Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:21][C:22]([CH2:25]Cl)=[N:23][N:24]=2)[CH:3]=1.[I-].[Na+].[N:29]1([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>C(#N)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([C:20]2[O:21][C:22]([CH2:25][NH:38][CH2:37][CH2:36][CH2:35][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[N:23][N:24]=2)[CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(Br)cc21
Reactant: NCCCN1CCOCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Brc1cc(-c2nnc(CNCCCN3CCOCC3)o2)c2cn[nH]c2c1
Temperature: 70 °C
Yield: 117.8 %

Procedure:
6-Bromo-4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-(phenylsulfonyl)-1H-indazole (300 mg, 0.661 mmol) and sodium iodide (99 mg, 0.661 mmol) were weighed into a round-bottomed flask and dissolved in acetonitrile (2 ml) before [3-(4-morpholinyl)propyl]amine (191 mg, 1.322 mmol, available from Sigma-Aldrich) and DIPEA (0.231 ml, 1.322 mmol) were added. The mixture was heated to 70° C. for 2 h, then cooled and the solvent removed under a stream of nitrogen. The crude residue was dissolved in DCM/MeOH (1:1) and preabsorbed onto silica which was then added to the top of a 20 g silica cartridge that was subsequently eluted with 0-15% MeOH (+1% triethylamine)/DCM over 20 mins. The appropriate fractions were combined and the solvent removed in vacuo to give the title compound as a yellow oily solid (328 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5](O)[CH:4]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:5]1[CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: Oc1cc(C(F)(F)F)c2ccccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(Cl)nc2ccccc12
Yield: 77.8 %

Procedure:
A round bottom was charged with 4-trifluoromethyl-quinolin-2-ol (1 g, 4.69 mmol) and POCl3 (10 ml, 107.28 mmol). The mixture was heated to reflux for 3 hours, and then concentrated to remove excess POCl3. The mixture was based with 5 N NaOH and extracted with DCM. The mixture was purified by flash chromatography to give intermediate 2-chloro-4-trifluoromethyl-quinoline (845 mg, 78%): LCMS found 232.22 [M+H]+.
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C[Si](N[Si](C)(C)C)(C)C>[C:12]1([C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:6]2[CH:7]=[N:8][C:9]3[C:10](=[O:11])[NH:1][C:2]([NH2:3])=[N:4][C:5]2=3)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: Nc1nc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 7 h
Yield: 90 %

Procedure:
Guanine 5 (1.51 g, 9.99 mmol) and (NH4)2SO4 (100 mg) were suspended in HMDS (150 mL) and refluxed for 24 h. The solvent was evaporated under reduced pressure and the residue was dissolved in CH3CN (150 mL). Triphenylmethyl chloride (2.79 g, 10.0 mmol) was added and the reaction mixture was stirred at 25° C. for 7.0 h. The solution was concentrated under reduced pressure and the residue was purified by use of column chromatography (hexanes/EtOAc=1.5:8.5) to afford 6 (3.54 g, 8.99 mmol) in 90% yield: mp 268-270° C.; Rf(hexanes/EtOAc=1:2) 0.34; UV (EtOH) λmax 254 (ε 13,870), 278 (sh); 1H NMR (DMSO-d6) δ 5.97 (s, 2 H, NH2), 7.09-7.39 (m, 16 H, HC8+C(C6H5)3), 10.45 (br s, 1H, NH); MS m/z 393 (M+). Anal. (C24H19N5O) C, H, N; calcd (%): 73.26, 4.87, 17.80; found (%): 73.20, 4.81, 17.78.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1>N1C=CC=CC=1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:36]([NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([C:28]([F:27])([F:38])[F:39])[CH:30]=2)=[O:37])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Compound 494 (0.03 g, 0.08 mmol) was dissolved in pyridine (0.2 mL) and 3-(trifluoromethyl)phenyl isocyanate (0.017 mL, 0.12 mmol) was added. The solution was stirred at room temperature for 1.5 h. Work up as described in the preparation of compound 259. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 2:3 as the eluent. This afforded the title compound as a slightly coloured solid. 13C NMR (CD3OD) δ 198.3, 161.1 (dd), 157.9 (dd), 155.0, 151.3, 141.5, 141.2, 138.1, 136.2, 135.0, 132.9, 132.8, 132.2 (q), 130.7, 128.8, 127.5 (dd), 126.0 (dd), 125.6 (q), 123.4, 123.0, 121.2, 120.0 (q), 116.6, 116.5 (q), 113.0, 112.6 (dd), 105.8 (dd), 19.7
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[CH2:13][N:14]([CH3:16])[CH3:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:23][CH3:24].Cl[C:26]1[N:31]=[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:39]([N:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])[C:29]([Cl:45])=[CH:28][N:27]=1.C(O)(C(F)(F)F)=O>>[Cl:45][C:29]1[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:39](=[O:41])(=[O:40])[N:42]([CH3:43])[CH3:44])=[N:31][C:26]([NH:1][C:2]2[CH:22]=[CH:21][C:5]3[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[CH2:13][N:14]([CH3:15])[CH3:16])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:23][CH3:24])=[N:27][CH:28]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)C(NC(=O)CN(C)C)CCc2c1ccc(N)c2OC
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)C(NC(=O)CN(C)C)CCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)c2OC

Procedure:
Following a procedure analogous to Example 113, N-(7-Amino-1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-2-dimethylamino-acetamide (50 mgs) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide was converted to the title compound as the TFA salt (24 mgs). 1H NMR (400 MHz, (CD3)2SO) δ 9.44 (s, 1H), 8.94 (d, J=7.3 Hz, 1H), 8.77 (s, 1H), 8.54 (d, J=7.6 Hz, 1H), 8.30 (s, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.17 (d, J=9.1 Hz, 1H), 4.14-4.30 (m, 2H), 3.92 (s, 2H), 3.70 (s, 3H), 3.54 (m, 1H), 3.07 (m, 1H), 2.78 (s, 6H), 2.66 (s, 6H), 2.42 (m, 1H), 2.20 (m, 1H), 2.07 (m, 1H), 1.04 (t, J=7.1 Hz, 3H). LCMS: found 646.18 (m+1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:19][CH2:20]OS(C)(=O)=O)=[C:14]([CH3:35])[CH:13]=1>C1COCC1>[C:31]([O:30][C:28]([N:27]1[CH2:20][CH2:19][CH:18]([C:15]2[CH:16]=[CH:17][C:12]([Br:11])=[CH:13][C:14]=2[CH3:35])[CH2:26]1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1cc(Br)ccc1C(CCOS(C)(=O)=O)CNC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
KHMDS (0.5 M in toluene, 186 mL, 0.09303 mol) was added at 0° C. to methanesulfonic acid 3-(4-bromo-2-methyl-phenyl)-4-tert-butoxycarbonylamino-butyl ester (36.9 g, 0.08457 mol) dissolved in THF (400 mL). The ice-bath was removed and the mixture was stirred at room temperature for 2 hours. A saturated solution of NH4Cl was added to the reaction mixture and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, 8/2) to give 27.3 g (95% yield) of 3-(4-bromo-2-methyl-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a clear oil.
Reaction SMILES: CN(C)C=O.[CH:6]1[CH:11]=[C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([SH:16])[C:9]2=[CH:8][CH:7]=1.Br[C:18]1[O:22][CH:21]=[C:20]([C:23]([OH:25])=[O:24])[CH:19]=1>O>[C:15]1([S:16][C:18]2[O:22][CH:21]=[C:20]([C:23]([OH:25])=[O:24])[CH:19]=2)[C:9]2[C:10](=[CH:11][CH:6]=[CH:7][CH:8]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: Sc1cccc2ccccc12
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1coc(Sc2cccc3ccccc23)c1

Procedure:
Following the procedure of Example 9, except that a total volume of 90 ml. of dimethylformamide was used, 1-thionaphthol (5.02 g., 31.4 mmoles) was reacted with 5-bromofuran-3-carboxylic acid. Crude product was isolated as an oil according to Example 16. The oil was solidified by trituration with water (988 mg.). Recrystallization from hexane gave purified 5-(1-naphthylthio)furan-3-carboxylic acid (250 mg., m.p. 118°-120° C., m/e 270).
Reaction SMILES: [C:1]1([N:7]2[C:15](=[O:16])[C:14]3[C@@H:13]4[C:17]([CH3:19])([CH3:18])[C@@:10]([CH3:20])([CH2:11][CH2:12]4)[C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:20][C@@:10]12[C:17]([CH3:19])([CH3:18])[C@@H:13]([C:14]3[C:15](=[O:16])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C:9]=31)[CH2:12][CH2:11]2
Reactant: CC(C)=CCBr
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)=CCn1c2c(c(=O)n1-c1ccccc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 7.2 %

Procedure:
A mixture of (4S,7R)-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 420 mg, 1.57 mmol), tetrabutylammonium iodide (2.31 g, 6.26 mmol) and 4-bromo-2-methyl-2-butene (720 μL, 6.26 mmol) in dimethylformamide (5 mL) was heated in an oil-bath at 100° C. for 8 h. The solvent was evaporated and the residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organic layers were washed with water (5×100 mL) and aqueous sodium thiosulfate (100 mL). The solvent was evaporated and the residue was purified using an ISCO 40 g column, eluting with 90-100% ethyl acetate/hexanes to give (4S,7R)-7,8,8-trimethyl-1-(3-methyl-but-2-enyl)-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (38 mg, 7%) as a viscous yellow oil. APCI(+)-MS (M+H) 337.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([C:14]1[CH:15]=[C:16]([Si:19]([CH3:22])([CH3:21])[CH3:20])[O:17][CH:18]=1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.I[CH3:24]>O1CCCC1>[CH3:24][O:3][CH:4]([C:14]1[CH:15]=[C:16]([Si:19]([CH3:22])([CH3:21])[CH3:20])[O:17][CH:18]=1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)c1cc(C(O)CCCc2ccccc2)co1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(CCCc1ccccc1)c1coc([Si](C)(C)C)c1
Temperature: 25 °C

Procedure:
To a stirred suspension of sodium hydride (0.063 g., 1.05 mmol) in 10 ml tetrahydrofuran at 0° under argon, was added dropwise via syringe 4-(1-hydroxy-4-phenylbutyl)-2-trimethylsilylfuran (0.274 g., 0.951 mmol). This was followed by the addition of iodomethane (0.352 g., 2.48 mmol) and warming of the reaction mixture to room temperature. Several more equivalents of sodium hydride and iodomethane were subsequently added in increments over 2.5 hours until TLC indicated that no starting material remained. The reaction mixture was carefully filtered through celite and partitioned between ethyl ether and 5% hydrochloric acid. The organic portion was washed with 5% sodium bicarbonate, water, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give an oil. Purification by flash chromatography (silica, hexane to 5% ethyl ether/hexane) yielded the desired methyl ether.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[F:8][C:9]([F:17])([F:16])[C:10]1([CH3:15])[CH2:14][CH2:13][CH2:12][NH:11]1.C(N(CC)CC)C.Cl>C1COCC1>[C:3]([N:11]1[CH2:12][CH2:13][CH2:14][C:10]1([C:9]([F:17])([F:16])[F:8])[CH3:15])(=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC1(C(F)(F)F)CCCN1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)N1CCCC1(C)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
A solution of 6.03 g (0.05 mol) of 2,2-dimethylpropionyl chloride in 25 ml of THF was added dropwise to a solution of 7.65 g (0.05 mol) of 2-trifluoromethyl-2-methylpyrrolidine in 15 ml of THF, to which 5.6 g (0.055 mol) of triethylamine had been added. The course of the reaction is exothermic. The dropwise addition was effected slowly enough that the temperature did not rise to above 35° C. Stirring was continued for one hour at room temperature, and the mixture was then poured into 200 ml of ice-water, the pH was adjusted to 4-5 using dilute hydrochloric acid, and the mixture was extracted twice using 60 ml portions of dichloromethane. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was stripped off under a water pump vacuum. The oil which remained was chromatographed over a short silica gel column (mobile phase toluene/ethyl acetate 1:1). After the mobile phase had been removed, 9.12 g (77% yield of theory) of N-pivaloyl-2-trifluoromethyl-2-methylpyrrolidine are obtained as a pale yellow oil having a refractive index of nD20 : 1,4615 (GC purity: 97.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][N:10]([CH3:14])[C:11](Cl)=[O:12]>N1C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:11](=[O:12])[N:10]([CH3:14])[CH3:9])[CH:3]=[N:4][CH:5]=1
Reactant: CN(C)C(=O)Cl
Reactant: Nc1cncc(Br)c1
Solvent: c1ccncc1
Product: CN(C)C(=O)Nc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3-Amino-5-bromo pyridine (XX) (1.0 g, 5.78 mmol) was dissolved in pyridine and cooled to 0° C. before adding dimethyl carbamyl chloride (XXI) (0.683 g, 6.35 mmol). The reaction mixture was stirred at room temperature for 2 h and then heated overnight at 60° C. under argon. The solution was cooled to room temperature, poured into ice water and extracted with EtOAc. The organic extract was dried over MgSO4, filtered and concentrated to a residue to afford 3-(5-bromopyridin-3-yl)-1,1-dimethylurea (XXII) as a brown solid, (1.24 g, 5.09 mmol, 88% yield). 1H NMR (DMSO-d6) δ ppm 8.67-8.64 (m, 2H), 8.23 (d, J=7.8 Hz, 1H), 2.93 (s, 6H); ESIMS found for C8H10BrN3O m/z 245.05 (M+H).
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:22])=O>CN(C)C=O.ClCCCl>[ClH:22].[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:1])=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1

Procedure:
An acylating agent, in acid chloride form, was prepared by combining 26.3 g. of 4-(2-piperidinoethoxy)benzoic acid, hydrochloride, 36.5 g. of thionyl chloride and 1 drop of dimethylformamide in 200 ml. of 1,2-dichloroethane, and stirring the mixture under reflux for 2 hours under a nitrogen atmosphere. The mixture was then evaporated to dryness under vacuum to obtain the desired 4-(2-piperidinoethoxy)benzoyl chloride, hydrochloride, which was dissolved in 1 liter of 1,2-dichloroethane. To the solution was added 20 g. of 6-acetoxy-2-(4-acetoxyphenyl)benzo[b]thiophene and the mixture was stirred vigorously. To it was then added, over about 3 minutes, 73.4 g. of aluminum chloride. During the addition, the reaction mixture turned dark brown and hydrogen chloride evolved. The mixture was then stirred for one hour, and was poured over 1 liter of ice-water. The layers were separated, and the aqueous layer was extracted three times with 200 ml. portions of warm chloroform. The organic layers were combined and dried over magnesium sulfate, and were then filtered and evaporated under vacuum to obtain a brownish-yellow oil, which are not purified. The presence of the desired product was confirmed by thin layer chromatography (TLC) on silica gel, eluting with 9/1 chloroform/methanol, which showed that the major constituent ran at the same Rf as authentic 6-acetoxy-2l -(4-acetoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-benzo[b]thiophene.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20]CC3C=CC=CC=3)[CH:15]=2)[CH:10]([O:28][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[CH:10]([O:28][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2cccc(C3CCN(Cc4ccccc4)CC3OCc3ccc4ccccc4c3)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: Oc1cccc(C2CCN(Cc3ccccc3)CC2OCc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 31.5 %

Procedure:
A solution of 250 mg (0.487 mmol) of (3RS,4RS)-1-benzyl-4-(3-benzyloxyphenyl)-3-(naphthalen-2-ylmethoxy)-piperidine in 1.1 ml of methylene chloride was treated at room temperature with 247 μl (236 mg, 1.946 mmol, 4 eq.) of N,N-dimethylaniline and 195 mg (1.46 mmol, 3.0 eq.) of aluminium trichloride and stirred at room temperature for 2.5 hours. Subsequently, the mixture was partitioned between methylene chloride and 5% sodium hydrogen carbonate solution, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel with a 4:1 mixture of methylene chloride and hexane as the eluent. There were obtained 65 mg (32% of theory) of (3RS,4RS)-1-benzyl-4-(3-hydroxyphenyl)-3-(naphthalen-2-ylmethoxy)-piperidine as a beige coloured solid; MS: 423 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:23]Cl.[NH:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[CH2:23][N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1
Reactant: C1CNCCNC1
Reactant: CC(C)c1ccc(S(=O)(=O)n2cc(CCl)c3cc(Br)ccc32)cc1
Product: CC(C)c1ccc(S(=O)(=O)n2cc(CN3CCCNCC3)c3cc(Br)ccc32)cc1

Procedure:
Using essentially the same procedure as described in example 127, 5-Bromo-1-(4-isopropylbenzenesulfonyl)-3-chloromethyl-1H-indole was reacted with homopiperazine to obtain the above derivative.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:15]O>>[CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:15])=[O:8])=[CH:4][CH:3]=1
Reactant: CO
Reactant: Cc1ccc(C(=O)O)s1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)s1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 5-methylthiophene-2-carboxylic acid (100 g, 703 mmol) in methanol (1.0 L) was added conc. sulfuric acid (10 ml) and the mixture was heated under reflux for 2 days. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Diethyl ether (1.0 L) was added to the residue. The mixture was washed successively with water (500 ml×4) and saturated brine (500 ml), and dried over magnesium sulfate. Filtration and concentration under reduced pressure gave methyl 5-methylthiophene-2-carboxylate (109 g, yield 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:17])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27][C:28]([C:30]1([C:33](O)=[O:34])[CH2:32][CH2:31]1)=[O:29].[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:36]([NH:43][C:33]([C:30]1([C:28]([NH:27][C:3]2[CH:4]=[CH:5][C:6]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]([CH3:26])[CH:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)=[O:17])[CH:10]=3)=[CH:7][C:2]=2[F:1])=[O:29])[CH2:32][CH2:31]1)=[O:34])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NCc1ccccc1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)O)CC4)c(F)c3)ccn2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)NCc5ccccc5)CC4)c(F)c3)ccn2)CC1
Reaction time: 32 h
Yield: 57 %

Procedure:
To a solution of 1-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylic acid (40 mg) in N,N-dimethylformamide (1.0 ml) were added benzylamine (0.018 ml), triethylamine (0.023 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (72.9 mg) at room temperature, followed by stirring for 32 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (27.1 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:16]([NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][CH:25]=1)(=[O:23])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(O)(=O)C.Cl>CO>[C:16]([NH:20][S:21]([C:24]1[CH:25]=[CH:26][C:27]([CH2:30][NH:15][C:13]2[NH:12][N:11]=[C:10]([NH:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:14]=2)=[CH:28][CH:29]=1)(=[O:22])=[O:23])([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(C=O)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)c1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (100 mg, 410 μmol) in MeOH (5 mL) was added N-tert-butyl-4-formylbenzenesulfonamide (109 mg, 451 μmol) followed by acetic acid (36.7 mg, 35 μl, 611 μmol). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (65.7 mg, 615 μmol) was added and the stirring was continued for 3 days. The reaction mixture was poured into 0.1N HCl solution (25 ml) and was extracted with EtOAc (3×30 ml). The combined organic solution was washed with brine, dried over Na2SO4 and concentrated to give a residue. The crude material was purified by flash chromatography (silica gel, 24 g, 3% to 5% MeOH in DCM) to give an off white solid as desired product (98 mg, 51% yield). MS +m/z: 469 (M+H)+