Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[I-].Cl[CH2:20][CH2:21][S+](C)C.[I-].[Na+].O>C(O)(C)(C)C>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:10]2([C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[O:17])[CH2:21][CH2:20]2)[CH:12]=1
Reactant: O=C(Cc1cccnc1)c1ccc(Cl)cc1Cl
Reactant: C[S+](C)CCCl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(c1ccc(Cl)cc1Cl)C1(c2cccnc2)CC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
54 g of 2',4'-dichloro-2-(3-pyridyl)-acetophenone are added portionwise under an inert gas to a suspension of 46.5 g of freshly sublimed potassium tert.butylate in 590 ml of tert.butanol and the reaction mixture is stirred at 45° C. for 2 hours. The mixture is treated at room temperature with 59.5 g of 2-chloroethyl-dimethylsulphonium iodide and a spatula tip of sodium iodide and the mixture is held at 50° C. for 16 hours while stirring vigorously. The mixture is poured into water and extracted three times with 300 ml of diethyl ether each time. The combined organic extracts are washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residue is chromatographed on silica gel with diethyl ether as the eluent and crystallized from diethyl ether/n-hexane. There are obtained 41.7 g of 2,4-dichlorophenyl 1-(3-pyridyl)-cyclopropyl ketone as white crystals, m.p. 83° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[NH:3][C:4]([N:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1)[OH:7])=[O:5].[OH-].[Na+].Cl[C:20](OCC)=[O:21]>O1CCOCC1>[CH3:14][C:10]1[CH:9]=[C:8]([N:6]2[C:4](=[O:5])[N:3]([C:2]([F:15])([F:16])[F:1])[C:20](=[O:21])[O:7]2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1cccc(N(O)C(=O)NC(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cccc(-n2oc(=O)n(C(F)(F)F)c2=O)c1

Procedure:
1-Trifluoromethyl-3-(3'-methylphenyl)-3-hydroxyurea (11.7 grams; 0.05 mol) is dissolved in dioxane (75 ml) and mixed with 2N aqueous sodium hydroxide (30 ml). Ethyl chloroformate (5.7 ml; 0.06 mol) is then added dropwise to the mixture with stirring, resulting in the formation of a precipitate. The precipitate is recovered by filtration, is washed and dried to yield 2-(3'-methylphenyl)-4-trifluoromethyl-1,2,4-oxadiazolidine-3,5-dione.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].C(OCCCCC)(=O)C>CC(C)=O.O>[ClH:13].[N:16]1([CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 95 °C

Procedure:
To two 125 mL 3 neck flasks with mechanical stirring, condensers, and a heating apparatus consisting of an RTD probe in the flask hooked via a temperature controller to a heating mantle the following were added: 7.61 g of methyl 4-hydroxybenzoate, 11.05 g of β-chloroethylpiperidine hydrochloride, 16.59 g of powdered potassium carbonate, and 60 mL of amyl acetate. The flasks were placed in an ambient oil bath and heated under nitrogen to 95° C.-100° C. The reaction was allowed to proceed until HPLC indicated 8% unreacted methyl 4-hydroxybenzoate in A, 12% unreacted in B. The flasks were then cooled to less than 50° C. 40 mL deionized water was added with stirring to dissolve solids. The aqueous layer was separated and discarded. The water wash was repeated and the aqueous layer was separated and discarded. HPLC of organic layers showed 6% 4-hydroxybenzoate remains in A, 3% in B. 25 mL of 8N hydrochloric acid was added with stirring to extract the intermediate. The layers were separated and the acid layers returned to reaction flasks. The acid solutions were heated at about 95° C. for about 4 hours. The flasks were then cooled to less than 40° C. and 25 mL of acetone was added. The mixture was then cooled to 0° C.-5° C. for 1 hour. The mixture was filtered and the cakes rinsed with approximately 25 mL of acetone and dried. A=11.50 g (80.5%), B=10.5 g (73.8%)
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:16][C@H:17]([CH3:21])[CH2:18][O:19][CH3:20])(=[O:15])=[O:14])=[CH:9][CH:8]=1.B(OC(C)C)(OC(C)C)OC(C)C.[ClH:35].C(=O)([O-])[O-].[Na+].[Na+].[NH2:42][C:43]1[C:44]([C:50]([NH:52][C:53]2[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=2)=[O:51])=[N:45][C:46](Br)=[CH:47][N:48]=1>O1CCCC1.C(Cl)Cl.C(OCC)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:35].[NH2:42][C:43]1[C:44]([C:50]([NH:52][C:53]2[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=2)=[O:51])=[N:45][C:46]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C@H:17]([CH3:21])[CH2:18][O:19][CH3:20])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:47][N:48]=1
Reactant: Nc1ncc(Br)nc1C(=O)Nc1cccnc1
Reactant: COC[C@@H](C)NS(=O)(=O)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)OB(OC(C)C)OC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC[C@@H](C)NS(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
n-Butyllithium (1.3 mL, 2.1 mmol) was added dropwise over 30 min to a cooled (−78° C.) solution of 4-bromo-N-[(1R)-2-methoxy-1-methylethyl]benzenesulfonamide (0.125 g, 0.406 mmol) and triisopropyl borate (0.28 mL, 1.2 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen atmosphere. The reaction mixture was stirred for 2 h at −78° C. HCl (aq, 3 M, 0.81 mL) was added to the reaction mixture and the mixture was allowed to warm to room temperature. Sodium carbonate (0.516 g, 4.9 mmol) was added followed by Pd(dppf)Cl2 (16 mg, 20 μmol) and 3-amino-6-bromo-N-pyridin-3-ylpyrazine-2-carboxamide (0.143 g, 0.487 mmol). Tetrahydrofuran (10 mL) was added and the mixture was heated to 65° C. for 15 h. The solvent was removed and purification by column chromatography using gradient methylene chloride to methylene chloride/methanol, (2:1), as the eluent gave a yellow solid. The solid was dissolved in methylene chloride (10 mL) and HCl in diethyl ether (1 M 2.5 ml) was added. A yellow precipitate was formed. Filtering and drying gave 73 mg (35% yield) of the title compound as yellow solid: 1H NMR (D2O, 400 Hz) δ 9.28 (s, 1H), 8.53 (s, 3H), 8.0 (m, 1H), 7.96 (d, J=8 Hz, 2H), 7.70 (d, J=8 Hz, 2H), 3.42 (m, 1H), 3.27 (m, 1H), 3.16 (s, 3H), 0.93 (d, J=7 Hz, 3H);
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:20][C:21]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:3]1.[CH:33](=O)[CH2:34][CH2:35][CH2:36][CH3:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:16][C:14]1[N:15]=[C:11]([C:9]([NH:8][C@H:7]2[CH2:6][CH2:5][N:4]([C:19]3[S:20][C:21]4[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[CH2:3][C@H:2]2[NH:1][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:10])[NH:12][C:13]=1[CH2:17][CH3:18]
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N)C3)sc12
Reactant: CCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCCN[C@@H]1CN(c2nc3cccc(C(=O)OCC)c3s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1

Procedure:
The same operation as in Example (77d) was performed using ethyl cis(±)-2-(3-amino-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained by the method described in Example (81e) (30 mg, 0.063 mmol), 1-pentanal (14 μL, 0.13 mmol) and sodium (triacetoxy)borohydride (120 mg, 0.57 mmol), to obtain 30.8 mg of the title compound as a colorless oily substance (90%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][N:22]=2)[C:16](OC)=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C1COCC1>[N:7]1([C:13]2[CH:14]=[C:15]([CH2:16][OH:17])[CH:20]=[CH:21][N:22]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)c1ccnc(N2CCCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccnc(N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
To a suspension of LAH (5.5 g, 0.145 mol) in dry THF (500 mL) at 0° C. was added methyl 2-piperidin-1-ylisonicotinate (18 g, 0.095 mol) in dry THF (100 mL) under N2 atmosphere. The reaction mixture was stirred at RT for 4 h and quenched with 10% aqueous NaOH solution at −20° C. The solid was filtered off, washed with THF and concentrated. The residue was dissolved in CH2Cl2 (250 mL), washed with water, brine and dried. The solvent was removed under vacuum and the crude was purified by column chromatography over silica gel (CHCl3/MeOH, 9:1) to give (2-piperidin-1-yl pyridin-4-yl)methanol (12 g, 65%). 1H NMR (DMSO-d6) δ 7.98 (d, J=5.2 Hz, 1H), 6.71 (s, 1H), 6.51 (br d, 1H), 5.24 (t, J=5.2 Hz, 1H), 4.41 (d, J=5.2 Hz, 2H), 3.49-3.46 (m, 4H), 1.58-1.50 (m, 6H).
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:23])[CH:22]=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[C:14]3[N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:10]1=[O:30])C1C=CC=CC=1.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[B+3].FC(F)(F)C([O-])=O>C(O)(C(F)(F)F)=O>[Br:23][C:21]1[CH:22]=[C:15]2[C:14]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:13][CH:12]=[C:11]3[C:16]2=[C:17]([CH:20]=1)[C:18](=[O:19])[N:9]([OH:8])[C:10]3=[O:30]
Reactant: O=C1c2ccc(N3CCCCC3)c3cc(Br)cc(c23)C(=O)N1OCc1ccccc1
Agent: O=C([O-])C(F)(F)F
Agent: [B+3]
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccc(N3CCCCC3)c3cc(Br)cc(c23)C(=O)N1O
Yield: 28.1 %

Procedure:
Following the procedure of Example 52, 2-benzyloxy-5-bromo-7-(piperidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.090 g, 0.19 mmol, from Example T1-B), and a 1.0 M solution of boron tris(trifluoroacetate) in TFA (2 mL) were reacted to give 0.020 g of the title compound as the trifluoroacetate salt, mp 134-136° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:33][C:34]([F:37])([F:36])[F:35].[N:38]1[CH:43]=[CH:42][C:41]([NH:44][C:45](=O)[O:46]C2C=CC=CC=2)=[CH:40][CH:39]=1>O1CCOCC1>[F:27][C:24]([F:25])([F:26])[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:45]([NH:44][C:41]4[CH:42]=[CH:43][N:38]=[CH:39][CH:40]=4)=[O:46])=[C:3]([O:33][C:34]([F:36])([F:37])[F:35])[CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1)([OH:32])[C:28]([F:29])([F:30])[F:31]
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1OC(F)(F)F
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1OC(F)(F)F
Temperature: 80 °C
Yield: 4.8 %

Procedure:
(4-Amino-3-(trifluoromethoxy)phenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (0.367 mmol, 200 mg) and phenyl pyridin-4-ylcarbamate (0.550 mmol, 118 mg) were combined in dioxane (2 mL) and heated to 80° C. overnight in a reactivial. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography (dichloromethane—4% methanol/dichloromethane) to afford title compound (11.7 mg). MS (ESI) m/z 666.3 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]([O:25]CCCC)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:32][CH2:33][CH2:34][CH3:35])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:32][CH2:33][CH2:34][CH3:35])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCCC)C2)oc1CC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCO[C@@H]1CN(c2nc(C(=O)O)c(CC)o2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 67.2 %

Procedure:
The same operation as in Example (91d) was performed using butyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (113i) (0.2 g, 0.39 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (3 mL) and THF (5 mL), to obtain 119 mg of the title compound as a colorless solid (67%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14]([OH:16])=O)[CH:9]=2)[CH2:4][CH2:3]1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1.N>>[OH:32][C:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][NH:21][C:14](=[O:16])[C:13]2[CH:17]=[CH:18][CH:19]=[N:20][C:12]=2[O:11][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH2:4][CH2:3][C:2]3=[O:1])=[CH:24][CH:25]=1)([CH3:31])[CH3:30]
Reactant: CC(C)(O)c1ccc(CN)cc1
Reactant: O=C1CCc2ccc(Oc3ncccc3C(=O)O)cc21
Agent: N
Product: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)C(=O)CC3)cc1

Procedure:
Prepared from 2-(3-Oxo-indan-5-yloxy)-nicotinic acid and 2-(4-aminomethyl-phenyl)-propan-2-ol. MS (m/e): 435 (M++NH3), 417 (M++1), 400 (100). NMR (CDCl3): 8.62 (dd, J=2,8 Hz, 1H), 8.15 (dd, J=2,5 Hz, 1H), 8.07 (m, 1H), 7.32 (m, 8H), 4.67 (d, J=6 Hz, 2H), 313 (t, J=6 Hz, 2H), 2.72 (dt, J=2,4 Hz, 2H), 1.53 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]12[CH2:18][CH:14]3[CH2:15][CH:16]([CH2:17]1)[C:12](C(O)=O)([CH2:13]3)[CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:24](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[OH-].[K+].OS([O-])(=O)=O.[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][C:10]12[CH2:18][CH:14]3[CH2:15][CH:16]([CH2:17]1)[C:12]([NH2:24])([CH2:13]3)[CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)C12CC3CC1CC(COCc1ccccc1)(C3)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [I-]
Solvent: Cc1ccccc1
Product: NC12CC3CC1CC(COCc1ccccc1)(C3)C2
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a stirred mixture of 1-[(benzyloxy)methyl]tricyclo[3.3.1.03,7]nonane-3-carboxylic acid (1.8 g, 6.3 mmol) obtained in step III, triethylamine (2.6 mL, 18.9 mmol) and toluene (25 mL) at ice bath temperature was added diphenylphosphoryl azide (1.5 mL, 6.93 mmol). The reaction mixture was warmed to r.t, stirred for one hour, and then refluxed for 4 h. Upon completion of the reaction, the reaction mixture was transferred to a separatory funnel and washed with water. The organic layer was stirred with aq. KOH solution (50% w/v, 12.6 mL), and nBu4NI (120 mg, 0.32 mmol) for 2 h. The reaction mixture was cooled to ice bath temperature, acidified with 2N KHSO4 to pH 2, extracted with ether, the aqueous layer was basified with aq. NaOH solution (50% w/v) and extracted with chloroform. The combined organic layers were dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure to obtain 1-[(benzyloxy)methyl]tricyclo[3.3.1.03,7]nonan-3-amine (0.82 g) as viscous liquid in 51% yield. m/z (M+1) 258; 1H NMR (CDCl3) 300 MHz δ 7.37-7.24 (m, 5H), 4.50 (s, 2H), 3.24 (s, 2H), 2.37-2.29 (m, 1H), 2.0-1.81 (m, 3H), 1.78-1.70 (m, 1H), 1.70-1.45 (m, 7H), 1.40 (dd, J=2.9, 10.7 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH2:17][F:18])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[C:20]([C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1)#[N:21]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:15])([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28](=[O:29])[C:25]3[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:27][N:26]=3)[CH:3]=[CH:4][C:5]=2[F:19])([CH2:17][F:18])[N:9]=1
Reactant: NC1=N[C@](CF)(c2cc(N)ccc2F)C(F)(F)CO1
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: N#Cc1ccc(C(=O)Nc2ccc(F)c([C@@]3(CF)N=C(N)OCC3(F)F)c2)nc1
Yield: 74 %

Procedure:
In a manner analogous to that described in Example 1, the condensation of (S)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-fluoromethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate F8.1) and 5-cyanopicolinic acid yielded the title compound (35 mg, 74% yield) as a light yellow foam. MS (ISP): m/z=408.4 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])=O.Cl.[CH3:39][O:40][NH2:41]>N1C=CC=CC=1>[CH3:39][O:40][N:41]=[CH:1][C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9]
Reactant: O=Cc1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=Cc1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
The product from Example 76E (132 mg, 0.26 mmol) in pyridine (5 mL) was treated with O-methylhydroxylamine hydrochloride (26 mg, 0.32 mmol). After stirring for 1 hour at room temperature, the volatiles were evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1N HCl, water, brine, dried (Na2SO4), filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 100:1:1 ethyl acetate:formic acid:water) to provide the title compound as a white solid (43 mg, 31%).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14](C)=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:31][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)s2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccs2)=CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-[5,6-dihydro-5,5-dimethyl-8-(5-methyl-2-thienyl)-2-naphthalenyl]ethynylbenzoate (Compound 33) (35.0 mg, 0.082 mmol) in 2 ml of EtOH and 1 ml THF at room temperature was added aqueous NaOH (1 ml, 1 M, 1 mmol). The resulting solution was stirred at room temperature overnight and then acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (d6-acetone): δ 8.03 (2H, d, J=8.6 Hz), 7.63 (2H, d, J=8.6 Hz), 7.54-7.48 (3H, m), 6.89 (1H, m), 6.18 (1H, t, J=4.7 Hz), 2.49 (3H, s), 2.35 (2H, d, J=4.7 Hz), 1.32 (6H, s).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:34]([O:38][C:39]([NH:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[C:49]1[CH:54]=[CH:53][C:52]([CH2:55]O)=[CH:51][CH:50]=1)=[O:40])([CH3:37])([CH3:36])[CH3:35].S([O-])(=O)(=O)C>CN(C)C=O>[CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:55][C:52]2[CH:51]=[CH:50][C:49]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[CH2:42][NH:41][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])=[CH:54][CH:53]=2)[C:18]1=[O:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1ccc(CO)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)OC(C)(C)C)cc2)C1=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
To a solution of 514 mg (1.22 mmol) of 3-[2(R)-benzyloxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide in 5 mL of dry dimethylformamide under nitrogen was added 53 mg (1.34 mmol) of 60% sodium hydride/oil dispersion. After stirring for 15 minutes, a solution of 499 mg (1.28 mmol) of 2'-[(t-Butoxycarbonylamino)methyl]-1,1-biphenyl-4-methanol, methanesulfonate ester (Example 11, Step I) in 2 mL of dry dimethylformamide was added by cannula. The flask which originally contained the mesylate was rinsed with 1 mL of dimethylformamide which was added to the reaction mixture. After stirring at room temperature for 2 hours, the reaction mixture was diluted with 200 mL of ethyl acetate, washed with water (2×40 mL) and 40 mL of saturated aqueous sodium chloride. The organic layer was removed, dried over sodium sulfate, filtered and the solvent removed under vacuum. The residue was purified by flash chromatography on silica gel eluting with chloroform/10% concentrated ammonium hydroxide in methanol (94:6) to afford 872 mg (100%) of the product as a white foam. FAB-MS: calculated for C44H54N4O5 718; found 719 (M+H,40%). 1H NMR (200 MHz, CD3OD): 1.11 (s,3H), 1.12 (s,3H), 1.18 (d,6 Hz,3H), 1.39 (s,9H), 1.80-2.05 (m,1H), 2.15-2.38 (m,3H), 2.45-2.70 (m,4H), 3.70 (m,1H), 4.05 (s,2H), 4.42 (dd;5.11 Hz,1H), 4.47 (d,11 Hz, 1H, 4.60 (d,11 Hz, 1H), 4.93 (d,15 Hz, 1H), 4.47 (d,11 Hz, 1H, 4.60 (d,11 Hz, 1H), 4.93 (d,15 Hz, 1H), 7.05-7.40 (m,17H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]([O:18]CC)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)Cc1cccc(OCc2ccc(C(F)(F)F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1cccc(OCc2ccc(C(F)(F)F)cc2)c1
Reaction time: 3 h

Procedure:
To a stirred solution Ethyl 2-(3-(4-(trifluoromethyl)benzyloxy)phenyl)acetate (Step A, 6 g, 17.7 mmol) in absolute ethanol (70 ml) was added 1N NaOH (36 ml) at room temperature. The reaction mixture was stirred for 3 hours, or until all the starting material is gone, concentrated and diluted with chloroform and acidified by 1M HCl to bring the pH to 3.5-4. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to give the title compound as white solid.
Reaction SMILES: Br[C:2]([CH3:13])([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].FC1C=CC([C:21](=[O:25])C(C)C)=CC=1.CC(C1C=CC(OCC(O)COC(C=C)=O)=CC=1)(C1C=CC(OCC(O)COC(C=C)=O)=CC=1)C.C[O-].[Na+]>CO.ClC1C=CC=CC=1>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([O:25][CH3:21])[C:2]([CH3:13])([CH3:12])[O:4]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)c1ccc(F)cc1
Reactant: CC(C)(Br)C(=O)c1ccc(F)cc1
Agent: C=CC(=O)OCC(O)COc1ccc(C(C)(C)c2ccc(OCC(O)COC(=O)C=C)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Clc1ccccc1
Product: COC1(c2ccc(F)cc2)OC1(C)C

Procedure:
100.32 g (0.41 mol) of 2-bromo-1-(4-fluorophenyl)-2-methylpropan-1-one, prepared by brominating 1-(4-fluorophenyl)-2-methylpropan-1-one (as is described in EP-A-3002), are dissolved in 80 ml of dry methanol and 24.3 g (0.45 mol) of sodium methoxide in a solvent mixture of 60 ml dry methanol and 120 ml of chlorobenzene are added dropwise at 20° C. The methanol is then distilled off and the chlorobenzene solution is concentrated. The liquid crude product (90.8 g) is further purified by distillation at 60° C. and 0.2 mm Hg.