Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15](Cl)=[N:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:28].C([O-])(O)=O.[Na+]>C(O)CO>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15]([NH2:28])=[N:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: Fc1cc2c(Cl)nccc2cc1N(Cc1ccccc1)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Product: Nc1nccc2cc(N(Cc3ccccc3)Cc3ccccc3)c(F)cc12
Temperature: 165 °C
Yield: 99 %

Procedure:
To a steel bomb charged with N,N-dibenzyl-1-chloro-7-fluoroisoquinolin-6-amine (3.953 g, 10.49 mmol, see WO 2007/002313 for preparation) was added 15 mL of 7N NH3 in ethylene glycol (prepared by condensing ammonia in ethylene glycol) and the reaction sealed and heated at 165° C. overnight (20 h). The reaction mixture was poured into sat. NaHCO3 (200 mL) and extracted with DCM (3×200 mL). The combined organics were washed with brine (150 mL) and dried (Na2SO4), filtered and concentrated to leave Intermediate 4A (3.71 g, 99% yield) as a yellow solid. MS (ESI) m/z: 358.1 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([N:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=3)[N:21]=[CH:20]2)[N:4]=1.[CH2:33]([O:35]CC)[CH3:34]>C(OC(=O)C)(=O)C>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([N:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([NH:30][C:33](=[O:35])[CH3:34])=[N:28][CH:29]=3)[N:21]=[CH:20]2)[N:4]=1
Reactant: Nc1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)cn1
Reactant: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)cn1
Yield: 84 %

Procedure:
A stirred solution of 5-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-pyridin-2-ylamine (example 13) (0.314 g, 0.7 mmol) in acetic acid anhydride (6 ml) was heated at 120° C. for 1 h. To the cooled reaction mixture was added diethyl ether (10 ml), the precipitate was collected by filtration and dried to yield the title compound as a light yellow solid (0.29 g, 84%). MS (ISP) 493.3 [(M+H)+]; mp 314° C.
Reaction SMILES: [C:1]([CH2:6][C:7]([N:9]([CH3:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)=[O:8])([O:3][CH2:4][CH3:5])=[O:2].Cl>[Zn].O>[C:1]([CH2:6][C:7]([N:9]([CH3:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])=[O:8])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CC(=O)N(C)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: O
Product: CCOC(=O)CC(=O)N(C)c1ccccc1N
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
11 g of N-carbethoxy acetyl N-methyl o-nitro aniline are admixed with 16.2 g of powdered zinc, and 100 g of cracked ice are added, whilst agitating; 62 c.c. of concentrated hydrochloric acid, diluted with 250 c.c. of iced water, are then added, and this is cooled to -5-10° C. for ten to fifteen minutes; the temperature is allowed to raise again to +5° C. within thirty minutes, this is filtered, the filtrate is alkalinized with ammonium hydroxide and extracted with chloroform; the chloroformic phases are washed with water, dried over sodium sulfate and evaporated under reduced pressure; the residue is dissolved in 30 c.c. of xylene and the solution is kept overnight at -10° C.; the formed precipitate is washed with ether and recrystallized in xylene, to obtain N-carbethoxy acetyl N-methyl o-phenylene diamine, melting at 63°-64° C.
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][CH2:9][NH:10][C:11](=[O:24])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[CH:8]([CH2:9][NH:10][C:11](=[O:24])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=1)=[O:7]
Reactant: CC(=O)Oc1ccc(COC(=O)NCCO)cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(COC(=O)NCC=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of pyridine (1.15 mL) in 20 mL of CH2Cl2 was cooled in an ice bath and chromium trioxide (711 mg) was added in one portion. The mixture was stirred at the same temperature for 5 min and at room temperature for 1 h. A solution of 62 (300 mg, 1.18 mmol) in 10 mL of CH2Cl2 was added in one portion and the mixture was stirred for 45 min at room temperature. The solution was decanted, diluted with 100 mL of CH2Cl2 and washed with aqueous NaHCO3 (2×75 mL), saturated NaCl (1×75 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude aldehyde which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 2.20 (s, 3H), 4.03 (s, 2H), 5.0 (s, 2H), 5.42 (broad s, 1H), 6.97 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 9.56 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[CH2:22]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)[CH2:23][CH2:24][CH3:25]>CO.C(Cl)Cl>[CH2:22]([C:26]1[CH:27]=[CH:28][C:29]([NH:30][CH2:1][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]3[S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:31][CH:32]=1)[CH2:23][CH2:24][CH3:25]
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Reactant: CCCCc1ccc(N)cc1
Solvent: CO
Solvent: ClCCl
Product: CCCCc1ccc(NCc2ccc3[nH]c(C(N)=O)c(Sc4ccccc4)c3c2)cc1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with 4-butylaniline (74 mg, 0.50 mmol) as described in General Procedure X to afford Iah (17 mg, 23.4%) as an ivory colored solid, tlc Rf=0.8 (5% MeOH/CH2Cl2-0.2% Et3N), m/z obs=430 (M+1).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[C:18]([CH3:19])=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[N:20]1[N:21]=[C:22]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27](O)=[O:28])[NH:23][CH:24]=1>>[CH3:19][C:18]1[C:9]([N:2]2[CH2:3][CH:4]3[CH:5]([CH2:6][N:7]([C:27]([C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[C:22]4[NH:23][CH:24]=[N:20][N:21]=4)=[O:28])[CH2:8]3)[CH2:1]2)=[N:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:17]=1
Reactant: O=C(O)c1ccccc1-c1nnc[nH]1
Reactant: Cc1nc2ccccc2nc1N1CC2CNCC2C1
Product: Cc1nc2ccccc2nc1N1CC2CN(C(=O)c3ccccc3-c3nnc[nH]3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 29 and 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calcd. for C24H23N7O, 425.49; m/z found, 426.3 [M+H]+. 1H NMR (CDCl3): 8.13 (d, J=7.3 Hz, 1H), 8.01 (s, 1H), 7.83 (dd, J=8.2, 1.1 Hz, 1H), 7.72 (dd, J=8.3, 1.0 Hz, 1H), 7.59-7.35 (m, 5H), 4.00-3.65 (m, 5H), 3.47 (s, 2H), 3.22-2.89 (m, 3H), 2.70 (s, 3H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C@H:2]([CH3:4])[OH:3].[CH3:7][CH2:8][CH:9](O)[CH2:10][CH3:11].OS(O)(=O)=O>O>[C:1]([O:6][CH:9]([CH2:10][CH3:11])[CH2:8][CH3:7])(=[O:5])[C@H:2]([CH3:4])[OH:3]
Reactant: CCC(O)CC
Reactant: C[C@H](O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC(CC)OC(=O)[C@H](C)O

Procedure:
A mixture of 180 g of L-lactic acid, 528 g of 3-pentanol and 1 ml of conc. H2SO4 was refluxed in a Dean-Stark apparatus, until no more water formed (ca. 3 hours). The mixture was washed with water, NaHCO3 solution and brine, dried (MgSO4) and distilled to yield the title compound, boiling point 79°-81° C. at 15 mm of Hg.
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH2:10][CH2:11]Cl)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC>C1COCC1>[C:1]([NH:5][S:6]([CH:9]1[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)CCCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)C1CC1
Temperature: 25 °C
Yield: 56.4 %

Procedure:
To a solution of N-tert-butyl-(3-chloro)propylsulfonamide (2.14 g, 10.0 mmol) in THF (100 mL) was added n-BuLi (2.5 M in hexane, 8.0 mL, 20.0 mmol) at −78° C. The reation mixture was allowed to warm up to room temperature over period of 1 h. The volatiles were removed in vacuo. The residue was partitioned between EtOAC and water (200 mL, 200 mL). The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was recrystallized from hexane to yield the desired product as a white solid (1.0 g, 56%). 1H NMR (CDCl3) δ 0.98-1.00 (m, 2H), 1.18-1.19 (m, 2H), 1.39 (s, 9H), 2.48-2.51 (m, 1H), 4.19 (b, 1H).
Reaction SMILES: C([O:8][C@H:9]1[CH2:14][C@H:13]2[CH2:15][C@@H:10]1[CH2:11][C:12]2([F:17])[F:16])C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:16][C:12]1([F:17])[CH2:11][C@H:10]2[CH2:15][C@@H:13]1[CH2:14][C@@H:9]2[OH:8]
Reactant: [H][H]
Reactant: FC1(F)C[C@H]2C[C@@H]1C[C@@H]2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O[C@H]1C[C@H]2C[C@@H]1CC2(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Palladium (10 wt. % on activated carbon, 0.28 g) was added to a solution of (1R,4R,5S)-5-(benzyloxy)-2,2-difluorobicyclo[2.2.1]-heptane (1.43 g, 6.0 mmol) in methanol (15 mL), and the mixture was placed under a balloon full of hydrogen.After stirring at ambient temperature for 4 h, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was adsorbed onto a small pad of silica gel, and eluted with 20% of ethyl acetate in hexanes. The solvents were removed in vacuo to give the title compound as a white solid.
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([CH3:17])[C:10]=1[CH3:18])=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:6][NH:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([CH3:17])[C:10]=1[CH3:18]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(C)c(C)c1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNc1cc(C)c(O)c(C)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.7 %

Procedure:
A solution of 15 g of N-t-butoxycarbonyl-4-hydroxy-2,3,5-trimethylaniline [prepared as described in step (d) above] in 200 ml of dehydrated tetrahydrofuran was added to a suspension of 6.8 g of lithium aluminum hydride in 300 ml of dehydrated tetrahydrofuran, whilst ice-cooling, and the resulting mixture was stirred at room temperature for 3 hours, after which it was heated under reflux for 2 hours. At the end of this time, a mixture of 10 ml of water and 30 ml of tetrahydrofuran was added to the reaction mixture in order to destroy any excess of lithium aluminum hydride. The reaction mixture was then stirred at room temperature for 1.5 hours, after which insoluble materials were filtered off with the aid of a Celite (trade mark) filter aid. These materials were washed with ethyl acetate, and the ethyl acetate washings were combined and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel using a 1:3 by volume mixture of ethyl acetate and hexane as the eluent, to give 5.1 g of the title compound, melting at 120-122° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:36][C:37]1[C:38]([CH3:47])=[C:39]([CH:44]=[CH:45][CH:46]=1)[C:40]([NH:42][CH3:43])=[O:41]>C(O)(C)C>[CH3:43][NH:42][C:40](=[O:41])[C:39]1[CH:44]=[CH:45][CH:46]=[C:37]([NH:36][C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=4)[CH2:10][CH2:9]3)[N:5]=[CH:4][N:3]=2)[C:38]=1[CH3:47]
Reactant: FC(F)(F)Oc1ccc(COC2CCN(c3ncnc(Cl)n3)CC2)cc1
Reactant: CNC(=O)c1cccc(N)c1C
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc(Nc2ncnc(N3CCC(OCc4ccc(OC(F)(F)F)cc4)CC3)n2)c1C
Temperature: 80 °C
Reaction time: 24 h
Yield: 15.1 %

Procedure:
To a solution of 2-chloro-4-(4-((4-(trifluoromethoxy)benzyl)oxy)piperidin-1-yl)-1,3,5-triazine (500 mg, 1.28 mmol) in isopropanol (4 mL, 3 mL/mmol) was added DIPEA (0.4 mL, 1.92 mmol) and 3-amino-N,2-dimethylbenzamide (211 mg, 1.29 mmol) and the reaction was stirred at 80° C. for 24 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×30 ml). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided N,2-dimethyl-3-((4-(4-((4-(trifluoromethoxy)benzyl)oxy)piperidin-1-yl)-1,3,5-triazin-2-yl)amino)benzamide (100 mg, 16%) as a solid. Observed mass (M+1): 517.1.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OC([N:24]([C:32]1[S:41][CH2:40][C@H:39]2[C@:34]([C:51]3[CH:56]=[C:55](Br)[CH:54]=[CH:53][C:52]=3[F:58])([CH2:35][O:36][C@@H:37]([CH2:42][O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:38]2)[N:33]=1)C(OC(C)(C)C)=O)=O)(C)(C)C>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:58][C:52]1[CH:53]=[CH:54][C:55]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:56][C:51]=1[C@@:34]12[N:33]=[C:32]([NH2:24])[S:41][CH2:40][C@@H:39]1[CH2:38][C@H:37]([CH2:42][O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[O:36][CH2:35]2
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC1=N[C@@]2(c3cc(-c4cccnc4F)ccc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1
Temperature: 85 °C
Reaction time: 7 h
Yield: 33.5 %

Procedure:
2-Fluoropyridine-3-boronic acid (44.0 mg), tetrakis(triphenylphosphine)palladium (18.0 mg) and a 1 N sodium carbonate solution (312 μl) were added to a solution of N,N-di-(tert-butyloxycarbonyl)-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-benzyloxymethyl-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]amine (95 mg) in DMF (6.79 ml). After replacement with nitrogen, the mixture was stirred at 85° C. for seven hours. After cooling to room temperature, the mixture was diluted with water. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. The resulting intermediate was dissolved in dichloromethane (4.0 ml). TFA (1.0 ml) was added and the mixture was stirred at room temperature for three hours. Ice was added to the reaction mixture, followed by neutralization with a sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (23.0 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=O)[C:8]([CH3:14])=[C:7]2[C:3]=1[C:4]1[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15][C:5]=1[NH:6]2.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24]>>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:24][CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])=[O:13])[C:8]([CH3:14])=[C:7]2[C:3]=1[C:4]1[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15][C:5]=1[NH:6]2
Reactant: CN(C)CCN
Reactant: Cc1cnc2[nH]c3c(C)c(C(=O)O)cc(Cl)c3c2c1
Product: Cc1cnc2[nH]c3c(C)c(C(=O)NCCN(C)C)cc(Cl)c3c2c1

Procedure:
The title compound was synthesized from 5-chloro-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxylic acid and N,N-dimethylethane-1,2-diamine using an analogous procedure to that described in the preparation of Compound 88. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.20 (s, 6H) 2.42 (t, J=6.69 Hz, 2H) 2.49 (br. s., 3H) 2.55 (s, 3 H) 3.35 (d, J=6.57 Hz, 2H) 7.18 (s, 1H) 8.31 (t, J=5.56 Hz, 1H) 8.40 (d, J=2.02 Hz, 1H) 8.53 (s, 1H) 12.14 (s, 1H). [M+H] calc'd for C18H21ClN4O 345; found, 345.4.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@H:7]2[O:13][C@@H:12]([CH2:14][OH:15])[C@H:10]([OH:11])[C@@H:8]2[OH:9])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].OO.C([OH:22])C>[OH-].[NH4+]>[NH2:1][C:2]1[N:6]([C@H:7]2[O:13][C@@H:12]([CH2:14][OH:15])[C@H:10]([OH:11])[C@@H:8]2[OH:9])[N:5]=[CH:4][C:3]=1[C:16]([NH2:17])=[O:22]
Reactant: N#Cc1cnn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c1N
Reactant: CCO
Agent: OO
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)c1cnn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
To a solution of (25) (4.60 g) in ammonium hydroxide (35 mL) was added 30% hydrogen peroxide (2 mL). The mixture was stirred in a pressure bottle at room temperature for 18 h, the pressure bottle was cooled, opened carefully and the volatile products were evaporated to dryness. The residue thus obtained was co-evaporated with ethanol (3×20 mL). The crude product on crystallization with ethanol/water gave pure compound 3.5 g (71%): 1H NMR (DMSO-d6) δ3.57 (m, 2H, C5′CH2), 3.86 (q, 1H, C4′H), 4.11 (q, 1H, C3′H) 4.43 (q, 1, C2′OH), 5.63 (d, 1H, J=3.99 Hz, C1′H), 6.51 (br s, 2H, NH2), 6.71 and 7.26 (2br s, 2H, CONH2) and 7.69 (s, 1H, C3H). Anal. Calc. for C9H14N4O5 (258.23): C, 41.86; H, 5.46; N, 21.69. Found: C, 41.57; H, 5.40; N, 21.61.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([F:22])=[C:12]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.Cl[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][N:26]=1>CC(O)C>[Si:1]([O:8][CH2:9][C:10]1[C:11]([F:22])=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][N:26]=3)[CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Clc1ccncn1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCNCC2)c1F
Agent: Cl
Solvent: CC(C)O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCN(c3ccncn3)CC2)c1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine (355 mg) was mixed with IPA (4.5 ml), and 4-chloro-pyrimidine hydrochloride (150 mg) and TEA (302 mg) were added thereto, followed by stirring at 60° C. overnight. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH/CHCl3) to obtain 4-{4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}pyrimidine (391 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61][C:62](=[O:64])[CH3:63])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH2:67](I)[CH3:68]>>[CH3:1][O:2][C:3](=[O:66])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([N:61]([C:62](=[O:64])[CH3:63])[CH2:67][CH3:68])=[N:58][C:57]=1[CH3:65])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CCI
Product: CCN(C(C)=O)c1nc(C)c(S(=O)(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccc(C#N)cc3)cc2)C(=O)OC)OC[C@@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)s1

Procedure:
(S)-2-({(3R,8S)-7-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (49 mg) was reacted with ethyl iodide (16 mg) according to General Procedure T to obtain (S)-2-({(3R,8S)-7-[2-(acetyl-ethyl-amino)-4-methyl-thiazole-5-sulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester. This was hydrolyzed according to General Procedures N and B to give the title compound (17 mg). LCMS: (m/z) 938.
Reaction SMILES: [CH:1]1([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[O:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][NH2:28])=[C:21]([CH3:29])[CH:20]=1.Cl>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][NH:28][C@H:4]2[CH2:5][CH2:6][C@H:1]([C:8]3[CH:17]=[CH:16][C:11]4[NH:12][C:13](=[O:15])[O:14][C:10]=4[CH:9]=3)[CH2:2][CH2:3]2)=[C:21]([CH3:29])[CH:20]=1
Reactant: Cc1cc(F)ccc1CCCN
Reactant: O=C1CCC(c2ccc3[nH]c(=O)oc3c2)CC1
Agent: Cl
Product: Cc1cc(F)ccc1CCCN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1

Procedure:
Coupling of ketone 5 and 3-(4-fluoro-2-methylphenyl)-1-propylamine, using the method given in Example 1, gave 6-(trans-4-[3-(4-fluoro-2-methylphenyl)propylamino]cyclohexyl}-3H-benzoxazol-2-one (630 mg, 56%) as the HCl salt: 1H NMR (500 MHz, DMSO-d6): δ 11.50 (s, 1H), 8.88 (s, 2H), 7.22-7.13 (m, 2H), 7.05-6.91 (m, 4H), 3.09-2.87 (m, 3H), 2.67-2.62 (m, 3H), 2.30 (s, 3H), 2.17-2.13 (m, 2H), 1.92-1.79 (m, 4H), 1.58-1.41 (m, 4H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:26]=[CH:25][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[O:22][N:21]=[C:20]([CH2:23][OH:24])[CH:19]=2)=[CH:8][CH:7]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:24][CH2:23][C:20]1[CH:19]=[C:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([C:2]3[O:1][CH2:5][CH2:4][N:3]=3)=[CH:26][CH:25]=2)[O:22][N:21]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1cc(CCCCCCCOc2ccc(C3=NCCO3)cc2)on1
Solvent: c1ccncc1
Product: CC(=O)OCc1cc(CCCCCCCOc2ccc(C3=NCCO3)cc2)on1
Temperature: 0 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A solution of 2.80 g of 5-{7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-isoxazolemethanol (Example 11) and 0.82 g of acetic anhydride in pyridine was allowed to stand overnight at room temperature. The reaction mixture was poured into ice water and the solid material which formed was collected, dried and recrystallized from isopropyl alcohol to give 2.5 g of 5-{7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-isoxazolemethanol acetate, colorless solid, m.p. 76°-77° C.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].[N+:7]([C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13])([O-:9])=[O:8]>CCCCCC.O1CCCC1>[N+:7]([C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]([OH:13])[C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])([O-:9])=[O:8]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: C#C[Si](C)(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC(O)c1ccccc1[N+](=O)[O-]
Temperature: -76 °C
Reaction time: 0.5 h

Procedure:
Into a round-bottomed flask was placed ethynyltrimethylsilane (4.90 mL), and tetrahydrofuran (THF) and was cooled to −76° C. A solution of 2.0 M n-butullithium in hexane (15.8 mL) was added dropwise. The reaction mixture was stirred at −76° C. for 30 minutes and a solution of o-nitrobenzaldehyde (3.0 g) in anhydrous THF was added. The reaction mixture was stirred at −76° C. for 60 minutes, and quenched with water. The reaction mixture was warmed up to room temperature and THF was removed under vacuum. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The crude material was purified by chromatography on silica gel giving a yield of 4.3 grams (87%).