Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH2:12])=[O:11])=[CH:5][CH:4]=1.C(C1C=C(O)C=C(C(C)(C)C)C=1C)(C)(C)C.Cl[C:30]([S:32]Cl)=[O:31].Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[O:11][C:30](=[O:31])[S:32][N:12]=2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)SCl
Reactant: COc1ccc(CC(N)=O)cc1
Agent: Cc1c(C(C)(C)C)cc(O)cc1C(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1ccc(Cc2nsc(=O)o2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
To a suspension of 4-methoxyphenylacetamide (5.06 g, 30.0 mmol) in toluene (10 mL) was added 2,6-di-t-butyl-4-hydroxytoluene (132 mg, 0.60 mmol) and chlorocarbonylsulfenyl chloride (5.52 mL, 60.0 mmol). The resulting mixture was warmed to 115° C. for 80 min during which time hydrochloric acid gas was evolved resulting in a yellow solution. To this solution additional chlorcarbonyl-sulfenylchloride (1.38 mL, 15.00 mmoles) was added and the mixture heated for 40 min and allowed to stand at room temperature overnight. The reaction mixture was cooled to 0° C. and stirred for 10 min before being filtered to remove a beige solid. The solid was washed with cold toluene (2×10 mL) and the filtrate was concentrated and purified by flash chromatography (silica gel, 20% ethyl acetate/hexanes) which afforded 5-(4-methoxy-benzyl)-[1,3,4]oxathiazol-2-one (1.12 g, 17%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH2:4][OH:5].[H-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[I-].[Na+]>CN(C)C=O.C(OCC)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH2:4][O:5][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][Cl:13]
Reactant: ClCCCCCBr
Reactant: OCc1cc(Br)ccc1F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Fc1ccc(Br)cc1COCCCCCCl

Procedure:
In a 50 ml flask, under a nitrogen atmosphere, 2-fluoro-5-bromobenzyl alcohol (2.139 g, 10.4 mmol) was dissolved in N,N-dimethylformamide (25 ml). To this solution sodium hydride (60%, 625 mg, 15.6 mmol) was added and the resulting mixture was stirred for twenty minutes. To the reaction mixture 5-chloropentyl bromide was added and the resulting mixture was stirred for two hours at ambient temperature. The progress of the reaction was monitored by thin layer chromatography. Sodium iodide (3.127 g, 20.9 mmol) was added and the resulting mixture was stirred at ambient temperature for three hours. The reaction mixture was diluted with diethyl ether and washed seven times with brine. The solvents were removed in vacuo. The title intermediate was further purified by silica gel.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=O)[CH2:11][CH2:12][CH3:13])=[N:8][CH:9]=1)([OH:3])=[O:2].Cl.[NH2:16][OH:17]>N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10](=[N:16][OH:17])[CH2:11][CH2:12][CH3:13])=[N:8][CH:9]=1)([OH:3])=[O:2]
Reactant: CCCC(=O)c1ccc(C(=O)O)cn1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(=NO)c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 1-(5-carboxy-2-pyridinyl)-1-butanone (2 mmol) in 20 ml of pyridine, hydroxylamine hydrochloride (4 mmol) is added. The reaction mixture is stirred at room temperature for 5 h. The solvent is distilled off and the residue crystallized from ethyl acetate; m.p. 203°-205°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:5]=[C:4](Cl)[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:5]=[C:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])[N:3]=1
Reactant: N#Cc1ccc(-c2cc(Cl)nc(N)n2)cc1F
Reactant: COc1ccccc1B(O)O
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: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccccc1-c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A mixture of 4-(2-amino-6-chloro-4-pyrimidinyl)-2-fluorobenzonitrile (298 mg, 1.2 mmol), [2-(methyloxy)phenyl]boronic acid (273 mg, 1.8 mmol) and Na2CO3 (318 mg in 2 mL of water) in 1,4-dioxane (8 mL), was degassed with N2. Pd(PPh3)4 (69 mg, 0.06 mmol) was added, and the reaction mixture was stirred overnight at 95° C. The reaction was poured onto water and EtOAc. The organic layer was separated, and the aqueous layer was further extracted with EtOAc (2×). The combined organic layers were dried (MgSO4), filtered and concentrated to afford the crude title compound (306 mg). LC-MS (ES) m/z=321 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14]I)[C:6]=2[CH:17]=1.[CH2:18]([CH:23]1[CH2:29][CH:28]2[NH:30][CH:25]([CH2:26][CH2:27]2)[CH2:24]1)[CH2:19][CH2:20][CH2:21][CH3:22]>CCCCCCC.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C@H:13]([CH3:16])[CH2:14][N:30]3[CH:25]4[CH2:26][CH2:27][CH:28]3[CH2:29][CH:23]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:24]4)[C:6]=2[CH:17]=1
Reactant: CCCCCC1CC2CCC(C1)N2
Reactant: C[C@H](CI)CN1C(=O)COc2ccc(F)cc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccc(F)cc21
Yield: 71 %

Procedure:
The compound (S)-6-Fluoro-4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF04) (0.208 g, 0.6 mmol) and 3-Pentyl-8-azabicyclo[3.2.1]octane (0.10 g, 0.56 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF27) (0.16 g, 58%). 1H NMR (CDCl3) δ 7.13 (dd, J=2.8 Hz, J=10.0 Hz, 1H), 6.90 (dd, J=5.2 Hz, J=8.8 Hz, 1H), 6.68-6.63 (m, 1H), 4.57 (q, J=14.8 Hz, J=40.0 Hz, 1H), 4.11-3.94 (m, 2H), 3.14-3.04 (m, 2H), 2.30 (dd, J=4.0 Hz, J=12.8 Hz, 1H), 2.20-2.09 (m, 2H), 2.06-2.00 (m, 1H), 1.95-1.82 (m, 3H), 1.71-1.52 (m, 3H), 1.40-1.34 (m, 2H), 1.32-1.19 (m, 8H), 0.89-0.85 (m, 6H); 13C NMR (CDCl3) δ 164.9, 158.5 (d, J=239.4 Hz), 141.6 (d, J=2.6 Hz), 130.0 (d, J=10.8 Hz), 117.5 (d, J=9.3 Hz), 109.4 (d, J=23.4 Hz), 103.8 (d, J=28.9 Hz), 67.8, 61.0, 59.0, 58.2, 45.5, 38.4, 36.6, 36.5, 32.8, 31.8, 28.4, 28.4, 28.2, 27.2, 22.8, 7.0, 14.2.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[CH:24]([NH2:28])([CH2:26][CH3:27])[CH3:25]>CN1C(=O)CCC1.CCOC(C)=O>[CH:24]([NH:28][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1)([CH2:26][CH3:27])[CH3:25]
Reactant: Clc1ccc2ncc(Cc3ccc4ncccc4c3)n2n1
Reactant: CCC(C)N
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCC(C)Nc1ccc2ncc(Cc3ccc4ncccc4c3)n2n1
Temperature: 180 °C
Reaction time: 29 h

Procedure:
6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-quinoline (Example 14, 70 mg, 0.237 mmol), KF (70 mg, 1.187 mmol) and sec-butylamine (484 μL, 4.75 mmol) were suspended in NMP (1 mL). The RM was stirred at 180° C. for 29 h. The mixture was diluted with EtOAc and washed with 1 M Na2CO3 (×1) and water (×2). The aqueous was further extracted with EtOAc (2×). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (Flashmaster) and then crystallized in Et2O to afford the title compound as a beige solid (tR 4.28 min (conditions 4), MH+ 332.3, 1H-NMR in DMSO-d6: 8.83 (m, 1H); 8.25 (m, 1H); 7.92 (d, 1H); 7.83 (m, 1H); 7.70 (m, 1H); 7.61 (d, 1H); 7.48 (dd, 1H); 7.32 (s, 1H); 6.66 (d, 1H); 6.56 (d, 1H); 4.34 (s, 2H); 3.70 (m, 1H); 1.46 (m, 2H); 1.07 (d, 3H); 0.80 (t, 3H)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:27])[CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH2:28](O)[CH2:29][OH:30].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:30][CH2:29][CH2:28][O:27]2)[CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(CCC1CCN(C(=O)OCc2ccccc2)CC1)c1ccc(F)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(CCC2(c3ccc(F)cc3)OCCO2)CC1
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 71 mg (0.19 mmol) of 4-(3-(4-fluorophenyl)-3-oxo-propyl)-1-(benzyloxycarbonyl) piperidine (from EXAMPLE 189, Step B), 0.05 mL (0.9 mmol) of ethylene glycol and 5 mg (0.26 mmol) of p-toluene sulfonic acid x H2O in 3 mL of toluene was heated at 80° C. After 1 h, and additional 5 mg of p-toluene sulfonic acid×H2O was added and the resulting mixture was heated at reflux. After 2 h, the mixture was cooled and partitioned between 30 mL of ether and 10 mL of 1.0 N NaOH. The organic layer was separated, dried and concentrated. Flash chromatography on 4 g of silica gel using 3:1 v/v hexanes/ether afforded 66 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.00-1.10 (m, 2H), 1.261.36 (3H), 1.50-1.60 (m, 2H), 1.86-1.89 (m, 2H), 2.65-2.75 (m, 2H), 3.71-3.78 (m, 2H), 3.96-4.03 (m, 2H), 4.064.16 (m, 2H), 5.10 (s, 2H), 6.99-7.04 (m, 2H), 7.26-7.40 (7H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/I)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.[S:26]1[C:30]([Sn](CCCC)(CCCC)CCCC)=[CH:29][C:28]2[CH:44]=[CH:45][CH:46]=[CH:47][C:27]1=2.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1CCCCC1>CN(C)C=O>[S:26]1[C:30](/[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:9]\[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:29][C:28]2[CH:44]=[CH:45][CH:46]=[CH:47][C:27]1=2
Reactant: COC(=O)COc1ccc(OC/C=C(\I)c2ccc(Br)cc2)cc1C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2ccccc2s1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(Br)cc2)c2cc3ccccc3s2)cc1C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Methyl (Z)-[4-[3-(4-bromophenyl)-3-iodoallyloxy]-2-methylphenoxy]acetate (760 mg, 1.47 mmol) and (benzo[b]thiophen-2-yl)-tributyltin (0.72 g, 1.7 mmol) were dissolved in anhydrous N,N-dimethylformamide (20 mL) and the solution was degassed. 0.15 M solution of tri-t-butylphosphine in cyclohexane (1.2 mL, 0.18 mmol) and tris(dibenzylidenacetone)dipalladium chloroform complex (46 mg, 0.044 mmol) were added; the reaction solution was degassed again and then stirred under inert atmosphere at 50° C. for 2 h. The reaction mixture was diluted with ethyl acetate (50 mL) and extracted with 10% aqueous solution of potassium fluoride (50 mL), water (2×50 mL) and brine (2×30 mL). The organic layer was dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 95:5-90:10) yielding methyl (Z)-[4-[3-(benzo[b]thiophen-2-yl)-3-(4-bromophenyl)allyloxy]-2-methylphenoxy]-acetate.
Reaction SMILES: [CH2:1]([CH:4]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][CH:5]1[CH2:11]O)[CH:2]=[CH2:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:44]1(=[O:54])[NH:48][C:47](=[O:49])[C:46]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:45]12>C1COCC1>[CH2:1]([CH:4]1[O:8][C:7]([CH3:9])([CH3:10])[O:6][CH:5]1[CH2:11][N:48]1[C:44](=[O:54])[C:45]2[C:46](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:47]1=[O:49])[CH:2]=[CH2:3]
Reactant: C=CCC1OC(C)(C)OC1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCC1OC(C)(C)OC1CN1C(=O)c2ccccc2C1=O
Reaction time: 0.33 h
Yield: 96.3 %

Procedure:
To a stirred solution of compound 2 (2.8 g, 16.3 mmol) in THF (120 mL) were added PPh3 (6.4 g, 24.4 mmol) and DEAD (40% in toluene, 10.6 mL, 24.3 mmol) at 0° C. After 20 min stirring, phthalimide (3.59 g, 24.4 mmol). The reaction mixture was stirred overnight at room temperature, concentrated, diluted with EtOAc (300 mL) and extracted with aq. NaHCO3 solution (100 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc=2/1) to give compound 3 (4.74 g, 15.7 mmol, 97%) as an oil. 1H NMR (CDCl3, 300 MHz) δ 7.80-7.85 (m, 2H), 7.68-7.73 (m, 2H), 5.82 (m, 1H), 5.13-5.24 (m, 2H), 4.48 (m, 1H), 4.26 (m, 1H), 3.90 (dd, 1H, J=10.5, 13.5), 3.52 (dd, 1H, J=3.0, 13.5), 2.37-2.57 (m, 2H), 1.53, 1.30 (2s, 6H); 13C NMR (CDCl3, 75 MHz) δ 168.5, 134.1, 133.9, 132.4, 123.5, 118.0, 109.1, 76.5, 74.3, 39.1, 33.5, 28.2, 26.1.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)=[C:5]([C:12]([OH:14])=O)[CH:4]=[N:3]1.N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:23]>ClCCl>[CH3:1][N:2]1[C:6]([N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)=[C:5]([C:12]([F:23])=[O:14])[CH:4]=[N:3]1
Reactant: Cn1ncc(C(=O)O)c1-n1cccc1
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1ncc(C(=O)F)c1-n1cccc1
Reaction time: 2 h

Procedure:
To a stirred solution of 1-methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid (7.65 g, 40 mmol) in dry dichloromethane (150 mL) and pyridine (3.2 mL, 40 mmol) under a nitrogen atmosphere was added cyanuric fluoride (5.4 g, 40 mmol) at 0° C. The reaction mixture was stirred for two hours during which time the reaction temperature was allowed to rise to room temperature. Crushed ice was then added along with additional dichloromethane. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. Concentration of the combined organic layers under reduced pressure gave 1-methyl-5-pyrrol-1-yl-1H-pyrazole-4-carbonyl fluoride which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][O:12][C:11]2[CH:15]=[CH:16][C:17](B(O)O)=[CH:18][C:10]=2[S:9]1(=[O:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].B1([O-])O[O:25]1.O.O.O.O.[Na+].[NH4+].[Cl-]>C1COCC1.O>[OH:25][C:17]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[S:9](=[O:23])(=[O:22])[C:10]=2[CH:18]=1
Reactant: [O-]B1OO1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2S1(=O)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOc2ccc(O)cc2S1(=O)=O

Procedure:
A suspension of 4.7 g (13.69 mmol) of the product of Step G of Example 1 in a mixture of 90 ml of THF and 90 ml of water is stirred at ambient temperature in the presence of 5.27 g (34 mmol) of sodium perborate tetrahydrate overnight. The reaction mixture is diluted by adding saturated aqueous NH4Cl solution and is then extracted with CH2Cl2. The organic phases are combined, washed (saturated NaCl), dried (MgSO4) and evaporated using a rotary evaporator. The residue from evaporation is taken up and triturated in heptane in the presence of a few drops of isopropyl ether; a precipitate is formed which is filtered off to yield the expected product.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:6]=[C:5]1[CH2:21][OH:22].Cl[CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]>CN(C=O)C.CN(P(N(C)C)(N(C)C)=O)C>[CH3:3][N:4]1[C:8]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:6]=[C:5]1[CH2:21][O:22][CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]
Reactant: CCOP(=O)(CCl)OCC
Reactant: Cn1c(CO)nc(-c2ccccc2)c1-c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOP(=O)(COCc1nc(-c2ccccc2)c(-c2ccncc2)n1C)OCC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 80% NaH in mineral oil (0.013 g, 0.452 mmol) in DMF at 0° C. was added 1-methyl-2-hydroxymethyl-4-phenyl-5-[4-pyridinyl]imidazole (0.100 g, 0.377 mmol) in DMF. The resulting bright yellow solution was stirred at 0° C. for 0.5 h when diethyl chloromethylphosphonate (0.070 mL, 0.452 mmol) dissolved in 0.079 mL, of HMPA was added. The resulting mixture was stirred at 0° C. for 15 min and then warmed to rt. After 5 h, the solution was partitioned between CH2Cl2 and H2O. The organic extract was washed with aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 50:1 CH2Cl2 /MeOH. The title compound was obtained as a light amber oil (0.088 g, 56%): ESMS (m/z): 416 (M+ +H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C@@:3]([OH:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=O.[F:16][C:17]1[C:22]([CH2:23][NH2:24])=[CH:21][C:20]([CH3:25])=[CH:19][N:18]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[F:14][C:2]([F:1])([F:15])[C@@:3]([OH:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([NH:24][CH2:23][C:22]1[C:17]([F:16])=[N:18][CH:19]=[C:20]([CH3:25])[CH:21]=1)=[O:6]
Reactant: Cc1cnc(F)c(CN)c1
Reactant: O=C(O)[C@](O)(c1ccccc1)C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(F)c(CNC(=O)[C@](O)(c2ccccc2)C(F)(F)F)c1
Reaction time: 14 h

Procedure:
A solution of (2R)-3,3,3-trifluoro-2-hydroxy-2-phenylpropanoic acid (6-e with R=CF3 and R′=H, 105 mg, 0.48 mmol), the amine (2-e, 67 mg, 0.48 mmol) and diisopropylethylamine (415 uL, 2.4 mmol) in N,N-dimethylformamide (1 mL) was treated at room temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 274 mg, 0.53 mmol). After 14 h, the reaction mixture was partitioned between ethyl acetate and 0.5N—NaOH. The aqueous layer was removed and the organic layer was washed with 0.5N—HCl. The aqueous layer was removed by filtering through a plastic frit. The organic layer was evaporated in vacuo to give the desired product (3-1); HRMS (M+H)=343.1059; 1H NMR (500 MHz, CDCl3) δ 7.89 (bs, 1 H), 7.63 (m, 2H), 7.43 (m, 3 H), 7.39 (d, 1 H, J=7.8 Hz), 6.67 (br, 1 H), 4.72 (m, 1 H), 4.48 (d, 2H, J=6.1 Hz), 2.26 (s, 3 H); compound 3-3 [(2R)-3,3,3-trifluoro-N-(2-fluoro-5-trifluoromethylbenzyl)-2-hydroxy-2-phenylpropanamide] was prepared by the same procedure (2-fluoro-5-trifluoromethylbenzylamine was purchased from Alfa Aesar); HRMS (M+H)=396.0825; 1H NMR (500 MHz, DMSO-6d) δ 8.95 (t, 1 H), 7.95 (s, 1 H), 7.65 (m, 3 H), 7.39 (m, 5 H), 4.40 (dq, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH2:30][CH:31]([F:33])[F:32])=[C:6]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:28]=[CH:27][C:21]5[CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:20]=5[CH:19]=4)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=1.Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH2:30][CH:31]([F:33])[F:32])=[C:6]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH:17][C:18]4[CH:28]=[CH:27][C:21]5[CH2:22][CH2:23][N:24]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:25][CH2:26][C:20]=5[CH:19]=4)[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: FC(F)COc1ccc(Cl)cc1-c1cccn2nc(Nc3ccc4c(c3)CCNCC4)nc12
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)CN1CCc2ccc(Nc3nc4c(-c5cc(Cl)ccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
2-(7-{8-[5-Chloro-2-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-N,N-dimethyl-acetamide was prepared from {8-[5-chloro-(2,2-difluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7yl)-amine (0.075 g, 0.160 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.025 mL, 0.239 mmol) in a manner analogous to Example 313 to give product (0.030 g, 34%). MP=190-191° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.54 (s, 1H), 8.78 (d, 1H), 7.80 (s, 1H), 7.65 (d, 1H), 7.50 (m, 3H), 7.30 (d, 1H), 7.05 (m, 2H), 6.25 (br m, 1H), 4.35 (m, 2H), 3.22 (s, 2H), 3.05 (s, 3H), 3.75 (m, 7H), 2.55 (m, 4H). MS=556 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:16][C:17]2[CH:28]=[CH:27][C:20]3[NH:21][C:22](=[O:26])[C@@H:23]([CH3:25])[O:24][C:19]=3[CH:18]=2)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:29]I>>[F:1][C:2]1[CH:3]=[C:4]([S:16][C:17]2[CH:28]=[CH:27][C:20]3[N:21]([CH3:29])[C:22](=[O:26])[C@@H:23]([CH3:25])[O:24][C:19]=3[CH:18]=2)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: CI
Reactant: COC1(c2cc(F)cc(Sc3ccc4c(c3)O[C@H](C)C(=O)N4)c2)CCOCC1
Product: COC1(c2cc(F)cc(Sc3ccc4c(c3)O[C@H](C)C(=O)N4C)c2)CCOCC1
Yield: 42 %

Procedure:
Using a similar procedure to that described in Example 16, (R)(-)-4-[5-fluoro-3-(2-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-ylthio)phenyl]-4-methoxytetrahydropyran was reacted with methyl iodide to give (R)-(-)-4-[5-fluoro-3-(2,4-dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-7-ylthio)phenyl]-4-methoxytetrahydropyran in 42% yield,
Reaction SMILES: [CH2:1]([N:3]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=2)[CH2:22]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].Cl.Cl[CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH2:1]([N:3]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=2)[CH2:22]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:35][CH2:36][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCN(CCc1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: ClCCN1CCCC1
Agent: Cl
Product: CCN(CCc1ccc(OCCN2CCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Yield: 84.9 %

Procedure:
Synthesized from 4-{2-{ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amino}ethyl}phenol (302 mg) and 1-(2-chloroethyl)pyrrolidine hydrochloride (155 mg) according to an analogous synthetic method to Preparation Example 40, the title compound (314 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:6]=2[CH:23]=1.Cl[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][O:29][C:28]1=[O:32]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=3[CH2:8][CH:7]([N:17]3[CH2:22][CH2:21][N:20]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH2:19][CH2:18]3)[C:6]=2[CH:23]=1
Reactant: O=C1OCCN1CCCl
Reactant: Cc1ccc2c(c1)CC(N1CCNCC1)c1cc(Cl)ccc1S2
Product: Cc1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1cc(Cl)ccc1S2

Procedure:
In a similar manner to that described in Example 1, from 1-(8-chloro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-piperazine and N-(betachloroethyl)oxazolidinone, there is obtained 3-{2-[4-(8-chloro-10,11-dihydro-2-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone, which after recrystallization from ethyl acetate/petroleum ether, has a melting point of 184°-186°. The maleate salt melts after recrystallization from methanol/ether at 174°-175°.