Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[CH:10][C:9]=2[CH2:25][CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[NH:45]1[C:49]([NH2:50])=[N:48][N:47]=[N:46]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[CH:10][C:9]=2[CH2:25][CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:50][C:49]3[NH:48][N:47]=[N:46][N:45]=3)=[O:32])=[CH:29][CH:28]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(CCc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2-c2cccc(Cl)c2)cc1
Reactant: Nc1nnn[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nnn[nH]1)c1ccc(CCc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2-c2cccc(Cl)c2)cc1
Temperature: 50 °C

Procedure:
A DMF solution (1 mL) containing 4-{2-[3-chloro-4″-(trifluoromethoxy)-1,1′:4′,1″-terphenyl-2′-yl]ethyl}benzoic acid (12 mg, 0.024 mmol), prepared using the procedures described in EXAMPLE 1, DIEA (21 μg, 0.12 mmol), 1H-tetrazol-5-amine (3 mg, 0.036 mmol), and BOP (21 mg, 0.048 mmol) was heated at 50° C. for 30 minutes. The solution was then purified directly by RP-HPLC to give the title compound. LCMS1 4.36 min (N+H)=564
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([OH:8])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18]Br>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:17][CH2:18][O:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc(O)c(O)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
A mixture of 4-methylbenzene-1,2-diol (10.0 g, 80.5 mmol) and potassium carbonate (111.3 g, 805.0 mmol) in acetone (300 mL) was stirred at room temperature for 1 h. After this time, 1,2-dibromoethane (27.7 mL, 322.0 mmol) was added and the reaction stirred at reflux for 5 d. After this time, the solvents were removed under reduced pressure and the solids redissolved in water (500 mL). The aqueous layer was then extracted three times with ethyl acetate (200 mL). The combined organic extracts were then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 1:20 ethyl acetate/hexanes) afforded 6-methyl-2,3-dihydrobenzo[b][1,4]dioxine (6.4 g, 54%) as a green oil: 1H NMR (500 MHz, CDCl3) δ 6.74 (d, J=8.5 Hz, 1H), 6.67 (d, J=2.0 Hz, 1H), 6.63 (dd, J 2.0, 8.0 Hz, 1H), 4.22 (m, 4H), 2.24 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH2:14][S:15][C:16]1[O:17][CH:18]=[CH:19][N:20]=1.[Br:22]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:22][C:18]1[O:17][C:16]([S:15][CH2:14][C:5]2[C:6]([C:10]([F:12])([F:13])[F:11])=[N:7][N:8]([CH3:9])[C:4]=2[O:3][CH:2]([F:1])[F:21])=[N:20][CH:19]=1
Reactant: Cn1nc(C(F)(F)F)c(CSc2ncco2)c1OC(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CSc2ncc(Br)o2)c1OC(F)F

Procedure:
2-({[5-(Difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfanyl)-1,3-oxazole (1.24 g, 4 mmol) is initially charged in 20 ml of dimethylformamide. N-Bromosuccinimide (0.892 g, 5 mmol) is then added a little at a time with stirring. The mixture is stirred at 40° C. for a further 6 hours. For work-up, the reaction mixture is added to water and extracted twice with dichloromethane, and the extracts are then washed with water and finally with saturated NaCl solution. The combined organic phases are dried over magnesium sulfate, filtered off and concentrated. The crude product is purified chromatographically (heptane:ethyl acetate, gradient 10:0 to 7:3). This gives 0.70 g of product (43.2% of theory).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[Cl:15][C:16]1[C:25]([N+:26]([O-])=O)=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>O.CO.O1CCCC1>[Cl:15][C:16]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cccc(N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
A solution of sodium dithionite (14.0 g, 20.0 mM) and sodium carbonate (6.7 g) in 200 mL of water was slowly added to a solution of methyl 2-chloro-3-nitrobenzoate (6.0 g, 27.9 mM) in 40 mL methanol and 40 mL of tetrahydrofuran at 25° C. over 30 minutes. The mixture was stirred at room temperature for an additional 30 minutes, then extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 1.2 g (33%) of methyl 2-chloro-3-aminobenzoate as a yellow oil, identical in all respects to the material derived via catalytic hydrogenation described above.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[C@H:22]1[C@H:27]([OH:28])[C@@H:26]([OH:29])[C@H:25]([OH:30])[C@@H:24]([CH2:31][OH:32])[O:23]1)[CH:2]=[CH2:3].C1C=C(Cl)C=C(C(OO)=[O:41])C=1>C(Cl)Cl>[Cl:12][C:10]1[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][C:7]([C@H:22]2[C@H:27]([OH:28])[C@@H:26]([OH:29])[C@H:25]([OH:30])[C@@H:24]([CH2:31][OH:32])[O:23]2)=[C:6]([CH2:5][O:4][CH2:1][CH:2]2[CH2:3][O:41]2)[CH:11]=1
Reactant: C=CCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(COCC3CO3)cc2Cl)cc1
Temperature: 40 °C

Procedure:
To a solution of (2S,3R,4R,5S,6R)-2-(2-(allyloxymethyl)-4-chloro-5-(4-ethylbenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (463 mg, 1 mmol) in CH2Cl2 (2 mL) at 0° C., was added mCPBA (350 mg, 2 mmol). The mixture was heated to 40° C. and kept at that temperature overnight. Upon being cooled to room temperature, 10 mL of CH2Cl2 was added to dilute the solution. The solution was then washed with aqueous NaHCO3 and brine prior to drying over Na2SO4. The solvent was removed under reduced pressure and purification of the resulting mixture with preparative TLC gave two isomers with undetermined absolute configurations.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:18][CH:19]([CH3:24])[C:20](=[O:23])[CH2:21][CH3:22])[CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pt]>[NH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:18][CH:19]([CH3:24])[C:20](=[O:23])[CH2:21][CH3:22])=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)C(C)Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCC(=O)C(C)Cc1ccc(N)c(OCc2ccccc2)c1
Reaction time: 18 h

Procedure:
A mixture of 1-(3-benzyloxy-4-nitrophenyl)-2-methylpentan-3-one (450 mg) and Pt/C (22 mg) in EtOAc (15 mL) is hydrogenated at 1 atm for 18 h. The catalyst is filtered and the filtrate evaporated to give the title compound which is used directly in the next step.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=[C:18]3[N:17]([CH2:25][CH3:26])[C:16]2=[O:27])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[Cl:24][C:22]1[CH:23]=[C:18]2[N:17]([CH2:25][CH3:26])[C:16](=[O:27])[N:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[C:19]2=[N:20][CH:21]=1
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(Cl)cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2ncc(Cl)cc21
Reaction time: 3 h
Yield: 18.4 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-6-chloro-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (500 mg) and 10% Pd—C (140 mg) in EtOAc (10 mL) was hydrogenated under balloon pressure at room temperature for 3 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give 6-chloro-1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (70 mg) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[NH:13][C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1.I[CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C>[CH:19]1([CH2:18][N:13]2[C:10]3[CH:11]=[CH:12][C:7]4[N:8]([C:4]([CH3:3])=[N:5][N:6]=4)[C:9]=3[CH:15]=[C:14]2[CH3:16])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Reactant: ICC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(ccc3nnc(C)n32)n1CC1CCCC1
Reaction time: 0.25 h

Procedure:
Sodium hydride (13 mg, 0.32 mmol, 60% in mineral oil) was added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (20 mg, 0.1 mmol, from Example 2, Step 5) in DMF (3.0 mL). After stirring for 15 minutes, (iodomethyl)cyclopentane (0.022 g, 0.11 mmol, Acros) was added. After stirring for 45 minutes at room temperature, excess NaH (13 mg, 0.32 mmol, 60% in mineral oil) and (iodomethyl)cyclopentane (0.022 g, 0.11 mmol) were added and the reaction was continued for 20 minutes and then was quenched by the addition of water and diluted to 5 mL volume with MeCN. The resulting solution was filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (4 mg, 10%).
Reaction SMILES: [O:1]=[C:2]1[N:14]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C@@H:24]([C:42]([OH:44])=[O:43])[CH2:25][C:26]3[CH:31]=[C:30]([CH3:32])[C:29]([O:33]CC4C=CC=CC=4)=[C:28]([CH3:41])[CH:27]=3)=[O:22])[CH2:17][CH2:16]2)[C:5]2[CH:6]=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:4]=2[NH:3]1.[H][H]>C1COCC1.CO.[Pd]>[O:1]=[C:2]1[N:14]([CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C@@H:24]([C:42]([OH:44])=[O:43])[CH2:25][C:26]3[CH:27]=[C:28]([CH3:41])[C:29]([OH:33])=[C:30]([CH3:32])[CH:31]=3)=[O:22])[CH2:19][CH2:20]2)[C:5]2[CH:6]=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:4]=2[NH:3]1
Reactant: [H][H]
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(n3c(=O)[nH]c4c5ccccc5ncc43)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3c(=O)[nH]c4c5ccccc5ncc43)CC2)C(=O)O)cc(C)c1O

Procedure:
A suspension of 1.80 g (3.03 mmol) (R)-1-carboxy-2-(4-benzyloxy-3,5-dimethyl-phenyl)-ethyl 4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carboxylate and 300 mg 10% Pd/C in 30 mL THF and 30 mL MeOH was hydrogenated at 3000 hPa hydrogen pressure and RT for 48 h. The catalyst was suction filtered, the filtrate was evaporated down and the residue was purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.[Li]CCCC.[CH3:38][C:39]1([CH:45]=[O:46])[CH2:44][CH2:43][S:42][CH2:41][CH2:40]1>O1CCCC1>[CH3:38][C:39]1([CH:45]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=4)[N:9]=3)[NH:4][CH:3]=2)[OH:46])[CH2:44][CH2:43][S:42][CH2:41][CH2:40]1
Reactant: CC1(C=O)CCSCC1
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3[nH]cc(C(O)C4(C)CCSCC4)c3n2)cc(OC)c1OC
Reaction time: 0.01 h
Yield: 32.3 %

Procedure:
A solution of 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (400 mg, 0.7 mmol) in anhydrous tetrahydrofuran (5 ml) was cooled to −78° C. and treated with nBuLi (2.23M in hexanes, 0.42 ml, 0.94 mmol) dropwise. The reaction mixture was stirred for 30 seconds and then treated with a solution of 4-methyl-tetrahydro-thiopyran-4-carbaldehyde (0.305 mg, 2.1 mmol) in anhydrous tetrahydrofuran (2 ml), dropwise. The reaction mixture was allowed to stir at −78° C. for 30 minutes. The reaction mixture was partitioned between EtOAc/saturated aqueous NH4Cl. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a yellowish oil. The oil was purified by silica gel chromatography using 3-100% EtOAc in hexanes as eluant to provide 97 mg (32%) of (4-methyl-tetrahydro-thiopyran-4-yl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanol as a pale yellow solid. M+H=430.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:3]=1[NH2:4].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([OH:33])([C:25]([F:26])([F:27])[F:28])[C:29]([F:30])([F:31])[F:32])=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[CH:8][C:2]=1[Cl:1]
Reactant: Nc1ccc(CC2CCNCC2)cc1Cl
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1Cl
Yield: 93.5 %

Procedure:
2-Chloro-4-(piperidin-4-ylmethyl)aniline (0.445 mmol, 100 mg), 2-(4-(bromomethyl)-phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.445 mmol, 150 mg) and potassium carbonate (0.890 mmol, 123 mg) were combined and stirred at room temperature in acetonitrile (5 mL) for 1.5 hours. The reaction mixture was filtered and filtrate was concentrated under vacuum. The residue was purified by SCX chromatography to give the title compound (200 mg). MS (ESI) m/z 480.9 [M+H]+
Reaction SMILES: [F:1]C1C=C2C(C(C=O)=CN2)=CC=1.C(O[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]([NH2:28])=[O:27])[CH:21]=[C:20]2[N:29]=[C:30]=[O:31])C=C>>[F:1][C:25]1[CH:24]=[C:23]2[C:19]([C:20]([N:29]=[C:30]=[O:31])=[CH:21][N:22]2[C:26]([NH2:28])=[O:27])=[CH:18][CH:17]=1
Reactant: O=Cc1c[nH]c2cc(F)ccc12
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Product: NC(=O)n1cc(N=C=O)c2ccc(F)cc21

Procedure:
was prepared from 6-fluoro-1H-indole-3-carbaldehyde [2795-41-7] using the protocol described for steps C, D and E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH:5]=[C:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[OH:21]O.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:6]3([C:14](=[O:15])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:7]3=[O:16])[O:21]2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: OO
Reactant: O=C1C(=Cc2ccc(Cl)c(Cl)c2)C(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1c2ccccc2C(=O)C12OC2c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a suspension of 2-(3,4-dichloro-benzylidene)-indane-1,3-dione (1c) (1.6 g, 5.2 mmol) in MeOH (13 mL) was added hydrogen peroxide (30% solution, 3 mL). The mixture was cooled to 0° C. and sodium hydroxide (1 N, 300 μL) was added dropwise. After addition was completed, stirring was continued at room temperature for 1 h. The mixture was then poured into water (5 mL) and the resulting solid was collected by filtration and washed with water and MeOH. After drying under high vacuum 3-(3,4-dichlorophenyl)-spiro (oxirane-2, 2′-indan)-1′,3′-dione (1d) (1.6 g, 95% yield) was obtained.
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[CH2:3][OH:4].[C:6](Cl)([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C(N(CC)CC)C>O1CCCC1.C1(C)C=CC=CC=1>[OH:4][CH2:3][CH:2]([NH:1][C:6](=[O:7])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:5]
Reactant: CC(N)CO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
In tetrahydrofuran (500 ml) was dissolved 22.53 g (300 mmol) of 2-aminopropanol, and then 155.1 g (300 mmol) of a 30% solution of carbobenzoxy chloride in toluene and a solution of 36.43 g (360 mmol) of triethylamine in tetrahydrofuran were slowly dropped thereinto under ice-cooling. After the resulting mixture was stirred at room temperature for 3 hours, the triethylamine hydrochloride precipitated was filtered under reduced pressure and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and diluted hydrochloric acid was added thereto, followed by three runs of extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then distilled to remove the solvent, whereby 49.8 g (yield 79%) of benzyl (2-hydroxy-1-methylethyl)carbamate was obtained.
Reaction SMILES: [CH2:1]([O:8][P:9]([O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[N+]([O-])([O-])=O.[Ag+:35].CCOC(C)=O>C1COCC1.O>[Ag+:35].[CH2:12]([O:11][P:9]([O:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([O-:26])=[O:25])=[CH:27][CH:28]=1)([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C([O-])c1ccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.1 %

Procedure:
4-(bis(benzyloxy)phosphoryloxy)benzoic acid (0.940 g, 2.36 mmol) was dissolved in THF (1.5 mL) and then diluted with water (50 mL). To the resulting suspension was added 1.000 N NaOH solution (2.30 mL, 2.30 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min before a solution of silver nitrate (0.421 g, 2.48 mmol) in water (4 mL) was added over 5 min. Precipitate formed during the addition. The heterogeneous mixture was stirred at rt for 45 min before AcOEt (30 mL) was poured. The whole was stirred at rt for 10 min. The title compound (1.05 g, 88% yield) was collected as a white solid by suction filtration and dried over Drierite® under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([C:12]([O:14]CC)=[O:13])=[C:7]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)[C:6]=2[CH:27]=1.O1CCOCC1.[OH-].[Na+].Cl>O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([C:12]([OH:14])=[O:13])=[C:7]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)[C:6]=2[CH:27]=1
Reactant: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(Cl)ccc2oc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2c(C(=O)O)c(=O)oc3ccc(Cl)cc23)cc1OC

Procedure:
A mixture of ethyl 6-chloro-4-(3,4-dimethoxyphenyl)-2-oxo-2H-1-benzopyran-3-carboxylate (1.0 g), dioxane (5 ml), ethanol (5 ml) and 2N-NaOH (12 ml) was refluxed for 1.5 hours, and then, adjusted to pH 2 by adding 2N-HCl. The mixture was stirred for 30 minutes at room temperature, to which water was added to obtain 6-chloro-4-(3,4-dimethoxyphenyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid as crystals. Recrystallization from acetone gave colorless prisms (0.54 g, 58.1%).
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([F:12])=[CH:7][C:6]=1[Cl:13])[CH3:2].[O:17]=[C:18](Cl)OC(Cl)(Cl)Cl>C(OCC)(=O)C>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4](=[O:14])[C:5]1[CH:10]=[C:9]([N:11]=[C:18]=[O:17])[C:8]([F:12])=[CH:7][C:6]=1[Cl:13])[CH3:16]
Reactant: CCN(CC)C(=O)c1cc(N)c(F)cc1Cl
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)c1cc(N=C=O)c(F)cc1Cl
Reaction time: 0.5 h

Procedure:
13.5 g of of N,N-diethyl-5-amino-2-chloro-4-fluorobenzamide in 150 ml of ethyl acetate are added dropwise while stirring within 30 minutes to a solution, heated to 70° C., of 6.7 ml of diphosgene in 50 ml of ethyl acetate. The reaction mixture is then heated at reflux temperature for 2 hours. Subsequently, the solvent is distilled off at normal pressure and the residue is distilled in a bulb-tube. There is obtained N,N-diethyl-2-chloro-4-fluoro-5-isocyanatobenzamide, b.p. 170° C./0.06 mmHg; nD 1.542, used as the starting material in Example 3.
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][NH:17][C:18]([N:20]([CH2:24][CH:25]=[CH2:26])[CH2:21][CH:22]=[CH2:23])=O)=[N:14][CH:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CO>[CH2:21]([N:20]([CH2:24][CH:25]=[CH2:26])[C:18]1[N:14]2[CH:15]=[C:10]([F:9])[CH:11]=[CH:12][C:13]2=[N:16][N:17]=1)[CH:22]=[CH2:23]
Reactant: C=CCN(CC=C)C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)c1nnc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
Hexachloroethane (4.34 g, 18.4 mmol) was added portionwise over 5 min at RT to a stirred mixture of Intermediate 101a (2.30 g, 9.2 mmol), triethylamine (3.71 g, 36.8 mmol) and triphenylphosphine (4.82 g, 18.4 mmol) in THF (90 mL). The reaction mixture was stirred at RT for 1 h, then diluted with MeOH and purified by FCC using SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 2M NH3 in MeOH. The compound containing fractions were combined and concentrated in vacuo. The resultant residue was subjected to the follow purification procedure; FCC on silica (0-6% [2M NH3 in MeOH] in DCM), then SCX-2 cartridge (conditions described above) and finally further FCC on silica (0-2% MeOH in EtOAc), to afford the title compound (1.34 g, 62%). 1H NMR (400 MHz, CDCl3): 3.87 (4H, d, J=6.2 Hz), 5.16-5.35 (4H, m), 5.85-6.02 (2H, m), 7.11 (1H, ddd, J=10.0, 7.6, 2.3 Hz), 7.58-7.67 (1H, m), 7.75-7.80 (1H, m).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[CH:29][C:30]([NH:33][CH2:34][CH2:35][OH:36])=[N:31][CH:32]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[CH:29][C:30]([NH:33][CH2:34][CH2:35][OH:36])=[N:31][CH:32]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: OCCNc1ccc(Br)cn1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: OCCNc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and 2-(5-bromo-pyridin-2-ylamino)-ethanol (example B.46) (195 mg, 0.9 mmol) according to general procedure II. Obtained as a red solid (50 mg, 10%). MS (ISP) 492.0 [(M+H)+]; mp 202–203° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])[N:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][S:30]([CH3:33])(=[O:31])=[O:32])[N:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CS(=O)(=O)Cc1cccc(Br)n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(CS(C)(=O)=O)n3)s2)c(F)c1

Procedure:
The title compound was prepared using the procedure described in Example 1 with 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.075 g, 0.24 mmol) and 2-bromo-6-[(methylsulfonyl)methyl]pyridine (0.060 g, 0.24 mmol) as starting materials.