Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4](OCC(N)=O)=[N:5][C:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].C[N:26](C)C=O>O.C(OCC)(=O)C>[NH2:26][C:4]1[N:5]=[C:6]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1ccc(-c2ccco2)nc1OCC(N)=O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(-c2ccco2)nc1N
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
A suspension of 2-[[3-cyano-6-(2-furyl)-2-pyridyl]oxy]acetamide (8.0 g, 32.9 mmol) and potassium carbonate (9.1 g, 65.9 mmol) in N,N-dimethylformamide (80 ml) was stirred at 120° C. for 1.5 hours. After cooling as it was, the reaction solution was diluted with water and ethyl acetate, and the insoluble matters were filtered off. The aqueous layer in the filtrate was extracted with ethyl acetate. The combined organic layer was washed with an aqueous saturated solution of ammonium chloride (×2), dried over anhydrous sodium sulfate, and concentrated. The residue was suspended in methanol, and the resulting solid was collected by filtration and washed with methanol, to give the title compound (3.81 g, 63%) as a brown solid.
Reaction SMILES: [F-].[K+].[Br:3][C:4]1[C:11]([OH:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.O>CS(C)=O>[Br:3][C:4]1[C:11]([O:12][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: COc1ccc(C=O)c(Br)c1O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(C=O)c(Br)c1Oc1ccc([N+](=O)[O-])cc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
To a stirred suspension of potassium fluoride (1.89 gm, 0.0326 mol) in dry DMSO (10 ml) was added a solution of 2-bromoisovanillin (5.0 gm, 0.0217 mol) in DMSO (10 ml). A solution of 4-fluoronitrobenzene (5.0 gm, 0.0260 mol) in DMSO (5 ml) was added to the above suspension and the reaction mixture was stirred at 140° C. for 4 h. The reaction mixture was cooled to room temperature and the contents were poured into water (150 ml) and extracted with ethyl acetate (50 ml×3). The organic extracts were combined and washed with 1N sodium hydroxide (25 ml×2), water and brine and dried over anhydrous sodium sulfate. The dried organic layer was concentrated in vacuo and the residue was purified by silica-gel column chromatography using 20% ethyl acetate-petroleum ether as the eluent to give 2-bromo-3-(p-nitrophenoxy)-4-methoxy benzaldehyde as a pale yellow solid (5.0 gm) mp: 132-140° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]1)=[CH:11][C:10]([C:29]1[CH:34]=[C:33]([O:35][CH3:36])[C:32]([OH:37])=[C:31]([Cl:38])[CH:30]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>>[NH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([NH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:29]4[CH:34]=[C:33]([O:35][CH3:36])[C:32]([OH:37])=[C:31]([Cl:38])[CH:30]=4)[CH:11]=3)[N:6]=[CH:5][C:4]=2[C:1](=[O:3])[CH3:2])[CH2:16][CH2:17]1
Reactant: COc1cc(-c2ccc3ncc(C(C)=O)c(N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c3c2)cc(Cl)c1O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2ccc3ncc(C(C)=O)c(N[C@H]4CC[C@H](N)CC4)c3c2)cc(Cl)c1O

Procedure:
Following general procedure A-2, tert-butyl trans-4-[3-acetyl-6-(3-chloro-4-hydroxy-5-methoxyphenyl)quinolin-4-ylamino]cyclohexylcarbamate (35 mg, 0.065 mmol) was reacted with TFA (2 mL) to afford the desired product (13.6 mg, 48%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 8.95 (s, 1H), 8.32 (d, J=1.8 Hz, 1H), 8.04 (dd, J=8.7, 1.9 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.27 (d, J=2.1 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 4.23 (t, J=11.1 Hz, 1H), 3.99 (s, 3H), 3.24-3.16 (m, 1H), 2.70 (s, J=6.3 Hz, 3H), 2.41 (d, J=12.4 Hz, 2H), 2.18 (d, J=12.1 Hz, 2H), 1.80-1.66 (m, 2H), 1.61-1.50 (m, 2H); ESI MS m/z 440 [C24H26ClN3O3+H]+; HPLC 97.6% (AUC), tR=8.45 min.
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][NH:4][CH2:5][CH:6]([OH:8])[CH3:7].C1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=C[C:19](S(O)(=O)=O)=[CH:18][CH:17]=1>O.C(C(C)=O)C(C)C>[CH3:19][C:18]1([CH2:17][CH:16]([CH3:26])[CH3:21])[N:4]([CH2:5][CH:6]([OH:8])[CH3:7])[CH2:3][CH:2]([CH3:1])[O:9]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(O)CNCC(C)O
Solvent: CC(=O)CC(C)C
Solvent: O
Solvent: c1ccccc1
Product: CC(C)CC1(C)OC(C)CN1CC(C)O

Procedure:
A reaction vessel equipped with a thermometer, a stirrer and a condenser having a water separator was charged with 133 g of diisopropanolamine, 100 g of benzene, 120 g of methyl isobutyl ketone and p-toluenesulfonic acid. The content was heated to reflux and reacted for another 5 hours with removing water. Benzene was removed under a reduced pressure and then distilled at 75° to 79° C./1 mmHg to obtain 152 g of 2-methyl-2-isobutyl-3-(2-hydroxypropyl)-5-methyloxazolidine.
Reaction SMILES: C1(CNC(C2NC=C(C(C3[C:16]([C:21]4[CH:26]=[CH:25][C:24](F)=CC=4)=[N:17]OC=3C)=O)C=2)=O)CC1.[F:28][C:29]1[CH:30]=[C:31]([C:37]2[C:41]([C:42]([C:44]3[CH:45]=[C:46]([C:49](=[O:54])C(Cl)(Cl)Cl)[NH:47][CH:48]=3)=[O:43])=[C:40]([CH3:55])[O:39][N:38]=2)[CH:32]=[C:33]([F:36])[C:34]=1[F:35].C1(N)CCCC1>>[CH:16]1([NH:17][C:49]([C:46]2[NH:47][CH:48]=[C:44]([C:42]([C:41]3[C:37]([C:31]4[CH:30]=[C:29]([F:28])[C:34]([F:35])=[C:33]([F:36])[CH:32]=4)=[N:38][O:39][C:40]=3[CH3:55])=[O:43])[CH:45]=2)=[O:54])[CH2:21][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1c[nH]c(C(=O)NCC2CC2)c1
Reactant: Cc1onc(-c2cc(F)c(F)c(F)c2)c1C(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Agent: NC1CCCC1
Product: Cc1onc(-c2cc(F)c(F)c(F)c2)c1C(=O)c1c[nH]c(C(=O)NC2CCCC2)c1

Procedure:
According to the procedure described for the synthesis of 4-(5-methyl-3-(4-fluorophenyl)-isoxazole-4-carbonyl)-1H-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (example 229, step 2), the title compound has been synthesized from 4-[3-(3,4,5-trifluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-2-trichloroacetyl-1H-pyrrole (intermediate 18) and cyclopentylamine (commercially available) in 49.6 yield. (m/e): 418.3 (MH+; 100%).
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([O:13][CH2:14][C:15]([OH:18])([CH3:17])[CH3:16])[C:7]([CH3:20])([CH3:19])[CH2:6]1)[CH:2]=[CH2:3].[CH2:21]([SiH:23]([CH2:25][CH3:26])[CH3:24])[CH3:22]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[OH:18][C:15]([CH3:17])([CH3:16])[CH2:14][O:13][N:8]1[C:7]([CH3:20])([CH3:19])[CH2:6][CH:5]([O:4][CH2:1][CH2:2][CH2:3][Si:23]([CH2:25][CH3:26])([CH2:21][CH3:22])[CH3:24])[CH2:10][C:9]1([CH3:12])[CH3:11]
Reactant: C=CCOC1CC(C)(C)N(OCC(C)(C)O)C(C)(C)C1
Reactant: CC[SiH](C)CC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CC[Si](C)(CC)CCCOC1CC(C)(C)N(OCC(C)(C)O)C(C)(C)C1

Procedure:
A mixture of 28.5 g (0.10 mol) of the compound obtained in Example 17, 14.5 ml (0.10 mol) of diethylmethylsilane, and 1 ml of a solution of 2% hydrogen hexachloroplatinate(IV) in isopropyl alcohol is heated at reflux for 4 hours. The reaction mixture is distilled under vacuum to obtain a viscous, pale yellow oil. Mass spectroscopy reveals that the reaction product has a molecular ion of 387, which is consistent with formation of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH:20]=1)[CH:18]=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:18][C:17]3[CH:20]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=3[F:21])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1cc(Cl)ccc1F
Product: O=C1Nc2cc(Cl)ccc2C1=Cc1cc(Cl)ccc1F

Procedure:
In a manner similar to the methods described in Examples 1a and 1b, 6-chloro-1,3-dihydro-indol-2-one (Aldrich) reacted with 5-chloro-2-fluoro-benzaldehyde to give 6-chloro-3-[1-(5-chloro-2-fluoro-phenyl)-methylidene]-2-oxo-2,3-dihydro-indole, which was subsequently protected with (t-BuOCO)2O and DMAP.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]2([C:15](=[N:16][O:17][CH3:18])[CH2:14][N:13]([C:19]3[C:28]([Cl:29])=[C:27]4[C:22]([C:23](=[O:36])[C:24]([C:33]([OH:35])=[O:34])=[CH:25][N:26]4[CH:30]4[CH2:32][CH2:31]4)=[CH:21][C:20]=3[F:37])[CH2:12]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.N1C=CC=CC=1.O>ClCCl>[CH:30]1([N:26]2[C:27]3[C:22](=[CH:21][C:20]([F:37])=[C:19]([N:13]4[CH2:14][C:15](=[N:16][O:17][CH3:18])[C:10]5([CH2:11][NH:8][CH2:9]5)[CH2:12]4)[C:28]=3[Cl:29])[C:23](=[O:36])[C:24]([C:33]([OH:35])=[O:34])=[CH:25]2)[CH2:31][CH2:32]1
Reactant: CON=C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CC12CN(C(=O)OC(C)(C)C)C2
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CON=C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CC12CNC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7-[2-(t-butoxycarbonyl)-8-(methoxyimino)-2,6-diazaspiro[3,4]oct-6-yl]-1-cyclopropyl-6-fluoro-8-chloro-4-oxo-1,4-dihydro-3-quinolinecaboxylic acid was dissolved in 5 ml of dichloromethane and thereto 0.2 ml of trifluoroacetic acid was added dropwise. The mixture was stirred for 18 hours at room temperature, and thereto 10 ml of pyridine and 10 ml of water were added. It was distilled under the reduced pressure to remove dichloromethane and stirred for 1 hour. The precipitated solid was filtered and dried to give the titled compound (67 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]2[S:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=3)=[N:12][N:13]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:28][N:29]1[CH2:34][CH2:33][CH:32]([C:35]([O:37]CC)=[O:36])[CH2:31][CH2:30]1)[CH3:2].[OH-].[Na+].Cl>C(O)(C)C.O>[CH2:1]([C:3]1[C:8]([C:9]2[S:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=3)=[N:12][N:13]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:28][N:29]1[CH2:30][CH2:31][CH:32]([C:35]([OH:37])=[O:36])[CH2:33][CH2:34]1)[CH3:2]
Reactant: CCOC(=O)C1CCN(Cc2cccc(-c3nnc(-c4ccc(OC(C)C)c(C(F)(F)F)c4)s3)c2CC)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCc1c(CN2CCC(C(=O)O)CC2)cccc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
To a solution of ethyl 1-[(2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}phenyl)methyl]-4-piperidinecarboxylate (D7) (130 mg) in isopropanol (5 mL) and water (5 mL) was added sodium hydroxide (50 mg). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized with 2N HCl till pH ˜6.0. The mixture was extracted with EA/THF for 3 times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated and the residue was purified by Mass Directed AutoPrep to give 1-[(2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}phenyl)methyl]-4-piperidinecarboxylic acid (E1) (50 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.10 (3H, t), 1.33 (6H, d), 1.54 (2H, m), 1.77 (2H, m), 2.06 (2H, m), 2.22 (1H, m), 2.76 (2H, m), 2.91 (2H, m), 4.93 (1H, m), 7.34 (1H, m), 7.51 (3H, m), 8.23 (2H, m), 12.13 (1H, br s). δF (DMSO-d6, 376 MHz): −61.3. MS (ES): C27H39F3N3O3S requires 533. found 534.2 (M+H+).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[O:8][C@H:7]1[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=O.[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30]>>[CH2:5]([CH:6]1[O:8][CH:7]1[CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH:7]1[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[O:8]1)=[O:21])[CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCC[C@H]1O[C@H]1C/C=C\CCCCCCCC(=O)OC
Reactant: NCCCCCCN
Product: CCCCCC1OC1CC=CCCCCCCCC(=O)NCCCCCCNC(=O)CCCCCCCC=CCC1OC1CCCCC

Procedure:
Precursor 9 was prepared from methyl vernolate and 1,6-diaminohexane according to the procedure described in Example 1(f) and shown in Scheme 11.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=O.[NH2:20][CH:21]([CH:24]([OH:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:22][OH:23]>C(OCC)(=O)C.CCCCCCC>[OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([NH:20][CH:21]([CH:24]([OH:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:22][OH:23])=[O:5]
Reactant: CCCCCCCCCCCCCCC(O)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(O)C(N)CO
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCC(O)C(CO)NC(=O)C(O)CCCCCCCCCCCCCC
Yield: 70 %

Procedure:
4.9 g (0.018 mol) of 2-hydroxyhexadecanoic acid and 5.4 g (0.018 mol) of 2-aminooctadecane-1,3-diol were mixed in a glass tube; the mixture was irradiated with microwaves with the aid of a Synthewave 402™ apparatus from Prolabo--frequency 2450±50 MHz--modulable power rating 300 W. After an irradiation of 15 minutes at 155° C.±5° C., the reaction mixture was solubilized at high temperature in a mixture of 80 ml of ethyl acetate and 20 ml of heptane. The precipitate obtained was recrystallized from ethanol and 7 g of expected pure product were obtained with a yield of 70%.
Reaction SMILES: F.F.F.C(N(CC)CC)C.[C:11]([NH:14][CH2:15][CH2:16][CH2:17][S:18]([O:21][CH2:22][C:23]([CH3:45])([CH3:44])[C@@H:24]([O:36][Si](C)(C)C(C)(C)C)[C:25]([O:27][CH2:28][C:29]1[O:30][C:31](=[O:35])[O:32][C:33]=1[CH3:34])=[O:26])(=[O:20])=[O:19])(=[O:13])[CH3:12]>O1CCCC1>[C:11]([NH:14][CH2:15][CH2:16][CH2:17][S:18]([O:21][CH2:22][C:23]([CH3:45])([CH3:44])[C@@H:24]([OH:36])[C:25]([O:27][CH2:28][C:29]1[O:30][C:31](=[O:35])[O:32][C:33]=1[CH3:34])=[O:26])(=[O:19])=[O:20])(=[O:13])[CH3:12]
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)OCc1oc(=O)oc1C
Agent: F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCc1oc(=O)oc1C
Temperature: 55 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
Following the general procedure for the cleavage of silyl ethers with triethylamine trihydrofluoride of Description 20, a mixture of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl (2R)-4-{[(3-acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(1,1,2,22-tetramethyl-1-silapropoxy)butanoate (48a) (100 mg, 0.18 mmol) and triethylamine trihydrofluoride (Et3N.3HF) 150 μL (149 mg, 0.93 mmol) in 2 mL of tetrahydrofuran (THF) was stirred overnight at ca. 50-60° C. (oil bath). After work-up and further purification by mass-guided preparative HPLC and lyophilization of the solvents, 6.2 mg (8.1% yield) of the title compound (48) was obtained as a colorless, viscous oil. 1H NMR (400 MHz, CDCl3): δ=1.03 (s, 3H), 1.11 (s, 3H), 2.01 (s, 3H), 2.04-2.11 (m, 2H), 2.22 (s, 3H), 3.10-3.23 (m, 2H), 3.31-3.46 (m, 2H), 4.00 (d, J=9.2 Hz, 1H), 4.07-4.10 (m, 2H), 4.93 (d, J=14.0 Hz, 1H), 5.03 (d, J=13.6 Hz, 1H), 5.86-5.88 (br. m, 1H) ppm. MS (ESI) m/z 424.01 (M+H)+, 446.01 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][C:21]([CH2:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([OH:29])=O)=[N:20][N:19]=2)=[CH:14][CH:13]=1)#[N:11].Br.Br.[N:35]1([C@H:41]2[CH2:50][CH2:49][C:44]3[N:45]=[C:46]([NH2:48])[S:47][C:43]=3[CH2:42]2)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>CN(C)C(=O)C.O.C(Cl)CCl>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][C:21]([CH2:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([NH:48][C:46]3[S:47][C:43]4[CH2:42][C@@H:41]([N:35]5[CH2:36][CH2:37][O:38][CH2:39][CH2:40]5)[CH2:50][CH2:49][C:44]=4[N:45]=3)=[O:29])=[N:20][N:19]=2)=[CH:14][CH:13]=1)#[N:11]
Reactant: N#Cc1ccc(-c2nnc(Cc3cccc(C(=O)O)c3)o2)cc1
Reactant: Nc1nc2c(s1)C[C@@H](N1CCOCC1)CC2
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(-c2nnc(Cc3cccc(C(=O)Nc4nc5c(s4)C[C@@H](N4CCOCC4)CC5)c3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.8 %

Procedure:
Add N,N-diisopropylethyl amine (0.17 mL, 0.95 mmol), 7-aza-hydroxybenzotriazole (0.040 g, 0.29 mmol) and EDC (0.06 g (0.31 mmol) to a solution of 3-[5-(4-cyano-phenyl)-[1,3,4]oxadiazol-2-ylmethyl]-benzoic acid (0.106 g, 0.24 mmol) in 3 mL of N,N-dimethylacetamide. Stir the mixture at room temperature for 1 h then add (S)-6-morpholin-4-yl-4,5,6,7-tetrahydro-benzothiazol-2-ylamine dihydrobromide (0.12 g, 0.30 mmol) in one portion and heat overnight at 60° C. Cool the reaction mixture to room temperature and dilute with H2O. Add an aqueous solution of sodium bicarbonate until the pH of the solution is alkaline causing a solid to precipitate from solution. Collect the solid by filtration, wash with H2O and dry on the filter pad. Purify the isolated material by preparative reverse phase HPLC to give 0.02 g, 13% yield of 3-[5-(4-cyano-phenyl)-1,3,4-oxadiazol-2-ylmethyl]-N—((S)-6-morpholin-4-yl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-benzamide as a white powder. MS, ES+ 527.67 (M+H), rt 1.24 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13](Br)=[C:12]([CH3:15])[N:11]([CH3:16])[N:10]=2)=[CH:5][C:4]=1[CH3:17].O1CCOC[CH2:19]1.CB(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH3:19])=[C:12]([CH3:15])[N:11]([CH3:16])[N:10]=2)=[CH:5][C:4]=1[CH3:17]
Reactant: COc1ccc(-c2nn(C)c(C)c2Br)cc1C
Reactant: C1COCCO1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB(O)O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2nn(C)c(C)c2C)cc1C

Procedure:
A mixture of 3-(4-methoxy-3-methyl-phenyl)-4-bromo-1,5-dimethyl-1H-pyrazole (described in Reference Preparation example 64) 1.3 g, 1,4-dioxane 30 ml, water 5 ml, methylboronic acid 1.0 g, 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane adducts 0.4 g and potassium phosphate 3.7 g was stirred with heating under reflux for nine hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 3-(4-methoxy-3-methyl-phenyl)-1,4,5-trimethyl-1H-pyrazole 0.6 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C)=[O:26])=[C:20]([F:29])[CH:19]=3)=[CH:13][CH:14]=2)[C:9]([CH3:31])([CH3:30])[CH2:8][CH:7]=1)=[O:5])[CH3:2].[OH-].[Li+]>C(O)C.O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[C:20]([F:29])[CH:19]=3)=[CH:13][CH:14]=2)[C:9]([CH3:30])([CH3:31])[CH2:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CCC(C)(C)c2cc(C#Cc3ccc(CC(=O)OC)c(F)c3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C1=CCC(C)(C)c2cc(C#Cc3ccc(CC(=O)O)c(F)c3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 27.3 %

Procedure:
A solution of 6-(3-fluoro-4-methoxycarbonylmethyl-phenylethynyl)-4,4-dimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 204, 0.15 g, 0.36 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with a 2M solution of lithium hydroxide (1.5 mL, 3 mmol) and the resulting reaction mixture was stirred at ambient temperature for 1.5 h. The volatiles were evaporated in vacuo, the residue was neutralized with saturated aqueous ammonium chloride solution and extracted with diethyl ether and ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that was purified by preparative reverse phase HPLC using 5% water in acetonitrile as the mobile phase to afford the title product (0.04 g, 27%). 1H NMR (300 MHz, CDCl3): δ 7.81 (d, J=8.2 Hz, 1H), 7.46 (d, J=1.7 Hz, 1H), 7.37 (dd, J=8.2 &1.7 Hz, 1H), 7.27-7.09 (m, 3H), 7.07 (t, J=4.8 Hz, 1H), 4.31 (q, J=7.0 Hz, 2H), 3.66 (s, 2H), 2.33 (d, J=4.8 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H), 1.27 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]5[NH:30][N:31]=[CH:32][C:25]=45)=[CH:19][CH:18]=3)=[O:15])=[CH:9][C:8]=2[C:33]([F:36])([F:35])[F:34])=[CH:4][CH:3]=1.[C:39](O)(=[O:42])[CH:40]=[O:41]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C:40]([OH:41])=[C:39]([OH:42])[N:16]([C:17]4[CH:18]=[CH:19][C:20]([O:23][C:24]5[CH:29]=[CH:28][N:27]=[C:26]6[NH:30][N:31]=[CH:32][C:25]=56)=[CH:21][CH:22]=4)[C:14]3=[O:15])=[CH:9][C:8]=2[C:33]([F:35])([F:36])[F:34])=[CH:37][CH:38]=1
Reactant: O=CC(=O)O
Reactant: O=C(Nc1ccc(Oc2ccnc3[nH]ncc23)cc1)Nc1ccc(Oc2ccc(F)cc2)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: O=c1n(-c2ccc(Oc3ccnc4[nH]ncc34)cc2)c(O)c(O)n1-c1ccc(Oc2ccc(F)cc2)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 7 %

Procedure:
1-[4-(4-Fluorophenoxy)-3-trifluoromethyl-phenyl]-3-[4-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl]urea (50 mg, 0.15 mmol) was dissolved in toluene (6 mL), and glyoxylic acid (45 μL) was added thereto, followed by stirring for 2 hours at 100° C. The reaction solution was concentrated and purified by reverse-phase HPLC (ODS column, 0.05% TFA-containing water/acetonitrile system, 5% to 95% linear gradient) to give the target product (6 mg, 7%).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15]([C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][N:18]=1)=[O:16].Cl>C(O)C.[OH-].[Na+]>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([CH2:4][C:3]([OH:24])=[O:2])=[C:6]([C:15]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][N:18]=3)=[O:16])[NH:7]2)=[CH:12][CH:11]=1
Reactant: COC(=O)Cc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12
Temperature: 50 °C
Yield: 93.3 %

Procedure:
A suspension of methyl[6-chloro-2-[4-chloropyridine-2-carbonyl]-1H-indol-3-yl]acetate (Example 33, 195 mg, 0.537 mmol) in ethanol (20 ml) and 2N sodium hydroxide (4 ml) was heated for 1 h at 50° C. After cooling to room temperature, 2N hydrochloric acid (4 ml) was added and the mixture was concentrated. The residue was diluted in ethyl acetate (100 ml), washed with water (50 ml×2), and dried (MgSO4). After removal of solvent, the crystalline residue was recrystallized from ethyl acetate to afford 175 mg (94%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.O1CCCC1.B.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: OCCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 3-(4-bromophenyl)propionic acid (1.0 g) in tetra hydrofuran (15 mL) was added borane tetra hydrofuran complex (1.0 mol/L tetra hydrofuran solution, 6.55 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 20% aqueous potassium carbonate solution under ice-cooling, and the resulting mixture was extracted with ethylacetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 3-(4-bromophenyl)propanol (0.93 g). The title compound was prepared in a similar manner to that described in Reference Example 55 using this material instead of 2-(4-bromo-phenyl)ethanol.