Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15][C:16](N(C)C)=O)=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[O-:22][CH2:23][CH3:24].[Na+].BrCCC[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[S:37][C:38]3[CH2:44][CH2:43][CH2:42][O:41][C:39]=3[N:40]=2)=[CH:32][C:31]=1[CH2:45][CH2:46][CH3:47].Cl>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([S:15][CH2:16][CH2:24][CH2:23][O:22][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[S:37][C:38]5[CH2:44][CH2:43][CH2:42][O:41][C:39]=5[N:40]=4)=[CH:32][C:31]=3[CH2:45][CH2:46][CH3:47])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(SC(=O)N(C)C)ccc21
Reactant: CC[O-]
Reactant: CCCc1cc(-c2nc3c(s2)CCCO3)ccc1CCCBr
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cc(-c2nc3c(s2)CCCO3)ccc1OCCCSc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
To a solution of ethyl((1S)-5-{[(dimethylamino)carbonyl]sulfanyl}-2,3-dihydro-1H-inden-1-yl)acetate (130 mg, 0.42 mmol) (Example 508) in DMF (5 mL) was added sodium ethoxide (0.63 mL, 1.69 mmol, 21% solution in EtOH), and the reaction mixture was stirred at rt. The solution turned purple, and after 2 h, the starting material had been consumed. A solution preparation of 2[4-(3-bromopropyl)-3-propylphenyl]-6,7-dihydro-5H-pyrano{2,3-d]thiazole (119 mg, 0.30 mmol) (Example 506) in DMF (1.5 mL) was added. After an additional 2 h of stirring at rt, HCl (4 mL, 1N aqueous solution) was added, followed by brine. The aqueous phase was extracted with ether, and the combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (8:1 hexanes/EtOAc) to give the title compound (55 mg, 33%). 1H NMR (400 MHz, CDCl3) 7.67 (d, 1H), 7.62 (dd, 1H), 7.21 (s, 1H), 7.15 (d, 1H), 7.07 (d, 1H), 6.77 (d, 1H), 4.30 (t, 2H), 4.17 (q, 2H), 4.08 (t, 2H), 3.58-3.48 (m, 1H), 3.11 (t, 2H), 2.92-2.73 (m, 2H), 2.77 (t, 2H), 2.72 (dd, 1H), 2.60 (t, 2H), 2.44-2.32 (m, 2H), 2.16-2.03 (m, 4H), 1.79-1.68 (m, 1H), 1.67-1.57 (m, 2H), 1.28 (t, 3H), 0.94 (t, 3H); LC-MS: RT=4.85 min, (M+H)+ 552.2.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][CH2:8][C:7]1=[O:17].BrCCCCN1C2C=CC=CC=2CCCC1=O.[C:35]([C:39]1[N:44]=[C:43]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH:42]=[C:41]([C:51]([F:54])([F:53])[F:52])[N:40]=1)([CH3:38])([CH3:37])[CH3:36].[Na+].[Br-].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[C:35]([C:39]1[N:44]=[C:43]([N:45]2[CH2:46][CH2:47][N:48]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[CH2:10][CH2:9][CH2:8][C:7]3=[O:17])[CH2:49][CH2:50]2)[CH:42]=[C:41]([C:51]([F:52])([F:53])[F:54])[N:40]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)c1nc(N2CCNCC2)cc(C(F)(F)F)n1
Reactant: O=C1CCCc2ccccc2N1CCCCCl
Agent: O=C1CCCc2ccccc2N1CCCCBr
Agent: [Br-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc(N2CCN(CCCCN3C(=O)CCCc4ccccc43)CC2)cc(C(F)(F)F)n1
Temperature: 120 °C

Procedure:
A mixture of 1-(4-chlorobutyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one and 1-(4-bromobutyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (0.40 g), 2-tert-butyl-4-piperazin-1-yl-6-(trifluoromethyl)pyrimidine (1.59 mmol, 0.46 g, prepared as in DE 19735410), NaBr (7.94 mmol, 0.82 g), diisopropylethylamine (15.57 mmol, 2.01 g) and N-methylpyrrolidinone (0.6 ml) was heated at 120° C. for 5 hours. The suspension was then filtered, and the filtrate was evaporated to dryness. The residue was taken up in ethyl acetate and extracted with saturated brine. The organic phase was dried, the desiccant was filtered off, and the solution was evaporated to dryness. The residue was purified by chromatography on silica gel (eluent: dichloromethane/MeOH (0-100%), resulting in 0.58 g of the title compound.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:25]([Si:29]([O:32][CH2:33][CH2:34]I)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:25]([Si:29]([CH3:31])([CH3:30])[O:32][CH2:33][CH2:34][CH:6]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OCCI
Reactant: N#Cc1ccc(Cn2ccnc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCC(c1ccc(C#N)cc1)n1ccnc1
Temperature: -60 °C

Procedure:
4-Imidazol-1-ylmethyl-benzonitrile (5.5 gms,30 mmol) was suspended in freshly distilled THF (150 mL) in dry glassware and stirred under argon in a -60° C. dry ice acetone bath then Lithium bis(trimethylsilyl)amide 1 molar in THF (33 mL) was added slowly. The mixture was stirred for 30 minutes and the temperature was reduced to -78° C. A suspension of tert-butyl-(2-iodo-ethoxy)-dimethyl-silane (9.5 gm, 33 mmol) in 20 mL of THF was cooled to -78° C. and added via cannula to the first solution and the resulting mixture was allowed to slowly warm to ambient temperature. After 16 hours the reaction was quenched by the addition of 10 mL of water and the solvent was removed in vacuo. The residue was suspended in ethyl acetate (200 mL) and extracted 2 times with saturated aqueous sodium bicarbonate (100 mL), then water (100 mL), then saturated sodium chloride solution (100 mL). The organic solvent was removed in vacuo and the residue was chromatographed on silica gel using 1:3 ethyl acatate: hexanes. The desired fractions were combined and the solvent was removed in vacuo to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([O-:30])=O)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[O:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]3[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:23][O:18][CH2:19][CH2:20]5)=[CH:13][CH:12]=3)[N:6]=[CH:5]4)=[O:30])=[CH:31][CH:32]=2)[CH2:22][CH2:23]1
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Product: O=C(Nc1ccc2c(cnn2-c2ccc(N3CCOCC3)cc2)c1)c1ccc(N2CCOCC2)cc1

Procedure:
Compound 537 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 4-morpholinobenzoate. [M+H]+ calcd for C28H29N5O3: 484.23; found: 484.11.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:16][C:17]1([CH2:21][CH2:22][CH3:23])[CH2:20][O:19][CH2:18]1)(=O)=O.O>CN(C)C=O>[CH2:1]([S:8][CH2:20][C:17]([CH2:16][S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH2:21][CH2:22][CH3:23])[CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: CCCC1(COS(C)(=O)=O)COC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CO)(CSCc1ccccc1)CSCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of benzyl mercaptan (25.0 ml) in dry dimethylformamide (100 ml) was stirred at 0° C., under a current of nitrogen. Sodium hydride (6.0 g., 80% dispersion in oil) was added carefully and the mixture was stirred at 0° for 1 hour. 3-n-Propyloxetan-3-ylmethyl methanesulphonate (10.0 g.) was added and the mixture was stirred at 0° C. for 1 hour. The mixture was refluxed with stirring for 6 hours. The mixture was cooled and poured into water. The aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was chromatographed on silica, eluting with 1:4; diethyl ether: hexane. 2,2-Di-(benzylthiomethyl)pentan-1-ol was obtained as a pale yellow oil (15.6 g.)
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:22].CC1C=CC(S(O[CH2:34][C@@H:35]2[CH2:37][O:36]2)(=O)=O)=CC=1>>[NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:34][C@@H:35]4[CH2:37][O:36]4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:22]
Reactant: N#Cc1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Product: N#Cc1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OC[C@@H]1CO1
Yield: 12.5 %

Procedure:
The title compound (147 mg, 0.400 mmol, 12.5%) was obtained as light brown crystals from a 4-(4-amino-3-chlorophenoxy)-6-cyano-7-hydroxyquinoline crude product (1.00 g, 3.21 mmol) and (2S)-oxiran-2-ylmethyl 4-methyl-1-benzene sulfonate, by the same procedure as in Example 7.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13](Cl)[C:12]([N+:16]([O-:18])=[O:17])=[C:11](Cl)[C:10]=2Cl)=[CH:4][N:3]=1.NC1N=C(N)C([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=2[Cl:36])=CN=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:10]=2[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=2[Cl:36])=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2cccc(Cl)c2Cl)c(N)n1
Reactant: Nc1ncc(-c2cc(Cl)c([N+](=O)[O-])c(Cl)c2Cl)c(N)n1
Product: Nc1ncc(-c2ccc([N+](=O)[O-])cc2-c2cccc(Cl)c2Cl)c(N)n1

Procedure:
This compound was made in an analogous manner to the compound of Example 5 from 2,4-diamino-5-(2,3-dichlorophenyl)pyrimidine (Example 21). The reaction gave a mixture of the 4-nitro and 5-nitro derivatives from which the title compound was separated by column chromatography (SiO2, EtOAc), mp. 237°-9° C. Also separated in this manner was 2,4-diamino-5-(2,3-dichloro-5-nitrophenyl)pyrimidine, mp. 264°-6° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12]C(C2C=NC3C(C=2Cl)=CC=CC=3C(F)(F)F)=O)[CH2:8][CH2:7]1>C(N(CC)CC)C>[ClH:3].[CH3:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8][CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: C[C@H]1CC[C@H](NC(=O)c2cnc3c(C(F)(F)F)cccc3c2Cl)CC1
Solvent: CCN(CC)CC
Product: C[C@H]1CC[C@H](N)CC1
Product: Cl

Procedure:
4-Hydroxy-8-trifluoromethyl-3-carboxylic acid (514 mg, 2 mmol), thionyl chloride, trans-4-methylcyclohexylamine hydrochloride (225 mg, 1.5 mmol), and triethylamine (2 mL) afforded crude N-(trans-4-methylcyclohexyl)-4-chloro-8-trifluoromethylquinoline-3-carboxamide:
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:19]=[CH:18][C:12]2[N:13]=[CH:14][N:15]=[C:16]([Cl:17])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[N:25]=[CH:24]2>>[ClH:17].[CH2:30]([N:26]1[C:27]2[C:23](=[CH:22][C:21]([NH:20][C:16]3[C:11]4[CH:10]=[C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[N:19]=[CH:18][C:12]=4[N:13]=[CH:14][N:15]=3)=[CH:29][CH:28]=2)[CH:24]=[N:25]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Nc1ccc2c(cnn2Cc2ccccc2)c1
Reactant: Clc1ncnc2cnc(OCc3ccccc3)cc12
Product: Cl
Product: c1ccc(COc2cc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3cn2)cc1
Yield: 75 %

Procedure:
6-Benzyloxy-4-chloro-pyrido[3,4-d]pyrimidine (0.54 g, ca. 2 mmol) and 5-amino-1-benzyl-1H-indazole (0.458 g, 2.05 mmol) were reacted according to Procedure A to give the title compound as a yellow solid (0.740 g, 1.50 mmol, 75%); δH [2H6]DMSO 11.50(1H,s), 9.00(1H,s), 8.77(1H,s), 8.16-8.33 (3H,m), 7.83(1H,d), 7.71 (1H,dd), 7.13-7.58 (10H,m), 5.69(2H,s), 5.55(2H,s); m/z (M+1+) 459.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:3]=1.[CH3:21][O-:22].[Na+]>CO>[CH3:21][O:22][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:3]=1
Reactant: COc1ccc(CCNc2cc(CO)nc(Cl)n2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CCNc2cc(CO)nc(OC)n2)cc1
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of {2-chloro-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-methanol (6.5 g mg, 22.1 mmol, Intermediate (57)] 25 wt % sodium methoxide in MeOH (15.2 mL, 66.3 mmol), in MeOH (20 mL) is heated to 90° C. and stirred for 3 hours and concentrated by rotary evaporator to remove the solvent. The solid is dissolved in water and the solution is acidified to pH 8 with the addition of saturated ammonium chloride solution. Extracted twice with 150 mL ethyl acetate, combined the extracts, Dried over magnesium sulfate, filtered and concentrated to afford {2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-methanol [5.66 g, 88%, Intermediate (58)] as a solid. LCMS: RT=2.35 minutes, MS: 290 (M+H).
Reaction SMILES: C(OC(C)C)(=O)C.[CH3:8][O:9][C:10]1[CH:25]=[CH:24][C:13]([CH2:14][N:15]2[CH:19]([C:20]([OH:22])=O)[CH2:18][S:17][C:16]2=[O:23])=[CH:12][CH:11]=1.CN1CCOCC1.C(Cl)(=O)C(C)(C)C.[CH3:40][O:41][NH:42][CH3:43]>CCCCCCC>[CH3:40][O:41][N:42]([CH3:43])[C:20]([CH:19]1[CH2:18][S:17][C:16](=[O:23])[N:15]1[CH2:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:25][CH:24]=1)=[O:22]
Reactant: COc1ccc(CN2C(=O)SCC2C(=O)O)cc1
Reactant: CNOC
Agent: CC(C)(C)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCCCCCC
Solvent: CC(=O)OC(C)C
Product: COc1ccc(CN2C(=O)SCC2C(=O)N(C)OC)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 69.4 %

Procedure:
A 22 L three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with an iso-propyl acetate solution of 3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid (310.0 g, 1.16 mol, approximately 3 L). The vessel was purged with nitrogen and cooled to 0° C. 4-Methyl-morpholine (130.0 g, 1.29 mol) was added while maintaining an internal reaction temperature below 5° C. Pivaloyl chloride (150.0 g, 1.24 mol) was added dropwise such that the internal reaction temperature was maintained below 5° C. The reaction was stirred at 0° C. for 45 minutes. N-Methoxy-methanamine (78.0 g, 1.28 mol) was added while maintaining an internal reaction temperature below 5° C. The reaction was monitored by HPLC and was considered complete when the ratio of the product to starting material was 4:1 (approximately 30 minutes after amine addition). The mixture was then washed with a 2.4 L portion of 0.1 M HCl, followed by 2.4 L of saturated NaHCO3. The organic phase was separated and concentrated to a final volume of 1.0 L by distillation. After a precipitate began to form, a 250 mL portion of n-heptane was added. The mixture was stirred vigorously. The solid was filtered and dried in a vacuum oven at 40° C. Approximately 250 g of 3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide was obtained (70% yield). 1H NMR (300 MHz, DMSO) δ 7.15 (d, 8.9 Hz, 2H), 6.86 (d, 8.9 Hz, 2H), 4.49 (AB, JAB=14.4 Hz, ΔvAB=387.9 Hz, 2H), 4.40 (dd, J=8.8, 5.2 Hz, 1H), 3.79 (s, 3H), 3.46 (dd, J=11.0, 8.5 Hz, 1H), 3.38 (s, 3H), 3.21 (s, 3H), 3.15 (dd, J=11.0, 5.5 Hz, 1H). 13C NMR (75 MHz, DMSO) δ 28.4, 32.9, 47.2, 55.8, 57.9, 61.9, 114.7, 128.5, 130.3, 159.5, 169.4, 172.3; [α]26.5D-93.5 0 (c=1.0 EtOH). The enantiomeric purity of (R)-(−)-3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide can be measure using the described HPLC method.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[NH:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1>C(O)(C)C>[ClH:1].[CH3:35][O:34][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[O:32][CH3:33])[C:25]([NH:24][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][C:17]=1[CH3:16])[NH:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1)=[O:36]
Reactant: COc1ccc(C(=O)Nc2cc(N)ccc2C)cc1OC
Reactant: COc1cc2nccc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1ccc(C(=O)Nc2cc(Nc3ccnc4cc(OC)c(OC)cc34)ccc2C)cc1OC
Product: Cl
Temperature: 85 °C
Yield: 36.2 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (315 mg) and N-(2-methyl-5-aminophenyl)-3,4-dimethoxybenzamide (443 mg) were stirred together in isopropanol (10 ml) and heated to 85° C. for 18 hours. After cooling to room temperature the precipitated solid was isolated and washed with isohexane to yield the title compound as a solid (260 mg, 36%); NMR: 2.32 (s, 3H), 3.82 (s, 6H), 3.97 (s, 3H), 3.99 (s, 3H), 6.75 (m, 1H), 7.07 (m, 1H), 7.25 (m, 1H), 7.46 (m, 2H), 7.51 (m, 1H), 7.58 (m, 1H), 7.64 (m, 1H), 8.1 (s, 1H), 8.36 (m, 1H), 9.85 (s, 1H), 10.62 (s, 1H); m/s: M+H+ 474.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([C:12](=[N:14][OH:15])[CH3:13])=[CH:10][N:11]=2)[CH:2]=1.C(=O)([O-])[O-].Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1>C(#N)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:8][C:9]([C:12](=[N:14][O:15][C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH3:13])=[CH:10][N:11]=2)[CH:2]=1
Reactant: CC(=NO)c1cnc(-c2cccnc2)s1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC(=NOc1ncccn1)c1cnc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 38 %

Procedure:
A suspension of 1-[2-(3-pyridyl)thiazol-5-yl]ethanone oxime (isomer A, 0.15 g, 0.657 mmol) in acetonitrile (5 ml) was stirred at ambient temperature and treated with carbonate (0.648 g, 1.97 mmol) and 2-chloropyrimidine (0.119 g, 0.985 mmol) and allowed to stir at ambient temperature. After 2 days (80% conversion), the reaction mixture was concentrated in vacuo and the residue was stirred with ethyl acetate, filtered and the ethyl acetate concentrated in vacuo. Purification by flash chromatography eluting with ethyl acetate gave 1-[2-(3-pyridyl)thiazol-5-yl]-N-pyrimidin-2-yloxy-ethanimine (0.074 g, 38%) as a single isomer as slightly yellow crystals.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[C:17]([F:29])=[CH:18][C:19]([Cl:28])=[C:20]([CH:27]=1)[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[Cl:28][C:19]1[CH:18]=[C:17]([F:29])[C:16]([NH:15][C:12]([C:11]2[S:10][CH2:9][CH2:8][O:7][C:6]=2[CH3:5])=[O:14])=[CH:27][C:20]=1[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]
Reactant: CC1=C(C(=O)O)SCCO1
Reactant: CC(C)OC(=O)c1cc(N)c(F)cc1Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)Nc2cc(C(=O)OC(C)C)c(Cl)cc2F)SCCO1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (4.2 g, 0.035 mole) was added to a stirring slurry of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid 4.8 g, 0.030 mole) in methylene chloride (40 ml). The mixture was warmed to 35° C. for 3 hours, then left stirring overnight at room temperature. The solution was then evaporated under reduced pressure at about 35° C. The solid residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (50 ml) and the solution chilled in ice and treated dropwise with a solution of 1-methylethyl 5-amino-2-chloro-4-fluorobenzoate (7.0 g, 0.030 mole) and triethylamine (3.5 g, 0.035 mole) in methylene chloride (50 ml). The addition was carried out over 2 hours, after which the reaction mixture was stirred at 20°-35° C. for 3 hours.
Reaction SMILES: [C:1]([C:3]([S:10][C:11](=[S:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:9])[CH2:4][CH2:5][C:6]([OH:8])=[O:7])#[N:2].CCN=C=NCCCN(C)C.[N:30]([CH2:33][CH2:34][CH2:35]O)=[N+:31]=[N-:32]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([C:3]([S:10][C:11](=[S:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([CH3:9])[CH2:4][CH2:5][C:6]([O:8][CH2:35][CH2:34][CH2:33][N:30]=[N+:31]=[N-:32])=[O:7])#[N:2]
Reactant: [N-]=[N+]=NCCCO
Reactant: CC(C#N)(CCC(=O)O)SC(=S)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C#N)(CCC(=O)OCCCN=[N+]=[N-])SC(=S)c1ccccc1
Reaction time: 0.08 h
Yield: 84.6 %

Procedure:
4-cyano-4-thiobenzoylsulfanyl-pentanoic acid (CTP, 1.0 g, 3.6 mmol) and DMAP (439.8 mg, 3.6 mmol) were dissolved in anhydrous DCM (50 mL). The solution was stirred for 5 min in ice bath, and EDCI (690.1 mg, 3.6 mmol) was added and stirred for 30 min. 3-Azidopropanol (364 mg, 3.6 mmol) was added and the solution was stirred in ice bath for 30 min and at room temperature for another 8 h. After reaction, the solution was washed with NaHCO3 aq. (satd.) and then H2O. The organic layer was dried (Na2SO4), solvent removed by rotary evaporation and the crude product was purified by column chromatography (silicagel 60 Å, 200-400 mesh, ethyl acetate:hexane, 1:4) to give rose-red oil in 84.6% yield. The structure of this compound was confirmed by 1H NMR and 13C NMR spectroscopy. 1H NMR (300 MHz, CDCl3, δ in ppm): 1.90-1.93 (m, 5 H, —CH2CH2N3, —CH3), 2.45-2.60 (m, 2 H, C(CN)CH2—), 2.68 (m, 2 H, C(CN)CH2CH2—), 3.40 (t, 2 H, —CH2N3), 4.21 (t, 4 H, —OCH2CH2—), 7.39 (m, 2 H, PH-2H), 7.57 (m, 1 H, PH-4H), 7.89 (m, 2 H, PH-3H). 13C NMR (75 MHz, CDCl3, δ in ppm): 222.40, 171.43, 144.74, 133.29, 128.82, 126.91, 118.68, 62.22, 48.34, 45.93, 33.60, 29.98, 28.27, 24.41.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[CH:13].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Agent: N
Product: Clc1cncc(-c2cc(-c3ccccc3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 1-ethynyl-benzene (Aldrich, 31 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.52-7.66 (m, 3H), 7.78 (s, 1H), 7.85-7.98 (m, 2H), 8.45 (t, J=2.1 Hz, 1H), 8.80 (d, J=2.4 Hz, 1H), 9.09 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 257 (M+H)+, 259 (M+H)+.
Reaction SMILES: [CH2:1](N(CC)CC)C.[NH:8]1C[CH2:19][CH2:18][C@H:9]1[C:10]([NH:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14])=[O:11].C(=O)=O.[N+](C1C=CC(O[C:34](=[O:54])[C@@H:35]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[NH:36][C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])=CC=1)([O-])=O.Cl>O1CCOCC1.O.C(OCC)(=O)C>[C:37]([NH:36][C@@H:35]([C:34]([NH:8][C@H:9]([C:10]([NH:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14])=[O:11])[CH:18]([CH3:19])[CH3:1])=[O:54])[CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)([O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:38]
Reactant: CCN(CC)CC
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)O
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Agent: Cl
Agent: O=C=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)[C@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
Triethylamine (9.0 mmol, 1.25 mL) was added to a mixture of L-prolyl-L-alanine (Sigma, 4.5 mmol, 838 mg) in 80 mL of 1:1 dioxane-water. After 15 minutes, pieces of solid carbon dioxide were added to the solution until the pH was reduced to pH 8. N-CBZ-D-Phenylalanine 4-nitrophenyl ester (Sigma, 4.5 mmol, 1.89 g) was then added, and the mixture was stirred at room temperature for four days. The clear yellow solution was acidified by gradual addition of 1N HCl, and diluted with ethyl acetate. The organic phase was then separated, washed with water (3×) and brine (2×), dried (MgSO4), and rotary evaporated to give an oil residue. A solution of this residue in ethyl acetate was fractionally extracted with three solutions of 80 mg NaHCO3 in 10 mL water. These aqueous extracts were combined, acidified, and extracted with ethyl acetate. The resulting ethyl acetate solution was washed with brine, dried (MgSO4), evaporated, and dried at high vacuum to provide 1.45 g (69%) of N-CBZ-D-phenylalanyl-L-valyl-L-alanine as a viscous oil, in sufficient purity for the next step.