Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([O:29][Si:30]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH3:31])[C:9]([CH3:28])([CH3:27])[C:10](=[O:26])[CH:11]([CH3:25])[CH:12]([OH:24])[CH:13]([CH3:23])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[Si:45](OS(C(F)(F)F)(=O)=O)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([O:29][Si:30]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH3:31])[C:9]([CH3:27])([CH3:28])[C:10](=[O:26])[CH:11]([CH3:25])[CH:12]([O:24][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH:13]([CH3:23])[CH2:14][O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC[Si](C)(CC)OC(CC(=O)OC(C)(C)C)C(C)(C)C(=O)C(C)C(O)C(C)COCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC[Si](C)(CC)OC(CC(=O)OC(C)(C)C)C(C)(C)C(=O)C(C)C(O[Si](C)(C)C(C)(C)C)C(C)COCc1ccccc1
Reaction time: 2 h
Yield: 111.5 %

Procedure:
To a solution of 71a (4.1 mg, 7.6 μmol) and 2,6-lutidine (10.0 μL, 43.5 mmol) in CH2Cl2 (0.2 mL) at −78° C. was added TBSOTf (10.0 μL, 85.8 mmol). After 2 h, more, 6-lutidine (10.0 μL, 43.5 mmol) and TBSOTf (10.0 μL, 85.8 mmol) were added. After 6 h, the mixture was diluted with sat aq NaHCO3. The aqueous layer was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (gradient hexane to hexane/EtOAc 91:9) to give 36 (5.4 mg, 82%) as a clear oil. Spectroscopic data agreed well with the reported values.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH3:11])=[C:5]([C:12](=O)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[CH:4]=1.[OH-].[K+].NN>C(O)COCCOCCO>[CH3:11][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1
Reactant: COc1ccc(CC(=O)c2cc(OC)c(OC)cc2C)cc1OC
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Product: COc1ccc(CCc2cc(OC)c(OC)cc2C)cc1OC
Yield: 82 %

Procedure:
Reaction of 8.0 of 4,5-dimethoxy-2(3,4-dimethoxyphenylacetyl) toluene and 10 g KOH in a solution of 6.5 ml 95% hydrazine in 84 ml triethylene glycol according to the procedures of Example II gave a yellow oil which was crystallized from alcohol to give 6.4 g (82%) of 2-methyl-3',4,4' ,5-tetramethoxybibenzyl as a white powder, mp 101.5°-102.5°. Nmr (δ): 2.20 (s, 3H), 2.82 (s, 4H), 3.80 (s, 3H), 3.84 (s, 9H), 6.58-6.80 (m, 5H); mass spectrum: m/e (rel intensity) 316(5), 165(100), 151 (15). Anal. Calcd. for C19H24O4 : C, 72.13; H, 7.65. Found: C, 72.15; H, 7.69.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:1]1([S:4]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(OCc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Cyclopropyl sulfonyl chloride (2 g, 14.2 mmol) was added drop-wise at 0° C. to a solution of Benzyl alcohol (2.1 g, 28.4 mmol) and Pyridine (2.35 g, 29.8 mmol) in DCM (20 mL) and continued stirring at 25° C. for 16 h. The reaction mixture was diluted with DCM (100 mL), washed with 1N aq.HCl solution followed by water and brine; Organic layer collected was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the Benzyl cyclopropanesulfonate. 1H NMR (300 MHz, CD3OD) δ ppm 4.3-4.1 (2H, t), 2.7-2.6 (1H, m), 1.8-1.6 (2H, m), 1.6-1.4 (2H, m), 1.2-1.1 (4H, m), 1.0-0.9 (3H, t).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([NH:9][C:10]2[C:11]3[CH2:38][CH2:37][CH2:36][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH:17]3[C:21]([NH:23][C@H:24]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)=[O:22])[N:15]=2)[NH:6][N:5]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([C:4]1[CH:8]=[C:7]([NH:9][C:10]2[C:11]3[CH2:38][CH2:37][CH2:36][C:12]=3[N:13]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[C:21]([NH:23][C@H:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)=[O:22])[N:15]=2)[NH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(Nc2nc(N3CCCC3C(=O)N[C@H]3CCN(C(=O)OC(C)(C)C)C3)nc3c2CCC3)[nH]n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc(Nc2nc(N3CCC[C@@H]3C(=O)N[C@H]3CCNC3)nc3c2CCC3)[nH]n1
Yield: 7.4 %

Procedure:
To a stirred solution of (3S)-tert-butyl 3-(1-(4-(3-isopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamido)pyrrolidine-1-carboxylate (350 mg, 0.667 mmol) in DCM (3.5 mL) was added TFA (0.15 ml, 2.003 mmol) dropwise under nitrogen atmosphere at 0° C. The resultant mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure. The crude obtained was purified by reverse phase HPLC. The stereoisomers obtained were separated by chiral HPLC to afford 21 mg of (R)-1-(4-(3-isopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N—((S)-pyrrolidin-3-yl)pyrrolidine-2-carboxamide. 1H NMR (400 MHz, CDCl3) δ (ppm) 1.30 (d, 6H), 1.94-2.15 (m, 6H), 2.60-2.77 (m, 4H), 2.79-3.10 (m, 6H), 3.58-3.66 (m, 1H), 3.70-3.80 (m, 1H), 4.05-4.13 (m, 1H), 4.58 (dd, 1H), 6.38 (s, 1H), 6.79 (s, 1H). The other diastereomers were prepared using appropriate chiral starting materials.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[H][H].Br[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>CN(C)C=O.O>[NH:1]1[CH:5]=[N:4][C:3]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[N:2]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: c1nc[nH]n1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Cc2nc[nH]n2)cc1
Reaction time: 2 h
Yield: 67.5 %

Procedure:
23.5 g of 1,2,4-triazole is combined under cooling in 250 ml of N,N-dimethylformamide in incremental portions with 14.15 g of sodium hydride, 60% in oil, and stirred at 25° for 1 hour until hydrogen release has ceased. To this solution is added 50 g of 4-(bromomethyl)benzonitrile in two portions under ice cooling at 5°, and the mixture is stirred for 2 hours at 25°. For working up purposes, 200 ml of water is added under ice cooling, the mixture is stirred for 1 hour, extracted with ethyl acetate, washed neutral with water, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with dichloromethane/methanol, yielding 31.73 g of 4-[1-(1,2,4-triazolyl)methyl]benzonitrile as colorless crystals, mp. 72°-73°.
Reaction SMILES: [OH:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]1[CH:4]=[C:5]([C:16]([O:18]CC)=[O:17])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:8]=1.[OH-].[Li+].Cl>O1CCOCC1.O>[OH:1][CH:2]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:3]1[CH:4]=[C:5]([C:16]([OH:18])=[O:17])[CH:6]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH:8]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C)cc2)cc(C(O)c2ccccc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(O)c3ccccc3)c2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 5-(hydroxy(phenyl)methyl)-4′-methylbiphenyl-3-carboxylate (230 mg, 0.66 mmol) in 1,4-dioxane (2 mL) and water (1 mL) was added lithium hydroxide (48 mg, 2 mmol). The reaction mixture was stirred at 60° C. overnight. After cooling, the mixture was acidified with 15% HCl (aq.) to pH=5, and extracted with EtOAc. The organic layer was dried and concentrated in vacuo to afford the title compound as a white solid. 1H NMR (300 MHz, acetone-d6): 8.14 (t, 1H, J=2.0 Hz), 8.09 (m, 1H), 7.97 (m, 1H), 7.60-7.47 (m, 4H), 7.37-7.19 (m, 5H), 6.00 (s, 1H), 2.37 (s, 3H).
Reaction SMILES: [Si]([O:8][C:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[C:38]1[CH:43]=[CH:42][CH2:41][C:40](OC)([Cl:44])[CH:39]=1.CN(C)[CH:49]=[O:50]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C.C(OC)(C)(C)C.O>[Cl:44][C:40]1[CH:41]=[CH:42][C:43]([CH:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:17][CH2:18][C:9]2=[O:8])=[CH:38][C:39]=1[O:50][CH3:49]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OC1=Cc2ccccc2CC1
Reactant: COC1(Cl)C=C(Br)C=CC1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: O
Product: COc1cc(C2C(=O)CCc3ccccc32)ccc1Cl
Temperature: 90 °C

Procedure:
Charge an oven dried, argon flushed 25-mL 2-necked round bottomed flask equipped with a stirring bar and reflux condenser with 2-t-butyldimethylsilyloxy-3,4-dihydronaphthalene (0.5007 grams, 1.9224 mmoles) and tetra-n-butylammonium fluoride (2.3 mL, 2.30 mmoles, 1 M in tetrahydrofuran), stir for a few minutes and then add 4-bromo-2-methoxy-2-chlorobenzene (0.4287 grams, 1.9356 mmoles), dichlorobis(tri-o-tolyl-phosphine)palladium (0.0154 grams, 0.0196 mmoles) and 5 mL dimethylformamide. Heat the reaction mixture for 18 hours (oil bath temperature about 90° C.), cool to RT and add 5 mL water and 10 mL t-butylmethyl ether. Separate the layers, extract the aqueous layers with 3×5 mL t-butylmethyl ether, wash the combined organic layers with water and saturated salt solution, dry over magnesium sulfate and concentrate using a Buchi rotavapor to yield the product.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O>C1COCC1>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(=O)c1c[nH]c2ccccc12
Solvent: C1CCOC1
Product: CC(=O)c1cn(C(=O)OC(C)(C)C)c2ccccc12

Procedure:
To a stirred solution of 3-acetylindole (0.01 mol) in THF is added (BOC)2O (0.01 mol) and a tertiary amine base (0.01 mol), and the mixture is stirred. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of desired product is formed, the mixture (or, optionally, the residue which is obtained after first rotary evaporating off the reaction solvent) is partitioned between ethyl acetate and an excess of about 0.1 M sodium hydroxide. The organic layer is washed with brine, dried over sodium sulfate, and rotary evaporated to give 3-acetyl-1-(tert-butoxycarbonyl)-indole, which may be purified, if needed or desired, by chromatography on silica gel or crystallization.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:23][C:24]([F:36])([F:35])[C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.Cl>CN(C)C1C=CN=CC=1.C(OCC)C.ClCCl>[F:36][C:24]([F:23])([F:35])[C:25]1[CH:26]=[CH:27][C:28]([S:31]([O:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][N:13]=3)[CH2:4][CH2:3]2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: N#Cc1ccc(N2CCC(O)CC2)nc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(N2CCC(OS(=O)(=O)c3ccc(C(F)(F)F)cc3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a dichloromethane (50 mL) solution of 6-(4-hydroxypiperidin-1-yl)pyridine-3-carbonitrile (3.19 g, 15.7 mmol) and triethylamine (9.0 mL, 65 mmol) was added 4-(trifluoromethyl)benzenesulfonyl chloride (4.31 g, 17.6 mmol). 4-(Dimethylamino)pyridine (0.19 g, 1.6 mmol) was then added, and the reaction mixture was stirred at room temperature for 2 hours. Diethyl ether (100 mL) was added, followed by 1.0 M hydrochloric acid (70 ml, 70.0 mmol). The organic layer was separated and washed with 1.0 M hydrochloric acid (2×50 mL), saturated brine, dried (magnesium sulfate) to afford the title compound as a solid. This crude product was used in the subsequent step without further purification. 1H NMR (500 MHz, CDCl3) δ 8.39 (d, J=2.3 Hz, 1H), 8.08 (d, J=8.3 Hz, 2H), 7.85 (d, J=8.2 Hz, 2H), 7.61 (dd, J=9.0, 2.4 Hz, 1H), 6.61 (d, J=9.1 Hz, 1H), 4.94-4.88 (m, 1H), 3.87 (ddd, J=13.7, 7.9, 3.8 Hz, 2H), 3.62 (ddd, J=13.8, 7.3, 3.9 Hz, 2H), 1.97-1.90 (m, 2H), 1.89-1.81 (m, 2H); LC-MS: m/z 412.0 (M+H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:22]([CH2:24][NH2:25])[OH:23]>>[C:1]([NH:25][CH2:24][CH2:22][OH:23])(=[O:6])[C:2]([CH3:4])=[CH2:3].[C:1]([O:6][CH2:24][CH2:22][OH:23])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: NCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: C=C(C)C(=O)NCCO
Product: C=C(C)C(=O)OCCO
Yield: 99.7 %

Procedure:
2-methacrylamidoethyl alcohol was prepared in substantially the same manner as in Example 11 except that 6.9 g of methacrylic acid and 16.5 g of dicyclohexylcarbodiimide and 4.9 g of ethanolamine were used. Subsequently, a polymer powder was obtained in substantially the same manner as in Example 11 except that 52.0 g of 2-methacryloyloxyethyl alcohol was used. The obtained polymer powder is referred to as "1T-40". Separately, 2-methacrylamidoethyl alcohol was prepared in substantially the same manner as in Example 11 except that 27.6 g of methacrylic acid and 66.0 g of dicyclohexylcarbodiimide and 19.6 g of ethanolamine were used. Subsequently, a polymer powder was obtained in substantially the same manner as in Example 11 except that 20.8 g of 2-methacryloyloxyethyl alcohol was used. The polymer powder is referred to as "4T-40".
Reaction SMILES: [N:1]1([C:4]2[C:5](=[O:18])[C:6]3[C:7]([CH3:17])=[C:8]([CH2:15][OH:16])[NH:9][C:10]=3[C:11](=[O:14])[C:12]=2[CH3:13])[CH2:3][CH2:2]1.CN(C1C=CC=CN=1)C.[C:28](OC(=O)C)(=[O:30])[CH3:29].[K+].[Br-]>C(Cl)(Cl)Cl.C(Cl)(Cl)Cl.CO>[C:28]([O:16][CH2:15][C:8]1[NH:9][C:10]2[C:11](=[O:14])[C:12]([CH3:13])=[C:4]([N:1]3[CH2:3][CH2:2]3)[C:5](=[O:18])[C:6]=2[C:7]=1[CH3:17])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=C(N2CC2)C(=O)c2c([nH]c(CO)c2C)C1=O
Agent: CN(C)c1ccccn1
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)OCc1[nH]c2c(c1C)C(=O)C(N1CC1)=C(C)C2=O
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a mixture of 10 mg of indole 1b (0.04 mmole), 5 mg (0.04 mmole) dimethylaminopyridine (DMAP) in 5 ml of chloroform, was added 100 mg of acetic anhydride. The reaction was stirred at room temperature for 25 min and then added directly to a silica gel chromatography column employing chloroform as the eluant. The purified indole 1c was recrystallized from chloroform/hexane: 11 mg (95%) yield; mp 210-212° C.; TLC (chloroform/methanol, 90:10) Rf=0.68; 1HNMR (CDCl3) δ 9.38 (1H, bs, indole proton), 5.03 (2H, s, 2-methylene), 2.32 (4H, s, ethylene), 2.31 (3H, s, 3-methyl) 2.08 and 2.05 (6H, 2s, methyls); IR (KBr pellet) 3207, 2924, 1734, 1664, 1624, 1566, 1500, 1361, 1350, 1242, 1209, 1155, 1020, 962, 817, 781 cm−1; MS (EI mode) m/z 288 (M+), 245 (M+-CH3—C═O), 228, 213, 201, 185. Anal. Calcd (C15H16N2O4) C, H, N.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:17]1([NH:20][C:21]([C:23]2[S:36][C:26]3=[N:27][C:28](S(C)=O)=[C:29]([Cl:32])[C:30]([CH3:31])=[C:25]3[C:24]=2[NH2:37])=[O:22])[CH2:19][CH2:18]1>C1COCC1>[CH3:6][O:5][C:1](=[O:4])[CH2:2][O:3][C:28]1[N:27]=[C:26]2[S:36][C:23]([C:21](=[O:22])[NH:20][CH:17]3[CH2:18][CH2:19]3)=[C:24]([NH2:37])[C:25]2=[C:30]([CH3:31])[C:29]=1[Cl:32]
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Reactant: COC(=O)CO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)COc1nc2sc(C(=O)NC3CC3)c(N)c2c(C)c1Cl
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 57.7 %

Procedure:
To a solution of methyl glycolate (6.55 g, 72.7 mmol) in THF (35 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes) (36.35 ml, 36.35 mmol). The resulting mixture is stirred for 20 minutes, then treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (5.0 g, 14.54 mmol). The reaction vessel is sealed and heated at 90° C. for 3 hours. The reaction is cooled to room temperature and quenched by the addition of water (50 ml). The mixture is partitioned between water and EtOAc (250 ml each), and the layers are shaken and separated. The aqueous layer is extracted with 2×100 ml of EtOAc. The combined organic layers are dried (anhydrous magnesium sulfate), filtered, concentrated, and flashed (1:1 hexane:EtOAc) to give the title compound as a yellow solid (3.1 g, 58%). Mass (m/z): 370.1 (M++1), 368.0 (M+−1).
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH3:2].C1(OC(=O)CC)CCCCC1.[H][H]>[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH3:2]
Reactant: CCOC1CCCCC1=O
Reactant: [H][H]
Agent: [Pd]
Agent: CCC(=O)OC1CCCCC1
Product: CCOc1ccccc1O

Procedure:
A solution of 10 gm. 2-ethoxycyclohexanone in 100 ml. cyclohexylpropionate was refluxed over 400 mg. of palladium on carbon until approximately 75% hydrogen had evolved. The catalyst was removed by filtration. o-Ethoxyphenol was obtained in high yield.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[CH:12]=[CH:11]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.I.CS[C:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=[NH:26]>[Pd].C(O)C>[N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:25]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[NH:26])[CH:17]=3)[CH:12]=[CH:11]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc2ccn(CCCN3CCOCC3)c2c1
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: CCO
Product: N=C(Nc1ccc2ccn(CCCN3CCOCC3)c2c1)c1cccs1
Reaction time: 15 h
Yield: 92.2 %

Procedure:
A solution of compound 149 (2.0 g, 6.912 mmol) in abs. ethanol (20 mL) was treated with Pd—C (0.25 g), purged with hydrogen gas and stirred for overnight (15 h) under hydrogen atm. (balloon pressure). The reaction mixture was filtered through a celite pad and washed with abs. ethanol (2×20 mL). The combined ethanol layer was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (3.94 g, 13.824 mmol) and the resulting mixture was stirred for overnight (16 h) at room temperature. The solvent was evaporated and the product was precipitated with ether (250 mL). The solid was dissolved into sat. NaHCO3 sol.: CH2Cl2 (100 mL, 1:1). The org. layer was separated and aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined CH2Cl2 layer was washed with brine (25 mL) and dried (Na2SO4). The solvent was evaporated and the crude product was purified by column chromatography (2M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 150 (2.348 g, 92%) as a foam. 1H-NMR (DMSO-d6) δ 1.83-1.91 (m, 2H), 2.19 (t, 2H, J=6.6 Hz), 2.30 (brs, 4H), 3.56 (t, 4H, J=4.8 Hz), 4.14 (t, 2H, J=6.6 Hz), 6.34-6.35 (m, 3H), 6.58 (dd, 1H, J=1.2, 8.2 Hz), 6.95 (brs, 1H), 7.09 (dd, 1H, J=3.9, 5.1 Hz), 7.21 (d, 1H, J=3.0 Hz), 7.44 (d, 1H, J=8.1 Hz), 7.59 (d, 1H, J=3.9 Hz), 7.72 (dd, 1H, J=0.9, 3.6 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[C:10]([O:14][C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)([CH3:13])([CH3:12])[CH3:11].[H-].[Na+].O>CN(C)C=O.C(O)(=O)C>[C:10]([O:14][C:15](=[O:25])[CH:16]([C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[C:7](=[O:9])[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)([CH3:12])([CH3:13])[CH3:11]
Reactant: O=C(O)c1cnccn1
Reactant: COc1ccc(CC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C(=O)OC(C)(C)C)C(=O)c2cnccn2)cc1
Temperature: -30 °C

Procedure:
N,N-Carbonylimidazole (14.86 g) was added to a slurry of pyrazine-2-carboxylic acid in dry dimethylformamide (100 cm3). After stirring for one hour 4-methoxyphenylacetic acid t-butyl ester (10.8 g) was added. The reaction mixture was cooled to −30° C. then sodium hydride (4.62 g) was added. The reaction mixture was stirred at −30° C. for 1h then allowed to warm to room temperature overnight. The reaction mixture was poured into water and acidified to pH 8 with acetic acid. The solution was extracted with ether (3×250 cm3). The ether extracts were combined, washed with brine, dried over magnesium sulphate filtered and evaporated under reduced pressure to give a solid. The solid was purified by chromatography using ethyl acetate/hexane (1:1) as eluant. The appropriate fractions were combined and evaporated under reduced pressure to give 2-(4-methoxyphenyl)-3-oxo-3-pyrazine-2-yl propionic acid t-butyl ester as a solid (9.8 g 61%) δH (250 MHz; CDCl3) 1.39 (9 H, s, C(CH3)3), 3.70 (3 H, s, OCH3), 5.87(1 H, s, tBuO2CCH), 6.90 (2H, d, J 9 Hz, methoxyphenyl H-2) 7.32 (2H, d, J 9 Hz, methoxyphenyl H-3) 8.66 (1H, dd pyrazine H-) 8.74 (1H, d pyrazine H-) 9.25 (1H, d pyrazine H-)
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:14]([NH:16][C:17]3[S:18][C:19]([O:22][C:23]4[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][CH:24]=4)=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[BH4-].[Na+]>CO.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:14]([NH:16][C:17]3[S:18][C:19]([O:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=4)=[CH:20][N:21]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(Oc2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1ncc(Oc2ccc(CO)cc2)s1)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reaction time: 1 h
Yield: 56.1 %

Procedure:
To a stirred solution of 2-(4-Cyclopropanesulfonyl-phenyl)-N-[5-(4-formyl-phenoxy)-thiazol-2-yl]-2-(tetrahydro-pyran-4-yloxy)-acetamide (Example A74; 0.2 g, 0.36 mmol) in 10 mL methanol, sodium borohydride (0.027 g, 0.73 mmol) was added in portions at 0° C. After complete addition reaction mixture was stirred for 1 hr at 0° C. to 10° C. Completion of the reaction was confirmed by TLC, then methanol was evaporated on rotavapour. Reaction mixture was diluted with ethyl acetate (3×20 mL), organic layer was washed with water and brine, dried (Na2SO4) and concentrated in vacuo. Purified by PREP TLC to afford title compound (0.110 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:21])[CH2:6][CH2:7][NH:8][C:9]([CH:11]1[C:16]([CH3:18])([CH3:17])[CH2:15][O:14][C:13]([CH3:20])([CH3:19])[O:12]1)=[O:10].[C:22](Cl)(=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C(N(CC)CC)C>O1CCCC1>[CH3:19][C:13]1([CH3:20])[O:12][CH:11]([C:9]([NH:8][CH2:7][CH2:6][C:5](=[O:21])[NH:4][CH2:3][CH2:2][NH:1][C:22](=[O:40])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:10])[C:16]([CH3:17])([CH3:18])[CH2:15][O:14]1
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)NCCN)O1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCNC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 19.4 %

Procedure:
A mixture of 1.1 g of N-[3-[(2aminoethyl)amino]-3-oxopropyl]-2,2,5,5-tetramethyl-1,3-dioxane-4-carboxamide, 1.1 g of oleoyl chloride and 3 ml of triethylamine in 100 ml of tetrahydrofuran was reacted as described in Example 11. The crude product was purified by flash chromatography, eluting with dichloromethane:methane (50:1, then 20:1), giving 400 mg of the desired product as a white solid, mp 110-112° C.