Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.CS(C)=O.[Si:12]([N:19]1[C@H:22]([C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C@H:21]([C@H:29]([OH:31])[CH3:30])[C:20]1=[O:32])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(N(CC)CC)C>C(Cl)Cl.O.C(OCC)(=O)C>[C:29]([C@@H:21]1[C@@H:22]([C:23]#[C:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[N:19]([Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:20]1=[O:32])(=[O:31])[CH3:30]
Reactant: C[C@@H](O)[C@@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C#C[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C#C[Si](C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
In an argon stream, a solution of dry trifluoroacetic acid (0.2 ml) in methylene chloride (3 ml) is added dropwise to a mixture of dimethyl sulfoxide (0.1 ml) and methylene chloride (10 ml) at -65° C. or lower, and the mixture is stirred at -70° C. for 0.5 hours. A solution of cis-1-(tert-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-trimethylsilylethynyl-2-azetidinone (0.4 g) in methylene chloride (4 ml) is added dropwise at -65° C. or lower and the mixture is stirred at the same temperature for 0.5 hour. After addition of triethylamine (0.3 ml) at the same temperature, the temperature is gradually raised to room temperature. The reaction mixture is poured into a mixture of ethyl acetate (70 ml) and water (100 ml), and the organic layer is separated, washed with aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (eluent: 3% ethyl acetate-97% n-hexane) to give trans i.e. (3S,4S)-3-acetyl-1-(tert-butyldimethylsilyl)-4-trimethylsilylethynyl-2-azetidinone (0.13 g)
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][C:5]1([CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][S:15][CH:14]2[CH2:19][CH2:20][CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(O)(=O)C>CCOCC>[OH:4][C:5]1([CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][S:15][CH:14]2[CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:3])=[O:27])=[CH:29][CH:30]=2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Reaction time: 6 h

Procedure:
A solution of diazomethane (approximately 2.5 g., 0.06 mole) in ether (100 ml.) is mixed with a solution of 4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid (11.7 g., 0.03 mole) in ether (100 ml.). The resulting solution is allowed to stand at room temperature for 6 hours. Acetic acid is then added to destroy the excess diazomethane, and the solution is washed with dilute sodium bicarbonate solution and dried over sodium sulfate. Evaporation of volatile materials in vacuo yields the title compound as a nearly colorless, viscous oil.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:10])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>C(OCC)(=O)C>[N+:1]([C:4]1[C:5](=[O:10])[N:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccnc1O
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cn1cccc([N+](=O)[O-])c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
Sodium hydride (1.57 g of a 60% dispersion in mineral oil, 0.039 mole) was washed with hexanes three times (10 mL each) and suspended in dimethylformamide (25 mL). The stirred suspension was cooled in an ice bath, then 3-nitro-2-hydroxypyridine (5.00 g, 0.036 mole) was added in small portions over a 25-minute period. After the addition was complete, the reaction was stirred at 0° C. for 10 minutes, then room temperature for 30 minutes. The reaction mixture was recooled in an ice bath. t-Butyl bromoacetate (5.25 mL, 0.036 mole) was added. The reaction was stirred at 0° C. for 1 hour, then 1.5 hours at room temperature. The reaction mixture was diluted with ethyl acetate (80 mL), and ice (80 g) was added. The aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with water (4×100 mL), brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was removed, and the resulting residue was chromatographed through silica Gel using 10% ethyl acetate/dichloromethane as eluent. The pure fractions were combined, and the solvent was removed under vacuum to afford 6.77 g (75% yield) of the title compound as yellow solid. Rf =0.30 (silica gel, 20% ethyl acetate in dichloromethane).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.C1COCC1.C(N(CC)CC)C.Cl[C:37](=[O:48])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45]>O>[O:22]=[C:20]1[NH:19][C:18](=[O:23])[CH:17]([CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][N:2]([CH3:1])[C:37]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])=[O:48])[CH:5]=3)=[CH:15][CH:14]=2)[S:21]1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Reactant: COC(=O)CCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCCCCCC(=O)N(C)Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Reaction time: 1 h

Procedure:
600 mg (1.36 mmol) of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione, 10 ml of THF and 600 μl (4.3 mmol) of triethylamine are introduced into a round-bottomed flask and under a nitrogen stream. 220 μl (1.55 mmol) of methyl 8-chloro-8-oxooctanoate are added dropwise and the mixture is stirred for one hour. The reaction medium is poured into water, extracted with dichloromethane, the organic phase decanted off, washed with water, dried over magnesium sulphate and evaporated off. The residue obtained is purified by chromatography on a silica column eluted with a dichloromethane and ethyl acetate (80–20) mixture. After evaporation of the solvents, 350 mg (50%) of methyl 7-{[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamoyl}heptanoate are recovered in the form of an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([F:11])[F:10])=[N:6][CH:7]=1.[CH3:12][CH2:13][CH2:14][CH2:15][O:16][CH:17]=[CH2:18].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:15]([O:16][C:17]([C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([F:11])[F:10])=[N:6][CH:7]=1)=[CH2:18])[CH2:14][CH2:13][CH3:12]
Reactant: C=COCCCC
Reactant: FC(F)Oc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(OCCCC)c1ccc(OC(F)F)nc1
Yield: 10.1 %

Procedure:
1 g (4.46 mmol) of 5-bromo-2-difluoromethoxypyridine in 20 mL of H2O/DMF (1/4: v/v), 1.46 mL (11.16 mmol) of N-butyl vinyl ether, 30.68 mg (0.13 mmol) of palladium(II) acetate, 125 mg (0.29 mmol) of 1,3-bis(diphenylphosphino)propane and 746 mg (5.36 mmol) of potassium carbonate are placed in a microwave tube. After microwave irradiation for 1 hour at 120° C., the crude product is taken up in water and extracted with DCM. The organic phase is dried over magnesium sulfate and then evaporated to dryness. The crude product is purified by chromatography on silica gel (eluent: 0/100 EtOAc/heptane to 20/80 EtOAc/heptane over 35 minutes) to give 110 mg of 5-(1-butoxyvinyl)-2-difluoromethoxypyridine, corresponding to the following characteristics:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:5]=12>ClCCCl.[O-2].[Mn+4].[O-2]>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:5]=12
Reactant: OCc1ccn2ccnc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCCl
Product: O=Cc1ccn2ccnc2c1
Temperature: 50 °C
Yield: 67.1 %

Procedure:
Imidazo[1,2-α]pyridin-7-ylmethanol (1.35 g, 9.38 mmol) was suspended in 1,2-dichloroethane (40 ml), manganese(IV) oxide (4.07 g, 46.9 mmol) added and the mixture heated at 50° C. for 16 h. The mixture was cooled to ambient temperature, filtered through Celite® and evaporated to dryness to give imidazo[1,2-α]pyridine-7-carboxaldehyde (0.92 g, 69%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δH 7.34 (1H, dd, J 7 and 1), 7.75 (1H, s), 7.87 (1H, s), 8.13 (1H, s), 8.21 (1H, d, J 7), 10.00 (1H, s).
Reaction SMILES: COC[O:4][CH2:5][CH:6]([CH2:38][O:39]COC)[CH2:7][CH2:8][C:9]1([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([N:23]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][N:32]=3)[C:24]([C:26]3[O:27][CH:28]=[CH:29][CH:30]=3)=[O:25])[CH2:19][CH2:18]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl>CO>[OH:39][CH2:38][CH:6]([CH2:5][OH:4])[CH2:7][CH2:8][C:9]1([CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH:20]([N:23]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][N:32]=3)[C:24]([C:26]3[O:27][CH:28]=[CH:29][CH:30]=3)=[O:25])[CH2:21][CH2:22]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COCOCC(CCC1(CCN2CCC(N(C(=O)c3ccco3)c3ccc(C)cn3)CC2)CCCCC1)COCOC
Agent: Cl
Solvent: CO
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCC(CO)CO)CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102 %

Procedure:
To a solution of N-[1-[2-[1-[4-(methoxymethoxy)-3-(methoxymethoxymethyl)butyl]cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide (300 mg) in methanol (10 mL) was added conc. hydrochloric acid (0.17 mL) at room temperature. The solution was stirred at room temperature for 16 hours. conc. Hydrochloric acid (0.17 mL) was further added to the solution, and it was stirred at 50 ° C. for 6 hours. The solution was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added to the residue, and it was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and then, concentrated under reduced pressure. The residue was purified by chromatography [silica gel, chloroform-methanol-aqueous ammonia (90:10:0.1)]to give the title compound (260 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21](=[O:23])[NH2:22])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1)[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:24][C:25](=[O:27])[N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([NH2:22])=[O:23])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCNCc1nccs1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccccc2C(N)=O)cc1
Product: CCN(Cc1nccs1)C(=O)CN(c1ccccc1C(N)=O)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(2-carbamoyl-phenyl)-amino]-acetic acid with ethyl-thiazol-2-ylmethyl-amine
Reaction SMILES: CN(C=O)C.[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[N:32]=[C:33]([CH3:36])[S:34][CH:35]=4)[CH2:28][CH2:27][C:26]([C:37]([OH:39])=O)=[CH:25][C:24]=3[CH:40]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O.[CH3:45][N:46]([CH2:53][C:54]1[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][CH:55]=1)[CH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>C(Cl)(Cl)Cl.O.C(N(CC)CC)C>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[N:32]=[C:33]([CH3:36])[S:34][CH:35]=4)[CH2:28][CH2:27][C:26]([C:37]([NH:58][C:57]4[CH:59]=[CH:60][C:54]([CH2:53][N:46]([CH3:45])[CH:47]5[CH2:52][CH2:51][O:50][CH2:49][CH2:48]5)=[CH:55][CH:56]=4)=[O:39])=[CH:25][C:24]=3[CH:40]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2csc(C)n2)cc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2csc(C)n2)cc1
Reaction time: 1 h
Yield: 17.5 %

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-[(2-methylthiazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (150 mg) in chloroform (10 ml). Then, thionyl chloride (47 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. Then, this solution was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (87 mg) and triethylamine (800 mg) in chloroform (20 ml) at 0° C. The mixture was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:3) to give 7-(4-butoxyethoxyphenyl)-1-[(2-methylthiazol-4-yl)methyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 76) (37 mg) as yellow amorphous.
Reaction SMILES: O=[C:2]([CH3:14])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>CO>[CH3:14][CH:2]([NH2:21])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1
Reactant: [BH3-]C#N
Reactant: CC(=O)CCn1cnc2ccccc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)CCn1cnc2ccccc21

Procedure:
A mixture of 7.0 grams of 1-(3-oxobutyl)-1H-benzimidazole, 28.7 grams of ammonium acetate and 1.6 grams of sodium cyanoborohydride in 100 ml. of methanol was stirred at room temperature for about 24 hours. The mixture was then acidified with about 40 ml. of concentrated hydrochloric acid and the solvent was evaporated. The residue was dissolved in 150 ml. of water and the aqueous solution was extracted first with ether and then it was made alkaline (pH greater than 10) with solid potassium hydroxide. The alkaline solution was extracted with several portions of methylene chloride and the organic extracts were combined, washed with water and dried over magnesium sulfate and the methylene chloride was evaporated. The reside was chromatographed on a silica gel column packed in acetonitrile and eluted with acetonitrile and acetonitrile containing increasing percentages of methanol. The fractions containing the desired product, as determined by thin-layer chromatography, were combined and the solvent evaporated to give α-methyl-1H-benzimidazole-1-propanamine as an oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:6]1[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1)[CH3:5])[CH3:2].[NH2:22][C@@H:23]([CH3:40])[CH2:24][N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:37]=[C:36]([F:38])[C:33]([C:34]#[N:35])=[C:32]([Cl:39])[CH:31]=2)=[N:26]1>>[Cl:39][C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][N:25]([CH2:24][C@@H:23]([NH:22][C:11]([C:9]3[N:10]=[C:6]([CH:4]([O:3][CH2:1][CH3:2])[CH3:5])[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=3)=[O:13])[CH3:40])[N:26]=2)[CH:37]=[C:36]([F:38])[C:33]=1[C:34]#[N:35]
Reactant: CCOC(C)c1nc(C(=O)O)cn1COCC[Si](C)(C)C
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: CCOC(C)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1COCC[Si](C)(C)C

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-(1-ethoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (1.27 mmol, 400 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.27 mmol, 350 mg). The product was purified by flash-chromatography. Yield 230 mg. LC-MS: [M+1]=575.28.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([OH:9])[CH2:7][Cl:8])(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:22]([O:24][CH2:25][CH3:26])=[CH2:23]>>[C:1]([O:4][CH2:5][CH:6]([O:9][CH:22]([O:24][CH2:25][CH3:26])[CH3:23])[CH2:7][Cl:8])(=[O:3])[CH3:2]
Reactant: C=COCC
Reactant: CC(=O)OCC(O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(C)OC(CCl)COC(C)=O
Reaction time: 2 h

Procedure:
To the crude acetate prepared in Example 8 was added 10 g of p-toluenesulfonic acid monohydrate and then dropwise, over a period of 2 hours, 815 g (11.3 moles) of ethyl vinyl ether. The reaction was midly exothermic and the temperature was maintained at 35°-37° C. by occasional cooling. After the addition was complete, the reaction mixture was heated at 35°-40° C. for 16 hours. The crude material was used in the subsequent step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[I-].[Cs+].[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18]Br.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2
Reactant: COC(CBr)OC
Reactant: O=C1NCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(COc1ccc2c(c1)CCNC2=O)OC

Procedure:
To a solution of 6-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline (25 g, 15.3 mmol), CsI (4 g, 15.3 mmol) and bromoacetaldehyde dimethyl acetal (40 ml, 338 mmol) in DMF (600 ml) is added Cs2CO3 (137.5 g, 460 mmol). The reaction mixture is heated at 60° overnight. After this time, the reaction is poured into 1 liter brine and the resulting suspension is extracted with EtOAc (4×400 ml). The combined EtOAc extracts are dried over MgSO4 and concentrated in vacuo. The residue is washed with Et2O to yield 6-(2,2-dimethoxyethoxy)-1-oxo-1,2,3,4-tetrahydroisoquinoline as a crystalline solid.
Reaction SMILES: [Li+].[BH4-].C([O:5][C:6](=O)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1)C.CO>CCOCC>[OH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[CH:13][CH:14]=1
Reactant: CCOC(=O)CCc1ccc(C#N)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: N#Cc1ccc(CCCO)cc1

Procedure:
To a solution of LiBH4 (14 g, 0.65 mol) in dry ether (400 mL) was added 3-(4-cyanophenyl)propionic acid ethyl ester (50 g, 0.249 mol; see step (ii) above), followed by methanol (27 mL) dropwise. The reaction mixture was refluxed for 3 h. After completion (monitored by TLC), the reaction was quenched by adding cold, saturated ammonium chloride solution (100 mL), followed by water (300 mL). The layers were then separated. The aqueous layer was extracted with ether (2×100 mL) and the combined organic layers were washed with brine. After drying over anhydrous sodium sulfate, the organic layer was concentrated to give the crude product. This crude product was purified by column chromatography over silica gel, using ethyl acetate in petroleum ether as eluent. This yielded 16.5 g (42%) of the sub-title compound as a pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([NH2:30])[CH:29]=3)=[O:23])=[CH:20][N:19]([CH:31]([CH3:33])[CH3:32])[C:15]=2[N:16]=[CH:17][N:18]=1.NC1C2C(C(C3C=C(NS(C4C=C(F)C=C(F)C=4)(=O)=O)C=NC=3)=O)=CN(C(C)C)C=2N=CN=1>>[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[C:28]([NH:30][S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])(=[O:10])=[O:9])[CH:27]=[N:26][CH:25]=3)=[O:23])=[CH:20][N:19]([CH:31]([CH3:33])[CH3:32])[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2c(N)ncnc21
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: CC(C)n1cc(C(=O)c2cncc(NS(=O)(=O)c3cc(F)cc(F)c3)c2)c2c(N)ncnc21
Product: CC(C)n1cc(C(=O)c2cncc(NS(=O)(=O)c3ccccc3Cl)c2)c2c(N)ncnc21

Procedure:
The title compound was prepared from 2-Chloro-benzenesulfonyl chloride (19.6 mg, 0.093 mmol) and (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-amino-pyridin-3-yl)-methanone (25 mg, 0.084 mmol) by procedures analogous to those described for the preparation of N-[5-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-3-yl]-3,5-difluoro-benzenesulfonamide. MS: 471.2 (MH+); HPLC Rf: 4.71 min. (HPLC method 4).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:22])[C:4]([C:11](=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].C([O-])(=O)C.S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[C:5]([CH3:10])=[C:4]([C:11](=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])[C:3]=1[OH:22]
Reactant: CC(=O)OCCCCCC(=O)C1=C(C)C(=O)C(C)=C(C)C1=O
Agent: CC(=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)OCCCCCC(=O)c1c(C)c(O)c(C)c(C)c1O
Reaction time: 3 h

Procedure:
To a stirred mixture of 2,3,5-trimethyl-6-(6'-acetoxy-1'-oxohexyl)-1,4-benzoquinone (formula IV-1 wherein R=H3C, n=4, in the form of acetate ) (0.5 part), sodium hydrosulfite (1 part) and 30% aqueous methanol (20 volume parts) was added dropwise 2 N aqueous sodium hydroxide (1.6 volume part) at 5° C. The mixture was allowed to stand for 3 hours at the same temperature. After removal of the methanol and acidification with phosphoric acid, the product was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was subjected to chromatography on silica gel and eluted with ethyl acetate to give 2,3,5-trimethyl-6(6'-acetoxy-1'-oxohexyl)hydroquinone (formula III-1 wherein R=H3C, X=Y=OH, n=4, in the form of acetate) (0.075 part). Further elution with the same solvent gave 2,3,5-trimethyl-6-(6'-hydroxy-1'-oxohexyl)-hydroquinone. (formula III- 1 wherein R=H3C, X=Y=OH, n=4, in the free form) (0.265 part).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH:6]([C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:2].O.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH:6]([C:22]1[CH:27]=[N:26][C:25]([CH3:28])=[N:24][CH:23]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH3:2]
Reactant: CCOC(=O)CC(C=CCCCCCNC(=O)OC(C)(C)C)c1cnc(C)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(CCCCCCCNC(=O)OC(C)(C)C)c1cnc(C)nc1
Yield: 92 %

Procedure:
A solution of 24-5 (650 mg, 1.60 mmol), water (100 mg), ammonium formate (512 mg, 8.12 mmol), and 10% palladium on carbon (75 mg) in ethanol (40 mL) was heated to 90 ° C. for 1 hour. The reaction mixture was filtered through celite and the filtrate evaporated in vacuo to afford the title compound 24-6 (600 mg). The crude product was used directly in the next reaction. ESLRMS m/e 408 g/mole (M++H, C22H37N3O4=408 g/mole.)
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]#[N:9].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[N+](C1C=CC([O:29][C:30]([C:32]2[C:40]3[S:39][C:38]([C:41]([F:44])([F:43])[F:42])=[N:37][C:36]=3[C:35]([O:45][CH3:46])=[CH:34][CH:33]=2)=O)=CC=1)([O-])=O>CN(C)C=O.O1CCCC1>[C:8]([C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:30]([C:32]1[C:40]2[S:39][C:38]([C:41]([F:44])([F:43])[F:42])=[N:37][C:36]=2[C:35]([O:45][CH3:46])=[CH:34][CH:33]=1)=[O:29])#[N:9]
Reactant: Cn1ncc(C#N)c1N
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2sc(C(F)(F)F)nc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2c(C#N)cnn2C)c2sc(C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
A solution of 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (93 mg) in dimethyl formamide (10 ml) was treated with a solution of sodium hexamethyldisilazide in tetrahydrofuran (0.76 ml, 1.0M). After three minutes the mixture was treated with 4-methoxy-2-trifluoromethylbenzothiazole-7-carboxylic acid 4-nitrophenyl ester (150 mg) and the reaction stirred at room temperature for 2 hours. The solvent was removed in vacuo. Purification by flash chromatography (eluent ethyl acetate) to yield the title compound as an off-white solid (50 mg). TLC Rf 0.48 (ethyl acetate); MS found M+1 382.