Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:21]([O-:23])=[O:22])=[C:17]([CH:20]=1)[CH:18]=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:24]([Mg]Br)=[CH2:25].Cl>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:21]([O-:23])=[O:22])=[C:17]([CH:18]([OH:19])[CH:24]=[CH2:25])[CH:20]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)[Si](C)(C)OCCCOc1ccc([N+](=O)[O-])c(C=O)c1
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(O)c1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 80 %

Procedure:
5-[3'-(t-Butyidimethylsilyloxy)propyloxy]-2-nitrobenzaldehyde (5.80 g) is dissolved in dry THF (35 ml), and thereto is added with stirring vinyl-magnesium bromide (1.7 equivalent) in THF solution in a dry ice-acetone bath. The mixture is stirred for two hours, and thereto is added 5% hydrochloric acid (30 ml). The mixture is stirred at room temperature, extracted with ethyl acetate, and purified by silica gel column chromatography to give 1-{5'-[3"-(t-butyldimethylsilyloxy)propyloxy]-2'-nitrophenyl}-2-propen-1-ol (5.02 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[Li]CCCC.CCCCCC.[NH2:20][C:21]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:22]=1[C:23](N(OC)C)=[O:24].Cl>C1COCC1>[NH2:20][C:21]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:22]=1[C:23]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:24]
Reactant: CON(C)C(=O)c1cccc(C)c1N
Reactant: Fc1cccc(I)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)c2cccc(F)c2)c1N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
In a 500 mL round-bottomed flask a solution of 1-fluoro-3-iodobenzene (13.61 mL, 116 mmol) in THF (120 mL) was cooled in −78° C. bath. A solution BuLi, 2.5M in hexane (46.3 mL, 116 mmol) was added dropwise over 10 minutes to give a slightly cloudy yellow solution. The solution was stirred at −78° C. for 30 minutes and then treated with a solution of 2-amino-N-methoxy-N,3-dimethylbenzamide (6.43 g, 33.1 mmol) in THF (30 mL). After 1.5 hours the reaction mixture was added to a mixture of ice and 1N HCl (149 mL, 149 mmol) and reaction flask rinsed with THF (5 ml) and combined with the aqueous mixture. The resulting mixture was diluted with 10% aq LiCl and the pH was adjusted to 4.00 with 1N NaOH. The mixture was extracted with Et2O, washed with brine, dried over MgSO4, filtered and concentrated. The resulting residue was purified on silica gel column (220 g ISCO) eluting with a gradient from 10% EtOAc/hexane to 30% EtOAc/hexane. The product was collected and concentrated to give (2-amino-3-methylphenyl)(3-fluorophenyl)methanone (7.11 g, 94% yield) as an oil. MS(ES):m/z=230.1 [M+H+]; HPLC: RT=2.820 min Purity=99%. (H2O/MeOH with TFA, CHROMOLITH® ODS S5 4.6×50 mm, gradient=4 min, wavelength=220 nm);
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:29]=[CH:28][C:18]([CH2:19][NH:20]C(=O)OC(C)(C)C)=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1.C(Cl)[Cl:31].CO>Cl.O1CCOCC1>[ClH:31].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:29]=[CH:28][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Reaction time: 48 h
Yield: 98 %

Procedure:
A solution of tert-butyl {4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzyl}carbamate (1.17 g; 3.00 mmol; 1.0 eq.) in HCl solution in 1,4-dioxane (7.5 mL, 4N) was stirred at RT. After 48 h, the reaction mixture was concentrated to dryness affording a sticky solid, which was sonicated in a 1:1 mixture of DCM/MeOH. The suspension obtained was concentrated to dryness to afford the title compound as a beige solid (967 mg, 98%). HPLC (Condition A): Rt 2.08 min (purity 95.3%). MS (ESI+): 291.1, MS (ESI−): 289.2. Purification by preparative HPLC of 50 mg of this crude by afforded a pure sample (35 mg): 1H NMR (300 Mz, DMSO-d6) δ: 13.40 (brs, 1H), 9.33 (s, 1H), 8.36 (dt, J=8.2 Hz, J=1.0 Hz, 1H), 8.07 (d, J=8.5 Hz, 2H), 7.68 (d, J=8.5 Hz, 2H), 7.62 (dt, J=8.2 Hz, 1.0 Hz, 1H), 7.47-7.42 (m, 1H), 7.29-7.24 (m, 1H), 4.02 (s, 2H). HPLC (Condition A): Rt 2.06 min (purity 97.5%). MS (ESI+): 291.1, MS (ESI−): 289.1.
Reaction SMILES: O[C:2]1([CH3:20])[O:6][C:5](=O)[CH:4]=[C:3]1[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[O:18][CH3:19].O.[NH2:22][NH2:23]>C(O)C>[CH3:19][O:18][C:9]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]=1[C:3]1[C:2]([CH3:20])=[N:23][NH:22][C:5](=[O:6])[CH:4]=1
Reactant: NN
Reactant: COc1ccc(C(F)(F)F)cc1C1=CC(=O)OC1(C)O
Solvent: O
Solvent: CCO
Product: COc1ccc(C(F)(F)F)cc1-c1cc(=O)[nH]nc1C
Temperature: 0 °C
Yield: 36.9 %

Procedure:
5-Hydroxy-4-[2-methoxy-5-(trifluoromethyl)phenyl]-5-methylfuran-2(5H)-one (Preparation 40, 3 g, 10 mmol) was dissolved in ethanol and cooled to 0° C. Hydrazine monohydrate (1.0 mL, 20 mmol) was added drop-wise to this solution, then the reaction mixture was heated to 90° C. for 16 hours. The reaction mixture was then concentrated in vacuo, azeotoped with toluene and the crude material purified by silica gel column chromatography (ISCO™ Companion, 50% ethyl acetate in heptane elution) to afford the title compound as an off-white solid (1.05 g).
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22].Br[CH2:28][CH:29]1[CH2:31][C:30]1([F:33])[F:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:32][C:30]1([F:33])[CH2:31][CH:29]1[CH2:28][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[O:9][C:10]3[C:2]([F:1])=[C:3]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])[CH:4]=[CH:5][C:6]=3[N:7]=2)=[CH:12][C:13]=1[F:18]
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1F
Reactant: FC1(F)CC1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCC4CC4(F)F)c(F)c3)oc2c1F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A suspension of N-((2S)-1-((7-fluoro-2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide (810 mg), 1-bromomethyl-2,2-difluorocyclopropane (573 mg) and potassium carbonate (463 mg) in DMF (10 mL) was stirred at 70° C. for 1 hr and 30 min. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine, and the organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated. The obtained solid was washed with diethyl ether to give the title compound (880 mg).
Reaction SMILES: N(OC(C)(C)C)=O.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2.C[Si]([N:22]=[N+:23]=[N-])(C)C>CC#N>[N:8]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)=[N+:22]=[N-:23]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Nc1ccc2[nH]ncc2c1
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: [N-]=[N+]=Nc1ccc2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 76.3 %

Procedure:
Neat tert-butyl nitrite (670 μL, 5633 μmol) was added to a suspension of 5-aminoindazole (500 mg, 3755 μmol) (commercially available from VWR Chemical Catalog (Order Number AAAL06705-14)) in MeCN (7 mL) at 0° C. followed by dropwise addition of trimethylsilyl azide (598 μL 4506 μmol). The mixture was stirred at 0° C. for 5 minutes room temperature for 18 hours, and at 50° C. for 24 hours. The mixture was concentrated under reduced pressure, and the resulting brown residue was absorbed onto silica gel and purified by flash chromatography (silica gel, 2% to 6% MeOH/DCM) to provide 5-azido-1H-indazole (456 mg, 76%) as a golden solid. LCMS (API-ES) m/z: 160.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].[C:13](OC(=O)C)(=O)C.O>CN(CN(C)C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH2:13])[C:10]([OH:12])=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1CC(=O)O
Agent: CN(C)CN(C)C
Solvent: O
Product: C=C(C(=O)O)c1ccccc1OC
Temperature: 20 °C
Reaction time: 24 h

Procedure:
36.6 g of (2-methoxyphenyl)acetic acid, in suspension in 110 cm3 of bis(dimethylamino)methane, were cooled to a temperature in the region of 0° C. 110 cm3 of acetic anhydride were added dropwise, the temperature of the reaction mixture not exceeding 40° C. The reaction mixture was stirred for 24 hours at a temperature in the region of 20° C. and then cooled to a temperature in the region of 0° C. 500 cm3 of distilled water were then added and stirring was continued for 2 hours at a temperature in the region of 0° C. The solid which had appeared was separated by filtration, washed with three times 100 cm3 of distilled water and dried under reduced pressure at 40° C. 23 g of 2-(2-methoxyphenyl)propenoic acid were thus obtained in the form of a cream solid, the characteristics of which were as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=1.[OH-].[Na+]>CO>[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:9]/[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(Cl)cc1Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(/C=C/C(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
A mixture of 1-(4-chloro-2-phenylaminophenyl)-ethanone (1.7 g, 6.9 mmol), 4-formyl-benzoic acid methyl ester (1.14 g, 6.9 mmol) and NaOH (2 M aq, 2 mL) in MeOH (30 mL) was stirred at RT overnight. The precipitate formed was collected by filtration and dried in a vacuum oven to afford 0.7 g of 4-[(E)-3-(4-chloro-2-phenylamino-phenyl)-3-oxo-propenyl]-benzoic acid methyl ester as an orange solid. The mother liquors were acidified by adding glacial HOAc (99%) to pH 5, and the resulting mixture extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and evaporated under reduced pressure to yield 4-[(E)-3-(4-chloro-2-phenylamino-phenyl)-3-oxo-propenyl]-benzoic acid (350 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:6]([C:7]([NH:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([N:33]=[C:34]=[S:35])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1>O1CCOCC1.C(Cl)Cl>[CH2:14]([O:13][C:11]1[C:6]([C:7](=[O:8])[NH:9][CH3:10])=[CH:5][N:4]=[C:3]([CH2:2][NH:1][C:34]([NH:33][C:31]([O:30][CH2:29][CH:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:28]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:32])=[S:35])[CH:12]=1)[CH3:15]
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: CCOc1cc(CN)ncc1C(=O)NC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOc1cc(CNC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)ncc1C(=O)NC
Reaction time: 1 h
Yield: 74.6 %

Procedure:
500 mg (2.39 mmol) of 6-aminomethyl-4-ethoxy-N-methylnicotinamide (Example 12f) were dissolved in 25 ml of dioxane and treated at RT with 672.4 mg (2.39 mmol) of fluoren-9-ylmethyloxycarbonyl isothiocyanate. After one hour, the mixture was freed from the solvent and the residue was taken up in DCM. It was washed three times with aqueous LiCl solution and once with water. After drying with MgSO4, the mixture was concentrated and the crude product (875 mg) thus obtained was reacted further without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][CH:8]=[N:7][C:6]=1[CH3:10].[C:11](OCC)(=[O:13])[CH3:12]>>[C:11]([C:8]1[S:9][C:5]([CH2:4][CH2:3][O:2][CH3:1])=[C:6]([CH3:10])[N:7]=1)(=[O:13])[CH3:12]
Reactant: COCCc1scnc1C
Reactant: CCOC(C)=O
Product: COCCc1sc(C(C)=O)nc1C

Procedure:
From 5-(2-methoxyethyl)-4-methylthiazole and ethyl acetate, following the procedure of Preparation 1.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(O[CH2:9][C@H:10]1[CH2:22][CH2:21][N:13]2[C:14]3[C:19]([CH:20]=[C:12]2[CH2:11]1)=[CH:18][CH:17]=[CH:16][CH:15]=3)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH:20]=[C:12]1[CH2:11][C@@H:10]([CH2:9][C:1]#[N:2])[CH2:22][CH2:21][N:13]12
Reactant: CS(=O)(=O)OC[C@H]1CCn2c(cc3ccccc32)C1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CC[C@H]1CCn2c(cc3ccccc32)C1
Temperature: 70 °C
Yield: 52.7 %

Procedure:
18.0 g (367 mmol) of sodium cyanide were added to a solution of 65.0 g (233 mmol) of (6,7,8,9-tetrahydropyrido[1,2-a]indol-8(S)-yl)methyl methanesulfonate in 500 ml of dimethylformamide and the mixture was heated at 70° C. for 24 hours. The mixture was partitioned between 1000 ml of water and 600 ml of ethyl acetate. The aqueous phase was extracted twice with 700 ml of ethyl acetate each time and the combined extracts were washed in twice with 500 ml of water each time, dried over magnesium sulfate and evaporated. The brown solid obtained was dissolved in ethyl acetate and the solution was filtered through a pad of silica gel. The solvent was removed in a vacuum and the residue was crystallized from methanol to give 25.8 g of 6,7,8,9-tetrahydropyrido[1,2-a]indole-8(S)-acetonitrile as a light brown solid of melting point 100°-101° C.; [α]D20 -40.6° (c=0.84%, CH2Cl2).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11](O)[CH3:12])[CH:8]=[CH:9][CH:10]=1.C1(P([N:33]=[N+:34]=[N-:35])(C2C=CC=CC=2)=O)C=CC=CC=1.O>C1(C)C=CC=CC=1>[N:33]([CH:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[O:4][C:3]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=1[NH2:1])[CH3:12])=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(O)c1cccc(Oc2ccc(Cl)cc2N)c1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(N=[N+]=[N-])c1cccc(Oc2ccc(Cl)cc2N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the product from Example 170c in toluene (25 mL) was added diphenylphosphoryl azide (1.72 g, 6.23 mmol), followed by 1,8-diazabicyclo[4.3.0]undec-7-ene (0.95 g, 6.2 mmol). The mixture was stirred at 25° C. for 18 h. The reaction was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound. The crude product was purified on silica gel, eluting with hexanes/ethyl acetate/methanol (85:17:3) to provide the title compound (700 mg, 50%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[N:15][N:16]3[CH:21]=[CH:20][C:19]([N:22]4[C@@H:26]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=5)[CH2:25][O:24][C:23]4=[O:34])=[N:18][C:17]=23)[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[CH:11][NH:10][N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[P:41]([O:53][CH2:54]Cl)([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CN(C=O)C.CCOC(C)=O>[P:41]([O:53][CH2:54][N:10]1[CH:11]=[N:12][C:8]([C:7]2[CH:6]=[CH:5][C:4]([C:13]3[CH:14]=[N:15][N:16]4[CH:21]=[CH:20][C:19]([N:22]5[C@@H:26]([C:27]6[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=6)[CH2:25][O:24][C:23]5=[O:34])=[N:18][C:17]=34)=[CH:3][C:2]=2[F:1])=[N:9]1)([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:42]
Reactant: O=C1OC[C@H](c2ccc(F)cn2)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OP(=O)(OCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccc(F)cn5)nc34)cc2F)n1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of (S)-3-(3-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-(5-fluoropyridin-2-yl)oxazolidin-2-one (0.66 g, 1.4 mmol) in DMF (10 mL) was added cesium carbonate (0.47 g, 1.4 mmol) followed by di-tert-butyl chloromethyl phosphate (1.1 g, 4.3 mmol) and the reaction mixture was stirred overnight at ambient temperature, then diluted with EtOAc (100 mL). The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was chromatographed twice on silica gel using EtOAc as eluent to yield (S)-di-tert-butyl (3-(2-fluoro-4-(5-(4-(5-fluoropyridin-2-yl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-1H-1,2,4-triazol-1-yl)methyl phosphate (0.27 g, 0.40 mmol, 28% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:21]1([S:27]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([C:6]([N:8]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:7])=[CH:4][CH:3]=2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(NS(=O)(=O)c2ccccc2)cc1)N1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.50 g), phenylsulfonyl chloride (0.29 ml), triethylamine (0.32 ml) and dichloromethane (30 ml) is stirred at room temperature overnight. The reaction mixture is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from methanol/diethyl ether to give 1-(4-phenylsulfonylaminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.27 g) as colorless prisms, m.p. 178°-182.5° C.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:24]([O-])=O)=[C:4]([CH:20]=[C:21]([F:23])[CH:22]=1)[NH:5][C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:24][C:3]1[C:2]([F:1])=[CH:22][C:21]([F:23])=[CH:20][C:4]=1[NH:5][C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1c(Nc2cc(F)cc(F)c2[N+](=O)[O-])sc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)cc(F)c2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(3,5-difluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-3,5-difluoroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(OC([N:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH2:21]2)[CH2:17][CH2:16]1)=O)C1C=CC=CC=1.CCN(CC)CC>C(Cl)Cl>[C:1]([N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]2([CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH2:21]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CNc1ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC2(CCNCC2)c2ccccc21
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
Acetyl chloride (1.4 mL, 19.9 mmol) was added to a solution of 5.35 g (16.6 mmol) of 1'-benzyloxycarbonyl-spiro(indoline-3,4'-piperidine) in 33 mL of CH2Cl2 and 3.2 mL (23.2 mmol) of Et3N keeping the temperature between 0-5° C. by cooling in ice bath. After 10 min the cold bath was removed and reaction was stirred for 30 min at which time a TLC indicated complete reaction. The solution was diluted with CH2Cl2 and washed with water, brine and dried over Na2SO4. The filtrate was concentrated to a thick oil and the oil was dissolved in 40 mL of EtOH. Acetic acid (3 mL) and 0.8 g of 10% Pd/C were added to the solution and the resulting mixture was hydrogenated on a Parr apparatus for 3 h. The catalyst was filtered and washed with EtOAc and the combined filtrate was concentrated. The residue was partitioned between CH2Cl2 and water and 2N NaOH was added to this mixture until the aqueous layer was basic. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4 and the filtrate was concentrated to give 2.93 g (77%) of the title compound sufficiently pure for use in the next reaction.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:33]#[CH:34])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>ClCCl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:33]#[CH:34])[C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: C#Cc1cc(C(=O)Cl)cc(C#N)c1OC
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#Cc1cc(C(=O)N2CSc3ccccc32)cc(C#N)c1OC
Reaction time: 2.5 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (570 mg) and 37% formalin (0.38 mL) in the same manner as in Example 1 was dissolved in dichloromethane (10 mL), and triethylamine (1.2 mL) and 3-cyano-5-ethynyl-4-methoxybenzoyl chloride were added to the solution, and then the mixture was stirred at mom temperature for 2.5 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the title compound (283 mg) as a yellow oily substance.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O-:13])=O)[C:6]([O:8]CC)=[O:7])C.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH2:20][CH2:19][CH2:18]2.C(O)C.[OH-].[Na+]>O>[Cl:14][C:15]1[CH:24]=[C:23]2[C:22]3[N:21]([CH:4]=[C:5]([C:6]([OH:8])=[O:7])[C:11]2=[O:13])[CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=1
Reactant: Clc1ccc2c(c1)CCCN2
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn2c3c(cc(Cl)cc3c1=O)CCC2
Temperature: 140 °C
Yield: 111.3 %

Procedure:
4.9 g of ethyl ethoxymethylenemalonate was added to 4 g of 6-chloro-1,2,3,4-tetrahydroquinoline and the mixture was heated on an oil bath at 110° C. during which time distillation of ethanol was observed. After heating the mixture at the same temperature as above for 30 minutes, 30 g of polyphosphoric acid was added thereto followed by heating at 140° C. for 30 minutes. After completion of the reaction, the reaction mixture was poured into 200 ml of water and the resulting mixture was rendered neutral with a 40% aqueous sodium hydroxide solution to precipitate light brown crystals. Without further purification, the crystals were mixed with 100 ml of a 10% aqueous sodium hydroxide solution and the mixture was heat-refluxed for 40 minutes during which time the crystals were dissolved to form a uniform solution. The solution was treated with activated carbon while hot and filtered. The filtrate was allowed to cool and adjusted pH value to pH 2 to obtain 7.0 g of 9-chloro-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as light yellow crystals having a melting point of 282° to 286° C.