Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS([O-])=O.[Na+].[OH-:6].[Na+].[CH3:8][N:9]1[C@@H:25]2[CH2:26][C:14]3[CH:15]=[CH:16][C:17]([OH:29])=[C:18]4[O:19][C@H:20]5[C:21]([O:27]C)=[CH:22][CH:23]=[C:24]2[C@:12]5([C:13]=34)[CH2:11][CH2:10]1.[OH-].[NH4+]>CC(O)=O>[CH3:8][N:9]1[C@@H:25]2[CH2:26][C:14]3=[CH:15][CH:16]=[C:17]([OH:29])[C:18]4[O:19][C@H:20]5[C:21]([CH2:22][CH2:23][C@:24]2([OH:6])[C@:12]5([C:13]=43)[CH2:11][CH2:10]1)=[O:27]
Reactant: [OH-]
Reactant: COC1=CC=C2[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: O=S([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Temperature: 38 °C
Reaction time: 0.07 h

Procedure:
To the above filtrate, NaHSO3 (0.1 g per g of oripavine) was added and nitrogen sweep was initiated. 50% Sodium Hydroxide, NaOH, (1.33 g per g of oripavine) was charged (pH=about 6.6). Temperature reached 35° C. during charging. The pH was adjusted with additional 50% NaOH (˜0.15 mL per g of oripavine) to 7.0. Note: The pH value would take 3 to 5 minutes to become steady. The pH adjustment was repeated until the pH change was within +/−0.2 over 5 minutes. The pH was adjusted to 6.6 to 7.0 with 50% NaOH or HOAc if necessary. The solution was heated and stirred at 38° C. (35° C. to 80° C.) for 2 hours to form a light brown solution (pH changed within +/−0.2). The solution was cooled to room temperature (20° C.). Concentrated ammonium hydroxide, c-NH4OH, (0.5 mL per g of oripavine) was added to form a precipitate (pH=9.0 to 10.0). The mixture was stirred at room temperature for 2 hours. The mixture was filtered, and the resulting solid was washed with water (3×1 mL per g of oripavine). The solid was dried under flowing air at room temperature for 1 hour to give product as a tan solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.F[C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH3:20])[C:17](=[O:19])[CH3:18])=[CH:12][C:11]=1[N+:21]([O-:23])=[O:22]>CCO>[CH3:20][N:16]([C:13]1[CH:14]=[CH:15][C:10]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[C:11]([N+:21]([O-:23])=[O:22])[CH:12]=1)[C:17](=[O:19])[CH3:18]
Reactant: CC(=O)N(C)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CCOCC1
Solvent: CCO
Product: CC(=O)N(C)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1
Yield: 96.3 %

Procedure:
4-Aminomethyltetrahydropyran (10.0 g, 86.5 mmol) was added to a mixture of N-(4-fluoro-3-nitrophenyl)-N-methylacetamide (15.6 g, 73.3 mmol) and TEA (15.3 mL, 11.1 g, 110 mmol) in EtOH (300 mL) at room temperature. The reaction mixture was heated for 6 h at reflux. Upon evaporation of ethanol, the residue was dissolved in EtOAc (400 mL), washed with H2O (3×50 mL), saturated NaCl (3×50 mL), and dried over Na2SO4. After filtration and concentration, 21.7 g (96%) of the title compound was obtained as an orange-red solid. 1H NMR (400 MHz, CHLOROFORM-D): δ 1.38-1.52 (m, 2 H), 1.72-1.81 (m, 2 H), 1.90 (s, 3 H), 1.93-2.02 (m, 1 H), 3.23 (s, 3 H), 3.23-3.27 (m, 2 H), 3.36-3.49 (m, 2 H), 4.01-4.07 (m, 2 H), 6.91 (d, J=9.18 Hz, 1 H), 7.29 (dd, J=9.08, 2.64 Hz, 1 H), 8.05 (d, J=2.34 Hz, 1 H), 8.22 (t, J=5.37 Hz, 1 H). MS (ESI) (M+H)+=309.12.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC1C=CC(C)=CC=1.[C:21]([NH2:30])(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)O>CC(N(C)C)=O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]2[O:9][C:28]3[CH:27]=[CH:26][CH:25]=[CH:23][C:22]=3[C:21](=[O:29])[N:30]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC(=O)c1ccccc1O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)N(C)C
Solvent: Cc1ccc(C)cc1
Product: O=c1nc(-c2ccc([N+](=O)[O-])cc2)oc2ccccc12
Temperature: 80 °C
Reaction time: 6 h
Yield: 100.2 %

Procedure:
36.6 g of 4-nitrobenzoyl chloride are added to 48 g of p-xylene over 5 minutes and the suspension warmed to 80° C. To this suspension is then added, over 90 minutes, at 80° C., a solution of 13.2 g of salicylic acid amide in 7.2 g of dimethylacetamide, with stirring. The temperature is then raised to 135° C. over 1 hour and the mixture stirred at this temperature for a further 6 hours. After this time, the mixture is treated with 48 g of p-xylene, cooled to 80° C., the precipitated solids filtered, washed with p-xylene and dried, to yield 25.87 g of 2-(4-nitrophenyl)-4H-1,3-benzoxazin-4-one melting at 249-251° C. and having the following elemental analysis:
Reaction SMILES: Cl[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(#N)C>[Cl:8][C:6]1[N:7]=[C:2]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Cl)nc(Cl)c2=O)c1
Reactant: CN1CCNCC1
Solvent: CC#N
Product: COC(=O)c1ccc(C)c(-n2cc(Cl)nc(N3CCN(C)CC3)c2=O)c1
Reaction time: 12 h

Procedure:
To a stirred solution of 3-(3,5-dichloro-2-oxo-1(2H)-pyrazinyl)-4-methyl-benzoic acid, methyl ester, (Example 107a, 250 mg) in acetonitrile (5 mL) was added 1-methyl-piperazine (0.2 mL). After 12 h, the reaction mixture was concentrated in vacuo. The residue was diluted with dichloromethane, washed with sat. aqueous NaHCO3, dried (MgSO4), filtered and the solvent removed to afford the subtitle compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[C:21](OC)(=O)[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[OH:23]>>[OH:23][CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21]1[NH:20][C:18](=[O:19])[C:3]2[N:4]=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:2]=2[N:1]=1
Reactant: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Reactant: COC(=O)C(O)c1ccccc1
Product: CC(CCCc1ccccc1)n1nnc2c(=O)[nH]c(C(O)c3ccccc3)nc21

Procedure:
Analogously to the procedure of Example 5, the title compound is prepared from 1.0 g (3.8 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-[1,2,3]triazole-4-carboxamide and 1.89 g (11.4 mmol) of methyl mandelate.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Cl.[NH3:11]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH2:11]
Reactant: N
Reactant: Fc1cccc(Cl)c1CCl
Solvent: c1ccccc1
Product: NCc1c(F)cccc1Cl
Temperature: 100 °C

Procedure:
An autoclave was charged with 89.0 g. (0.5 mole) of 2-chloro-6-fluorobenzyl chloride, 170.0 g. (10 mole) ammonia and 50 ml. benzene. The reaction vessel was sealed and the contents heated at 100° C. for 15 hours. The excess ammonia was carefully evaporated off from the cooled contents of the autoclave with a stream of nitrogen. The residue was washed with water, and the organic phase after drying with anhydrous MgSO4, fractionated to afford 72.4 g. (90%) of product as a clear liquid; b.p. 99°-100° C./20 mm; NMR (CDCl3) δ 1.46 (s, 2H); 3.88 (d, 2H); 7.00 (m, 3H).
Reaction SMILES: [CH2:1]([CH:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH3:24])[CH:17]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][C:8]([F:26])=[C:9]([F:25])[CH:10]=2)[N:5]2[CH:27]=[CH:28][CH:29]=[C:4]12)[CH3:2].ClS([N:34]=[C:35]=O)(=O)=O.CN(C=O)C>C1COCC1>[CH2:1]([CH:3]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([CH3:24])[CH:17]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][C:8]([F:26])=[C:9]([F:25])[CH:10]=2)[N:5]2[C:27]([C:35]#[N:34])=[CH:28][CH:29]=[C:4]12)[CH3:2]
Reactant: CCC1c2cccn2-c2cc(F)c(F)cc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCC1c2ccc(C#N)n2-c2cc(F)c(F)cc2N1S(=O)(=O)c1ccc(OC)c(C)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a 250 ml round bottom flask with addition funnel was added 2 g (4.8 mmol) of the product from Example 4 and 50 ml of THF. The solution was cooled to −78° C. and 0.50 ml (5.76 mmol) of chlorosulfonyl isocyanate in 20 ml of THF added dropwise via the addition funnel. After the addition was complete the solution was stirred at this temperature for 3 hr until all of the product had disappeared by TLC. Added 1 ml of DMF and allowed the solution to warm to room temperature, whereupon product begins to form. After stirring overnight the reaction was quenched with saturated sodium bicarbonate solution, then extracted 3 times with ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated to afford an oil, which was chromatographed on silica gel eluting with 30% ethyl acetate:hexane to afford 1.81 g (83%) of product as a solid, which was recrystallized from ethyl acetate hexane, mp 176-178° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[C:23]([CH3:33])[CH:22]=4)[CH:19]=3)[N:14]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:13]=2)[CH:9]=[N:8]1.[CH3:47][C@H:48]1[CH2:50][O:49]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][N:30]([CH2:47][C@@H:48]([OH:49])[CH3:50])[CH2:31][CH2:32]5)=[C:23]([CH3:33])[CH:22]=4)[CH:19]=3)[N:14]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:35])=[O:36])[CH:13]=2)[CH:9]=[N:8]1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)c(C)c4)cnc32)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)c(C)c4)cnc32)cc1
Yield: 97.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(3-methyl-4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (172 mg. 0.277 mmol) was alkylated using (S)-2-methyloxirane (24 mg, 0.416 mmol), DIPEA (54 mg, 0.416 mmol) and ethanol (4 mL) to get 183 mg (97.3% yield) of the titled compound. MS: m/z=679.3 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)=O>>[CH3:1][N:2]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(CC(F)(F)F)c1ccccc1
Temperature: 105 °C

Procedure:
Fluorinated light-absorbing electron donors were prepared. N-Methyl-N-2,2,2-trifluoroethylaniline was prepared as follows. Into a flask were placed N-methylaniline (6.0 g) and potassium carbonate (10.0 g) the flask was assembled with a refluxing condenser. To the flask was slowly added 2,2,2-trifluoroethyl trifluoromethanesulfonate (13 g). After addition, the reaction mixture was stirred and heated to 100-110° C. overnight. The reaction mixture was then quenched by addition of 100 mL of water. The water solution was extracted with diethyl ether (2×50 mL). The organic layer was separated and dried over MgSO4. Ether was removed under vacuum. The organic liquid was distilled to receive a fraction (a clear yellow liquid, 9.2 g) at 44-45° C. (at 0.05 mm Hg). The clear liquid was sampled and analyzed by 1H and 19F NMR. 1H NMR: δ7.28 (t, 2H, J=8 Hz), 6.81 (m, 3H), 3.83 (q, 2H, J=9H), 3.04 (s, 3H); 19F NMR: δ−73.37 (t, 3F. J=9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[O:18][C:17]([C:19]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:33][CH2:32][CH:31]([C:34]([O:36]C)=[O:35])[CH2:30][CH2:29]5)=[N:26][CH:27]=4)=[O:20])=[N:16][N:15]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:39]=[CH:38][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[O:18][C:17]([C:19]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:33][CH2:32][CH:31]([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]5)=[N:26][CH:27]=4)=[O:20])=[N:16][N:15]=3)=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCN(c2ccc(NC(=O)c3nnc(Nc4ccc(Oc5ccc(Cl)cc5)cc4)o3)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccc(N2CCC(C(=O)O)CC2)nc1)c1nnc(Nc2ccc(Oc3ccc(Cl)cc3)cc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a stirred solution of methyl 1-(5-{[(5-{[4-(4-chlorophenoxy)phenyl]amino}-1,3,4-oxadiazol-2-yl)carbonyl]amino}pyridin-2-yl)piperidine-4-carboxylate (Example 638; 340 mg, 0.62 mmol) in MeOH (5 mL) was added 2M NaOH (1.5 mL, 3.10 mmol) and the reaction mixture was allowed to stir at ambient temperature overnight. The solvent was evaporated and the aqueous residue adjusted to pH ˜1-2 with 2M HCl, the solid was filtered and dried to give the title compound (284 mg, 0.531 mmol, 86%); 1H NMR δ 1.79-1.90 (m, 2H), 2.14-2.19 (m, 2H), 2.78-2.84 (m, 1H), 3.33-3.40 (m, 2H), 4.35-4.39 (m, 2H), 7.23 (d, 2H), 7.37 (d, 2H), 7.43 (d, 1H), 7.64 (d, 2H), 7.88 (d, 2H), 8.33 (d, 1H), 8.73 (s, 1H), 11.26 (s, 1H), 11.36 (s, 1H); CO2H not seen; MS m/e MH+ 535.
Reaction SMILES: [C:1]([O:4][CH:5]([C@H:8]1[O:12][C@@H:11]([N:13]2[C:17]3[N:18]=[C:19]([NH2:23])[NH:20][C:21](=[O:22])[C:16]=3[S:15][C:14]2=[O:24])[C@@H:10](CC([O-])=O)[CH2:9]1)[CH2:6][CH3:7])(=[O:3])[CH3:2].C([O-])([O-])=[O:30].[K+].[K+].CC(O)=O>CO>[C:1]([O:4][CH:5]([C@@H:8]1[CH2:9][C@@H:10]([OH:30])[C@H:11]([N:13]2[C:17]3[N:18]=[C:19]([NH2:23])[NH:20][C:21](=[O:22])[C:16]=3[S:15][C:14]2=[O:24])[O:12]1)[CH2:6][CH3:7])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCC(OC(C)=O)[C@@H]1C[C@H](CC(=O)[O-])[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CCC(OC(C)=O)[C@@H]1C[C@@H](O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
To a solution of [(2R,3R,5S)-5-(1-acetoxypropyl)-2-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-3-yl]acetate (compound 1g, 7.0 g, 16.9 mmol) in methanol (200 mL) was added K2CO3 (1.18 g, 8.5 mmol). After being stirred at room temperature for 12 hours, the reaction mixture was adjusted to pH 6.0 by addition of HOAc (1.2 g, 17 mmol), concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:2 EtOAc in petroleum ether) to afford 2.8 g of 1-[(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl acetate (compound 22a) as a yellow solid. MS obsd. (ESI−) [(M−H)+]: 369.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH2:5][S:4][CH2:3]1.[N:14]1[CH:18]=[C:17]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])[NH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N:21]1([C:19]([C:17]2[N:16]([CH:2]3[C:11]4[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=4)[CH2:5][S:4][CH2:3]3)[CH:15]=[N:14][CH:18]=2)=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(c1cnc[nH]1)N1CCCC1
Reactant: N#Cc1ccc2c(c1)CSCC2O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)CSCC2n1cncc1C(=O)N1CCCC1
Temperature: 0 °C

Procedure:
To a solution of 4-hydroxy-isothiochroman-7-carbonitrile, which can be prepared as described in Example 12, (300 mg, 1.6 mmol) in THF (20 mL) is added (3H-imidazol-4-yl)-pyrrolidin-1-yl-methanone (200 mg, 1.2 mmol), and triphenylphosphine (420 mg, 1.6 mmol). The reaction is cooled to 0° C. and diisopropyl azodicarboxylate (310 μL, 1.6 mmol) is added. The reaction is permitted to warm to room temperature and stirred until LC-MS analysis indicates complete consumption of 4-hydroxy-isothiochroman-7-carbonitrile. The reaction mixture is diluted with saturated aqueous NaHCO3 and ethyl acetate. The layers are separated and the organic layer is dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:1) to afford 4-[5-(Pyrrolidine-1-carbonyl)-imidazol-1-yl]-isothiochroman-7-carbonitrile; MS: (ESI) m/z 339.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 1.88-2.08 (m, 4 H), 3.17-3.37 (m, 2 H), 3.53-3.68 (m, 2 H), 3.69-3.77 (m, 2 H), 3.79-3.98 (m, 2 H), 6.55 (t, J=4.6 Hz, 1 H), 7.19 (d, J=8.1 Hz, 1 H), 7.39 (s, 1 H), 7.43-7.48 (m, 2 H), 7.50 (s, 1 H). The HCl salt of the title compound can be prepared by dissolution in diethyl ether followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 4-[5-(Pyrrolidine-1-carbonyl)-imidazol-1-yl]-isothiochroman-7-carbonitrile.
Reaction SMILES: [CH3:1][C:2]([C:25]([O:27][CH3:28])=[O:26])([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[NH:3][C:4]([O:6][CH:7]1[CH:14]2[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2)=[O:5].[C:29](=O)([O-])[O-].[K+].[K+].IC>>[CH3:29][O:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C:2]([CH3:1])([C:25]([O:27][CH3:28])=[O:26])[NH:3][C:4]([O:6][CH:7]2[CH:8]3[CH2:16][CH:12]4[CH2:11][CH:10]([CH2:15][CH:14]2[CH2:13]4)[CH2:9]3)=[O:5])=[CH:23][CH:22]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(C)(Cc1ccc(O)cc1)NC(=O)OC1C2CC3CC(C2)CC1C3
Agent: [K+]
Solvent: CI
Product: COC(=O)C(C)(Cc1ccc(OC)cc1)NC(=O)OC1C2CC3CC(C2)CC1C3

Procedure:
The title compound was prepared from methyl α-methyl-N-[(tricyclo[3.3.1.13,7 ]dec-2-yloxy)carbonyl]-DL-tyrosinate (0.671 g, 0.0017 mmol, prepared usingthe procedure described in Example 47, Step A), potassium carbonate (0.345 g, 0.0025 mmol) and iodomethane (0.368 g, 0.0025 mol) using the procedure described in Example 47, Step B. MS: 402.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[BH4-].[Na+]>O1CCCC1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:18])[CH3:17])=[CH:12][CH:11]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1-c1ccc(C(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ncc(F)cc1-c1ccc(C(C)O)cc1
Yield: 51.2 %

Procedure:
A mixture of 3-bromo-5-fluoro-2-methoxy-pyridine (1.0 g, 4.9 mmol), 4-acetylphenylboronic acid (1.59 g, 9.7 mmol), tetrakis(triphenylphosphine)palladium (0) (0.28 g, 0.24 mmol), 2M aqueous sodium carbonate solution (2.4 ml) and 1,2-dimethoxyethane (5 ml) was heated in a microwave oven at 150° C. for 20 min. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water, brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue chromatographed on silica gel eluting with 3:1 heptane/ethyl acetate to give 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethanone (1.0 g, 4.0 mmol, 82%). 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethanone (1.0 g, 4.1 mmol) was treated with sodium borohydride (4.0 eq) in tetrahydrofuran and dichloromethane at room temperature. The solvent was evaporated to give 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethanol (0.51 g, 2.1 mmol, 51%). To a solution 1-[4-(5-fluoro-2-methoxy-pyridin-3-yl)-phenyl]-ethanol (0.5 g, 2.0 mmol) in tetrahydrofuran (5 ml) was added triphenylphosphine (0.63 g, 2.4 mmol) and pthalimide (0.35 g, 2.4 mmol). The reaction was cooled to below 5° C. before adding diethylazodicarboxylate (0.42 g, 2.4 mmol) in a dropwise manner maintaining the temperature below 5° C. The reaction mixture was stirred for 24 h at room temperature. The solvent was evaporated and the residue partitioned between ethyl acetate and water.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[C:48]([NH2:52])([CH3:51])([CH3:50])[CH3:49]>>[C:48]([NH:52][C:42](=[O:43])[CH2:41][N:38]1[CH2:39][CH2:40][N:35]([C:33]([N:13]2[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=[C:12]2[C:9]2[CH:10]=[N:11][C:6]([C:2]([CH3:3])([CH3:4])[CH3:5])=[CH:7][C:8]=2[O:45][CH2:46][CH3:47])=[O:34])[CH2:36][CH2:37]1)([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(C)(C)N
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)(C)C)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with tert-butylamine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H51Cl2N6O3 [(M+H)+] 721.3394, observed 721.3399.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[CH2:4][N:5]=[C:6]=[S:7].[CH2:13]([CH2:15][NH2:16])[OH:14]>C(O)(C)C.C1C=CC=CC=1>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[CH2:4][NH:5][C:6]([NH:16][CH2:15][CH2:13][OH:14])=[S:7]
Reactant: Cc1ccc(CN=C=S)c(C)c1
Reactant: NCCO
Solvent: CC(C)O
Solvent: c1ccccc1
Product: Cc1ccc(CNC(=S)NCCO)c(C)c1
Yield: 58 %

Procedure:
2,4-Dimethylbenzyl isothiocyanate (15.7 grams; 0.08 mole) was mixed with 23 milliliters (ml) of isopropyl alcohol and a solution of ethanolamine (5.8 grams; 0.08 mole) in 23 ml of isopropyl alcohol added dropwise thereto with stirring. The temperature of the reaction mixture was maintained below about 50°C during the ethanolamine addition and then stirred at ambient temperatures for a period of about 16 hours. The reaction mixture was then concentrated to dryness and the residue obtained taken up in benzene. The resulting benzene solution was cooled to give crystals which were filtered off. The title product was thus obtained in about a 58% yield as a crystalline solid having a melting point of 101-103°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[H-].[Na+].I[CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:32][CH2:33][CH2:34][C:35]([F:38])([F:37])[F:36])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: FC(F)(F)CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCCC(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
Treat a stirred solution of 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepan (1.50 g, 4.74 mmol, Preparation 9), tetrahydrofuran (45 mL) and dimethylformamide (5 mL) at 0° C. with sodium hydride (0.228 g, 5.69 mmol, 60% oil dispersion) under an argon atmosphere. Stir at room temperatue for 30 minutes, cool to 0° C. and treat with 1-iodo-4,4,4-trifluorobutane (1.35 g, 5.69 mmol, Lancaster Synthesis). Allow to warm slowly to room temperature and stir overnight at room temperature. Cool to 5° C., quench by addition of ice and saturated ammonium chloride solution (5 mL) and concentrate in vacuo to remove the tetrahydrofuran. Dissolve the residue in ethyl acetate (150 mL), wash the organic phase with water (3×40 mL), dry (Na2SO4), filter and concentrate to afford a yellow oil. Purify by flash chromatography (silica gel, 7×40 cm) eluting with 60% ethyl acetate in hexane. Concentrate the appropriate fractions in vacuo and dry the residue (1.2 Torr, 50° C., 2 hours) to afford 1.93 g of 4-[1-(4,4,4-trifluoro-butyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester as an oil, Rf=0.40 (silica gel, ethyl acetate).