Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:31][OH:32].C(N(CC)CC)C>C1(C)C=CC=CC=1.ClCCl.CN(C)C=O>[OH:32][NH:31][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:8]=2)=[CH:16][CH:17]=1)=[O:23]
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1OC1CCCC1
Reactant: NO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(C(=O)NO)cc2)cc1OC1CCCC1
Yield: 9 %

Procedure:
A solution of 3'-cyclopentyloxy-4'-methoxy-biphenyl-4-carboxylic acid (0.5 g, 1.602 mmol) in toluene (30 mL) was treated with a 2M solution of oxalyl chloride (0.840 mL, 1.68 mmol) in dichloromethane and 1 drop of dimethyl formamide was added. This mixture was heated to reflux for ten minutes, cooled and concentrated in vacuo to an oil. This oil is dissolved in dichloromethane and added dropwise to a mixture of hydroxylamine hydrochloride (0.139 g, 1.25 eq) and triethylamine (0.405 g, 2.5 eq) in dichloromethane (10 mL). After about thirty minutes the reaction the reaction appears to go no further, some of the starting acid remains (by tlc). The reaction is washed with water dried and concentrated. The material is purified via reversed phase HPLC, using a Dynamax-60A Phenyl column wand 70% acetonitrile/water as carrier. This provided the title compound in 9% yield as a crystalline solid (CH2Cl2). mp 181°-183° C.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:9]2[CH2:11][O:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C>CO.[Pd]>[CH:1]1([CH2:7][C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:9]([OH:10])[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H]1CO1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a solution of tert-butyl (S)-2-cyclohexyl-1-((S)-oxiran-2-yl)ethylcarbamate (0.63 g, 2.5 mmol) and triethylamine (0.65 mL, 5 mmol) in methanol (15 mL) was added Pd/C (0.1 g), and the mixture was hydrogenated under 30 psi pressure at rt overnight. The mixture was filtered and the filtrate was concentrated to give tert-butyl (2S,3R)-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (0.44 g, 70%). 1H NMR (400 MHz, CDCl3): 4.48 (brs, 1H), 3.78 (m, 2H), 2.30 (brs, 1H), 1.82 (m, 1H), 1.66 (m, 4h), 1.45 (s, 9H), 1.40-1.00 (m, 6H), 1.10 (d, J=6.4 Hz, 3H), 1.00-0.70 (m, 2H); MS (E/Z): 272 (M+H+).
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:41]=[CH:40][C:15]([CH2:16][C@H:17]2[C:21](=[O:22])[NH:20][C@H:19]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)=[O:24])[CH2:18]2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:20]2[C:21](=[O:22])[C@H:17]([CH2:16][C:15]3[CH:40]=[CH:41][C:12]([F:11])=[CH:13][CH:14]=3)[CH2:18][C@H:19]2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:28][CH:27]=2)=[O:24])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C1N[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C[C@H]1Cc1ccc(F)cc1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2)C(=O)N1C(=O)Cn1cncn1
Yield: 4 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide, gave Compound 71, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)-5-oxopyrrolidine-2-carboxamide (18.2 mg, 4%). 1H-NMR (400 MHz, CDCl3): σ 8.17 (s, 1H), 8.01 (s, 1H), 7.79 (s, 1H), 7.39 (d, 2H), 7.19-7.15 (m, 1H), 7.04-6.99 (m, 4H), 9.95-6.91 (m, 4H), 5.67 (d, 1H), 5.59 (d, 1H), 4.67 (d, 1H), 3.48-3.40 (m, 1H), 3.25 (dd, 1H), 2.78 (dd, 1H), 2.46 (dd, 1H), 2.06-1.97 (m, 1H). MS (EI) for C28H23F2N5O4. found 532.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10].C(OC([N:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[C:38](O)=[O:39])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[CH2:21][CH2:22][N:23]([C:38]([C@H:34]4[CH2:35][CH2:36][CH2:37][NH:33]4)=[O:39])[CH2:24][CH:25]=3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(C3=CCNCC3)cc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(C3=CCN(C(=O)[C@H]4CCCN4)CC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a stirred solution of (R)-1-(1-(2,4-dichlorophenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole (0.038 g, 0.10 mmol) and (R)-1-(t-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.044 g, 0.20 mmol) in dichloromethane (1 mL) was added HATU (0.078 g, 0.20 mmol) and Et3N (0.10 mL g, 0.72 mmol). The reaction mixture was stirred at room temperature for 30 min, followed by dilution with dichloromethane. The mixture was washed with deionized water, and the aqueous layer was extracted with dichloromethane (2×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 50% ethyl acetate in hexanes) to afford the desired product (0.037 g, 0.065 mmol, 65%).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C@:5]([C:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)[S:11][CH:12]=2)([CH3:7])[CH2:4][O:3]1.Cl.[NH2:25][OH:26]>>[CH3:1][C:2]1([CH3:23])[O:6][C@:5]([C:8]2[CH:9]=[C:10]([S:13][C:14]3[CH:19]=[CH:18][C:17](/[C:20](=[N:25]/[OH:26])/[CH3:21])=[CH:16][CH:15]=3)[S:11][CH:12]=2)([CH3:7])[CH2:4][O:3]1
Reactant: CC(=O)c1ccc(Sc2cc([C@@]3(C)COC(C)(C)O3)cs2)cc1
Reactant: NO
Agent: Cl
Product: C/C(=N\O)c1ccc(Sc2cc([C@@]3(C)COC(C)(C)O3)cs2)cc1
Yield: 95 %

Procedure:
Using an analogous procedure to that described in Example 68, 4'-{4-[(4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl]thien-2-ylthio}acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-{4-[(4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl]thien-2-ylthio}acetophenone oxime in 95% yield as a gum.
Reaction SMILES: C1(C[O:5][C:6]2[C:7]3[C:11]([CH:12]=[CH:13][CH:14]=2)=[N:10][N:9]([CH3:15])[C:8]=3[S:16]([NH2:19])(=[O:18])=[O:17])CC1.Cl>C(O)(=O)C>[OH:5][C:6]1[C:7]2[C:11]([CH:12]=[CH:13][CH:14]=1)=[N:10][N:9]([CH3:15])[C:8]=2[S:16]([NH2:19])(=[O:18])=[O:17]
Reactant: Cn1nc2cccc(OCC3CC3)c2c1S(N)(=O)=O
Agent: Cl
Solvent: CC(=O)O
Product: Cn1nc2cccc(O)c2c1S(N)(=O)=O
Yield: 69.9 %

Procedure:
A mixture comprising 62 g (221 mmol) of 4-cyclopropylmethoxy-2-methyl-2H-indazole-3-sulfonamide, 120 ml of acetic acid and 120 ml of concentrated hydrochloric acid, was stirred at 80° C. for one hour. After concentrating acetic acid.hydrochloric acid, the mixture was poured into ice water. Crystals were collected by filtration and washed with water. Further, the crystals were washed with IPE and dried to obtain 35.1 g (yield: 70%) of the desired product. Melting point: 180°-181° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:5][CH2:4][CH2:3][CH2:2][N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=2)[CH2:18][CH2:17]1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(N2CCN(CCCCl)CC2)cc1

Procedure:
1-(3-Chloropropyl)-4-(4-fluorophenyl)piperazine can be obtained as follows: a solution of 1-bromo-3-chloropropane (68 cc) and 4-(4-fluorophenyl)piperazine (50 g) in acetonitrile (400 cc) is stirred at 25° C. for 20 hours with potassium carbonate (97 g). The mixture is filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063-mm particle size, 9-cm diameter, 60-cm height) and eluted with ethyl acetate, 500-cc fractions being collected. Fractions 5 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give 1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine (44.4 g) in the form of a yellow oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([SH:15])[C:9]([SH:14])=[CH:10][CH:11]=[CH:12][CH:13]=1.F[C:17]1[CH:22]=[C:21]([Br:23])[C:20]([Br:24])=[CH:19][C:18]=1F.ClCCl>CN(C=O)C>[Br:24][C:20]1[C:21]([Br:23])=[CH:22][C:17]2[S:15][C:8]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[S:14][C:18]=2[CH:19]=1
Reactant: Fc1cc(Br)c(Br)cc1F
Reactant: Sc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Brc1cc2c(cc1Br)Sc1ccccc1S2
Temperature: 80 °C
Yield: 58 %

Procedure:
To a solution of triethylamine (0.1 mL) in 10 mL DMF, 1,2-benzenedithiol (272 mg, 1 mmole) in 1 mL DMF and 1,2-difluoro-4,5-dibromobenzene (171 mg, 1.2 mmole) in 1 mL DMF was slowly added separately at the same time with continued stirring and under Ar. The reaction mixture was heated at 80° C. for over night. The solution was then turned dark yellow. The reaction mixture was cooled and poured into dichloromethane (50 mL). The organic layer was further washed with 1N HCl and water (twice), dried by MgSO4, and the solvent was removed in vacao. The crude product was further purified by column chromatography (hexane/dichloromethane 6/1) to yield white solids (217 mg, 58%). mp 160˜161° C. 1H NMR (300 MHz, CDCl3) δ: 7.67 (s, 2H), 7.40 (dd (AA′XX′), 2H, JAX=5.7 Hz and JAX′=3.3 Hz), 7.24 (dd (AA′XX′), 2H, JAX=3.3 Hz and JAX′=2.7 Hz). 13C NMR (75 MHz, CDCl3) δ: 136.4, 134.4, 132.3, 128.8, 128.0, 123.6. FT-IR (KBr)v/cm−1: 3059, 1451, 1429, 1304, 1106, 1056, 879, 826, 746, 662, 576, 473, 441. HR-MS (EI): calcd. for Cl2H6Br2S2 371.8272 [M+]. Found 371.8283.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:23])[C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[C:5]=2[O:6][C:7]=1[CH3:8].[C:24](=O)([O-])[O-:25].[K+].[K+].O>CO>[Cl:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:22])[C:15]=1[C:14]([NH:13][C:9]1[C:5]2[O:6][C:7]([O:25][CH3:24])([CH3:8])[C:3](=[CH2:2])[C:4]=2[CH:12]=[CH:11][CH:10]=1)=[O:23]
Reactant: O=C([O-])[O-]
Reactant: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CCl
Agent: [K+]
Solvent: O
Solvent: CO
Product: C=C1c2cccc(NC(=O)c3c(Cl)cccc3Cl)c2OC1(C)OC
Yield: 25.3 %

Procedure:
A mixture of 3-chloromethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo[b]furan (20 mg) and potassium carbonate (7.5 mg) in methanol was refluxed for 1 hour. The mixture was cooled and poured into water. The separated oil was extracted with ethyl acetate and the extract was washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was purified by preparative TLC to give 7-(2,6-dichlorobenzoylamino)-2,3-dihydro-2-methoxy-2-methyl-3-methylenebenzo[b]furan (5 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[C:17]([NH2:23])[N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:24]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]5[N:19]([CH:20]([CH3:21])[CH3:22])[N:18]=[C:17]([NH2:23])[N:16]=5)[N:14]=[C:7]4[C:6]=3[CH:24]=2)=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1cc(-c3ccc(Cl)cc3)ccc1OCC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
A mixture of 5-(10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-2-yl)-1-isopropyl-1H-1,2,4-triazol-3-amine (0.5 mmol), 4-chlorophenylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490 mg, 1.5 mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed by the addition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbled with N2 gas for 10 min, the reaction tube was sealed, and the contents were stirred at 130° C. under microwave irradiation for 30 min. The mixture was filtered through celite and the filtrate was concentrated and purified with prep-HPLC to give 561 (76.4 mg, 18.1%). 1H NMR (CDCl3, 400 MHz): δ8.71-8.69 (d, J=2.4 Hz, 1H), 7.63 (s, 1H), 7.56-7.43 (m, 5H), 7.12-7.10 (d, J=8.8 Hz, 1H), 5.75 (m, 1H), 4.52-4.51 (d, J=5.6 Hz, 2H), 4.46-4.45 (d, J=5.6 Hz, 2H), 4.13 (s, 2H), 1.53-1.51 (s, J=6.4 Hz, 6H). MS (ESI) m/z 420.15 [M+H+]
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14](Br)[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:21][NH:22][CH3:23]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14]([N:22]([CH3:23])[CH3:21])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Reactant: CNC
Product: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(N(C)C)n1
Yield: 8 %

Procedure:
2.5 g (0.007 mol) of 4-amino-N-(2-bromo-6-methylamino-pyridin-4-yl)-benzenesulfonamide were stirred with 80 ml of dimethylamine in an autoclave at 160° C. for 7 hours. The residual dimethylamine was left to evaporate and the residue was chromatographed on silica gel with ethyl acetate/hexane 1:1, then 2:1 and finally 3:1. The polar fractions were chromatographed twice on silica gel with ethyl acetate/hexane 2:3 and 1:1 as the eluent. There was obtained 0.175 g (8%) of 4-amino-N-(2-dimethylamino-6-methylamino-pyridin-4-yl)-benzenesulfonamide as beige crystals: MS (ISP): me/e=322 (C14H20N5O2S+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13](=O)[C:10]2([CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[Zn][CH2:18][Zn]C[Zn]Br.C1OCCC1>O1CCCC1>[CH2:1]([N:8]1[CH2:14][C:13](=[CH2:18])[C:10]2([CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Zn]C[Zn]C[Zn]Br
Reactant: O=C1CN(Cc2ccccc2)CC12CC2
Solvent: C1CCOC1
Product: C=C1CN(Cc2ccccc2)CC12CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5-benzyl-5-azaspiro[2.4]heptan-7-one (300 mg) was dissolved into anhydrous tetrahydrofuran (10 ml) and Nysted reagent (1.5 eq, 20% solution) was added to the reaction. The reaction was stirred at RT for two days and quenched with NH4Cl solution and extracted with EtOAc followed by washing with water, then brine and dried over Na2SO4 and purified with silica gel column to give the titled compound. Mass: (M+1), 200
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][C:6]2[CH:7]3[C:14]4([CH2:15][CH2:16][C:5]=2[CH:4]=1)[CH:10]([CH2:11][N:12]([C:17](=[O:19])[CH3:18])[CH2:13]4)[CH2:9][CH2:8]3.[Cl-].[Al+3].[Cl-].[Cl-]>C(S)C>[OH:2][C:3]1[CH:21]=[CH:20][C:6]2[CH:7]3[C:14]4([CH2:15][CH2:16][C:5]=2[CH:4]=1)[CH:10]([CH2:11][N:12]([C:17](=[O:19])[CH3:18])[CH2:13]4)[CH2:9][CH2:8]3
Reactant: COc1ccc2c(c1)CCC13CN(C(C)=O)CC1CCC23
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: CC(=O)N1CC2CCC3c4ccc(O)cc4CCC23C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
1-(2-Methoxy-5,6,6a,7,10,11-hexahydro-4bH-benzo[4,5]indeno[1,7a-c]pyrrol-8-yl)-ethanone (Example 5A) (55.0 mg, 0.19 mmol) was dissolved in ethanethiol (4 mL). Aluminum chloride powder (128 mg, 0.96 mmol) was added. The mixture was stirred at 0° C. for 1 h, quenched with NaHCO3 (satd.aq., 4 mL), and extracted with CH2Cl2 (5 mL×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 5% methanol in dichloromethane, providing 46.2 mg (88.3%) of the title compound.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:3])=[O:2].CC(C)([O-])C.[K+].[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH:40]=O.[OH-].[Na+]>O1CCCC1>[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH:40]=[CH:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: O=Cc1ccccn1
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCCCC=Cc1ccccn1
Reaction time: 1 h
Yield: 52.1 %

Procedure:
(5-Carboxypentyl)triphenyl phosphonium (13.7 g, 30.0 mmol) was suspended in tetrahydrofuran (50 ml), and potassium tert-butoxide (6.3 g, 56.0 mmol) was added thereto under ice cooling condition. The mixture was stirred for 1 hr. Successively, a solution of 2-pyridinecarbaldehyde (2.0 g, 18.7 mmol) in tetrahydrofuran (10 ml) was added to the mixture, and the mixture was stirred at 0° C. for 3 hrs. The reaction mixture was combined with 2 N aqueous sodium hydroxide solution (50 ml), washed with diethyl ether, neutralized with 6 N HCl and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (100 g) column chromatography. The fractions eluted with hexane-ethyl acetate (1:1, v/v) were collected and concentrated to give Z-form of the titled compound (2.0 g, 52%). And the fractions eluted with hexane-ethyl acetate (1:2, v/v) were collected and concentrated to give a mixture of E-form and Z-form of the titled compound (0.97 g, 25%)
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:26])[CH2:4][CH2:5][CH:6]1[CH2:10][C:9]2[C:11]([CH3:25])=[C:12]([O:17]CC3C=CC=CC=3)[C:13]([CH3:16])=[C:14]([CH3:15])[C:8]=2[O:7]1.[K+].[Br-]>>[ClH:1].[CH3:26][N:3]([CH3:2])[CH2:4][CH2:5][CH:6]1[CH2:10][C:9]2[C:11]([CH3:25])=[C:12]([OH:17])[C:13]([CH3:16])=[C:14]([CH3:15])[C:8]=2[O:7]1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC(CCN(C)C)O2
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: Cc1c(C)c2c(c(C)c1O)CC(CCN(C)C)O2

Procedure:
The de-benzylation of the 2-(RS)-(2-dimethylaminoethyl)-2,3-dihydro-5-benzyloxy-4,6,7-trimethylbenzofurane hydrochloride is done by carrying out the procedure given in example 15. A white solid is obtained m.p. 171°-173° C.; IR (KBr): 3406 (νOH), 2651, 2438 cm-1 (νNH+); 1H-NMR (CD3OD); δ3.5-2.7 (8H,m), 2.5-2.2 (2H,m), 2.1 (6H,s), 2.0 (3H,s), 1.4 (6H,t).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C(Cl)(=O)C(Cl)=O.Cl.[CH3:32][NH:33][O:34][CH3:35].C(N(CC)CC)C>ClCCl>[CH3:35][O:34][N:33]([CH3:32])[C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:4]1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)N(C)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution of 6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoic acid (31.0 g, 95.3 mmol) in dichloromethane (200 mL) in an ice bath was added oxalyl chloride (21.9 g, 172 mmol) dropwise over a 30 minute period. The reaction mixture was then stirred for one hour at room temperature then concentrated under reduced pressure, and dichloromethane (400 mL) and N,O-dimethylhydroxylamine hydrochloride (18.6 g, 190 mmol) were added to the residue followed by the dropwise addition of triethylamine (38.5 g, 380 mmol). After stirring at room temperature overnight, the reaction mixture was washed successively with a saturated aqueous sodium bicarbonate solution and brine (100 mL each), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide N-methoxy-N-methyl-6-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanamide (28.0 g) as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([C:42]([OH:44])=O)[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:28]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[C:31]([F:41])[CH:30]=4)[O:26][N:25]=3)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:48])=O>ClCCl.CN(C)C=O>[CH2:1]([O:8][C:9]([C:11]1([C:42]([Cl:48])=[O:44])[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:28]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[C:31]([F:41])[CH:30]=4)[O:26][N:25]=3)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 1-{4-[5-(2-fluorobiphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]benzyl}piperidine-4,4-dicarboxylic acid benzyl ester (0.8 g, 0.0014 mol) in dichloromethane (20 mL), oxalyl chloride (0.343 g, 0.0027 mol) is added slowly at 0-50 C. A few drops of N,N-dimethyl formamide is added into it. The reaction mixture is stirred at room temperature for 1.5 hrs. It is then concentrated under reduced pressure to get 4-chlorocarbonyl-1-{4-[5-(2-fluorobiphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]benzyl}piperidine-4-carboxylic acid benzyl ester.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:10]C)[C:5]([O:12]C)=[CH:4][CH:3]=1.B(Br)(Br)Br.O(CC)CC.Cl>ClCCl>[F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[C:5]([OH:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c(C=O)c1OC
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1c(F)ccc(O)c1O
Temperature: -60 °C
Reaction time: 4 h

Procedure:
To a solution of 6-fluoro-2,3-dimethoxy-benzaldehyde (18.0 g, 97.74 mmol) in anhydrous dichloromethane (100 mL) under nitrogen at −60° C. was added dropwise BBr3.OEt2 (195 mL, 195.48 mmol) over 30 min and the solution was allowed to warm up to r.t and stirred for 4 h. The reaction mixture was cooled to −60° C. and 2N HCl (250 mL) was carefully added drop wise. The mixture was stirred at r.t overnight. The two layers were separated and the aqueous layer extracted with DCM. The combined organic layers were washed with water, sat. NaHCO3 solution, water and brine and dried over MgSO4. The solvent was removed in vacuo to provide the title compound which was used in the next step without further purification. Yield 11.15 g (74%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.53 (s, 1H), 10.23 (s, 1H), 7.11 (dd, J=8.8, 5.3 Hz, 1H), 6.57 (t, J=9.6 Hz, 1H), 5.48 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −132 ppm.