Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:30][C:31](=[O:33])[CH3:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:16]=[C:17]([CH:18]=[CH2:19])[C:10]=12.B.[OH-:35].[Na+].OO>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:30][C:31](=[O:33])[CH3:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:21])=[O:22])[CH:16]=[C:17]([CH2:18][CH2:19][OH:35])[C:10]=12
Reactant: C=Cc1cn(S(=O)(=O)c2ccc(C)cc2)c2nccc(Oc3ccc(NC(C)=O)cc3F)c12
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Oc2ccnc3c2c(CCO)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 0° C., 890 mg (1.91 mmol) of N-[3-fluoro-4-({1-[(4-methylphenyl)sulfonyl]-3-vinyl-1H-pyrrolo[2,3-b]-pyridin-4-yl}oxy)phenyl]acetamide are initially charged in 28 ml of THF. 7.65 ml (7.65 mmol) of a 1M solution of borane in THF are added dropwise, and the mixture is stirred at RT for one hour. 14 ml of 1N aqueous sodium hydroxide solution and 14 ml of 30% strength hydrogen peroxide solution are then added carefully to the reaction mixture. The mixture is heated at 60° C. for one hour. For work-up, the reaction solution is partitioned between ethyl acetate and sodium bicarbonate solution. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried over sodium sulfate. The solvent is removed under reduced pressure. The product is purified by chromatography-on silica gel (mobile phase: dichloromethane/acetone 20:1 to 6.5:1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[NH:11][C:12]1[C:21]2[CH:22]=[CH:23][N:24]=[C:25]([O:26]C)[C:20]=2[C:19]2[C:14](=[CH:15][CH:16]=[N:17][CH:18]=2)[N:13]=1.[Si]([N:32]=[N+:33]=[N-:34])(C)(C)C.C(Cl)(Cl)Cl.B(Br)(Br)Br>C(OCC)(=O)C>[Cl:10][C:4]1[CH:5]=[C:6]([C:8]2[N:32]=[N:33][NH:34][CH:9]=2)[CH:7]=[C:2]([Cl:1])[C:3]=1[NH:11][C:12]1[C:21]2[CH:22]=[CH:23][NH:24][C:25](=[O:26])[C:20]=2[C:19]2[C:14](=[CH:15][CH:16]=[N:17][CH:18]=2)[N:13]=1
Reactant: C#Cc1cc(Cl)c(Nc2nc3ccncc3c3c(OC)nccc23)c(Cl)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=c1[nH]ccc2c(Nc3c(Cl)cc(-c4c[nH]nn4)cc3Cl)nc3ccncc3c12
Temperature: 150 °C

Procedure:
N-(2,6-Dichloro-4-ethynylphenyl)-10-methoxypyrido[4,3-c]-1,6-naphthyridin-6-amine (66 mg, 0.167 mmol) and TMS-N3 (1.5 mL, 11.30 mmol) were combined and heated in a sealed tube to 150° C. for 16 h. Volatiles were evaporated under vacuum. To the residue was added chloroform (1 mL) and boron tribromide (1.2 mL, 1.2 mmol, 1M in dichloromethane) and the mixture was heated at 85° C. for 45 min in a sealed tube. After cooling to room temperature, the reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, followed by brine. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in THF/MeOH, filtered and purified by reverse phase HPLC to afford the title compound.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C1CCCCC1>[CH:1]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccccc1
Reactant: [H][H]
Solvent: C1CCCCC1
Product: c1ccc(C2CCCCC2)cc1

Procedure:
FIG. 2 is a diagram of a reactive distillation unit for conducting the dealkylation step of the process shown in FIG. 1. The embodiment shown in FIG. 2 includes a vertical distillation tower 111 which is provided with a cracking zone 112 located near the base of the tower, which also receives the optional benzene and hydrogen feeds. The product of the hydroalkylation reactor, after removal of the unreacted benzene, is introduced by line 113 into the tower mid-way along the tower 111. On entering the distillation tower 111, the hydroalkylation product is separated into a C18 fraction, which descends through the tower to the cracking zone 112, and a C12 fraction which leaves the tower as overhead 114. The C18 fraction is dealkylated in the cracking zone to produce monocyclohexylbenzene product cyclohexene, and/or cyclohexane, which exit the tower 111 as part of the overhead 114. The overhead is then passed through a cooler 115 to remove any unreacted PCHB, which is recycled to the tower via line 116 and any unreacted hydrogen, which is vented from the cooler via line 117. The remaining overhead, which is composed mainly of cyclohexylbenzene, cyclohexene, and/or cyclohexane, is then passed to a distillation system (not shown) to separate the C6 and C12 fractions. Any unreacted C18 and heavier compounds (i.e., heavies) exit through the bottoms stream of the column.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH3:19][C:20]1[C:28]([NH2:29])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][N:24]2[CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1.[CH2:36]([N:43]1[CH:48]2[CH2:49][CH2:50][CH:44]1[CH2:45][C:46](=O)[CH2:47]2)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])O.[Na+]>ClCCCl>[CH2:36]([N:43]1[CH:48]2[CH2:49][CH2:50][CH:44]1[CH2:45][CH:46]([NH:29][C:28]1[C:20]([CH3:19])=[C:21]3[C:25](=[CH:26][CH:27]=1)[N:24]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[N:23]=[CH:22]3)[CH2:47]2)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Reactant: Cc1c(N)ccc2c1cnn2C1CCCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1c(NC2CC3CCC(C2)N3Cc2ccccc2)ccc2c1cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 38 %

Procedure:
Sodium triacetoxyborohydride (477 mg, 2.25 mmol) and then acetic acid (99 μl, 1.73 mmol) were added to a suspension of 4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine (400 mg, 1.73 mmol) and 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (410 mg, 1.90 mmol) in 1,2-dichloroethane (5 ml), and the resulting mixture was stirred at room temperature for 1 day. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and then extracted with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=100/2) to obtain N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine (283 mg, 38%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:17]([CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(COc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.3 %

Procedure:
3-Bromomethylbenzonitrile (5.00 g, 25.5 mmol) was dissolved in N,N-dimethylformamide (50 mL), phenol (2.40 g, 25.5 mmol) and potassium carbonate (10.6 g, 77 mmol) were added. The mixture was stirred at room temperature for 16 hours. The mixture was poured into water (400 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with water (2×100 mL), dried (MgSO4) and evaporated in vacuo to afford 5.19 g (97%) 3-(phenoxymethyl)benzonitrile as an oil.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]([I:8])=[C:5](I)[N:6]=1.S(=O)(=O)(O)O.O.N.[N+:16]([O-])([OH:18])=[O:17]>>[Cl:1][C:2]1[NH:3][C:4]([I:8])=[C:5]([N+:16]([O-:18])=[O:17])[N:6]=1
Reactant: Clc1nc(I)c(I)[nH]1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1nc(Cl)[nH]c1I
Temperature: 25 °C
Reaction time: 15 h
Yield: 81.2 %

Procedure:
2-Chloro-4,5-diiodoimidazole (354 mg) was suspended in concentrated nitric acid (d. 1.42)(5 ml), under ice-cooling, concentrated sulfuric acid (1 ml) was added, and was stirred at a room temperature for 15 hours. Reaction mixture was poured in ice-water, and ammonia water was added to adjust pH 3, the deposited matters were collected by filtration and dried, there was obtained 2-chloro-5-iodo-4-nitroimidazole (222 mg, yield: 81.2%) as yellow solid product.
Reaction SMILES: C[Li].[CH:3]([Mg]Cl)([CH3:5])[CH3:4].[F:8][C:9]1([F:22])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[C:12](=[O:20])[CH:11]([OH:21])[CH2:10]1>C1COCC1>[F:22][C:9]1([F:8])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=2)[C:12]([CH:3]([CH3:5])[CH3:4])([OH:20])[CH:11]([OH:21])[CH2:10]1
Reactant: CC(C)[Mg]Cl
Reactant: O=C1c2ccc(F)cc2C(F)(F)CC1O
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(C)C1(O)c2ccc(F)cc2C(F)(F)CC1O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A THF solution (3.75 mL) of methyl lithium (3.05 mL, 4.88 mmol) was cooled to −78° C. with a dry ice/acetone cooling bath. A hexanes solution of isopropyl magnesium chloride (1.44 mL, 2.68 mmol) was introduced by syringe. This mixture was allowed to age for one hour at this temperature. Then a THF solution (1.75 mL) of 4,4,6-trifluoro-2-hydroxy-3,4-dihydronaphthalen-1(2H)-one (0.263 mg, 1.22 mmol) was added to the cooled solution dropwise by syringe pump over one hour. The reaction was allowed to stir at −78° C. for 4 hours and then quenched by pouring into an aqueous solution of ammonium chloride, volatiles were removed and the mixture was re-dissolved in ethyl acetate. The aqueous phase was extracted with ethyl acetate (3×), dried over sodium sulfate, filtered and concentrated to give an orange oil. The desired product, 4,4,6-trifluoro-2-hydroxy-3,4-dihydronaphthalen-1(2H)-one, was purified with a gradient heptanes/ethyl acetate eluent system on silica gel by a ISCO companion system to give the desired product, 4,4,6-trifluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalene-1,2-diol, as a colorless oil (0.189 g, 0.727 mmol, 60% yield). 1H NMR (400 MHz, CDCl3) δ: 7.65 (m, 1H), 7.34 (d, J=8 Hz, 1H), 7.19 (m, 1H), 4.32 (m, 1H), 2.69 (m, 2H), 1.96 (q, J=8 Hz, 1H) 0.98 (d, J=4 Hz, 1H) 0.93 (d, J=4 Hz, 1H). MS (ESI−, infusion) 259 [(M−H)−].
Reaction SMILES: Br[CH:2]([C:4]1[C:8]2[CH:9]=[C:10]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[CH:11]=[CH:12][C:7]=2[S:6][N:5]=1)[CH3:3].[CH3:26][OH:27]>FC(F)(F)S([O-])(=O)=O.[Ag+].ClCCCl>[CH3:26][O:27][CH:2]([C:4]1[C:8]2[CH:9]=[C:10]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])[CH:11]=[CH:12][C:7]=2[S:6][N:5]=1)[CH3:3]
Reactant: CC(Br)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reactant: CO
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCCl
Product: COC(C)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reaction time: 1 h
Yield: 100 %

Procedure:
To a mixture of 3-[3-(1-bromoethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.720 g, 0.00166 mol), methanol and 1,2-dichloroethane is added silver trifluoromethane sulfonate (0.510 g, 0.00199 mol). The resultant mixture is stirred 23 hours at room temperature and filtered through diatomaceous earth with ethyl acetate. Saturated sodium bicarbonate is added to the filtrate and the resultant mixture is stirred vigorously for one hour. The organic layer is saved while the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried over magnesium sulfate, filtered and concentrated in vacuo to a syrup, which is chromatographed on silica gel with hexanes:ethyl acetate to give the title compound as a white solid (0.660 g, 100%, mp 133-135° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [CH2:1]([OH:77])[C@H:2]1[O:7][C@@H:6]2[O:8][C@H:9]3[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H:18]4[C@H:23]([OH:24])[C@@H:22]([OH:25])[C@@H:21]([O:26][C@H:27]5[C@H:32]([OH:33])[C@@H:31]([OH:34])[C@@H:30]([O:35][C@H:36]6[C@H:41]([OH:42])[C@@H:40]([OH:43])[C@@H:39]([O:44][C@H:45]7[C@H:50]([OH:51])[C@@H:49]([OH:52])[C@@H:48]([O:53][C@H:54]8[C@H:60]([OH:61])[C@@H:59]([OH:62])[C@@H:57]([O:58][C@H:3]1[C@H:4]([OH:76])[C@H:5]2[OH:75])[O:56][C@@H:55]8[CH2:63][OH:64])[O:47][C@@H:46]7[CH2:65][OH:66])[O:38][C@@H:37]6[CH2:67][OH:68])[O:29][C@@H:28]5[CH2:69][OH:70])[O:20][C@@H:19]4[CH2:71][OH:72])[O:11][C@@H:10]3[CH2:73][OH:74].[Cu:78](Cl)Cl>>[CH2:67]([OH:68])[C@H:37]1[O:38][C@@H:39]2[O:44][C@H:45]3[C@H:50]([OH:51])[C@@H:49]([OH:52])[C@@H:48]([O:53][C@H:54]4[C@H:60]([OH:61])[C@@H:59]([OH:62])[C@@H:57]([O:58][C@H:3]5[C@H:4]([OH:76])[C@@H:5]([OH:75])[C@@H:6]([O:8][C@H:9]6[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H:18]7[C@H:23]([OH:24])[C@@H:22]([OH:25])[C@@H:21]([O:26][C@H:27]8[C@H:32]([OH:33])[C@@H:31]([OH:34])[C@@H:30]([O:35][C@H:36]1[C@H:41]([OH:42])[C@H:40]2[OH:43])[O:29][C@@H:28]8[CH2:69][OH:70])[O:20][C@@H:19]7[CH2:71][OH:72])[O:11][C@@H:10]6[CH2:73][OH:74])[O:7][C@@H:2]5[CH2:1][OH:77])[O:56][C@@H:55]4[CH2:63][OH:64])[O:47][C@@H:46]3[CH2:65][OH:66].[Cu:78]
Reactant: Cl[Cu]Cl
Agent: OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Product: [Cu]

Procedure:
The beta-cyclodextrin-copper biaffinity column was prepared by mixing 0.5 ml each of the sulfated beta-cyclodextrin polymer and chelating Sepharose (Pharmacia) that had been saturated with copper (II) chloride. A sample (16 ml) of Chondrosarcoma-derived growth factor partially purified by batchwise adsorption to heparin-Sepharose® was applied directly to this biaffinity column (1×1.3 cm) preequilibrated with 2 M NaCl, 10 mM Tris, pH 7. The column was rinsed consecutively with 40 ml each of the following four reagents in 10 mM Tris, pH 7: (i) 2 M NaCl, (ii) 0.6 M NaCl, (iii) 0.6 M NaCl plus 10 mM imidazole, and (iv) 0.6 M NaCl. Finally, the growth factor was eluted at a flow rate of 20 ml/hour with a linear NaCl/imidazole gradient from 100 mM imidazole in 10 mM Tris, pH 7. Fractions (4 ml) were collected, monitored for conductivity (Radiometer American conductivity meter) and assayed for growth factor activity.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH3:16])[N:6]=1)([CH3:4])[CH3:3].[H-].[Na+].[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24]Cl>O1CCCC1>[CH3:4][C:2]([C:5]1[C:10]([O:11][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH3:16])[N:6]=1)([CH3:1])[CH3:3]
Reactant: Cc1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCOc1c(C(C)(C)C)nc(C)nc1C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4,6-Bis(1,1-dimethylethyl)-5-hydroxy-2-methyl pyrimidine (9.8 g, 44.1 moles) is dissolved in 100 mL of tetrahydrofuran and added dropwise to a suspension of sodium hydride (1.2 g, 48.5 mmoles) in THF (50 mL) at 0° C. The reaction mixture is warmed to room temperature over 15 minutes. 2-Methoxyethoxymethyl chloride (7.1 g, 57.3 mmoles) is added to the reaction mixture at room temperature. After being stirred at room temperature for 4 hours, the reaction is quenched by the addition of saturated ammonium chloride and the tetrahydrofuran is evaporated. The organics are extracted into 300 mL of ether. The ether is washed with 100 mL of brine and dried over magnesium sulfate. Evaporation of the solvent gives the crude product which is purified by flash chromatography (silica, 10% ether/hexane). Yield of 4,6-bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-2-methylpyrimidine=11.3 g (82%) as a clear oil.
Reaction SMILES: C1(=O)O[CH2:4][CH2:3][O:2]1.[Cl:7][C:8]1[C:13]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[N:20]([CH:24]([CH3:26])[CH3:25])[N:21]=[CH:22][N:23]=3)[N:18]=2)=[CH:12][N:11]=[C:10]([O:27][CH3:28])[CH:9]=1>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]([O:27][CH3:28])[N:11]=[CH:12][C:13]=1[C:14]1[N:15]([CH2:4][CH2:3][OH:2])[CH:16]=[C:17]([C:19]2[N:20]([CH:24]([CH3:25])[CH3:26])[N:21]=[CH:22][N:23]=2)[N:18]=1
Reactant: COc1cc(Cl)c(-c2nc(-c3ncnn3C(C)C)c[nH]2)cn1
Reactant: O=C1OCCO1
Solvent: ClCCl
Product: COc1cc(Cl)c(-c2nc(-c3ncnn3C(C)C)cn2CCO)cn1
Temperature: 130 °C
Yield: 75.6 %

Procedure:
To warmed ethylene carbonate (34 g) was added 4-chloro-5-[4-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-1H-imidazol-2-yl]-2-methoxy-pyridine (8.74 g, 27.4 mmol) and the mixture heated at 130° C. for 3 h. The cooled reaction mixture was diluted with DCM and loaded onto silica (150 g). The silica was washed with DCM then 5% methanol in DCM. Methanolic fractions were combined and concentrated in vacuo to give the title compound as a brown foam (7.52 g, 75%). LCMS RT=2.65, [M+H]+=363/365. 1H NMR 400 MHz (CDCl3) δ: 8.27 (1H, s), 8.02 (1H, s), 7.85 (1H, s), 6.93 (1H, s), 5.98-5.82 (1H, m), 4.00 (5H, m), 3.88 (2H, t, J=5.11 Hz), 1.51 (6H, d, J=6.62 Hz).
Reaction SMILES: [CH2:1](OCC)C.[OH-].[K+].CN(N=O)C(N[N+]([O-])=O)=N.[CH2:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>O1CCCC1.C(O)(=O)C>[CH2:1]1[C:19]2([CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH2:18]1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOCC
Agent: CN(N=O)C(=N)N[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
To a mixture of diethyl ether (25 mL) and 30% aqueous potassium hydroxide solution (5 mL) was added 1-methyl-3-nitro-1-nitrosoguanidine (containing 50% water, 2.17 g), and the mixture was stirred at room temperature for 10 min. To a solution (25 mL) of tert-butyl 4-methylidenepiperidine-1-carboxylate (1.00 g, 5.07 mmol) in tetrahydrofuran was added dropwise the above-mentioned ether layer, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added a ether layer prepared from diethyl ether (25 mL), 30% aqueous potassium hydroxide solution (5 mL), and 1-methyl-3-nitro-1-nitrosoguanidine (containing 50% water, 3.77 g), and the mixture was further stirred for 16 hr. To the reaction mixture was added acetic acid (1 mL), and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→90/10) to give the title compound (261 mg, 24%) as a white powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][C:14]23C[CH2:20][N:17]([CH2:18][CH2:19]2)[CH2:16][CH2:15]3)=[O:11])=[CH:2]1.N12CC([CH2:29][OH:30])(CC1)CC2>>[CH3:29][O:30][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[C:3]2[C:10]([O:12][CH2:13][C:14]12[CH2:20][N:17]([CH2:16][CH2:15]1)[CH2:18][CH2:19]2)=[O:11]
Reactant: O=C(OCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Reactant: OCC12CCN(CC1)C2
Product: COc1ccc2[nH]cc(C(=O)OCC34CCN(CC3)C4)c2c1

Procedure:
1-Azabicyclo[2.2.1]heptan-4-ylmethyl 5-methoxy-1H-indole-3-carboxylate was synthesized using the procedure described for (Quinuclidin-4-yl)methyl 1H-indole-3-carboxylate using 1-Azabicyclo[2.2.1]heptan-4-ylmethanol. MS: (m/e) 300.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=1)([O-:17])=[O:16].OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][C:25]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)=[CH:9][CH:10]=2)=[O:26])=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)Nc1ccc(Nc2ccccc2)cc1
Reaction time: 15 h

Procedure:
1.84 g (10 mmol) of 4-aminodiphenylamine, 1.81 g (10 mmol) of 4-nitrophenylacetic acid and 1.48 g (11 mmol) of hydroxybenzotriazole in 40 ml of THF are dissolved successively in a 100 ml flask. Then 2.27 g (11 mmol) of 1,3-dicyclohexylcarbodiimide (DCC) is added and the reaction mixture is agitated for 15 hours. A precipitate of dicyclohexylurea (DCU) forms which is filtered and rinsed with 100 ml of ethyl acetate. The filtrate is then washed successively with 50 ml of a saturated solution of Na2CO3, 50 ml of water, 50 ml of a molar solution of HCl and finally 2×50 ml of salt water. The organic phase is dried over magnesium sulphate, filtered and concentrated under vacuum. The residue is purified rapidly on a silica gel column (eluent:heptane/ethyl acetate 1/1). The purest fractions are collected and evaporated under vacuum in order to produce a brown powder. The product is used as it is in the following stage.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[I-].C[N+]1C=CN([C:16](=[O:25])[N:17]([CH3:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)C=1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:16](=[O:25])[N:17]([CH3:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6][CH:7]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1ccc(Cl)cn1)c1ccccc1
Yield: 99 %

Procedure:
A solution of 5-chloro-2-pyridol (0.39 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70)) yielding the title compound (0.78 g, 99% yield) as a white solid.
Reaction SMILES: [Cl:1]Cl.[CH:3](=[N:10][OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:3](=[N:10][OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCl
Reactant: ON=Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: ON=C(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
A solution of chlorine (1.5 g) in carbon tetrachloride (42 ml) was added in portions to a stirred partial solution of benzaldehyde oxime [2.5 g; 1H NMR: δ8.18(1H,s), 9.40(1H,brs) ppm] in carbon tetrachloride (20 ml) at room temperature. Following the addition, the reaction mixture was stirred at room temperature for 3 hours then poured into water. The organic layer was separated, dried and concentrated to give almost pure α-chlorobenzaldehyde oxime (3.2 g) as a yellow liquid. A solution of sodium methanethiolate (0.68 g) in methanol (15 ml) was added dropwise to an ice-cooled and stirred solution of part of this α-chlorobenzaldehyde oxime (1.5 g) in methanol (15 ml). Following the addition, the reaction mixture was stirred for 2 hours with continued cooling in iced-water. The methanol was removed under reduced pressure and the residue was chromatographed using dichloromethane as eluant to give a single stereoisomer of α-methylthiobenzaldehyde oxime (0.670 g, 42% yield) as a white crystalline solid, m.p. 76°-78° C., 1H NMR: δ2.08(3H,s), 9.12(1H,s) ppm.