Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[N:21][CH:22]=1>C(O)C.C(OCC)(=O)C.Cl.CCO>[Br:16][C:17]1[CH:18]=[CH:19][C:20](=[O:23])[N:21]([CH2:12][C:11]2([OH:13])[CH2:14][CH2:15][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)[CH:22]=1
Reactant: c1ccc(CN2CCC3(CC2)CO3)cc1
Reactant: Oc1ccc(Br)cn1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=c1ccc(Br)cn1CC1(O)CCN(Cc2ccccc2)CC1
Yield: 78.5 %

Procedure:
Referring to the method 2 of Example 1, N-benzyl-1-oxa-6-azaspiro[2,5]-octane and 5-bromo-2-hydroxy-pyridine were used for preparing a free base. Melting point: 146-148° C. The product was dissolved in ethanol-ethyl acetate and salified with HCl-EtOH to obtain a hydrochloride, yield 78.5%. Melting point: 148-150° C. 1H-NMR (D2O, ppm) δ: 7.594 (1H, d, J=2.80 Hz), 7.495 (1H, dd, J1=9.52 Hz, J2=2.52 Hz), 7.24-7.34 (5H, m), 6.365 (1H, d, J=9.52 Hz), 4.112 (2H, s), 3.891 (2H, s), 3.208 (2H, d, J=13.15 Hz), 3.031 (2H, t, J1=11.20 Hz, J2=12.60 Hz), 1.742 (2H, t×d, J1=11.20 Hz, J2=3.95 Hz), 1.573 (2H, J=14.57 Hz).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[CH:8][NH:9]2)=[N:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15].[OH-].[Na+].C(Cl)Cl.CO.[NH4+].[OH-]>C(Cl)Cl>[Cl:15][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([F:1])=[CH:11]2
Reactant: O=c1cc[nH]c2cc(F)cnc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Fc1cnc2c(Cl)ccnc2c1
Temperature: 110 °C
Reaction time: 16 h
Yield: 64.3 %

Procedure:
5-((5-fluoropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione. A 150 mL sealed tube was charged with 2,2-dimethyl-1,3-dioxane-4,6-dione (6.0 g, 41.6 mmol) and trimethyl orthoformate (41.6 mL, 41.6 mmol). This was heated to 100° C., and stirred at this temperature for 2 hours. Reaction then cooled to 30° C. and 5-fluoropyridin-3-amine (4.7 g, 41.6 mmol) added portion-wise. Reaction vessel resealed and mixture stirred at 100° C. for 3 hours. LC/MS shows completion. Reaction mixture was cooled to room temperature, diluted with hexane, filtered, and air dried to yield 5-((5-fluoropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (9.1 g, 82% yield) as a bright yellow solid. MS [M+H]=267.2. Calc'd for Cl2H11FN2O4=266.2. 2) 7-fluoro-1,5-naphthyridin-4(1H)-one. A 500 mL round bottom flask equipped with a reflux condenser was charged with 5-((5-fluoropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.0 g, 30.0 mmol) and diphenyl ether (83.5 mL). This was heated to 250° C. in heating mantle and allowed to stay at this temperature for five minutes. Cooled to room temperature, diluted with hot hexanes, and filtered to afford 7-fluoro-1,5-naphthyridin-4(1H)-one (2.2 g, 45% yield) as a crude brown solid. The title compound was used without further purification. MS [M+H]=165.2, Calc'd for C8H5FN2O=164.14. 3) 8-chloro-3-fluoro-1,5-naphthyridine. A pressure resistant vial was charged with 7-fluoro-1,5-naphthyridin-4(1H)-one (600 mg, 3.66 mmol) and POCl3 (6.8 mL, 73.1 mmol). Vessel sealed and stirred at 110° C. for 16 hrs. Reaction mixture was cooled to room temperature and poured onto ice while stirring vigorously. While keeping reaction mixture at 0° C., it was basified to pH˜8 with 6N NaOH. Product extracted with dichloromethane. Organic layer collected, dried over sodium sulfate and concentrated to afford desired material. This was passed through a silica plug in 1-5% (90:10:1 DCM/MeOH/NH4OH)/DCM to afford 8-chloro-3-fluoro-1,5-naphthyridine (430 mg, 64% yield) as a tan solid. MS [M+H]=182.9. Calc'd for C8H4ClFN2=182.58
Reaction SMILES: [O:1]=[S:2]1(=[O:45])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH2:25]OP(OC5C=CC=CC=5)(OC5C=CC=CC=5)=O)[N:22]=[N:21]4)[O:16][C:15]3=[O:43])=[CH:10][C:9]=2[F:44])[CH2:4][CH2:3]1.[SH:46][C:47]1[NH:48][CH:49]=[CH:50][N:51]=1.[H-].[Na+]>CN(C=O)C>[O:45]=[S:2]1(=[O:1])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH2:25][S:46][C:47]5[NH:48][CH:49]=[CH:50][N:51]=5)[N:22]=[N:21]4)[O:16][C:15]3=[O:43])=[CH:10][C:9]=2[F:44])[CH2:4][CH2:3]1
Reactant: Sc1ncc[nH]1
Reactant: O=C1O[C@@H](Cn2cc(COP(=O)(Oc3ccccc3)Oc3ccccc3)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1O[C@@H](Cn2cc(CSc3ncc[nH]3)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-[(diphenoxyphosphinyl)oxymethyl]-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (Example 15) (0.125 g, 0.19 mmol) was added to a solution of 2-mercaptoimidazole (38 mg, 0.38 mmol) in DMF (2 ml) and the resulting solution was added to a suspension of sodium hydride (15 mg, 0.38 mmol) in DMF (2 ml). The reaction mixture was stirred for 30 minutes and then quenched with excess of aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, was washed with sodium bicarbonate, water and brine, dried over sodium sulfate and concentrated in vacuo to give 40 mg (42%) of the title compound as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][C:40]2[C:41]([O:55][CH3:56])=[N:42][CH:43]=[C:44](B3OC(C)(C)C(C)(C)O3)[CH:45]=2)(=[O:38])=[O:37])=[CH:32][C:31]=1[CH3:57].C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:44]2[CH:45]=[C:40]([NH:39][S:36]([C:33]3[CH:34]=[CH:35][C:30]([OH:29])=[C:31]([CH3:57])[CH:32]=3)(=[O:38])=[O:37])[C:41]([O:55][CH3:56])=[N:42][CH:43]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(=O)(=O)c1ccc(O)c(C)c1
Yield: 52.4 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (63 mg, 0.14 mmol) was treated with 4-hydroxy-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-3-methylbenzenesulfonamide (90 mg, 0.21 mmol), 2M cesium carbonate (430 μl, 0.86 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (12 mg, 0.01 mmol) according to the method described in Example 3 to give 48 mg (51% yield) of the title compound. Purity 100%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14](Br)[C:13]([O:20][CH2:21][O:22][CH3:23])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:31]1[CH:32]=[CH:33][C:28]([C:26]([OH:27])=[O:25])=[CH:29][CH:30]=1)[C:13]([O:20][CH2:21][O:22][CH3:23])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1cc2cc(OCc3ccccc3)ccc2cc1Br
Reactant: COC(=O)c1ccc(B(O)O)cc1
Product: COCOc1cc2cc(OCc3ccccc3)ccc2cc1-c1ccc(C(=O)O)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
Followed the coupling procedure described in Step 1 of Example 20, where the starting materials were 6-(benzyloxy)-2-bromo-3-(methoxymethoxy)naphthalene (Intermediate 11) and 4-methoxycarbonylphenylboronic acid and where the reaction was stirred at 90° C. for 3 hours. The desired product (1.30 g, yield 72%) was obtained as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:36]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][Br:36])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
To 3.4 g of 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (15.79 mmol) in 80 ml of THF, cooled in an ice/water bath, was added 4.76 g triphenylphosphine (18.16 mmol) and then 6.05 g total of carbon tetrabromide (18.16 mmol) in two portions. The reaction was stirred to room temperature over 16 hours. 1.2 g carbon tetrabromide (3.6 mmol) was added twice more over 24 hours before the reaction mixture was filtered. Approximately 240 ml of diethyl ether was added and the resulting mixture was filtered and evaporated. The residue was purified by chromatography on silica gel in 5-10% ethyl acetate/hexanes to give 3.3 g 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (MS: M+H=263/265).
Reaction SMILES: [C:1]([C:4]1[CH:39]=[CH:38][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([C:36]#[N:37])=[C:15]([NH:19][C:20]([C:22]3[N:26](CC4C=CC(OC)=CC=4)[N:25]=[N:24][N:23]=3)=[O:21])[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH2:40][CH2:41][C:42]([F:45])([F:44])[F:43])[C:5]=1[OH:46])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:1]([C:4]1[CH:39]=[CH:38][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([C:36]#[N:37])=[C:15]([NH:19][C:20]([C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[O:21])[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH2:40][CH2:41][C:42]([F:43])([F:45])[F:44])[C:5]=1[OH:46])(=[O:3])[CH3:2]
Reactant: COc1ccc(Cn2nnnc2C(=O)Nc2cccc(OCCCOc3ccc(C(C)=O)c(O)c3CCC(F)(F)F)c2C#N)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ccc(OCCCOc2cccc(NC(=O)c3nnn[nH]3)c2C#N)c(CCC(F)(F)F)c1O

Procedure:
A solution of 7.05 g of N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-2-cyano-phenyl}}-1-(4-methoxybenzyl)-tetrazole-5-carboxamide in 150 ml of trifluoroacetic acid and 15 ml of anisole is refluxed for 30 minutes. The reaction mixture is concentrated under reduced pressure, about 200 ml of ether and 300 ml of petroleum ether are added and the crystals are filtered off. The N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-2-cyano-phenyl}}-1H-tetrazole-5-carboxamide thus obtained of melting point 206°-208°, is dissolved hot in 50 ml of acetone, and the calculated amount of triethanolamine in 30 ml of acetone is added. After addition of ether, crystallisation starts. The triethanolammonium salt of N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)phenoxy]-propoxy}-2-cyano-phenyl}}-1H-tetrazole-5-carboxamide is thus obtained.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30])C.Cl>O1CCCC1.O>[Cl:29][C:24]1[CH:23]=[C:22]([C:16]2([C:18]([F:20])([F:19])[F:21])[O:15][N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:31])=[O:5])=[C:8]([CH3:30])[CH:9]=3)[CH2:17]2)[CH:27]=[C:26]([Cl:28])[CH:25]=1
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 50 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
Lithium hydroxide (51 mg) was added at ambient temperature to a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid ethyl ester (0.27 g) (Example I4) in tetrahydrofuran (3 ml) and water (0.75 ml). The reaction mixture was stirred at 50° C. for 18 hours. The reaction mixture was cooled to ambient temperature and diluted with water, acidified by addition of aqueous hydrochloric acid (2M) and extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to give 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid (0.25 g), which was used without further purification. 1H-NMR (DMSO-d6, 400 MHz): 13.1 (s, 1H), 7.90 (d, 1H), 7.80 (s, 1H), 7.65 (m, 4H), 4.40 (m, 2H), 2.55 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:10][C:11]([F:24])([F:23])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][C:21]#[N:22]>>[F:10][C:11]([F:23])([F:24])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]1[C:21]([NH2:22])=[N:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: N#CCCc1ccccc1OC(F)(F)F
Reactant: Nc1ccccc1C=O
Product: Nc1nc2ccccc2cc1Cc1ccccc1OC(F)(F)F

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-aminobenzaldehyde and 3-(2-trifluoromethoxyphenyl)propionitrile.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[CH2:13]([NH:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])[CH3:14].C(=O)([O-])[O-].[Na+].[Na+]>O>[C:1]([N:15]([CH2:13][CH3:14])[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CCNCC(=O)c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCN(CC(=O)c1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add, in a dropwise manner, 20.4 g. of carbobenzyloxy chloride to a stirred ice-cooled mixture of 16.3 g. of N-ethyl-α-aminoacetophenone hydrochloride and 12.7 g. of sodium carbonate in 125 ml. of water and maintain the reaction temperature at about 20°-25° C. When the addition is complete, stir for one hour at room temperature and extract the product with ether. Wash the ether extract successively with 5% hydrochloric acid, water saturated aqueous sodium bicarbonate and finally with water. Dry over magnesium sulfate and filter. Remove the ether in vacuo and obtain the product of this step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:20]=[C:21](/[CH3:25])\[C:22]([OH:24])=[O:23])[C:6]2[C:11]([C:12]=1[O:13]COC)=[C:10]([CH2:17][CH2:18][CH3:19])[CH:9]=[CH:8][CH:7]=2.O>CC(C)=O.Cl>[OH:13][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:17][CH2:18][CH3:19])[C:5](/[CH:20]=[C:21](/[CH3:25])\[C:22]([OH:24])=[O:23])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCCc1cccc2c(/C=C(/C)C(=O)O)cc(OC)c(OCOC)c12
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCCc1cccc2c(/C=C(/C)C(=O)O)cc(OC)c(O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
2.2 g of (Z)-3-(3-methoxy-4-methoxymethoxy-5-propyl-1-naphthyl)-2-methylpropenoic acid was dissolved in 40 ml of acetone, to which 2.5 ml of concentrated hydrochloric acid was added under light-shielding conditions, followed by stirring in a stream of nitrogen at room temperature for 2 hours. The reaction mixture was poured into water, and the resultant crystals were filtered, washed with hexane and dried in vacuo to obtain 1.7 g of the titled compound as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:6]=1[CH2:7][C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH3:30]O>>[Cl:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:6]=1[CH2:7][C:8]([O:10][CH3:30])=[O:9]
Reactant: CO
Reactant: Cc1ccc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccc(C)cc1
Reaction time: 2 h

Procedure:
In 100 ml of methanol was dissolved 1.8 g of 4-chloro-1-(4-methylbenzyl)-2-phenylimidazole-5-acetic acid, and 0.5 ml of concentrated sulfuric acid was added to the solution to boil for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, and 50 ml each of ethyl acetate and a 10% aqueous sodium bicarbonate solution were added to the residue to shake. The ethyl acetate layer, after washing with water, was evaporated to dryness under reduced pressure. The residue was dissolved in a small amount of methanol and there was obtained, upon standing, 1.5 g of methyl 4-chloro-1-(4-methylbenzyl)-2-phenylimidazole-5-acetate as colorless, prism-formed crystals, m.p. 92°-95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][C:12](=[O:18])[C:13]([O:16][CH3:17])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12](=[O:18])[C:13]([O:16][CH3:17])([CH3:15])[CH3:14]
Reactant: COC(C)(C)C(=O)CBr
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(C)(C)C(=O)COc1ccc(Cl)cc1Cl
Temperature: -20 °C
Yield: 85.7 %

Procedure:
A stirred mixture of 13.04 g (0.08 mole) of 2,4-dichlorophenol, 15.61 g (0.08 mole) 1-bromo-3-methoxy-3-methyl-2-butanone, and 11.1 g (0.08 mole) powdered potassium carbonate in 300 ml acetonitrile was heated at reflux temperature for 30 minutes. The reaction mixture was cooled, filtered, and the solvent evaporated from the filtrate. The residual oil was taken up in hexane and cooled to -20° C., whereupon the product separated as a white crystalline solid. There was thus obtained 19 g (85.7% yield) of 1-(2,4-dichlorophenoxy)-3-methoxy-3-methyl-2-butanone, m.p. 45.5°-47.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[CH:28]=[CH:29][C:30]5[O:46][CH2:45][N:33]6[C:34]7[CH:35]=[CH:36][CH:37]=[C:38]([C:41]([O:43]C)=[O:42])[C:39]=7[CH:40]=[C:32]6[C:31]=5[N:47]=4)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.O[Li].O.Cl>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18]([C:27]4[CH:28]=[CH:29][C:30]5[O:46][CH2:45][N:33]6[C:34]7[CH:35]=[CH:36][CH:37]=[C:38]([C:41]([OH:43])=[O:42])[C:39]=7[CH:40]=[C:32]6[C:31]=5[N:47]=4)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(C(=O)OC)cccc5n3CO4)cc12
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(C(=O)O)cccc5n3CO4)cc12
Yield: 78 %

Procedure:
To a solution of methyl 2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-11-carboxylate (160 mg, 0.24 mmol) in dioxane (2 mL) and water (2 mL), LiOH.H2O (30 mg, 0.71 mmol) was added and the mixture was heated to reflux for 2 hours. Then removed dioxane and the mixture was diluted with water, adjusted to pH=3˜4 by 1 N HCl, and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified using PTLC (dichloromethane:MeOH=20:1) to provide 2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-11-carboxylic acid (120 mg, yield: 76%). 1H-NMR (Methanol-d4, 400 MHz) δ 7.97˜8.02 (m, 2H), 7.86˜7.91 (m, 3H), 7.81 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.59 (s, 2H), 7.31˜7.36 (m, 1H), 7.24˜7.29 (m, 2H), 6.14 (s, 2H), 3.35 (s, 3H), 2.96 (s, 3H), 2.88 (s, 3H). MS (M+H)+: 641.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21](Br)([F:23])[F:22].[C:25]([O:29][C:30]([N:32]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([CH:41]=O)[CH:38]=2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C.[Zn]>[C:25]([O:29][C:30]([N:32]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([CH:41]=[C:21]([F:23])[F:22])[CH:38]=2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C=O)cc2C1
Reactant: FC(F)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2ccc(C=C(F)F)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a stirred solution of 4.69 mmol triphenylphosphine in 5 ml DMF at 0° C. was added dropwise a solution of 4.69 mmol dibromodifluoromethane in 1 ml DMF and the mixture was stirred at RT for 30 min. 2.35 mmol 5-formyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester was then added at 0° C. and then 4.69 mmol zinc dust was added in small portions. The mixture was stirred at RT for 16 and then concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid (31% yield). MS (m/e): 226.1 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C:5]([N:7]1[CH2:28][CH2:27][C:10]2[C:11]3[C:16]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=4)=[N:15][CH:14]=[N:13][C:12]=3[S:26][C:9]=2[CH2:8]1)=[O:6].[NH:29]1[CH2:32][CH2:31][CH2:30]1>CN(C=O)C.C(OC)(C)(C)C>[N:29]1([CH2:2]/[CH:3]=[CH:4]/[C:5]([N:7]2[CH2:28][CH2:27][C:10]3[C:11]4[C:16]([NH:17][C:18]5[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=5)=[N:15][CH:14]=[N:13][C:12]=4[S:26][C:9]=3[CH2:8]2)=[O:6])[CH2:32][CH2:31][CH2:30]1
Reactant: O=C(/C=C/CCl)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Reactant: C1CNC1
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: O=C(/C=C/CN1CCC1)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Temperature: 50 °C
Yield: 13.1 %

Procedure:
To a suspension of Example 59A (100 mg, 0.20 mmol) in DMF (2 mL) was added azetidine (23 mg, 0.40 mmol), and the mixture was heated to 50° C. for 1 h. It was then diluted with methyl tert-butyl ether, washed with water and dried over sodium sulfate. The solvent was removed in vacuo, and the residue was purified by preparative HPLC to yield 12.4 mg (13%) of the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]1([O:13][C:14]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[CH:21]=[C:20]3[CH2:27][C:28]2[CH:51]=[CH:50][C:31]([C:32]([NH:34][S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]#[C:45][C:46]([OH:49])([CH3:48])[CH3:47])(=[O:37])=[O:36])=[O:33])=[CH:30][C:29]=2[O:52][CH3:53])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(OCC)(=O)C>[CH:8]1([O:13][C:14]([NH:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[CH:21]=[C:20]3[CH2:27][C:28]2[CH:51]=[CH:50][C:31]([C:32]([NH:34][S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]#[C:45][C:46]([O:49][C:1](=[O:3])[CH3:2])([CH3:48])[CH3:47])(=[O:36])=[O:37])=[O:33])=[CH:30][C:29]=2[O:52][CH3:53])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C#CC(C)(C)O)ccc1Cc1cn(C)c2ccc(NC(=O)OC3CCCC3)cc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C#CC(C)(C)OC(C)=O)ccc1Cc1cn(C)c2ccc(NC(=O)OC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.44 g of acetic anhydride and 0.1 g of 4-dimethylaminopyridine are added to a solution of 1.0 g of N-[4-[5-(cyclopentyloxycarbonylamino)-1-methyl-indol-3-yl-methyl]-3-methoxybenzoyl]-2-(3-hydroxy-3-methyl-but-1-yn-1-yl)-benzenesulfonamide in 6 ml of pyridine. The reaction solution is stirred for 20 hours at room temperature under argon. The reaction mixture is subsequently diluted with 100 ml of ethyl acetate. The ethyl acetate phase is washed twice with 80 ml of 1N hydrochloric acid each time, with 50 ml of water and with 50 ml of saturated sodium chloride solution. The ethyl acetate phase is dried over magnesium sulfate and concentrated by evaporation at 20 torr and 40°. The residue is chromatographed on 50 g of silica gel (Merck, ST 60, 40-63 μm) with hexane/ethyl acetate=1/1 to yield the title compound in the form of a white amorphous solid. 1H-NMR (400 MHz, DMSO-d6): 8.87 (b, 1H); 8.06 (d, d, 1H); 7.61 (m, 3H); 7.55 (d, 1H); 7.50 (d, 1H); 7.41 (d, d, 1H); 7.22 (d, 1H); 7.14 (d, d, 1H); 7.13 (d, 1H); 6.94 (s, 1H); 5.06 (m, 1H); 3.95 (s, 2H); 3.90 (s, 3H); 3.66 (s, 3H); 1.91 (s, 3H); 1.89-1.52 (m, 8H); 1.61 (s, 6H).