Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:8]([C:17]([OH:19])=O)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.C[O:23][C:24]1[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][N:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Br>CN1C(=O)CCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:8]([C:17]([NH:30][C:28]3[CH:27]=[CH:26][NH:25][C:24](=[O:23])[CH:29]=3)=[O:19])=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:20][CH:21]=1
Reactant: O=C(O)c1nc2ccccc2nc1Oc1ccc(F)cc1
Reactant: COc1cc(N)ccn1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(Nc1cc[nH]c(=O)c1)c1nc2ccccc2nc1Oc1ccc(F)cc1
Temperature: 100 °C
Yield: 8.9 %

Procedure:
A solution of 3-(4-fluorophenoxy)quinoxaline-2-carboxylic acid (42.6 mg, 0.15 mmol), 2-methoxypyridin-4-amine (22.3 mg, 0.18 mmol), HATU (62.7 mg, 0.16 mmol) and N-methylmorpholine (32.98 μL, 0.30 mmol) in NMP (0.5 mL) was stirred at 25° C. for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The organics were combined, washed with water, brine, dried with Na2SO4, filtered through a short plug of silica and evaporated to dryness. The residue was taken up in HBr (0.5 mL of 33% w/v in acetic acid, 2.04 mmol) and heated at 100° C. for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The organics were combined, evaporated and purified by reverse phase HPLC using a gradient of acetonitrile in water (1-99%) and HCl as a modifier to give 3-(4-fluorophenoxy)-N-(2-oxo-1H-pyridin-4-yl)quinoxaline-2-carboxamide (35) (5.0 mg, 9%) as a pale yellow solid. ESI-MS m/z calc. 376.10, found 377.3 (M+1)+; Retention time: 1.31 minutes (3 minutes run).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH3:13])[N:8]([CH2:14][CH2:15][O:16][CH3:17])[C:7]2=[O:18].N(C[CH2:23][O:24][CH2:25]COC)=C=S>>[I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH3:13])[N:8]([CH2:14][CH2:15][O:16][CH2:17][CH2:23][O:24][CH3:25])[C:7]2=[O:18]
Reactant: COCCn1c(SC)nc2c(I)cccc2c1=O
Reactant: COCCOCCN=C=S
Product: COCCOCCn1c(SC)nc2c(I)cccc2c1=O

Procedure:
This compound (0.81 g, 1.92 mmol) was prepared according to the procedures described for Intermediate 715a, starting from 1-isothiocyanato-2-(2-methoxyethoxyl)ethane (716a; 0.67 g, 4.21 mmol). m/z (ESI, +ve ion) 421.0 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([OH:3])=O.[NH:20]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[N:20]1([C:1]([CH2:4][C@@H:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[O:3])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCCNCCC1
Reactant: CC(C)C[C@H](CC(=O)O)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)C[C@H](CC(=O)N1CCCCCCC1)C(=O)OCc1ccccc1
Yield: 86.8 %

Procedure:
Benzyl (2R)-2-carboxymethyl-4-methylvalerate (320 mg), octahydroazocin (165 mg) and WSCD·HCl (280 mg) were reacted in methylene chloride (20 ml) in a similar manner to that of Preparation 18 to give benzyl (2R)-2-(octahydroazocin-1-ylcarbonylmethyl)-4-methylvalerate (378 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32](Cl)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:16]=[C:17]([F:24])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].C([O-])([O-])=O.[K+].[K+]>>[F:24][C:17]1[CH:16]=[C:15]([CH:25]([NH:27][C:28]([C:30]2[N:31]=[C:32]([O:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=3)[O:33][CH:34]=2)=[O:29])[CH3:26])[CH:14]=[C:13]([F:12])[C:18]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CC(C)Oc1cccc(O)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)Oc1cccc(Oc2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 62.8 %

Procedure:
3-Isopropoxyphenol (80 mg, 0.53 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (35 mg, 0.09 mmol) was reacted using K2CO3 (60 mg, 0.43 mmol) as described above to give the title compound (28 mg, 61%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:7][N:6]1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[O:4].[I-].[Na+].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[O:25]>>[CH3:1][O:2][C:3]([CH:5]1[CH2:7][N:6]([S:8]([CH:11]([CH3:12])[CH3:13])(=[O:9])=[O:10])[C:24](=[O:25])[N:23]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[Cl:16])=[O:4]
Reactant: COC(=O)C1CN1S(=O)(=O)C(C)C
Reactant: O=C=Nc1ccccc1Cl
Agent: [I-]
Agent: [Na+]
Product: COC(=O)C1CN(S(=O)(=O)C(C)C)C(=O)N1c1ccccc1Cl

Procedure:
In analogy to example 1, the crude 1-(propane-2-sulfonyl)-aziridine-2-carboxylic acid methyl ester from example 82, step 1 was reacted with sodium iodide and 2-chlorophenyl isocyanate to give (RS)-3-(2-chloro-phenyl)-2-oxo-1-(propane-2-sulfonyl)-imidazolidine-4-carboxylic acid methyl ester as a light yellow oil. MS: 361.1 ([M+H]+)
Reaction SMILES: N[C:2]1[NH:3][C:4](=[O:45])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:44])[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C@@H:23]([O:24][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C@H:13]3[O:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]=2[N:7]=1.N(OC(C)(C)C)=O>O1CCCC1>[C:15]([O:14][C@@H:13]1[C@H:23]([O:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:33]([CH2:35][O:36][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:34][C@H:12]1[N:8]1[C:6]2[N:7]=[CH:2][NH:3][C:4](=[O:45])[C:5]=2[S:10][C:9]1=[O:11])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)[nH]1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: O=C(OC[C@H]1O[C@@H](n2c(=O)sc3c(=O)[nH]cnc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1

Procedure:
Treatment of 6 with sodium methoxide in methanol gave the deprotected guanosine analog, 5-amino-3-β-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(6H)-dione (7). When 7 was deaminated with excess nitrous acid the xanthosine analog, 3-β-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,5,7(4H,6H)-trione (8) was produced. Replacement of the 5-amino group of compound 6 by a hydrogen atom was accomplished by treatment of 6 with t-butyl nitrite in tetrahydrofuran to yield 3-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)thiazolo[4,5-d]pyrimidine-2,7(6H)-dione (9). Deprotection of 9 using sodium methoxide in methanol or methanolic ammonia provided the inosine analog, 3-β-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(6H)-dione (10).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH3:13][NH:14][CH2:15][CH2:16][OH:17].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:14]([CH3:13])[CH2:15][CH:16]=[O:17])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: CNCCO
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CC=O)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
4-Cyanobenzenesulfonyl chloride (6 g, 0.0297 mol) in 50 ml of dry DCM was added at 0° C. to a solution of N-methylethanolamine (2.67 g, 0.0356 mol) and triethylamine (7.49 g, 0.0742 mol) in dry dichloromethane (75 ml) under nitrogen atmosphere and stirred at RT for 2 h. The reaction mixture was quenched with water and extracted with dichloromethane. Organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure afforded crude product as solid. This solid was then washed with petroleum ether (three times) and dried under vacuum to give the sub-title compound (5.18 g) as white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=1[SH:26]>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=1[S:26][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: Sc1cc(Br)ccc1Br
Product: O=C1CCc2cc(OCCCCSc3cc(Br)ccc3Br)ccc2N1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-3,4-dihydro-carbostyril (m.p.: 142°-147° C.) and 2,5-dibromo-thiophenol.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH:11]1([C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17])[CH2:13][CH2:12]1>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:15]([C:14]([CH:11]2[CH2:13][CH2:12]2)=[O:19])[C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(=O)CC(=O)C1CC1
Product: CC(=O)C(=Cc1ccc(C#N)cc1)C(=O)C1CC1

Procedure:
The procedure described in Example 19 was repeated by using 2.6 g 4-cyanobenzaldehyde and 2.5 g 4-cyclopropyl-2,4-butanedione. The product was purified by column chromatography. Yield 0.37 g, mp 83°-85° C.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]=[C:13]=[S:14]>C1COCC1>[C:1]([NH:9][NH:10][C:13]([NH:12][CH3:11])=[S:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CN=C=S
Solvent: C1CCOC1
Product: CNC(=S)NNC(=O)c1ccccc1

Procedure:
To a stirred solution of benzoic acid hydrazide (2.35 g, 1.73×10-2 mole) and THF (50 ml) was added a solution of methyl isothiocyanate (1.14 g, 1.56×10-2 mole) and THF (50 ml). The reaction was then refluxed for 2 hours before being cooled. The precipitate was collected by filtration and crystallized from ethanol, affording a colorless solid, Mp 199°-200° C.
Reaction SMILES: [CH2:1]([S:4]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-])=O)[CH:7]=1)=[O:5])[CH2:2][CH3:3].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O.N>[CH2:1]([S:4]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([NH2:13])[CH:7]=1)=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)c1ccc(N)c([N+](=O)[O-])c1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCS(=O)c1ccc(N)c(N)c1
Yield: 59.8 %

Procedure:
To a solution of 6.84 g (0.03 mol) of 4-(1-propylsulfinyl)-2-nitroaniline in 100 ml ethanol is added 18.02 g (0.103 mol) sodium hydrosulfite in 100 ml water and 22 mg concentrated aqueous NH3. The resulting solution is heated to reflux for 1 hour, cooled, alcohol stripped and the aqueous layer extracted with CH2Cl2. The organics are combined, dried, filtered and evaporated in vacuo to yield 3.56 g of 4-(1-propylsulfinyl)-1,2-diaminobenzene in the form of an oil, 60% yield.
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[CH:3][C:2]1=[O:6].[Cl:7][C:8]1[CH:9]=[C:10]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[C:23]([O:26][CH2:27][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:11]=[CH:12][C:13]=1[F:14]>CO>[Cl:7][C:8]1[CH:9]=[C:10]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:33][CH2:34][CH2:35][N:36]4[CH2:37][CH2:38][N:39]([CH:4]5[CH2:5][O:1][C:2](=[O:6])[CH2:3]5)[CH2:40][CH2:41]4)=[C:23]([O:26][CH2:27][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: O=C1C=CCO1
Reactant: Fc1ccc(Nc2ncnc3cc(OCCN4CCNCC4)c(OCC4CCCC4)cc23)cc1Cl
Solvent: CO
Product: O=C1CC(N2CCN(CCOc3cc4ncnc(Nc5ccc(F)c(Cl)c5)c4cc3OCC3CCCC3)CC2)CO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
46 mg of (5H)-furan-2-one are added to a solution of 230 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentylmethoxy-7-[2-(piperazin-1-yl)-ethoxy]-quinazoline in 2 ml of methanol. The reaction mixture is stirred for 24 hours at ambient temperature, then for another six at 50° C. In total, six more drops of (5H)-furan-2-one are added until the reaction is complete. The solvent is distilled off using the rotary evaporator and the crude product is purified by chromatography over an Alox column (activity stage III) with methylene chloride/methanol (98:2) as eluant. The desired product is obtained as a colourless solid.
Reaction SMILES: [Li]CCCC.[CH2:6]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[F:24])=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH2:9][CH3:10].FC1C=CC=CC=1F.C(C1CCC(=O)CC1)CCCC.[CH2:45]([C:48]1[CH:53]=[CH:52][C:51]([CH2:54][CH2:55]I)=[CH:50][CH:49]=1)[CH2:46][CH3:47]>CCCCCC.C1COCC1.CN1C(=O)N(C)CCC1>[CH2:6]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:55][CH2:54][C:51]3[CH:50]=[CH:49][C:48]([CH2:45][CH2:46][CH3:47])=[CH:53][CH:52]=3)=[C:19]([F:23])[C:18]=2[F:24])=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCc1ccc(CCI)cc1
Reactant: CCCCCc1ccc(-c2cccc(F)c2F)cc1
Agent: CCCCCC1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: Fc1ccccc1F
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(CCc3ccc(CCC)cc3)c(F)c2F)cc1
Temperature: -40 °C

Procedure:
0.15 mol of a solution of n-BuLi in hexane is added dropwise to a mixture of 0.1 mol of 4'-n-pentyl-2,3-difluorobiphenyl (prepared from 1,2-difluorobenzene and 4-pentylcyclohexanone analogously to Example 3), in 250 ml of THF and 0.1 mol of potassium tert. butylate at -90° C. After stirring for 10 minutes at -85° C. a solution of 0.1 mol of 1-(4-propylphenyl)-2-iodoethane in 50 ml of THF and 2 ml of DMPU is added dropwise. After warming up to -40° C. and customary work-up 1-(4'-n-pentyl-2,3-difluorobiphenyl-4-yl)-2-(4-propylphenyl)-ethane is obtained.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=1[CH:10]=[O:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=2[CH:10]=[O:11])=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC1(C)CCC(Cl)=C(C=O)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(C=O)C1

Procedure:
reacting the 2-chloro-5,5-dimethylcyclohex-1-enecarbaldehyde, 4-chlorophenylboronic acid, tetrabutyl ammonium bromide, potassium carbonate, and palladium (II) acetate to provide 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde and isolating or not isolating the 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-ene-1-carbaldehyde;
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[NH:8][C:9]([CH3:20])=[C:10]([N+:17]([O-:19])=[O:18])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].C1(P(Cl)([Cl:30])=O)C=CC=CC=1>O>[Cl:30][C:7]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([N+:17]([O-:19])=[O:18])=[C:9]([CH3:20])[N:8]=1
Reactant: CCOC(=O)c1c([N+](=O)[O-])c(C)[nH]c(=O)c1C(=O)OCC
Reactant: O=P(Cl)(Cl)c1ccccc1
Solvent: O
Product: CCOC(=O)c1c(Cl)nc(C)c([N+](=O)[O-])c1C(=O)OCC
Temperature: 170 °C

Procedure:
To 1.0 g of 3,4-diethoxycarbonyl-6-methyl-5-nitro-2-pyridone was added 1.3 ml (3.2 eq.) of phenylphosphonic dichloride. The mixture was heated at 170° C. for 20 mintues. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluent:ethyl acetate) to give an oily product.
Reaction SMILES: C1(C2CC2C(Cl)=O)C=CC=CC=1.[C:13]1([CH:19]2[CH2:21][CH:20]2[C:22]([N:24]=[C:25]=[S:26])=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.C1(C)C=CC=CC=1>C(O)C>[C:13]1([CH:19]2[CH2:21][CH:20]2[C:22]([N:24]=[C:25]=[S:26])=[O:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH:46][C:25]([NH:24][C:22]([CH:20]2[CH2:21][CH:19]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:23])=[S:26])=[CH:44][CH:43]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)C1CC1c1ccccc1
Agent: O=C(N=C=S)C1CC1c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)C4CC4c4ccccc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
2-Phenyl-1-cyclopropanecarbonyl isothiocyanate was prepared using commercially available 2-phenyl-1-cyclopropanecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Phenyl-1-cyclopropanecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (50 mg, yield 60%).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.Br[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([F:31])[CH:22]=1.O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:31][C:23]1[CH:22]=[C:21]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1ccc(Br)cc1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccccn2)cc1F
Yield: 35.6 %

Procedure:
2-(Tributylstannyl)pyridine (11.2 g, 30.4 mmol) was dissolved in toluene (240 mL), methyl 4-bromo-2-fluorobenzoate (7.4 g, 33.4 mmol) and tetrakis(triphenyl-phosphine) Pd (1.75 g) were added thereto. The mixture was poured into water, extraction was carried out with ethyl acetate, the organic phase was dried and the solvent was evaporated. The residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 50:1 to 10:1) to give methyl 2-fluoro-4-(pyridin-2-yl)benzoate (2.5 g, yield 35%). 1H-NMR (400 MHz, CDCl3) δ (ppm): 3.93 (s, 3H), 7.31-7.34 (m, 1H), 7.76-7.85 (m, 4H), 8.05 (t, J=7.6 Hz, 1H), 8.72-8.74 (m, 1H); LC-MS (ESI) m/z: 232 (M+1)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9]O)=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>C(Cl)(Cl)Cl>[Br:12][CH2:9][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCc1ccncc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: BrCCCc1ccncc1
Reaction time: 2 h
Yield: 111.1 %

Procedure:
3.0 g of 4-pyridinepropanol was dissolved in 90 ml of chloroform, 9.4 g of carbon tetrabromide and 7.5 g of triphenylphosphine was added under ice cooling, and the mixture was stirred for 2 hours. Ether was added to the reaction solution, and the mixture was extracted with 1N hydrochloric acid, and then the aqueous layer was washed with ether. The aqueous layer was adjusted to be basic with 6N sodium hydroxide, and extracted with ether. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give 4.86 g of 4-(3-bromopropyl)pyridine.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([CH3:30])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])(C)(C)C.[CH3:39][O:40][C:41]1[CH:63]=[CH:62][C:44]([CH2:45][C@H:46]([CH2:50][C:51]([N:53]([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH3:54])=[O:52])C(O)=O)=[CH:43][CH:42]=1>>[CH2:26]([NH:25][C:23](=[O:24])[C@H:22]([CH3:30])[CH2:21][C@H:20]([OH:31])[C@@H:19]([NH:18][C:16](=[O:17])[C@H:9]([CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)[NH:8][C:6](=[O:7])[C@H:46]([CH2:45][C:44]1[CH:62]=[CH:63][C:41]([O:40][CH3:39])=[CH:42][CH:43]=1)[CH2:50][C:51]([N:53]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH3:54])=[O:52])[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:27][CH2:28][CH3:29]
Reactant: COc1ccc(C[C@H](CC(=O)N(C)Cc2ccccc2)C(=O)O)cc1
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N(C)Cc1ccccc1)Cc1ccc(OC)cc1
Yield: 69.7 %

Procedure:
The procedure described in Example 6(b) was repeated, but using 150 mg (0.27 mmole) of (2R, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-N-butyl-6-cyclohexyl-4-hydroxy-2-methylhexanamide [prepared as described in Example 6(a)] and 92 mg (0.27 mmole) of 2(R)-(4-methoxybenzyl)-3-(N-benzyl-N-methylaminocarbonyl)propionic acid, to afford 146 mg of the title compound as a white powder, melting at 112°-114° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:6][O:7][CH2:8][C:9]([CH3:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][OH:11].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]([F:26])([F:27])[C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:21]=1)[CH2:6][O:7][CH2:8][C:9]([CH3:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:10]=[O:11]
Reactant: CC(CO)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C=O)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Yield: 0.1 %

Procedure:
3-(3,5-bis(trifluoromethyl)benzyloxy)-2-methyl-2-phenylpropan-1-ol (500 mg, 1.28 mol) was treated with Dess-Martin periodinane (5.76 g, 15 wt % in CH2Cl2, 2.03 mmol) in methylene chloride for 2 hour at room temperature. The reaction mixture was loaded directly onto silica column and eluted with 5% ethyl acetate in haxanes. 375 mg (75%) of the desired aldehyde was obtained. 1H NMR (500 MHz, CDCl3) δ: 1.60 (s, 3 H) 3.80 (m, 1 H) 4.02 (m, 1 H) 4.62 (m, 2 H) 7.27 (m, 2 H) 7.33 (m, 1 H) 7.39 (m, 2 H) 7.67 (s, 2 H) 7.78 (s, 1 H) 9.61 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]=3[CH:8]=2)=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=[CH:3]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:54]=[CH:55][C:56]=1[O:57][CH3:58])CN1C(C2SC3N=CN=C(SC)C=3C=2)=C(C2C=CC=CC=2)N=C1>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:54]=[CH:55][C:56]=1[O:57][CH3:58])[CH2:1][N:2]1[C:6]([C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]=3[CH:8]=2)=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=[CH:3]1
Reactant: COc1ccc(Cn2cnc(-c3ccccc3)c2-c2cc3c(SC)ncnc3s2)cc1OC
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Product: COc1ccc(Cn2cnc(-c3ccccc3)c2-c2cc3c(S(C)(=O)=O)ncnc3s2)cc1OC
Yield: 75 %

Procedure:
The title compound was prepared in 75% yield according to a procedure similar to the one described for intermediate 17 above but starting from 6-[1-(3,4-dimethoxybenzyl)-4-phenyl-1H-imidazol-5-yl]-4-(methylthio)thieno[2,3-d]pyrimidine (example 9) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (example 7);