Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:24][CH2:23][C:13]3([O:18][CH2:17][C:16](=[O:19])[N:15]([CH:20]4[CH2:22][CH2:21]4)[CH2:14]3)[CH2:12][CH2:11]2)[CH3:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:20]1([N:15]2[CH2:14][C:13]3([CH2:23][CH2:24][N:10]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:31]5[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=5)=[CH:3][C:4]=4[F:25])[CH3:9])[CH2:11][CH2:12]3)[O:18][CH2:17][C:16]2=[O:19])[CH2:22][CH2:21]1
Reactant: CC(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(C(C)N3CCC4(CC3)CN(C3CC3)C(=O)CO4)c(F)c2)cc1
Yield: 47.9 %

Procedure:
A solution of 9-[1-(4-bromo-2-fluorophenyl)ethyl]-4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one (0.219 mmol) in 1,4-dioxane (2 mL) was treated with (4-methoxyphenyl)boronic acid (0.241 mmol), PdCl2(dppf)-CH2Cl2 adduct (10.94 μmol), and 2M aq potassium carbonate (0.656 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture was irradiated in a Biotage Initiator Microwave at 130° C. for 20 min. The resulting black mixture was diluted with water (50 mL) and extracted three times with dichloromethane. The combined organic layers were treated with Silicycle Si-thiol (20 mg), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude material was purified by reverse phase HPLC (15-45% acetonitrile with 0.1% TFA/water with 0.1% TFA). Fractions containing the desired product were combined and the pH of the resulting mixture was adjusted to ˜10 with 30% w/v ammonium hydroxide solution. This mixture was concentrated to a minimal volume in vacuo and was then extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the resulting solid by silica gel chromatography (3-10% methanol/dichloromethane) afforded the title compound as a white solid (46 mg, 45%). MS(ES)+ m/e 439.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[NH2:9][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[N:4]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1nc(=O)[nH]cc1F
Solvent: c1ccncc1
Product: Nc1nc(OS(=O)(=O)c2ccccc2)ncc1F
Yield: 28.1 %

Procedure:
To a suspension of 5-fluorocytosine (0.177 g, 1.4 mmol) in pyridine (5 mL) was added and benzene sulfonyl chloride (0.284 g, 1.6 mmol) and the mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness and the crude material purified by reverse phase chromatography to yield the title compound (0.106 g, 29% yield) as a white solid: mp 145-146° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.05-8.00 (m, 3H), 7.9-7.75 (m, 3H), 7.70-7.63 (m, 2H); HPLC-MS (ESI) m/z 270 (M+H)+, 268 (M−H)−.
Reaction SMILES: [NH:1]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[CH3:13][OH:14]>S(=O)(=O)(O)O>[CH3:13][O:14][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[NH2:1]
Reactant: O=C1CCCc2ccccc2N1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCc1ccccc1N
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To 1,3,4,5-tetrahydro-benzo[b]azepin-2-one (1 g, 6.2 mmol) in MeOH (8 mL), concentrated sulfuric acid (0.5 mL) was added and the mixture was stirred at room temperature for 2 hrs and at 70° C. for an additional hr. The solvent was removed and DCM and water were added. The organic layer was removed and the aqueous layer was basified with sat NaHCO3 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to yield 4-(2-amino-phenyl)-butyric acid methyl ester (0.93 g). MS [M+H]+: 194.1; tR=1.49 min. (method 1)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:21]=[C:17]([C:18](O)=O)[C:16]([OH:22])=[CH:15][CH:14]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:18]([C:17]3[CH:21]=[C:13]([F:12])[CH:14]=[CH:15][C:16]=3[OH:22])=[N:9][C:7](=[O:8])[C:6]=2[CH:10]=1
Reactant: NC(=O)c1cc(F)ccc1O
Reactant: O=C(O)c1cc(F)ccc1O
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Solvent: O=S(Cl)Cl
Product: O=c1nc(-c2cc(F)ccc2O)oc2ccc(F)cc12
Reaction time: 1 h

Procedure:
4.3 g of 5-fluoro-salicylamide and 4.7 g of 5-fluorosalicylic acid are boiled under reflux in 50 ml of xylene after addition of 0.3 ml of pyridine. 4.4 ml of thionyl chloride are added in the course of 2 h, the mixture is stirred for a further 1 h and the solvent is then distilled off under reduced pressure. The residue is suspended in 30 ml of ethanol, filtered off and washed with ethanol. After drying, 6-fluoro-2-(5-fluoro-2-hydroxyphenyl)benz[e][1,3]oxazin-4-one is obtained as slightly yellow crystals of m.p. 250-252 C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[C:12]([S:15]([CH3:17])=[O:16])[S:13][CH3:14].[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C>[CH2:25]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]=[C:12]([S:15]([CH3:17])=[O:16])[S:13][CH3:14])[C:3]1[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:2]=1[Cl:1])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CSC(=Cc1ccccc1Nc1c(Cl)cccc1Cl)S(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSC(=Cc1ccccc1N(Cc1ccccc1)c1c(Cl)cccc1Cl)S(C)=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
In 25 ml of DMF, 3.8 g (0.010 mole) of 1-[o-(2,6-dichloroanilino)phenyl]-2-methylsulfinyl-2-methylthioethylene was dissolved and 0.98 g (0.022 mole) of sodium hydride (55%; oil dispersion) was added at 20° to 30° C. and the mixture was stirred at 80° C. for 1 hour and cooled to 20° C. and 44 g (0.026 mole) of benzyl bromide was further added and the mixture was stirred at room temperature (20° to 30° C.) for 12 hours and the reaction mixture was poured into a large amount of water to precipitate yellow crystals and the resulting crystals were filtered and dried under a reduced pressure and further recrystallized from benzene to obtain 4.5 g of 1-[N-benzyl-o-(2,6-dichloroanilino)phenyl]-2-methylsulfinyl-2-methylthioethylene as pale yellow crystals. Yield: 98%
Reaction SMILES: [S:1](=[O:37])(=[O:36])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9]C(C)(C)[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])[O:6]1)[NH2:2]>C(O)(C(F)(F)F)=O.O>[S:1](=[O:36])(=[O:37])([O:3][CH2:4][C@@H:5]1[C@@H:12]([OH:11])[C@@H:8]([OH:9])[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])[O:6]1)[NH2:2]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(N)(=O)=O)O[C@H]2n1cnc2c(C#Cc3ccccc3C(F)(F)F)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NS(=O)(=O)OC[C@H]1O[C@@H](n2cnc3c(C#Cc4ccccc4C(F)(F)F)ncnc32)[C@H](O)[C@@H]1O
Yield: 51.5 %

Procedure:
[(3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-{[2-(trifluoromethyl)phenyl]ethynyl}-9H-purin-9-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl sulfamate (0.185 g, 0.343 mmol) was stirred in 3 mL of 90% TFA/H2O for 4 h at r.t. The solvent was removed and the crude product was purified by flash chromatography (1 to 10% MeOH/CH2Cl2) to isolate the title compound (0.0882 g, 52%).
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([O-])=O>O1CCOCC1>[NH2:1][C:4]1[S:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1
Reactant: Cc1ccc(-c2ccsc2[N+](=O)[O-])cc1
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccsc2N)cc1
Reaction time: 5 h

Procedure:
After dissolving 0.5 g of 2-nitro-3-(4-tolyl)thiophene in 20 ml of dioxane, 0.25 g of 5% pd/C was added and catalytic reduction was carried out at room temperature for 5 hours. The solution obtained was filtered to recover the catalyst and the filtrate was used as intact for the next reaction.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)/[CH:5]=[CH:6]/[CH3:7].CCN(C(C)C)C(C)C.FC(F)(F)S(O[Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])(=O)=O>C(Cl)Cl>[Si:41]([O:1][CH2:2][C@@H:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)/[CH:5]=[CH:6]/[CH3:7])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C/C=C/[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C/C=C/[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 78.2 %

Procedure:
tert-Butyl (2S,3S,E)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)hex-4-en-2-ylcarbamate (1.94 g, 5.4 mmol) (prepared as shown in Scheme 19) was taken up in 50 mL of DCM and chilled to 0° C. DIEA (2.4 mL, 13 mmol) was added, followed by slow addition of tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) (1.5 mL, 6.5 mmol). After 45 minutes, an additional 0.20 mL of TBSOTf was added. After an additional 20 minutes, the reaction was quenched with 50 mL of aq NaHCO3. The mixture was partitioned, and the aqueous portion was extracted twice with 50 mL of DCM. The combined organic extracts were dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (1% to 7.5% EtOAc/hexanes), afforded tert-butyl (2S,3S,E)-1-(tert-butyldimethylsilyloxy)-3-(4-(trifluoromethyl)phenyl)hex-4-en-2-ylcarbamate (2.0 g, 78% yield) as a clear oil. The oil crystallized over 12 hours. 1H NMR (400 MHz, CDCl3) δ ppm 7.54 (d, J=8.02 Hz, 2 H) 7.35 (d, J=8.02 Hz, 2 H) 5.61 (s, 1 H) 5.59 (d, J=5.87 Hz, 1 H) 4.62-4.60 (m, 1H) 3.97-3.92 (m, 1H) 3.79-3.76 (m, 1H) 3.66-3.59 (m, 2H) 1.69 (d, J=5.28 Hz, 3 H) 1.26 (s, 9 H) 0.92-0.97 (m, 9 H) 0.06 (s, 6 H).
Reaction SMILES: NC1C=C(OC)C(OC(C)C)=CC=1C(C1C=CC=CC=1Cl)=O.NC1C(C)=NN(CC=C)C=1Cl.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1[C:47]2[CH:48]=[C:49]([O:54][CH:55]([CH3:57])[CH3:56])[C:50]([O:52][CH3:53])=[CH:51][C:46]=2[N:45]=[C:44]2[N:58](CC=C)[NH:59][C:60]([CH3:61])=[C:43]2[N:42]=1.[H-].C([Al+]CC(C)C)C(C)C>>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1[C:47]2[CH:48]=[C:49]([O:54][CH:55]([CH3:57])[CH3:56])[C:50]([O:52][CH3:53])=[CH:51][C:46]=2[N:45]=[C:44]2[NH:58][NH:59][C:60]([CH3:61])=[C:43]2[N:42]=1
Reactant: C=CCN1NC(C)=C2N=C(c3ccccc3Cl)c3cc(OC(C)C)c(OC)cc3N=C21
Agent: C=CCn1nc(C)c(N)c1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: COc1cc(N)c(C(=O)c2ccccc2Cl)cc1OC(C)C
Product: COc1cc2c(cc1OC(C)C)C(c1ccccc1Cl)=NC1=C(C)NNC1=N2

Procedure:
5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-7-(1-methylethoxy)-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVjj) was prepared by reacting 0.0023 moles of (2-amino-4-methoxy-5-(1-methylethoxy)phenyl)-(2-chlorophenyl)-methanone (Xjj) with 4-amino-5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole (XIII), and subsequent dealkylation of the intermediate, 5-(2-chlorophenyl)-1,2-dihydro-8-methoxy-7-(1-methylethoxy)-3-methyl-1-(2-propenyl)-pyrazolo[3,4-b][1,4]benzodiazepine (XIVjj) with diisobutylaluminum hydride in a manner analogous to Example 72. MH+/Z=397.
Reaction SMILES: [C:1]([CH:4]([C:11]1[N:19]2[C:14]([C:15](=[O:29])[NH:16][C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[N:18]2)=[C:13]([CH3:30])[N:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:3])[CH3:2].[BH4-].[Na+]>>[OH:3][CH:1]([CH:4]([C:11]1[N:19]2[C:14]([C:15](=[O:29])[NH:16][C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[N:18]2)=[C:13]([CH3:30])[N:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2]
Reactant: CCCCCCC(C(C)=O)c1nc(C)c2c(=O)[nH]c(Cc3ccc(OC)cc3)nn12
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCCC(c1nc(C)c2c(=O)[nH]c(Cc3ccc(OC)cc3)nn12)C(C)O

Procedure:
100 mg (0.24 mmol) of 7-(1-acetylheptyl)-2-(4-methoxybenzyl)-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (Example 5) are reacted analogously to Example 8 with 17 mg (0.45 mmol) of sodium borohydride to give 7-[1-(1-hydroxyethyl)heptyl]-2-(4-methoxybenzyl)-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:15][C:16]([OH:18])=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH3:19][N:20](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].C[NH3+].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:19][NH:20][C:16](=[O:18])[CH2:15][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1cc2ccccc2n1CC(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2ccccc2n1CC(=O)NC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-(2-(ethoxycarbonyl)-1H-indol-1-yl)acetic acid (3.78 g), HATU (6.98 g), methylammonium chloride, and Hunig's base (6.33 mL) in DMF (77 mL) was stirred at room temperature for 24 hr. The reaction was worked up by the addition of water and the aqueous phase was extracted with EtOAc (2×65 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by CombiFlash (0-100% EtOAc/hexane) to afford the title compound as a yellowish solid.
Reaction SMILES: CS(C)=O.[OH-:5].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15]([F:18])([F:17])[F:16]>C(O)(C)(C)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([OH:5])=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:10]=1
Reactant: FC(F)(F)c1cc(Cl)ccc1Cl
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: Oc1ccc(Cl)cc1C(F)(F)F
Reaction time: 24 h

Procedure:
To a 300 ml, 3-necked flask fitted with a stirrer, condenser, thermometer and drying tube is added dimethylsulfoxide (100 ml), tert-butanol (20 ml), powdered potassium hydroxide (KOH) pellets (85%, 30 g) and 2,5-dichlorobenzotrifluoride (21.5 g, 0.10 mole). The reaction mixture is warmed to 71°-73° C. for 60 hours, then additional KOH (10 g) is added and heating is continued at 73°-75° C. for 24 hours. The reaction mixture is cooled and the solvent partially removed by distillation at 0.9 mm, bp 55° C.). The cooled pot residue is then poured into ice water (1000 g) which had been preacidified to pH 1 with conc. HCl (50 ml). The aqueous mixture is extracted with carbon tetrachloride (CCl4), the CCl4 layer decanted and dried and the solvent removed under vacuum to afford 10.8 g of 4-chloro-2-trifluoromethylphenol, which is sublimed to afford pure product, mp 81° -81.5° C. Elemental Anal. Calcd for C7H4ClF3O: C, 42.75; H, 2.06; Cl, 18.04: Found: C, 42.54; H, 2.36; Cl, 18.16. ##STR10##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:21]3[CH2:22][C:23]([CH3:26])([CH3:25])[O:24][C:20]=3[CH:19]=[C:18]([C:27]([O:29]C)=[O:28])[CH:17]=2)[CH:5]=[N:6][C:7]=1[C:8]([N:10]1[CH2:13][CH:12]([F:14])[CH2:11]1)=[O:9].CO.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:21]3[CH2:22][C:23]([CH3:26])([CH3:25])[O:24][C:20]=3[CH:19]=[C:18]([C:27]([OH:29])=[O:28])[CH:17]=2)[CH:5]=[N:6][C:7]=1[C:8]([N:10]1[CH2:11][CH:12]([F:14])[CH2:13]1)=[O:9]
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N3CC(F)C3)c(F)c2)c2c(c1)OC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Cc2c(Oc3cnc(C(=O)N4CC(F)C4)c(F)c3)cc(C(=O)O)cc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a solution of methyl 4-(5-fluoro-6-(3-fluoroazetidine-1-carbonyl)pyridin-3-yloxy)-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylate (1.520 g, 3.633 mmol), in 10 mL THF and 10 mL MeOH was added 4.25 mL of 1N aqueous NaOH. The resulting solution was stirred at room temperature for 2 hr. The solvent was removed in vacuo. Water was added, and the mixture was washed with EtOAc. The aqueous layer was acidified with 1N HCl until pH˜1, and extracted with 3×EtOAc. The combined organic layer was dried over Na2SO4 and concentrated to give a white foam (1.32 g, 90% yield), which contains ˜15% impurity. LCMS for C20H18F2N2O5 m/z 405.20 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:11][C:12]1[CH:13]=[C:14](O)[CH:15]=[CH:16][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[I:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]=1
Reactant: Oc1cccc(I)c1
Reactant: OCCCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Ic1cccc(OCCCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
In a 100 mL round-bottom flask was placed 3-phenyl-1-propanol (2.00 g, 14.7 mmol, 1.5 equiv.), 3-iodophenol (2.16 g, 9.82 mmol) , triphenylphosphine (3.85 g, 14.7 mmol, 1.5 equiv.) and THF (40 mL). The mixture was stirred in a small ice bath. Neat diethyl azodicarboxylate (2.30 mL, 14.6 mmol, 1.5 equiv.) was added over a period of 30 min. The mixture was stirred in the ice bath for 20 h, then the bath was removed, and stirring was continued for 24 h at room temperature. The resulting mixture was concentrated under vacuum and diluted with EtOAc (200 mL). The solution was washed with brine (60 mL) and dried over Na2SO4. After evaporation, the residue was chromatographed on silica gel with EtOAc/petroleum ether 1:50. This resulted in 3.30 g (99%) of 1-iodo-3-(3-phenylpropoxy)benzene as light-yellow oil. 1H NMR (CDCl3, TMS, 300 MHz) δ 7.34-7.25 (m, 7H), 6.98 (t, 1H, J=8.0 Hz), 6.84 (dd, 1H, J=2.0, 8.2 Hz), 3.92 (t, 2H, J=6.5 Hz), 2.79 (t, 2H, J=7.7 Hz), 2.08 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C@H:8]1[CH2:13][C@@H:12]([CH2:14][OH:15])[O:11][C:10]([CH3:17])([CH3:16])[O:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6](=[O:18])[CH2:7][C@H:8]1[CH2:13][C@@H:12]([CH2:14][O:15][S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[O:11][C:10]([CH3:17])([CH3:16])[O:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@H](CC(=O)OC(C)(C)C)OC(C)(C)O2)cc1
Reaction time: 3 h
Yield: 79.3 %

Procedure:
To a stirred solution of ((4R,6S)-6-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid t-butyl ester (2.24 g, 7.73 mmol), N,N-diisopropylethylamine (2.00 g, 15.46 mmol), 4-dimethylaminopyridine (0.95 g, 7.3 mmol) in dichloromethane (50 mL) was added p-toluenesulfonyl chloride (2.23 g, 11.59 mmol) at 23° C. under nitrogen and stirred for 3 h. The reaction mixture was diluted with dichloromethane and washed with 2N hydrochloric acid, saturated sodium chloride solution and the organic layer separated, dried over magnesium sulfate and concentrated in vacuo which afforded [(4R,6S)-2,2-dimethyl-6-(toluene-4-sulfonyloxymethyl)-[1,3]dioxan-4-yl]-acetic acid t-butyl ester (2.54 g, 80%) as a yellow waxy solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[NH:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:27][C:28]1[CH:47]=[CH:46][C:31]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([O:44]C)=[O:43])=[CH:36][CH:35]=2)=[CH:30][CH:29]=1.Cl>CO.O1CCCC1.[OH-].[Na+].O.CN(C)C=O>[C:1]1([CH2:7][CH2:8][C:9]2[N:13]([CH2:27][C:28]3[CH:47]=[CH:46][C:31]([CH2:32][O:33][C:34]4[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:36][CH:35]=4)=[CH:30][CH:29]=3)[N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Reactant: FC(F)(F)c1ccc(-c2cc(CCc3ccccc3)[nH]n2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(O)CCc1ccc(OCc2ccc(Cn3nc(-c4ccc(C(F)(F)F)cc4)cc3CCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
A mixture of 5-(2-phenylethyl)-3-[4-(trifluoromethyl)phenyl]-1H-pyrazole (350 mg, 1.11 mmol), sodium hydride (60% in oil, 40 mg, 1.00 mmol) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 1 hr. Methyl 3-(4-([4-(chloromethyl)benzyl]oxy)phenyl)propanoate (318 mg, 1.00 mmol) was added to the reaction mixture at room temperature and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was poured into 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (Manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1-1:1) to give a yellow oil. The yellow oil was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (5 mL), and 2 N aqueous sodium hydroxide solution (2 mL) was added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water, and neutralized with 1 N hydrochloric acid. The mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (Manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure to give the title compound (550 mg, yield 75%) as colorless crystals. MS: m/z 585 (MH+), 1H NMR (CDCl3) δ: 2.58-2.67 (2H, m), 2.80-2.94 (6H, m), 5.00 (2H, s), 5.26 (2H, s), 6.46 (1H, s), 6.86 (2H, d, J=8.9 Hz), 7.06-7.14 (6H, m), 7.18-7.32 (3H, m), 7.36 (2H, d, J=8.3 Hz), 7.63 (2H, d, J=8.1 Hz), 7.90 (2H, d, J=8.1 Hz).
Reaction SMILES: Cl[CH:2]([CH:8]=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[S:10]([N:20]1[C:28]2[C:23](=[N:24][C:25]([NH2:29])=[CH:26][N:27]=2)[CH:22]=[CH:21]1)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].C(O)CCC>O1CCOCC1>[S:10]([N:20]1[C:28]2[N:27]=[CH:26][C:25]3[N:24]([C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:8][N:29]=3)[C:23]=2[CH:22]=[CH:21]1)([C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[CH:18][CH:19]=1)(=[O:11])=[O:12]
Reactant: CCOC(=O)C(Cl)C=O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(N)cnc32)cc1
Solvent: CCCCO
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of ethyl 2-chloro-3-oxopropanoate (1.60 g, 7.65 mmol, prepared as described in US2009005359A1) and 1,4-dioxane (10.0 mL) was added to 5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-amine (1.45 g, 5.03 mmol, Preparation #E.1.1) under nitrogen. Anhydrous butan-1-ol (30.0 mL) was added, a reflux condenser was attached, and the system was sealed. After about 30 min, the mixture was warmed to about 80° C. The solution was allowed to cool to ambient temperature. A solution of ethyl 2-chloro-3-oxopropanoate (2.78 g, 13.3 mmol) and 1,4-dioxane (5 mL) was added. After about 30 min, the reaction mixture was warmed to about 80° C. After about 30 min, the mixture was warmed to about 125° C. After about 48 h, the brown solution was allowed to cool to ambient temperature. The volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 5-50% EtOAc in heptane to give ethyl 3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-carboxylate (1.16 g, 60%): LC/MS (Table 1, Method b) Rt=2.52 min; MS m/z 385 (M+H)+.