Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([OH:40])[CH:34]=[C:35]([O:37][CH2:38][CH3:39])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:40][C:33]2[CH:34]=[C:35]([O:37][CH2:38][CH3:39])[CH:36]=[C:31]([Br:30])[CH:32]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOc1cc(O)cc(Br)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCC)c2)c1CCC(=O)OCC
Yield: 82.1 %

Procedure:
A similar procedure as described in Example 43, step 3 was used, starting from 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (8.07 g, 17.13 mmol), 3-bromo-5-ethoxy-phenol (3.38 g, 15.57 mmol), and potassium carbonate (4.3 g, 31.14 mmol) to obtain 4-[3-[6-(3-bromo-5-ethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (7.77 g, 82%) as a colorless oil: ES(+)-HRMS m/e calcd for C31H43BrO7 (M+H)+ 607.2265. found 607.2270.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].Br[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([O:10][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:2]([F:1])[CH:3]=1)#[N:6]
Reactant: CCOC(=O)CCCBr
Reactant: N#Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1ccc(C#N)cc1F
Temperature: 80 °C
Yield: 97.1 %

Procedure:
3-fluoro-4-hydroxybenzonitrile (ABCR F03756F.AB, 2 g; 14.59 mmol; 1 eq.) was dissolved in DMF (40 mL). Then ethyl 4-bromobutyrate (4.27 g; 21.88 mmol; 1.50 eq.) and potassium carbonate (3.02 g; 21.88 mmol; 1.50 eq.) were added to the reaction mixture and it was heated to 80° C. for 2 hours. The reaction mixture was cooled to RT and diluted with EtOAc. The organic layer was washed with water (3×), brine, dried over MgSO4 and concentrated affording the title compound as a yellow solid (3.56 g, 97%). 1H NMR (DMSO-d6, 300 MHz) δ 7.86-7.83 (d, J=11.43 Hz, 1H), 7.68-7.66 (d, J=8.73 Hz, 1H), 7.37-7.32 (m, 1H), 4.20-4.03 (m, 4H), 2.46-2.44 (m, 2H), 2.03-1.99 (m, 2H), 1.19-1.15 (t, J=6.62 Hz, 3H). HPLC (Method A) Rt 4.47 min (Purity: 98.8%).
Reaction SMILES: [C:1]([C:4]1[NH:20][C:7]2=[CH:8][C:9]3[C:10]([CH3:19])([CH3:18])[C:11](=[O:17])[N:12]([CH2:15][CH3:16])[C:13]=3[CH:14]=[C:6]2[N:5]=1)(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:33]1[CH:38]=[CH:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[C:1]([C:4]1[N:20]([CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][O:33]2)[C:7]2=[CH:8][C:9]3[C:10]([CH3:19])([CH3:18])[C:11](=[O:17])[N:12]([CH2:15][CH3:16])[C:13]=3[CH:14]=[C:6]2[N:5]=1)(=[O:3])[CH3:2]
Reactant: C1=COCCC1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(C(C)=O)nc3cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCN1C(=O)C(C)(C)c2cc3c(cc21)nc(C(C)=O)n3C1CCCCO1
Yield: 44.4 %

Procedure:
2-Acetyl-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (11.7 g, 43.1 mmol) and p-toluenesulfonic acid monohydrate (0.82 g, 4.3 mmol) were dissolved in dichloromethane (200 mL). To this solution 3,4-dihydro-2H-pyrane (4.81 g, 56 mmol) was added and the mixture stirred at reflux for 24 h. The mixture was filtered, the filtrate washed with water (2×100 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica (dichloromethane/methanol 93:3) yielding 6.8 g (44%) of a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[C:12](OC)(OC)(OC)[CH3:13]>CO>[CH3:12][C:13]1[O:11][C:3]2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: COC(C)(OC)OC
Reactant: Nc1ccc(C(=O)O)cc1O
Solvent: CO
Product: Cc1nc2ccc(C(=O)O)cc2o1
Temperature: 100 °C
Yield: 40.6 %

Procedure:
A mixture of 4-amino-3-hydroxybenzoic acid (500 mg, 3.7 mmol) and trimethyl orthoacetate (1.0 mL, 7.9 mmol) is heated in an oil bath to 100° C. for 2 h. The mixture is cooled to rt and diluted with MeOH. The resulting solution is filtered through a pad of Celite, and the filtrate is concentrated in vacuo to give 2-methyl-1,3-benzoxazole-6-carboxylic acid as an off-white solid (266 mg, 46%): 1H NMR (DMSO-d6) δ 13.1, 8.2, 8.0, 7.7, 2.7.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:13])=[C:7]2[OH:23].[C:31](N1C=CN=C1)(N1C=CN=C1)=[O:32].O>CN(C=O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:8]2[C:7](=[O:23])[C:6]3[C:11]4=[C:2]([NH:1][C:31](=[O:32])[N:10]4[CH:9]=2)[CH:3]=[C:4]([CH2:24][N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[CH:5]=3)=[O:13])=[CH:17][CH:18]=1
Reactant: Nc1cc(CN2CCOCC2)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c(=O)[nH]c3cc(CN4CCOCC4)cc(c1=O)c32
Temperature: 80 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A mixture of 8-amino-N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (Preparation 3, 331 mg) and 1,1′-carbonyl diimidazole (215 mg) in DMF (2.5 mL) is heated at 80° C. for 1 h. A second portion of 1,1′-carbonyl diimidazole (167 mg) is added and heating is continued for an additional 1 h. After cooling, water (8 mL) is added and the resulting precipitate is filtered off, washed with water and dried to afford 261 mg of the title compound. Physical characteristics: M.p. 286° C. (dec); 1H NMR (300 MHz, DMSO-d6) δ2.39, 3.57, 3.62, 4.57, 7.39, 7.61, 8.88, 10.0, 12.0. Anal. Found: C, 60.37; H, 4.78; N, 12.49.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13](I)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[CH3:21][C:22]([OH:39])([CH3:38])[CH2:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:27]4[CH:26]=[N:25][N:24]([CH2:23][C:22]([OH:39])([CH3:38])[CH3:21])[CH:28]=4)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: NC(=O)c1nc2n(c1I)C1CC(C1)c1ccc(Br)cc1-2
Product: CC(C)(O)Cn1cc(-c2c(C(N)=O)nc3n2C2CC(C2)c2ccc(Br)cc2-3)cn1

Procedure:
10-bromo-3-iodo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carb oxamide was reacted with 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]propan-2-ol similarly to as described in Example 4 to produce crude 10-bromo-3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. This intermediate was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol via General Procedure E to afford 39 mg (24%) of 10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-3-[1-(2-hydroxy-2-methyl-propyl)pyrazol-4-yl]-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. M+1=527.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:16]3=[C:17]4[C:3]=1[C:4]([S:26]([O-:29])(=[O:28])=[O:27])=[C:5]([S:22]([O-:25])(=[O:24])=[O:23])[C:6]([S:18]([O-:21])(=[O:20])=[O:19])=[C:7]4[CH:8]=[CH:9][C:10]3=[CH:11][CH:12]=[CH:13]2.[Na+:30].[Na+].[Na+].[C:33](OC(=O)C)(=[O:35])[CH3:34].C([O-])(=O)C.[Na+]>CN(C)C=O>[Na+:30].[Na+:30].[Na+:30].[C:33]([O:1][C:2]1[CH:15]=[C:14]2[C:16]3=[C:17]4[C:3]=1[C:4]([S:26]([O-:29])(=[O:28])=[O:27])=[C:5]([S:22]([O-:25])(=[O:23])=[O:24])[C:6]([S:18]([O-:21])(=[O:20])=[O:19])=[C:7]4[CH:8]=[CH:9][C:10]3=[CH:11][CH:12]=[CH:13]2)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)([O-])c1c(S(=O)(=O)[O-])c2ccc3cccc4cc(O)c(c1S(=O)(=O)[O-])c2c34
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2cccc3ccc4c(S(=O)(=O)[O-])c(S(=O)(=O)[O-])c(S(=O)(=O)[O-])c1c4c32

Procedure:
10 grams of trisodium hydroxypyrenetrisulfonate, 50 mls of acetic anhydride and 1.6 grams of sodium acetate are added to 200 mls of dimethylformamide in a 500 ml flask. The flask is equipped with a condenser having a drying tube and a stirring bar. The contents of the flask are stirred at 50° to 70° C. for one to two hours. The reaction mixture is filtered and the filtrate collected. The filtrate is vacuum evaporated to yield a crude solid product. This crude solid product is extracted into boiling methanol. The volume of the methanol is reduce to 100 mls and cooled. The first batch of product crystallizes out and is filtered. The methanol is again reduced to approximately 20 mls to yield a second crop of product. This is filtered and combined with the first batch and dried for twenty to forty minutes at 60° C.
Reaction SMILES: C(OC([N:11]1C2C=CC=CC=2OC(C=O)C1)=O)C1C=CC=CC=1.C[Si](C(P(OCC)(OCC)=O)C([O-])=O)(C)C.[H-].[Na+].[CH2:41]([O:48][C:49]([N:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH2:54][CH:53]([CH:61]=[CH:62][C:63]([OH:65])=O)[CH2:52]1)=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:41]([O:48][C:49]([N:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH2:54][CH:53]([CH:61]=[CH:62][C:63](=[O:65])[NH2:11])[CH2:52]1)=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(O)C=CC1Cc2ccccc2N(C(=O)OCc2ccccc2)C1
Reactant: O=CC1CN(C(=O)OCc2ccccc2)c2ccccc2O1
Agent: CCOP(=O)(OCC)C(C(=O)[O-])[Si](C)(C)C
Agent: [H-]
Agent: [Na+]
Product: NC(=O)C=CC1Cc2ccccc2N(C(=O)OCc2ccccc2)C1

Procedure:
The reaction of 1.48 g of N-benzyloxycarbonyl-2(R,S)-formyl-3,4-dihydro-2H-1,4-benzoxazine (Example 107) with 2.15 ml of trimethylsilyl-diethylphosphonoacetate and 0.3 g of sodium hydride (80% dispersion in oil) gives, after customary working up, 1.7 g of N-benzyloxycarbonyl-3(R,S)-[(2-carboxy)ethen-1-yl]-1,2,3,4-tetrahydroquinoline. The title compound is obtained therefrom in a manner analogous to that described in Example 1a): Rf (X)=0.47.
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[C:8]([F:11])[C:5]([C:6]#[N:7])=[C:4]([F:12])[C:3]=1[F:13].C[Al](C)C.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C@@:26]([OH:52])([CH2:46][N:47]1[CH:51]=[N:50][CH:49]=[N:48]1)[C@H:27]([S:29][C@@H:30]1[CH2:35][O:34][C@@H:33]([C:36]2[CH:45]=[CH:44][C:39]([C:40](OC)=[O:41])=[CH:38][CH:37]=2)[O:32][CH2:31]1)[CH3:28]>>[C:6]([C:5]1[C:4]([F:12])=[C:3]([F:13])[C:2]([NH:1][C:40](=[O:41])[C:39]2[CH:44]=[CH:45][C:36]([C@H:33]3[O:32][CH2:31][C@H:30]([S:29][C@H:27]([CH3:28])[C@:26]([C:20]4[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=4[F:18])([OH:52])[CH2:46][N:47]4[CH:51]=[N:50][CH:49]=[N:48]4)[CH2:35][O:34]3)=[CH:37][CH:38]=2)=[C:9]([F:10])[C:8]=1[F:11])#[N:7]
Reactant: N#Cc1c(F)c(F)c(N)c(F)c1F
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)cc1
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3c(F)c(F)c(C#N)c(F)c3F)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4), a reaction was carried out using commercially available 4-amino-2,3,5,6-tetrafluorobenzonitrile (227 mg, 1.2 mmol), trimethylaluminium (1.1 ml, 1.07M n-hexane solution, 1.2 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (150 mg, 0.30 mmol), obtained in Example 12(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (84 mg, yield 42%) as a colorless oil which was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]([CH3:42])[CH3:41])[C:35]=1[N:43]=[C:44]=[O:45])([CH3:33])[CH3:32]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:21][CH:22]=2)[C:44]([NH:43][C:35]2[C:34]([CH:31]([CH3:32])[CH3:33])=[CH:39][CH:38]=[CH:37][C:36]=2[CH:40]([CH3:42])[CH3:41])=[O:45])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCc1ccc(NCc2ccc(OCc3ccccc3)cc2)cc1
Product: CCCCCCCCc1ccc(N(Cc2ccc(OCc3ccccc3)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 6.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (4-benzyloxyphenylmethyl)(4-octylphenyl)amine (5.45 g) and 2,6-diisopropylphenyl isocyanate (3.14 g) as starting materials, N-(4-benzyloxyphenylmethyl)-N′-(2,6-diisopropylphenyl)-N-(4-octylphenyl)urea (0.56 g) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][CH:14]=[C:10]3[CH2:9][N:8]([CH3:15])[C:7](=[O:16])[C:6]=2[CH:17]=1.[I:18]I.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([I:18])=[C:10]3[CH2:9][N:8]([CH3:15])[C:7](=[O:16])[C:6]=2[CH:17]=1
Reactant: CN1Cc2cncn2-c2ccc(F)cc2C1=O
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2c(I)ncn2-c2ccc(F)cc2C1=O

Procedure:
2.31 g of 8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at 95° for 1.5 hours with 8.88 g (35 mmol) of iodine in 25 ml of N,N-dimethylformamide. The reaction mixture was then poured into 300 ml of water, decolorized with sodium thiosulphate solution and extracted four times with methylene chloride. The organic extracts were washed three times with water, dried over magnesium sulphate and evaporated. After recrystallization of the residue from ethyl acetate there was obtained 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 187°-188°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C@@H:6](O)[CH3:7])[CH3:2].O=S(Cl)[Cl:12]>C1C=CC=CC=1.[Cl-].[Cl-].[Zn+2]>[CH2:1]([O:3][C:4](=[O:9])[C@H:5]([Cl:12])[CH2:6][CH3:7])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C[C@H](C)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cl)CC
Yield: 65 %

Procedure:
0.24 moles (S)-(+)-3-hydroxy-butyric acid ethyl ester in 100 ml benzene are added to 0.07 moles anhydrous ZnCl2 while agitating and while excluding moisture. Subsequently, 0.72 moles SOCl2 are added, and the product is agitated at room temperature for two days. Then the reaction mixture is treated with saturated NaHClO3 solution. After separating off the aqueous phase, it is dried with Na2SO4. The solvent is distilled off, and the residue is fractionally distilled. One obtains (R)-(-)-chlorobutyric acid ethyl ester with a yield of 65 percent.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH2:16])[N:3]=1.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][CH2:23][OH:24])=[CH:20][CH:19]=1>>[NH2:16][C:4]1[N:3]=[C:2]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([CH2:22][CH2:23][OH:24])=[CH:20][CH:19]=2)[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=1
Reactant: Cc1ccc(C)c(-c2cc(Cl)nc(N)n2)c1
Reactant: Nc1ccc(CCO)cc1
Product: Cc1ccc(C)c(-c2cc(Nc3ccc(CCO)cc3)nc(N)n2)c1

Procedure:
Following the method described in Example 4, 4-chloro-6-(2,5-dimethyl-phenyl)-pyrimidin-2-yl-amine and 4-aminophenethyl alcohol provided the title compound as hydrochloride salt (85% yield). 1H NMR (DMSO-d6) δ 2.29 (s, 6H, CH3), 6.30 (s, 1H, Ar), 7.24-7.31 (m, 5H, Ar), 7.68 (d, 2H, J=8.0 Hz, Ar), 10.67 (s, 1H), 12.54 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])=[O:17])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O.[H][H]>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])=[O:17])[CH2:14][CH2:15]2)=[N:8][CH:9]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nc1
Yield: 86.3 %

Procedure:
A mixture of [4-(5-nitropyridin-2-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)-methanone (0.15 g, 0.4 mmol) and Pd—C (76 mg) in THF (5 mL) and MeOH (5 mL) was exposed to a hydrogen atmosphere at 25° C. for 2 h. The reaction mixture was filtered and the solution was concentrated in vacuo to provide the title compound as a dark purple solid (0.121 g, 86% yield). MS (ES+) m/z 351.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:15])[CH2:13][CH3:14])[C:9]2[C:4](=[C:5]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:25][N:26]=[C:27]=[O:28]>ClC(Cl)C>[CH3:25][NH:26][C:27]([NH:15][CH:12]([C:10]1[C:9]2[C:4](=[C:5]([C:16]3[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=3[CH3:22])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[CH:11]=1)[CH2:13][CH3:14])=[O:28]
Reactant: CN=C=O
Reactant: CCC(N)c1cc(C)nc2c(-c3c(C)cc(C)cc3C)cccc12
Solvent: CC(Cl)Cl
Product: CCC(NC(=O)NC)c1cc(C)nc2c(-c3c(C)cc(C)cc3C)cccc12

Procedure:
A mixture of 1-[2-methyl-8-(2,4,6-trimethyl-phenyl)-quinolin-4-yl]-propylamine (55 mg), methyl isocyanate (0.3 ml), in dichloroethane (1 ml) was heated at 60° C. for 1 hrs. The mixture was quenched with water and extracted with chloroform. The organic layer was separated, dried and concentrated to give the crude material as a colorless oil. The oil was purified by preparative thin layer chromatography using 3% methanol in chloroform as solvent to give 42 mg of the title compound as a white glass foam.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:36])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][CH:30]([C:33]([OH:35])=O)[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.Cl.[CH3:38][NH:39][CH3:40].CCN=C=NCCCN(C)C.Cl.O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][CH2:3][C@H:4]([CH3:36])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][CH:30]([C:33]([N:39]([CH3:40])[CH3:38])=[O:35])[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCC(C(=O)O)O3)[nH]2)c1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NCC(C(=O)N(C)C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.1 %

Procedure:
2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-4,5-dihydro-1,3-oxazole-5-carboxylic acid (154 mg, 0.299 mmol) synthesized in Example (28a) was dissolved in dichloromethane (10 mL), and dimethylamine hydrochloride (75.0 mg, 0.920 mmol), WSCI•HCl (115 mg, 0.600 mmol) and 4-dimethylaminopyridine (110 mg, 0.900 mmol) were added, followed by stirring at room temperature for 2 days under nitrogen atmosphere. Water (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=70%-100%) to afford the desired product (107 mg, yield 66%) as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:3]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:32][S:33]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:5]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1csc(N2CC(O)C2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (350 mg, 0.782 mmol) (obtained as described in Reference Example 52(6)) in methylene chloride (18 ml) were added methanesulfonyl chloride (182 μl, 2.35 mmol) and triethylamine (329 μl, 2.35 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (98:2) as the eluant to afford 3-methanesulfonyloxy-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (410 mg, yield 99%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)[C:13]([Cl:15])=[O:14]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][CH2:9][C:13]([Cl:15])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)OCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of carbonic acid monobenzyl ester (3.50 g, 21.0 mmol) in the 50 ml of DCM and 0.50 ml of DMF was cooled to −78° C. followed by addition of oxalyl chloride (11.79 ml, 105 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. After the completion of the reaction mixture (TLC monitoring), concentrated it to give 2-benzyloxyacetyl chloride (3.0 g, 96%). To an ice cold solution of 3-amino-4-chloro-benzoic acid methyl ester in 10 ml of DCM was added triethylamine (2.47 ml, 17.78 mmol) followed by addition of 2-benzyloxyacetyl chloride (3.0 g, 17.78 mmol) in 10 ml of DCM. The reaction mixture was stirred at 25° C. for 12 hr. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (5:95) as the eluent to provide the title compound (1.70 g, 31%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1)[OH:4].O=[C:18]([CH3:32])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:31][O:30][C:28]([CH2:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH:18]([NH:1][CH2:2][CH:3]([C:5]2[CH:6]=[C:7]([O:15][CH3:16])[C:8]([O:13][CH3:14])=[C:9]([O:11][CH3:12])[CH:10]=2)[OH:4])[CH3:32])=[CH:26][CH:25]=1)=[O:29]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: COc1cc(C(O)CN)cc(OC)c1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cc(OC)c(OC)c(OC)c2)cc1
Yield: 82.3 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(3,4,5-trimethoxyphenyl)ethanol (prepared as described in Preparation 14), 2.35 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 70 ml of benzene, 60 ml of absolute methanol and 4.8 g of sodium cyanoborohydride, 3.14 g of the title compound were obtained having an Rf=0.21 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).