Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:24]([CH3:26])[CH3:25])[C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[N:5]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:4](=[O:37])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:49][C:50]1[C:58]2[C:53](=[CH:54][C:55]([F:59])=[CH:56][CH:57]=2)[N:52]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[N:51]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[F:59][C:55]1[CH:54]=[C:53]2[C:58]([C:50]([CH2:49][CH:3]3[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:24]([CH3:26])[CH3:25])[C:13]4[CH:14]=[CH:15][C:16]([O:19][C:20]([F:22])([F:23])[F:21])=[CH:17][CH:18]=4)=[O:11])[C:7]4[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=4[N:5]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:4]3=[O:37])=[N:51][N:52]2[C:60]([O:62][C:63]([CH3:65])([CH3:64])[CH3:66])=[O:61])=[CH:57][CH:56]=1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccc(F)cc21
Reactant: CC(C)N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)c1ccc(OC(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3cc(F)ccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
To a solution of 250 mg of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-trifluoromethoxy-phenyl) acetamide, prepared as in Part C, in 5 mL of dry DMF at 0° C. is added 1.5 mL of a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene. The reaction mixture is stirred for 30 min at 0° C. and a solution of 170 mg of 3-Bromomethyl-6-fluoro-1-tert-butoxycarbonyl-indazole in 3 mL of dry DMF is added dropwise. The reaction mixture is stirred overnight at RT, poured into water and the product extracted with ethyl acetate (2×15 mL). The solvent is removed in vacuo and the residue is purified by silica gel flash column chromatography using hexane/EtOAc 1/1 as eluent to afford 100 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ7.98-6.95 (m,16H) 5.07 (m, 1H), 4.30 (m, 3H), 3.86 (dd, 1H, J=16.5, 6.4), 3.65 (dd, 1H,J=16.5,6.4), 1.69 (s, 9H), 1.13 (d, 6H, J=6.8).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].[NH2:9][C@H:10]1[C@@H:15]2[C@@H:13]([C@H:14]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C@:12]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C@@H:11]1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:4][CH2:5][C:6]([NH:9][C@H:10]1[C@@H:15]2[C@@H:13]([C@H:14]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C@:12]([NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C@@H:11]1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H]2[C@H](N)[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@H]12
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1[C@@H]2[C@H](NC(=O)COC(C)=O)[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@H]12
Reaction time: 2.5 h
Yield: 76.4 %

Procedure:
Add acetoxyacetyl chloride (0.116 mL, 1.08 mmol) to a solution of diethyl (1S,2R,3R,4S,5R,6S)-4-amino-2-(tert-butoxycarbonylamino)-3-[(3,4-dichlorophenyl)methoxy]bicyclo[3.1.0]hexane-2,6-dicarboxylate (0.47 g, 0.89 mmol) and diisoproylethylamine (0.32 mL, 1.83 mmol) in dichloromethane (9 mL) at room temperature. After 2.5 hours, wash the solution with saturated NaHCO3 (2×), brine (1×), dry over MgSO4, filter, and conc. under reduced pressure. Purify by flash chromatography eluting with a gradient of 0 to 100% ethyl acetate in hexanes over 30 min. to yield the title compound as a white solid (0.43 g, 0.68 mmol, 76%). MS (m/z): 531 (M+H-BOC).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].CN(P(N(C)C)(N(C)C)=O)C.I[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1>C1COCC1.[Li]CCCC>[CH2:26]([O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[CH2:25][CH2:24][CH2:23][CH2:22][C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C#CCCCCCCC
Reactant: ICCCCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCCCCCC#CCCCCCOC1CCCCO1
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
1-Nonyne 11 (1.0 g, 8.06 mmol) in THF (20 ml) was treated with n-BuLi (1.7 M in hexanes, 6.6 ml, 0.011 mmol) at 0° C. and the resulting pale yellow solution stirred for a 15 min. HMPA (15 ml) was then added and the mixture stirred for a further 15 min at 0° C. To the resultant dark yellow/orange solution was then added 10 (3.6 g, 0.0121 mol) at 0° C. which resulted in a immediate colour change in the solution to light yellow. This light yellow solution was stirred at r.t. overnight at which stage it was triturated with water and extracted with hexanes. The hexane extract were well washed with water, dried (MgSO4) and concentrated invacuo to afford a light yellow residue which was purified by flash column chromatography (eluent—8.5% EtOAc in hexanes) to yield a the pure 12 (1.6 g, 70%); δH(270 MHz, CDCl3); 0.86 (3H, t, J 6.2), 1.15-1.85 (13H, m), 2.11 (4H, m), 3.30-3.55 (2H, m), 3.69-3.90 (2H, m) and 4.56 (1H, m); δC(67.5 MHz, CDCl3) 14.17, 18.82, 18.82, 19.74, 22.71, 25.57, 25.57, 28.91, 28.91, 29.08, 29.24, 29.38, 30.49, 30.84, 31.84, 62.40, 62.40, 67.57, 67.57, 98.90. MS (EI) 295 (M+H)+; HRMS: Found 295.2616 [M+H]+. Calc. for C19H35O2: 295.263706 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH3:4].FC1C(O[C:17](=[O:30])[O:18][C:19]2[C:24]([F:25])=[C:23]([F:26])[C:22]([F:27])=[C:21]([F:28])[C:20]=2[F:29])=C(F)C(F)=C(F)C=1F.[F-].[Cs+].[O:37]1CCC[CH2:38]1>>[C:17](=[O:30])([O:18][C:19]1[C:20]([F:29])=[C:21]([F:28])[C:22]([F:27])=[C:23]([F:26])[C:24]=1[F:25])[O:1][CH2:2][C:3]1([CH3:4])[CH2:7][O:8][C:38](=[O:37])[O:6][CH2:5]1
Reactant: C1CCOC1
Reactant: CC(CO)(CO)CO
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)Oc1c(F)c(F)c(F)c(F)c1F
Agent: [Cs+]
Agent: [F-]
Product: CC1(COC(=O)Oc2c(F)c(F)c(F)c(F)c2F)COC(=O)OC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
To a 100 mL round bottom flask, 1,1,1-tris(hydroxymethyl)ethane (2.0 g, 16.7 mmol) was combined with bis(pentafluorophenyl)carbonate (15.1 g, 38.3 mmol, 2.3 eq.) and cesium fluoride (0.76 g, 5.0 mmol, 0.3 eq.) in anhydrous tetrahydrofuran (THF) (11.9 mL) and stirred for four hours at room temperature. Initially the reaction was heterogeneous, but after one hour the reaction formed a clear homogeneous solution. The reaction was concentrated in vacuo (100 mm Hg, 30° C.) and the residue was dissolved in methylene chloride (˜50 mL). Upon standing (˜10 min), the pentafluorophenol byproduct precipitated from solution and was recovered by filtration. The mother liquor was washed with aqueous sodium bicarbonate (3×50 mL) until the pH of aqueous layer was ˜8 and then with brine (1×50 mL). The organic layer was separated and dried over anhydrous sodium sulfate. The solution was concentrated to give the crude product that was purified by recrystallization. The crude product was dissolved in ethyl acetate (24 mL) at 65° C. n-Hexane (35 mL) was added at the same temperature, and the resulting solution was allowed to cool to room temperature. After stirring the solution overnight, the white crystalline product TMCPFP was separated by filtration (4.0 g, 67% yield). m.p. 130-131° C. 1H NMR (CDCl3, 400 Hz) 1.22 (s, 3H), 4.23 (d, 2H, J=11 Hz), 4.37 (s, 2H), 4.38 (d, 2H, J=11 Hz). 19F NMR (CDCl3, 376 Hz) −154.3˜−154.3 (m, 2F), −157.8 (t, 1F, J=22 Hz), −162.6˜−162.7 (m, 2F). 13C NMR (CDCl3, 100 Hz) 16.8, 32.6, 70.3, 73.0, 125.4, 137.9, 140.1, 141.3, 147.4, 151.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:25][CH2:24][C:19]4([O:23][CH2:22][CH2:21][O:20]4)[CH2:18][CH2:17]3)[CH2:12][CH:11]=2)=[C:6]([F:26])[C:5]=1[F:27])[CH3:2].C([OH:30])C.[OH-].[Na+].OO>C1COCC1.O>[O:23]1[C:19]2([CH2:24][CH2:25][CH:16]([CH:13]3[CH2:14][CH:15]([OH:30])[CH:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([F:27])[C:6]=4[F:26])[CH2:11][CH2:12]3)[CH2:17][CH2:18]2)[O:20][CH2:21][CH2:22]1
Reactant: CCO
Reactant: CCOc1ccc(C2=CCC(C3CCC4(CC3)OCCO4)CC2)c(F)c1F
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(C2CCC(C3CCC4(CC3)OCCO4)CC2O)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
550 ml (0.55 mol) of borane/THF complex (1 M solution) are added at −5° C. to a solution of 154.0 g (0.41 mol) of 8-[4-(4-ethoxy-2,3-difluorophenyl)-cyclohex-3-enyl]-1,4-dioxaspiro[4.5]decane in 1500 ml of THF, and the reaction mixture is stirred at room temperature for 3 h. 99 ml (1.7 mol) of ethanol, 250 ml (1.0 mol) of aqueous sodium hydroxide solution (16%) and 140 ml (1.6 mol) of aqueous hydrogen peroxide soln. (35%) are added successively to the batch, during which the internal temperature does not exceed 46° C. (ice bath). When the addition is complete, the mixture is refluxed for 2 h, and the solution is cooled, added to water and stirred vigorously. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the crude product is purified by column chromatography (SiO2, toluene:ethyl acetate=8:2), giving 5-(1,4-dioxaspiro[4.5]dec-8-yl)-2-(4-ethoxy-2,3-difluorophenyl)cyclohexanol as colourless, viscous oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[NH2:20][C:21]1[CH:26]=[C:25]([OH:27])[C:24]([CH3:28])=[CH:23][CH:22]=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:27][C:25]1[CH:26]=[C:21]([NH:20][C:2]2[C:11]3[C:6](=[C:7]([O:16][CH3:17])[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:22]=[CH:23][C:24]=1[CH3:28]
Reactant: COc1cc2c(Cl)c(C#N)cnc2c(OC)c1OC
Reactant: Cc1ccc(N)cc1O
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc2c(OC)c1OC
Yield: 76.3 %

Procedure:
A mixture of 0.279 g of 4-chloro-6,7,8-trimethoxy-quinoline-3-carbonitrile, 0.148 g of 5-amino-o-cresol, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 100 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 0.279 g of 4-(3-hydroxy-4-methyl-phenylamino)-6,7,8-trimethoxy-quinoline-3-carbonitrile as a solid, mp 200° C. (decomposed); mass spectrum (EI, m/e): M 365.1356.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([C:14]([O-:16])=[O:15])[O:7][CH2:6][CH2:5]2.O[Li].O>CO.C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([C:14]([OH:16])=[O:15])[O:7][CH2:6][CH2:5]2
Reactant: COc1cc2c(cc1Br)CCOC2C(=O)[O-]
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1Br)CCOC2C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-bromo-7-(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxylate (12 g, 38 mmol) in 50 mL of MeOH/THF/H2O (2/2/1) was added LiOH.H2O (4.79 g, 114 mmol), and the mixture was stirred at ambient temperature overnight. The solvents were removed under vacuum, and to the residue was added 50 mL of water and the mixture was extracted with ether. The aqueous layer was then acidified with 4 N HCl to pH=3 in ice bath, and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to give 6-bromo-7-(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxylic acid.
Reaction SMILES: C[O-].[Na+].[CH2:4]1[O:14][C:13]2[C:6](=[CH:7][C:8]([NH2:15])=[C:9]([CH:12]=2)[CH:10]=O)[O:5]1.[C:16]([CH2:18][C:19]([NH2:21])=[O:20])#[N:17]>CO>[CH2:4]1[O:5][C:6]2[CH:7]=[C:8]3[C:9]([CH:10]=[C:18]([C:19]([NH2:21])=[O:20])[C:16]([NH2:17])=[N:15]3)=[CH:12][C:13]=2[O:14]1
Reactant: N#CCC(N)=O
Reactant: Nc1cc2c(cc1C=O)OCO2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cc2cc3c(cc2nc1N)OCO3
Yield: 89.3 %

Procedure:
To sodium methoxide (1.90 g., 0.03 mole) in methanol (50 ml.) is added 4,5-methylenedioxy-2-aminobenzaldehyde (5.0 g., 0.03 mole) and 2-cyanoacetamide (2.50 g., 0.03 mole). The mixture is heated to reflux for 15 minutes and then cooled in an ice bath. The bright yellow solid is filtered off and recrystallized from acetic acid to give 6.18 g. (89.3%) of the desired product. M.P. 308° C. (dec.). (m/e) = 231).
Reaction SMILES: [S:1](S([O-])=O)([O-:4])(=[O:3])=[O:2].[Na+].[Na+].[NH2:10][C:11]1[N:16]=[CH:15][C:14]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:13]2[N:12]=1>O.C(O)C>[NH2:10][C:11]1[NH:16][CH:15]([S:1]([OH:4])(=[O:3])=[O:2])[C:14]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:13]2[N:12]=1
Reactant: CCCc1nc(C)c2cnc(N)nn12
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1nc(C)c2n1N=C(N)NC2S(=O)(=O)O

Procedure:
Sodium metabisulphite (1.5 g.) in water (45 ml.) was added to 2-amino-5-methyl-7-propylimidazo[5,1-f]-as-triazine (Example 4) (1.9 g.) in ethanol (20 ml.). The solid was collected and dried and had m.p. 232°-234°.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][N:16]([CH3:18])[CH3:17])[CH:13]=2)[NH:8][C:7]=1[C:19]([F:22])([F:21])[F:20])C.[NH3:24]>CO>[CH3:17][N:16]([CH2:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:19]([F:22])([F:21])[F:20])=[C:6]2[CH2:5][C:4]([NH2:24])=[O:3])[CH3:18]
Reactant: N
Reactant: CCOC(=O)Cc1c(C(F)(F)F)[nH]c2ccc(CN(C)C)cc12
Solvent: CO
Product: CN(C)Cc1ccc2[nH]c(C(F)(F)F)c(CC(N)=O)c2c1
Temperature: 80 °C
Reaction time: 144 h
Yield: 100 %

Procedure:
A solution of (5-dimethylaminomethyl-2-trifluoromethyl-1H-indol-3-yl)-acetic acid ethyl ester (200 mg, 0.609 mmol) in a mixture of methanol (5 mL) and liquid ammonia (30 mL) is stirred for 6 days in an autoclave at 80° C. After careful evaporation of the ammonia, the remaining solvent is evaporated in vacuo to afford the title compound as a red solid (182 mg, 0.609 mmol, 100%). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=12.18 (bs, 1H), 7.75 (s, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.42 (bs, 1H), 7.35 (d, J=8.6 Hz, 1H), 6.95 (bs, 1H), 3.67 (s, 2H), 3.16 (s, 2H), 2.62 (s, 6H). MS (ES+): 248 (M(C14H17NO3)+H)+. MS (ES+): 300 (M(C14H16F3N3O)+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]([CH3:15])[CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[C:16]([O-])(=O)[CH3:17].[Na+].[BH4-].[Na+].[C:23](O)(=O)C>C(O)C.O.CC(C)=O>[CH3:11][C:7]1([CH3:10])[C:6]2[CH:12]=[C:2]([NH:1][CH:16]([CH3:17])[CH3:23])[CH:3]=[C:4]([CH:13]([CH3:15])[CH3:14])[C:5]=2[O:9][CH2:8]1
Reactant: CC(C)c1cc(N)cc2c1OCC2(C)C
Reactant: CC(=O)[O-]
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCO
Product: CC(C)Nc1cc(C(C)C)c2c(c1)C(C)(C)CO2
Yield: 56.6 %

Procedure:
Following general procedure J and using 5-amino-3,3-dimethyl-7-isopropyl-2,3-dihydro-benzofuran (Compound 13, 0.296 g, 1.5 mmol), sodium acetate (0.53 g, 3.9 mmol) and sodium borohydride (1.47 g, 25 mmol) in 5 mL of ethanol, 5 mL of water, 5 mL of acetone (excess) and acetic acid (1.25 mL, 32.74 mmol), the title compound (0.21 g, 60%) was obtained as an oil which was purified by flash column chromatography using 5% ethyl acetate in hexanes as the eluent. 1H NMR (300 MHz, CDCl3): δ 6.30 (d, 1H, J=2.3 Hz), 6.26 (d, 1H, J=2.3 Hz), 4.14 (s, 2H), 3.54 (heptet, 1H, J=6.3 Hz), 3.03 (heptet, 1H, J=7.0 Hz), 1.29 (s, 6H), 1.22 (d, 6H, J=7.0 Hz), 1.19 (d, 6H, J=6.3 Hz).
Reaction SMILES: C1(P(=[N:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=1[N:44]=[C:45]=O.[Cl:47][C:48]1[CH:49]=[C:50]([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH:51]=[CH:52][CH:53]=1>>[Cl:47][C:48]1[CH:49]=[C:50]([N:54]2[CH2:59][CH2:58][N:57]([C:45]3[N:44]([C:35]4[CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=[CH:39][C:34]=4[F:33])[CH:27]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:22]4[C:21](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=3)[CH2:56][CH2:55]2)[CH:51]=[CH:52][CH:53]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)/C=C/c1ccccc1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Clc1cccc(N2CCNCC2)c1
Product: COC(=O)CC1c2ccccc2N=C(N2CCN(c3cccc(Cl)c3)CC2)N1c1cc(C(F)(F)F)ccc1F

Procedure:
Starting with 150 mg (0.34 mmol) of the iminophosphorane from Example 3A, 74 mg (0.34 mmol) of 2-fluoro-5-(trifluoromethyl)phenyl isocyanate and 67 mg (0.34 mmol) of N-(3-chlorophenyl)piperazine, the general procedure [E] and chromatographic purification (method 2) give 95 mg (50% of theory) of product.
Reaction SMILES: C([N:9]1[CH2:18][C:17]2[CH:16]=[N:15][C:14]3[CH:19]=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:13]=3[C:12]=2[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.O[Li].O.C(O)(C)C>CO.O>[CH3:26][O:25][C:20]1[C:21]([O:23][CH3:24])=[CH:22][C:13]2[C:12]3[CH2:11][CH2:10][NH:9][CH2:18][C:17]=3[CH:16]=[N:15][C:14]=2[CH:19]=1
Reactant: COc1cc2ncc3c(c2cc1OC)CCN(C(=O)c1ccccc1)C3
Agent: [Li]O
Solvent: CC(C)O
Solvent: CO
Solvent: O
Product: COc1cc2ncc3c(c2cc1OC)CCNC3
Temperature: 64 °C
Yield: 58.3 %

Procedure:
A 2 L three-necked, round-bottomed flask, was equipped with a magnetic stirrer and stir bar, condenser, heating bath, thermocouple and nitrogen inlet. A stirred solution of 3-benzoyl-8,9-dimethoxy-1,2,3,4-tetrahydrobenzo[c]-2,7-naphthyridine (25.9 g, 74.4 mmol) and LiOH.H2O (34.4 g, 819 mmol) in methanol (800 mL) and water (55 mL) was heated at gentle reflux (internal temperature 62-66° C.) for 20 hours. Solvents were removed under reduced pressure and the residue was stirred in a mixture of methanol (180 mL) and dichloromethane (3 L) overnight. The batch was washed with saturated aqueous sodium chloride (0.5 L) diluted with water (0.4 L), and the separated organic layer was dried over anhydrous sodium sulfate (100 g). Removal of the drying agent by filtration and evaporation of solvent in vacuo gave a crude dark brown solid (12.1 g). The crude product was stirred in refluxing isopropanol (35 mL) for 1 hour, cooled to 22° C., and collected on a fritted glass funnel to afford the title compound as a grey solid (10.6 g, 58% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[OH:19])=O)=[CH:6][C:5]([C:20]2[CH:21]=[N:22][N:23]([CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[CH:24]=2)=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.N>C(O)(=O)C.CN(C=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]2[N:10]=[C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:20]4[CH:21]=[N:22][N:23]([CH:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)[CH:24]=4)[CH:6]=3)[O:19][C:12]=2[CH:13]=1
Reactant: COc1ccc(NC(=O)c2cc(-c3cnn(C4CCN(C)CC4)c3)cnc2N)c(O)c1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3cc(-c4cnn(C5CCN(C)CC5)c4)cnc3N)oc2c1
Temperature: 200 °C
Yield: 23.7 %

Procedure:
To a solution of 2-amino-N-(2-hydroxy-4-methoxy-phenyl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridine-3-carboxamide (110 mg) in acetic acid (1.8 ml) was added TFA (1.8 ml). The clear mixture was sealed into a microwave tube. The reaction was heated to 200° C. a 300 W microwave for 20 minutes. The solvents were evaporated. The residue was trituratred in diethyl ether, dried to give a yellow solid. The solid was dissolved in DMF (1.5 ml) and two drops of a 30% aqueous ammonia solution. The precipitate was filtered, washed with Ether and dried at 50° C. for 48 h to afford 3-(6-methoxy-1,3-benzoxazol-2-yl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (25.00 mg). NMR Spectrum: (DMSOd6) 1.93-2.12 (m, 6H), 2.22 (s, 3H), 2.94-2.91 (m, 2H), 3.86 (s, 3H), 4.07-4.16 (m, 1H), 7.03 (dd, 1H), 7.40 (d, 1H), 7.57 (bs, 2H), 7.72 (d, 1H), 7.89 (d, 1H), 8.30 (s, 1H), 8.36 (d, 1H), 8.49 (d, 1H). Mass spectrum: M+H+ 405.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:29][CH2:30][C:31]([OH:33])=O)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=[N:40]C=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:29][CH2:30][C:31]([NH2:40])=[O:33])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(OCC(F)(F)F)cc1)N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)OC1=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc(OCC(F)(F)F)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.6 %

Procedure:
To a solution of 3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1,3-oxazinan-6-yl)propanoic acid (145 mg, 1.37 mmol) in CH2Cl2 (5 mL) was added HOBt (167 mg, 1.24 mmol), EDCl (243 mg, 1.24 mmol) and DIEA (194 mg, 1.55 mmol) under NH3 at 0° C. The mixture was stirred at rt overnight. 1N HCl was added and the mixture was extracted with CH2Cl2. The organic layer was dried and concentrated to give the residue, which was purified by preparative HPLC to give 3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1,3-oxazinan-6-yl)propanamide (21 mg, 15%). LC-MS Method 2 tR=1.16 min, m/z=491, 469, 425. 1H NMR (CDCl3, 400 MHz): 1.43 (d, 3H), 1.88-1.95 (m, 1H), 2.07-2.19 (m, 5H), 2.40 (m, 1H), 2.83 (m, 1H), 4.21 (m, 1H), 5.18 (s, 1H), 5.33 (s, 1H), 5.56 (m, 1H), 6.64 (d, 2H), 6.85 (d, 2H), 6.97 (t, 2H), 7.17 (m, 2H).
Reaction SMILES: [C:1]1(=O)[N:5]([CH2:6]/[CH:7]=C/CBr)[C:4](=O)[C:3]2=[CH:12][CH:13]=CC=[C:2]12.C([NH:19]CC)C.[F-].[K+].[ClH:24]>C(#N)C.C(O)(=O)C>[ClH:24].[ClH:24].[CH2:1]([N:5]([CH2:6][CH3:7])[CH2:4]/[CH:3]=[CH:12]/[CH2:13][NH2:19])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1C/C=C/CBr
Reactant: CCNCC
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCN(CC)C/C=C/CN
Yield: 41 %

Procedure:
(E)-1-Phthalimido-4-bromobut-2-ene (4.2 g, 15 mmol), diethylamine (1.1 g, 15 mmol) and KF supported on Celite (7.5 g) were stirred together in acetonitrile (75 ml) at 40° C. for 18 h. The solution was filtered, and the filtrate was concentrated in vacuo to afford an oil, which was dissolved in glacial acetic acid (30 ml) and conc. HCl (30 ml). The mixture was heated at reflux for 30 h. The solution was cooled, filtered and the solvents were removed in vacuo to afford (E)-N,N-diethyl-1,4-diaminobut-2-ene dihydrochloride as an oil (1.32 g, 41%). δH (90 MHz, D2O) 1.19 (6H, m) 3.24 (4H, q), 4.05 (4H, m) and 5.96 (2H, m).