Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:28]=[C:29](F)[CH:30]=1)[CH2:5][C@@H:6]([C@@H:10]([C@H:12]1[CH2:16][C@@H:15](OCC=C)[CH2:14]N1C(OC(C)(C)C)=O)O)C(O)=O.[F:32][C:33]1[CH:34]=[C:35]([CH:49]=[C:50]([F:52])[CH:51]=1)[CH2:36][C@H:37]1[C@@H:41]([CH:42]2[CH2:47][O:46][CH2:45][CH2:44][NH:43]2)[O:40][C:39](=[O:48])[NH:38]1.FC1C=C(C=C(F)C=1)C[C@H](C(N1[C@@H](CC2C=CC=CC=2)COC1=O)=O)[C@@H]([C@H]1C[C@@H](OCC=C)CN1C(OC(C)(C)C)=O)O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:32][C:33]1[CH:34]=[C:35]([CH:49]=[C:50]([F:52])[CH:51]=1)[CH2:36][C@H:37]1[C@@H:41]([C@H:42]2[CH2:47][C@H:45]([OH:46])[CH2:44][N:43]2[CH:5]([C:4]2[CH:3]=[CH:2][CH:30]=[CH:29][CH:28]=2)[C:6]2[CH:10]=[CH:12][CH:16]=[CH:15][CH:14]=2)[O:40][C:39](=[O:48])[NH:38]1
Reactant: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H](C2COCCN2)O1
Reactant: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)N(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Step L (6): (4S,5S)-4-(3,5-Difluorobenzyl)-5-(morpholin-3-yl)oxazolidin-2-one. A solution of tert-butyl 3-((4S,5S)-4-(3,5-difluorobenzyl)-2-oxooxazolidin-5-yl)morpholine-4-carboxylate (step L (5), 230 mg) in CH2Cl2 (4 mL) was treated with TFA (3 mL). This reaction mixture was stirred at rt for 1.5 h. The mixture was then concentrated in vacuo. Diethyl ether (50 mL) was added and the mixture was washed with 1N HCl solution (40 mL) twice. Aqueous layer was neutralized with 50% aqueous NaOH to pH=12. The mixture was extracted with ethyl acetate (80 mL) twice. The combined organic layers were dried (Na2SO4), and concentrated in vacuo to give 180 mg of the title compound: MS (ESI) (M+H)+ 299.17.
Reaction SMILES: C1(C2C=CC(C(OC)=O)=CC=2)C=CC=C(C(OC)=O)C=1.[C:21]1([C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39][CH3:40])=[O:38])=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=1>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C(O)CO>[C:31]12[C:21]3[CH:26]=[CH:25][C:24](=[CH:23][CH:22]=3)[C:27](=[O:28])[O:29][CH2:30][CH2:40][O:39][C:37](=[O:38])[C:34]([CH:35]=[CH:36]1)=[CH:33][CH:32]=2
Reactant: COC(=O)c1ccc(-c2ccc(C(=O)OC)cc2)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: COC(=O)c1ccc(-c2cccc(C(=O)OC)c2)cc1
Solvent: OCCO
Product: O=C1OCCOC(=O)c2ccc(cc2)-c2ccc1cc2
Temperature: 280 °C
Reaction time: 2 h

Procedure:
Dimethyl 3,4'-biphenyldicarboxylate (6.00 g, 0.0222 mole), 18.00 g (0.0666 mole) of dimethyl 4,4'-biphenyldicarboxylate, 12.83 g of ethylene glycol and 20 μL of titanium tetraisopropoxide are added to a 100 mL round bottom flask equipped with a paddle stirrer, 15-cm heated Vigreaux column, distillation head, condenser and graduated receiver. The apparatus is evacuated and refilled with nitrogen three times. A molten salt bath preheated to 220° C. is raised around the flask. After 2 hours, the temperature is slowly increased to 280° C. This takes 41 minutes. During this time, 6.9 mL of distillate is collected. Over the next 34 minutes, the pressure is slowly reduced to 1 mm of Hg and the temperature is raised to 321° C. The excess ethylene glycol is distilled. After an additional 10 minutes, the reaction mass is a viscous clear polymeric melt and the polymerization is stopped. As the molten polymer cools, it solidifies to an opaque off-white solid. The polymer is ground to a course powder in a centrifugal mill. Its inherent viscosity is 1.47 dL/g and its peak melting point as determined by differential scanning calorimetry is 280° C.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])(C)(C)C.[C:31]([C:33]1[CH:41]=[CH:40][C:36](C(Cl)=O)=[CH:35][CH:34]=1)#[N:32].C(N(CC)CC)C.C(OCC)(=O)C>Cl.O1CCOCC1>[C:31]([C:33]1[CH:41]=[CH:40][C:36]([C:6]([NH:8][C@@H:9]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)[CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])=[O:7])=[CH:35][CH:34]=1)#[N:32]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1cccc(C#N)c1)CC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C(=O)N[C@@H](COc2cccc(C#N)c2)CC(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
1.8 g (4.38 mmol) of benzyl (3R)-3-t-butoxycarbonylamino-4-(3-cyanophenoxy)butyrate was dissolved in 20 ml of 4 N solution of hydrogen chloride in dioxane, and the solution was stirred at 0° C. for 6 hours. The solvent was evaporated, and the oily residue was dissolved in 5 ml of dichloromethane. 1.09 g (6.58 mmol) of 4-cyanobenzoyl chloride and 1.22 ml (8.76 mmol) of triethylamine were added to the solution under cooling with ice, and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extractant in an ordinary manner, the crude product was obtained, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:9][NH2:10])=[C:4]([CH3:20])[CH:3]=1.[C:21]([C:23]1[CH:24]=[C:25]([C:33](O)=[O:34])[C:26]2[CH2:27][CH2:28][CH2:29][CH2:30][C:31]=2[CH:32]=1)#[N:22].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:21]([C:23]1[CH:24]=[C:25]([C:33]([NH:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[CH3:20])[CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[O:34])[C:26]2[CH2:27][CH2:28][CH2:29][CH2:30][C:31]=2[CH:32]=1)#[N:22]
Reactant: Cc1cc(F)ccc1C(CN)CCOC1CCCCO1
Reactant: N#Cc1cc2c(c(C(=O)O)c1)CCCC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1cc(F)ccc1C(CCOC1CCCCO1)CNC(=O)c1cc(C#N)cc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
[2-(4-Fluoro-2-methylphenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butyl]amine (0.40 g, 1.4 mmol), 3-cyano-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid (see WO 00/34243; 0.32 g, 1.6 mmol) and DCC (0.35 g, 1.7 mmol) were mixed with CH2Cl2 (5 mL). The mixture was stirred at room temperature overnight and then filtrated and the solvent was evaporated. The product was purified by chromatography on silica gel using methanol and CH2Cl2 (0%-2% methanol). There was obtained 600 mg (91%) of 3-cyano-N-[2-(4-fluoro-2-methylphenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butyl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide as a foam. 1H NMR (500 MHz, CDCl3): 1.0-1.9 (m, 9H), 2.0-2.1 (m, 1H), 2.4 (d, 3H), 2.6-2.8 (m, 4H), 3.2-3.8 (m, 7H), 4.4-4.5 (d, 1H), 6.0-6.2 (m, 1H), 6.9 (m, 2H), 7.1-7.3 (m, 2H), 7.4 (s, 1H). LCMS: m/z 463 (M−1)−.
Reaction SMILES: C(N(CC)CC)C.[C:8](=[O:23])([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)OC1C=CC=CC=1.[N+]([O-])(O)=O.[O:28]([CH2:32][CH2:33][NH2:34])[N+:29]([O-:31])=[O:30]>C(#N)C>[O:28]([CH2:32][CH2:33][NH:34][C:8](=[O:23])[O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[N+:29]([O-:31])=[O:30]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Solvent: O=[N+]([O-])O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCCO[N+](=O)[O-])Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
0.4 ml of triethylamine was added to a suspension of 0.5 g of diphenyl carbonate and 0.4 g of 2-nitroxyethylamine nitrate in 10 ml of acetonitrile. The mixture was stirred at room temperature for 2 hours and was then allowed to stand overnight at room temperature. The solvent was distilled off under reduced pressure, water was added to the residue, and it was extracted with ethyl acetate 3 times. The extracts were dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel (eluent; hexane: ethyl acetate=5:1) to give 0.22 g of the title compound as colorless powdery crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:16]([OH:18])=O)[NH:7]2.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:16]([N:19]1[CH2:24][CH2:23][N:22]([C:16]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=4)=[O:18])[CH2:21][CH2:20]1)=[O:18])[NH:7]2
Reactant: C1CNCCN1
Reactant: COc1cc2[nH]c(C(=O)O)cc2c(OC)c1OC
Product: COc1cc2[nH]c(C(=O)N3CCN(C(=O)c4cc5c(OC)c(OC)c(OC)cc5[nH]4)CC3)cc2c(OC)c1OC

Procedure:
4,5,6-Trimethoxyindole-2-carboxylic acid (290 mg) and piperazine (50 mg) were reacted in the same manner as in Preparation Example 37 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([OH:20])[C:17]([F:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:24]=1[S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C.O>C(Cl)Cl.C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([O:20][S:31]([C:24]2[C:25]([CH3:30])=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=2[CH3:22])(=[O:33])=[O:32])[C:17]([F:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1cc(F)c(OS(=O)(=O)c2c(C)cc(C)cc2C)nc1Nc1ccc(F)cc1F
Yield: 81.9 %

Procedure:
In 10 ml of methylene chloride was suspended 500 mg of methyl 2-(2,4-difluorophenylamino)5-fluoro-6-hydroxynicotinate, and to the resulting suspension were added 440 mg, of 2,4,6-trimethylbenzenesulfonyl chloride and 220 mg of triethylamine, after which the resulting mixture was subjected to reaction at room temperature for 3 hours. To this solution was added 15 ml of water, and the organic layer was separated, washed with 15 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 15 ml of diethyl ether, after which crystals were collected by filtration to obtain 660 mg (yield 81.9%) of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-(2,4,6-trimethylbenzenesulfonyloxy)nicotinate having a melting point of 153°-155° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[CH:8][CH:7]=1.[OH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[CH:14]1([C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:20]3[CH2:21][CH2:22][C@@H:18]([OH:17])[CH2:19]3)=[CH:7][CH:8]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: O=C(c1ccc(OCCCCl)cc1)C1CC1
Reactant: O[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(c1ccc(OCCCN2CC[C@@H](O)C2)cc1)C1CC1
Yield: 62 %

Procedure:
(4-(3-Chloropropoxy)phenyl)(cyclopropyl)methanone (150 mg, 0.63 mmol), 3-(3R)-hydroxypyrrolidine (55 mg, 0.63 mmol), potassium carbonate (152 mg) and potassium iodide (183 mg) in 25 mL of 2-butanone were heated at 110° C. for 72 hours. The mixture was evaporated under reduced pressure and the residue was purified by chromatography (CHCl3:MeOH:NH4OH, 9:1:0.1) to provide the title compound (62% yield).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:28][CH3:29])=[C:13](/[C:15](/[C:22]2[S:23][C:24]([CH3:27])=[CH:25][N:26]=2)=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:14]=1)C1C=CC=CC=1.CC(O)=O.O>CCO.C1COCC1.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:28][CH3:29])=[C:13]([CH:15]([C:22]2[S:23][C:24]([CH3:27])=[CH:25][N:26]=2)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:14]=1
Reactant: CCOC(=O)/C=C(\c1ncc(C)s1)c1cc(OCc2ccccc2)ccc1OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC(c1ncc(C)s1)c1cc(O)ccc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.3 %

Procedure:
To a mixture of (Z)-ethyl 3-(5-(benzyloxy)-2-methoxyphenyl)-3-(5-methylthiazol-2-yl)acrylate (4.0 g, 9.8 mmol), HOAc (2.0 mL), and H2O (5.0 mL) in EtOH (100 mL) and THF (60 mL) was added Pd/C (10%, dry, 5.0 g) under nitrogen atmosphere. The mixture was stirred at room temperature under H2 atmosphere for 48 hrs. After filtration through a pad of Celite and evaporation of the solvent, the residue was purified by silica gel chromatography eluting with petroleum ether/EtOAc (3:1) to afford ethyl 3-(5-hydroxy-2-methoxyphenyl)-3-(5-methylthiazol-2-yl)propanoate (1.9 g, 60%) as a yellow-green gel.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:36]2[S:40][C:39]([C:41]3([O:45]COC)[CH2:44][CH2:43][CH2:42]3)=[N:38][CH:37]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][CH:21]([F:24])[CH2:20][CH2:19]4)=[C:13]([F:25])[CH:12]=3)[N:8]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.Cl>CO>[Cl:1][C:2]1[C:3]([C:36]2[S:40][C:39]([C:41]3([OH:45])[CH2:44][CH2:43][CH2:42]3)=[N:38][CH:37]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][CH:21]([F:24])[CH2:20][CH2:19]4)=[C:13]([F:25])[CH:12]=3)[N:8]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3ccc(CN5CCC(F)CC5)c(F)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2c(-c3ccc(CN4CCC(F)CC4)c(F)c3)cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc32)cc1
Temperature: 60 °C

Procedure:
A 4 mL reaction vial was charged with 5-(5-chloro-2-(3-fluoro-4-((4-fluoropiperidin-1-yl)methyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(1-(methoxymethoxy)cyclobutyl)thiazole (Example 30B) (60.6 mg, 0.085 mmol), methanol (1.0 mL) and 2 normal aqueous hydrochloric acid solution (0.200 ml, 0.658 mmol). The mixture was heated to 60° C. for about 2 hours, and then to 40° C. overnight. The reaction was cooled to room temperature, and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×1 mL). The combined organics were concentrated to give the title compound, which was used without further purification. MS APCI(+) m/z 669.33 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])O[C:3]1([O:17]C)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[CH3:19][C:2]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:17]
Reactant: C1COCCN1
Reactant: COC1(c2ccc(N3CCCCC3)cc2)OC1(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C(=O)c1ccc(N2CCCCC2)cc1)N1CCOCC1
Temperature: 130 °C

Procedure:
12.1 g (46.3 mmol) of 3,3-dimethyl-2-methoxy-2-(4-piperidinophenyl)-oxirane and 26.1 g (0.30 mol) of morpholine are added together, and the mixture is heated to the refluxing temperature (about 130° C.). After 6 hours the mixture is cooled down and the morpholine is dissolved off under reduced pressure. The residue is taken up in toluene and is extracted with dilute hydrochloric acid. The hydrochloric acid solution is rendered alkaline and is extracted with toluene. The toluene solution is dried with K2CO3 and concentrated. The residue is recrystallised from methanol. Melting point 159°-162° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:43])([CH3:42])[CH:5]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]=2)=[CH:26][CH:25]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:8][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH3:42][C:4]([CH3:43])([CH:5]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]=2)=[CH:26][CH:25]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:8][CH:7]=1)[CH2:3][OH:2]
Reactant: COC(=O)C(C)(C)C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO)C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
To a stirred solution in THF (50 mL) at ambient temperature of 2,2-dimethyl-3,3-bis(4-(2-quinolylmethoxy)phenyl)propionic acid methyl ester (1.33 g, 2.28 mmole), prepared as in Example 26, step 2, was added LiAlH4 (0.09 g, 2.5 mmol) in a single portion. The mixture was stirred 3 hours at ambient temperature. Water (0.1 mL) was added followed by aqueous 1N NaOH (0.1 ml) and water (0.5 mL). The mixture was then concentrated to dryness and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by chromatography on silica gel (60% ethylacetate/hexanes) gave 1.01 g (80%) of 2,2-dimethyl-3,3-bis(4-(2-quinolylmethoxy)phenyl)-propan-1-ol as a yellow foam.
Reaction SMILES: Br[CH2:2][CH2:3][Cl:4].[SH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:4][CH2:3][CH2:2][S:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1
Reactant: ClCCBr
Reactant: Sc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCSc1nccs1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
1.2 cm3 of 1-bromo-2-chloroethane were run, at a temperature in the region of 20° C., into a stirred solution of 1.47 g of 2-mercaptothiazole and 1.95 g of potassium carbonate in 12.5 cm3 of dimethylformamide. The mixture was subsequently stirred for 2 hours at a temperature in the region of 20° C. The insoluble material was filtered off and washed with 2 times 5 cm3 of dimethylformamide. The filtrate was run onto a mixture of 50 g of crushed ice and 50 cm3 of distilled water, 50 cm3 of ethyl ether were then added and the mixture was stirred and then separated by settling. The aqueous phase was separated by settling and then extracted with 2 times 25 cm3 of ethyl ether. The combined ethereal phases were washed with 2 times 25 cm3 of water and then dried over magnesium sulfate. After filtering through paper, the organic solution was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 2.11 g of 2-(2-chloroethylthio)thiazole were obtained in the form of a mobile oil with a yellow color.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH2:14][CH:15]=[CH2:16])[C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[CH:1]([C:3]1[CH:4]=[C:5]([CH2:14][CH:15]=[CH2:16])[C:6]([O:13][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C=CCc1cc(C=O)cc(C(=O)OC)c1O
Product: C=CCc1cc(C=O)cc(C(=O)OC)c1OCC(=O)OC(C)(C)C

Procedure:
Phenol 36b was alkylated with t-butyl bromoacetate the usual way to give a yellow oil (quant.). 1H-NMR (300 MHz, CDCl3): 9.94 (s, 1H), 8.21 (d, 1H, J=2 Hz), 7.90 (d, 1H, J=9 Hz), 6.05-5.92 (m, 1H), 5.15-5.05 (m, 2H), 4.51 (s, 2H), 3.93 (s, 3H), 3.61 (br d, 2H, J=7 Hz), 1.49 (s, 9H). Anal. Calc'd for C18H22O6 : C, 64.66; H, 6.63; Found: C, 64.54; H, 6.62.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[O-2].[Zn+2:7].[Zn].C(O)C(O)C>O>[NH2:1][CH2:2][C:3]([O-:5])=[O:4].[Zn+2:7].[NH2:1][CH2:2][C:3]([O-:5])=[O:4]
Reactant: NCC(=O)O
Agent: [O-2]
Agent: [Zn+2]
Agent: [Zn]
Solvent: CC(O)CO
Solvent: O
Product: NCC(=O)[O-]
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Thirty five (35.0) pounds of water were added to a 22 liter vessel and heated to 90° C. Glycine (4.337 lbs.) was then added with stirring, and the solution was heated to 95° C. Zinc oxide (1.766 lbs.) was then added with stirring and heating continued for two hours until the solution was clear (gly/Zn=2.7/1; PG/Zn=3.0/1). Propylene glycol (4.94 lbs.) was then added and heating continued for an additional one-half hour.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:34]1[CH:39]=[CH:38][C:37]([C:40]2([NH2:43])[CH2:42][CH2:41]2)=[N:36][CH:35]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:43][C:40]5([C:37]6[CH:38]=[CH:39][N:34]=[CH:35][N:36]=6)[CH2:42][CH2:41]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NC1(c2ccncn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccncn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.096 g, 0.221 mmol, 1.0 eq), 1-(pyrimidin-4-yl)cyclopropanamine HCl (0.03 g, 0.221 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.12 g, 1.188 mmol, 5.0 eq) and BOP reagent (0.146 g, 0.330 mmol, 1.5 eq). The reaction mixture was stirred as RT overnight. The reaction mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 3% MeOH/CHCl3 as eluent. Yield: 0.070 g (57.33%). 1H NMR (400 MHz, CD3OD): δ 8.99 (d, J=1.0 Hz, 1H), 8.61 (d, J=5.6 Hz, 1H), 7.99-7.93 (m, 2H), 7.79 (s, 1H), 7.69-7.54 (m, 3H), 7.39-7.23 (m, 3H), 7.16 (s, 1H), 4.08 (s, 3H), 2.96 (s, 3H), 2.34 (s, 3H), 1.85-1.82 (m, 2H), 1.61-1.49 (m, 2H).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1>C1COCC1.O.C(N(CC)CC)C.C(#N)C>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:45][CH2:46][CH2:47][N:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)=[O:14])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reactant: NCCN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCN1CCCCC1)c1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 4-(4-biphenylylmethoxy)benzoic acid (1.008 g) in THF (20 ml)/acetonitrile (20 ml) were added WSC (0.775 g), HOBt (0.504 g), 1-(2-aminoethyl)piperidine (0.56 ml), and triethylamine (1.2 ml). After stirring at room temperature for 17 hr, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 10% aqueous potassium carbonate and saturated aqueous sodium chloride sequentially, dried, and concentrated. The residue was recrystallized from ethyl acetate/diisopropyl ether to obtain the titled compound (0.993 g).