Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.F[C:32]1[CH:37]=[CH:36][C:35]([S:38]([N:41]2[CH2:44][CH2:43][CH2:42]2)(=[O:40])=[O:39])=[CH:34][CH:33]=1.[H-].[Na+].O>CN1CCCC1=O>[N:41]1([S:38]([C:35]2[CH:36]=[CH:37][C:32]([O:1][C:2]3[CH:3]=[C:4]([C:14]4[NH:15][C:16]([C:19]5[S:20][CH:21]=[CH:22][N:23]=5)=[CH:17][CH:18]=4)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=3)=[CH:33][CH:34]=2)(=[O:40])=[O:39])[CH2:44][CH2:43][CH2:42]1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Reactant: O=S(=O)(c1ccc(F)cc1)N1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N3CCC3)cc2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 57.5 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (60.0 mg, 0.139 mmol) synthesized in Example (38d) and 1-[(4-fluorophenyl)sulfonyl]azetidine (60.0 mg, 0.279 mmol) synthesized in Example (55a) were dissolved in N-methylpyrrolidone (5.0 mL), and sodium hydride (60%, 24 mg, 0.60 mmol) was added, followed by stirring at 100° C. for 6 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was carried out with ethyl acetate (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-35%) to afford the desired compound (42 mg, yield 57%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.C(O[C:13]([NH:15][N:16]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[F:25])C)=O)(C)(C)C.[CH3:26][C@:27]12[C:33]([CH3:35])([CH3:34])[C@H:30]([CH2:31][CH2:32]1)[CH:29]([C:36](Cl)=[O:37])[C:28]2=O.Cl.O1CCOCC1>ClCCCl.C(OCC)(=O)C>[F:25][C:19]1[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=1[N:16]1[C:36](=[O:37])[C:29]2[C@@H:30]3[C:33]([CH3:35])([CH3:34])[C@@:27]([CH3:26])([CH2:32][CH2:31]3)[C:28]=2[N:15]1[CH3:13]
Reactant: CN(NC(=O)OC(C)(C)C)c1cc(F)ccc1F
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: ClCCCl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1c2c(c(=O)n1-c1cc(F)ccc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 27.5 %

Procedure:
Triethylamine (1 mL, 7.2 mmol) was added dropwise to a solution of N′-(2,5-difluoro-phenyl)-N′-methyl-hydrazinecarboxylic acid tert-butyl ester (305 mg, 1.2 mmol) in 1,2-dichloroethane (6 mL) over 1 min. The reaction mixture was stirred for 5 min and then a solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 800 mg, 3.7 mmol) in 1,2-dichloroethane (14 mL) was added over 2 min. The reaction mixture was heated in an oil bath at 50° C. for 1 h. The solution was allowed to cool and a solution of HCl in dioxane (4 M; 6 mL, 24 mmol) was added and the mixture was heated at reflux for 1.5 h and then allowed to cool to room temperature. The solvent was evaporated and the residue was purified by preparative HPLC to give a yellow foam. This was taken up in ethyl acetate and washed with water. The organic layer was evaporated and the residue was further purified on an ISCO system, eluting with 50-90% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, co-evaporated successively with methanol, and diethyl ether, and then dried under high vacuum at 75° C. overnight to give (4S,7R)-2-(2,5-difluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (105 mg, 27%) as a white solid. ES(+)-MS (M+H) 319.
Reaction SMILES: [CH:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].COB(OC)OC.Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].[NH4+].[OH-]>[Zn].OCC(CO)O.C1COCC1>[CH3:24][O:23][C:21](=[O:22])[CH2:20][CH:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC=O
Reactant: COC(=O)CBr
Agent: COB(OC)OC
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: OCC(O)CO
Product: CCCCCCCCCC(O)CC(=O)OC
Temperature: 20 °C
Reaction time: 1 h

Procedure:
6.5 g of zinc, 15.5 g of decanal, 25 ml of trimethoxyborane, and 25 ml of dried THF were put into a 300 ml four-neck round-bottom flask, and 17.5 g of methyl bromoacetate was dripped at 20° C. for two hours in a nitrogen gas stream. After dripping, a resultant thereof was agitated at 20° C. for one hour, and thereafter, 25 ml of saturated ammonia aqueous solution and 25 ml of glycerin were added and agitated for ten minutes. An organic layer was separated and an aqueous solution layer was extracted two times by using diethyl ether. Thereafter, the organic solution was collected and subjected to desolvation. A residue thereof was purified by distillation to obtain a β-hydroxydodecanoic acid methyl ester.
Reaction SMILES: [C:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:11]3[NH:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)=O.[H-].[Na+].[C:24](N1C=CN=C1)(N1C=CN=C1)=[S:25]>O1CCCC1.CC(C)=O>[C:1]1([C:7]2[N:12]3[C:11]4[N:10]([C:24](=[S:25])[NH:18][C:16](=[O:17])[C:15]=4[CH:14]=[N:13]3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NC(=O)c1cnn2c1NCC=C2c1ccccc1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=c1[nH]c(=S)n2c3c1cnn3C(c1ccccc1)=CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
A mixture of 7.6 g of 4,5-dihydro-7-phenylpyrazolo[1,5-a]pyrimidine-3-carboxamide (prepared as described in Example 3) in 304 ml of dry tetrahydrofuran was stirred and cooled at -78° C. (dry-ice, acetone), under nitrogen and 2.17 g of sodium hydride (60% dispersion in mineral oil) was added. The mixture was stirred at -78° C. for 30 minutes, then 4.84 g of 1,1'-thiocarbonyldiimidazole was added in one portion. The temperature was kept at -78° C. for 2 hours, then was allowed to warm slowly to room temperature while stirring was continued for 48 hours. The reaction mixture was quenched with 500 ml of water and neutralized to pH 6-7 with 5% aqueous hydrochloric acid. A crystalline solid formed which was collected by filtration, triturated with ether, filtered and dried to give 3.2 g of the desired product as white crystals, m.p. 289°-291° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:9]1[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:32]C)[CH:28]=2)[CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:9]1[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([OH:32])[CH:26]=[CH:25]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCc1c(-c2ccc3cc(OC)ccc3c2)n(Cc2ccccc2)c2ccccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCc1c(-c2ccc3cc(O)ccc3c2)n(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Yield: 85 %

Procedure:
In such processes, a solution of 1-benzyl-2-(6-methoxy-naphthalen-2-yl)-3-pentyl-1H-indole in methylene chloride generally is treated with 0.75 equivalents of boron tribromide in methylene chloride at 0° C., the resulting mixture is slowly heated to 25° C., and the reaction is quenched with a 5% solution of sodium hydroxide in water. The organic and aqueous layers are separated, and the organic layer is replaced with toluene. Heptane is added to the solution and the product is crystallized at 0° C. to produce 85% to 90% of 6-(1-benzyl-3-pentyl-1H-indol-2-yl) -naphthalen-2-ol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:9]=2[C:10]=1[NH2:11])=[O:5])[CH3:2].Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:9]=2[C:10]=1[NH:11][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1oc2ccc(Cl)cc2c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)Nc1c(C(=O)OCC)oc2ccc(Cl)cc12
Yield: 100 %

Procedure:
To a solution of 3-amino-5-chloro-benzofuran-2-carboxylic acid ethyl ester (2.8 g, 11.7 mmol) in benzene (35 mL) was added ethyl chloroformate (1.3 mL, 14.0 mmol) followed by K2CO3 (4.5 g, 35.1 mmol). After heating at reflux for 14 h, the mixture was filtered, washing with benzene. The filtrate was concentrated to afford the desired product (100%), which was used in the next step without further purification. 1H NMR (CDCl3): 8.69 (s, 1H), 8.45 (s, 1H), 7.47-7.39 (m, 2H), 4.48 (q, J=7.1 Hz, 2H), 4.30 (q, J=7.1 Hz, 2H), 1.55 (t, J=7.1 Hz, 3H), 1.35 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:29])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH2:30]OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+].CCOC(C)=O>CN(C=O)C.O>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:29])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH2:30][N:36]=[N+:37]=[N-:38])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of (2R,5S)-2-methanesulfonyloxymethyl-5-(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (589 mg, 1.14 mmol) in DMF (4.5 mL) was added a solution of sodium azide (371 mg, 5.7 mmol) in water (0.5 mL) and the mixture was stirred at 80° C. under nitrogen atmosphere overnight. EtOAc and a water were added, the layers were separated and the aqueous one back-extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 100:0 to 6:5) to give the desired compound. MS (LC-MS): 464 [MH−Boc]+; tR (HPLC conditions b) 5.73 min.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:11][C:12]1[N:17]=[C:16](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[CH:22]=[O:23])[CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>C(OCC)C>[Br:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16](/[CH:18]=[CH:19]/[CH:20]=[CH:21]/[CH:22]([OH:23])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:17]=1
Reactant: CCCCCCCC[Mg]Br
Reactant: O=C/C=C/C=C/c1cccc(Br)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCCCCC(O)/C=C/C=C/c1cccc(Br)n1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 196.3 %

Procedure:
A solution of octylmagnesium bromide (produced from 150 mg of magnesium in 5 ml of diethyl ether and 1.14 g of octyl bromide in 2.5 ml of diethyl ether) is instilled in a solution of 1.17 g of 5-(6-bromo-2-pyridyl)-(E,E)-2,4-pentadienaldehyde in 25 ml of diethyl ether with stirring and under argon atmosphere at -20° C. After 1.5 hours at -20° C., the reaction mixture is mixed with 15 ml of saturated ammonium chloride solution, shaken out with diethyl ether, dried on sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel with hexane/ethyl acetate=95/5. 477 mg of 2-bromo-6-[(1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl]-pyridine is obtained as crude product.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:3]=[N:2]1.C([N-]C(C)C)(C)C.[Li+].[C:23]1(=[O:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>O1CCCC1>[OH:29][C:23]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:4]2[N:3]=[N:2][NH:1][CH:5]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCCC1
Reactant: N#Cc1ccc(Cc2c[nH]nn2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(c2c[nH]nn2)C2(O)CCCCC2)cc1
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
5 g of 4-[1-(1,2,3-triazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -50° with 20 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour, further stirred with 2.9 g of cyclohexanone for 1 hour at -70°, and heated to 25°. Then water is added, the mixture is extracted three times with ethyl acetate, washed with water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 7.6 g of crude 4-[1-hydroxycyclohex-1-yl-1-(1,2,3-triazolyl)methyl]benzonitrile.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:37])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:36][O:35][C:32]1[N:31]=[CH:30][C:29]([C:26]2[CH:25]=[CH:24][C:23]([C:20]3([C:17]4[N:13]5[CH2:14][CH2:15][S:16][C:10]([CH2:9][OH:8])([CH3:37])[CH2:11][C:12]5=[N:19][N:18]=4)[CH2:22][CH2:21]3)=[CH:28][CH:27]=2)=[CH:34][CH:33]=1
Reactant: COc1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)cn1
Yield: 108.1 %

Procedure:
A solution of the compound (200 mg, 0.37 mmol) obtained in Example 59-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 15 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (169 mg, quant.) as a colorless solid.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:27]=[N:28][C:29]([S:32][CH3:33])=[CH:30][CH:31]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:35].[Na+]>CO.O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:27]=[N:28][C:29]([S:32]([CH3:33])=[O:35])=[CH:30][CH:31]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cn1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.8 %

Procedure:
A solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methylsulfanyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (400 mg, 0.84 mmol) in methanol (12 mL) was added a sodium metaperiodate (540 mg, 2.53 mmol) solution in water (4 mL). The resulting mixture was stirred for 12 h at room temperature, extracted with ethyl acetate (3×20 mL), dried over anhydrous sodium sulfate, concentrated in vacuo to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfinyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (412 mg, 100%) which was used in the next step without purification: LC/MS m/e calcd for C26H25N3O3S2 [M+H]+ 492.64, observed 492.2.
Reaction SMILES: Cl[C:2]1[C:3]([C:19]#[N:20])=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:7]=1.[CH3:21][C:22]1[CH:23]=[CH:24][C:25](B2OC(C)(C)C(C)(C)O2)=[C:26]([NH:28]C(=O)OC(C)(C)C)[CH:27]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>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].O.C(O)CCC>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]#[C:8][C:6]2[CH:5]=[N:4][C:3]3[C:2]([CH:7]=2)=[C:25]2[CH:24]=[CH:23][C:22]([CH3:21])=[CH:27][C:26]2=[N:28][C:19]=3[NH2:20])=[C:11]([CH3:18])[CH:12]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Reactant: COc1ccc(C#Cc2cnc(C#N)c(Cl)c2)c(C)c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCO
Solvent: O
Product: COc1ccc(C#Cc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a round bottom flask with refluxing condenser were added 3-chloro-5-((4-methoxy-2-methylphenyl)ethynyl)picolinonitrile (B-1) (1 eq.), tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (A-1) (1.25 eq.), K3PO4 (2 eq.), tris(dibenzylideneacetone)dipalladium(0) (0.05 eq.), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (Sphos) (0.1 eq.). n-butanol and water (5:2, 0.2 M) were added, and the content was degas sed (vacuum followed by nitrogen flush) for three times. The reaction mixture was stirred vigorously under nitrogen at 100° C. overnight in an oil bath. The content was cooled and taken up in 200 mL of water followed by extraction with methylene chloride. Combined organic layers were dried (Na2SO4) and concentrated. Flash chromatography (silica gel, 0-50% EtOAc in CH2Cl2) afforded the product 2-((4-methoxy-2-methylphenyl)ethynyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine (B-2).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5](CC2C=NC(C)=NC=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].[F:35][C:36]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:37]=1[CH:38]=O>>[F:35][C:36]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:37]=1[CH2:38][N:5]1[CH2:6][C@@H:2]([CH3:1])[C@H:3]([C:15]2[NH:16][C:17](=[O:30])[C:18]3[CH:23]=[N:22][N:21]([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:19]=3[N:20]=2)[CH2:4]1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Reactant: O=Cc1ccc(F)cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@@H]1CN(Cc2ccc(F)cc2F)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyanoborohydride and 2,4-difluorobenzaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.01 (s, 1H), 7.40-7.38 (m, 2H), 6.90-6.79 (m, 2H), 4.81-4.77 (m, 2H), 4.14-4.08 (m, 2H), 3.88 (m, 2H), 3.62-3.54 (m, 2H), 3.32 (t, J=8.7 Hz, 1H), 3.02 (d, J=9.5 Hz, 1H), 2.86-2.83 (m, 1H), 2.65 (m, 1H), 2.43-2.20 (m, 3H), 2.00-1.83 (m, 2H), 1.21 (d, J=6.6 Hz, 3H). MS: (M+H m/z 430.2).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH:8]1([C:14]([O:16][CH2:17][CH2:18][O:19][C:20](ON2C(=O)CCC2=O)=[O:21])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([C:14]([O:16][CH2:17][CH2:18][O:19][C:20]([NH:1][C@H:2]([CH2:3][OH:4])[C:5]([OH:7])=[O:6])=[O:21])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: N[C@H](CO)C(=O)O
Reactant: O=C(OCCOC(=O)C1CCCCC1)ON1C(=O)CCC1=O
Product: O=C(N[C@H](CO)C(=O)O)OCCOC(=O)C1CCCCC1
Yield: 57.7 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, D-serine (252 mg, 2.4 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl cyclohexanecarboxylate (626 mg, 2.0 mmol) were reacted to provide 350 mg (58% yield) of the title compound (27) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.79 (m, 1H), 6.05 (t, 1H), 5.45 (br s, 1H), 4.41 (m, 1H), 4.04 (m, 1H), 3.92 (m, 1H), 2.30 (m, 1H), 1.09-1.95 (m, 13H). MS (ESI) m/z 321.13 (M+NH4)+; 326.09 (M+Na)+; 302.06 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].O.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1ccc(I)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(I)cc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
2-Chloro-4-iodobenzoic acid (5.0 g, 18 mmol) was dissolved in tetrahydrofuran (7 mL), and a solution of a borane-tetrahydrofuran complex in tetrahydrofuran (1 M, 21 mL, 23 mmol) was added at 0° C., followed by stirring at room temperature for 3 days. Water and a saturated aqueous sodium hydrogencarbonate solution were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure to afford (2-chloro-4-iodophenyl)methanol (4.8 g, 18 mmol) as a white solid (quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[H-].[Na+].[CH3:19]I>CN(C=O)C>[Cl:13][C:12]1[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]([N+:14]([O-:16])=[O:15])[C:2]=1[NH:1][CH3:19]
Reactant: CI
Reactant: CCOC(=O)c1ccc(Cl)c(N)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cl)c(NC)c1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
3.18 g (13.0 mmol) of ethyl 3-amino-4-chloro-2-nitrobenzoate were introduced in DMF and admixed under a nitrogen atmosphere with 0.624 g (15.6 mmol) of sodium hydride. The mixture was left with stirring for 30 minutes and then 2.21 g (15.6 mmol) of methyl iodide were added. After a further 2.5 h of stirring at room temperature the mixture was concentrated and the residue was extracted with ethyl acetate, washed with water, and then dried over MgSO4. The product was then subjected to chromatographic separation (silica gel, heptane/ethyl acetate 9:1).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1.C(O)(=O)C.[CH2:26]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48](=O)[C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:38][CH2:37]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>C(O)C>[CH2:26]([O:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C@@H:48]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]3[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=3[O:4][CH2:3]2)[C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:40][CH2:41]1)=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)COc2ccccc21
Reactant: CCOC(=O)C(=O)CCCCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H](CCCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reaction time: 0.17 h
Yield: 7.5 %

Procedure:
A mixture of tert-butyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (2 g), ethanol (10 ml), acetic acid (0.49 g), ethyl 8-(1-benzyloxycarbonyl-4-piperidyl)-2-oxooctanoate (3 g) and molecular sieves 3A (10 g) is stirred for 10 minutes. To the stirred mixture is added dropwise a solution of sodium cyanoborohydride (0.47 g) in ethanol (40 ml) for 3 hours at room temperature. After standing overnight at room temperature, the mixture is concentrated in vacuo and diluted with a mixture of water (100 ml) and ethyl acetate (200 ml). The resulting mixture is agitated thoroughly and filtered. The ethyl acetate layer is washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue is chromatographed on silica gel using hexane-ethyl acetate (5:2-2:1) as an eluent. Evaporation of the first fraction affords tert-butyl 3(S)-[7-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) as a colorless oil.