Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])[O:9][C:8]([CH3:13])([CH3:12])[O:7][C:6]=2[CH:14]=1.CC1C=CC(S(O[CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[CH3:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])[O:9][C:8]([CH3:12])([CH3:13])[O:7][C:6]=2[CH:14]=1
Reactant: CC1(C)OC(=O)c2ccc(O)cc2O1
Reactant: COCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCCOCCOc1ccc2c(c1)OC(C)(C)OC2=O
Yield: 74.2 %

Procedure:
A solution of 7-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one, (19.4 g, 100 mmol), 2-(2-methoxyethoxy)ethyl 4-methylbenzenesulfonate (27.4 g, 100 mmol) and K2CO3 (41 g, 300 mmol) in CH3CN (500 mL) was refluxed for 4.5 hours. The mixture was poured in H2O (1000 mL) and extracted twice with CH2Cl2 (500 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (PE/EtOAc=9/1) to give the title compound (22 g) as white solid. LC-MS (ES, m/z): 297 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=1)[CH3:3]
Reactant: CCOC(=O)CN
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)CNCc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
To a suspension of glycine ethyl ester hydrochloride (1.2 eq.) in DCE was added TEA (2 eq.) The reaction was stirred for 10 min at 20° C. then 4-chlorobenzaldehyde (1 eq.), acetic acid (4 eq.) and sodium triacetoxyborohydride (2 eq.) were added. The reaction was stirred for 15 h at 20° C. The crude was partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous layer was then extracted twice with DCM. The organic layers were combined, washed with brine, dried on MgSO4, filtered and concentrated under reduced pressure to afford (4-chloro-benzylamino)-acetic acid ethyl ester.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[C:15]([CH3:16])=[C:14](F)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].Cl.[NH2:19][C@H:20]([C@H:24]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]([F:28])([F:27])[F:26])[C:21]([OH:23])=[O:22]>CS(C)=O>[CH2:30]([O:29][C@H:24]([C:25]([F:26])([F:28])[F:27])[C@@H:20]([NH:19][C:14]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([Cl:7])[C:15]=1[CH3:16])[C:21]([OH:23])=[O:22])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: N[C@@H](C(=O)O)[C@H](OCc1ccccc1)C(F)(F)F
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1c(N[C@@H](C(=O)O)[C@H](OCc2ccccc2)C(F)(F)F)ccc(C#N)c1Cl
Temperature: 80 °C
Reaction time: 48 h
Yield: 21.9 %

Procedure:
Cs2CO3 (3.5 g, 10.7 mmol) was added to a mixture of 2-chloro-4-fluoro-3-methylbenzonitrile (0.79 g, 4.65 mmol) and (2R,3S)-2-amino-3-(benzyloxy)-4,4,4-trifluorobutanoic acid hydrochloride salt (0.93 g, 3.1 mmol) in DMSO (18 mL) at room temperature. The resulting mixture was heated to 80° C. and stirred for 2 days. After cooling to room temperature, the reaction mixture was poured into ice-water (150 mL) and extracted with 10% EtOAc in hexanes (2×50 mL). The aqueous phase was acidified to pH=2˜3 with 2N HCl and extracted with EtOAc (2×100 mL). The EtOAc extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent gave a residue, which was purified by flash chromatography to afford the crude (2R,3S)-3-(benzyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)-4,4,4-trifluorobutanoic acid (280 mg) as a mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:31]=[CH:30][C:13]([O:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][NH:26][CH2:27][CH2:28]C)=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:32](N)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][NH:26][CH:27]([CH3:28])[CH3:32])=[CH:23][CH:24]=3)=[CH:30][CH:31]=2)=[CH:6][CH:7]=1
Reactant: CCCNCc1ccc(CNCCOc2ccc(C#Cc3ccc(Cl)cc3)cc2)cc1
Reactant: CC(C)N
Product: CC(C)NCc1ccc(CNCCOc2ccc(C#Cc3ccc(Cl)cc3)cc2)cc1

Procedure:
Compound 4 was synthesized using the procedure described for Compound 2 except that isopropylamine was used in the last reductive amination step. Compound 4 was obtained as a yellow gum. MS 433; 1H NMR (CDCl3) δ 4.10 (t, 2H), 3.86 (d, 2H, becomes singlet with D2O exchange), 2.80 (m, 1 H), 1.09 (d, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:17][C:18](=[O:23])[O:19][CH:20]([CH3:22])[CH3:21])[CH:7]=[C:8]([O:13][CH:14]([F:16])[F:15])[C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].I[CH3:25].[OH-].[K+]>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:25][N:17]([C:6]1[CH:7]=[C:8]([O:13][CH:14]([F:16])[F:15])[C:9]([O:10][CH2:11][CH3:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[C:18](=[O:23])[O:19][CH:20]([CH3:21])[CH3:22]
Reactant: CI
Reactant: CCOc1cc(NC(=O)OC(C)C)cc(OC(F)F)c1OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1cc(N(C)C(=O)OC(C)C)cc(OC(F)F)c1OCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 89.9 %

Procedure:
Isopropyl N-(3,4-diethoxy-5-difluoromethoxyphenyl)carbamate (3.33 g) and iodomethane (4.30 g) were dissolved in tetrahydrofuran (10 ml). The resultant solution was dropwise added to a solution containing potassium hydroxide (1.68 g) and tetra-n-butylammonium bromide (1.0 g). After being allowed to stand at room temperature for 12 hours, the reaction mixture was poured into ice-water and extracted with toluene. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-methyl-N-(3,4-diethoxy-5-difluoromethoxyphenyl)carbamate (Compound No. 55) (3.12 g) in a yield of 89.8%.
Reaction SMILES: C=O.[Cl-].[Mg+2].[Cl-].[Br:6][C:7]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[CH:9][C:8]=1[OH:15].C[CH2:17][O:18]CC>C1COCC1>[Br:6][C:7]1[C:8]([OH:15])=[C:9]([CH:10]=[C:11]([S:13][CH3:14])[CH:12]=1)[CH:17]=[O:18]
Reactant: CSc1ccc(O)c(Br)c1
Reactant: CCOCC
Agent: C=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CSc1cc(Br)c(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Anhydrous paraformaldehyde (2.14 g) and anhydrous magnesium chloride (−10 mesh, 99.9%, 4.53 g) were suspended in anhydrous THF (120 mL) under nitrogen atmosphere. Freshly distilled TEA (6.7 mL) was added to the above suspended solution and stirred for 30 minutes. To the above mixture, a solution of 2-bromo-4-methylthiophenol (XXI, 5.22 g) in anhydrous THF (40 mL) was added. The resultant mixture was heated at gentle reflux and stirred for 6 h. After the mixture was cooled down to ambient temperature, ether (100 ml) was added. The organic layer was washed with 1N HCl (60 mL×3) and water (60 mL×3), and dried over MgSO4, filtered and solvent removed in vacuo. The mixture was recrystallized from hexane to afford the product (3.60 g, 61%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:4]1[C@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:7]2[N:6]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]1=[O:19])[CH:2]=[CH2:3].O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH2:1]([N:4]1[C@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:7]2[N:6]([CH:13]2[CH2:14][CH2:15][N:16]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]3)[CH2:17][CH2:18]2)[C:5]1=[O:19])[CH:2]=[CH2:3]
Reactant: C=CCN1C(=O)N(C2CCNCC2)[C@H]2CCCC[C@@H]21
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: C=CCN1C(=O)N(C2CCN(C3CCN(C(=O)OCC)CC3)CC2)[C@H]2CCCC[C@@H]21
Reaction time: 3 h
Yield: 43.4 %

Procedure:
(3aS,7aS)-1-allyl-3-piperidin-4-yloctahydro-2H-benzimidazol-2-one (183 mg, 0.69 mmol) was dissolved in MeOH (2 mL) and ethyl 4-oxopiperidine-1-carboxylate (100 μL, 0.66 mmol) was added. A solution of sodium cyanoborohydride (82 mg, 1.19 mmol) and zinc chloride (47 mg, 0.34 mmol) in MeOH (1 mL) was then added drop wise at room temperature. The mixture was then stirred for 3 hours and then more sodium cyanoborohydride (40 mg) was added and the mixture stirred at room temperature over night. The solvent was then removed under reduced pressure and the residue was diluted in dichloromethane (80 mL). Washed with 1N NaOH (5 mL) and brine, dried and concentrated in vacuo. The residue was purified by high pH prep LCMS to provide the title compound (120 mg). 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.24 (t, J=7.03 Hz, 3H), 1.28-1.48 (m, 6H), 1.53-1.64 (m, 1H), 1.65-1.74 (m, 1H), 1.77-1.99 (m, 6H), 1.99-2.10 (m, 1H), 2.22-2.36 (m, 3H), 2.42-2.58 (m, 1H), 2.69-2.86 (m, 3H), 2.89-3.11 (m, 3H), 3.56-3.71 (m, 1H), 3.72-3.78 (m, 2H), 4.09 (q, J=7.16 Hz, 2H), 4.17 (d, J=13.28 Hz, 2H), 5.03-5.26 (m, 2H), 5.62-5.84 (m, 1H). MS (M+1): 419.2
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=O)[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:20]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[CH2:20]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:16](=[O:18])[C@H:9]([CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
A solution of N-(tert-butyloxycarbonyl)-3-(4-thiazolyl)-L-alanine (2.72 g, 10 mmol), L-proline benzyl ester hydrochloric acid (2.42 g, 10 mmol), and HOBT (135 mg, 1 mmol) in tetrahydrofuran (60 ml) was added triethylamine (1.4 ml, 10 mmol) and DCC (2.43 g, 11.8 mmol) and the resulting mixture was stirred for 18 h at room temperature. After the precipitation which appeared was filtered off, the filtrate was concentrated in vacuo. The residue (5.5 g) was subjected to silica gel column chromatography with Lobar® column C (Merck inc.) (toluene:acetone=9:1) to give 4.16 g of the compound (30).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[C:37]([O:39][CH3:40])=[O:38]>>[CH3:40][O:39][C:37]([C:36]1[CH:35]=[CH:34][C:33]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=4[CH:26]=3)[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=2)=[CH:32][C:31]=1[O:30][CH3:29])=[O:38]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1OC
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cc1OC

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 3-methoxy-4-methoxycarbonylphenylboronic acid to give the title compound as an off-white solid. MS (m/e, ISP neg. ion)=562.2 [M−H+].
Reaction SMILES: C1(S([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=2I)(=O)=O)C=CC=CC=1.C(N(CC)CC)C.[C:29]([C:31]1[O:32][CH:33]=[CH:34][CH:35]=1)#[CH:30].O>CN(C)C=O>[O:32]1[CH:33]=[CH:34][CH:35]=[C:31]1[C:29]1[NH:10][C:11]2[C:12]([CH:30]=1)=[CH:13][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:15][CH:16]=2
Reactant: CS(=O)(=O)c1ccc(NS(=O)(=O)c2ccccc2)c(I)c1
Reactant: C#Cc1ccco1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc2[nH]c(-c3ccco3)cc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 29.3 %

Procedure:
To a suspension of the compound obtained in Example 8 (5) (2.00 g), bistriphenylphosphine palladium dichloride (321 mg), cuprous iodide (87.0 mg) and triethylamine (1.38 g) in N,N-dimethylformamide (46 ml), a solution of 2-ethynylfuran (842 mg) in N,N-dimethylformamide (46 ml) was slowly added dropwise under nitrogen atmosphere and the mixture was stirred at 60° C. for 3 hours. The reaction solution was then poured into water, extracted with chloroform, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (methanol:chloroform=1:100). To a solution of the obtained colorless amorphous compound (1.10 g) in methanol (28 ml) was added a 1N aqueous potassium hydroxide solution (5.52 ml) and the mixture was stirred at 60° C. for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The resulting residue was poured into water, extracted with chloroform, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (methanol:chloroform=1:20) to obtain 350 mg of the desired product as a brown crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([NH:13][CH3:14])[C:6]([C:15]([OH:17])=[O:16])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].C(=O)([O-])O.[Na+]>C1COCC1>[CH2:35]([O:34][C:32]([N:13]([CH3:14])[N:7]1[C:6]([C:15]([OH:17])=[O:16])=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[C:8]1=[O:12])=[O:33])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNn1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
To a solution (76 ml) of 6-chloro-2-methylamino-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (3.8 g) in THF were added triethylamine (4.0 ml) and benzyl chloroformate (3.6 ml) at 0° C. with stirring, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-dichloromethane/methanol/acetic acid=50/10/1) to give the title compound (2.5 g) as yellow powder.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[CH2:37]([P:48](=[O:57])([O:53][CH:54]([CH3:56])[CH3:55])[O:49][CH:50]([CH3:52])[CH3:51])P(=O)(OC(C)C)OC(C)C.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:37]/[P:48](=[O:57])([O:49][CH:50]([CH3:51])[CH3:52])[O:53][CH:54]([CH3:55])[CH3:56])=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/P(=O)(OC(C)C)OC(C)C)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 15 h
Yield: 65.3 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.70 g), tetraisopropyl methylenediphosphonate (0.59 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.06 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diisopropyl (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.61 g, yield 67%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 152-153° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]2=3)[CH2:3][CH2:2]1.[C:17]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[CH:17]1([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10](=[O:12])[NH:9][C:8]4[CH:13]=[CH:14][CH:15]=[CH:16][C:7]3=4)[CH2:5][CH2:6]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCCCCC1
Reactant: O=C1Nc2ccccc2C2(CCNCC2)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1Nc2ccccc2C2(CCN(C3CCCCCC3)CC2)O1
Temperature: 25 °C
Reaction time: 90 h

Procedure:
Spiro[4H-3,1-benzoxazine-4,4′-piperidin]-2(1H)-one (A4) (353 mg, 1.62 mmol) was dissolved in anhydrous 1,2-dichloroethane (10 mL) and treated with cycloheptanone (iiia) (273 mg, 2.43 mmol), followed by glacial acetic acid (195 mg, 3.24 mmol) and sodium triacetoxyborohydride (687 mg, 3.24 mmol). The reaction was stirred at room temperature under nitrogen for 90 hours. The reaction was diluted with dichloromethane (50 mL), quenched with 1.0 N NaOH (20 mL), and stirred vigorously at room temperature for 30 minutes. The layers were separated and the aqueous layer was extracted with dichloromethane (2×20 mL). The pooled organic layers were washed with (20 mL each) water and saturated brine; and dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford crude 1′-cycloheptylspiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1.[C:17]1(=[O:27])[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:17]([C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[C:20]([OH:22])=[O:21])=[O:27])=[CH:7][C:6]=3[C:5]2([CH3:16])[CH3:15])=[CH:13][CH:14]=1
Reactant: CC1(C)c2ccccc2-c2ccc(Br)cc21
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)c2cc(Br)ccc2-c2ccc(C(=O)c3ccccc3C(=O)O)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.9 %

Procedure:
2-Bromo-9,9-dimethyl-9H-fluorene (40 g, 1 eq, 0.146 mol) and phthalic anhydride (23.8 g, 1.1 eq, 0.161 mol) were placed in a reaction vessel, and dichloromethane (1 l) was added thereto. Aluminum chloride (29.2 g, 1.5 eq, 0.219 mol) was gradually added at 0° C., and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was terminated, distilled water was gradually added at 0° C., and the reaction solution was extracted with an excess of dichloromethane and several times washed with distilled water. After solvent removal, the resultant solid was placed in a hexane (2 l)-containing vessel, washed, filtered, and dried to give 2-(7-bromo-9,9-dimethyl-9H-fluorene-2-carbonyl)benzoic acid (50.4 g, yield=82%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][N:11]([CH3:23])[C:12]=2[C:13]2[S:22][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33]>O1CCCC1.C(Cl)Cl>[NH2:21][C:20]1[C:15]2[CH:14]=[C:13]([C:12]3[N:11]([CH3:23])[CH:10]=[N:9][C:8]=3[C:4]3[CH:3]=[C:2]([NH:1][C:32]([NH:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[F:24])=[O:33])[CH:7]=[CH:6][CH:5]=3)[S:22][C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: Cn1cnc(-c2cccc(N)c2)c1-c1cc2c(N)ncnc2s1
Reactant: O=C=Nc1ccccc1F
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1cnc(-c2cccc(NC(=O)Nc3ccccc3F)c2)c1-c1cc2c(N)ncnc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
6-[4-(3-Aminophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (64 mg) in anhydrous tetrahydrofuran (10 mL) was added to 2-fluorophenyl isocyanate (34 mg) and stirred under an inert atmosphere at ambient temperature for 1 hr. The mixture was diluted with DCM (5 mL) then purified by chromatography on silica eluting with a gradient of 0-50% EtOAc/DCM, then 0-50% MeOH (containing 1% concentrated aqueous amnmonia)/DCM to give the title compound as a solid (76 mg, 82%).
Reaction SMILES: Cl.N[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([NH:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)=[O:21])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:9].N([O-])=[O:35].[Na+].Cl>O.C(#N)C.O1CCOCC1>[OH:35][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([NH:19][C:20]([C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:26][CH:27]=1)=[O:21])[C:8]([NH:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[O:9]
Reactant: NCCCCC(NC(=O)c1ccc(-c2ccccc2)cc1)C(=O)NCc1ccc(Cl)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC(CCCCO)C(=O)NCc1ccc(Cl)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
6-Amino-2-(4-phenylbenzenecarbonyl)amino-N-(4-chlorobenzyl)hexanamide hydrochloride (173) (1.29 g) was dissolved in water (50 ml) and acetonitrile (20 ml). To the solution were added sodium nitrite (4.02 g) and a solution of 4 N hydrochloric acid in 1,4-dioxane (3.31 ml) under cooling with ice, and the mixture was stirred for 1.0 hour under cooling with ice. After 1.5 hours, the reaction liquid was warmed to room temperature and stirred for 2.0 hours. The reaction liquid was concentrated and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (100 ml), dried over anhydrous sodium sulfate, and filtered. After that, the filtrate was concentrated and the residue was purified by silica gel flash column chromatography (developing solvent: chloroform:methanol=100:1 to chloroform:methanol=30:1) to give a compound (175) (561 mg, yield: 47%) as a white solid. 1H NMR data on the compound (175) is shown below.