Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Si]([O:9][C@@H:10]([CH2:20][C@H:21]([O:61][Si](C(C)(C)C)(C)C)/[CH:22]=[CH:23]\[C@H:24]([CH3:60])[C@H:25]([O:52][Si](C(C)(C)C)(C)C)[C@@H:26]([CH3:51])[CH2:27][C@@H:28]([CH3:50])[CH2:29][CH2:30][C@@H:31]([O:42][Si](C(C)(C)C)(C)C)[C@H:32]([CH3:41])[C@@H:33]([OH:40])[C@@H:34]([CH3:39])/[CH:35]=[CH:36]\[CH:37]=[CH2:38])[C@H:11]([CH3:19])/[CH:12]=[CH:13]/[CH:14]=C\C(O)=O)(C(C)(C)C)(C)C.C[CH2:70][O:71][C:72]([CH3:74])=[O:73]>C1COCC1.O>[CH3:70][O:71][C:72](=[O:73])/[CH:74]=[CH:14]\[CH:13]=[CH:12]\[C@@H:11]([CH3:19])[C@@H:10]([OH:9])[CH2:20][C@H:21]([OH:61])/[CH:22]=[CH:23]\[C@H:24]([CH3:60])[C@H:25]([OH:52])[C@@H:26]([CH3:51])[CH2:27][C@@H:28]([CH3:50])[CH2:29][CH2:30][C@@H:31]([OH:42])[C@H:32]([CH3:41])[C@@H:33]([OH:40])[C@@H:34]([CH3:39])/[CH:35]=[CH:36]\[CH:37]=[CH2:38]
Reactant: CCOC(C)=O
Reactant: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](CC[C@H](C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/C=C\C(=O)O)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O)CC[C@H](C)C[C@H](C)[C@@H](O)[C@@H](C)/C=C\[C@@H](O)C[C@H](O)[C@H](C)/C=C/C=C\C(=O)OC
Reaction time: 24 h
Yield: 36 %

Procedure:
3N HCl (10 mL, prepared by adding 2.5 mL of conc. HCl to 7.5 mL MeOH) was added to a stirred solution of the macrolactonization precursor 48 (23 mg, 23 μmol) in THF (3 mL) at 0° C. After 24 h at room temperature, the reaction mixture was diluted with EtOAc (4 mL) and H2O (4 mL). The organic phase was retained and aqueous phase was extracted with EtOAc (2×4 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (10 mL), dried with MgSO4, filtered and concentrated. The residue was purified by flash chromatography (EtOAc/hexane 3:2) to yield the product 50 (4.5 mg, 36%) as a colorless oil: IR (CHCl3) 3399, 2917, 2849, 1713, 1635, 1600, 1461, 1439, 1197, 1178, 970, 757 cm−1; 1H NMR (600 MHz, CD3OD) δ 7.36 (dd, J=15.3, 11.2 Hz, 1H), 6.67 (ddd, J=16.9, 11.1, 10.6 Hz, 1H), 6.63 (dd, J=11.3, 11.3 Hz, 1H), 6.14 (dd, J=15.4, 8.3 Hz, 1H), 6.03 (dd, J=11.0, 1.0 Hz, 1H), 5.59 (d, J=11.4 Hz, 1H), 5.43 (dd, J=10.7, 10.7 Hz, 1H), 5.42 (dd, J=10.8, 9.2 Hz, 1H), 5.32 (dd, J=10.4, 10.4 Hz, 1H), 5.17 (dd, J=16.8, 2.0 Hz, 1H), 5.08 (d, J=10.2 Hz, 1H), 4.61 (ddd, J=12.9, 8.5, 4.6 Hz, 1H), 3.80 (ddd, J=8.9, 4.4, 4.4 Hz, 1H), 3.69 (s, 3H), 3.63 (m, 1H), 3.46 (t, J=5.8 Hz, 1H), 3.13 (dd, J=8.0, 3.2 Hz, 1H), 2.93 (m, 1H), 2.71 (m, 1H), 2.38 (m, 1H), 1.73 (m, 1H), 1.56-1.53 (m, 3H), 1.52-1.46 (m, 2H), 1.44-1.36 (m, 3H), 1.09 (d, J=6.9 Hz, 3H), 0.98 (d, J=6.8 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H), 0.95 (m, 2H), 0.94 (d, J=6.9 Hz, 3H), 0.87 (d, J=6.6 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H); 13C NMR (150 MHz, CD3OD) δ 168.4, 148.5, 146.9, 135.7, 135.4, 133.85, 133.82, 130.6, 128.2, 117.7, 116.2, 79.2, 78.5, 74.8, 72.4, 65.8, 51.5, 45.1, 43.2, 43.0, 41.0, 37.2, 36.5, 34.0, 33.3, 33.1, 31.0, 20.7, 18.6, 18.4, 16.7, 13.8, 7.8; LRMS (ESI) 587.5 [M+Na]+, 559.2, 485.2, 413.3, 355.1, 212.1; HRMS (ESI) calcd for C33H56O7Na 587.3924 [M+Na]+, found 587.3953; [α]20D+8.7 (c 0.30, CDCl3).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17][OH:18])[CH2:3][CH2:2]1.O[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]=[C:31]([C:36]([O:38][CH3:39])=[O:37])[CH:30]=[CH:29]3)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:10]([Cl:16])=[CH:11][CH:12]=[CH:13][C:14]=3[Cl:15])[C:5]=2[CH2:17][O:18][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]=[C:31]([C:36]([O:38][CH3:39])=[O:37])[CH:30]=[CH:29]4)=[CH:24][CH:25]=2)[CH2:3][CH2:2]1
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3)ccc2n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To a solution of [5-cyclopropyl-3-(2,6-dichlorophenyl) -4-isoxazolyl]methanol (0.10 g, 0.36 mmol), methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (0.10 g, 0.36 mmol) and triphenylphosphine (0.10 g, 0.39 mmol) in dichloromethane (2.5 mL) was added diisopropyl azodicarboxylate (0.071 mL, 0.39 mmol) dropwise. The solution was heated in a microwave reactor to 90° C. for 10 minutes and then allowed to sit overnight. The solution was adsorbed onto silica gel and purified by chromatography (silica gel, 0-45% ethyl acetate in hexanes gradient elution) to afford methyl 6-[4-({[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (62 mg, 32%). 1H-NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=9 Hz, 1H), 8.28 (s, 1H), 8.18-8.10 (m, 3H), 7.73 (d, J=9 Hz, 2H), 7.62-7.50 (m, 3H), 6.95 (d, J=9 Hz, 2H), 4.93 (s, 2H), 3.93 (s, 3H), 2.50-2.42 (m, overlapping DMSO ˜1H), 1.20-1.12 (m, 4H). LRMS (APCI) m/z 545 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[N:14]=[C:13]([C:15]([O:17]C)=O)[CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.[CH3:19][C:20]#[N:21]>>[O:17]=[C:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([O:8][CH2:7][CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[N:14]=1)[CH2:19][C:20]#[N:21]
Reactant: COC(=O)c1cccc(OCC2CCOCC2)n1
Reactant: CC#N
Product: N#CCC(=O)c1cccc(OCC2CCOCC2)n1

Procedure:
Reaction between methyl 6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinate and CH3CN following the method used in Example 6 gives 3-oxo-3-(6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-2-yl)propanenitrile.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH2:19][CH2:18]2.CI.[NH4+].[Cl-]>C1COCC1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[CH:19]([CH3:1])[CH2:18]2
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC(C)C2=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
To a solution of diisopropylamine (5.2 mL, 36.9 mmol), in THF (20 mL) is added n-BuLi (14.8 mL, 36.9 mmol, 2.5 M in hexane) at −78° C. After 30 min, 5-methoxyindan-1-one (5.0 g, 30.8 mmol) in THF (35 mL) is added. After it is stirred at −78° C. for 1 h, the mixture is warmed to 10° C. for 30 min. The mixture is cooled again to −78° C. and methyl iodide (2.3 mL, 36.9 mmol) is added. The mixture is then warmed to RT over 1 h. NH4Cl solution is added and extracted with EtOAc. The organic extract is dried with MgSO4, concentrated and purified by chromatography to give the title compound (2.38 g): (M+H)+=177.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=[O:6].[C:15]([Mg]Cl)#[CH:16]>C1COCC1>[OH:6][CH:5]([C:4]1[CH:7]=[C:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])[C:15]#[CH:16]
Reactant: COc1cc(OC)c(OC)cc1C=O
Reactant: C#C[Mg]Cl
Solvent: C1CCOC1
Product: C#CC(O)c1cc(OC)c(OC)cc1OC

Procedure:
3-Hydroxy-3-(2,4,5-trimethoxyphenyl)-1-propyne was prepared according to Method A above from 2,4,5-trimethoxybenzaldehyde (0.784 g, 4 mmol) (Aldrich) in THF (20 mL) and ethynylmagnesium chloride (5 mmol, 10 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 548 mg, 71%).
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([NH:15][C:16]([CH3:18])=[O:17])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])C=C.O.CN1C[CH2:24][CH2:23][C:22]1=O>>[OH:4][C:5]1[C:14]([CH2:24][CH:23]=[CH2:22])=[C:13]([NH:15][C:16]([CH3:18])=[O:17])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CN1CCCC1=O
Reactant: C=CCOc1cc(NC(C)=O)ccc1C(=O)OC
Solvent: O
Product: C=CCc1c(NC(C)=O)ccc(C(=O)OC)c1O

Procedure:
84 g of methyl 2-allyloxy-4-acetaminobenzoate and 84 g of N-methylpyrrolidone were introduced into a 500 ml round-bottomed flask. The contents were heated quickly to reflux which was then maintained for 30 minutes, and the solution was then cooled slightly and poured into water. Crystallation was immediate. The same operations were repeated with the same quantities of methyl 2-allyloxy-4-acetaminobenzoate and N-methylpyrrolidone and the products from the two trials were combined and cooled, drained, washed with water and dried at 50° C.
Reaction SMILES: [CH2:1]([C:3]1([CH2:26][CH2:27][OH:28])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][C:11]=3[CH:23]([CH3:25])[CH3:24])[CH3:2].[H][H]>Cl.CCO.[Pd]>[CH2:1]([C:3]1([CH2:26][CH2:27][OH:28])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][C:13]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][C:11]=3[CH:23]([CH3:24])[CH3:25])[CH3:2]
Reactant: CCOC(=O)/C=C/c1cc(C(C)C)c2[nH]c3c(c2c1)CCOC3(CC)CCO
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCc1cc(C(C)C)c2[nH]c3c(c2c1)CCOC3(CC)CCO
Yield: 37 %

Procedure:
To a suspension of (E)-ethyl 3-(1-ethyl-1,3,4,9-tetrahydro-1-(2-hydroxyethyl)-8-isopropylpyrano[3,4-b]indol-6-yl)acrylate (0.8 g, 2.3 mmol) in 2% HCl in EtOH (80 ml) was added palladium on carbon (10%, 0.5 g). The mixture was stirred under an atmoshphere of hydrogen (1 am) at room temperature for 24 hr. The catalyst filtered through celite. The filtrate was evaporated at reduced pressure. The residue was neutralized with sat. NaHCO3, extracted with EtOAc, and dried over MgSO4. The solvent was concentrated under reduced pressure and purified by silica gel flash column chromatography hexane/EtOAc (6:4) to give the product (0.33 g, 38%). 1H NMR (300 MHz, CDCl3) δ 7.72 (br, NH), 7.18 (d, 1H), 6.91 (d, 1H), 4.15 (qrt, 2H), 4.02 (m, 2H), 3.70 (m, 2H), 3.17 (m, 1H), 3.04 (t, 2H), 2.83 (m, 1H), 2.68 (m, 3H), 2.18 (m, 1H), 2.05 (m, 1H), 1.96 (m, 2H), 1.36 (d, 6H), 1.26 (t, 3H), 0.94 (t, 3H); ESI (+) MS m/e=388 (MH+), ESI (−) MS m/e=386 (MH−).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([C:26]3[CH2:27][CH2:28][O:29][CH2:30][CH:31]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:33]1[C:38]([F:39])=[CH:37][C:36]([C:40]([F:43])([F:42])[F:41])=[CH:35][N:34]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@@H:24]([C:33]3[C:38]([F:39])=[CH:37][C:36]([C:40]([F:43])([F:41])[F:42])=[CH:35][N:34]=3)[OH:25])=[C:11]([C:26]3[CH2:27][CH2:28][O:29][CH2:30][CH:31]=3)[C:10]1=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)c1nc2c(c(C3=CCOCC3)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: Fc1cc(C(F)(F)F)cnc1Br
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@H](O)c1ncc(C(F)(F)F)cc1F)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-(3,6-dihydro-2H-pyran-4-yl)-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 2-bromo-3-fluoro-5-(trifluoromethyl)pyridine.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]1([S:19]([CH3:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[CH:24]([C:30](N(C)OC)=[O:31])[CH2:23]2.P(=O)(O)(O)O>O1CCCC1>[N:22]12[CH2:29][CH2:28][CH:25]([CH2:26][CH2:27]1)[CH:24]([C:30](=[O:31])[CH2:21][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:20])[CH2:23]2
Reactant: CON(C)C(=O)C1CN2CCC1CC2
Reactant: CS(=O)c1ccccc1
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(CS(=O)c1ccccc1)C1CN2CCC1CC2
Temperature: -20 °C
Yield: 109.2 %

Procedure:
To a stirred solution of n-butyllithium (2.7 ml of a 1.6M solution in hexanes, 4.3 mmol) in dry tetrahydrofuran (5 ml) cooled to -78° C. under nitrogen was added dropwise a solution of diisopropylamine (0.44 g, 4.3 mmol) in dry tetrahydrofuran (5 ml). The mixture was allowed to warm to -20° C., and was maintained at this temperature for 15 min. After cooling to -78° C. a solution of methyl phenyl sulphoxide (0.55 g, 3.9 mmol) in dry tetrahydrofuran (2 ml) was added dropwise while maintaining the temperature below -65° C. The reaction was stirred for a further 5 rain and then a solution of (±) 1-azabicyclo[2.2.2] oct-3-yl-N-methyl-N-methoxycarboxamide (EP 322182, Description 22) (0.65 g, 3.3 mmol) in dry tetrahydrofuran (5 ml) was added rapidly while ensuring that the temperature did not rise above -60° C. After stirring at -78° C. for 1 h, the reaction was allowed to warm to -30° C., and maintained at this temperature for 30 min. The reaction was then poured into vigorously stirred orthophosphoric acid (20ml of a 5% H3PO4 solution) cooled below 0° C. The aqueous layer was separated, washed with ether (3×20 ml) and then saturated with potassium carbonate. After extraction with chloroform (3×25 ml) the combined organic extracts were dried over sodium sulphate and concentrated in vacuo to give the title compound (D1) as an oil (1.0 g) consisting of a 1:1 mixture of diastereomeric keto sulphoxides. 1H NMR (CDCl3) δ:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:42])[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)[CH:9]=[C:8]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH:7]=1>>[CH2:32]([O:31][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:22]=2)[CH:9]=1)[C:5]([OH:42])=[O:4])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCOc1cc(OCCCOc2ccc(OCc3ccccc3)cc2)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCOc1cc(OCCCOc2ccc(OCc3ccccc3)cc2)cc(C(=O)O)c1
Yield: 95 %

Procedure:
Sodium hydroxide hydrolysis of 3-(decyloxy)-5-[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoic acid methyl ester gave 3-(decyloxy)-5-[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoic acid (95% yield, mp 107°-109°)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:54]=[CH:53][C:12]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([CH2:23][N:24]([CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])[C:25](=[O:44])[C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:43])[CH2:34][C:35]5[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=5)=[CH:28][CH:27]=4)=[CH:22][C:16]=3[N:15]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:54]=[CH:53][C:12]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([CH2:23][N:24]([CH2:45][C:46]([OH:48])=[O:47])[C:25](=[O:44])[C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:43])[CH2:34][C:35]5[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=5)=[CH:28][CH:27]=4)=[CH:22][C:16]=3[N:15]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(Cc2nc3cc(CN(CC(=O)OC(C)(C)C)C(=O)c4ccc(NC(=O)Cc5ccc(OC)cc5)cc4)ccc3[nH]2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCOc1ccc(Cc2nc3cc(CN(CC(=O)O)C(=O)c4ccc(NC(=O)Cc5ccc(OC)cc5)cc4)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a stirring solution of tert-butyl 2-(N-((2-(4-(heptyloxy)benzyl)-1H-benzo[d]imidazol-5-yl)methyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-49 (40 mg, 0.055 mmol) in DCM (2 mL) was added TFA (1 mL). After stirring at room temperature for 2 h, the solvents were concentrated and the residue purified by preparative HPLC to afford 15 mg (40%) of 2-(N-((2-(4-(heptyloxy)benzyl)-1H-benzo[d]imidazol-5-yl)methyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetic acid 366 as a white powder. LCMS-ESI (m/z) calculated for C40H44N4O6: 676; found 677 [M+H]+, tR=6.77 min (Method 4). 1H NMR (400 MHz, DMSO) 12.82 (br s, 1H), 12.21 (br s, 1H), 10.29 (s, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.30-7.57 (m, 4H), 7.27-7.15 (m, 4H), 7.15-6.92 (m, 1H), 6.89-6.75 (m, 4H), 4.71 (s, 1H), 4.62 (s, 1H), 4.08 (s, 2H), 3.91 (m, 3H), 3.81-3.69 (m, 4H), 3.57 (s, 2H), 1.73-1.61 (m, 2H), 1.43-1.20 (m, 8H), 0.90-0.80 (m, 3H).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3]2.[OH-].[Na+].[CH2:13](O)[CH2:14][OH:15]>>[CH2:14]1[O:15][C:4]2([CH:5]3[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]3)[CH2:3]2)[O:10][CH2:13]1
Reactant: OCCO
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C1COC2(CN3CCC2CC3)O1
Temperature: 200 °C
Yield: 100 %

Procedure:
A mixture of 3-quinuclidinone hydrochloride (5 g, 31 mmol) and ethylene glycol (20 ml) was heated under nitrogen at 200° C. (bath temperature) for 2 h. After cooling, the reaction mixture was poured in an excess of 1 M aqueous sodium hydroxide. Extraction with three portions of ethyl acetate was followed by drying over magnesium sulfate, and evaporation of the solvent to yield the product (5.2 g, 31 mmol, 100%) as a colorless oil.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2].O.[OH-].[Li+:36]>CCO.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O-:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=2)[CH2:6][C@@H:5]1[CH3:33])(=[O:3])[CH3:2].[Li+:36]
Reactant: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C)cn2)C[C@H](C)N3C(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)[O-])cc3)cc2[C@H](Nc2ccc(C)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 106.1 %

Procedure:
Crude ethyl 4-((2S,4R)-1-acetyl-2-methyl-4-((5-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (Intermediate 59) (238 mg) in EtOH (2 mL) and water (1 mL) was treated with lithium hydroxide monohydrate (26 mg, 0.620 mmol). The solution was stirred at ambient temperature for 5 h. A further portion of lithium hydroxide monohydrate (4 mg, 0.095 mmol) was added and the mixture left at ambient temperature overnight. The mixture was concentrated to dryness to give crude lithium 4-((2S,4R)-1-acetyl-2-methyl-4-((5-methylpyridin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoate as a brown foam (240 mg) which was used directly in the next step without further purification. LCMS: (Formate, 2 min), Rt=0.65 min, MH+416.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[N+:20]([O-:22])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1.O>CCOCC>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(N(Cc2ccc(Cl)cc2)S(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Yield: 120.9 %

Procedure:
72.8 g of 2-(4-methylbenzenesulfonylamino)-5-methoxynitrobenzene, prepared in A), are added to 56.5 ml of 4N sodium hydroxide solution and 29.2 g of 4-chlorobenzyl chloride. The mixture is refluxed for 4 hours, a further 43.7 g of 4-chlorobenzyl chloride are then added and the resulting mixture is refluxed for another 45 minutes. After cooling, 12.2 ml of 35% sodium hydroxide solution are added to the reaction mixture, the latter is refluxed for three hours 45 minutes and then cooled and water and ether are added. The insoluble material is filtered off and washed with water and ether to give 98 g of N-(4-chlorobenzyl)-N-(4-methylbenzenesulfonyl)-2-nitro-4-methoxyaniline in the form of crystals melting at 124° C. Evaporation of the ether phase yields an additional 10 g of crystals melting at 124° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[F:29][C:30]1[CH:46]=[C:45]([N+:47]([O-:49])=[O:48])[CH:44]=[CH:43][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[CH:39]=[C:40](I)[S:41][C:34]=12.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(Cl)Cl.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>[F:29][C:30]1[CH:46]=[C:45]([N+:47]([O-:49])=[O:48])[CH:44]=[CH:43][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]2[CH:39]=[C:40]([C:18]3[CH:17]=[N:16][N:15]([CH2:14][CH2:13][N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:10])[CH3:11])[CH:19]=3)[S:41][C:34]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: COCCN(CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1)C(=O)OC(C)(C)C
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: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: COCCN(CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1)C(=O)OC(C)(C)C

Procedure:
A mixture of 78 (369.3 mg, 0.93 mmol), 7-(2-fluoro-4-nitrophenoxy)-2-iodothieno[3,2-b]pyridine (24) [US 2006/0287343 A1] (466.6 mg, 1.12 mmol), Pd(PPh3)4 (54 mg, 0.05 mmol) and Na2CO3 (305 mg, 2.8 mmol) in DME (1.9 mL) was heated to reflux overnight under nitrogen. It was then diluted with DCM, washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography, eluents EOAc/Hex 1:1, EtOAc, 5% MeOH in DCM affording title compound 79 (203 mg, 39%) as brown syrup. MS (m/z): 558.2 (100%) (M+H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[N+:30]([C:27]1[CH:28]=[CH:29][C:24]([C:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:13][CH:12]=2)=[N:25][CH:26]=1)([O-:32])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])cn2)CC1

Procedure:
To a mixture of N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (1.52 g, 4.93 mmol), 2-bromo-5-nitropyridine (1.00 g, 4.93 mmol) and PdCl2(PPh3)2 (173 mg, 0.246 mmol) under nitrogen was added 1,4-dioxane (30 mL) followed by 3 M aqueous sodium carbonate (4.93 mL, 14.8 mmol). The resulting mixture was degassed with nitrogen for 10 minutes then heated at reflux for 16 hours. On cooling EtOAc (150 mL) was added and the resulting solution was washed with water (3×50 mL), brine (50 mL) then dried (Na2SO4). The volatiles were evaporated under reduced pressure to give a brown solid that was purified using silica gel column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-30% EtOAc in petroleum benzine 40-60° C.) to give the title compound I8 as a yellow solid (1.43 g, 95%); 1H NMR (400 MHz, CDCl3) δ 9.37 (dd, J=2.6, 0.5 Hz, 1H), 8.43 (dd, J=8.8, 2.7 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 6.95-6.83 (m, 1H), 4.20 (d, J=3.0 Hz, 2H), 3.67 (t, J=5.6 Hz, 2H), 2.70-2.63 (m, 2H), 1.49 (s, 9H). LCMS-A: rt 6.140 min; m/z 304 [M−H]−.