Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CNCCNC.Br[C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[C:10]([O:20][CH3:21])[CH:9]=1.[Cl:22][C:23]1[CH:37]=[CH:36][C:26]([CH2:27][S:28][C:29]2[CH:34]=[CH:33][NH:32][C:31](=[O:35])[N:30]=2)=[CH:25][CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(Cl)Cl.[Cu]I>[Cl:22][C:23]1[CH:37]=[CH:36][C:26]([CH2:27][S:28][C:29]2[CH:34]=[CH:33][N:32]([C:8]3[CH:19]=[CH:18][C:11]([O:12][CH2:13][C:14]([OH:16])([CH3:17])[CH3:15])=[C:10]([O:20][CH3:21])[CH:9]=3)[C:31](=[O:35])[N:30]=2)=[CH:25][CH:24]=1
Reactant: COc1cc(Br)ccc1OCC(C)(C)O
Reactant: O=c1nc(SCc2ccc(Cl)cc2)cc[nH]1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(-n2ccc(SCc3ccc(Cl)cc3)nc2=O)ccc1OCC(C)(C)O
Temperature: 105 °C
Reaction time: 7 h
Yield: 7 %

Procedure:
N1,N2-dimethylethane-1,2-diamine (356 mg, 4.04 mmol) was added to a stirred mixture of 1-(4-bromo-2-methoxyphenoxy)-2-methylpropan-2-ol Part 1B of Procedure 1 (222 mg, 0.807 mmol), 4-(4-chlorobenzylthio)pyrimidin-2(1H)-one Part A (170 mg, 0.67 mmol), copper(I) iodide (77 mg, 0.404 mmol) and potassium phosphate, tribasic (857 mg, 4.04 mmol) in dioxane (8 mL). The mixture was stirred at 105° C. for 7 h. The reaction mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, dried (MgSO4) and concentrated. The crude product was subjected to ISCO flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient, used LC/MS to identify fractions containing the desired product) to afford the title compound 4-(4-chlorobenzylthio)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-2(1H)-one A-1 (22 mg, 0.048 mmol, 7% yield, eluted with 100% EtOAc) as a pale gummy solid.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].[Li+].[OH-].O.Cl>CCO>[CH3:8][C:2]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)c1cccnc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C(=O)O)c1cccnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Ethyl α,α-dimethyl-3-pyridylacetate (disclosed in EP Application 0 288 279, published Oct. 26, 1988) (2.67 grams, 13.8 mmoles) was dissolved in EtOH (11.1 ml.) and a 1.0M LiOH in water (33.3 mi.) (33.4 mmoles) was added. The mixture was stirred at 25° C. for 4 hours. 1N HCl (38.73 ml.) was added and after 5 minutes the mixture was evaporated to dryness to give the title compound (Yield: 100%).
Reaction SMILES: [N:1]1[CH2:2][O:3][CH:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[C-]#[N:12].[K+]>>[NH:12]=[C:2]1[C:4](=[O:3])[C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:1]1
Reactant: [C-]#N
Reactant: C1=c2ccccc2=NCO1
Agent: [K+]
Product: N=C1Nc2ccccc2C1=O

Procedure:
The process according to claim 1 in which the 3,1-benzoxazine is reacted with potassium cyanide in an equimolar ratio or in the presence of a slight excess of potassium cyanide at a temperature of 100° C., to decarboxylate said 3,1-benzoxazine and obtain a 2-imino-3-indolinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[S:7]C(=O)[O:9][C:5]=2[CH:4]=1.[OH-].[K+].Cl>CO.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([SH:7])=[C:5]([OH:9])[CH:4]=1
Reactant: COc1ccc2sc(=O)oc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(S)c(O)c1
Reaction time: 0.17 h
Yield: 91.6 %

Procedure:
4.50 g (24.8 mmol) 6-methoxy-1,3-benzoxathiol-2-one was suspended in 56 mL methanol and mixed with 4.40 g (66.4 mmol) 85% potassium hydroxide, which had previously been dissolved in 11 mL methanol and 17 mL water. The suspension dissolved, forming a yellow color and was stirred for approximately 10 minutes (TLC control). After the end of the reaction the reaction mixture was cautiously acidified to a pH of 1 using 1N aqueous hydrochloric acid, the methanol was removed under a reduced pressure and the residue was extracted twice with ethyl acetate. The organic phases were combined and each was washed twice with water, saturated sodium chloride solution and again with water. After drying with sodium sulfate and removing the solvent under a reduced pressure, 3.55 g (92%) 5-methoxy-2-mercaptophenol was obtained as a light-yellowish fluid. The raw product (GCMS 100%, M=156) was used further without further purification.
Reaction SMILES: BrCC(N1C[CH2:9][N:8]([C:11](=O)[C:12]2[CH:17]=[C:16](C)[CH:15]=[C:14](C)[CH:13]=2)[CH2:7][CH:6]1[C:21]1[CH:26]=[CH:25]C(Cl)=C(Cl)C=1)=O.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].C([O-])(O)=[O:44].[Na+]>C1COCC1>[CH2:11]([N:8]1[CH2:7][CH2:6][C:21](=[O:44])[CH:26]([CH3:25])[CH2:9]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(C)cc(C(=O)N2CCN(C(=O)CBr)C(c3ccc(Cl)c(Cl)c3)C2)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CCC1=O
Temperature: -23 °C
Reaction time: 2 h

Procedure:
To a cooled solution of compound 3 from step 1 (8.65 g, 34.8 mmol) in THF (100 mL) at -23° C. was added 27.8mL of 1M L-selectride (27.8 mmol). The mixture was stirred at -23° C. for 2 h. After warming to RT, the reaction mixture was added to sat. NaHCO3 and partitioned. The aqueous layer was extracted with Et2O (2×50 mL). The combined organic layers were washed with brine (50 mL), dried with MgSO4 and concentrated. The product was purified by silica gel chromatography eluting with 6:1 to 3:1 hexane-EtOAc to give 2.47 g of compound 4 and 2.75 g of recovered starting material.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C1(C)C(C([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)=O)=CC=CC=1.O.Cl.C([O:27][CH2:28][CH3:29])C>>[OH:13][C:14]1[CH:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[C:19]=1[C:28]([C:29]1[CH:18]=[CH:19][CH:14]=[CH:15][C:16]=1[CH3:17])=[O:27]
Reactant: CCOCC
Reactant: Cc1cc(C)cc(OC(=O)c2ccccc2C)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1cc(C)c(C(=O)c2ccccc2C)c(O)c1

Procedure:
Anhydrous aluminum chloride (20 g.) was added in portions during 5 minutes to 3,5-dimethylphenyl o-toluate (36.3 g.) and the mixture was heated at 140°-150° C. for 3 hours. After cooling, water (300 ml.) and concentrated hydrochloric acid (25 ml.) were added and the mixture was stirred and heated on the steam-bath until hydrolysis was complete. After cooling, the mixture was stirred with diethyl ether (110 ml.) and filtered through charcoal and kieselguhr. The layers were separated and the aqueous phase was extracted with more diethyl ether (2×50 ml.). The combined ethereal solutions were washed with water, dried over sodium sulphate and evaporated in vacuo. The residue crystallised slowly. Light petroleum (b.p. 40°-60° C.; 50 ml.) was added and the solid was filtered off, washed with light petroleum (b.p. 40°-60° C.) at 0° C. and dried in a vacuum desiccator. The solid was recrystallised from methanol to give 2-hydroxy-2',4,6-trimethylbenzophenone (15.9 g.), m.p. 65° -67° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][C:10]([CH3:14])([CH3:13])[O:11][CH2:12][C:7]=2[CH:6]=1)[OH:4].C(N(C(C)C)CC)(C)C.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:47]=[C:46]2[C:41]([CH2:42][CH2:43][CH2:44][S:45]2(=[O:49])=[O:48])=[CH:40][CH:39]=1>O1CCCC1.CN(C)C=O>[CH3:14][C:10]1([CH3:13])[O:9][C:8]2[CH:15]=[CH:16][C:5]([C@@H:3]([OH:4])[CH2:2][NH:1][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]3[CH:47]=[C:46]4[C:41]([CH2:42][CH2:43][CH2:44][S:45]4(=[O:49])=[O:48])=[CH:40][CH:39]=3)=[CH:6][C:7]=2[CH2:12][O:11]1
Reactant: CC1(C)OCc2cc([C@@H](O)CN)ccc2O1
Reactant: O=S1(=O)CCCc2ccc(CCCCOCCCCCCBr)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCCCc3ccc4c(c3)S(=O)(=O)CCC4)ccc2O1
Temperature: 50 °C
Yield: 83.3 %

Procedure:
To a solution of (1R)-2-amino-1-(2,2-dimethyl4H-1,3-benzodioxin-6-yl)ethanol (128 mg) in dry tetrahydrofuran (6 ml) and dimethylformamide (2 ml) was added diisopropylethylamine (0.066 ml) and 7-{4[(6-bromohexyl)oxy]butyl}thiochromane 1,1-dioxide (120 mg). The reaction mixture was heated at 50° C. for 17 h. The mixture was then concentrated in vacuo and the residue was purified by chromatography on a Biotage cartridge (8 g) eluting with dichloromethane-ethanol-aqueous ammonia solution (100:8:1) to give the title compound (134 mg). LCMS RT=2.74 min
Reaction SMILES: O[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].P(Br)(Br)[Br:19]>C1C=CC=CC=1>[Br:19][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(O)c1ccc(OC)c(OC)c1
Reactant: BrP(Br)Br
Solvent: c1ccccc1
Product: CCOC(=O)C(Br)c1ccc(OC)c(OC)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of ethyl 2-hydroxy-2-(3,4-dimethoxyphenyl)acetate (19.5 g) in benzene (200 ml) was added phosphorus tribromide (8.18) dropwise at 50° C. and the mixture was stirred at 60° C. for one hour. The reaction mixture was then washed successively with water, saturated aqueous solution of NaHCO3 and water and dried (MgSO4). The benzene was distilled off and the residue was subjected to silica gel chromatography. From the fraction eluted by ethyl acetate-hexane (1:3, v/v), ethyl 2-bromo-2-(3,4-dimethoxyphenyl)acetate (18.5 g, yield 75%) was obtained as an oil.
Reaction SMILES: [OH:1][C:2]1[C:19]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:14]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:15]=3)[C:10]3[C:5](=[CH:6][C:7]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[C:8]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:9]=3)[C:4]=2[CH:3]=1.Br[CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH3:62].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[O:1]([C:2]1[C:19]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:14]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:15]=3)[C:10]3[C:5](=[CH:6][C:7]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[C:8]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:9]=3)[C:4]=2[CH:3]=1)[CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH3:62]
Reactant: CCCCCCOc1cc2c(cc1O)c1cc(OCCCCCC)c(OCCCCCC)cc1c1cc(OCCCCCC)c(OCCCCCC)cc21
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCOc1cc2c3cc(OCCCCCC)c(OCCCCCC)cc3c3cc(OCCOCCOC)c(OCCCCCC)cc3c2cc1OCCCCCC
Yield: 14.2 %

Procedure:
A mixture of 2-hydroxy-3,6,7,10,11-pentahexyloxytriphenylene (0.37 g, 0.5 mmol), 1-bromo-2-(2-methoxyethoxy)ethane (0.37 g) and potassium carbonate (0.4 g, 3 mmol) in ethanol (10 ml) was heated under reflux for 72 hours. After which time, it was filtered, extracted with dichloromethane (25 ml), concentrated in vacuo, and the product isolated by column chromatography (silica gel eluting with ethyl acetate) and recrystallised from ethanol to give the title compound as a white solid (0.06 g, 14%, K→D 55.4° C., D→I 69.3° C.). Elemental Analysis: C, 74.95; H, 9.55. C53H82O8 requires: C, 75.14; H, 9.75. Mass Spectrum: m/z (FAB) 869 ([M+23]+, 100%); 846 (M+, 94.5%). 1H-NMR: δH (CDCl3) 0.93 (15H, t, J=6.7 Hz, O(CH2)5CH3), 1.10-1.70 (30H, m, OCH2CH2(CH2)3), 1.94 (10H, m, OCH2CH2), 3.41 (3H, s, OCH2CH2OCH2CH2CH3), 3.61 (2H, t, J=5.0 Hz, OCH2CH2OCH2CH2), 3.82 (2H, t, J=5.0 Hz, OCH2CH2OCH2), 4.00 (2H, t, J=5.0 Hz, OCH2CH2), 4.23 (10H, t, J=6.5 Hz, OCH2), 4.42 (2H, t, J=5.0 Hz, OCH2), 7.83 (5H, s, ArH), 7.90 (1H, s, ArH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)=[N:8][CH:7]=[C:6]2[CH2:26]O.S(Cl)([Cl:30])=O>C(Cl)Cl>[Cl:30][CH2:26][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)=[N:8][CH:7]=1
Reactant: COc1ccc(Cc2ncc(CO)c3cc(OC)c(OC)cc23)cc1OC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A cold mixture of 26.8 g of 6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]-4-isoquinoline methanol in 600 ml of methylene chloride was treated dropwise with 27 ml of thionyl chloride over 15 minutes. The cooling bath was removed and the solution was allowed to stir at ambient temperature for 3 hours after which the volatiles were removed in vacuo. The residue was mixed with methylene chloride and water followed by careful addition of excess sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, evaporated, and crystallized from ethyl acetate to give 23.1 g of 4-chloromethyl-6,7-dimethoxy-1-[(3,4-dimethoxyphenyl)methyl]isoquinoline as a yellow solid, mp 153° dec. Recrystallization from ethyl acetate provided the analytically pure material, mp 153° dec.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C@H:10]1[C@H:15](O)[CH2:14][CH2:13][N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11]1>>[C:20]([O:19][C:17]([N:12]1[CH2:13][CH2:14][C@H:15]([O:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C@H:10]([F:9])[CH2:11]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](F)C1
Reactant: Oc1ccc(Cl)nc1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(Cl)nc2)[C@H](F)C1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-1, using 6-chloropyridin-3-ol and trans(±)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (0.490 g, 48%); MS: 332.2 (M+1).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:15][CH2:14][N:13]([O:16][CH3:17])[CH2:12][CH2:11][N:10]1C(OC(C)(C)C)=O)=O)(C)(C)C.Cl.O1CCOCC1>C(OCC)(=O)C>[ClH:1].[CH3:17][O:16][N:13]1[CH2:14][CH2:15][NH:9][NH:10][CH2:11][CH2:12]1
Reactant: CON1CCN(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CON1CCNNCC1
Temperature: 90 °C

Procedure:
A solution of 5-methoxy-[1,2,5]triazepane-1,2-dicarboxylic acid di-tert-butyl ester in diethyl ether was treated with gaseous hydrogen chloride to generate a white precipitate. The solid was filtered, washed with diethyl ether and dried to afford 5-methoxy-[1,2,5]triazepane-1,2-dicarboxylic acid di-tert-butyl ester hydrochloride salt. To a suspension of 5-methoxy-[1,2,5]triazepane-1,2-dicarboxylic acid di-tert-butyl ester hydrochloride salt (2.5 g, 6.8 mmol) in ethyl acetate (10 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 9 ml, 36.0 mmol) at room temperature dropwise. The reaction mixture was heated at 90° C. for one hour, the solvent evaporated, the residue washed with diethyl ether and dried in vacuo. Yield: 1.4 g of 5-methoxy-[1,2,5]triazepane hydrochloride salt (compound P4.2) as a yellowish solid, this material was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH:27]1([NH:31][C:32]2[NH:36][C:35]([CH3:37])=[N:34][N:33]=2)[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([N:31]2[C:17](=[O:18])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:22]([CH2:23][CH2:24][CH3:25])[N:33]3[N:34]=[C:35]([CH3:37])[N:36]=[C:32]23)[CH2:28][CH2:29][CH2:30]1
Reactant: Cc1nnc(NC2CCC2)[nH]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC2)c2nc(C)nn12
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 54.8 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1.8 g) and N-cyclobutyl-5-methyl-4H-1,2,4-triazol-3-amine (0.4 g) was stirred at 250° C. for 15 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.63 g, 52%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])[NH2:23]>>[F:19][C:20]1[CH:21]=[C:22]([NH:23][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccc(F)c(F)c1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(F)c1
Yield: 60.2 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 400 mg of 3,4-difluoroaniline in place of the 2,4-difluoroaniline. 210 mg of N-(3,4-difluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Si:19]([O:36][CH2:37][CH2:38][C@@H:39]([CH3:42])[CH2:40]O)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH:43]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45].C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCCCCC>[Si:19]([O:36][CH2:37][CH2:38][C@@H:39]([CH3:42])[CH2:40][N:43]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])([C:32]([CH3:33])([CH3:34])[CH3:35])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: C[C@@H](CO)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 56.8 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (6.33 g) was added to a solution of (2R)-4-{[tert-butyl(diphenyl)silyl]oxy}-2-methylbutan-1-ol (Synthesis, 2002, p. 1993) (4.30 g), di-tert-butyl iminodicarboxylate (5.45 g), and tributylphosphine (4.65 mL) in toluene (130 mL) with stirring at 0° C. The mixture was heated to room temperature and stirred overnight. Then, the reaction solution was diluted with hexane, and insoluble matter was filtered off through celite. The filtrate was concentrated under reduced pressure, and the obtained crude product was then purified by silica gel column chromatography to obtain the title compound (3.86 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[OH-].[Na+]>>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([NH:11][C:12](=[O:14])[CH3:13])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: CC(=O)Nc1cccc2cnccc12
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)NC1CCCc2cnccc21
Yield: 45.2 %

Procedure:
Reaction of N-(isoquinol-5-yl)acetamide (171 mg, 0.918 mmol) using the general procedure for small scale hydrogenations (workup with NaOH in place of saturated NaHCO3) provided N-(5,6,7,8-tetrahydroisoquinolin-5-yl)acetamide (79 mg, 45%): 1H NMR δ 1.60–1.70 (m, 1H), 1.70–1.09 (m, 2H), 1.98 (s, 3H), 1.98–2.08 (m, 0.1H), 2.65–2.68 (m, 2H), 5.03–5.11 (m, 1H), 6.63 (br d, 1H), 7.08 (d, 1H, J=5 Hz), 8.17 (s, 1H), 8.20 (d, 1H, J=5 Hz); 13C NMR δ 20.7, 23.7, 26.4, 30.1, 47.1, 122.9, 133.3, 146.3, 147.5, 150.7, 170.1; MS m/z: 191 (M+H+). N-(1,2,3,4-tetrahydroisoquinolin-5-yl)acetamide also was isolated (35 mg, 20%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[CH2:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH3:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: C=Cc1cccc2oc(C(=O)OCC)c(C)c12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc2cccc(CC)c2c1C

Procedure:
To a solution of 0.40 g (1.74 mmol) of 3-methyl-4-vinylbenzofuran-2-carboxylic acid ethyl ester in 25 mL of ethyl acetate under nitrogen was added 0.050 g of 10% palladium on carbon. The reaction was shaken on a Parr hydrogenator under 40 psi of hydrogen for 4 h. The reaction was then filtered through a pad of celite. The celite was washed with an additional 150 mL of ethyl acetate and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:30) to provide 0.395 of 3-methyl-4-ethylbenzofuran-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[N:17](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:18]=[CH:19][C:12]=23)[S:9][CH:10]=1)([CH3:5])[C:3]#[N:4].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:17]1[C:13]2=[N:14][CH:15]=[CH:16][C:11]([C:8]3[S:9][CH:10]=[C:6]([C:2]([CH3:5])([CH3:1])[C:3]#[N:4])[N:7]=3)=[C:12]2[CH:19]=[N:18]1
Reactant: CC(C)(C#N)c1csc(-c2ccnc3c2cnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C#N)c1csc(-c2ccnc3[nH]ncc23)n1
Reaction time: 1 h
Yield: 77.5 %

Procedure:
A solution of 2-methyl-2-[2-(1-tritylpyrazolo[5,4-b]pyridin-4-yl)thiazol-4-yl]propanenitrile (239 mg, 0.4671 mmol) in DCM (6 mL) was treated with triethylsilane (727.8 mg, 999.7 μL, 6.259 mmol) followed by dropwise addition of TFA (296.0 mg, 200.0 μL, 2.596 mmol). The mixture was allowed to stir for 1 hour and then concentrated in vacuo and purified by column chromatography (EtOAc) to give the desired product as a yellow solid (97.5 mg, 78% Yield). 1H NMR (DMSO, 400 MHz) δ 1.84 (6H, s), 7.73 (1H, d), 8.04 (1H, s), 8.64 (1H, s), 8.67 (1H, d), 13.98 (1H, br s); MS (ES+) 270.03
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][C:8](=[O:23])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27]I.Cl>CN(C)C=O>[C:1]([O:5][C:6](=[O:24])[CH:7]([CH3:27])[C:8](=[O:23])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)CC(=O)CCc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C(=O)CCc1ccc(-c2ccccc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A solution of 5-biphenyl4-yl-3-oxo-pentanoic acid tert-butyl ester (Intermediate 2, 0.30 g, 0.93 mmol) in dimethyl formamide (1.5 mL) was added to a suspension of sodium hydride (60%; 38 mg, 0.94 mmol) in dimethyl formamide (1 mL) at 0° C. under nitrogen. After stirring for 20 minutes methyl iodide (58 μL, 0.93 mmol) was added and the reaction warmed to room temperature at which stirring was continued for 2 hours. 0.5 M Hydrochloric acid (5 mL) was added and the quenched reaction mixture extracted with diethyl ether (3×5 mL). The organic phases were combined, washed with brine (5 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure and the residue was purified by column chromatography on silica gel (1:6 diethyl ether: 40–60 petroleum ether) to give the title compound (163 mg, 52%) as a colourless oil. LC/MS: 3.81 min; z/e 356, calcd (M+NH4) 356. 1H NMR (400 MHz: CDCl3): 7.59 (2 H), 7.51 (2 H), 7.42 (2 H), 7.32 (1 H), 7.22 (2 H), 3.42 (1 H), 2.97 (3 H), 2.83 (1 H), 1.42 (9 H), 1.28 (3 H).