Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][N:5]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([Br:19])[CH:18]=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:6]1=[O:25])C=C.C1([SiH3])C=CC=CC=1>C(Cl)Cl.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>[Br:19][C:17]1[CH:18]=[C:11]2[C:10]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:9][CH:8]=[C:7]3[C:12]2=[C:13]([CH:16]=1)[C:14](=[O:15])[N:5]([OH:4])[C:6]3=[O:25]
Reactant: C=CCON1C(=O)c2ccc(N3CCCC3)c3cc(Br)cc(c23)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: ClCCl
Product: O=C1c2ccc(N3CCCC3)c3cc(Br)cc(c23)C(=O)N1O
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
To a 0° C. solution of 2-allyloxy-5-bromo-7-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.81 g, 2.0 mmol, from Example G2) in CH2Cl2 (40 mL) was added phenylsilane (0.32 g, 3.0 mmol) and Pd(PPh3)4 (0.050 g, 0.043 mmol). The reaction was stirred for 15 minutes, and the resulting precipitate removed by filtration, washed with CH2Cl2, and dried to give 0.60 g of the title compound, mp 234-235° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[CH:15][CH:14]=1
Reactant: Ic1ccc2[nH]ccc2c1
Reactant: COc1ccc(S)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: COc1ccc(Sc2ccc3[nH]ccc3c2)cc1
Yield: 89.3 %

Procedure:
The general procedure in example 39 was followed. 5-Iodoindole (243 mg, 1.0 mmol), 4-methoxythiophenol (123 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 5-(4-methoxyphenyl)sulfanylindole (228 mg, 90% yield) as white solid. Column chromatographic solvent (hexane/ethyl acetate=5/1). Rf=0.3 (hexane/ethyl acetate=5/1). 1H NMR (CDCl3, 300 MHz) δ 8.14 (brs, 1 H), 7.69 (s, 1 H), 7.30 (d, 1 H, J=8.4 Hz), 7.12-7.28 (m, 4 H), 6.79 (dt, 2 H, J=2.1 Hz, 9.0 Hz), 6.47-6.49 (m, 1 H), 3.76 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 158.7, 135.2, 132.1, 128.9, 128.8, 126.5, 126.2, 125.2, 124.9, 114.8, 112.1, 102.9, 55.7. IR (neat, cm−1) 3417 (broad), 2958, 2939, 2834. MS (EI) m/z (relative intensity) 255 (100), 223 (15). HRMS (EI), Cald. for C15H13NOS 255.0712; Found 255.0702. Anal. Cald. for C15H13NOS, Cald. C: 70.56, H: 5.13; Found C: 70.37, H: 5.09.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([C:26]1[C:31]([OH:32])=[CH:30][CH:29]=[CH:28][N:27]=1)#[N:25].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:32][C:31]4[C:26]([C:24]#[N:25])=[N:27][CH:28]=[CH:29][CH:30]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: N#Cc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4cccnc4C#N)ncnc32)CC1
Temperature: 160 °C
Yield: 58.5 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 2-cyano-3-hydroxypyridine (Matrix Scientific, Columbia, S.C., USA; 26 mg, 0.19 mmol), and potassium carbonate (27 mg, 0.19 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Ethyl acetate and water were added, and the aqueous layer was extracted twice with ethyl acetate. The ethyl acetate layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted three times with dichloromethane and the solvent was evaporated to give 4-[4-(2-cyano-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (37 mg, 59%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.51 (s, 9H), 1.85-2.11 (m, 2H), 2.15-2.43 (m, 2H), 2.85-3.15 (m, 2H), 4.34 (br s, 2H), 4.88-5.09 (m, 1H), 7.68 (dd, 1H, J=8.4, 4.7 Hz), 7.88 (d, 1H, J=8.4 Hz), 8.27 (s, 1H), 8.49 (s, 1H), 8.69 (d, 1H, J=4.7 Hz). Mass spectrum (ES) MH+=422. HRMS Calcd. for C21H24N7O3 (MH+): 422.1935. Found: 422.1934.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](=[O:11])[C:8]([O-:10])=[O:9].[OH-].[Na+].Cl>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](=[O:11])[C:8]([OH:10])=[O:9]
Reactant: O=C([O-])C(=O)Cc1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(=O)Cc1ccco1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 57.1 %

Procedure:
To a 100 mL flask, 3-(furan-2-yl)-2-oxopropanoate (940 mg) along with 23 mL cold 6N NaOH was added. The insoluble mixture was stirred in a 90° C. bath for 5 min until dissolved. Cold 1N HCl was added until solution was acidic (approx 120 mL). Solution was extracted 2×50 mL EtOAc. Combined organic layers were washed with 40 mL brine and dried with Na2SO4. Solution was evaporated to yield 540 mg brown solid. Solid was further purified by reversed-phase high-performance liquid chromatography (HPLC) ramping from 97% aqueous trifluoroacetic acid (TFA) to acetonitrile (ACN).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15].[BH3-]C#N.[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[F:11][C:12]1[CH:13]=[C:14]([NH:15][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1cccc(F)c1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2cccc(F)c2)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a stirred solution of anisaldehyde (0.30 ml) at r.t. in methanol (15 ml) under an argon atmosphere were added 3-fluoroaniline (0.22 ml), ZnCl2 (1.21 g) and NaBH3CN (0.43 g). The mixture was stirred at 40° C. for 1 h, then cooled to r.t. and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient:heptane->heptane/EtOAc 7:3) to give (3-fluoro-phenyl)-(4-methoxy-benzyl)-amine (617 mg) as a light yellow oil. MS (ISP): 232.1 ([M+H]+)
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.CN1CCOCC1.[N:30]([C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=1)=[C:31]=[O:32]>ClCCl>[F:41][C:40]([F:42])([F:43])[O:39][C:36]1[CH:35]=[CH:34][C:33]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:22])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:32])=[CH:38][CH:37]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(OC(F)(F)F)cc1

Procedure:
A solution of 0.050 g (0.16 mmol) of (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 13) and 0.053 ml (0.48 mmol) of 4-methylmorpholine in 1 ml of dichloromethane was treated at RT with 0.033 g (0.16 mmol) of 1-isocyanato-4-trifluoromethoxy-benzene (intermediate 14) in 1 ml of dichloromethane. After 1 h again 0.005 g of 0.033 g (0.16 mmol) of 1-isocyanato-4-trifluoromethoxy-benzene (intermediate 14) were added and after 30 min the reaction was extracted with aqueous 10% KHSO4/EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4 to yield, after precipitation with dichloromethane/pentane, 0.077 g (93%) of the titled compound as white amorphous solid. MS: 513.23 (MH+).
Reaction SMILES: [ClH:1].Cl.C([S:6][CH:7]1[CH2:12][CH2:11][N:10]([CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[CH2:9]/[C:8]/1=[CH:26]\[C:27]1[N:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:29]=[CH:30][N:31]=1)(=O)C>C(O)C>[ClH:1].[CH:16]1([C:14](=[O:15])[CH:13]([N:10]2[CH2:11][CH2:12][CH:7]([SH:6])/[C:8](=[CH:26]/[C:27]3[N:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:29]=[CH:30][N:31]=3)/[CH2:9]2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:18][CH2:17]1
Reactant: CCOC(=O)Cn1ccnc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1SC(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cn1ccnc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 47 %

Procedure:
Hydrogen chloride was passed through a solution of (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-2-yl]methylidene}piperidine hydrochloride (169.4 mg) in ethanol (4 ml) at 0° C. and the sealed mixture was stirred at room temperature for 6.5 hours. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.026 N aqueous trifluoroacetic acid solution, 25/75, v/v). The thus obtained trifluoroacetic acid salt of the title compound was neutralized with an aqueous sodium hydrogen carbonate solution, and the liberated free base was extracted twice with dichloromethane. The extract was dried over anhydrous sodium sulfate and solvents were removed under reduced pressure to afford the free base of the title compound (67.7 mg, yield: 47%) as a colourless oil. The oil thus obtained was treated with a 4N hydrogen chloride dioxane solution (120 μl) in acetonitrile (3 ml). The solvent and excess hydrogen chloride were removed by evaporation under reduced pressure to afford the title compound (88.9 mg) as a pale yellow amorphous solid.
Reaction SMILES: [NH:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:9]2[N:8]=[CH:7][NH:6][C:5]=2[C:4](=[O:16])[NH:3]1.[NH2:17]N>O>[NH2:17][N:3]1[C:4](=[O:16])[C:5]2[NH:6][CH:7]=[N:8][C:9]=2[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:2]1=[NH:1]
Reactant: NN
Reactant: CCCCCn1c(=N)[nH]c(=O)c2[nH]cnc21
Solvent: O
Product: CCCCCn1c(=N)n(N)c(=O)c2[nH]cnc21

Procedure:
A solution of 2-imino-3-pentyl-1,2,3,7-tetrahydro-6h-purin-6-one (750 mg, 3.39 mmol) and 18 m of hydrazine in water (30 ml) was stirred at 150° C. for 30 min on a microwave reactor. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo to yield the crude product for next step without further purification. LCMS calculated for C10H17N6O (M+H): 237.1. found: 237.2.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:21])=[C:7](C(OCC)=O)[C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[CH2:14])=[CH:4][CH:3]=1.Cl>[OH-].[Na+]>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:21])=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[CH2:14])=[CH:4][CH:3]=1
Reactant: C=CCn1c(=O)c(C(=O)OCC)c(O)c2ccc(F)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C=CCn1c(=O)cc(O)c2ccc(F)cc21
Yield: 81.4 %

Procedure:
Ethyl 7-fluoro-4-hydroxy-2-oxo-1-(2-propen-1-yl)-1,2-dihydro-3-quinolinecarboxylate (4.46 g, 15.3 mmol) was suspended in 2N sodium hydroxide solution (70 ml) and heated at reflux for 4 h. After cooling, the pH was adjusted to ˜pH6 using 2N hydrochloric acid and the resulting precipitate filtered off, washed with water and dried under vacuum to provide the title compound as an off-white solid (2.73 g, 81%).
Reaction SMILES: [F:1][C:2]1[CH:40]=[CH:39][C:5]([C:6]([NH:8][C@:9]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([OH:38])[CH:32]=2)([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[CH:4][C:3]=1[C:41]([F:44])([F:43])[F:42].C([O-])([O-])=O.[Na+].[Na+].[C:51](OC=C)(=O)[CH3:52]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:40]=[CH:39][C:5]([C:6]([NH:8][C@:9]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([O:38][CH:51]=[CH2:52])[CH:32]=2)([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:28])([F:29])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[CH:4][C:3]=1[C:41]([F:44])([F:43])[F:42]
Reactant: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(O)c1)c1ccc(F)c(C(F)(F)F)c1
Reactant: C=COC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=COc1cc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-4-fluoro-N-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (Example 264, 100 mg, 0.158 mmol) in toluene (0.2 ml) was added Na2CO3 (25 mg, 0.235 mmol) and catalytic amount of [Ir(cod)Cl]2 (2 mg), followed by vinyl acetate (68 mg, 0.79 mmol). The reaction mixture was stirred at 100° C. for 16 h. The resulting mixture was filtered and the solid was washed with CH2Cl2. The CH2Cl2 layer was washed with 1 N NaOH, H2O and the organic portion dried over Na2SO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column using 0 to 60% EtOAc in hexane to afford (R)-4-fluoro-N-(1-(4-fluoro-3-(vinyloxy)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide eluting out at 20% EtOAc in hexane as colorless oil (80 mg, 77%). LCMS: RT=2.237 min [M+H] 658.3 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm. NMR: 400 MHz 1H (CD3OD) ppm 3.87 (d, J=12.74 Hz, 1H), 4.05-4.15 (m, 1H), 4.35 (dd, J=5.93, 1.98 Hz, 1H), 4.55 (dd, J=13.84, 1.98 Hz, 1H), 6.12-6.41 (m, 1H), 6.48 (dd, J=13.62, 6.15 Hz, 1H), 6.72 (d, J=7.03 Hz, 2H), 6.87-7.24 (m, 9H), 7.37-7.51 (m, 1H), 7.88-8.04 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][CH2:11][CH2:10][O:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[Cl:14][CH2:15][C:16](Cl)=[O:17].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Cl:14][CH2:15][C:16]([N:12]1[CH2:11][CH2:10][O:9][C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]1=2)=[O:17]
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(CCl)N1CCOc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A suspension of 7-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (8 g, 44.4 mmol) in anhydrous toluene (100 mL) under positive argon pressure was treated dropwise with 2-chloroacetyl chloride (3.91 mL, 48.8 mmol). The mixture was heated at reflux for 25 minutes and became a bright yellow solution. The solution was allowed to cool to room temperature, and a saturated NaHCO3 solution (150 mL) was added. The mixture was transferred to a separatory funnel, and the product was extracted with CH2Cl2 (2×200 mL). The combined organic layers were filtered through a pad of silica gel, washed with CH2Cl2 (50 mL), and concentrated to give a yellow solid (10 g, 88%). 1H-NMR (DMSO-d6) δ 8.22 (d, J=9.0 Hz, 1H), 7.80 (dd, J=2.7, 9.3 Hz, 1H), 7.72 (d, J=2.7 Hz, 1H), 4.74 (s, 2H), 4.40 (t, J=4.2 Hz, 2H), 3.94 (t, J=4.8 Hz, 2H); ESI-MS (m/z, %): 279 (MNa+, 30), 257 (MH+, 100).
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:18][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:13][CH:12]=1
Reactant: OCc1ccc(Oc2ccccc2)nc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1ccc(Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.8 %

Procedure:
To a dichloromethane (5.00 mL) solution of (6-phenoxy-pyridin-3-yl)-methanol (458 mg, 2.28 mmol) described in Manufacturing Example 193-1-1 was added dropwise thionyl chloride (333 μL, 4.56 mmol) on an ice bath (0° C.) under nitrogen atmosphere, which was stirred for 5 minutes at room temperature. Aqueous sodium bicarbonate was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure to obtain the title compound (450 mg, 89.8%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[CH:13]=2)=[C:7]([NH2:20])[CH:6]=1)[CH3:2].[CH2:22](OC(OCC)OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[CH:13]=3)[CH:22]=[N:20][C:7]=2[CH:6]=1)=[O:21])[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2cccc(CO)c2)c(N)c1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)ncn2-c1cccc(CO)c1
Yield: 77 %

Procedure:
A solution of compound 6 (8.5 g), triethylorthoformate (7.55 mL), p-toluene sulphonic acid (2 g) in THF (75 mL) was stirred at reflux for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (600 mL), washed with 20% NaHCO3 solution and brine, successively, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel using a 4:6 mixture of ethyl acetate and pet-ether as the eluent to afford compound 7 (7.9 g, 77%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=[O:21])[C:7]3[C:8]([CH:19]=[CH:20][C:4]=2[CH:3]=1)=[N:9][CH:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:12]=3.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>N1C=CC=CC=1>[CH2:24]([NH:26][C:27]([NH:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6](=[O:21])[C:7]3[C:8]([CH:19]=[CH:20][C:4]=2[CH:3]=1)=[N:9][CH:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:12]=3)=[O:28])[CH3:25]
Reactant: Nc1ccc2c(=O)c3cc(-c4ccccc4)cnc3ccc2c1
Reactant: CCN=C=O
Solvent: c1ccncc1
Product: CCNC(=O)Nc1ccc2c(=O)c3cc(-c4ccccc4)cnc3ccc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 0° C. solution of 8-amino-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (6.4 mg, 0.021 mmol) in pyridine (0.3 mL) was ethyl isocyanate (0.1 mL, 0.38 M in CH2Cl2) The mixture was then stirred at room temperature for 4 hours followed by heating at 50° C. After 3 hours, more ethyl isocianate (3 μL, 0.038 mmol) was added and the mixture was heated at 70° C. After stirring for 14 hours, a new addition of ethyl isocyanate (9 μL, 0.114 mmol) was followed by heating at 80° C. More ethyl isocyanate (20 μL, 0.253 mmol) was added 2 hours later and heating was continued for 14 hours. The mixture was then concentrated to dryness. The crude residue was purified by flash chromatography (100-85% CH2Cl2/MeOH gradient) and reverse phase HPLC (30-100% acetonitrile/water gradient, 0.1% trifluoroacetic acid modifier) to afford the title compound. 1H NMR (600 MHz, DMSO-D6) δ 9.24 (d, 1H), 8.69 (d, 1H), 8.14 (d, 1H), 7.85 (d, 2H), 7.80 (d, 1H), 7.67 (dd, 1H), 7.53 (t, 2H), 7.45 (t, 2H), 7.31 (s, 2H), 2.95 (m, 2H), 0.93 (t, 3H). LRMS (APCI) calculated for C23H20N3O2 [M+H]+, 370.1; found 370.1
Reaction SMILES: [N+]([O-])(O)=O.N([O-])=O.[Na+].[CH2:9]([N:13]1[C:17](S)=[N:16][N:15]=[C:14]1[CH2:19][OH:20])[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:9]([N:13]1[CH:17]=[N:16][N:15]=[C:14]1[CH2:19][OH:20])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCn1c(S)nnc1CO
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: CCCCn1cnnc1CO
Temperature: 25 °C
Yield: 81.8 %

Procedure:
To a mixture of 90% nitric acid (17 ml) and water (25 ml) was added sodium nitrite (0.07 g) and then 4-n-butyl-3-hydroxymethyl-5-mercapto-4H-1,2,4-triazole (10.0 g) was slowly added for 0.5 hours at 45° C. After cooling to room temperature, sodium carbonate was slowly added thereto to adjust pH to 7 at 0° C. The reaction mixure was concentrated under reduced pressure, methanol was added to the residue, and the precipitates were removed by filtration. The mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetate 1:9), to give 4-n-butyl-3-hydroxymethyl-4H-1,2,4-triazole (6.78 g) as orange oil. To 4-n-butyl-3-hydroxymethyl-4H-1,2,4-triazole (6.78 g) was slowly added thionyl chloride (44 ml) at 0° C. The mixture was heated to reflux for 1 hour, and concentrated under reduced pressure. To the residue was added ethyl acetate, and the precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate, to give 4-n-butyl-3-chloromethyl-4H-1,2,4-triazole hydrochloride (7.03 g) as pale yellow crystals.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH:8]=1)(=O)=O.[F:19][C:20]1[C:25](B(O)O)=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:19][C:20]1[C:25]([C:7]2[CH2:16][CH2:15][C:10]3([O:11][CH2:12][CH2:13][O:14]3)[CH2:9][CH:8]=2)=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: O=S(=O)(OC1=CCC2(CC1)OCCO2)C(F)(F)F
Reactant: OB(O)c1cccnc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Fc1ncccc1C1=CCC2(CC1)OCCO2
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a mixture of 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate (10.2 g, 35.4 mmol) and 2-fluoropyridin-3-ylboronic acid (5.00 g, 35.5 mmol) in 1,2-dimethoxyethane (200 mL) and aqueous sodium carbonate (53.2 mL, 106 mmol, 2N) under argon atmosphere was added palladium tetrakis(triphenylphosphine) (1.23 g, 1.06 mmol). The mixture was heated and stirred at 85° C. for 1 h., then cooled to room temperature. Ethyl acetate was added and the mixture was washed with water, saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give 2-fluoro-3-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine. MS (ESI, pos. ion) m/z: 236.1 (M+1).
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14]([CH:16]1[CH2:18][CH:17]1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:21]([Cl:33])[CH:20]=1)=[O:15])C1C=CC=CC=1.C(C1C[O:44]C(=O)N1)C1C=CC=CC=1>>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([CH:17]2[CH2:18][CH:16]2[C:14]([OH:15])=[O:44])=[CH:20][C:21]=1[Cl:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1NC(Cc2ccccc2)CO1
Reactant: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)C1CC1c1ccc(OCc2ccccc2)c(Cl)c1
Product: O=C(O)C1CC1c1ccc(OCc2ccccc2)c(Cl)c1

Procedure:
(R)-4-benzyl-3-[2-(4-benzyloxy-3-chloro-phenyl)-cyclopropanecarbonyl]-oxazolidin-2-on (918 mg, 1.98 mmol) obtained in Step C was reacted in the same manner as in Step A of Preparation Example 59 to obtain the mixture (650 mg) of the title compound and 4-benzyloxazolidin-2-on.