Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].Cl([O-])(=O)(=O)=O.[C:7]([N+:11]1[O:12][C:13]([CH3:16])=[CH:14][CH:15]=1)([CH3:10])([CH3:9])[CH3:8]>C(Cl)Cl>[C:13]([C:14]1[C:15]([NH:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[N:1][C:15]([NH:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:14][C:13]=1[CH3:16])(=[O:12])[CH3:16]
Reactant: Cc1cc[n+](C(C)(C)C)o1
Reactant: N
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(=O)c1c(C)cc(NC(C)(C)C)nc1NC(C)(C)C
Temperature: -30 °C
Reaction time: 96 h

Procedure:
About 60 ml. of anhydrous ammonia were condensed into a flask containing 60 ml. of methylene chloride. The reaction mixture was maintained at a temperature not in excess of -30° C. under nitrogen and a solution of 50 g. of 2-t-butyl-5-methylisoxazolium perchlorate in 100 ml. of methylene chloride was added rapidly. The reaction mixture was allowed to come to room temperature and stirred for 4 days at room temperature. The methylene chloride was then removed at reduced pressure to obtain a gummy solid which was triturated with water to obtain a yellow solid. Recrystallization of the yellow solid from methanol/water yielded the product, m.p. 128°-129° C. Its spectra were identical with those of the product of Example 4(a).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C@@H:5]([N:7]2[CH:15]=[N:14][C:13]3[C:8]2=[N:9][C:10]([Cl:58])=[N:11][C:12]=3[NH:16][C@@H:17]2[CH2:21][CH2:20][N:19]([C:22]3[N:30]=[C:29]4[C:25]([N:26]=[CH:27][N:28]4[C@@H:31]4[CH2:35][C@H:34]([NH:36][C:37](=[O:40])[CH2:38][CH3:39])[C@@H:33]([OH:41])[C@H:32]4[OH:42])=[C:24]([NH:43][CH2:44][CH:45]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[N:23]=3)[CH2:18]2)[C@H:4]([OH:59])[C@@H:3]1[OH:60].CO.[C:63](Cl)(=[O:66])[CH2:64][CH3:65]>C1COCC1>[Cl:58][C:10]1[N:9]=[C:8]2[C:13]([N:14]=[CH:15][N:7]2[C@@H:5]2[CH2:6][C@H:2]([NH:1][C:63](=[O:66])[CH2:64][CH3:65])[C@@H:3]([OH:60])[C@H:4]2[OH:59])=[C:12]([NH:16][C@@H:17]2[CH2:21][CH2:20][N:19]([C:22]3[N:30]=[C:29]4[C:25]([N:26]=[CH:27][N:28]4[C@@H:31]4[CH2:35][C@H:34]([NH:36][C:37](=[O:40])[CH2:38][CH3:39])[C@@H:33]([OH:41])[C@H:32]4[OH:42])=[C:24]([NH:43][CH2:44][CH:45]([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[N:23]=3)[CH2:18]2)[N:11]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](Nc5nc(Cl)nc6c5ncn6[C@@H]5C[C@H](N)[C@@H](O)[C@H]5O)C4)nc32)[C@H](O)[C@@H]1O
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](Nc5nc(Cl)nc6c5ncn6[C@@H]5C[C@H](NC(=O)CC)[C@@H](O)[C@H]5O)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-{(1S,2R,3S,4R)-4-[2-{(R)-3-[9-((1R,2S,3R,4S)-4-Amino-2,3-dihydroxy-cyclopentyl)-2-chloro-9H-purin-6-ylamino]-pyrrolidin-1-yl}-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (32 mg, 0.038 mmol) and TEA (0.016 mL, 0.113 mmol) are suspended in THF (0.5 mL). MeOH (0.5 mL) is added to aid solubility. Propionic acid chloride (0.0035 mL, 0.040 mmol) is added and the reaction mixture is stirred at room temperature overnight. The reaction mixture is reduced in vacuo and purified by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water-0.1% TFA) to yield the title compound (MH+ 894/895).
Reaction SMILES: [Cl:1][CH:2]([C:4]1[N:5]=[C:6]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:7]2[C:8](=[O:10])[CH:9]=1)[CH3:3].[Br:16]Br>C(Cl)Cl>[Br:16][C:9]1[C:8](=[O:10])[N:7]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:6]2=[N:5][C:4]=1[CH:2]([Cl:1])[CH3:3]
Reactant: BrBr
Reactant: Cc1cccc2nc(C(C)Cl)cc(=O)n12
Solvent: ClCCl
Product: Cc1cccc2nc(C(C)Cl)c(Br)c(=O)n12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(1-chloroethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (3.16 g, 14.2 mmol) in methylene chloride (30 mL) was added drop-wise bromine (0.804 mL, 15.6 mmol) in methylene chloride (7 mL). The reaction mixture was stirred at room temperature for 2 h. The product precipitated out and was collected by filtration (2.42 g, 56.6%). LCMS calculated for C11H11BrClN2O (M+H)+: m/z=301.0. Found: 301.1.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[SH:26][C:27]1[NH:28][CH:29]=[CH:30][N:31]=1>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:26][C:27]3[NH:28][CH:29]=[CH:30][N:31]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: Sc1ncc[nH]1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Solvent: O
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3ncc[nH]3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 2-mercaptoimidazole was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) δ 1.50-1.64 (m, 8H) 1.89 (m, 2H) 2.71 (d, J=15.0 Hz, 1H) 3.80 (s, 3H) 7.03 (d, J=8.5 Hz, 1H) 7.08 (d, J=5.0 Hz, 1H) 7.21 (d, J=1.9 Hz, 1H) 7.46 (s, 2H). MS (APCI) calcd for C22H25ClN2O4S: 448.97; found M=449.0.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:11])=[O:10])=[C:5]([N+:23]([O-])=O)[CH:4]=1)#[N:2].Cl[Sn]Cl>Cl.CCO>[NH2:23][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][C:6]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)(=[O:11])=[O:10]
Reactant: N#Cc1ccc(S(=O)(=O)Nc2cccc3cccnc23)c([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: N#Cc1ccc(S(=O)(=O)Nc2cccc3cccnc23)c(N)c1
Yield: 62.7 %

Procedure:
In a similar fashion using route 1 general procedure 4, 4-cyano-2-nitro-N-quinolin-8-yl-benzenesulfonamide (Intermediate 250) (0.63 g, 1.77 mmol), SnCl2 (2.0 g, 10.6 mmol), conc.HCl (5 drops) and EtOH (15 ml) gave the title compound (0.36 g, 61%) which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[CH3:30].[OH-].[Na+]>C(O)C>[I:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]([C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=2)=[CH:14][CH2:13][S:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])=[C:7]([CH3:30])[CH:8]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)COc1ccc(SCC=C(c2ccc(I)cc2)c2ccc(I)cc2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(SCC=C(c2ccc(I)cc2)c2ccc(I)cc2)ccc1OCC(=O)O
Reaction time: 1 h

Procedure:
{4-[3,3-Bis-(4-iodo-phenyl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid methyl ester (342 mg, 0.5 mmol) was dissolved in warm ethanol (20 ml). 1N NaOH was added at room temperature and the reaction mixture was stirred for 1 h after which it was evaporated. The residue was treated with 1N HCl (1.0 ml) and extracted with dichloromethane (3×20 ml). The combined organic phases were dried and evapotated to give the title compound in 320 mg (96%) yield.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[CH:8]1([NH:11][C:12]2[N:13]=[C:14]3[CH2:36][CH2:35][NH:34][CH:33]([CH3:37])[C:15]3=[N:16][C:17]=2[N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[CH2:20][CH2:19]2)[CH2:10][CH2:9]1.C=O.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:8]1([NH:11][C:12]2[N:13]=[C:14]3[CH2:36][CH2:35][N:34]([CH3:2])[CH:33]([CH3:37])[C:15]3=[N:16][C:17]=2[N:18]2[CH2:19][CH2:20][CH:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[CH2:22][CH2:23]2)[CH2:10][CH2:9]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC1NCCc2nc(NC3CC3)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc21
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1c2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NC3CC3)nc2CCN1C

Procedure:
A solution of N-cyclopropyl-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (15 mg, 0.028 mmol), formaldehyde (1.5 μL, 0.057 mmol), and DIPEA (5.0 μL, 0.028 mmol) in DCM (283 μL) was stirred for 10 min. To this was then added sodium triacetoxyborohydride (18.0 mg, 0.085 mmol) and the reaction mixture was stirred overnight. Purification by HPLC Method A afforded the title compound as a TFA salt (4 mg). 1H NMR (400 MHz, methanol-d4) 6 ppm 0.60-0.67 (m, 2H), 0.83-0.92 (m, 2H), 1.64-1.80 (m, 3H), 1.87-2.04 (m, 2H), 2.05-2.21 (m, 2H), 2.74 (tt, J=7.0, 3.6 Hz, 1H), 2.98-3.21 (m, 7H), 3.35-3.51 (m, 2H), 3.59 (d, J=6.6 Hz, 1H), 3.78 (br s, 1H), 4.42 (br s, 1H), 4.49 (td, J=7.4, 3.7 Hz, 1H), 6.86-6.93 (m, 1H), 6.96-7.05 (m, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3S[CH2:19][CH2:18][C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=3[CH:26]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].OO.[S:29]([O-:32])([O-])=[O:30].[Na+].[Na+].O>C(O)(=O)C>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[S:29](=[O:32])(=[O:30])[CH2:19][CH2:18][C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=3[CH:26]=2)=[CH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: O=S([O-])[O-]
Reactant: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OCC)CCS3)cc1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OCC)CCS3(=O)=O)cc1
Temperature: 56 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Ethyl 7-(4-propoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate (15 g, 40.707 mmol) was suspended in 135 ml of acetic acid and was heated to 56° C. to dissolve. A solution of 30% hydrogen peroxide (9.5 g, 83.449 mmol) in 15 ml of acetic acid was dropped slowly and then was stirred at 65-70° C. for 3 hours. At that temperature, 60 ml of an aqueous sodium sulfite solution was dropped and disappearance of the peroxide was checked with iodo-starch paper. At that temperature, 15 ml of water was dropped. Crystals were formed and the mixture was cooled and stirred for 2 hours. After filtration, the residue was washed with 15 ml of a mixed solution of acetic acid/water =3/2 and subsequently with 150 ml of water. After vacuum drying (40° C.), 15.4 g (Yield 94%) of ethyl 7-(4-propoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate was obtained as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[S:11]([Cl:14])([Cl:13])=[O:12]>>[S:11]([Cl:14])([Cl:13])=[O:12].[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1cccnc1Cl
Yield: 125.7 %

Procedure:
2-Chloro nicotinic acid (5 g, 31.8 mmol) was heated to reflux with redistilled thionyl chloride (5.6 g, 47 mmol) for 8 hr, resulting in a clear solution. The reaction mixture was concentrated to dryness and the traces of thionyl chloride co-distilled with toluene (15 ml) to give 2-chloro-nicotinoyl chloride (5.2 g, 94%) as oil.
Reaction SMILES: C(N)(=O)C.C=O.O.[C:8]([OH:11])(=[O:10])[CH3:9].N(CC(O)=O)CC(O)=O.[C:21]([NH:24][CH2:25][C:26]([OH:28])=[O:27])(=[O:23])[CH3:22]>CC(C)=O>[C:21]([N:24]([CH2:25][C:26]([OH:28])=[O:27])[CH2:9][C:8]([OH:11])=[O:10])(=[O:23])[CH3:22]
Reactant: CC(=O)O
Reactant: CC(=O)NCC(=O)O
Agent: C=O
Agent: CC(N)=O
Agent: O=C(O)CNCC(=O)O
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)N(CC(=O)O)CC(=O)O
Temperature: 110 °C
Yield: 95 %

Procedure:
A 300 mL autoclave was charged with acetamide (VII) (11.8 g, 0.2 mole), 95% paraformaldehyde (13.6 g, 0.43 mole), water (12.9 g, 0.72 mole), acetic acid (2.1 g, 0.035 mole), acetone (90 mL) and Co2 (CO)8 (2.1 g, 0.006 mol) and pressurized to 3200 psi (22,069 kPa) CO:H2 (95:5) at 25° C. This mixture was heated to 110° C. for 30 min. HPLC analysis of this stream indicated a 95% yield of (XVI), 0.5% (XIV), and 4.5% (XVIII).
Reaction SMILES: [C:1]1([CH3:7])C=CC=C[CH:2]=1.Br[C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(B(O)O)CC1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:7]1([C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=2[F:24])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:1][CH2:2]1
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(F)c(C2CC2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
Under N2, a toluene (4.70 mL)/water (0.235 mL) solution of tert-butyl 3-bromo-4-fluorobenzylcarbamate (0.300 g, 0.986 mmol) was treated with potassium phosphate tribasic (0.733 g, 3.45 mmol), cyclopropylboronic acid (0.110 g, 1.282 mmol), and tricyclohexenylphosphene (0.028 g, 0.099 mmol) in was added palladium(II) acetate (0.011 g, 0.049 mmol). The reaction was stirred at 100° C. for 3 h. The solution was diluted with water (15 mL) then extracted with ethyl acetate (2×15 mL). The organic extracts were combined, washed with brine (20 mL), then dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage flash chromatography system; 60 g SiO2; 0-20% ethyl acetate:hexane over 900 mL) to give the title compound as a white crystalline solid (0.230 g, 88% yield). 1H NMR (500 MHz, CDCl3) δ: 6.98-7.05 (1 H, m), 6.90-6.97 (1 H, m), 6.79 (1 H, dd, J=7.02, 1.53 Hz), 4.75 (1 H, brs), 4.21 (2 H, d, J=5.49 Hz), 2.02-2.09 (1 H, m), 1.45 (9 H, s), 0.93-1.01 (2 H, m), 0.66-0.75 (2 H, m).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][N:15]1[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]1)[CH:8]=[CH:7]2.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]Cl)[CH:34]=1.O>CN(C)C=O>[C:20]1([C:18]2[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16][N:15]([CH2:14][C:9]3[CH:8]=[CH:7][C:6]4[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH2:39][C:35]5[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=5)[CH:5]=4)[CH:10]=3)[CH:19]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc3cc(O)ccc3c2)cc1-c1ccccc1
Reactant: ClCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc3cc(OCc4cccnc4)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(6-hydroxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]propionate (599 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 3-Picolyl chloride (230 mg) was added to the mixture, which was stirred at room temperature for 15 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[4-phenyl-1-[6-(3-pyridylmethoxy)-2-naphthylmethyl]-3-pyrrolyl]propionate (647 mg, yield: 88%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(OCC)C)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])[N:36]=2)[OH:34])=[C:7]([Cl:47])[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][N:42]([CH2:43][CH3:44])[CH2:45][CH3:46])[N:36]=2)[OH:34])=[C:7]([Cl:47])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(O)c2cccc(CN(CC)CC)n2)n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCc1nc(Cl)c(C(O)c2cccc(CN(CC)CC)n2)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
49.7 mg (0.076 mmole) of the compound obtained in step 1 was dissolved in 1 ml of tetrahydrofuran and to the resulting solution was added 0.5 ml of aqueous 1N HCl solution. The resultant was stirred for 8 hours at room temperature, neutralized with aqueous 1N NaOH solution, concentrated under reduced pressure and purified with silica gel column chromatography to obtain 34.4 mg of the title compound (yield 77%).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([F:11])[CH:3]=1.[CH2:12]([N:19]1[CH2:23][CH:22]=[CH:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.[Li+].[Cl-].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C)C=O.C(OCC)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH2:12]([N:19]1[CH2:23][CH2:22][CH:21]([C:2]2[C:10]3[O:9][CH:8]=[CH:7][C:6]=3[CH:5]=[C:4]([F:11])[CH:3]=2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Fc1cc(Br)c2occc2c1
Reactant: C1=CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Fc1cc(C2CCN(Cc3ccccc3)C2)c2occc2c1
Temperature: 100 °C
Yield: 18.7 %

Procedure:
A mixture of 0.675 g (3.14 mMol) 7-bromo-5-fluorobenzofuran, 5.0 g (31.40 mMol)1-benzyl-3-pyrroline, 2.19 mL (12.56 mMol), N,N-diisopropylethylamine, 0.399 g (9.42 mMol) LiCl, 0.154 g (0.66 mMol) tri-2-furylphosphine, and 0.070 g (0.314 mMol) palladium diacetate in 10 mL N,N-dimethylformamide was heated under nitrogen at 100° C. for 48 hours. The mixture was diluted with 10 mL diethyl ether and filtered through celite. The filtrate was concentrated under reduced pressure and the oily residue was submitted to kugelrohr distillation to remove most of the pyrrole and pyrrolidine side-products. Flash chromatography of the residue (Et3N/Et2O/hexane 1:39:60) yielded 1-benzyl-3-(5-fluorobenzofur-7-yl)pyrrolidine (173 mg, 19%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:22]=1.[Cl:23][C:24]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:25]=1[C:26]([NH2:28])=[O:27]>>[C:26]([C:25]1[CH:29]=[CH:30][C:31]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:22]=2)=[CH:32][C:24]=1[Cl:23])(=[O:27])[NH2:28]
Reactant: CC1(C)OB(c2ccc(C(N)=O)c(Cl)c2)OC1(C)C
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Product: CC(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)c(Cl)c4)ccc3o2)CC1
Yield: 16.6 %

Procedure:
Following the General Procedure-2, the titled compound (30 mg) was prepared from Intermediate 13 (150 mg, 0.41 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (110 mg, 0.41 mmol) as a pale-yellow solid. M.P.: 178-181° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.04 (d, J 1.7, 1H), 7.88 (bs, 1H), 7.80 (d, J 1.7, 1H), 7.77 (d, J 8.5, 1H), 7.73-7.68 (m, 2H), 7.62-7.58 (m, 1H), 7.52 (d, J 8, 1H), 4.78 (septet, J 6.2, 1H), 3.97 (d, J 13.2, 2H), 3.34-3.24 (m, 1H), 3.10-3.00 (m, 2H), 2.15-2.05 (m, 2H), 1.75-1.65 (m, 2H), 1.19 (d, J 6.2, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9]2)=[N:6][CH:7]=1.Cl.[F:19][C@@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([N:22]3[CH2:23][CH2:24][C@@H:20]([F:19])[CH2:21]3)[CH2:9]2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)O[C@@H]1CCN(c2ccc(Br)cn2)C1
Reactant: F[C@@H]1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: F[C@@H]1CCN([C@H]2CCN(c3ccc(Br)cn3)C2)C1
Temperature: 70 °C
Yield: 98.6 %

Procedure:
Dissolve methanesulfonic acid (R)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-yl ester (0.23 g, 0.71 mmol) and (R)-3-fluoro-pyrrolidine hydrochloride (107 mg, 0.85 mmol) in DMF (5 mL) and add Cs2CO3 (0.69 g, 2.13 mmol). Warm to 70° C. overnight. Dilute with EtOAc (100 mL) and wash with H2O (3×100 mL). Dry with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 75-100% EtOAc/hexane to give 0.22g (100%) of the title compound. 1H-NMR (CDCl3), δ 1.87-2.00 (m, 1H), 2.00-2.09 (m, 1H), 2.18-2.30 (m, 2H), 3.40-3.80 (m, 9H), 5.10-5.28 (m, 1H), 5.34-5.40 (m, 1H), 6.28 (d, J=9.0 Hz, 1H), 7.51 (dd, J=9.0, 2.4 Hz, 1H), 8.18 (d, J=2.4 Hz, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH3:5].FC1C=CC(C2C=CC=CC=2)=CC=1.ClCCC(Cl)=[O:36].FC1C=CC(C2C=CC(C(=O)CCCl)=CC=2)=CC=1.C[Mg]I>>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)([OH:36])[CH3:5]
Reactant: O=C(Cl)CCCl
Reactant: CC(CCCl)c1ccc(-c2ccc(F)cc2)cc1
Agent: C[Mg]I
Agent: Fc1ccc(-c2ccccc2)cc1
Agent: O=C(CCCl)c1ccc(-c2ccc(F)cc2)cc1
Product: CC(O)(CCCl)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
A solution of 26.25 g of 1-chloro-3-(4'-fluoro-4-biphenylyl)-butane [obtainable by a Friedel-Crafts reaction of 4-fluoro-biphenyl with 3-chloropropionyl chloride to give 4'-fluoro-4-(3-chloropropionyl)-biphenyl (m.p. 96° - 97° ), reaction with CH3MgI to give 1-chloro-3-(4'-fluoro-4-biphenylyl)-butan-3-ol (m.p. 78° - 79° ) and reduction using HI] in 150 ml of absolute ethanol is added dropwise at 0° to a solution of 10 g of NH3 in 150 ml of absolute ethanol. The solution is stirred for a further 2 hours at 20°, concentrated and worked up with aqueous sodium hydroxide solution and ether to give 3-(4'-fluoro-4-biphenylyl)-butylamine; hydrochloride, m.p. 222° - 224°.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[N+:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[C-:12]>C1COCC1>[CH2:17]([O:16][C:14]([C:13]1[N:11]=[CH:12][O:7][C:6]=1[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1)=[O:15])[CH3:18]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ncoc1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
To a solution of 4-iodobenzoyl chloride (14.0 g, 0.052 mol) in 100 ml THF was added TEA (15.6 g, 0.156 mol) in a dropwise manner and the mixture was stirred for 10 minutes before slowly adding ethyl 2-isocyanoacetate (6.5 g, 0.058 mol). The reaction mixture was stirred at room temperature for 16 hours, the solvent was removed and the residue was treated with EtOAc and water. The organic layer was separated, dried over Na2SO4 and the solvent was removed. The crude product was purified by column to give the title compound (11.0 g, 61.7%) as an orange solid.