Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][CH:20](OC(=O)C)[C:21]2[CH:30]=[CH:29][C:28]3[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=3[CH:22]=2)[CH:15]=[CH:14][C:3]=1[C:4]([O:6]CC1C=CC=CC=1)=[O:5].C(O)C.C(O)(=O)C>[Pd].CCCCCC>[OH:1][C:2]1[CH:17]=[C:16]([O:18][CH2:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=3[CH:22]=2)[CH:15]=[CH:14][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(=O)OC(COc1ccc(C(=O)OCc2ccccc2)c(O)c1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(CCOc3ccc(C(=O)O)c(O)c3)ccc21
Reaction time: 4 h
Yield: 45.3 %

Procedure:
2 g (3.89 mmol) of benzyl 2-hydroxy-4-[2-acetoxy-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethoxy]benzoate obtained in Example 5(a), 100 ml of ethanol, 10 ml of acetic acid and 1.2 g of palladium on charcoal (10% to 50% water) are introduced into a reactor. The mixture is hydrogenated at 70° C., under a pressure of 7 bar, for 4 hours. The catalyst is filtered and washed with ethanol, and the filtrate is evaporated. The residue obtained is taken up in hexane, filtered and dried. 650 mg (46%) of the expected product of melting point 210°-212° C. are obtained.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1.O.[OH-].[Na+].[I:14]I>C(O)C>[ClH:1].[ClH:1].[I:14][C:7]1[NH:8][CH:9]=[N:10][C:6]=1[CH2:5][CH2:4][NH2:3]
Reactant: NCCc1c[nH]cn1
Reactant: II
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NCCc1nc[nH]c1I
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a 250 ml round-bottomed flask equipped with a stir bar and addition funnel was added 4.0 g (21.7 mmol) of histamine dihydrochloride and 6.0 ml of distilled water and the pH adjusted to 8.0 with concentrated NaOH. The addition funnel was charged with a solution of 2.76 g (10.86 mmol, 0.5 equivalent) of I2 in 100 ml of ethanol (abs.) and the solution added slowly dropwise with stirring at room temperature over 6 hours. The pH was periodically monitored and maintained at an apparent pH=8.0 with concentrated NaOH. The dark suspension was then stirred overnight, readjusted to pH=8.0 and allowed to stir an additional 3 hours. The suspension was filtered and evaporated to a red oil. Purification of this material was accomplished by electrophoresis using a 1M HOAc buffer titrated to pH 5 with pyridine. Approximately 400 mg of crude material, dissolved in methanol, was applied in a 1 cm band to an 8"×16" paper which was run for 1 hour at 20 V/cm and 150-180 mA. A thin strip was then removed from the paper and visualized with ninhydrin spray. The iodohistamine band was then cut out of the remaining sheet and eluted with several portions of methanol. The methanol extracts were acidified (con.HCl) and evaporated in vacuo. The remaining residue was re-evaporated with one volume of absolute ethanol followed by recrystallization from absolute ethanol. In this manner 620 mg (19%) of the analytically pure title compound was isolated, m.p. 210° C. with decomposition. The mother liquor was pooled, evaporated, and the residue recrystallized to yield an additional 205 mg of somewhat inferior material.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:34]([C:36]1[CH:41]=[CH:40][C:39]([CH:42](O)[CH3:43])=[CH:38][C:37]=1[F:45])#[N:35].C(N(CC)C(C)C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl.CO>[Si:1]([O:8][CH2:9][C:10]1[N:11]([CH:42]([C:39]2[CH:40]=[CH:41][C:36]([C:34]#[N:35])=[C:37]([F:45])[CH:38]=2)[CH3:43])[CH:12]=[N:13][CH:14]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(O)c1ccc(C#N)c(F)c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1ccc(C#N)c(F)c1)n1cncc1CO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(tert-butyldimethylsilyloxymethyl)-1-(triphenylmethyl)imidazole, as described above in Step D, (485 mg, 1.07 mmol), 1-(4-cyano-3-fluorophenyl)ethanol, as described above in Step C, (160 mg, 0.969 mmol), and N,N-diisopropylethylamine (0.219 mL, 1.26 mmol) in CH2Cl2 (12 mL) was cooled to −78° C., under argon. Trifluoromethanesulfonic anhydride (0.196 mL, 1.17 mmol) was added dropwise, and the mixture was stirred for 18 hours while it slowly warmed to ambient temperature. Methanol (15 mL) was added and the CH2Cl2 was distilled off in vacuo. The resulting methanolic solution was heated to reflux for 3 hours, then concentrated in vacuo to give a residue which was partitioned between saturated aqueous Na2CO3 (10 mL) and CH2Cl2 (20 mL). The aqueous layer was extracted further with CH2Cl2 (20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2—0% to 5% MeOH, to yield the titled product as a pale foam.
Reaction SMILES: [C:1]([C@:9]1([OH:47])[C@@:16]([C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:17])[C@:15]([C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([OH:26])[C@@H:14]([CH:35](S(C2C=CC(C)=CC=2)(=O)=O)[OH:36])[O:13][C@@H:10]1[O:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:48]=[N+:49]=[N-:50].[Na+].O>CN(C=O)C>[C:1]([C@:9]1([OH:47])[C@@:16]([C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:17])[C@:15]([C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([OH:26])[C@@H:14]([CH:35]([N:48]=[N+:49]=[N-:50])[OH:36])[O:13][C@@H:10]1[O:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1O[C@H](C(O)S(=O)(=O)c2ccc(C)cc2)[C@](O)(C(=O)c2ccccc2)[C@@](O)(C(=O)c2ccccc2)[C@@]1(O)C(=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@H]1O[C@H](C(O)N=[N+]=[N-])[C@](O)(C(=O)c2ccccc2)[C@@](O)(C(=O)c2ccccc2)[C@@]1(O)C(=O)c1ccccc1
Reaction time: 24 h

Procedure:
10 g of compound 2 and 3 g of NaN3 were dissolved in 100 cc of DMF. Reaction was allowed to proceed for 24 hrs at 70° C. after which the reaction mass was poured into 1 liter of water. Compound 5, obtained as a solid, was recrystallized from acetone giving 8 g (quant.) after drying over P2O5. M.p. 111° C.; 1H NMR (CDCl3): δ 8.22, 8.07, 7.92 (d,d,d, 2H each, benzoyl), 7.38-7.66 (m, 9H, benzoyl), 6.0—5.96 (m, 2H, H2,3), 5.8 (m, 1H, H4), 5.13 (d, 1H, H1), 4.47 (m, 1H, H5), 3.69 (s, 3H, OMe), 3.62 (AB, 2H, H6.6′).
Reaction SMILES: C(OC([NH:11][CH:12]([C:14]1[C:15]([O:33][CH3:34])=[C:16]([CH:22]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]2)[C:17]([Cl:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13])=O)C1C=CC=CC=1.O.[H][H]>CO.Cl.[Pt]>[NH2:11][CH:12]([C:14]1[C:15]([O:33][CH3:34])=[C:16]([CH:22]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:23]2)[C:17]([Cl:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13]
Reactant: [H][H]
Reactant: COc1c(C(C)NC(=O)OCc2ccccc2)cc(Cl)c(Cl)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [Pt]
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1c(C(C)N)cc(Cl)c(Cl)c1C1CN(C(=O)OC(C)(C)C)C1
Yield: 98.2 %

Procedure:
A solution of tert-butyl 3-[3-(1-{[(benzyloxy)carbonyl]amino}ethyl)-5,6-dichloro-2-methoxyphenyl]azetidine-1-carboxylate [peak 2 isomer from step 6] (0.29 g, 0.57 mmol) in methanol (17 mL) and 0.25 M HCl in water (5.7 mL, 1.4 mmol) was degassed with nitrogen, treated with 5% Pt/C (Degussa type) (73 mg, 25 wt %), and stirred under a balloon of hydrogen for 1 hour. The reaction mixture was treated with additional 5% Pt/C (Degussa type) (100 mg) and stirred under a balloon of hydrogen for an additional 1 hour. The reaction mixture was filtered over Celite and neutralized with saturated sodium bicarbonate solution. The reaction mixture was concentrated to remove the methanol, extracted with dichloromethane, and concentrated to give the desired product (0.21 g, 99%) as a colorless foam that was used without further purification. LCMS for C13H14C12NO3 (M−[NH2]−[t-Bu]+H)+: m/z=302.0, 304.0. Found: 301.9, 304.0.
Reaction SMILES: [CH:1]([CH:5]1[CH:9]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:8][N:7]([CH3:18])[C:6]1=[O:19])=[CH:2][CH2:3]C.[O:20]=[O+][O-].CSC>[Cl-].CO>[CH:3]([CH2:2][CH2:1][CH:5]1[CH:9]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:8][N:7]([CH3:18])[C:6]1=[O:19])=[O:20]
Reactant: O=[O+][O-]
Reactant: CCC=CC1C(=O)N(C)CC1COC1CCCCO1
Agent: [Cl-]
Solvent: CSC
Solvent: CO
Product: CN1CC(COC2CCCCO2)C(CCC=O)C1=O

Procedure:
11.0 g (41 m mols) of 3-(butenyl)-1-methyl-4-(2-tetrahydropyranyl-oxy-methyl)-pyrrolidone were dissolved in a mixture of 60 ml of absolute methyle chloride and 30 ml of absolute methanol. At -70° C ozone was introduced into this solution, while stirring, until the solution had a blue color. The reduction of the ozonide with dimethyl sulfide and the isolation of the aldehyde was effected in analogy to Example (5).
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=S)[C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:30])=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=1)[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1.[H-].[Na+].C(I)C.[N:41]#[C:42][NH2:43]>O1CCCC1>[C:42]([NH:43][C:19](=[N:18][CH2:17][CH2:16][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)[C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([OH:30])=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:21]=1)#[N:41]
Reactant: CN(CCCNC(=S)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCOc1ccc2c(c1)OCO2
Reactant: N#CN
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Solvent: C1CCOC1
Product: CN(CCCN=C(NC#N)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCOc1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a solution of N-[3-[N-methyl-N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-3,5-di-tert-butyl-4-hydroxybenzothioamide (1.0 g) obtained in Example 60 in dry tetrahydrofuran was added sodium hydride (0.16 g) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hour. To the mixture was added ethyl iodide (0.31 g), followed by stirring at room temperature for 2 hours. The mixture was again cooled to 0° C., and cyanamide (0.84 g) was added thereto, followed by stirring at room temperature for 15 hours. After completion of the reaction, the mixture was poured into ice-water, and the product was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform-methanol, 99:1) to afford 0.70 g (69%) of the title compound as pale yellow crystals. mp 129-130° C. NMR (CDCl3) (200 MHz) δ: 1.45 (18H, s), 1.6-2.1 (2H, m), 2.20 (3H, s), 2.6-3.0 (4H, m), 3.6-3.8 (2H, m), 3.83 (2H, t, J=5.7 Hz), 5.56 (1H, s), 5.84 (2H, s), 5.8-6.8 (3H, m), 7.48 (2H, s), 8.44 (1H, brs)
Reaction SMILES: [Cl:1][Si:2]([Cl:5])(Cl)Cl.[CH:6]1([Li])[CH:10]=[CH:9][CH:8]=[CH:7]1.[Cl-].[Li+]>CCCCC.CCOCC>[CH:6]1([Si:2]([CH:9]2[CH:8]=[CH:7][CH:6]=[CH:10]2)([Cl:5])[Cl:1])[CH:10]=[CH:9][CH:8]=[CH:7]1
Reactant: [Li]C1C=CC=C1
Reactant: Cl[Si](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCCCC
Product: Cl[Si](Cl)(C1C=CC=C1)C1C=CC=C1
Reaction time: 0.17 h

Procedure:
50 ml of dry n-pentane, 20 ml of dry ether and 8.09 g (47.6 mmol) of tetrachlorosilane were charged in a 200 ml Schlenk tube reactor equipped with a stirring apparatus in a stream of nitrogen, and a liquid having 7.20 g (100 mmol) of the above prepared cyclopentadienyl lithium slurried with 70 ml of n-pentane was dropwise added thereto by means of an injector at room temperature over a period of 10 minutes. After completion of the dropwise addition, stirring was carried out at room temperature for 24 hours. After completion of the reaction, lithium chloride was removed from the reaction liquid slurry by means of a glass filter, and n-pentane was distilled off to obtain dicyclopentadienyldichlorosilane.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[O:12][C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2].Cl[CH:22]([O:24]C)Cl>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]2[O:12][C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([CH:22]=[O:24])[C:14]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2oc3c(OC)cccc3c2C1
Reactant: COC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)N1CCc2oc3c(OC)ccc(C=O)c3c2C1
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
2-ethyoxycarbonyl-6-methoxy-1,2,3,4-tetrahydro[1]benzofuro[3,2-c]pyridine (from step 7) (0.420 g, 1.52 mmol) was dissolved in dichloromethane (25 ml). To this stannic chloride (0.675 g, 2.59 mmol) was added followed by addition of dichloromethylmethylether (0.17 g, 1.52 mmol) at −10° C. and stirred for 30 min. Reaction was quenched by pouring on crushed ice and extracted with ethyl acetate. Ethyl acetate layer was washed with water (10 ml×2), brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography using 100-200 mesh silica gel and eluted in 10% ethyl acetate in petroleum ether to get 170 mg of the product as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:18][C:17]3[CH:16]=[N:15][C:14]4[N:19](CC5C=CC(OC)=CC=5)[N:20]=[CH:21][C:13]=4[C:12]=3[C:11]3[CH:31]=[CH:32][CH:33]=[CH:34][C:10]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=C(C2C3C(=CC=CC=3)C(=O)/C(=C/N(C)C)/C2)C=CC=1Cl.Cl.COC1C=CC(CN2C(N)=CC=N2)=CC=1.CCN(C(C)C)C(C)C>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:18][C:17]3[CH:16]=[N:15][C:14]4[NH:19][N:20]=[CH:21][C:13]=4[C:12]=3[C:11]3[CH:31]=[CH:32][CH:33]=[CH:34][C:10]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CC(c2ccc(Cl)c(Cl)c2)c2ccccc2-4)cc1
Agent: CN(C)/C=C1\CC(c2ccc(Cl)c(Cl)c2)c2ccccc2C1=O
Agent: COc1ccc(Cn2nccc2N)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: Clc1ccc(C2Cc3cnc4[nH]ncc4c3-c3ccccc32)cc1Cl
Temperature: 110 °C
Yield: 53 %

Procedure:
Synthesis of 7-(3,4-dichlorophenyl)-3-(4-methoxybenzyl)-6,7-dihydro-3H-benzo[f]pyrazolo[3,4-c]isoquinoline. To the mixture of (E)-4-(3,4-dichlorophenyl)-2-((dimethylamino)methylene)-3,4-dihydronaphthalen-1(2H)-one (0.20 g, 0.58 mmol) and 1-(4-methoxybenzyl)-1H-pyrazol-5-amine hydrochloride (0.14 g, 0.58 mmol) was added glacial acetic acid (5 mL) and Hunig's Base (0.4 mL). The mixture was heated at 110° C. for 1 hour, then transferred to microwave vial and heated at 220° C. for 90 minutes. The reaction mixture was evaporated and dissolved in dichloromethane (100 mL), washed with water (30 mL), brine (30 mL), dried over sodium sulfate and concentrated to dryness. The crude was purified by flash column chromatography (SiO2, 10% EtOAc in hexane) to give the pure desired product as a brown solid (0.15 g, 53%). M.p.=76-78° C.; 1H NMR (CDCl3, 400 MHz) δ 9.53 (d, J=8 Hz, 1H), 8.32 (s, 1H), 8.02 (s, 1H), 7.54 (t, J=6.8 Hz, 1H), 7.45 (t, J=8 Hz, 1H), 7.35-7.26 (m, 4H), 7.06 (d, J=8 Hz, 1H), 6.96 (d, J=8 HZ, 1H), 6.843 (d, J=7.2 Hz, 2H), 4.28 (t, J=8 Hz, 1H), 4.17 (s, 2H), 3.77 (s, 3H), 3.29-3.26 (m, 2H); LCMS: 486 [M+1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([OH:16])=O)=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][CH:28]=1.C(N(CC)CC)C>O1CCCC1.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=3)=[O:16])=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:5]=2[CH:4]=1
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: COc1ccc2sc(C(=O)O)c(OC(C)C)c2c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(NC(=O)c2sc3ccc(OC)cc3c2OC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid (500 mg, 2.0 mmoles) in 20 mL of dry tetrahydrofuran is added oxalyl chloride (262 μL, 3.0 mmoles) followed by one drop of dimethylformamide. The HCl salt of methyl 4-aminophenylacetate (605 mg, 3.0 mmoles) is added, followed by triethylamine (1.4 mL, 10 mmoles). The mixture is stirred at room temperature overnight. The mixture is partitioned between ethyl acetate and 1N HCl. The organic layer is washed with water, then brine. The organic layer is next dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography, eluting with a gradient of 1:1 ethyl acetate:hexane to only ethyl acetate to provide 692 mg (84%) of product; mp 111°-113° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)(=[O:12])=[O:11])([O-])=O.[In].Cl>O.O1CCCC1>[N:13]1([S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])(=[O:12])=[O:11])[CH2:14][CH:15]=[CH:16][CH2:17]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CC=CC1
Agent: Cl
Agent: [In]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccccc1S(=O)(=O)N1CC=CC1
Reaction time: 24 h

Procedure:
A 250 mL round bottom flask was equipped with a magnetic stirrer and charged with 1-(2-nitrobenzenesulfonyl)-2,5-dihydro-1H-pyrrole (Example 87, 9.32 mmol, followed by 3:1 water/tetrahydrofuran v/v (50 mL). Indium powder (37.3 mmol) was added, followed by concentrated HCl (55.9 mmol). The reaction gives a slight exotherm and the indium forms a solid metal chunk. After 24 hours, TLC (dichloromethane/silica) indicated the reaction was mostly complete. The indium was removed with a pair of tweesers to a separate waste stream and the reaction was neutralized with sodium bicarbonate. The aqueous mixture was extracted with ethyl acetate (150 mL), the organic layer dried (Na2SO4), filtered, and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and loaded onto a 600 mL sintered glass funnel charged with silica gel (400 g). The silica plug was eluted with 9:1 dichloromethane:ethyl acetate, collecting 100 mL fractions. Fractions containing the desired product were combined and the solvent was removed under diminished pressure to afford 2-(2,5-dihydropyrrole-1-sulfonyl)-aniline as a pale yellow, crystalline solid. 1.66 g, (62%). m.p.: 104-105° C. LC/MS: m/z 225.2 [C10H12N2O2S+H]+. 1H-NMR (CDCl3): δ 4.20 (s, 4H); 5.05 (b, 2H); 5.69 (s, 2H); 6.71-6.79 (m, 2H); 7.26-7.32 (t, 1H, J=8.1 Hz); 7.64-7.67 (d, 1H, J=7.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[C:10](=[O:21])([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])N.[CH3:22][O-:23].[Na+]>C(O)CCCCCCC>[CH2:13]([O:12][C:10]([NH:1][C:2]1[CH:7]=[C:6]([NH:8][C:22]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:23])[CH:5]=[CH:4][C:3]=1[CH3:9])=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Cc1ccc(N)cc1N
Reactant: CCCCCCCCOC(N)=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CCCCCCCCO
Product: CCCCCCCCOC(=O)Nc1ccc(C)c(NC(=O)OCCCCCCCC)c1
Reaction time: 23 h
Yield: 81.7 %

Procedure:
In a reaction vessel, 61 parts of 2,4-diaminotoluene with 432 parts of octyl carbamate and 1.5 parts of sodium methanolate in 1950 parts of octanol are heated to the boiling point (195° C.). After 23 hours, the mixture is allowed to cool and excess octanol and excess octyl carbamate is removed by distillation to a sump temperature of 180° C. Using high pressure liquid chromatography, the residue is analyzed using the external standard method. It is determined that 57 percent of the 2,4-diaminotoluene reacted, resulting in 101 parts (81.7 percent of theory) of 2,4-bis(octoxycarbonylamino)toluene, C25H42O4N2 (molecular weight 434) and 10.9 parts (13.8 percent of theory) of a mixture consisting of 2-amino-4-(octoxycarbonylamino)toluene and 4-amino-2-(octoxycarbonylamino)toluene.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([N:19]3[C:23]4=[C:24]5[S:30][CH:29]=[CH:28][C:25]5=[N:26][CH:27]=[C:22]4[N:21]=[C:20]3[C@H:31]([OH:33])[CH3:32])[CH2:15][O:14]2)(=O)=O)=CC=1.[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C=O)C.CO>[N:34]([CH2:12][C@@H:13]1[O:14][CH2:15][C@@H:16]([N:19]2[C:23]3=[C:24]4[S:30][CH:29]=[CH:28][C:25]4=[N:26][CH:27]=[C:22]3[N:21]=[C:20]2[C@H:31]([OH:33])[CH3:32])[CH2:17][CH2:18]1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](n3c([C@@H](C)O)nc4cnc5ccsc5c43)CO2)cc1
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN=[N+]=[N-])OC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A mixture of ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (25 mg, 0.052 mmol) and sodium azide (5.0 mg, 0.077 mmol) in DMF (0.5 mL) was stirred at 60° C. overnight. After cooling to room temperature, the mixture was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give desired product (12 mg, 65%). LCMS calculated for C16H19N6O2S (M+H)+: m/z=359.1. Found: 359.0.
Reaction SMILES: [CH3:1][CH:2]([N:9]1[CH2:12][CH:11]([O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-:22].[K+].O>C(O)(C)(C)C>[CH3:1][CH:2]([N:9]1[CH2:10][CH:11]([O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH2:19])=[O:22])=[CH:20][CH:21]=2)[CH2:12]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: CC(c1ccccc1)N1CC(Oc2ccc(C#N)cc2)C1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(c1ccccc1)N1CC(Oc2ccc(C(N)=O)cc2)C1

Procedure:
To 45.0 g. (0.16 mole) of 4-[1-(α-methylbenzyl)-3-azetidinyloxy]benzonitrile in 500 ml of t-butyl alcohol was added 45.0 g. of finely ground potassium hydroxide. The mixture was stirred and refluxed for 30 minutes. Ice and water were added and a thick white solid separated. The solid was recrystallized from toluene to give 30.0 g. (63%) of product melting at 174°-178° C.