Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH2:36][CH2:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH2:36][CH2:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: CCCOc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1c[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCOc1ccc2c(c1CN1CCNCC1)O/C(=C\c1c[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-3-oxo-6-propoxy-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0705 g, 0.136 mmol) in methylene chloride (7 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (7 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate (14 mL), and the precipitated solid was collected by filtration. The resulting solid was washed with water, and then further washed with acetonitrile to obtain (Z)-2-[(1H-indol-3-yl)methylene]-7-(piperazin-1-ylmethyl)-6-propoxybenzofuran-3(2H)-one (0.0306 g, 53%).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:4]([NH:6][C@H:7]([C:15]([NH:17][C@H:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:20][S:21][CH3:22])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:3].[ClH:34].C1(OC)C=CC=CC=1.CCOC(C)=O>>[NH2:1][C@@H:2]([C:4]([NH:6][C@H:7]([C:15]([NH:17][C@H:18]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:20][S:21][CH3:22])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:3].[ClH:34]
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Product: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)N

Procedure:
Boc-DAla-Phe-Met-OCH3 (9.4 g) was treated with HCl/anisole/EtOAc as described in Step B to give H-DAla-Phe-Met-OCH3.HCl which was used without further purification.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:29]([O:36][CH2:37][C@@H:38]1[C@@H:43]([O:44][CH3:45])[C:42]([CH3:47])([CH3:46])[CH2:41][CH2:40][C@H:39]1[CH:48]=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C.[Li]CCCC>[CH3:45][O:44][C@H:43]1[C:42]([CH3:46])([CH3:47])[CH2:41][CH2:40][C@@H:39](/[CH:48]=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C@@H:38]1[CH2:37][O:36][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CO[C@@H]1[C@@H](COCc2ccccc2)[C@H](C=O)CCC1(C)C
Reactant: CCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCCCCC/C=C/[C@@H]1CCC(C)(C)[C@H](OC)[C@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
To a stirred solution of n-octyltriphenylphosphonium bromide (313 mg) in dry tetrahydrofuran (0.5 ml) and dry HMPA (0.5 ml), n-BuLi (0.44 ml, 1.6M solution in n-hexane) was added at 0° C. After the mixture was stirred at 0° C. for 30 min, a solution of (1R,2R,3R)-2-(benzyloxymethyl)-3-methoxy-4,4-dimethylcyclohexane-1-carbaldehyde (68 mg) in dry tetrahydrofuran (0.5 ml) was added to the resulting orange solution. The mixture was stirred at 0° C. for 30 min, and at room temperature for 2 hrs. The reaction was quenched by addition of saturated aqueous ammonium chloride solution. The mixture was extracted with diethyl ether, and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (using n-hexane:ethyl acetate=10:1 as an eluent) to give benzyl [(1R,2R,6S)-2-methoxy-3,3-dimethyl-6-[(E)-1-nonenyl]cyclohexyl]methyl ether (54 mg 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C@:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:12][C:11]3=[O:19].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[CH2:29]=O>CO>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]2[C@:10]3([CH2:20][O:21][C:5]=2[CH:4]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:22][N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)[C:11]3=[O:19]
Reactant: COc1cc2c(cc1C)[C@@]1(CO2)C(=O)Nc2ccccc21
Reactant: C=O
Reactant: CN1CCNCC1
Solvent: CO
Product: COc1cc2c(cc1C)[C@@]1(CO2)C(=O)N(CN2CCN(C)CC2)c2ccccc21
Yield: 91.8 %

Procedure:
A stirred solution of (3S)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.50 g, 1.8 mmol), N-methylpiperazine (1.80 g, 17.8 mmol) and formaldehyde (37% wt solution in water, 1.45 mL, 17.8 mmol) in methanol was refluxed for 3 h. The solution was concentrated in vacuo to dryness and dissolved in methanol (5 mL) and hydrochloric acid saturated methanol (10 mL). The solution was again concentrated in vacuo to dryness, dissolved in distilled water (25 mL) and the product was precipitated upon addition of 5 M NaOH (15 mL). The solid was filtered and air dried to afford (3S)-6-methoxy-5-methyl-1′-[(4-methylpiperazin-1-yl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.65 g, 93%). To a stirred solution of the above product (0.20 g) in methanol (1 mL) was added hydrochloric acid saturated methanol (2 mL). The solution was stirred for 20 min, then diethyl ether (25 mL) was added and the suspension was filtered and air dried to afford (3S)-6-methoxy-5-methyl-1′-[(4-methylpiperazin-1-yl)methyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one hydrogen chloride (0.19 g, 71%) as a colorless solid: mp>200° C. (dec.); 1H NMR (300 MHz, CDCl3) δ7.71 (s, 2H), 7.42 (d, J=7.9 Hz, 1H), 7.33 (dd, J=7.5, 7.5 Hz, 1H), 7.17-7.03 (m, 2H), 6.69 (s, 1H), 6.62 (s, 1H), 4.89-4.70 (m, 2H), 4.65 (d, J=9.40 Hz, 1H), 3.77 (s, 3H), 3.52-2.91 (m, 5H), 2.72 (s, 3H), 1.98 (s, 3H); MS (ES+) m/z 394.0 (M+1); Anal. Calcd. for C23H27N3O3.2.5HCl.2.5H2O: C, 52.15; H, 6.57; N, 7.93. Found: C, 52.07; H, 6.32; N, 8.50.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH2:6](N(CC)CC)C.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[S:24])=[CH:18][CH:17]=1)([O-:15])=[O:14].CI>CN(C=O)C>[CH3:6][S:24][C:23]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=1)=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: CCN(CC)CC
Reactant: N#CCC#N
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Solvent: CI
Solvent: CN(C)C=O
Product: CSC(Nc1ccc([N+](=O)[O-])cc1)=C(C#N)C#N
Reaction time: 0.08 h

Procedure:
Dissolved malononitrile (5.0 g) in DMF (50 mL), added triethylamine (1 eq), and stirred for 5 minutes before adding 4-nitrophenyl isothiocyanate (1 eq) dropwise, then stirred until complete by TLC (absence of 4-Nitrophenyl isothiocyanate, 3 hrs). Added methyl iodide (1 eq) dropwise, then stirred until intermediate was fully consumed (absent on TLC, 18 hrs); poured into 500 mL ice water, then filtered resulting solution to obtain 2-((methylthio)((4-nitrophenyl)amino)methylene)malononitrile as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C:29](=O)[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.Cl.[NH2:34][OH:35]>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:23][C@@H:24]3[CH2:28][O:27][C@@H:26]4[C:29](=[N:34][OH:35])[CH2:30][O:31][C@H:25]34)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: O=C1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: ON=C1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (3R,3aR,6aS)-3-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-2,3,3a,6a-tetrahydrofuro[3,2-b]furan-6-one (88 mg, 0.196 mmol) and hydroxylamine hydrochloride (39.5 mg, 0.568 mmol) in pyridine (0.5 ml) was stirred at room temperature for 2 hours. Then the reaction mixture was evaporated to give a foam, which was dissolved in methanol (2 mL) and purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water to give the title compound. Major Oxime stereoisomer LC-MS: calculated for C24H19ClN4O4 462.11 observed m/e: 463.18 (M+H)+ (Rt 1.20/2 min); 1H NMR δ (ppm) (CD3OD): 7.94 (s, 1H), 7.76 (ABq, 4H), 7.71 (d, 2H), 7.49 (dd, 2H), 7.39 (dd, 1H), 5.62 (m, 1H), 5.14 (t, 1H), 5.00 (d, 1H), 4.63 (s, 2H), 4.27 (dd, 2H) and 4.08 (dd, 1H). (Contains a small amount of minor oxime stereoisomer).
Reaction SMILES: [N:1]([CH2:4][C:5]1([CH2:9][N:10]=[N+:11]=[N-:12])[CH2:8][S:7][CH2:6]1)=[N+:2]=[N-:3].C(O)=[O:14].ClCCl.OO.[OH2:21]>>[N:10]([CH2:9][C:5]1([CH2:4][N:1]=[N+:2]=[N-:3])[CH2:6][S:7](=[O:14])(=[O:21])[CH2:8]1)=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=NCC1(CN=[N+]=[N-])CSC1
Reactant: O=CO
Reactant: O
Agent: OO
Solvent: ClCCl
Product: [N-]=[N+]=NCC1(CN=[N+]=[N-])CS(=O)(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 3,3-bis(azidomethyl)thietane (2.5 g, 13.59 mmol) in the mixture of formic acid (5 mL) and dichloromethane (6 mL) was added hydrogen peroxide (9.2 g, 81.54 mmol) slowly at 0° C. After being warmed slowly to room temperature and stirred at room temperature overnight, the mixture was diluted with water (10 mL) and extracted with dichloromethane (15 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography to afford 2.8 g of the desired product as a white solid (yield of two steps was 96%).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=O.COC(OC)[N:11]([CH3:13])C.Cl.[C:17]1([CH3:25])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23]N>C(O)(=O)C>[CH3:25][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[C:2]([C:1]([O:6][CH3:7])=[O:5])=[CH:4][CH:13]=[N:11]1
Reactant: Cc1ccccc1NN
Reactant: COC(OC)N(C)C
Reactant: COC(=O)C(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1ccnn1-c1ccccc1C
Temperature: 80 °C
Reaction time: 24 h
Yield: 49.6 %

Procedure:
A neat mixture of methyl pyruvate (11.37 mL, 125.9 mmol) and dimethylformamide dimethylacetal (16.72 mL, 125.9 mmol) was stirred at 80° C. for 24 h. The mixture was cooled and concentrated. A portion of the residue (4.00 g, 25.45 mmol) was dissolved in 50 mL of glacial acetic acid and then there was added o-tolylhydrazine hydrochloride (4.44 g, 27.99 mmol). This mixture was stirred at 100° C. for 18 h and then was cooled and concentrated. The residue was dissolved in ethyl acetate, washed with sat'd aq sodium carbonate and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (elution with 2:1 hexanes/ethyl acetate) to afford 3.0 g (55%) of the title compound. 1H NMR (CDCl3) δ7.70 (d, 1H), 7.4-7.2 (m, 4H), 7.00 (d, 1H), 3.71 (s, 3H), 2.00 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)=[CH:19][CH:18]=1)=[O:15].C1(O)C=CC=CC=1>ClCCl>[F:32][C:30]([F:31])([F:33])[C:27]1[CH:28]=[CH:29][C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:14]([N:10]3[CH2:11][CH2:12][CH:7]([CH2:6][NH:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:8][CH2:9]3)=[O:15])=[CH:18][CH:19]=2)=[N:25][CH:26]=1
Reactant: C1CC(CNCC2CC2)CCN1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(CNCC2CC2)CC1
Reaction time: 8 h

Procedure:
Cyclopropylmethyl-piperidine-4-ylmethyl-amine (0.65 mmol, 110 mg) was dissolve in dichloromethane. 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate (0.65 mmol, 0.208 g) (prepared from the corresponding phenol by conventional methods) was added at −15° C. for 15 min and stired at room temperature overnight and evaporated to dryness. The crude product was purified by preparative HPLC (Method C) (16%, colourless crystals). HPLC-MS m/z=450.1 (M+1), Rt: 2.98 min.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C1(C)C=CC(S(O[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)(=O)=O)=CC=1>>[CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:4]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(F)cc2)cc1
Reactant: CNC1CCNC1
Product: CNC1CCN(CCc2ccc(F)cc2)C1

Procedure:
3-Methylaminopyrrolidine and 2-(4-fluorophenyl)ethyl p-toluenesulfonate are reacted under the same conditions as in Starting Material Synthetic Example 4 to give 3-methylamino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([O:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([N:15]=[CH:16][N:17]([CH2:19][CH3:20])[CH3:18])=[C:10]([CH3:21])[CH:9]=2)=[N:4][C:3]=1[CH:22]=O.Cl.[NH2:25][O:26][C:27]([CH3:30])([CH3:29])[CH3:28].CO>O>[C:27]([O:26][N:25]=[CH:22][C:3]1[N:4]=[C:5]([O:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([N:15]=[CH:16][N:17]([CH2:19][CH3:20])[CH3:18])=[C:10]([CH3:21])[CH:9]=2)[S:6][C:2]=1[Cl:1])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCN(C)C=Nc1cc(C)c(Oc2nc(C=O)c(Cl)s2)cc1C
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: O
Solvent: CO
Product: CCN(C)C=Nc1cc(C)c(Oc2nc(C=NOC(C)(C)C)c(Cl)s2)cc1C
Temperature: 25 °C
Reaction time: 120 h
Yield: 74 %

Procedure:
A solution of 0.23 g (0.50 mmol) of N′-{4-[(5-chloro-4-formyl-1,3-thiazol-2-yl)oxy]-2,5-dimethylphenyl}-N-ethyl-N-methylimidoformamide and 63 mg (0.50 mmol) of 2-(aminooxy)-2-methylpropane hydrochloride in a solvent mixture of 10 ml of methanol and 3 ml of water was stirred at ambient temperature for 5 days. Evaporation of the solvents and column chromatography of the crude mixture (gradient cyclohexane->ethyl acetate) yielded 130 mg (0.37 mmol) 61% of N′-[4-({4-[(tert-butoxyimino)methyl]-5-chloro-1,3-thiazol-2-yl}oxy)-2,5-dimethylphenyl]-N-ethyl-N-methylimidoformamide. Log P (pH 2.3)=2.65
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([O:17][CH3:18])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:19]I>O1CCCC1.O>[CH3:19][C:13]1([C:15]([O:17][CH3:18])=[O:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CI
Reactant: COC(=O)C1c2ccccc2Oc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(C)c2ccccc2Oc2ccccc21
Reaction time: 0.17 h

Procedure:
9.61 g (0.04 mol) of methyl 9-xanthenecarboxylate (obtainable according to step 1.1.a) are dissolved in 150 mL of tetrahydrofuran, combined with a solution of 5.0 g (0.042 mol) potassium lert-butoxide in THF, and stirred for 10 minutes. 5 mL (0.08 mol) of methyl iodide are then added dropwise with gentle cooling; after all has been added, the mixture is stirred for 1 hour at ambient temperature. The reaction mixture is diluted with water to a total volume of 800 mL, extracted with diethyl ether, and the organic phase is extracted with saturated, aqueous Na2CO3 solution, washed with water, dried over magnesium sulfate, and the solvent is distilled off. The product is purified by recrystallization from methanol. Yield: 6.05 g of white crystals (70% of theoretical yield); melting point: 91° C.-92° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:20])[C@H:12]([C:17](O)=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.O>O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+].COC(C)(C)C>[CH2:1]([O:8][C:9](=[O:10])[N:11]([C@@H:12]([C@@H:13]([CH3:14])[CH2:15][CH3:16])[CH2:17][OH:18])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Agent: B
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)C
Product: CC[C@H](C)[C@@H](CO)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
To a solution of N-[(benzyloxy)carbonyl]-N-methyl-L-isoleucine (52.37 g, 187.5 mmol, 1 eq.) in tetrahydrofuran (524 mL, 0.35 M) was added borane-tetrahydrofuran complex (1 M in tetrahydrofuran, 375 mL, 375 mmol, 2 eq.) slowly over 1 hour and the reaction was allowed to stir for 18 hours at room temperature. The reaction was cooled to 0° C. and water (30 mL) was added over 30 minutes. The reaction mixture was diluted with 1 M aqueous sodium carbonate solution (100 mL) and tert-butyl methyl ether (250 mL). The aqueous layer was back-extracted with tert-butyl methyl ether (100 mL). The combined organic layers were washed with 1 M aqueous sodium carbonate solution (100 mL), washed with brine (200 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to provide #1 (48.44 g, 97% yield) as a pale yellow oil, which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers: δ 7.26-7.41 (m, 5H), [5.06 (AB quartet, JAB=12.9 Hz, ΔνAB=22.8 Hz) and 5.06 (AB quartet, JAB=9.0 Hz, ΔνAB=9.0 Hz), total 2H], [4.65 (t, J=5.3 Hz) and 4.59 (t, J=5.4 Hz), total 1H], 3.67-3.80 (m, 1H), 3.51-3.60 (m, 1H), 3.41-3.51 (m, 1H), 2.75 and 2.71 (2 s, total 3H), 1.49-1.64 (br m, 1H), 1.24-1.37 (br m, 1H), 0.90-1.02 (br m, 1H), 0.74-0.87 (m, 6H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]([OH:28])[CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:29]3[CH:34]=[CH:33][C:32]([O:35]C)=[CH:31][CH:30]=3)[S:8][C:7]=2[CH:37]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(OCC)(=O)C.CO>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]([OH:28])[CH2:22][N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:29]3[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=3)[S:8][C:7]=2[CH:37]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCC(O)CN3CCCC3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCS
Product: O=C(c1ccc(OCC(O)CN2CCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Yield: 67 %

Procedure:
[6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl][4-(2-hydroxy-3-pyrrolidinylpropoxy)phenyl]methanone (250 mg, 0.50 mmol) was converted to 164 mg of the title compound by the procedure of Example 32 using 0.18 mL (2.48 mmol) of ethanethiol (0.18 mL, 2.48 mol) and 398 mg (2.98 mmol) of aluminum chloride except that 6:4 ethyl acetate/methanol gradient was used as the chromatography eluent.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[CH:12]2[CH2:13][C:14](=[O:16])[CH2:15][CH:11]2[CH2:10][NH:9]1.C(=O)([O-])[O-].[K+].[K+].[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(#N)C>[N:23]1([C:29]([N:9]2[CH2:10][CH:11]3[CH2:15][C:14](=[O:16])[CH2:13][CH:12]3[CH2:8]2)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C1CC2CNCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C1CC2CN(C(=O)N3CCOCC3)CC2C1
Yield: 100 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one trifluoroacetate 1f (574 mg, 2.4 mmol) was dissolved in 20 mL of acetonitrile with stirring followed by addition of potassium carbonate (0.397 g, 2.88 mmol), and morpholine-4-carbonyl chloride (0.323 mL, 2.64 mmol) upon cooling by an ice-water bath. The reaction mixture was reacted overnight at the same temperature. The mixture was concentrated under reduced pressure and diluted with 50 mL of water. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2-(morpholine-4-carbonyl)-hexahydro-cyclopenta[c]pyrrol-5-one 7a (0.572 g, yield 77.3%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:8]2=[N:9][CH:10]=1)=[O:4].C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[CH:49](=[O:54])[CH2:50][CH:51]([CH3:53])[CH3:52]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([CH:49]([OH:54])[CH2:50][CH:51]([CH3:53])[CH3:52])[N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: CC(C)CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COC(=O)c1cnc2c(c1)cc(C(O)CC(C)C)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 36.8 %

Procedure:
To a suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (2.0 g, 6.33 mmol) in dry tetrahydrofuran (15 mL) at −78° C. was added freshly prepared lithium diisopropylamide [prepared by adding 1.6 M n-butyllithium in n-hexane (5.3 mL, 8.55 mmol) to a 0° C. solution of diisopropylamine (1.3 mL, 9.2 mmol) in dry tetrahydrofuran (40 mL)] dropwise. The mixture was stirred at −78° C. for 5 min and then treated with isovaleraldehyde (1.4 mL, 13.3 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and then quenched with brine. The mixture was extracted with ethyl acetate (2×150 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 15% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-(1-hydroxy-3-methyl-butyl)-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester as a colorless oil (938 mg, 35%): LC/MS m/e calcd for C20H23N2O5S [M+H]+ 403.47, observed 403.3; 1H NMR (400 MHz, CDCl3) δ ppm 1.04 (d, J=6.4 Hz, 3H), 1.06 (d, J=6.4 Hz, 3H), 1.82 (m, 1H), 1.94-2.03 (m, 2H), 3.30 (br, 1H), 3.94 (s, 3H), 5.45 (m, 1H), 6.70 (s, 1H), 7.49 (m, 2H), 7.59 (m, 1H), 8.19 (m, 2H), 8.41 (d, J=2.0 Hz, 1H), 9.01 (d, J=2.0 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([F:12])=[C:7]([OH:13])[CH:6]=[CH:5]2.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[F:26])(O)O>>[F:26][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:17]=1[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:13])[C:8]=2[F:12])[CH:3]=1)[C:21]([OH:23])=[O:22]
Reactant: O=C(O)c1ccc(B(O)O)c(F)c1
Reactant: Oc1ccc2cc(Br)ccc2c1F
Product: O=C(O)c1ccc(-c2ccc3c(F)c(O)ccc3c2)c(F)c1

Procedure:
Followed the coupling procedure described in Example 29 starting from 6-bromo-1-fluoronaphthalen-2-ol (Intermediate 13) and 4-borono-3-fluorobenzoic acid. 1H-NMR (DMSO-d6, 300 MHz, TMS): δ 13.32 (b, 1H), 10.28 (b, 1H), 8.14 (s, 1H), 7.98 (d, 1H), 7.78 (d, 1H), 7.73-7.76 (m, 4H), 7.32 (t, 1H), MS (ESI): m/z=299.40 [M−1]−.