Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[S:22](Cl)(=[O:24])=[O:23]>C([O-])(O)=O.[Na+].C(OCC)C.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=1[S:22]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)(=[O:24])=[O:23]
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2cc(C(F)(F)F)ccc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 2-chloro-5-trifluoromethylbenzenesulfonyl chloride (2.79 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 3% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (1.50 g, 41%). 1H-NMR (300 MHz, CDCl3) δ 8.24 (d, J=1.9 Hz, 1H), 7.83 (dd, J=8.3, 2.1 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 6.57 (s, 1H), 6.55 (s, 1H), 6.46 (s, 1H), 5.07 (br s, 1H), 2.24 (s, 3H).
Reaction SMILES: [Cl-].[CH2:2]([P+:6]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][CH2:8][OH:9])[CH2:3][CH2:4][CH3:5].COC1C=CC(O)=CC=1.[C:27]([Cl:32])(=[O:31])[C:28]([CH3:30])=[CH2:29]>C(#N)C>[Cl-:32].[CH2:10]([P+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:7][CH2:8][O:9][C:27](=[O:31])[C:28]([CH3:30])=[CH2:29])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC[P+](CCO)(CCCC)CCCC
Reactant: C=C(C)C(=O)Cl
Agent: COc1ccc(O)cc1
Agent: [Cl-]
Solvent: CC#N
Product: C=C(C)C(=O)OCC[P+](CCCC)(CCCC)CCCC
Reaction time: 2 h

Procedure:
Into a 1 L-four-necked flask equipped with a stirrer, a thermometer and a distillation line, was added the obtained tri-n-butyl(2-hydroxyethyl)phosphonium chloride dissolved in 500 ml of acetonitrile. The solution was heated under a normal pressure while stirring and about 200 ml of acetonitrile was distilled. A condenser having a calcium chloride tube was installed, 1.5 g of hydroquinone monomethyl ether was added as a polymerization inhibitor, and 76.3 g (0.730 mol) of methacryloyl chloride was added thereto dropwise at 50° C. over 2 hours through a dropping funnel, then the solution was maturated for 3 hours at the same temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:33])([CH3:32])[C:13](=[O:31])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[OH:30])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].I[CH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>C(#N)C>[CH:41]1([O:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:22]([N:19]2[CH2:20][CH2:21][CH:16]([N:14]3[C:13](=[O:31])[C:12]([CH3:33])([CH3:32])[C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:15]3)[CH2:17][CH2:18]2)=[O:23])[CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4O)CC3)C(=O)C2(C)C)cc1OC
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4OC4CCCC4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
1.0 g of 5-(3,4-dimethoxyphenyl)-2-{1-[(2-hydroxyphenyl)carbonyl]piperidin-4-yl}-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 94) and 1.0 g potassium carbonate are suspended in 20 ml of acetonitrile. 0.5 g of iodocyclopentane are added and the reaction mixture is heated to reflux for 5 h until the reaction is completed according to TLC analysis. The solvent is evaporated under reduced pressure, and the remaining residue is taken up in EA. The organic phase is washed with water, dried over MgSO4, and the solvent is removed under reduced pressure. Purification of the resulting crude product by crystallization from methanol yields the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:23](=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:32])[CH3:31])[CH:12]=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.Cl(O)(=O)(=O)=O.[H][H]>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:32])[CH3:31])[CH:12]=[CH:13][C:14]=1[OH:15]
Reactant: CC(=O)CCCCCCC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCO
Product: CC(=O)CCCCCCCc1ccc(O)c(O)c1

Procedure:
Using 0.5 g of 10% palladium-carbon, 3.2 g of 1-(3,4-dibenzyloxyphenyl)-1,8-nonanedione was catalytically reduced in a mixture of 50 ml of ethanol and 1.5 ml of an aqueous 5% perchloric acid solution at room temperature and under atomospheric pressure until the absorption of hydrogen stopped. After the reaction was over, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was applied to silica gel (50 ml) column chromatography and eluted with a mixture of toluene and ethyl acetate (4:1). The crystals thus obtained were recrystallized from a mixture of toluene and n-hexane to provide 1-(3,4-dihydroxyphenyl)-8-nonanone.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[C:19]1([CH2:25][C:26]([OH:28])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:29][Si:30]([CH3:33])([CH3:32])Cl>O1CCCC1>[CH3:29][Si:30]([CH3:33])([CH3:32])[O:27][C:26]([O:28][Si:30]([CH3:33])([CH3:32])[CH3:29])=[CH:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)OC(=Cc1ccccc1)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of butyllithium in hexane (0.4 mol, 250 ml of 1.6 M solution) was added to a solution of 40 g (0.4 mol) of diisopropylamine in 300 ml of tetrahydrofuran cooled in an ice-bath. A solution of 27.23 g (0.2 mol) of benzeneacetic acid in 200 ml of tetrahydrofuran was added near 0° C. and the reaction mixture was stirred for 30 minutes at 0° C. A 100 g portion of trimethylchlorosilane was added, the mixture was warmed to room temperature, stirred for 1.5 hours, and then filtered under nitrogen. The filtrate was evaporated to dryness under reduced pressure; the residue was dissolved in 80 ml of diethyl ether and filtered. The filtrate was evaporated to dryness and then distilled to give 37.2 g of β,β-[bis(trimethylsiloxy]styrene as a colorless liquid: bp 95° C. (0.5 mm).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:9]=[N:10][O:11][C:12]=2[CH:13]2[CH2:15][CH2:14]2)=[O:7])=[C:4]([N:18]([CH3:23])S(C)(=O)=O)[C:3]=1[O:24][CH2:25][CH3:26].S(=O)(=O)(O)O.O.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:9]=[N:10][O:11][C:12]=2[CH:13]2[CH2:15][CH2:14]2)=[O:7])=[C:4]([NH:18][CH3:23])[C:3]=1[O:24][CH2:25][CH3:26]
Reactant: CCOc1c(Br)ccc(C(=O)c2cnoc2C2CC2)c1N(C)S(C)(=O)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCOc1c(Br)ccc(C(=O)c2cnoc2C2CC2)c1NC
Temperature: 70 °C
Reaction time: 4 h
Yield: 23.3 %

Procedure:
A mixture of 4-[4-bromo-3-ethoxy-2-(N-methyl-N-methylsulphonylamino)benzoyl]-5-cyclopropylisoxazole (0.5 g) and concentrated sulphuric acid (6 ml) in acetic acid (9 ml) was heated at 70° C. for 4 hours, then at 90° C. for 4 hours. The mixture was poured into excess water and carefully brought to pH 5.5 by the addition of 2M sodium hydroxide solution, extracted with ethyl acetate, dried (anhydrous magnesium sulphate), evaporated and purified by column chromatography to yield 4-[4-bromo-3-ethoxy-2-(methylamino)benzoyl]-5-cyclopropylisoxazole (0.096 g), NMR 1.15(m,2H), 1.25(m,2H), 1.4(t,3H), 2.5(m,1H), 2.9(s,3H), 3.9(q,2H), 6.8(d,1H), 7.05(d,1H), 7.1(s,1H), 8.25(s,1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:22])=[C:4]([C:8]([I:21])=[C:9]([C:12](=[O:20])[N:13]([CH2:17][CH:18]=[CH2:19])[CH2:14][CH:15]=[CH2:16])[C:10]=1[I:11])[C:5]([Cl:7])=[O:6].[C:23]([O:26][CH2:27][C:28](Cl)=[O:29])(=[O:25])[CH3:24]>C(Cl)Cl>[Cl:7][C:5]([C:4]1[C:3]([I:22])=[C:2]([NH:1][C:28]([CH2:27][O:26][C:23](=[O:25])[CH3:24])=[O:29])[C:10]([I:11])=[C:9]([C:12](=[O:20])[N:13]([CH2:14][CH:15]=[CH2:16])[CH2:17][CH:18]=[CH2:19])[C:8]=1[I:21])=[O:6]
Reactant: C=CCN(CC=C)C(=O)c1c(I)c(N)c(I)c(C(=O)Cl)c1I
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Product: C=CCN(CC=C)C(=O)c1c(I)c(NC(=O)COC(C)=O)c(I)c(C(=O)Cl)c1I
Temperature: 40 °C

Procedure:
The mono-diallylamide (9) (6.56 g, 10 mmol) was dissolved in anhydrous DCM (10 ml), and stirred. The acetoxy acetyl chloride (2.1 ml, 20 mmol) was added to the solution, and heated to 40° C. for 3 days. The solvent was removed at reduced pressure and the reaction mixture was absorbed onto silica gel. The crude mixture was separated by silica gel chromatography 10% EtOAc/Petrol=>100% EtOAc over 11 CVs. The main peak was collected, concentrated at reduced pressure and analysed by both LCMS (m/z 756.83 (+ve) and NMR. This indicated the desired material had been made in good purity. The yield was 6.5 g (86%).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>[OH-].[Na+]>[C:14]([NH:1][CH:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)[C:11]([OH:13])=[O:12])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(NC(Cc1ccc(OC(=O)c2ccccc2)cc1)C(=O)O)c1ccccc1
Reaction time: 2 h

Procedure:
Tyrosine (5.0 g) was dissolved in 30 ml of 2N sodium hydroxide at 0° C. To this solution, 7 ml of benzoyl chloride was added portion-wise. The pH of the solution was constantly monitored and kept at approximately 10. After approximately 4 hours with constant pH the solution was acidified to pH 3.0 with concentrated hydrochloric acid, yielding a precipitate which was left at 0° C. for 2 hours. The precipitate was filtered, boiled over carbon tetrachloride and recrystallized from ethanol-water (1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:23][CH3:24])=[C:5]([O:21][CH3:22])[C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1.O.O.Cl[Sn]Cl>C(O)C>[CH3:1][O:2][C:3]1[C:4]([O:23][CH3:24])=[C:5]([O:21][CH3:22])[C:6]2[S:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)=[N:8][C:7]=2[CH:20]=1
Reactant: COc1cc2nc(-c3ccc([N+](=O)[O-])cc3)sc2c(OC)c1OC
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1cc2nc(-c3ccc(N)cc3)sc2c(OC)c1OC

Procedure:
To a stirred solution of 3,4,5-trimethoxybenzenamine (16d, 5g, 27.2 mmol) in pyridine as solvent and base to this 4-nitrobenzoyl chloride (17, 5.5g, 29.9 mmol) is added slowly and reflux for 3h, after completion of the reaction, reaction mixture is poured in water, filter and washed with dil HCl and dried to afford compound 4-nitro-N-(3,4,5-trimethoxyphenyl)benzamide (18d). To a stirred solution of amide (18d, 6g, 18.0 mmol) taken in toluene lawessons reagent (5.1g, 12.6 mmol) is added and refluxed at 110° C. for 6h. after completion of the reaction toluene is evaporated under vacuum and water is added and extracted into chloroform and finally purified by column chromatography to afford pure compound 4-nitro-N-(3,4,5-trimethoxyphenyl) benzothioamide (19d). Treating the thioamide product (19d, 4g, 11.4 mmol) with potassium ferricyanide (4 eq) in aqueous sodium hydroxide (8 eq) solution at 90° C. for 2h cyclization takes place to obtain the 5,6,7-trimethoxy-2-(4-nitrophenyl) benzo[d]thiazole (20d) solid is precipitated from the reaction mixture filtered and washed with water and dried to afforded product 20d. Reduction of the nitro compound (20d, 1 g, 2.8 mmol) is proceeded with SnCl2.2H2O in ethanol and reflux at 80° C. for 2h, after completion of reaction ethanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered in celite bed and purified in silica column (60-120) to afforded pure compound (21d). The compound 4-(5,6,7-trimethoxybenzo[d]thiazol-2-yl)benzenamine (21d, 250 mg, 0.79 mmol) on reaction with 3,5-dimethoxybenzaldehyde (22d, 131 mg, 0.79 mmol) in ethanol using catalytic amount of acetic acid and refluxed for 2h after completion reaction mixture is cooled to 0° C. solid is precipitated from the reaction mixture it is filtered and washed with ethanol to gave the enamine product, and immediately proceeded for the next reaction with using (p-tolylsulfonyl) methyl isocyanide (tosmic) (1.5 eq), and potassium carbonate (2 eq) as base, in 10 mL of methanol and 5 mL of DME was heated under reflux for 12 h after completion of reaction as monitored by TLC. It was cooled to room temperature (27° C.); the solution was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc and Hexane to gave compound 7d as a brown solid (62%).
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][O:6][C:7](=[O:17])[CH2:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=1.CO.C(OCC)(=O)C>O.C(O)(=O)C.[Zn]>[Br:16][C:12]1[CH:11]=[C:10]([N:9]([CH2:8][C:7]([O:6][CH3:5])=[O:17])[NH2:1])[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)CNc1cccc(Br)c1
Reactant: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CN(N)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
A solution of sodium nitrite (30 g) in water (200 ml) was added dropwise to a solution of N-(3-bromophenyl)glycine methyl ester (94 g) in aqueous acetic acid (850 ml) at 0°. After 1 h, methanol (200 ml) was added and the mixture was cooled to -10°. Zinc dust (351 g) was added portionwise over 2 h during which time the temperature was maintained at -10° to 0°. The mixture was then allowed to warm to room temperature, poured into ethyl acetate (1000 ml) and filtered. The filtrate was poured into water (1000 ml) and the layers were separated. The organic extract was washed with 2N sodium carbonate solution (500 ml) and solid sodium carbonate was added until the solution was basic. The aqueous extract was re-extracted using ethyl acetate (1000 ml) and the combined organic extracts were dried and evaporated. The residue was purified by FCC eluting with System A (1:1) to give the title compound (25.1 g) as an oil, t.l.c. (System A, 1:1) Rf 0.26.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[N:4][C:3]=1[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]1.[CH:30]1(B(O)O)[CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH:30]1([C:2]2[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=3)=[N:4][C:3]=2[NH:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]2)[CH2:32][CH2:31]1
Reactant: OB(O)C1CC1
Reactant: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)c(Br)nc2C(N)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)c(C3CC3)nc2C(N)=O)c1
Temperature: 115 °C
Reaction time: 8 h

Procedure:
A mixture of 6-bromo-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Example 181) (50 mg), cyclopropylboronic acid (18 mg), tetrakistriphenylphosphine palladium (24 mg), potassium carbonate (71 mg), dioxane (2.5 mL) and water (0.5 mL) was stirred at 115° C. overnight. After cooling, the reaction liquid was partitioned using chloroform, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. After drying, the organic layer was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform:methanol:saturated aqueous ammonia=100:0:0 to 10:1:0.1). The resulting residue was solidified with ethyl acetate-hexane to give 6-cyclopropyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (10 mg) as a yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:34][C:20]3[N:21]=[CH:22][N:23]=[C:24]([NH:25][C@@H:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH3:27])[C:19]=3[CH:18]=2)=[CH:13][CH:12]=1)C.O.[OH-].[Na+]>C1COCC1>[C:28]1([C@H:26]([NH:25][C:24]2[C:19]3[CH:18]=[C:17]([C:14]4[CH:13]=[CH:12][C:11]([CH2:10][OH:9])=[CH:16][CH:15]=4)[NH:34][C:20]=3[N:21]=[CH:22][N:23]=2)[CH3:27])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1ccc(-c2cc3c(N[C@H](C)c4ccccc4)ncnc3[nH]2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CO)cc3)cc12)c1ccccc1

Procedure:
570 mg (15 mmol) lithium aluminum hydride are suspended in 150 ml dry THF at RT. 1.23 g (3 mmol) 4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoic acid ethyl ester are added and the mixture heated to reflux for 1 h. The mixture is cooled in an ice bath and treated sequentially with water (0.57 ml), 15% sodium hydroxide solution (0.57 ml) and water (1.71 ml). The solid aluminum complex is removed by filtration (Hyflo Super Cel®; Fluka, Buchs, Switzerland), the filtrate dried over sodium sulfate evaporated. The residue is suspended in water, filtered and dried to give the title compound; m.p. >300° C.; Rf (dichloromethane/ethanol 9:1 plus 1% conc. ammonia)=0.43; HPLC tR=8.71 min.
Reaction SMILES: [NH2:1]N.[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]C2C=CC=C3C(NC(=O)C=23)=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>CO>[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:1])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: O=C1NC(=O)c2c(CCCCCN3CCOCC3)cccc21
Reactant: NN
Solvent: CO
Product: NCCCCCN1CCOCC1

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 5-morpholinylpentylphthalimide (242 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]2[CH:6]([C:15]3[C:16](=[O:22])[NH:17][C:18](=[O:21])[NH:19][CH:20]=3)[C:7]3[C:8]([CH:13]=[CH:14][C:4]=2[CH:3]=1)=[N:9][CH:10]=[CH:11][CH:12]=3.[H-].[Na+].I[CH3:28]>CN(C)C=O.O>[CH3:28][N:19]1[CH:20]=[C:15]([CH:6]2[C:7]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:13]=[CH:14][C:4]3[CH:3]=[C:2]([CH3:1])[CH:24]=[CH:23][C:5]2=3)[C:16](=[O:22])[NH:17][C:18]1=[O:21]
Reactant: Cc1ccc2c(c1)C=Cc1ncccc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C=Cc1ncccc1C2c1cn(C)c(=O)[nH]c1=O
Reaction time: 16 h

Procedure:
A solution of the product of example 22 step (iv) (0.68 g) in dry N,N-dimethylformamide (10 ml) was treated in one portion with sodium hydride (60% dispersion by wt, 0.086 g). After 1 hr iodomethane (0.13 ml) was added and the solution was stirred for 16 hr. The reaction mixture was diluted with water (50 ml) and the mixture was extracted with ethyl acetate (3×20 ml). The combined extracts were dried (Na2SO4) and the solvent was evaporated under reduced pressure. Purification was by chromatography eluting with 50-60% acetone in isohexane.
Reaction SMILES: CC([O:5][C:6](=[O:50])[C@H:7]([CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:49])[NH2:48])[NH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([NH:27][C@H:28]([C:36]([O:38]C(C)(C)C)=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:35])[NH2:34])=[O:26])=[O:10])(C)C>ClCCl.FC(F)(F)C(O)=O>[C:11]1([C:9]([NH:8][C@H:7]([C:6]([OH:50])=[O:5])[CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:48])[NH2:49])=[O:10])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([NH:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:34])[NH2:35])=[O:26]
Reactant: CC(C)(C)OC(=O)[C@H](CCCNC(=N)N)NC(=O)c1ccccc1SSc1ccccc1C(=O)N[C@@H](CCCNC(=N)N)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCC[C@H](NC(=O)c1ccccc1SSc1ccccc1C(=O)N[C@@H](CCCNC(=N)N)C(=O)O)C(=O)O
Yield: 59.8 %

Procedure:
This compound was prepared according to the general method of Example 122 using N,N'-[Dithiobis (2,1-phenylenecarbonyl)bis-L-arginine-bis(1,1-dimethylethyl) ester, (1.31 g, 2.0 mmol) from Example 127 in 15 mL of dichloromethane and 15 mL of trifluoroacetic acid. The residue was triturated with ethanol and 1N HCl to yield 0.74 g of the title compound, mp 208-211° C.;
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[C:7]([C:11](O)=[O:12])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:3]=1>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]2[C:7]([CH2:11][OH:12])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: Cc1cc2cccc(C(=O)O)c2s1
Solvent: C1CCOC1
Product: Cc1cc2cccc(CO)c2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
The carboxylic acid (509) (0.240 g, 1.25 mmol) was dissolved in anhydrous tetrahydrofuran (12 mL) and cooled to 0° C. under nitrogen. BH3-tetrahydrofuran complex (3.12 mL, 3.12 mmol, 1.0 M in tetrahydrofuran) was added slowly. After the addition was complete, the solution was allowed to warm to room temperature and stirred for an additional 1 hour. The solution was cooled to 0° C. and quenched by the addition of methanol (5 mL) followed by a saturated sodium sulfate aqueous solution (5 mL). The mixture was diluted with ethyl acetate and washed with brine and dried over sodium sulfate, filtered, and concentrated in vacuo to provide (2-methylbenzo[b]thiophen-7-yl)methanol (510) (0.203 g, 91.2%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:14]/[O:15][CH2:16][C:17]#[N:18])/[C:8]([O:10]CC=C)=[O:9])[N:6]=1.C(N(CC)CC)C>C(OCC)(=O)C.[Pd](Cl)Cl.P(OCC)(OCC)(OCC)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:14]/[O:15][CH2:16][C:17]#[N:18])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: C=CCOC(=O)/C(=N\OCC#N)c1csc(N)n1
Agent: Cl[Pd]Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCOP(=O)(OCC)OCC
Product: N#CCO/N=C(\C(=O)O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.8 %

Procedure:
2.66 g (0.01 mol) of allyl 2-(2-amino-4-thiazolyl)-2-[(Z)-(cyanomethoxy)imino]-acetate in 100 ml of ethyl acetate are treated while stirring with 17.73 mg (0.0001 mol) of palladium chloride and 0.083 ml (0.0005 mol) of triethyl phosphate. After the addition of 1.54 ml (0.011 mol) of triethylamine, the mixture is stirred at room temperature for 24 hours. Crude 2-(2-amino-4-thiazolyl)-2-[(Z)-(cyanomethoxy)imino]-acetic acid triethylamine salt precipitates out. The filtered-off crude salt (2.9 g) is dissolved in 30 ml of methanol. The solution is adjusted to pH 3 with 2N aqueous hydrochloric acid. Crystallization occurs. The crystals obtained are filtered off and washed with methanol and ether. There are obtained 1.24 g (51.2%) of 2-(2-amino-4-thiazolyl)-2-[(Z)-(cyanomethoxy)imino]-acetic acid of melting point 140°-142° C. (decomposition).