Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.[CH3:19][O:20][CH:21]([O:27]C)[CH2:22][C:23](OC)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4]1[C:3]2[C:2](=[C:16]([CH3:17])[CH:15]=[C:14]([CH3:18])[CH:13]=2)[N:1]=[CH:23][C:22]=1[C:21]([O:20][CH3:19])=[O:27]
Reactant: Cc1cc(C)c(N)c(C(=O)c2ccccc2Cl)c1
Reactant: COC(=O)CC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1cnc2c(C)cc(C)cc2c1-c1ccccc1Cl
Yield: 58.5 %

Procedure:
A mixture of 2-amino-2'-chloro-3,5-dimethylbenzophenone (2.59 g), methyl 3,3-dimethoxypropionate (3.7 g), p-toluenesulfonic acid hydrate (0.19 g) and benzene (30 ml) was refluxed for 16 hrs., with removal of water by a Dien-Stark apparatus. The mixture was distilled to remove the solvent, and the residue was purified by a column chromatography on silica gel to give methyl 4-(2-chlorophenyl)-6,8-dimethyl-3-quinolinecarboxylate as crystals (1.90 g, 58.5%), which was recrystallized from isopropyl ether as colorless prisms. m.p. 117°-118° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[C:10]([CH3:14])([CH3:13])[C:11]#[N:12].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:10]([CH3:14])([CH3:13])[C:11]#[N:12]
Reactant: COc1ccc(C(C)(C)C#N)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-(2-Fluoro-4-methoxy-phenyl)-2-methyl-propionitrile (1.5 g, 7.8 mmol) in CH2Cl2 (75 mL) at −78° C. was added Boron tribromide (1M solution in CH2Cl2) (16 mL, 16 mmol). The solution was allowed to warm to room temperature and stir for 48 hours. The reaction was quenched with 0.5N HCl (50 mL) and poured into water (100 mL). The organic layer was separated and the aqueous was extracted with CH2Cl2 (50 mL). The combined organics were washed with water (100 mL), dried over Na2SO4, filtered and concentrated. The resulting oil was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([O:9][CH2:10][C@@H:11]2[CH2:15][CH2:14]C[NH:12]2)[CH:6]=[N:7][CH:8]=1)=[CH2:2].[ClH:16].CO>CCOCC>[ClH:16].[ClH:16].[NH:12]1[CH2:14][CH2:15][C@H:11]1[CH2:10][O:9][C:5]1[CH:6]=[N:7][CH:8]=[C:3]([CH:1]=[CH2:2])[CH:4]=1
Reactant: C=Cc1cncc(OC[C@@H]2CCCN2)c1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: C=Cc1cncc(OC[C@@H]2CCN2)c1

Procedure:
To a solution of 5-ethenyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine in Et2O was added hydrogen chloride (1.0 M in Et2O) carefully to afford the tittle compound: mp 88-90° C. 1H NMR (D2O) δ 2.64-2.78 (m, 2H), 4.04-4.22 (m, 2H), 4.50 (d, 1H, J=4.0 Hz), 4.80 (m, 1H), 4.96 (m, 1H), 5.58 (dd, 1H, J=11.0 Hz), 6.04 (d, 1H, J=18.0 Hz), 6.83 (dd, 1H, J=11.0, 18.0 Hz), 7.85 (t, 1H, J=2.0 Hz), 8.31 (br s, 1H), 8.36 (br s, 1H); MS (CI/NH3) m/z 191 (M+H)+. Anal. Calcd for C11H14N2O.1.8 HCl: C, 51.64; H, 6.22; N, 10.95. Found: C, 51.59; H, 5.92; N, 10.75. [α]25D +2.58 (c 0.62, MeOH
Reaction SMILES: [CH3:1][C:2]1([C@@H:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[OH:6])[CH2:4][O:3]1.[CH2:17]([O:19][CH:20]=[CH2:21])[CH3:18].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.CCN(CC)CC>C(Cl)Cl>[CH2:17]([O:19][CH:20]([O:6][CH:5]([C@@:2]1([CH3:1])[CH2:4][O:3]1)[C:7]1[CH:8]=[CH:9][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][CH:12]=1)[CH3:21])[CH3:18]
Reactant: C=COCC
Reactant: CC1([C@H](O)c2ccc(S(C)(=O)=O)cc2)CO1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(C)OC(c1ccc(S(C)(=O)=O)cc1)[C@@]1(C)CO1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of the product from Step 4 (7.2 g) and ethylvinyl ether (50 mL) in 200 mL of CH2Cl2 cooled to 0° C. was added 50 mg of camphorsulfonic acid. The reaction mixture was stirred at r.t. for 20 min. and then treated with 1 mL of Et3N, concentrated to give the crude title compound (9 g).
Reaction SMILES: [C:1]1([N:7]2[N+:11]([O-])=[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>>[C:1]1([N:7]2[N:8]=[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]3=[N:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [O-][n+]1c2ccccc2nn1-c1ccccc1
Reactant: [H][H]
Product: c1ccc(-n2nc3ccccc3n2)cc1

Procedure:
A 2-phenylbenzotriazole-N-oxide which is the chosen starting material is dissolved in a solvent contained in a reaction vessel into which a hydrogenation catalyst and a basic substance are then placed. After the air in the reaction vessel has been replaced by hydrogen, a given amount of hydrogen is charged into the reaction vessel, and the reaction is then allowed to proceed under atmospheric pressure or a given pressure at a temperature of room temperature to 170° C. under agitation. After the reaction has been completed, the catalyst is filtered off, the solvent layer is washed with water, and the solvent is distilled off. The crude product is then purified by recrystallization to obtain the corresponding 2-phenylbenzotriazole as a pure product.
Reaction SMILES: Cl.Cl.[O:3]1[CH2:7][CH2:6][C@H:5]([C@:8]2([C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)=[O:15])[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]2)[CH2:4]1.[CH3:32][O:33][CH:34]1[C:39](=O)[CH2:38][CH2:37][O:36][CH2:35]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:32][O:33][CH:34]1[C@H:39]([NH:13][C@@H:10]2[CH2:11][CH2:12][C@:8]([C@H:5]3[CH2:6][CH2:7][O:3][CH2:4]3)([C:14]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=4)[CH2:20][CH2:21]3)=[O:15])[CH2:9]2)[CH2:38][CH2:37][O:36][CH2:35]1
Reactant: N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)([C@H]2CCOC2)C1
Reactant: COC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1COCC[C@H]1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)([C@H]2CCOC2)C1
Temperature: 25 °C
Yield: 25 %

Procedure:
To a solution of (1R,3S)-3-[(3R)-tetrahydrofuran-3-yl]-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (73.8 mg, 0.152 mmol), 3-methoxytetrahydro-4H-pyran-4-one (59.4 mg, 0.456 mmol) and triethylamine (0.0848 mL, 0.608 mmol) in dry methylene chloride (4.1 mL) was added sodium triacetoxyborohydride (96.7 mg, 0.456 mmol). After being stirred at room temperature under N2, the reaction was quenched with aqueous NaHCO3 and diluted with CH2Cl2. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 three times. The organics were combined, dried over MgSO4, filtered, concentrated and purified by silica gel chromatography (Combi-Flash system, 0 to 40% MeOH in EtOAc, gradient, 12 gram column) to provide the desired product (20 mg, 41%). MS calculated for C26H37F3N4O4: (M+H) 527.3; found 527.3.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].C(N(CC)CC)C>CS(C)=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:25]2[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=2)[N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3[nH]ncc3c2)nc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(-n2ncc3cc(Oc4ccc([N+](=O)[O-])cn4)ccc32)cc1
Reaction time: 72 h

Procedure:
To a solution of 5-(5-Nitro-pyridin-2-yloxy)-1H-indazole (1.0 g, 3.9 mmol) in 15 mL of DMSO is added copper (II) acetate (0.71 g, 3.9 mmol), powdered 4A molecular sieves (0.2 g), 4-cyanophenylboronic acid (4.3 mmol) and triethylamine (2.7 mL, 20 mmol). The resulting mixture is stirred under an oxygen atmosphere for 3 days. After filtering through a plug of Celite and silica gel, the mixture is concentrated in vacuo, adsorbed to silica gel, and purified by column chromatography eluting with 0-20% ethyl acetate-hexanes, affording 4-[5-(5-Nitro-pyridin-2-yloxy)-indazol-1-yl]-benzonitrile.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[NH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:20]([O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27](F)=[CH:26][C:25]=1[O:31][CH2:32][O:33][CH3:34])[CH3:21].O>CN(C)C=O>[CH2:20]([O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27]([N:5]2[C:6]3[C:11](=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=3)[C:3]([C:1]#[N:2])=[CH:4]2)=[CH:26][C:25]=1[O:31][CH2:32][O:33][CH3:34])[CH3:21]
Reactant: N#Cc1c[nH]c2cc(F)c(F)cc12
Reactant: CCOC(=O)c1ccc(F)cc1OCOC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(F)c(F)cc32)cc1OCOC
Temperature: 75 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
To a solution of 3-cyano-5,6-difluoroindole (0.25 g) in N,N-dimethylformamide (10 mL) were added cesium carbonate (0.91 g), 4-fluoro-2-methoxymethoxybenzoic acid ethyl ester (0.32 g), and this mixture was stirred at 75° C. overnight. This reaction mixture was poured into water, and this resulting mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=10/90-75/25) to give the title compound (0.12 g).
Reaction SMILES: [CH:1]([Si:4]([O:11][C:12](=[O:52])[N:13]([C@H:40]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41]1)[CH2:14][CH2:15][C:16]1[N:17]=[CH:18][N:19](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:20]=1)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[C:53]([C:55]1[CH:62]=[CH:61][C:58]([CH2:59]O)=[CH:57][C:56]=1[F:63])#[N:54].C(N(CC)C(C)C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[CH:1]([Si:4]([O:11][C:12](=[O:52])[N:13]([C@H:40]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[CH2:41]1)[CH2:14][CH2:15][C:16]1[N:17]([CH2:59][C:58]2[CH:61]=[CH:62][C:55]([C:53]#[N:54])=[C:56]([F:63])[CH:57]=2)[CH:18]=[N:19][CH:20]=1)([CH:5]([CH3:6])[CH3:7])[CH:8]([CH3:10])[CH3:9])([CH3:3])[CH3:2]
Reactant: CC(C)[Si](OC(=O)N(CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)[C@H]1CCN(C(=O)OC(C)(C)C)C1)(C(C)C)C(C)C
Reactant: N#Cc1ccc(CO)cc1F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[Si](OC(=O)N(CCc1cncn1Cc1ccc(C#N)c(F)c1)[C@H]1CCN(C(=O)OC(C)(C)C)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (S)-N-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-N-{2-[1-(triphenylmethyl)-1H-imidazol-4-yl]ethyl}carbamic acid triisopropylsilyl ester, as described above in Step F, (519 mg, 0.715 mmol) and 4-cyano-3-fluoro-benzyl alcohol, as described in Example 31, Step H, (108 mg, 0.715 mmol) in CH2Cl2 (7 mL) was added N,N-diisopropylethylamine (0.311 mL, 1.78 mmol), followed by dropwise addition of trifluoromethanesulfonic anhydride (0.120 mL, 0.715 mmol). The reaction mixture was allowed to warm slowly to ambient temperature and was stirred for 18 hours, then concentrated in vacuo. The residue was dissolved in MeOH (10 mL) and the resulting solution was heated to 40° C. for 2 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel, eluting with a gradient of CH2Cl2—1% to 4% MeOH—0.1% to 0.4% NH4OH, to yield the above-titled compound.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:8])([F:7])[F:1])(=[O:19])=[O:18]
Reactant: OCCCC(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCC(F)(F)F
Reaction time: 0.5 h
Yield: 988 %

Procedure:
A stirred solution of 4,4,4-trifluorobutanol (35 g; 0.027 mol) and triethylamine (28.3 g; 0.280 mol) in 200 ml of dichloromethane was treated dropwise at 0° C. with a solution of methanesulphonyl chloride (32.1 g; 0.280 mol) in 100 ml of dichloromethane. After the end of the addition, the mixture was stirred for a further 30 min, then poured onto ice and the phases were subsequently separated. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. 55 g of crude 4,4,4-trifluorobutyl methanesulphonate were obtained as an orange oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[O:12])[C:4]=2[N:3]=[N:2]1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25]>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10](=[CH:23][N:24]([CH3:26])[CH3:25])[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[O:12])[C:4]=2[N:3]=[N:2]1
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1cccc2[nH]nnc12)c1ccc(Cl)cc1Cl
Product: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1cccc2[nH]nnc12

Procedure:
2-benzotriazolyl-1-(2,4-dichlorophenyl)ethan-1-one was dissolved in dimethyl-formamide dimethyl acetal (5 mL) and the solution refluxed for 8 h. Evaporation of the solvent gave 2-benzotriazolyl-1-(2,4-dichlorophenyl)-3-(dimethylamino)prop-2-en-1-one as an air sensitive red solid which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[F:23].FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[F:23]
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(Cl)c(F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(Cc2ccc(Cl)c(F)c2)CC1
Reaction time: 2 h
Yield: 39.2 %

Procedure:
tert-Butyl 1-(4-chloro-3-fluorobenzyl)-4-piperidinylcarbamate (1.80 g) in dichloromethane (20 ml) was stirred under nitrogen. Trifluoroacetic acid (5 ml) was then added dropwise and the reaction was left to stir for 2 hours. 1M sodium hydroxide was added to the reaction until basic, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. Product purified by chromatography (5% ethanol/dichloromethane to 10% ethanol/dichloromethane) and solvent removed under reduced pressure to leave an oil which crystallised over the period of 48 hours. The resulting solid was triturated with diethyl ether and filtered to leave 1-(4-chloro-3-fluorobenzyl)-4-piperidinamine (0.500 g) as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14]([O:16]C(C)(C)C)=[O:15])[CH2:3]1.[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[C:21]([OH:27])=[O:22].[CH3:1][C@@H:2]1[CH2:6][NH:5][C@H:4]([C:14]([OH:16])=[O:15])[CH2:3]1
Reactant: C[C@H]1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN[C@H](C(=O)O)C1
Reaction time: 2 h

Procedure:
To di(tert-butyl) (2S,4S)-4-methylpyrrolidine-1,2-dicarboxylate (Ref: J. Amer. Chem. Soc., 1996, 118, 36, 8700–8706, 2.4 g, 8.42 mmol) in CH2Cl2 (15 mL) was added TFA (15 mL) and the reaction was stirred for 2 hours. The reaction was concentrated in vacuo and re-dissolved in CH2Cl2 (15 mL), TFA (15 mL) was added and the reaction was stirred for 1 hour. The reaction was concentrated in vacuo to afford (4S)-4-methyl-L-proline trifluoroacetate and used directly in the next step.
Reaction SMILES: C([Li])CCC.[C:6]1([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:17]1([CH:23]([CH3:26])[CH:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>CCCCCC.O1CCCC1>[C:17]1([CH:23]([CH3:26])[CH:24]([C:14]2[S:13][C:12]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:16][CH:15]=2)[OH:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C=O)c1ccccc1
Reactant: c1ccc(-c2cccs2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(c1ccccc1)C(O)c1ccc(-c2ccccc2)s1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
Under a nitrogen atmosphere 13.7 mL of a 2.6M solution of n-butyllithium in n-hexane was added to a cold (-78° C.) stirred solution of 5.2 grams (0.0325 mole) of 2-phenylthiophene in 61 mL of tetrahydrofuran. This mixture was stirred at -78° C. for 1.5 hours. To this cold mixture was added 2-phenylpropionaldehyde (4.6 gram, 0.0336 mole), and the mixture was stirred for 15 minutes. The mixture was allowed to warm to room temperature and stir for two days. The mixture was cooled to 0° C., and approximately 45 mL of 1.2 N hydrochloric acid was added. The organic phase was separated from the aqueous phase and the aqueous phase, was extracted with chloroform. The chloroform extract was combined with the organic phase and washed with an aqueous, ammonium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with ethyl acetate:n-hexane (10:90), to yield 9.2 g of 2-phenyl-1-(5-phenylthien-2-yl)-1-propanol as an oil.
Reaction SMILES: F.[Si]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][C:18]3[C:24]([CH:25]=[CH2:26])=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:12][C:11]=1[F:27])(C(C)(C)C)(C)C.C1C[O:31]CC1.C(#N)C>O>[F:27][C:11]1[CH:12]=[C:13]([C:16]2[O:17][C:18]3[C:24]([CH:25]=[CH2:26])=[CH:23][C:22]([OH:31])=[CH:21][C:19]=3[N:20]=2)[CH:14]=[CH:15][C:10]=1[OH:9]
Reactant: C=Cc1cccc2nc(-c3ccc(O[Si](C)(C)C(C)(C)C)c(F)c3)oc12
Reactant: C1CCOC1
Agent: F
Solvent: O
Solvent: CC#N
Product: C=Cc1cc(O)cc2nc(-c3ccc(O)c(F)c3)oc12
Temperature: 65 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Hydrofluoric acid (48 wt. % in water, 1 mL) was added into a solution of 5-{[tert-butyl)dimethyl)silyl]oxy}-2-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-fluorophenyl)-7-vinyl-1,3-benzoxazole (1.5 g, 3.0 mmol), THF (6 mL) and acetonitrile (3 mL). The reaction mixture was stirred at 65° C. for 8 h, and then poured into water. The precipitated solid was filtered oft and dried. Crystallization of the product from acetone/ethyl ether gave a white solid (0.72 g, 81% yield, m.p. 249-251° C.); MS m/e 272 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:19][C:20]([CH3:25])=[CH:21][C:22](Cl)=[O:23].O>C(Cl)(Cl)Cl>[CH3:19][C:20]([CH3:25])=[CH:21][C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)=[O:23]
Reactant: CC(C)=CC(=O)Cl
Reactant: CCCCCC(C(=O)OCC)c1ccc(N)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCC(C(=O)OCC)c1ccc(NC(=O)C=C(C)C)cc1
Temperature: 25 °C

Procedure:
10.4 g of (RS)-ethyl 2-(4-aminophenyl)-heptanoate dissolved in 100 ml of chloroform was treated dropwise with 4.64 ml of 3,3-dimethylacryloyl chloride. The mixture was heated to reflux for 6 hours. After cooling to room temperature, 100 ml of water were added. The phases were separated and the aqueous phase was extracted with two portions of 50 ml of chloroform. The combined organic extracts were washed with two portions of 100 ml of saturated aqueous sodium bicarbonate solution and one portion of 100 ml of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated in vacuo. The product was used without purification. 1H NMR (CDCl3): 7.48 (br. d, J=8.4 Hz, 2H), 7.39 (br. s, 1H), 7.24 (d, J=8.5 Hz, 2H), 5.71 (br. s, 1H), 4.20-4.00 (m, 2H), 3.48 (t, J=7.7 Hz, 1H), 2.21 (br. s, 3H), 2.15-1.95 (m, 1H), 1.87 (s, 3H), 1.80-1.65 (m, 1H), 1.35-1.15 (m, 6H), 1.20 (t, J=7.1 Hz, 3H), 0.85 (t, J=6.7 Hz, 3H).
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Cl[C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=1.Cl>C(O)C>[O:10]=[C:1]1[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]12
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: Nc1ccccc1C(=O)O
Agent: Cl
Solvent: CCO
Product: O=C(O)c1ccc2nc3ccccc3c(=O)n2c1
Yield: 44.5 %

Procedure:
A reaction mixture containing 4.35g (31.8 mmol) of anthranilic acid, 5.00g (31.8 mmol) of 6-chloronicotinic acid, 3ml of conc. HCl and 80ml of ethanol was heated at reflux for 21 hours. The mixture was cooled and filtered to give 3.40g (38.9%) of the expected product, mp. 323° -325° dec. The analytical sample was obtained by recrystallization from methanol-ether, mp. 323° -325° dec.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1)=[C:9]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([CH3:21])[CH:20]=1)=[C:9]2[CH2:23][CH2:24][N:25]([C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccncc3)c2c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccncc3)C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3.19 g (6.83 mmol) of 2-(3,5-dimethylphenyl)- 3-[2-[4-(pyridin-4-yl)butylamino] ethyl]-1H-indole-5-carboxylic acid ethyl ester in 25 mL of dry methylene chloride was stirred under nitrogen and cooled to -78° C. in a dry ice-acetone bath as 2.38 mL (1.76 g, 13.7 mmol) of N,N-diisopropylethylamine was added, followed by gradual addition of 3.4 mL (4.06 g; 23.7 mmol) of benzyl chloroformate by syringe, in portions. After about 2.5 hours, the solution was removed from the cooling bath and allowed to warm to room temperature. It was then partitioned between ethyl acetate and 5% potassium bisulfate aqueous solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (elution with a gradient of 0.5-10% methanol in methylene chloride) afforded a quantitative yield of the product as a yellow foam. 500 MHz 1H NMR was complex, owing to the existence of rotamers, but was consistent with the assigned structure. Mass spectrum (PB-NH3 /CI): m/e=604.3 (M+H).
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].[OH-].[Na+]>C1COCC1>[CH3:10][S:11]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)N1CCC(=O)CC1
Temperature: 29 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a stirred solution of 4-piperidone hydrate hydrochloride (40.00 g, 0.260 mol) and THF (320 ml) was added CH3SO2Cl (31.0 ml, 0.402 mol) and 15% aq. NaOH (156 ml) such that the temperature of the reaction mixture was maintained at 26-32° C. After this addition, the reaction mixture was stirred at RT for 2 hours and transferred to a separatory funnel. The organic layer was collected and the aqueous layer was extracted with THF (2×250 ml). The combined organic layers were dried over Na2SO4. After filtration, the concentrated residue was washed with hexane to give the product (46.0 g, 100%). 1H NMR (CDCl3) δ 3.59 (t, J=6.00 Hz, 4H), 2.89 (s, 15 3H), 2.59 (t, J=5.6 Hz, 4H).