Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[C:15]([OH:17])=O.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[C:15]([Cl:21])=[O:17]
Reactant: COc1cc2c(c(C(=O)O)c1OC)CCCC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(c(C(=O)Cl)c1OC)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,3-dimethoxy-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (0.20 g, 0.85 mmol) in DCM (5 mL) was added oxalyl chloride (0.09 mL, 1.06 mmol) and 1 drop of DMF. The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the 2,3-dimethoxy-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride was used without purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]2[NH:17][C:18]([C:21]3[CH:22]=[C:23]4[CH2:36][O:35][C:34]5[C:25]6=[C:26]([CH:31]=[C:32]([C:37]7[NH:41][C:40]([C@@H:42]8[CH2:46][C@H:45]([CH3:47])[CH2:44][NH:43]8)=[N:39][CH:38]=7)[CH:33]=5)[CH2:27][O:28][C:29]([CH:30]=3)=[C:24]46)=[CH:19][N:20]=2)[CH2:5]1.[CH3:48][O:49][C:50]([NH:52][C@H:53]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:54](O)=[O:55])=[O:51].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.C(=O)(O)[O-].[Na+]>CCN(C(C)C)C(C)C.CN(C=O)C>[CH3:48][O:49][C:50]([NH:52][C@H:53]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:54]([N:43]1[CH2:44][C@@H:45]([CH3:47])[CH2:46][C@H:42]1[C:40]1[NH:41][C:37]([C:32]2[CH:33]=[C:34]3[O:35][CH2:36][C:23]4[C:24]5[C:25]3=[C:26]([CH2:27][O:28][C:29]=5[CH:30]=[C:21]([C:18]3[NH:17][C:16]([C@@H:6]5[CH2:5][C@H:4]([CH2:3][O:2][CH3:1])[CH2:8][N:7]5[C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[N:20][CH:19]=3)[CH:22]=4)[CH:31]=2)=[CH:38][N:39]=1)=[O:55])=[O:51]
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7C[C@H](C)CN7)[nH]6)cc(c3-5)OC4)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1C[C@@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7C[C@H](C)CN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)cc(c3-5)OC4)[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 185.7 %

Procedure:
A mixture of (2S,4S)-tert-butyl 4-(methoxymethyl)-2-(5-(7-(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (102 mg, 0.159 mmol), (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (33 mg, 0.159 mmol), COMU (75 mg, 0.175 mmol) in 1.59 mL 10% DIPEA in DMF was stirred at room temperature for 1 hr. Saturated sodium bicarbonate was added and the crude product was extracted into ethyl acetate. Concentration and purification by silica gel chromatography gave product (245 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([CH:20]=[O:21])=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])=[CH2:2].[BH4-].[Na+]>O1CCCC1.C(O)C.C(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:11]=2[CH2:20][OH:21])[CH:9]=1)([CH3:3])=[CH2:2]
Reactant: C=C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCO
Product: C=C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CO)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
5′-Isopropenyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (5.0 g) is dissolved in a mixed solvent of tetrahydrofuran (100 ml), ethanol (30 ml) and methylene chloride (10 ml), and thereto is added sodium borohydride (646 mg) and the mixture is stirred at room temperature for 10 minutes. The reaction solution is concentrated under reduced pressure and thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=49:1→4:1) to give (5′-isopropenyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-yl)-methanol (4.73 g). MS (m/z): 307 [M+H]+
Reaction SMILES: Br[C:2]1[C:3]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[N:4][CH:5]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[CH3:22][N:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[C:26]2[CH:38]=[CH:39][N:40]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[C:25]=2[C:24]1=[O:51].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[O:13][C:3]1[C:2]([C:27]2[C:26]3[CH:38]=[CH:39][N:40]([S:41]([C:44]4[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=4)(=[O:43])=[O:42])[C:25]=3[C:24](=[O:51])[N:23]([CH3:22])[CH:28]=2)=[CH:7][C:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][N:4]=1
Reactant: CS(=O)(=O)Cc1cnc(Oc2ccc(F)cc2F)c(Br)c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(CS(C)(=O)=O)cnc4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
The product from Example 311e (0.075 g, 0.198 mmol), the product from Example 6a (0.085 g, 0.198 mmol), tris(dibenzylideneacetone)dipalladium(0) (5.45 mg, 5.95 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (5.80 mg, 0.020 mmol) and potassium phosphate (0.126 g, 0.595 mmol) were combined and sparged with argon for 15 minutes. Meanwhile a solution of 4:1 dioxane/water (2 mL) was sparged with nitrogen for 15 minutes and transferred by syringe into the reaction vessel under argon. The mixture was stirred for 2 hours at 60° C. and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (Na2SO4), treated with 3-mercaptopropyl functionalized silica gel, filtered, and concentrated. Purification by trituration in dichloromethane afforded the title compound (0.083 g, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH2:11])=O)[N:6]=[C:5]([C:12]([NH2:14])=O)[CH:4]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.N1C=CC=CC=1>ClCCl>[C:9]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([C:12]#[N:14])[N:6]=1)#[N:11]
Reactant: COc1cc(C(N)=O)nc(C(N)=O)c1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COc1cc(C#N)nc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
4-methoxypyridine-2,6-dicarboxamide (900 mg, 4.6 mmol) was mixed with trifluoroacetic anhydride (2.32 g, 11.1 mmol) and pyridine (1.6 g, 20.2 mmol) in dichloromethane (20 mL) and stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane and washed with water. Standard work up, afforded 461 mg of 2,6-dicyano-4-methoxypyridine.2,6-Dicyano-4-methoxypyridine (460 mg, 2.89 mmol) and 5M hydroxylamine hydrochloride (0.578 mL, 2.89 mmol) in ethanol (3 mL) and 1N sodium hydroxide (2.89 mL, 2.89 mmol), were stirred at room temperature overnight. Standard work up afforded 180 mg (32.4%) of 6-cyano-4-methoxypyrid-2-yl-amidoxime.
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.FC1C=C([N+]([O-])=O)C=CC=1OC1C2SC(C(NCCN3CCOCC3)=O)=CC=2N=CN=1.[Cl:42][C:43]1[CH:44]=[C:45]([OH:52])[CH:46]=[CH:47][C:48]=1[N+:49]([O-:51])=[O:50]>>[Cl:42][C:43]1[CH:44]=[C:45]([CH:46]=[CH:47][C:48]=1[N+:49]([O-:51])=[O:50])[O:52][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2ccsc12
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Agent: O=C(NCCN1CCOCC1)c1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Product: O=[N+]([O-])c1ccc(Oc2ncnc3ccsc23)cc1Cl
Yield: 72 %

Procedure:
Starting from the chloride 20 (scheme 4) and following the procedure described above for the synthesis of compound 24 (scheme 4, example 22) replacing 2-fluoro-4-nitrophenol with 3-chloro-4-nitrophenol, title compound 171 was obtained in 72% yield. LRMS (M+1) 307.7 (100%).
Reaction SMILES: [CH:1]1[N:5]([CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:4]2[N:11]=[C:12]([NH2:16])[N:13]=[C:14]([OH:15])[C:3]=2[N:2]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=O.N>CN(C=O)C>[OH:10][CH2:9][CH2:8][O:7][CH2:6][N:5]1[C:4]2[N:11]=[C:12]3[N:13]([CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[NH:16]3)[C:14](=[O:15])[C:3]=2[N:2]=[CH:1]1
Reactant: Nc1nc(O)c2ncn(COCCO)c2n1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ncn(COCCO)c2nc2[nH]c(-c3ccc(Cl)cc3)cn12
Reaction time: 5 h
Yield: 72 %

Procedure:
A solution of 1.4 g (6.22 mmol) acyclovir, 30 mL DMF, and 400 mg sodium hydride (80%) was stirred at room temperature for 30 min, then 0.7 mL 2-bromo-4′-chloroacetophenone was added dropwise into the solution. Changing to orange color, the solution was added 17 mL ammonia, and continuously stirred for 5 hr. The solvent was removed to obtain a residue, which was washed with water. The product, 3-(2-hydroxy-ethoxymethyl)-6-(4-chlorophenyl)-3,5-dihydro-1,3,4,5,7a-pentaaza-s-indacen-8-one, was produced and weighted 1.62 g (white solid, yield 72%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[CH:22]=[N:23][CH:24]=[C:25]([F:27])[CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[O:34]1[CH2:39][CH2:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH2:35]1.O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO.O>[O:34]1[CH2:39][CH2:38][CH:37]=[C:36]([C:2]2[CH:3]=[C:4]3[C@:15]4([CH2:19][S:18][C:17]([NH2:20])=[N:16]4)[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:21]5[CH:22]=[N:23][CH:24]=[C:25]([F:27])[CH:26]=5)[CH:13]=4)[O:8][C:5]3=[N:6][CH:7]=2)[CH2:35]1
Reactant: NC1=N[C@@]2(CS1)c1cc(-c3cncc(F)c3)ccc1Oc1ncc(Br)cc12
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: NC1=N[C@@]2(CS1)c1cc(-c3cncc(F)c3)ccc1Oc1ncc(C3=CCCOC3)cc12
Temperature: 100 °C
Yield: 50 %

Procedure:
A microwave vial was charged with (S)-3-bromo-7-(5-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (90 mg, 0.20 mmol), potassium carbonate (140 mg, 1.02 mmol), 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (85 mg, 0.41 mmol), tetrakis(triphenylphosphine)palladium(0) (23.46 mg, 0.020 mmol), dioxane (1.35 mL) and water (0.68 mL). The reaction was heated in the microwave at 100° C. for 40 min. After cooling for rt, the organic layer was separated with a separatory funnel, dried over sodium sulfate, filtered, and concentrated to afford a yellow oil which was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (12 g), 0-100% EtOAc in 90:10 CH2Cl2:CH3OH to provide a white solid, (S)-3-(5,6-dihydro-2H-pyran-3-yl)-7-(5-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (45 mg, 0.10 mmol, 50% yield). MS m/z=447.2 [M+H]+. Calc'd for C24H19FN4O2S: 446.5.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH2:29][CH3:30])[C:16]3[C:21]([C:22]=2[C:23]#[N:24])=[CH:20][CH:19]=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:17]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:29]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[C:18]([C:25]([F:27])([F:28])[F:26])[CH:17]=2)[C:22]([C:23]#[N:24])=[C:14]1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH3:30]
Reactant: CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)c(C#N)c2ccc(C(F)(F)F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c(N2CCNCC2)c(C#N)c2ccc(C(F)(F)F)cc21
Yield: 10.2 %

Procedure:
4-(3-cyano-1-ethyl-6-trifluoromethyl-1H-indol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.26 g, 6.1 mmol) is treated with TFA (5 mL) in dichloromethane (5 mL) for 1 h at room temperature. After the removal of the volatiles, the residue is treated with saturated NaHCO3 and the precipitate is collected via filtration, washed with water thoroughly and dried in air to furnish essentially pure 1-ethyl-2-piperazin-1-yl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (0.20 g, 100%).
Reaction SMILES: [CH3:1][C@H:2]1[C@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[C@:18]2([CH3:25])[C@H:4]([C@H:5]3[C@:15]([F:27])([C@@H:16]([OH:26])[CH2:17]2)[C@:14]2([CH3:28])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[CH2:7][CH2:6]3)[CH2:3]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].Cl>N1C=CC=CC=1>[CH3:1][C@H:2]1[C@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[C@:18]2([CH3:25])[C@H:4]([C@H:5]3[C@:15]([F:27])([C@@H:16]([OH:26])[CH2:17]2)[C@:14]2([CH3:28])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[CH2:7][CH2:6]3)[CH2:3]1.[S:30]([O-:32])(=[O:11])(=[O:31])[CH3:29]
Reactant: CS(=O)(=O)Cl
Agent: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 200 mL Erlenmeyer flask equipped with a magnetic stir bar and a rubber septum was charged with 5 grams of dexamethasone (12.7 mmol, 1 equivalent) and 16 mL of anhydrous pyridine. The flask was cooled to 0° C. with an ice bath, and 1.2 mL of methanesulfonyl chloride was added. After 1 hour, 0.8 mL of additional methanesulfonyl chloride was added. At two hours, the solution was poured into 100 mL of cold 1M HCl, forming a precipitate. The precipitate was filtered and redissolved in 250 mL of ethanol, and precipitated into 250 mL of 1M HCl. The precipitate was filtered and recrystallized in ethanol, filtered, and dried under vacuum yielding 4.95 g (82.6%) of dexamethasone mesylate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10].[CH3:14][O:15][C:16](=[O:45])[N:17]=[C:18]([S:43][CH3:44])[C:19]([C:33]1[CH:38]=[C:37]([CH2:39][CH3:40])[CH:36]=[C:35]([OH:41])[C:34]=1[F:42])=[N:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)=[CH:23][CH:22]=1.C(OCC)(=O)C>CN(C=O)C.O>[CH3:14][O:15][C:16](=[O:45])[N:17]=[C:18]([S:43][CH3:44])[C:19]([C:33]1[CH:38]=[C:37]([CH2:39][CH3:40])[CH:36]=[C:35]([O:41][CH2:8][C:9](=[O:10])[N:11]([CH3:13])[CH3:12])[C:34]=1[F:42])=[N:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)=[CH:23][CH:22]=1
Reactant: CCc1cc(O)c(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(OCC(=O)N(C)C)c(F)c(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
After adding 0.163 g of potassium carbonate and 0.14 ml of 2-chloro-N,N-dimethylacetamide to a solution of 0.41 g of {2-(5-ethyl-2-fluoro-3-hydroxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 15 ml of DMF, the reaction mixture was stirred at room temperature for 60 hours, and then 200 ml of ethyl acetate and 100 ml of water were added. The organic layer was washed twice with 100 ml of water and once with 100 ml of saturated aqueous sodium chloride in that order, and dried over anhydrous magnesium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (0.41 g) as a light yellow solid.
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[C:17]([C:18]([O:20]C)=[O:19])=[CH:16][C:15]3[C:14](=[O:22])[N:13]([CH:23]4[CH2:28][CH2:27][N:26]([CH2:29][C:30]5[C:35]([O:36][CH2:37][CH3:38])=[CH:34][C:33]([C:39]6[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=6)=[C:32]([CH:46]6[CH2:48][CH2:47]6)[CH:31]=5)[CH2:25][CH2:24]4)[CH2:12][CH2:11][C:10]=3[N:9]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]3[C:14](=[O:22])[N:13]([CH:23]4[CH2:24][CH2:25][N:26]([CH2:29][C:30]5[C:35]([O:36][CH2:37][CH3:38])=[CH:34][C:33]([C:39]6[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=6)=[C:32]([CH:46]6[CH2:47][CH2:48]6)[CH:31]=5)[CH2:27][CH2:28]4)[CH2:12][CH2:11][C:10]=3[N:9]=2)[CH2:6][CH2:7]1
Reactant: CCOc1cc(-c2ccc(F)cc2)c(C2CC2)cc1CN1CCC(N2CCc3nc(C4CC4)c(C(=O)OC)cc3C2=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(-c2ccc(F)cc2)c(C2CC2)cc1CN1CCC(N2CCc3nc(C4CC4)c(C(=O)O)cc3C2=O)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (2 mL)-THF (2 mL) solution of methyl 2-cyclopropyl-6-(1-((2-cyclopropyl-5-ethoxy-4′-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (480 mg), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was neutralized with hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the mixture was concentrated. The deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (ethanol/hexane) to obtain the title compound (320 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:22](COCC[Si](C)(C)C)[C:21]([O:31][C@H:32]3[CH2:41][O:40][C@H:39]4[C@@H:34]([O:35]C(C5C=CC=CC=5)[O:37][CH2:38]4)[CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:10][CH:9]=1.C(O)=O.S([O-])(O)(=O)=O.[K+].[OH-].[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:31][C@H:32]3[CH2:41][O:40][C@H:39]([CH2:38][OH:37])[C@@H:34]([OH:35])[CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)C#Cc1ccc(-c2nc3nc(O[C@H]4CO[C@@H]5COC(c6ccccc6)O[C@H]5C4)n(COCC[Si](C)(C)C)c3cc2Cl)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: C#Cc1ccc(-c2nc3nc(O[C@H]4CO[C@H](CO)[C@@H](O)C4)[nH]c3cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-chloro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-5-(4-((trimethylsilyl)ethynyl)phenyl)-1H-imidazo[4,5-b]pyridine (220 mg, 0.319 mmol) was dissolved in formic Acid (4.5 ml, 117 mmol) and sat. potassium hydrogen sulfate (0.5 ml, 0.319 mmol). The mixture was stirred at rt for 1 h, and then diluted with EtOAc. Then 3 M NaOH was added until a pH of pH 14 was reached. The mixture was stirred for 15 minutes at rt and then the layers were separated. The aqueous phase was extracted with EtOAc (×2). The combined organic extracts were washed with brine and dried over Na2SO4, filtered and concentrated. The resulting crude product was purified by column chromatography on Biotage™ 25 g column by eluting with 50% EtOAc in DCM to yield the title compound. LC-MS: m/e=400.32 (M+H)+ (Rt 1.71/4 min).
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][O:6][C:5]2[C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.[Br:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([CH2:36]Cl)=[C:31]([O:38][CH3:39])[CH:30]=[CH:29]2.[Na+].[I-].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Br:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([CH2:36][N:3]1[C:2](=[O:1])[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:7][O:6][C:5]3[C:17]([C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=[CH:20][C:4]1=3)=[C:31]([O:38][CH3:39])[CH:30]=[CH:29]2
Reactant: COc1ccc2cc(Br)ccc2c1CCl
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2c(cccc2C(F)(F)F)NC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2c1cccc2C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.1 %

Procedure:
A mixture of (S)-tert-butyl 4-oxo-9-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (389 mg, 1.12 mmol), 6-bromo-1-(chloromethyl)-2-methoxynaphthalene (481 mg, 1.68 mmol), NaI (253 mg, 1.68 mmol) and Cs2CO3 (549 mg, 1.68 mmol) in DMF (15.6 mL) was stirred at RT for 6 h and diluted with EtOAc. The mixture was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated to give a residue that was purified by silica gel chromatography to afford (S)-tert-butyl 5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-9-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (321 mg, 48%) as a colorless waxy solid. MS m/z 617/619 (MNa)+
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([C@H:12]2[CH2:14][C@H:13]2[C:15](O)=[O:16])=O)=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3].O.[NH2:21][NH2:22]>C(O)C>[C:1]([NH:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]2[CH:12]3[CH:13]([C:15](=[O:16])[NH:21][N:22]=2)[CH2:14]3)=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Nc1ccc(C(=O)[C@H]2C[C@H]2C(=O)O)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCC(=O)Nc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 81.8 %

Procedure:
1.0 g (3.8 millimoles) of cis-2-(p-propionylaminobenzoyl)-cyclopropanecarboxylic acid, 0.22 g (4.4 millimoles) of hydrazine hydrate and 20 ml of ethanol are refluxed for 5 hours. After filtering off the product at 25° C. and drying it under reduced pressure at 50° C., 0.8 g (81% of theory) of 2-(p-propionylaminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as almost colorless crystals, of melting point 268°-270° C.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:14])[CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:16])([CH3:15])[CH2:4][CH2:3]1.[CH3:17][O:18][CH2:19]Cl.C(N(CC)CC)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:17][O:18][CH2:19][O:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:14])[CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:16])([CH3:15])[CH2:4][CH2:3]1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2O
Reactant: COCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOC1CCC(C)(C)c2cc(C(C)=O)ccc21
Yield: 61.7 %

Procedure:
A solution of (+/−) 1-hydroxy-6acetyl-1,2,3,4-tetrahydro-4,4-dimethyl-naphthalene (Compound D25, 24.8 mg, 0.11 mmol), chloromethyl methyl ether (0.12 mmol), triethyl amine (0.02 ml, 0.13 mmol) and catalytic amount of tetrabutylammonium bromide in 2 ml of CH2Cl2 was stirred at room temperature for 5 h. Purification by column chromatography (silica) with ethyl acetate/hexane (1/10) afforded the title compound as an oil (17.8 mg).