][C:12]#[N:14])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCc1cccc(Br)c1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: N#CCCCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-(3-Bromophenyl)propane-1-ol (0.59 g), triethylamine (0.57 mL) and 4-dimethylaminopyridine (0.03 g) were dissolved in dichloromethane (6.8 mL), p-toluenesulfonyl chloride (0.62 g) was added, and the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was partitioned between ethyl acetate (35 mL) and 10% aqueous citric acid (10 mL) The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylsulfoxide (9.1 mL), sodium cyanide (0.17 g) was added, and the resulting mixture was stirred at 50° C. for 24 hours. The reaction mixture was partitioned between ethyl acetate (55 mL) and water (30 mL) The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.59 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:35]=[CH:34][C:20]([C:21]([N:23]([CH3:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][NH:31][CH3:32])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C=O.[C:38]([BH3-])#N.[Na+]>CO.C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH2:30][N:31]([CH3:38])[CH3:32])=[O:22])=[CH:34][CH:35]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: [BH3-]C#N
Reactant: CNCc1ccccc1N(C)C(=O)c1ccc(NC(=O)c2ccccc2-c2ccc(C)cc2)cc1
Agent: C=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3CN(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41 %

Procedure:
To a solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-methylaminomethylphenyl)benzamide (154 mg) in a mixture of methanol (10 ml) and acetic acid (0.5 ml) were added aqueous formaldehyde (0.2 ml) and sodium cyanoborohydride (20.9 mg) and the solution was stirred at ambient temperature for 4 hours. The mixture was diluted with chloroform and the solution was washed with saturated aqueous sodium hydrogen carbonate and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give crude oil. The oil was purified by silica gel column (10 g, 2% methanol in chloroform) and the product was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-dimethylaminomethylphenyl)benzamide (65 mg) as a white powder.
Reaction SMILES: [OH-].[K+].Cl.[CH3:4][NH:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.Cl>O.C1COCC1.C(Cl)Cl>[CH3:4][N:5]([S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:24])[F:25])[CH:15]=1)(=[O:22])=[O:21])[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CNCCCC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CN(CCCC(=O)O)S(=O)(=O)c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To a solution of KOH (16.5 g, 294 mmol) in H2O (75 ml) was added 4-(methylamino)butyric acid hydrochloride (10, 15.1 g, 98.1 mmol) and the reaction mixture was cooled with an icebath. A solution of 3-(trifluoromethyl)benzenesulfonyl chloride (9, 12.0 g, 49.1 mmol) in THF (75 ml) was dropwise added to the reaction mixture and stirring was continued at room temperature overnight. Aqueous 6 M HCl (75 ml) was added to the reaction mixture while cooling with an icebath, after which CH2Cl2 was added. The organic layer was separated, washed with brine, dried (Na2SO4), concentrated and co-evaporated with a minimal amount of Et2O. Crystallization of the residue out of EtOAc/heptane resulted in AC-08 (11.32 g, 71%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:27]([CH3:29])[CH3:28])=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:24])[F:23])[CH:16]=1)=[CH:12][C:11]([Cl:26])=[CH:10][CH:9]=2)=[O:4].[I-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1.O.C(OCC)(=O)C>[Cl:26][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([CH:27]([CH3:28])[CH3:29])[C:5]([C:3]([OH:4])=[O:2])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:24])([F:23])[F:25])[CH:16]=1
Reactant: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1-c1cccc(OC(F)(F)F)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1nc2ccc(Cl)cc2c(-c2cccc(OC(F)(F)F)c2)c1C(=O)O
Yield: 51.7 %

Procedure:
To the stirred solution of 6-chloro-2-isopropyl-4-(3-trifluoromethoxy-phenyl)-quinoline-3-carboxylic acid methyl ester (50 mg, 0.118 mmol) in 3 ml of pyridine under nitrogen was added lithium iodide (158 mg, 1.18 mmol) at RT. Then the reaction mixture was refluxed for 16 h. Volatiles were removed under vacuo to afford a crude residue which was diluted with water and ethyl acetate. The organic phase was discarded and the aqueous layer was made acidic to pH 3 with 10% aqueous citric acid under cooling. The aqueous phase was then extracted with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by prep TLC (mobile phase: 5% MeOH in DCM) to afford 6-chloro-2-isopropyl-4-(3-trifluoromethoxy-phenyl)-quinoline-3-carboxylic acid (25 mg, 52%) as an off white solid. LC-MS: 410 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=4[Cl:28])[C:22](O)=[O:23])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:60][NH:61][CH2:62][CH2:63][OH:64]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([C:22](=[O:23])[N:61]([CH2:62][CH2:63][OH:64])[CH3:60])[CH:25]=[CH:26][C:27]=4[Cl:28])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1
Reactant: CNCCO
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)O)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CN(CCO)C(=O)c1ccc(Cl)c(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c1
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a mixture of 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoic acid (3 g, 6.09 mmol) in THF (50 mL) was added EDCI (2.34 g, 12.18 mmol), HOBt (1.23 g, 9.13 mmol), DIPEA (5 mL) and 2-(methylamino)ethanol (0.69 g, 9.13 mmol) by sequence under nitrogen atmosphere at room temperature. The reaction mixture was stirred overnight, diluted with water. The resulting precipitate was washed with water and EtOAc to give 8-bromo-N-(2-chloro-5-((2-hydroxyethyl)(methyl)carbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (2.8 g, yield: 87%). LC-MS: (ESI, m/z)=549 [M+H]+