Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[S:7][C:8]=1[CH3:9])([O-:3])=[O:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH3:19])/[CH:18]=[CH:9]/[C:8]1[S:7][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Reactant: COC(OC)N(C)C
Product: COC(=O)c1cc([N+](=O)[O-])c(/C=C/N(C)C)s1
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of methyl 4-nitro-5-methylthiophene-2-carboxylate (23 g, 114 mmol) in N,N-dimethylformamide dimethyl acetal (115 ml) was stirred at 110° C. for 1 hr. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to about half amount, and poured into water (500 ml). The precipitated solid was collected by filtration, washed with water (500 ml×2), and dried under reduced pressure to give methyl (E)-5-(2-dimethylaminovinyl)-4-nitrothiophene-2-carboxylate (28 g, yield 96%).
Reaction SMILES: [NH:1]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O>[N+:13]([C:10]1[CH:11]=[CH:12][C:2]2[NH:1][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=2[CH:9]=1)([O-:15])=[O:14]
Reactant: O=C1CCCc2ccccc2N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1CCCc2cc([N+](=O)[O-])ccc2N1
Reaction time: 0.5 h

Procedure:
A solution of 4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (1.42 g, 8.81 mmol) in conc. H2SO4 (25 mL) was treated with fuming HNO3 (414 μL, 8.81 mmol) at −5 to −10° C. (ice/MeOH). The resulting solution was stirred at the same temperature for 30 minutes. The reaction was quenched with the addition of crushed ice. The resulting suspension was diluted with H2O (50 mL) and filtered. The solid was washed with 4×50 mL H2O, collected and dried under reduced pressure overnight. Yield: 1.0 g, 55.1%. 1H-NMR (DMSO-d6) δ 10.08 (s, 1H), 8.19 (d, J=2.4 Hz, 1H), 8.11 (dd, J=2.4, 8.7 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H), 2.83-2.79 (m, 2H), 2.26-2.13 (m, 4H). MS (EI): 206 (M+).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12](=[O:22])[N:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:14]=[C:15](I)[CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1(OB(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([C:11]1[C:12](=[O:22])[N:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCn1cc(I)cc(C(=O)NCc2ccccc2)c1=O
Reactant: OB(O)Oc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCn1cc(-c2ccccc2)cc(C(=O)NCc2ccccc2)c1=O
Temperature: 90 °C
Reaction time: 18 h
Yield: 87.6 %

Procedure:
To a solution of 1-butyl-5-iodo-2-oxo-1,2-dihydropridine-3-carboxylic acid benzylamide (3-067) (100 mg) in DMF (2.0 mL) were added Pd(PPh3)4 (20 mg), phenyl boric acid (89 mg), and an aqueous solution of potassium carbonate (2 mole/L, 0.24 mL) at room temperature. After stirred at 90° C. for 18 h, to the reaction mixture were added a saturated aqueous solution of ammonium chloride and ethyl acetate. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by the preparative thin-layer chromatography (toluene/acetone=7/1) to give 1-butyl-2-oxo-5-phenyl-1,2-dihydropridine-3-carboxylic acid benzylamide (3-068) (77 mg, 88%) as an oil.
Reaction SMILES: C([Li])CCC.CCCCCC.[Br:12][C:13]1[CH:17]=[C:16](Br)[N:15]([CH3:19])[N:14]=1.Cl[C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1.[Cu](I)I.O>[Br:12][C:13]1[CH:17]=[C:16]([C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:15]([CH3:19])[N:14]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cn1nc(Br)cc1Br
Agent: I[Cu]I
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(=O)c1cc(Br)nn1C
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 62.5 %

Procedure:
Under nitrogen atmosphere, n-butyllithium 1.6M in hexane (6.5 mL, 10.42 mmol) was added dropwise to a solution of 3,5-dibromo-1-methyl-1H-pyrazole (11d) (2.00 g, 8.34 mmol) in anhydrous tetrahydrofuran (40 mL) at −78° C. After 30 minutes stirring at the same temperature, copper iodide (5.56 g, 29.18 mmol) was added. The temperature was allowed to reach 0° C. for 40 minutes, then cooled to −78° C. Ethyl chlorooxoacetate (2.80 mL, 25.01 mmol) was dropwise added. The mixture was stirred at room temperature for 2 hours. Water (20 mL) was added and the mixture was extracted with ethyl acetate (2×30 mL). The organic layer was washed with a saturated solution of sodium hydrogenocarbonate (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 100/0 to 80/20) to provide ethyl 2-(3-bromo-1-methyl-1H-pyrazol-5-yl)-2-oxoacetate (11e) (1.36 g, 5.21 mmol, 62%).
Reaction SMILES: C([N:8]1[C@@H:13]([CH:14]=[CH:15][CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:19])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH3:19][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH:14]=[CH:15][CH:16]([CH3:18])[CH3:17])[NH:8]1
Reactant: CC(C)C=C[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C=C[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-methyl-6-(1-isopentenyl)piperidine (1.5 g, 5.56 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 90 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-methyl-6-(1-isopentenyl)piperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occurred. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 157.5-156.5° C.; 1H NMR (250 MHz) δ 9.37 (br. d, 2H), 5.59-5.46 (m, 2H), 4.19 (s, 1H), 3.59 (s, 1H), 2.66-2.59 (m, 1H), 1.8-1.5 (m, 9H), 1.0 (pair of d, 6H); 13C NMR (62.7 MHz) δ 143.6 (s), 120.6 (s), 48.3 (s), 47.9 (s), 28.9 (s), 28.6 (s), 27.3 (s), 23.01 (s), 22.6 (s), 17.5 (s), 16.9 (s). FT-IR (neat): 3426, 3188, 3018, 2952, 1625, 1584, 1464, 1359, 1180, 1099, 958, 881. Elemental Analysis for C11H22NCl: C, 64.84%; H, 10.91%; N, 6.87%. Found: C, 64.06%; H, 10.77%; N, 6.78%.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:10]([OH:12])=O)[CH2:6][CH2:7][S:8][CH3:9])(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].II.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>C(Cl)Cl.C(O)(=O)C.O1CCCC1.C(#N)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:10](=[O:12])[C@H:5]([CH2:6][CH2:7][S:8][CH3:9])[NH:4][C:1](=[O:3])[CH3:2])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CSCC[C@H](NC(C)=O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: II
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC#N
Product: CSCC[C@H](NC(C)=O)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 108.6 %

Procedure:
A solution of 4.78 g (0.025 mol) of N-acetyl-L-methionine in CH2Cl2: acetonitrile (120 ml) was cooled to 0° C. To this solution was added 5.36 g (0.025 mol) of dicyclohexylcarbodiimide (DCC) followed by the rapid addition of 3.90 g (0.021 mol) of N-t-butoxycarbonylpiperazine in 6 ml of dichloromethane. The progress of the reaction was followed on silica gel TLC plates developed with 4:1 acetonitrile: tetrahydrofuran and visualized with either iodine or ninhydrin spray. The reaction was complete within 2 h. A few drops of glacial acetic acid were added to the reaction mixture and the solvent was removed on a rotary evaporator. The residue was taken up in ether and filtered. The clear filtrate was washed with dilute acid followed by dilute base. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated to give 8.2 g of 1-(t-butoxycarbonyl) -4-(N-acetyl-L-methionyl)piperazine, a colorless oil which required no further purification: IR (film) 3304, 3058, 2973, 2931, 2868, 1701, 1645, 1539, 1420, 1237, 1173 cm−1; NMR (CDCl3) δ 1.47 (s, 9 H), 1.80 (m, 2 H), 2.02 (s, 3 H), 2.10 (s, 3 H), 2.46 (m, 2 H), 3.53 (m, 8 H), 5.10 (M, 1 H), 6.35 (b, 0.5 H), 6.43 (b, 0.5 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1([CH3:24])[C:20]2[CH:21]=[CH:22][S:23][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[S:23][CH:22]=[CH:21][C:20]=4[C:15]3([CH3:24])[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1(C)NCCc2sccc21
Product: CC1(C)c2ccsc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4,4-dimethyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:32][CH3:33])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[NH:22][C:23]([CH:30]=O)=[C:24]([C:27](=[O:29])[CH3:28])[C:25]=1[CH3:26])=[O:20])[CH3:13].C(OC(C1NC(C=O)=C(C(=O)C)C=1C)=O)C>>[CH2:32]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[NH:22][C:23]([CH:30]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[C:24]([C:27](=[O:29])[CH3:28])[C:25]=1[CH3:26])=[O:20])[CH3:33]
Reactant: CCN(CC)CCCNC(=O)c1[nH]c(C=O)c(C(C)=O)c1C
Reactant: O=C1Cc2cc(Br)ccc2N1
Agent: CCOC(=O)c1[nH]c(C=O)c(C(C)=O)c1C
Product: CCN(CC)CCCNC(=O)c1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C(C)=O)c1C

Procedure:
5-Bromo-1,3-dihydro-indol-2-one was condensed with 4-acetyl-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide (prepared from 4-acetyl-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester by method B then C) to give the title compound.
Reaction SMILES: C1(O[C:8](=[S:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)[CH2:33][CH2:32]2)=[S:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: COc1nc(C)c(C)cc1NC(=S)Oc1ccccc1
Reactant: Clc1cccc(N2CCNCC2)c1
Product: COc1nc(C)c(C)cc1NC(=S)N1CCN(c2cccc(Cl)c2)CC1
Yield: 69 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH:6]([CH3:9])[C:7]#[N:8].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH:6]([CH3:9])[CH2:7][NH2:8]
Reactant: COc1ccccc1OC(C)C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccccc1OC(C)CN
Temperature: 65 °C
Yield: 6.5 %

Procedure:
To a solution of 2-(2-methoxy-phenoxy)-propionitrile (3.91 g, 0.022 mol) in anhydrous ethyl ether (30 ml) was added lithium aluminum hydride (1.0 M, 44 ml, 0.044 mol). The mixture was heated at 65° C. for 18 hours and the reaction was quenched with water (3 ml), 15% NaOH (3 ml) and water (9 ml). The resulting material was filtered through celite. The celite was washed with methanol (200 ml), and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride) afforded 0.26 g (7%) of product as yellow oil. MS EI m/e 181 (M+).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:12]2[CH:22]=[CH:21][C:15]([C:16](OCC)=[O:17])=[CH:14][CH:13]=2)=[CH:5][N:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([C:3]1[C:4]([C:12]2[CH:13]=[CH:14][C:15]([CH2:16][OH:17])=[CH:21][CH:22]=2)=[CH:5][N:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2)[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cn3ccccc3c2CC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1c(-c2ccc(CO)cc2)cn2ccccc12
Yield: 94 %

Procedure:
The general synthetic pathway outlined in example 1, step 1-2, have been applied to proper starting materials in the preparation of ethyl 4-(1-ethylindolizine-2-yl)benzoate, which was reduced with lithium aluminium hydride by the general synthetic principles outlined in example 1, step 4, to afford 1-ethyl-2-(4-hydroxymethylphenyl)indolizine in 94% yield. 1H-NMR (CDCl3, 200 MHz) δ: 1.20 (t, 3H); 2.88 (q, 2H); 4.72 (s, 2H); 6.41 (ddd, 1H); 6.61 (ddd, 1H); 7.29-7.52 (m, 6H); 7.83 (d, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]([CH3:32])[C:23]3[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:24]=3[N:25]=2)=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13])[CH2:8][CH3:9].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[NH2:31][CH2:30][C:28]1[CH:27]=[CH:26][C:24]2[N:25]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([CH2:14][N:10]([CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12][CH3:13])=[CH:16][CH:17]=3)[N:22]([CH3:32])[C:23]=2[CH:29]=1
Reactant: CCCN(CCC)Cc1ccc(-c2nc3ccc(C#N)cc3n2C)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)Cc1ccc(-c2nc3ccc(CN)cc3n2C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
Lithium aluminum hydride (64.0 mg) was suspended in THF (5.0 ml) and the whole was cooled to 0° C. A THF solution (5.0 ml) containing the compound (155 mg) obtained in Example 29-5 was dropped therein and the whole was stirred at 0° C. for 1 hour. After completion of the reaction, sodium sulfate decahydrate was added thereto until bubbling was stopped, and a 1 mol/l sodium hydroxide aqueous solution was then added thereto until a white precipitate was generated. A solid was separated by filtration and the solvent in the filtrate was then distillated off under reduced pressure, and the residue was dried under vacuum, thereby obtaining the subject compound (93.5 mg) as a yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([CH3:21])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([CH:12]=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[Cl:22]Cl>C(O)(=O)C>[CH3:21][C:16]1[CH:17]=[C:18]([F:20])[CH:19]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([Cl:22])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: ClCl
Reactant: Cc1cn2cccc(OCc3c(C)cc(F)cc3C)c2n1
Solvent: CC(=O)O
Product: Cc1cc(F)cc(C)c1COc1cccn2c(Cl)c(C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a solution of 8-(2,6-dimethyl-4-fluorobenzyloxy)-2-methylimidazo[1,2-a]pyridine (0.6 g, 2.1 mmol) in acetic acid (13 ml) was added dropwise 1.1 M Cl2 in acetic acid (2.2 ml, 2.43 mmol). The reaction mixture was stirred for 2 h. at room temperature and the solvent was evaporated under reduced pressure. The residue weas solved in methylene chloride and was washed with water. The organic layer was separated, dried and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride:ethyl acetate (100:4) as eluent. Treating the residue with diethyl ether and filtration gave 0.3 g (45%) of the title compound.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=1)=[O:14].Br[C:31]1[S:35][C:34]([C:36]([N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:37])=[CH:33][CH:32]=1>>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:31]2[S:35][C:34]([C:36]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:37])=[CH:33][CH:32]=2)=[CH:17][CH:16]=1)=[O:14]
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C(c1ccc(Br)s1)N1CCCCC1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2ccc(C(=O)N3CCCCC3)s2)cc1
Yield: 48 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure A using [2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (550 mg, 1.4 mmol) and (5-Bromo-thiophen-2-yl)-piperidin-1-yl-methanone (CAS 626242-11-3) (315 mg, 1.2 mmol) to give 260 mg (48% yield). MS (ES+) 466.2 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][O:29]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: OCCc1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: c1ccc(COc2ccc(CCOC3CCCCO3)cc2)cc1
Reaction time: 4 h

Procedure:
To a solution of 1-benzyloxy-4-(2-hydroxyethyl)benzene (7, 20 g, 87.7 mmoles) in CH2Cl2 (175 mL) was added 4-toluenesulfonic acid (TsOH, 0.17 g, 0.9 mmoles) and dihydropyran (9.9 mL dropwise, 108 mmoles). The mixture was stirred for 4 h and the solvent evaporated under reduced pressure to yield 28 g of crude product. This was purified by flash chromatography (solvent=70:30 ethyl acetate:heptane). The pure fractions were pooled and the solvent evaporated to give 1-benzyloxy-4-(2-tetrahydropyran-2-yloxyethyl)benzene (8, 26.5 g). NMR (CDCl3)δppm: 7.30(s, 5H); 6.97(q, 4H); 4.95(s, 2H); 7.87(s, 1H); 4.2-3.4(m, 4H); 2.8(t, 2H); 1.9-1.3(m, 6H). (Scheme II, Step 3.)
Reaction SMILES: C(OC([N:8]([C:13]1[CH:51]=[CH:50][C:16]([C:17]([O:19][CH2:20][C:21]([O:23][C@H:24]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]3[CH2:49][CH2:48]3)[CH:36]=2)[CH2:25][C:26]2[C:31]([Cl:32])=[CH:30][N+:29]([O-:33])=[CH:28][C:27]=2[Cl:34])=[O:22])=[O:18])=[CH:15][C:14]=1[O:52][CH2:53][CH:54]1[CH2:56][CH2:55]1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.O1CCOCC1>C(Cl)Cl.Cl>[Cl:34][C:27]1[CH:28]=[N+:29]([O-:33])[CH:30]=[C:31]([Cl:32])[C:26]=1[CH2:25][C@@H:24]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:43])[F:44])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)[O:23][C:21](=[O:22])[CH2:20][O:19][C:17](=[O:18])[C:16]1[CH:50]=[CH:51][C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:14]([O:52][CH2:53][CH:54]2[CH2:55][CH2:56]2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of (S)-4-(2-(2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (2.457 g, 2.91 mmol) in dry DCM (85 ml), HCl 4M in dioxane (7.26 ml, 29.1 mmol) was added, and the reaction was stirred at RT overnight. Then the solvent was evaporated and the residue was purified by flash chromatography on silica gel (eluent: DCM/MeOH 99:1). Combined fractions were evaporated and the resulting solid was triturated with EtOH/MeOH 95:5 to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)-benzoyloxy)acetoxy)ethyl)pyridine 1-oxide as a white solid (1.761 g, 2.362 mmol, 81% yield, MS/ESI+ 745.13 [MH]+, [αD]=−34.69, c=0.49, DCM).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([Br:19])[CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3Br)=[CH:4][CH:3]=1.[F:28][C:29]([F:41])([F:40])[S:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)(=[O:32])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>CCOC(C)=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2]>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([Br:19])[CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[NH:39][CH:36]2[CH2:37][CH2:38][N:33]([S:30]([C:29]([F:40])([F:41])[F:28])(=[O:32])=[O:31])[CH2:34][CH2:35]2)=[CH:26][CH:25]=1
Reactant: Clc1ccc(C(c2ccc(Cl)cc2)c2cc(Br)c3nccc(Br)c3c2)cc1
Reactant: NC1CCN(S(=O)(=O)C(F)(F)F)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)(N1CCC(Nc2ccnc3c(Br)cc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1)C(F)(F)F
Temperature: 95 °C

Procedure:
A mixture of 6-(bis(4-chlorophenyl)methyl)-4,8-dibromoquinoline (40 mg, 0.0766 mmol), 1-((trifluoromethyl)sulfonyl)piperidin-4-amine (22.6 mg, 0.0843 mmol), Pd2(dba)3 (3.5 mg, 0.00383 mmol), dppf (7.2 mg, 0.013 mmol), Cs2CO3 (62.4 mg, 0.192 mmol) and 1,4-dioxane (0.9 mL) was heated under argon to 95° C. overnight. The reaction was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organics were concentrated and purified by silica column (45% EtOAc/hexanes) chromatography to yield 6-(bis(4-chlorophenyl)methyl)-8-bromo-N-(1-((trifluoromethyl)sulfonyl)piperidin-4-yl)quinolin-4-amine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:36][CH2:35][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26](OS(C)(=O)=O)[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26]([N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:35][CH2:36]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(OS(C)(=O)=O)CC3)cc1F)C2=O
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(N4CCCC4)CC3)cc1F)C2=O
Temperature: 80 °C

Procedure:
2-[2-Fluoro-4-(4-methanesulfonyloxy-cyclohexyl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (Intermediate 28) (150 mg, 0.3 mmol, 1 equiv.) and pyrrolidine (84.3 mg, 1.19 mmol) were dissolved in anhydrous CH3CN (2 mL). To this colorless solution was added powder K2CO3 at r.t. The suspension was heated in an oil bath maintained at 80° C. for 24 h. The suspension was concentrated to dryness. The residue was taken in water (2 mL) and DCM (2 mL). The two layers were separated, and the aqueous layer was extracted with DCM (2 mL×2). The combined DCM extracts were washed with sodium bicarbonate (2 mL), brine (2 mL), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo. The crude product was purified on a silica gel column, eluted with 5% of MeOH in DCM and 5% 7N NH3 of MeOH solution in DCM to afford the title compound.