Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:18])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[S:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]2=[O:17])(=[O:3])C.II.[OH-:21].[K+].[OH-].[Na+]>O.C(O)CO.N1C=CC=CC=1>[C:1]([C:4]1[C:5]([CH3:18])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[S:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]2=[O:17])([OH:3])=[O:21]
Reactant: [OH-]
Reactant: CC(=O)c1cc(C)c2c(c1C)C(=O)C(C)(C)CS2
Agent: II
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: OCCO
Product: Cc1cc(C(=O)O)c(C)c2c1SCC(C)(C)C2=O
Yield: 95 %

Procedure:
A mixture containing 10.8 g (41 mmol) of 6-acetyl-3,3,5,8-tetramethylthiochroman-4-one, 12.6 g (50 mmol) of iodine and 9.8 g (124 mmol) of pyridine was heated at 110~110° C. for 6 hours. After the completion of the reaction, excess pyridine was distilled off under reduced pressure, and to the residue were added 50 ml of ethylene glycol, 20 ml of water and 11 g (167 mmol) of potassium hydroxide. The mixture was refluxed under heat for 2 hours. After the reaction mixture was allowed to cool, 200 ml of a 1 wt % sodium hydroxide aqueous solution was added, and an aqueous layer was washed with chloroform twice and then acidified with a 5 wt % hydrochloric acid aqueous solution. A precipitated grey solid was collected by filtration under reduced pressure, washed with water and then dried under reduced pressure to give 10.3 g (yield 95%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:6][C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@@H:20]1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)=O.CSC.CO>C1COCC1>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[O:31][CH3:32])[CH2:24][C@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:7]1[CH2:6][C:5]1[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C[C@H]2CCCN2C(=O)CCCCC(=O)N2CCC[C@@H]2Cc2ccc(OC)c(OC)c2)cc1OC
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C[C@H]2CCCN2CCCCCCN2CCC[C@@H]2Cc2ccc(OC)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R,R)-1,6-bis[2-(3,4-dimethoxybenzyl)pyrrolidin-1-yl]-1,6-dioxohexane (0.001 mol) in dry THF was added to a solution containing 0.5 mL (0.005 mol) 10M BH3.DMS, and the solution was heated under reflux in an argon atmosphere. Heating was maintained for 2 hours, after which time the mixture was cooled and 10 mL anhydrous methanol was added dropwise. After gas evolution had subsided, 10 mL of saturated HCL-MeOH was added dropwise and the mixture heated under reflux for 15 minutes. The mixture was cooled to room temperature and the solvent removed in vacuo, leaving an oily residue whose volume was further reduced by Kugelrohr distillation (100° C., 0.05 Torr). Finally, the residue was dissolved in isopropyl alcohol, and ether was added until the solution became cloudy. Crystallization occurred overnight, giving (R,R)-1,6-bis[2-(3,4-dimethoxybenzyl)pyrrolidin-1-yl]hexane.
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]([CH2:18][CH2:19][C:20]([O:22]C)=O)[C:10]([CH2:12][C:13]([O:15][CH2:16]C)=[O:14])=[O:11])[CH:3]=1>CO.C1C=CC=CC=1>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[CH2:18][CH2:19][C:20](=[O:22])[CH:12]([C:13]([O:15][CH3:16])=[O:14])[C:10]2=[O:11])[CH:3]=1
Reactant: CCOC(=O)CC(=O)N(CCC(=O)OC)Cc1cccnc1
Agent: [Na]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C1C(=O)CCN(Cc2cccnc2)C1=O
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Sodium (0.77 g) is dissolved in methanol (30 ml), and thereto is added dropwise a solution of ethyl [N-(3-pyridylmethyl)-N-(methoxycarbonylethyl)carbamoyl]acetate (10.0 g) in benzene (170 ml) at 3°-8° C. The mixture is stirred at the same meperature for 2 hours. The mixture is distilled to remove the solvent, and the residue is dissolved in water. The aqueous solution is extracted with benzene, and the aqueous layer is neutralized with 10% HCl, and extracted with chloroform. The extract is dried and distilled to remove the solvent to give methyl 1-(3-pyridylmethyl)-2,4-dioxopiperidine-3-carboxylate (8.50 g, quantitative) as oil.
Reaction SMILES: [N:1]([CH:4]([CH:10]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>O>[NH2:1][CH:4]([CH:10]([O:18][Si:19]([C:22]([CH3:23])([CH3:25])[CH3:24])([CH3:21])[CH3:20])[C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(N=[N+]=[N-])C(O[Si](C)(C)C(C)(C)C)c1cccnc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(N)C(O[Si](C)(C)C(C)(C)C)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 113 %

Procedure:
A mixture of 5.6 g of ethyl 2-azido-3-t-butyl-dimethylsilyloxy-3-(2-chloropyridin-3-yl)propionate (prepared as described in Preparation 77), 7.5 g of triphenylphosphine and 18 ml of a 8:1 by volume mixture of tetrahydrofuran and water was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation. The residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate and subsequently a 50:1 by volume mixture of methylene chloride and methanol as the eluent, to give 5.9 g of the title compound having Rf=0.59 (on silica gel thin layer chromatography using a 15:1 by volume mixture of methylene chloride and methanol as the developing solvent).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[CH2:7][CH:8]([CH2:10][OH:11])[O:9][C:5]=2[CH:4]=1.CCN(CC)CC.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[CH2:7][CH:8]([CH2:10][O:11][S:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)OC(CO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a solution of (RS)-(6-methoxy-2,3-dihydro-benzofuran-2-yl)-methanol (0.09 g, 0.5 mmol), Et3N (0.1 ml, 0.75 mmol), DMAP (1 mg, 0.01 mmol) in CH2Cl2 (1.5 ml) at 0° C. was added dropwise a solution of p—toluenesulfonylchloride (115 mg, 0.6 mmol). The reaction mixture was allowed to warm to room temperature and was stirred during 4 hr before the addition of H2O (2 ml). The aqueous phase was extracted with CH2Cl2 (2×5 ml). Combined organic phases were dried over Na2SO4, and concentrated. The residue was chromatographed over SiO2 (Merck 230-400 mesh) eluting with nHexane-EtOAc (4:1) to provide (RS)-toluene-4-sulfonic acid 6-methoxy-2,3-dihydro-benzofuran-2-ylmethyl ester (120 mg, 72%) as a colorless oil, MS:m/e=334 (M+).
Reaction SMILES: C([Li])CCC.C[Si](C)(C)[CH:8]1[S:13][CH2:12][CH2:11][CH2:10][S:9]1.[CH2:16]([N:23]1[C:31]2[C:30](=[O:32])[N:29]([CH2:33][CH2:34][CH3:35])[C:28](=[O:36])[N:27]([CH2:37][CH2:38][CH3:39])[C:26]=2[N:25]=[C:24]1[CH:40]1[CH2:44][CH2:43][C:42](=O)[CH2:41]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CCCCCC.O1CCCC1>[CH2:16]([N:23]1[C:31]2[C:30](=[O:32])[N:29]([CH2:33][CH2:34][CH3:35])[C:28](=[O:36])[N:27]([CH2:37][CH2:38][CH3:39])[C:26]=2[N:25]=[C:24]1[CH:40]1[CH2:41][CH2:42][C:43](=[C:8]2[S:13][CH2:12][CH2:11][CH2:10][S:9]2)[CH2:44]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCn1c(=O)c2c(nc(C3CCC(=O)C3)n2Cc2ccccc2)n(CCC)c1=O
Reactant: C[Si](C)(C)C1SCCCS1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCn1c(=O)c2c(nc(C3CCC(=C4SCCCS4)C3)n2Cc2ccccc2)n(CCC)c1=O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
At -75° C. 14.37 ml (0.023 mol) of a 1.6M solution of butyl lithium in n-hexane is added dropwise to 4.0 g of 2-trimethylsilyl-1,3-dithiane (0.021 mol) in 15 ml of absolute tetrahydrofuran and the mixture is stirred for a further 30 minutes at -70° C. Then at the same temperature a solution of 8.0 g (0.020 mol) of 7-benzyl-8-(3-oxocyclopentyl)-1,3-dipropylpurine-2,6-dione in 70 ml of absolute tetrahydrofuran is added dropwise. The mixture is stirred for 2 hours at -70° C. and then for 2 hours at -30° C., then water is carefully added at -30° C. The phases are separated, the organic phase is evaporated down, the residue is taken up in dichloromethane, washed with water and the solution is dried and evaporated down. Purification is carried out by chromatography on silica gel using a mixture of cyclohexane/ethyl acetate as eluant in the ratio 3:1. 3.55 g (35.5% of theory) of the title compound are obtained in the form of a yellowish oil which crystallises when left to stand.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([OH:23])=[O:22].C(N(C(C)C)CC)(C)C.O>C(OC(=O)C)(=O)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[CH:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[C:21]([OH:23])=[O:22]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COc1ccccc1CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccccc1C(=Cc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
25 g of 2-nitrobenzaldehyde, 28 g of 2-methoxyphenylacetic acid and 0.16 mol of diisopropylethylamine are boiled under reflux in 90 ml of acetic anhydride under nitrogen for 8 hours. After cooling to 60° C. , the mixture is poured onto 200 ml of hot water. The mixture is stirred for a further 2 hours, while cooling, and the product is filtered off with suction and washed with a little cold ethanol. Recrystallization from ethanol gives 38.7 g of the title compound of melting point 217°-219° C.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[CH:28](O)([CH3:30])[CH3:29].CCCP(=O)=O.C(Cl)[Cl:39]>N1C=CC=CC=1>[NH2:1][C@H:2]([C:15]([O:17][CH:28]([CH3:30])[CH3:29])=[O:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:8][CH:9]=1.[ClH:39]
Reactant: CC(C)O
Reactant: ClCCl
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Agent: CCCP(=O)=O
Solvent: c1ccncc1
Product: CC(C)OC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: Cl

Procedure:
18.6 g (50 mmoles) of Z-Tyr(But)-OH in 30 ml of pyridine are reacted with 30 ml of isopropanol and 40 ml of a 50 percent solution of propylphosphonic anhydride in methylene chloride analogously to Example 30 A. The resulting oil is subjected to catalytic hydrogenation analogously to Example 25 B. The substance crystallizes from ether. Yield 13.15 g (83%), melting point 161°-163°, [α]D23 =+15.7° (c=1, methanol).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9](F)[CH:8]=2)=[CH:4][CH:3]=1.Br.[CH:17]1([CH2:20][S:21]C(=N)N)[CH2:19][CH2:18]1>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([S:21][CH2:20][CH:17]3[CH2:19][CH2:18]3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: N=C(N)SCC1CC1
Reactant: N#Cc1ccc(-c2ccc(Cl)s2)cc1F
Agent: Br
Product: N#Cc1ccc(-c2ccc(Cl)s2)cc1SCC1CC1
Yield: 89.9 %

Procedure:
0.9 g (4.0 mmol) of 4-(5-chlorothiophen-2-yl)-2-fluorobenzonitrile and 0.9 g (4.3 mmol) of S-cyclopropylmethylisothiourea hydrobromide were allowed to react in the same manner as described above in Example 8 (4), and purification of the crude product by silica gel column chromatography afforded 1.1 g of 4-(5-chlorothiophen-2-yl)-2-cyclopropylmethylthiobenzonitrile (yield 91%) as yellow feathery crystals (m.p. 123-124° C.).
Reaction SMILES: [F:1][C:2]1[N:3]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=[C:5]([CH2:7][CH2:8][NH:9][C:10]([NH:12][CH3:13])=[O:11])[N:6]=1>C(Cl)Cl>[N:3]1[CH:4]=[CH:5][CH:7]=[C:8]([N:9]=[C:10]=[O:11])[CH:14]=1.[F:1][C:2]1[N:3]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=[C:5]([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[CH:2]=[N:3][CH:4]=[CH:5][CH:7]=2)=[O:11])[N:6]=1
Reactant: CNC(=O)NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Solvent: ClCCl
Product: O=C(NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1)Nc1cccnc1
Product: O=C=Nc1cccnc1

Procedure:
Using the same procedure as for the starting material of Example 36, except that CH2Cl2 was used as solvent, and 3-pyridylisocyanate in place of methyl isocyanate, there was obtained 1-[2-(2-fluoro-1-triphenylmethylimidazol-4-yl)ethyl]-3-(pyrid-3-yl)urea, having the following n.m.r. spectrum in d6DMSO: 2.5 (t, 2H); 3.28 (t, 2H); 6.33 (s, 1H); 7.0-7.5 (m, 16H); 7.83 (d, 1H); 8.17 (s, 1H); 8.6 (s, 1H).
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Mn+2:6].[NH2:7][C@H:8]([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][C:11]([OH:13])=[O:12]>C(O)C>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[NH2:7][C@H:8]([C:14]([O-:16])=[O:15])[CH2:9][CH2:10][C:11]([O-:13])=[O:12].[Mn+4:6]
Reactant: [Mn+2]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: N[C@@H](CCC(=O)[O-])C(=O)[O-]
Product: [Mn+4]
Reaction time: 5 h

Procedure:
15.1 grams (0.1 Mole) of manganese sulfate, 28 grams (0.1 Mole) of glutamic acid and 100 ml ethanol were placed into a beaker provided with a reflux condenser. The mixture was stirred and boiled for 5 hours. The mixture was then cooled and thereafter filtered yielding 43.1 grams of manganese glutamate sulfate complex in the form of a fine white (slightly pink) powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH2:15]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH2:22])[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH:22][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure H′ above and using 3-nitrophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by recrystallization from butyl chloride.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:26][CH3:27])=[C:21]([CH:25]=1)[C:22](Cl)=[O:23]>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:26][CH3:27])=[C:21]([CH:25]=1)[C:22]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)=[O:23].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:26][CH3:27])=[C:21]([CH:25]=1)[C:22]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1)=[O:23]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCOC(=O)Cc1ccc(CCN)cc1
Product: CCOC(=O)Cc1ccc(CCNC(=O)c2cc(Cl)ccc2OC)cc1
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(CC(=O)O)cc1

Procedure:
In an analogous mannner, by the reaction of ethyl 4-(2-aminoethyl)-phenylacetate with 5-chloro-2-methoxybenzoyl chloride, there is obtained, via ethyl 4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenylacetate (oil), 4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenylacetic acid; m.p. 127°-128° C., after recrystallization from 75% acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][C:17]1[C:18]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:35][CH3:36])[CH:31]=3)[CH:26]2[CH3:37])=[N:19][C:20]([Cl:24])=[N:21][C:22]=1[CH3:23]>CN(C)C=O>[ClH:24].[CH3:16][C:17]1[C:18]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([O:35][CH3:36])[CH:31]=3)[CH:26]2[CH3:37])=[N:19][C:20]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[N:21][C:22]=1[CH3:23]
Reactant: COc1ccc2c(c1)CCN(c1nc(Cl)nc(C)c1C)C2C
Reactant: Nc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(c1nc(Nc3ccc(F)cc3)nc(C)c1C)C2C
Product: Cl
Yield: 58.8 %

Procedure:
After 4-fluoroaniline(0.72 ml, 7.5 mmol) and triethylamine(1.0 ml, 7.3 mmol) were added to a solution of 5,6-dimethyl-2-chloro4-(6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(1.6 g, 5.0 mmol) in dimethylformamide(10 ml), 1.26 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 25.
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:7]=2[CH:6]=1.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>C(#N)C.CO>[C:19]([NH:23][CH2:18][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:7]=2[CH:6]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: NS(=O)(=O)c1nc2ccc(OCC3CO3)cc2s1
Reactant: CC(C)(C)N
Solvent: CC#N
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 50 °C

Procedure:
A solution of 6-(2,3-epoxypropoxy)benzothiazole-2-sulfonamide (1.14 gm, 4.0 mmol) in acetonitrile (16 mL) and methanol (4 mL) containing t-butylamine (0.88 mL, 0.4 mmol) was warmed at 50° C. for 15-20 hours. The solvents were evaporated and the residue (1.1 gm) was chromatographed on silica gel eluting with 20-30% methanol/chloroform (V/V). The appropriate fractions were combined and evaporated. The residue was digested in acetonitrile, cooled and the produce collected (0.62 gm), m.p. 195°-196° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH3:9])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C([Li])CCC.CON(C)[C:18](=[O:33])[CH2:19][C@H:20]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:21][C:22](O)=[O:23].[C:35]1([C@@H:41]([NH-:43])[CH3:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CCCCCC.O1CCCC1>[CH2:1]([O:3][P:4]([CH2:9][C:18](=[O:33])[CH2:19][C@@H:20]([O:25][Si:26]([C:29]([CH3:31])([CH3:30])[CH3:32])([CH3:28])[CH3:27])[CH2:21][C:22](=[O:23])[NH:43][C@H:41]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:42])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CON(C)C(=O)C[C@@H](CC(=O)O)O[Si](C)(C)C(C)(C)C
Reactant: C[C@H]([NH-])c1ccccc1
Reactant: CCOP(C)(=O)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=O)C[C@H](CC(=O)N[C@@H](C)c1ccccc1)O[Si](C)(C)C(C)(C)C)OCC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 4-necked, round bottomed flask, equipped with a mechanical stirrer, digital thermometer, nitrogen inlet-outlet and a condenser is charged with methanphosphonic acid diethyl ester (4.65 g, 30.59 mmol) and tetrahydrofuran (11 mL). The solution is cooled down to −78° C. and butyllithium (15.3 mL of a 1.6 M solution in hexane, 24.47 mmol) is added. After stirring for additional 60 min at −78° C., a solution of (S)-3-(tert-butyl-dimethyl-silanyloxy)-pentanedioic acid methoxy-methyl-amide-((S)-1-phenyl-ethyl)amide (2.5 g) in tetrahydrofuran (10 mL) is added to the reaction mixture while maintaining the temperature at −78° C. Stirring is continued for 1 h at this temperature and the reaction is quenched by slow addition of a solution of acetic acid (1.84 g) in tetrahydrofuran (1.25 ml) at −78° C. The reaction mixture is then allowed to warm up to room temperature and poured onto ethyl acetate (125 mL) and brine (125 mL). The biphasic mixture is stirred for 10 min and the organic layer is separated. The water layer is extracted with ethyl acetate. The organic layers are combined, washed with water, dried over anhydrous magnesium sulfate and the solvent is evaporated in vacuo to obtain the crude [(R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-oxo-5-((S)-1-phenyl-ethylcarbamoyl)-pentyl-phosphonic acid diethyl ester as a viscous oil. The crude product is purified by column chromatography with ethyl acetate/hexane (1:1) as eluent to obtain [(R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-oxo-5-((S)-1-phenyl-ethylcarbamoyl)-pentyl]-phosphonic acid diethyl ester as a highly viscous oil. [α]D20=−40.2° (CHCl3, c=1); MS (ES+, m/z): 522 ([M+Na]+, 100%); IR(Film): strong absorbtions at 3297, 2930, 1717, 1652, 1542, 1254, 1026, 837 cm−1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl[CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[C:20]([O-:23])([O-])=O.[Cs+].[Cs+].O>CN1C(=O)CCC1>[O:17]1[CH2:18][CH2:19][CH:14]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([O:12][CH:4]4[CH2:3][CH2:20][O:23][CH2:6][CH2:5]4)=[O:11])=[CH:7][CH:8]=3)[CH:3]=[N:2]2)[CH2:15][CH2:16]1
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: ClC1CCOCC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(OC1CCOCC1)c1ccc2c(cnn2C2CCOCC2)c1
Yield: 48.5 %

Procedure:
A mixture of 1H-indazole-5-carboxylic acid (400 mg, 2.47 mmol), 4-chlorotetrahydro-2H-pyran (1.49 g, 12.33 mmol) and Cs2CO3 (2.41 g, 7.40 mmol) in NMP (5 mL) was irradiated with microwave (180° C., 80 min). The mixture was poured into H2O, extracted with EtOAc, dried over Na2SO4, filtered and concentrated. The residual oil was purified by silica gel column chromatography (30-60% EtOAc in hexane), then the mixture was purified by amino gel column chromatography (0-35% EtOAc in hexane) to give tetrahydro-2H-pyran-4-yl 1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-carboxylate (198 mg, 24% yield) as a white solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16](SC)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C([Sn](CCCC)(CCCC)[C:34]1[CH:35]=[N:36][C:37]2[N:42]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[CH:41]=[N:40][C:38]=2[CH:39]=1)CCC>COCCOC.C(OCC)(=O)C.[Cu]Br.CSC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][S:2]([N:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16]([C:34]4[CH:39]=[C:38]5[N:40]=[CH:41][N:42]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:37]5=[N:36][CH:35]=4)=[N:15][C:14]=3[CH:13]=2)[CH2:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: CSc1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)cc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2c(c1)ncn2COCC[Si](C)(C)C
Agent: [Cu]Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CSC
Product: C[Si](C)(C)CCOCn1cnc2cc(-c3nc(N4CCOCC4)c4sc(CN5CCN(S(C)(=O)=O)CC5)cc4n3)cnc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (90 mg) in 1,2-dimethoxyethane (10 mL) was added 6-tributylstannanyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-]pyridine (219 mg) and copper(I)bromide-dimethylsulfide (84 mg) and the reaction stirred at room temperature for 10 min. Then, tetrakis(triphenylphosphine)palladium (0) (12 mg) was added and the reaction heated at reflux for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (2×30 mL), aqueous brine solution (2×20 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give 6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-2-[3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-thieno[3,2-d]pyrimidine as a white solid.