Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:25])[N:7]([C@@H:8]2[C:14](=[O:15])[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[S:10][CH2:9]2)[C:6](=[O:20])[C:5]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:4]12.Cl[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C)C=O>[O:15]=[C:14]1[N:13]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10][CH2:9][C@@H:8]1[N:7]1[C:6](=[O:20])[C:5]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:4]2[C:3]1=[O:25]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: O=C1Nc2ccccc2SC[C@@H]1N1C(=O)c2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N2C(=O)c3ccccc3C2=O)CSc2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 74 %

Procedure:
To a stirred mixture of 50 ml of N,N-dimethylformamide and 0.5 g of sodium hydride (60% in oil) is added 4 g of 3(R)-phthalimido-2,3-dihydro-1,5(5H)-benzothiazepin-4-one obtained in Reference Example 2 at ice bath temperature. After 5 minutes, 2 g of tert-butyl chloroacetate is added at ice bath temperature. The resulting mixture is stirred in an ice bath for b 15 minutes and diluted with ice water (200 ml). The deposited crystals are collected by filtration, dried and purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give 4 g of tert-butyl 4-oxo-3(R)-phthalimido-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as colorless crystals. Recrystallization of a part of the crystals from ethyl ether yields colorless prisms, m.p. 181°-184° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>Cl>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1cc(F)ccc1N
Reactant: Clc1ccnc2c(Cl)cccc12
Agent: Cl
Product: COC(=O)c1cc(F)ccc1Nc1ccnc2c(Cl)cccc12
Reaction time: 8 h
Yield: 37.2 %

Procedure:
A mixture of 11.88 g of 4,8 dichloroquinoline, 10.4 g of methyl 2-amino-5-fluoro-benzoate and 60 ml of 2 N hydrochloric acid was refluxed for 21/2 hours and was then cooled to ≃0° C. and vacuum filtered. The moist residue was dissolved in 125 ml of lukewarm methanol and triethylamine was added to the resulting solution to make the pH alkaline. The mixture stood overnight at room temperature and was vacuum filtered and the recovered product was washed with water and dried to obtain 8.3 g of raw product which was crystallized from methanol to obtain 7.39 g of methyl 2-(8-chloro-4-quinolinylamino)-5-fluoro-benzoate melting at 196° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/[CH3:18])[CH3:13])[CH3:8])[CH3:3].[CH3:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][C:41](O)=[O:42].CCCCCC>C(CC(C)(C)C)(C)C>[C:41]([O:21][CH2:20]/[CH:19]=[C:17](/[CH2:16][CH2:15][CH2:14][C@@H:12]([CH2:11][CH2:10][CH2:9][C@@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH3:8])[CH3:13])\[CH3:18])(=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=[CH:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Solvent: CC(C)CC(C)(C)C
Solvent: CCCCCC
Product: CCCCCCCCCC=CC=CC=CC=CC=CC(=O)OC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Temperature: 60 °C
Reaction time: 24 h

Procedure:
There were dissolved, in 1 g of isooctane, 100 mg of phytol and 600 mg of ethyl ester of eicosapentaenoic acid, followed by the addition of lipase in an amount of 1% relative to the total amount of the resulting solution and then stirring the mixture at 60° C. for 24 hours. After confirming whether the reaction system reached its equilibrium state or not by the GC technique, the reaction solution was diluted by the addition of hexane to the solution in an amount of 10 times the volume thereof, followed by the removal of the lipase from the reaction solution through filtration and then the removal of the hexane through distillation to thus give a crude reaction product. The crude product was purified by silica gel column chromatography to give 94 mg of phytyl eicosapentaenoate.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])[CH3:2].[NH:26]1[CH:30]=[C:29]([CH:31]=O)[CH:28]=[N:27]1>C1COCC1>[NH:26]1[CH:30]=[C:29](/[CH:31]=[CH:6]/[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:28]=[N:27]1
Reactant: O=Cc1cn[nH]c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cn[nH]c1
Temperature: 70 °C

Procedure:
[(Ethoxycarbonyl)methylene]triphenylphosphorane (0.836 g, 2.4 mmol) was added to a solution of 1H-pyrazole-4-carbaldehyde (0.192 g, 2 mmol) in THF (6 mL) at room temperature. This solution was heated at 70° C. under a nitrogen atmosphere for 8 h.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:16][CH2:17][C@@H:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.C(OCC)(=O)C.O=[Pt]=O>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[NH:19][C@H:18]([C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H]1CCC(c2ccc(OCc3ccccc3)cc2)=N1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1CC[C@@H](c2ccc(OCc3ccccc3)cc2)N1
Reaction time: 6 h

Procedure:
To a solution of methyl (2S)-5-{4-[(phenylmethyl)oxy]phenyl}-3,4-dihydro-2H-pyrrole-2-carboxylate (D7, 13.7 g, 32.4 mmol) in MeOH (200 ml) was added PtO2 (240 mg) and the mixture was stirred under hydrogen atmosphere (2 atm) for 6 hours. Then the catalyst was filtered off and the solvent removed under reduced pressure to give a red oil which was dissolved in ethyl acetate and washed with NaHCO3 solution. The resulting crude material was purified by chromatography on silica gel eluting with cyclohexane/ethyl acetate (9:1 to 8:2) to afford the title compounds:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O.[CH3:15][C:16]1[C:24]2[C:23]([NH2:25])=[N:22][CH:21]=[N:20][C:19]=2[O:18][CH:17]=1.N[C:27]1[CH:31]=[C:30]([CH3:32])N[C:28]=1[C:33]([O:35][CH2:36]C)=O>[Cu](I)I.CN(C=O)C>[CH3:36][O:35][C:33]1[CH:28]=[CH:27][C:31]([NH:25][C:23]2[C:24]3[C:16]([CH3:15])=[CH:17][O:18][C:19]=3[N:20]=[CH:21][N:22]=2)=[CH:30][CH:32]=1
Reactant: Cc1coc2ncnc(N)c12
Reactant: CCOC(=O)c1[nH]c(C)cc1N
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ncnc3occ(C)c23)cc1
Temperature: 110 °C
Reaction time: 0.05 h
Yield: 54.8 %

Procedure:
A 50 mL round bottom flask with a stir bar was charged with copper iodide (66.5 mg, 0.35 mmol), anhydrous potassium carbonate (480 mg, 3.5 mmol), L-proline (80 mg, 0.7 mmol), 5 (150 mg, 1 mmol) and 6 (350 mg, 3.5 mmol). The flask was connected to vacuum for 3 min followed by the addition of anhydrous DMF (15 mL) using syringe. The flask was purged with argon for 5 min and then heated in an oil bath maintained at 110° C. On heating the suspension became bluish grey which lasted for about 2 h. The reaction was stirred for additional 22 h at 110° C. at the end of which the mixture was allowed to cool to room temperature. Ethyl acetate (25 mL) was added and the mixture was poured into water (100 mL). The product was extracted with ethyl acetate (100 mL×2) The combined organic extracts were washed with brine (100 mL) and dried (anhydrous sodium sulfate) and concentrated under reduced pressure. Silica gel (500 mg) was added and solvent evaporated to obtain a plug. Purification by column chromatography using hexanes and ethyl acetate (10:1 to 2:1) afforded 7 (140 mg, 56%) as light brown solid. TLC Rf0.77 (CHCl3:MeOH, 10:1); mp 99-101.6° C.; 1HNMR (400 MHz) (DMSO-d6). δ 2.383-2.386 (d, 3H, CH3, J=1.2 Hz); 3.747 (s, 3H, OCH3), 6.919-6.941 (d, 2H, C6H4, J=8.8 Hz), 7.466-7.488 (d, 2H, C6H4, J=8.8 Hz), 7.65-7.653 (d, 1H, C6-CH, J=1.2 Hz), 8.234 (s, 1H, C2-CH), 8.381 (s, 1H, 4-NH, exch). Anal. Calcd for C14H13N3O2: C, 65.87; H, 5.13; N, 16.46; Found: C, 65.94; H, 5.13; N, 16.42.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([Li])CCC.CI>C(OCC)C>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:14])=[CH:12][C:13]=1[CH3:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: CI
Product: Cc1cc(Cl)ncc1NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
(6-Chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (14.11 g) was dissolved in dry diethyl ether (310 mL), N,N,N′,N′-tetramethyl-ethylene-1,2-diamine (23.1 mL) was added. The solution was cooled to −78° C., n-butyl lithium (97 mL, 1.59 M in hexane) was added, the cool bath replaced by an ice/sodium chloride cool bath and the suspension was stirred for 2 h at −10° C. The suspension was cooled again to −78° C. and methyl iodide (5.8 mL) was added slowly. The cool bath was removed and the reaction was quenched after 1 h by addition of water. Ethyl acetate was added and the mixture was neutralized by addition of 2 M hydrochloric acid. The layers were separated and the aqueous layer was extracted 2× with ethyl acetate, the combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography (silica 60, hexane/ethyl acetate 5:1, Rf=0.10) to afford 4.24 g of the title compound of the formula
Reaction SMILES: ClC1C=C(C(CCO)C[NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C=CC=1Cl.CC[O:25]CC.[OH-].[Na+]>O1CCCC1.Cl.O>[OH:25][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]([NH2:11])=[O:19]
Reactant: O=C(NCC(CCO)c1ccc(Cl)c(Cl)c1)c1ccccc1
Reactant: CCOCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1ccccc1O

Procedure:
N-[2-(3,4-Dichlorophenyl)-4-hydroxybutyl]benzamide. A solution of the above ether (4.0 g) in tetrahydrofuran (20 mL) and 3 N hydrochloric acid (20 mL) was stirred for 2 hours. The reaction mixture was diluted with water, neutralized with 1 N sodium hydroxide, and extracted with dichloromethane. The organic extracts were dried, evaporated, and chromatographed, with dichloromethane:methanol (95:5) as eluent, to give the hydroxy benzamide compound as a viscous oil (2.9 g); NMR: 7.63 (m,2), 7.47 (m,1), 7.37 (m,3), 7.32 (d,1, J=2.1), 7.06 (dd,1, J=2.1, 8.3), 6.46 (m,1), 3.82 (m,1), 3.69 (m,1), 3.57-3.39 (m,2), 3.12 (m,1), 2.60 (m,1), 1.97 (m,1), 1.82 (m,1); MS: m/z=338(M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH2:7][O:6]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:31][S:32]([O:1][CH2:2][CH2:3][CH2:4][C:5]1([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH2:7][O:6]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C2(CCCO)OCc3cc(C#N)ccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2(CCCOS(C)(=O)=O)OCc3cc(C#N)ccc32)cc1
Reaction time: 1 h
Yield: 96.9 %

Procedure:
15.0 g (48.5 mmol) of the 1-(3-hydroxypropyl)-1-(4-methoxyphenyl)-1,3-dihydro-5-isobenzofurancarbonitrile prepared in step 5 was dissolved in 200 ml of dichloromethane, and 7.4 g (727 mmol) of triethylamine and 6.7 g (58.2 mol) of methanesulfonylchloride were added dropwise at 0° C. The solution was then stirred for 1 hr. The reaction mixture was washed with water and saturated NaCl solution. An organic layer was dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure to afford 18.2 g of the yellow target compound (yield: 79%). The compound thus obtained was used in the next reaction without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[OH:24][C:25]1[CH:29]=[C:28]([CH2:30][CH2:31][P:32](=[O:39])([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])[N:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:26]=1.CN(C)C=O.[H-].[Na+]>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:24][C:25]3[CH:29]=[C:28]([CH2:30][CH2:31][P:32](=[O:39])([O:33][CH2:34][CH3:35])[O:36][CH2:37][CH3:38])[N:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:26]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: CCOP(=O)(CCc1cc(O)nn1-c1ccccc1)OCC
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(CCc1cc(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)nn1-c1ccccc1)OCC
Reaction time: 15 h
Yield: 48.7 %

Procedure:
To a mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (0.32 g), diethyl 2-(3-hydroxy-1-phenyl-1H-pyrazol-5-yl)ethylphosphonate (0.40 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.040 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl 2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}ethylphosphonate as colorless crystals (0.29 g, yield 47%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 76-77° C.
Reaction SMILES: C([NH:4][C:5]1[C:6]([F:15])=[C:7]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:8]([OH:10])=[O:9])(=O)C.Cl>>[NH2:4][C:5]1[C:6]([F:15])=[C:7]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:8]([OH:10])=[O:9]
Reactant: CC(=O)Nc1c(Cl)ccc(C(=O)O)c1F
Agent: Cl
Product: Nc1c(Cl)ccc(C(=O)O)c1F
Yield: 96 %

Procedure:
The sub-title compound was prepared from 3-acetylamino-4-chloro-2-fluoro-benzoic acid and 6 M HCl-solution in analogy to step 5b.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[K].C([O:8][CH:9](OCC)[CH:10]([CH:13]=O)[C:11]#[N:12])C.C[O-].[Na+].CO>CCO>[NH2:12][C:11]1[C:10]([CH:9]=[O:8])=[CH:13][N:4]=[C:2]([SH:3])[N:1]=1
Reactant: NC(N)=S
Reactant: CCOC(OCC)C(C#N)C=O
Agent: C[O-]
Agent: [K]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Nc1nc(S)ncc1C=O
Temperature: 50 °C
Yield: 72.3 %

Procedure:
A slurry of thiourea (92.8 g, 1.22 moles) in EtOH (90 mL) was heated under reflux and vigorously stirred. To this slurry was added a suspension of 3,3-diethoxy-2-formylpropionitrile potassium salt (P-5A) (222.20 g, 1.06 moles) in 25% sodium methoxide/MeOH (85.5 mL, 0.37 mole) and EtOH (285 mL) in five aliquots over a 10 minute period, while maintaining reflux conditions (alternatively, the latter slurry may be heated to 50° C. to give a homogenous solution for the addition). An additional portion of EtOH (150 mL) was added to facilitate stirring. The thick slurry became a bright yellow color following the addition and was held under reflux for an additional 1 hour. The mixture was then cooled and evaporated to near dryness on a rotoevaporator. The residue was dissolved in water (940 mL). Crude product was precipitated from solution by the addition of 30% acetic acid (280 mL) and isolated via filtration using a medium frit sintered glass filtration funnel. The cake was washed with water (800 mL). Purification via trituration in hot water (1 L) for 30 minutes, followed by cooling and filtration gave 118.9 grams (72.3%) of product as a bright yellow solid after drying overnight at 60° C. in a vacuum oven (subsequent preparations have demonstrated that this trituration is unnecessary). An HPLC gave purity as 98.67%. 1H-NMR (DMSO-d6) was consistent with the above desired structure (P-5B).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[CH3:14])N.N([O-])=[O:16].[Na+]>O>[Cl:6][C:7]1[CH:8]=[C:9]([OH:16])[CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: O=N[O-]
Reactant: Cc1ccc(N)cc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(O)cc1Cl
Temperature: 104 °C
Reaction time: 1 h

Procedure:
1.3 liters of concentrated sulfuric acid was added to a stirred mixture of 566 g of 3-chloro-4-methylaniline and 3 liters of water. The mixture warmed to 104° C. The mixture was cooled to 10°-15° C. and stirred while a solution of 290 g sodium nitrite in 1 liter of water was added drop-by-drop (over 2 hours). The mixture was stirred for 1 hour at about 10° C., then was added drop-by-drop (over 2 hours) to a stirred solution of 1 liter of concentrated sulfuric acid in 1.5 liters of water, at 110°-115° C. The resulting mixture was stirred at reflux temperature for one hour, cooled to room temperature and extracted with ether. The extract (4 liters) was mixed with 4 liters of water. The resulting mixture was stirred at 15° C. while 700 ml of a 50% aqueous solution of sodium hydroxide was slowly added (over 1 hour). The aqueous phase was separated, cooled to 15°-20° C. and stirred while 1.3 liters of concentrated hydrochloric acid was added. The resulting mixture was extracted with ether, the extract was dried (MgSO4) and the solvent was evaporated to give 3-chloro-4-methylphenol (4A), as an amber oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:28][O:27]2)=[CH:22][CH:21]=1)(=[O:19])=[O:18].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][NH2:40])[CH:34]=1>C(O)C>[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][NH2:40])[CH:34]=1.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH:26]([OH:27])[CH2:28][NH:40][CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[CH:22][CH:21]=1)(=[O:18])=[O:19]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C3CO3)cc2)c(C)c1
Agent: NCc1cccnc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(C(O)CNCc3cccnc3)cc2)c(C)c1
Temperature: 40 °C

Procedure:
A solution of pyridin-3-ylmethanamine (10.38 mg, 0.096 mmol) in ethanol (0.25 mL) was prepared in a 4 mL reaction vial and triethylamine (0.027 mL, 0.192 mmol) added. A solution of N-(2,4-dimethylphenyl)-N-isobutyl-4-(oxiran-2-yl)benzenesulfonamide (28.8 mg, 0.08 mmol) in ethanol (0.75 mL) was then added and the reaction heated at 40° C. overnight. After this time, further pyridin-3-ylmethanamine (10.38 mg, 0.096 mmol) was added and the reaction heated at 50° C. for an additional 2 hours. The reaction mixture was then concentrated under a stream of nitrogen and the crude mixture purified by high-pH MDAP to give the required product, 10.6 mg. LCMS (M+1) 468, RT 1.24 mins.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11]O)=[CH:8][C:6]=2[N:7]=1.P(Br)(Br)[Br:20]>C1C=CC=CC=1>[Br:20][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[CH:8]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: c1ccccc1
Product: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Temperature: 25 °C

Procedure:
To a solution of (2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanol 29 (100 mg, 0.4 mmol) in benzene (3.0 mL) at 0° C. was added PBr3 (30 μl, 0.4 mmol). The reaction was heated at reflux for 1 hour. After cooling to room temperature the reaction was quenched by the addition of water. The aqueous layer was extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude product 30 did not require further purification (115 mg, 94%). MS (Q1) 350 (M)+
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23](C(NC3C=CC=CC=3)=O)[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])C)=CC=3)[NH:8][C:5]2=[N:6][CH:7]=1.NC1C([N+]([O-])=O)=C(N2CCN([CH2:51][C:52]([NH:54][C:55]3[S:56][CH:57]=[CH:58][N:59]=3)=[O:53])CC2)C(Br)=CN=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].N1C=CC=C(C=O)C=1>CN(C=O)C>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([CH2:51][C:52]([NH:54][C:55]3[S:56][CH:57]=[CH:58][N:59]=3)=[O:53])[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:19]=[N:17][CH:14]=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=Cc1cccnc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2c(Br)cnc3[nH]c(-c4cccnc4)nc23)CC1)Nc1nccs1
Reaction time: 16 h
Yield: 38 %

Procedure:
This was prepared using, the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide (50 mg, 0.11 mmol), DMF (1 mL), 1M Na2S2O4 (3 eq, 0.33 mmol, 0.33 mL) and 3-pyridinecarboxaldehyde (1.05 eq, 0.12 mmol, 0.011 mL). After 16 h, the DMF was removed in vacuo, the residue taken up in water (2 mL) and extracted with EtOAc (2×3 mL) and CH2Cl2 (2×3 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the product (21 mg, 38%) as a pale brown solid; 1H-NMR (500 MHz, DMSO-d6) 3.30 (hidden by water-in-DMSO peak, 6H, NCH2CO and piperazine N(CH2)2), 3.89 (br s, 4H, piperazine N(CH2)2), 7.28 (br s, 1H, thiazole H-4 or H-5), 7.52 (d, J=3.5 Hz, 1H, thiazole H-4 or H-5), 7.60 (dd, J=7.9, 4.8 Hz, 1H, pyridine H-5), 8.32 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.52 (d, br, J=8.0 Hz, 1H, pyridine H-4), 8.71 (d, br, J=4.7 Hz, 1H, pyridine H-6), 9.38 (s, 1H, pyridine H-2), 13.80 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:38]=[CH:39][CH:40]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[C:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[C:24]([N+:33]([O-])=O)=[C:23]([F:36])[CH:22]=3)[CH2:14][S:15](=[O:19])(=[O:18])[CH2:16]2)[O:11][C:10]1=[O:37])([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1>[NH2:33][C:24]1[C:25]([O:27][CH2:28][C:29]([F:31])([F:32])[F:30])=[CH:26][C:21]([CH2:20][C@H:13]2[C@H:12]3[C@@H:17]([N:9]([CH2:8][C:7]4[CH:38]=[CH:39][CH:40]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=4)[C:10](=[O:37])[O:11]3)[CH2:16][S:15](=[O:19])(=[O:18])[CH2:14]2)=[CH:22][C:23]=1[F:36]
Reactant: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c([N+](=O)[O-])c(OCC(F)(F)F)c4)CS(=O)(=O)C[C@@H]32)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c(N)c(OCC(F)(F)F)c4)CS(=O)(=O)C[C@@H]32)c1

Procedure:
The title compound was prepared in analogous manner as described for example 1j) from (3aR,7S,7aS)-3-(3-tert-butyl-benzyl)-7-[3-fluoro-4-nitro-5-(2,2,2-trifluoro-ethoxy)-benzyl]-5,5-dioxo-hexahydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (1.32 g, 2.24 mmol) to yield a white foam: TLC Rf=0.60 (toluene-ETA 85:15); ESIMS [M+NH4]+=576; LCMS RtH1=3.60 min API ESI pos. [M+H]+=559; 1H NMR (600 MHz, DMSO-d6): δ 7.39 (s, 1H), 7.32 (d, 1H), 7.28 (t, 1H), 7.10 (d, 1H), 6.66 (s, 1H), 6.65 (d, 1H), 4.70 (q, 2H), 4.60 (s, 2H), 4.41 (d, 1H), 4.20 (d, 1H), 4.14 (t, 1H), 3.73 (m, 1H), 3.63 (m, 1H), 3.45 (t, 1H), 3.05 (m, 1H), 2.97 (m, 1H), 2.80 (m, 1H), 2.41 (m, 2H), 1.25 (s, 9H).