Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:20]3[N:21]=[CH:22][C:23]([C:25]([OH:27])=O)=[CH:24][C:19]3=[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]=2[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[CH3:42])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:44][NH:45][O:46][CH3:47].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:20]3[N:21]=[CH:22][C:23]([C:25](=[O:27])[N:45]([O:46][CH3:47])[CH3:44])=[CH:24][C:19]3=[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]=2[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[CH3:42])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2cc(C(=O)O)cnn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CON(C)C(=O)c1cnn2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1
Yield: 91.9 %

Procedure:
A solution of the compound of example 8, step 11 (1.002 g, 1.75 mmol), N,O-dimethylhydroxylamine hydrochloride (0.213 g, 2.19 mmol), EDIA (0.76 ml, 4.38 mmol) and TBTU (0.702 g, 2.19 mmol) in 15 ml of anhydrous DCM was stirred at room temperature for 4 h. DCM (15 ml) was then added and the solution was washed with 0.5 N hydrochloric acid (30 ml), a saturated solution of sodium hydrogencarbonate (15 ml) and brine (15 ml), dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA, 50:50, then 40:60, then 35:65) to give 0.99 g of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][CH:9]=1)([CH3:7])[CH3:6])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:28]([O:30][CH2:31][CH2:32][N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[C:34]1[CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)[CH3:29].CO>O>[CH2:1]([O:3][C:4](=[O:21])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:45]2[CH2:46][CH2:47][CH:42]([C:34]3[N:33]([CH2:32][CH2:31][O:30][CH2:28][CH3:29])[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[N:35]=3)[CH2:43][CH2:44]2)=[CH:10][CH:9]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1ccc(CCOS(C)(=O)=O)cc1
Reactant: CCOCCn1c(C2CCNCC2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOCCn1c(C2CCN(CCc3ccc(C(C)(C)C(=O)OCC)cc3)CC2)nc2ccccc21
Yield: 89.9 %

Procedure:
In a reaction vessel, 2-[4-(2-methanesulfonyloxy-ethyl)-phenyl]-2-methyl-propionic acid ethylester (3.2 g) prepared in the Example 8, sodium carbonate (1.1 g), 1-(2-ethoxyethyl)-2-piperidin-4-yl-1H-benzoimidazole (3.0 g) prepared in the Example 12 and methylalcohol (30 mL) were introduced, and the mixture was reacted for 14 hours under reflux condition. Distilled water (50 mL) was added thereto, and the mixture was stirred and crystallized. The crystals were filtered under reduced pressure, and washed with distilled water, and then dried to obtain 2-[4-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-piperidin-1-yl}-ethyl)-phenyl]-2-methyl-propionic acid ethylester (4.5 g, yield 90%, HPLC purity 98.5% or more).
Reaction SMILES: Br[C:2]1C(Cl)=NC(Cl)=NC=1.[Br:10][C:11]1[C:12]([NH:18][CH:19]([CH:29]([CH3:31])[CH3:30])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1>>[Br:10][C:11]1[C:12]([NH:18][C@@H:19]([CH:29]([CH3:31])[CH2:30][CH3:2])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Product: CCC(C)[C@@H](CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br

Procedure:
Intermediate I was hydrogenated using 10% Pd/C under hydrogen at 50 psi in a pressure vessel to afford tert-butyl N-[(2S)-2-amino-3-methyl-pentyl]carbamate which was reacted with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate to afford tert-butyl N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-pentyl]carbamate. 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.88-0.95 (m, 6H) 1.11-1.20 (m, 1H) 1.34 (s, 9H) 1.44-1.54 (m, 1H) 1.64-1.72 (m, 1H) 3.17-3.27 (m, 1H) 3.33-3.43 (m, 1H) 4.11-4.21 (m, 1H) 4.81 (s, 1H) 5.92 (d, J=8.20 Hz, 1H) 8.05 (s, 1H). LCMS (ESI) 407.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:42]=[CH:43][N:44]=5)=[O:59])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCn1ccnc1CSc1ccc(NC(=O)C2=Cc3cc(-c4ccc(OCCOCCCC)cc4)ccc3N(CC(C)C)CC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCn1ccnc1CS(=O)c1ccc(NC(=O)C2=Cc3cc(-c4ccc(OCCOCCCC)cc4)ccc3N(CC(C)C)CC2)cc1
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-pentylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (680 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (362 mg) in dichloromethane (15 ml) at −78° C. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-pentylimidazole-2-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (411 mg) (Compound 354) as yellow amorphous.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:22])[CH2:20]Cl)=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]=1[NH:23][C:24](=[O:35])[C:25]([O:31]C(=O)C)([CH3:30])[C:26]([F:29])([F:28])[F:27]>O.CC(C)=O>[Cl:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:22])[CH2:20][N:2]([CH3:3])[CH3:1])=[CH:16][CH:17]=2)[CH:8]=[CH:7][C:6]=1[NH:23][C:24](=[O:35])[C@:25]([OH:31])([CH3:30])[C:26]([F:28])([F:29])[F:27]
Reactant: CNC
Reactant: CC(=O)OC(C)(C(=O)Nc1ccc(Sc2ccc(NC(=O)CCl)cc2)cc1Cl)C(F)(F)F
Solvent: CC(C)=O
Solvent: O
Product: CN(C)CC(=O)Nc1ccc(Sc2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1

Procedure:
Dimethylamine (0.17 ml of a 40% solution in water) was added to a solution of (R)-N-{2-chloro-4-[4-(2-chloroacetylamino)phenylsulphanyl}phenyl -2-acetoxy-2-methyl-3,3,3-trifluoropropanamide (Method 19) (0.25 g) in acetone (1.5 ml). After 24 hours volatile material was removed by evaporation and the residue was dissolved in ethyl acetate, washed with water, and the organic layer was poured onto a Varian Chem Elut column. Elution with ethyl acetate gave the title compound (0.25 g) as a foam. NMR: 1.6 (s, 3H), 3.1 (s, 2H), 3.3 (s, 6H), 7.2 (d, 1H), 7.3 (s, 1H), 7.4 (d, 2H), 7.7 (m, 3H), 7.9 (d, 1H), 9.7 (s, 1H), 9.9 (s, 1H); MS (ESP−): 474.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([CH:12]=[CH:13][C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.CCN(CC)CC>CN(C=O)C.[Pd]>[CH3:17][O:16][C:14](=[O:15])[CH:13]=[CH:12][C:8]1[C:9]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: COC(=O)C=Cc1ccc(C(C)(C)C)nc1Cl
Reactant: C1COCCN1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1ccc(C(C)(C)C)nc1N1CCOCC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 22.5 %

Procedure:
3-(6-tert-Butyl-2-chloro-pyridin-3-yl)-acrylic acid, methyl ester (0.28 μg, 1.11 mmol) was dissolved in DMF, and morpholine (0.15 ml), NEt3 (0.31 ml) and palladium reagent (48 mg) were added stepwise and then the reaction mixture was stirred at 80° C. for 18 hours. The resulting mixture was extracted with EtOAc, and the organic phase was dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex/EtOAc=8/1) to give 3-(6-tert-butyl-2-morpholin-4-yl-pyridin-3-yl)-acrylic acid methyl ester (76 mg, 0.25 mmol, 22.5%). The methyl ester was dissolved in 1,4-dioxane, treated with water and KOH, stirred and heated at reflux for 18 hrs. The reaction mixture was cooled to room temperature, diluted with water, and then washed with ether. The aqueous phase was acidified with 1N HCl, and then extracted with EtOAc, and the combined organic phase was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure to give 3-(6-tert-butyl-2-morpholin-4-yl-pyridin-3-yl)-acrylic acid (67 mg, 92%).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]O)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:21]>C(OCC)C>[CH2:1]([O:8][N:9]=[C:10]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][Br:21])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: CC(=NOCc1ccccc1)c1cccc(CO)c1
Solvent: CCOCC
Product: CC(=NOCc1ccccc1)c1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 194.2 %

Procedure:
To a solution of 2.55 g (10 mmol) of 3-(1-(benzyloxyimino)ethyl)benzylalcohol in 20 ml of dry diethyl ether was added dropwise 1.35 g (4.5 mmol) of phosphorous tribromide with ice-cooling. The mixture was removed from an ice bath and stirred at room temperature for 6 hours. To the reaction mixture were added ice water and diethyl ether. The mixture was stirred for 30 minutes and separated. The organic layer was washed successively with an about 5% aqueous solution of sodium bicarbonate and water, then dried and concentrated to obtain 2.78 g (8.74 mmol) of 3-(1-(benzyloxyimino)ethyl)benzylbromide.
Reaction SMILES: CS(O[CH2:6][C:7]1[O:8][CH:9]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:28][CH:29]=3)[N:24]=[CH:23][CH:22]=2)[C:11](=[O:13])[CH:12]=1)(=O)=O.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>ClCCl>[F:34][C:31]([F:33])([F:32])[C:27]1[CH:26]=[C:25]2[C:30]([C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:10]3[C:11](=[O:13])[CH:12]=[C:7]([CH2:6][N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)[O:8][CH:9]=3)=[CH:22][CH:23]=[N:24]2)=[CH:29][CH:28]=1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ccnc3cc(C(F)(F)F)ccc23)co1
Solvent: ClCCl
Product: CN1CCN(Cc2cc(=O)c(OCCCCCOc3ccnc4cc(C(F)(F)F)ccc34)co2)CC1
Temperature: 45 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
Methanesulfonic acid 4-oxo-5-[5-(7-trifluoromethyl-quinolin-4-yloxy)-pentyloxy]-4H-pyran-2-ylmethyl ester 17 (130 mg, 0.26 mmol) was dissolved in dichloromethane (5 mL). 1-Methyl-piperazine (75 μL, 0.67 mmol) was added via syringe. The mixture was stirred at 45° C. for 3 h. After cooling to room temperature CH2Cl2 (75 ml) was added and the mixture was washed with NaHCO3 10% (3×50 mL) and brine (3×50 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=9:1. 5-(5-(7-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-((4-methylpiperazin-1-yl)methyl)-4H-pyran-4-one EHT 0079 was obtained (30 mg, 23% yield) as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[CH2:19][C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:27][C:22]1[CH:21]=[C:20]([C@H:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH:8]([NH2:7])[CH3:9])[CH2:19]2)[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: CC(NC(=O)OC(C)(C)C)C1=Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)C1=Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of tert-butyl-1-((S)-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-2-yl)ethylcarbamate 49b (100 mg, 0.24 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL). The reaction mixture was stirred for 2 h before being concentrated. The residue was subjected reverse phase column chromatography (CH3CN/H2O/0.1% Formic acid=5% to 100%) to give 1-((S)-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-2-yl)ethanamine 45 (65 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J=8.0 Hz, 1 H), 7.23 (d, J=2.4 Hz, 1 H), 7.19 (d, J=7.2 Hz, 1 H), 7.14-7.08 (m, 2 H), 6.98 (dd, J=2.4, 8.4 Hz, 1H), 6.82 (d, J=7.2 Hz, 1 H), 6.46 (s, 1 H), 4.08 (t, J=8.4 Hz, 1 H), 3.61 (q, J=6.4 Hz, 1 H), 2.69 (dd, J=7.6, 16.8 Hz, 1 H), 2.46 (dd, J=8.8, 16.8 Hz, 1 H), 2.10 (broad, 2 H), 1.14 (d, J=8.0 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 144.75, 143.04, 136.16, 134.41, 132.52, 130.53, 130.41, 127.96, 127.80, 127.62, 127.52, 126.80, 121.07, 52.17, 43.68, 32.41, 21.53; ESI MS m/z 318.0.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-])=O)[CH:2]([CH3:4])[CH3:3]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC(C)Cc1c(N)cnc2ccccc12

Procedure:
The nitroxide group on the 4-isobutyl-3-nitro quinoline produced in Example 1 is reduced by catalytic reduction using toluene as solvent, Pd/C 5% (50% wet) as catalyst, at 40–45° C. and atmospheric pressure to produce 4-isobutyl 3-amino quinoline. The rate of reaction depends on efficiency of stirring. After catalyst filtration the solution is ready for the next step.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[NH2:7][S:8]([C:11]1[C:12]([Cl:38])=[CH:13][C:14]([NH:31][CH2:32][C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)=[C:15]([CH:30]=1)[C:16]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:29])[CH2:24]CC(O)=O)=[O:17])(=[O:10])=[O:9]>ClCCl>[NH2:7][S:8]([C:11]1[C:12]([Cl:38])=[CH:13][C:14]([NH:31][CH2:32][C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)=[C:15]([CH:30]=1)[C:16]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23](=[O:29])[CH2:24][CH2:1][C:2]([Cl:4])=[O:3])=[O:17])(=[O:9])=[O:10]
Reactant: NS(=O)(=O)c1cc(C(=O)OCCCOC(=O)CCC(=O)O)c(NCc2ccco2)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(C(=O)OCCCOC(=O)CCC(=O)Cl)c(NCc2ccco2)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of oxalyl chloride (0.040 mole) in dichloromethane (20 mL) is added dropwise to an ice bath cooled solution of 4-(3-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)propoxy)(4-oxo)butanoic acid (810) (0.040 mole) in dichloromethane (50 mL). The reaction is stirred at ambient temperature for 5 hours. The reaction solution is washed with 5% aqueous sodium bicarbonate, with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to provide 4-(3-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)propoxy)(4-oxo)butanoyl chloride (813). See eg., D. L. Musso, et. al., J. Med. Chem., (2003) 46: 409.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:12]2=[C:13]3[CH:19]=[CH:18][NH:17][C:14]3=[N:15][CH:16]=[C:11]2[NH:10][C:9]1=[O:20].[CH3:21][N+:22]([CH3:24])=[CH2:23].[I-]>CN(C)C=O.CCOC(C)=O>[CH3:21][N:22]([CH2:24][C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]3[NH:10][C:9](=[O:20])[N:8]([C@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]4[CH3:1])[C:12]3=2)[NH:17][CH:18]=1)[CH3:23]
Reactant: C=[N+](C)C
Reactant: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc3[nH]cc(CN(C)C)c3c21
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 53.3 %

Procedure:
To a solution of 1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (30 mg, 0.111 mmol) in N,N-dimethylformamide (0.6 mL) was added N,N-dimethylmethyleneiminium iodide (26.7 mg), and stirred at 85° C. for 1.5 hours. To the mixture was added Eschenmoser's salt (12.3 mg), and stirred at 80° C. for 30 minutes. The mixture was diluted with EtOAc, washed with saturated aqueous sodium hydrogencarbonate, 10% NaCl solution (×5), and brine, dried over MgSO4, evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1 to 10:1) to give 8-[(dimethylamino)methyl]-1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (11.6 mg) as a pale yellow amorphous solid.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]1=O)=[O:4].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18]([CH:22]=1)[C:19]([NH2:21])=[NH:20]>C(O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([F:23])=[C:18]([C:19]2[N:20]=[C:3]([OH:4])[C:5]3[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=3[N:21]=2)[CH:22]=1
Reactant: N=C(N)c1cc(Cl)ccc1F
Reactant: COC(=O)C1CC(C)(C)CC1=O
Solvent: CCO
Product: CC1(C)Cc2nc(-c3cc(Cl)ccc3F)nc(O)c2C1
Yield: 58.8 %

Procedure:
A solution of 4,4-Dimethyl-2-oxo-cyclopentanecarboxylic acid methyl ester (2.08 g, 12.21 mmol) and 5-Chloro-2-fluoro-benzamidine (2.32 g, 13.44 mmol) in 100% ethanol (40 mL) was heated to reflux overnight, then cooled and evaporated. The residue was dissolved in 1N (aq.) NaOH (50 mL) and washed with methylene chloride (2×50 mL). The aqueous layer was then acidified with glacial acetic acid to pH4 and extracted with methylene chloride (2×100 mL). The organic extracts were dried (brine and MgSO4) and evaporated to give crude product, purified by chromatography (CH2Cl2, 0-10% MeOH) to give the desired product as a cream solid (2.10 g, 59% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[OH-].[K+].Cl.Cl[CH2:15][CH2:16][N:17]([CH3:19])[CH3:18]>CS(C)=O>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CN(C)CCOc1cccc([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
3-Nitro phenol (1 g, 7.19 mmol) was added to a solution of potassium hydroxide (1.6 g, 28.76 mmol) in anhydrous DMSO (6 ml) at room temperature. After 30 min, (2-chloro-ethyl)-dimethyl-amine hydrochloride (1.03 g, 7.19 mmol) was added and the reaction mixture was heated at 80-90° C. for 12 hr. The reaction mixture was cooled to room temperature and diluted with ice water. The product was extracted with toluene and the organic layer was washed with 5% sodium hydroxide solution, then brine and dried. Evaporation under reduced pressure gave dimethyl-[2-(3-nitro-phenoxy)-ethyl]-amine (600 mg, 40%) as oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:7])[S:5][CH:6]=1.C([Li])CCC.[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].O>C1COCC1>[CH3:7][C:4]1[S:5][CH:6]=[C:2]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1
Reactant: Cc1nc(Br)cs1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1csc(C)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 111.8 %

Procedure:
To a solution of 4-bromo-2-methylthiazole (950 mg, 5.3 mmol) in absolute THF (40 mL) at −78° C. was added dropwise n-butyllithium (2.7 mL, 1.6 M in hexane). The solution was stirred at −78° C. for 1 h, then tributyltinchloride (2.2 g, 6.8 mmol) was added, and the mixture was allowed to warm to room temperature. Water (90 mL) was poured into the reaction mixture and the phases were separated. The aqueous layer was extracted with diethyl ether (4×30 mL). The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. The resulting oil was purified by fractionated Kugelrohr distillation to give the title compound (2.3 g). The product was used without further purification.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O-].[Na+].[Na].CI>CO>[CH3:11][S:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: C[O-]
Reactant: Sc1nc2ccccc2o1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CI
Product: CSc1nc2ccccc2o1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
2-Mercaptobenzoxazole (6.0 g, 0.04 mole) was slowly added, with stirring, to a solution of sodium methoxide prepared by the addition of sodium (1.0 g) to anhydrous methanol (150 ml). Methyl iodide (5 ml) was added and the mixture was stirred at a temperature of 50° C. for a period of 3 hours and allowed to stand overnight at room temperature. The methanol was removed by distillation under reduced pressure and the solid residue was triturated with ice water and the insoluble material was collected by filtration. The solid was dissolved in chloroform, dried over anhydrous magnesium sulfate and the solvent removed to give 2-(methylthio)benoxazole (5.8 g) as a brown oil.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH2:23][NH2:24])[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[N:33]=[C:34]=[O:35]>>[NH2:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH2:23][NH:24][C:34]([NH:33][C:27]1[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:26]=1[F:25])=[O:35])[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8]
Reactant: O=C=Nc1c(F)cccc1F
Reactant: NCc1ccc(C(=O)N2CCCCc3ccccc32)cc1N
Agent: Cl
Product: Nc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)Nc1c(F)cccc1F

Procedure:
The amine hydrochloride from. Example 12B (0.132 g, 0.35 mmol) was reacted with 2,6-difluorophenylisocyanate (0.055 g, 0.35 mmol) according to the procedure in Example 1C. The product was purified by flash chromatography on silica (eluant EtOAc:pet. eth r 70:30) and then by preparative HPLC (gradient water:acetonitrile 80:20–20:80; 0.1% TFA). The HPLC fractions were freeze-dried to give a white solid; yield 0.027 g (17%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([F:9])=[C:6]([SH:8])[CH:7]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28]>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([F:9])=[C:6]([S:8][CH2:24][C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:7]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: COc1cc(Cl)cc(S)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC(=O)CSc1cc(Cl)cc(OC)c1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 5-chloro-2-fluoro-3-methoxybenzenethiol (303 mg) and DMF (dry) (12 mL) were added K2CO3 (239 mg) and methyl 4-chloro-3-oxobutanoate (0.204 mL) at 0° C. The mixture was stirred at room temperature for 45 min. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (402 mg).