Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][N:9]=[CH:8]1)(=[O:3])[CH3:2].[CH2:15]=[O:16]>CS(C)=O>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][N:9]=[C:8]1[CH2:15][OH:16])(=[O:3])[CH3:2]
Reactant: C=O
Reactant: CC(=O)OCCn1cncc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(=O)OCCn1c([N+](=O)[O-])cnc1CO

Procedure:
A mixture of 24.25 g. of 1-(2'-acetoxyethyl)-5-nitroimidazole prepared as in Example 4, 15 g. of paraformaldehyde and 150 ml. of dimethylsulfoxide is heated in a sealed tube overnight at 100°-150° C. The dimethylsulfoxide is removed completely at reduced pressure, and the residue is dissolved in water and extracted with chloroform. The chloroform extract is dried and concentrated. The residue is dissolved in ethyl acetate, and the solution is charged on a column of alumina. Elution with ethyl acetate and evaporation of the solvent yields 1-(2'-acetoxyethyl)-2-hydroxymethyl-5-nitroimidazole, m.p. 138°-145° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH3:9][C:10]1[CH:11]=[C:12]([C:14](I)=[CH:15][C:16]=1[CH3:17])[NH2:13]>>[CH3:17][C:16]1[CH:15]=[C:14]2[C:12](=[CH:11][C:10]=1[CH3:9])[NH:13][C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=[CH:2]2
Reactant: Cc1cc(N)c(I)cc1C
Reactant: C#Cc1cccnc1
Product: Cc1cc2cc(-c3cccnc3)[nH]c2cc1C

Procedure:
3-Ethynylpyridine and 3,4-dimethyl-6-iodoaniline are processed according to the method described in Example 86 to give 5,6-dimethyl-2-pyridin-3-yl-1H-indole. MS (ESI) m/z 223.13 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[N:33].N1CCOCC1>CN(C=O)C.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[N:33])[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
Reactant: N#CCCCCBr
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: [Cs+]
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CCCCCn1c(=O)n(CCCCC#N)c(=O)c2[nH]c(Cl)nc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
A solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (4.0 g, 13.5 mmol) in DMF (100 ml) was treated with caesium carbonate (4.83 g, 14.8 mmol) and 5-bromopentanenitrile (1.73 ml, 14.8 mmol). The mixture was heated at 50° C. in a nitrogen atmosphere for 19 h and then cooled. The mixture was then degassed by the repeated successive application of a vacuum and then nitrogen pressure. The mixture was then treated with tetrakis(triphenylphosphine)palladium(0) (1.1 g, 0.94 mmol) and morpholine (11.8 ml, 136 mmol). The mixture was stirred in a nitrogen atmosphere for 3 h and then partitioned between EtOAc and 2M aqueous hydrochloric acid. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated to reveal a yellow, oily residue. This was dissolved in MeOH, divided equally into four portions and each portion applied to a 20 g aminopropyl SPE which was then washed through with MeOH. The desired product was eluted from the cartridge with a 5% v/v solution of AcOH in MeOH. The product-containing fractions were combined and concentrated to yield the title compound as a pale yellow solid (4.03 g, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[N:21][C:5]2[NH:6][C:7](=[O:20])[CH2:8][N:9](CC3C=CC(OC)=CC=3)[CH2:10][C:4]=2[CH:3]=1.CC(Cl)OC([Cl:28])=O>ClC(Cl)C.CO>[ClH:28].[Br:1][C:2]1[CH:22]=[N:21][C:5]2[NH:6][C:7](=[O:20])[CH2:8][NH:9][CH2:10][C:4]=2[CH:3]=1
Reactant: COc1ccc(CN2CC(=O)Nc3ncc(Br)cc3C2)cc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CO
Product: Cl
Product: O=C1CNCc2cc(Br)cnc2N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.5 %

Procedure:
A solution of 7-bromo-4-(4-methoxybenzyl)-1,3,4,5-tetrahydropyrido[2,3-e][1,4]diazepin-2-one (3.37 g, 9.30 mmol) in dichloroethane (180 mL) was cooled in an ice bath and treated with ACE-Cl (1.1 mL, 10 mmol). After stirring at 0° C. under N2 for 30 min and then at room temperature for 30 min, the mixture was heated to reflux for 1 h. The mixture was allowed to cool and then concentrated to dryness. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 99:1) gave a white solid. A portion of the solid (1.02 g, 2.93 mmol) was suspended in methanol (50 mL) and heated to reflux for 3 h. The mixture was allowed to cool and the solid was isolated by filtration, washed with MeOH and dried under vacuum at 50° C. overnight to give the title compound (0.66 g, 46%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.05 (s, 1H), 10.30 (br s, 2H), 8.57 (d, J=2.3 Hz, 1H), 8.15 (d, J=2.3 Hz, 1H), 4.24 (s, 2H), 3.79 (s, 2H); MS (ESI) m/e 242 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH2:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]3[CH2:25][CH2:24][C:23](=O)[C:21]3=2)[O:16][CH2:15]1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH2:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]3[CH2:25][CH2:24][C:23](=[CH:5][C:3]#[N:4])[C:21]3=2)[O:16][CH2:15]1
Reactant: O=C1CCc2cnc3c(c21)CCO3
Reactant: CCOP(=O)(CC#N)OCC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC=C1CCc2cnc3c(c21)CCO3
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a suspension of 60% sodium hydride (137 mg, 3.42 mmol) in tetrahydrofuran (15 mL) was added diethyl cyanomethylphosphonate (600 μL, 3.71 mmol) under ice-cooling, and the mixture was stirred for 15 min. A solution of 1,2,6,7-tetrahydro-8H-cyclopenta[d]furo[2,3-b]pyridin-8-one (500 mg, 2.85 mmol) in tetrahydrofuran (15 mL) was added thereto, and the mixture was further stirred for 15 min. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→80/20) to give the title compound (514 mg, yield 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[O:8][C:9]3[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([OH:19])[C:10]=3[C:11](=[O:13])[CH2:12][C:6]=2[CH:5]=1)([O-])=O.[Sn](Cl)Cl.O>C(O)C.O1CCOCC1>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]2[O:8][C:9]3[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([OH:19])[C:10]=3[C:11](=[O:13])[CH2:12][C:6]=2[CH:5]=1
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2Oc2cc(O)cc(O)c21
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc2c(c1)CC(=O)c1c(O)cc(O)cc1O2
Yield: 51 %

Procedure:
1.40 g of 2-nitro-7,9-dihydroxy-10,11-dihydrodibenz[b,f]oxepin-10,11 -one (Compound 70) and 4.40 g of tin (II) chloride.2H2O were suspended in 20 ml of ethanol and 20 ml of 1,4-dioxane, followed by reflux under heating for 3 hours. Water was added to the reaction solution, which was then extracted in ethyl acetate. The extracted solution was sequentially washed in water and then an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography (elution solvent; dichloromethane:methanol=95:5), to recover the entitled Compound 71 represented by the formula (0.64 g; yield of 51%). The melting point of the amorphous powder recovered by recrystallization in hexane and ethyl acetate was 227-229° C.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1[N:6]=[C:7]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][C:9]=1[CH3:10].[OH-].[Na+]>CO>[CH3:10][C:9]1[O:8][C:7]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:6][C:5]=1[CH2:4][C:3]([OH:19])=[O:2]
Reactant: COC(=O)Cc1nc(CCc2ccccc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1oc(CCc2ccccc2)nc1CC(=O)O
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 63.3 %

Procedure:
(5-Methyl-2-phenethyl-oxazol-4-yl)-acetic acid methyl ester (8.75 g, 33.8 mmol), in MeOH (120 mL) was treated with 5N NaOH (40 mL) and then the solution was warmed to 40° C. After 40 min, the reaction mixture was concentrated under reduced pressure, suspended in water, and then acidified to pH=1 with 5N HCl. The mixture was extracted with EtOAc (2×), dried (MgSO4), and concentrated to provide 5.25 g (63%) of the product as an off-white solid. 1H NMR (400 MHz, CDCl3) •• 1H NMR (400 MHz, CDCl3) δ 7.33-7.20 (m, 5H), 3.52 (s, 2H), 3.06-3.03 (m, 4H), 2.24 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[C:14]([NH2:19])([CH2:17][CH3:18])([CH3:16])[CH3:15]>C(#N)C>[CH3:15][C:14]([NH:19][CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4])([CH3:16])[CH2:17][CH3:18]
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: CCC(C)(C)N
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC(C)(C)CC
Reaction time: 48 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.03 g, 0.152 mmol, Example 8D) in acetonitrile (3 mL) at room temperature under nitrogen was added tert-amylamine (0.027 g, 0.228 mmol). The reaction mixture was stirred for two days and then concentrated under reduced pressure. The residue was flash chromatographed with 5% MeOH/CH2Cl2 to provide the titled compound. MS (DCI) m/z 248 (M+H)+.
Reaction SMILES: [CH3:1][I:2].[C:3]1([C:9]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][N:12]=[CH:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(Cl)(Cl)Cl>[I-:2].[CH3:1][NH+:12]1[CH2:13][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:15][N:10]([C:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:11]1
Reactant: CI
Reactant: COC(=O)C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C[NH+](C)C1
Product: [I-]
Reaction time: 12 h
Yield: 124.6 %

Procedure:
Methyliodide (47 μl, 0.6 mmol) is added to a stirred solution of 1-triphenylmethyl-5-methoxycarbonyl-1,4,5,6-tetrahydropyrimidine (288 mg, 0.75 mmol) in chloroform (5 ml), in a round bottom flask with a septum, at room temperature. After 12 hours stirring the solvents are evaporated in vacuo giving 395 mg (100%) white crystals identified by 300 MHz nmr.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:8]([OH:9])[C@@H:7]([OH:10])[CH2:6][O:5][CH:3]1[OH:4].S(=O)(=O)(O)O>CO>[F:1][C@@H:2]1[C@@H:8]([OH:9])[C@H:7]([CH2:6][OH:5])[O:10][CH:3]1[OH:4]
Reactant: OC1OC[C@H](O)[C@H](O)[C@H]1F
Agent: O=S(=O)(O)O
Solvent: CO
Product: OC[C@@H]1OC(O)[C@H](F)[C@H]1O
Yield: 80 %

Procedure:
Treatment of unprotected 2-deoxy-2-fluoro-L-arabinopyranose with one equivalent of either sulfuric or hydrochloric acid at room temperature failed to give the desired furanoside. Only unreacted starting material was detected. Using nine equivalents of hydrochloric acid gave the desired product 2-deoxy-2-fluoro-L-arabinofuranose, which was contaminated with starting material (2:1 ratio). The best result, so far, was achieved by refluxing 2-deoxy-2-fluoro-L-arabinopyranose with 1 equivalent of sulfuric acid in dry methanol. After 6 hours all of the starting material had disappeared affording 2-deoxy-2-fluoro-L-arabinofuranose as an oil in 80% yield. 1H—, 13C- and 19F-NMR indicated a 3:1 α:β mixture of anomers, with some minor impurities. L-ribo- and L-arabinopyranoside as well as L-ribofuranoside are the possible side products. The D-isomer of 2-deoxy-2-fluoro-L-arabinofuranose was previously made by two different groups, but in less efficient ways (Wright, J. A.; Taylor, N. F.; Fox, J. J. J. Org. Chem 1969, 34, 2632. and Wysocki, R. J.; Siddiqui, M. A.; Barchi, J. J.; Driscoll, J. S.; Marquez, V. E. Synthesis 1991, 1005).
Reaction SMILES: OP([O-])(O)=O.[K+].[CH3:7][C:8]([OH:11])([CH3:10])[CH3:9].C([O-])([O-])=[O:13].[K+].[K+].[CH2:18]([C:22]1[CH:27]=[CH:26]C(C(C)=C)=[CH:24][CH:23]=1)[CH:19]([CH3:21])[CH3:20]>O=[Os](=O)(=O)=O.O>[CH2:18]([C:22]1[CH:27]=[CH:26][C:7]([C@:8]([OH:11])([CH3:10])[CH2:9][OH:13])=[CH:24][CH:23]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: O=C([O-])[O-]
Reactant: C=C(C)c1ccc(CC(C)C)cc1
Reactant: CC(C)(C)O
Agent: O=[Os](=O)(=O)=O
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: O
Product: CC(C)Cc1ccc([C@@](C)(O)CO)cc1
Yield: 100 %

Procedure:
The cathode compartment of the above described glass H-cell is charged with an aqueous solution of KH2PO4 (0.4M, 50 mL) and the anode is charged with the following: t-BuOH (50 mL), H2O (50 mL), K2CO3 (2.65 g, 20 mmol), K4Fe(CN)6.3H2O(0.633 g, 1.5 mmol). The solution is kept at 22° C. and the electrolysis is commenced at a controlled potential of 0.20-0.25 V (vs reference Ag/AgCl). After ca. 144 coulombs of electricity is consumed, the anode compartment is charged with the chiral ligand, MEQ-DHQD, (94 mg, 0.2 mmol), OsO4 in toulene (0.1 mL, 0.196M) and 2-(4-isobutylphenyl)propene (0.45 g, 2.5 mmol). After a total of 448 coulombs of electricity is further consumed, the reaction is stopped and is worked up as above to give the diol, (R)-2-(4-isobutylphenyl)-1,2-propanediol, in ca. 100% yield and 81.4% ee (crude ee by HPLC analysis on the chiracel OJ column).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>C(#N)C>[CH:1]1([NH:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC1CCCCC1
Reactant: NCCCN1CCCC1
Solvent: CC#N
Product: O=C(NCCCN1CCCC1)NC1CCCCC1

Procedure:
In an argon atmosphere 10 mmol of cyclohexylisocyanate was added slowly to 10 mmol of 1-(3-aminopropyl)pyrrolidine in 10 ml of acetonitrile. The product preci-pitated instantly as a pure white solid. The solvent was removed under reduced pressure and the product was crystallized with oxalic acid from diethyl ether/ethanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:46])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:30]=[C:31]([NH:35][C:36]([NH:38][C:39]5[CH:44]=[CH:43][CH:42]=[C:41](I)[CH:40]=5)=[O:37])[CH:32]=[CH:33][CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[C:47]1([C:53]#[CH:54])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]1([CH3:46])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:30]=[C:31]([NH:35][C:36]([NH:38][C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([C:54]#[C:53][C:47]6[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=6)[CH:40]=5)=[O:37])[CH:32]=[CH:33][CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5cccc(I)c5)c4)C(=O)O3)ccc2O1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5cccc(C#Cc6ccccc6)c5)c4)C(=O)O3)ccc2O1
Reaction time: 0.08 h
Yield: 86.5 %

Procedure:
A solution of N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]-N′-(3-iodophenyl)urea (393 mg) and phenylacetylene (77 mg) in DMF (6 ml) was treated with diisopropylethylamine (5 ml) and nitrogen was passed through the solution for 5 min. Copper (I) iodide (10 mg) and dichlorobis(triphenylphosphine)palladium(II) (47 mg) were added and the mixture was stirred under nitrogen at 20° for 21.5 h. The solvent was evaporated in vacuo and EtOAc (15 ml) was added. The supernatant solution was collected and the solvent evaporated in vacuo to give a residue which was purified by Biotage. Elution with dichloromethane-ethanol-ammonia (325:8:1) gave the title compound (328 mg). LCMS RT=3.93 min, ES+ve 718 (MH)+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.Cl[C:18]1[N:19]=[CH:20][C:21]([C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[N:22][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:27][N:26]([CH3:28])[C:24]([C:21]1[N:22]=[CH:23][C:18]([O:1][C:2]2[C:7]3[CH:8]=[C:9]([CH3:11])[O:10][C:6]=3[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=2)=[N:19][CH:20]=1)=[O:25]
Reactant: CN(C)C(=O)c1cnc(Cl)cn1
Reactant: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)c2cc(C)oc2c1
Temperature: 90 °C
Yield: 82.3 %

Procedure:
The flask was charged with ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate (I-1c: 6.07 g, 27.6 mmol), 5-chloro-N,N-dimethylpyrazine-2-carboxamide (SM-1: 5.06 g, 27.3 mmol), cesium carbonate (9.78 g, 30 mmol). The solids were dissolved in dimethylformamide (60 mL). The reaction was heated to 90° C. for 3 hours. After the reaction was cooled down to ambient temperature, dimethylformamide was removed in vacuo. The crude reaction mixture was partitioned between ethyl acetate (100 ml) and water (30 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layer was washed with water, brine, dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography (silica gel, 30 to 80% gradient of ethyl acetate in heptane) to give desired ethyl 4-(5-(dimethylcarbamoyl)pyrazin-2-yloxy)-2-methylbenzofuran-6-carboxylate (I-1d) as a light brown solid (8.3 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:6]([OH:11])=[N:7][NH:8][C:9]=1[CH3:10].[C:30]([O:35][CH3:36])(=[O:34])[C@H:31]([CH3:33])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)(=O)C.C1(C)C=CC=CC=1.CCCCCC>[CH3:36][O:35][C:30]([C@H:31]([O:11][C:6]1[C:5]([O:4][C:3]2[CH:12]=[C:13]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[C:14]([F:16])=[CH:15][C:2]=2[Cl:1])=[C:9]([CH3:10])[NH:8][N:7]=1)[CH3:33])=[O:34]
Reactant: Cc1[nH]nc(O)c1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reactant: COC(=O)[C@H](C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)[C@@H](C)Oc1n[nH]c(C)c1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
To a solution of 0.13 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxy-5-methylpyrazole in 2.0 ml of ethyl acetate were added 0.10 g of (S)-(−)-methyl lactate, 0.26 g of triphenylphosphine and 0.5 ml of a 40% solution of diisopropyl azodicarboxylate in toluene, and the mixture was stirred for 3 hours at room temperature. 6 ml of n-hexane was poured into this reaction solution, and the precipitated insoluble substance was filtrated off. This solution was subjected to silica gel column chromatography to obtain 0.09 g of (R)-3-{1-(methoxycarbonyl)ethoxy}-4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin -1-yl]phenoxy}-5-methylpyrazole [R optical isomer of present compound 5-12, hereinafter, represented as 5-12-R].
Reaction SMILES: FC(F)(F)S(O)(=O)=[O:4].[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[CH:10]([CH3:12])[OH:11].ClC(Cl)(Cl)C(=N)O[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CCCCC1>ClCCl>[CH2:21]([O:11][C:10]([CH3:12])([OH:4])[C:9]([O:14][CH2:15][CH3:16])=[O:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CCOC(=O)C(C)O
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CCOC(=O)C(C)(O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoromethanesulfonic acid (1.0 mL) was added gradually to a stirred mixture of ethyl lactate (8.90 g, 75 mmole), benzyl 2,2,2-trichloroacetimidate (22.7 g, 90 mmole), anhydrous cyclohexane (100 mL), and anhydrous dichloromethane (50 mL). The mixture was stirred overnight at room temperature under argon atmosphere. The mixture was filtered, and the filtrate was washed with saturated solution of sodium hydrogen carbonate (250 mL), and with distilled water (250 mL). Then, the solution was dried with anhydrous sodium sulfate and the solvents were distilled under reduced pressure using a rotary evaporator. The residue was subjected to fractional vacuum distillation giving 9.6 g of colorless product. NMR (CDCl3): 1.21 ppm (t, —CH2CH3, 3H), 1.32 ppm (d, —CH2—, 3H), 4.13 ppm (m, —CH— and —CH2CH3, 3H), 4.50 ppm (m, —CH2—, 2H), 7.32 ppm (m, 5H).
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.Br[C:29]1[C:30]([O:50][CH3:51])=[C:31]([C:36]([CH2:39][S:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[OH:49])(=[O:42])=[O:41])=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33]>>[O:25]1[CH:26]=[CH:27][C:23]([C:29]2[C:30]([O:50][CH3:51])=[C:31]([C:36]([CH2:39][S:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[OH:49])(=[O:42])=[O:41])=[CH:37][CH:38]=2)[C:32]([O:34][CH3:35])=[O:33])=[CH:24]1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2O)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2O)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-6-(2-hydroxybenzenesulphonylmethyl)-2-methoxybenzoate (Intermediate 138).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].C([O-])([O-])=O.[Cs+].[Cs+].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26]Br.CCOCC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[O:14][CH2:26][C:22]1[O:21][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccco1
Reactant: Oc1cc(Nc2nccs2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: Clc1ccc(Nc2nccs2)cc1OCc1ccco1
Yield: 32 %

Procedure:
Following the general procedure for O-alkylation, Method B, a mixture of 2-chloro-5-(thiazol-2-ylamino)phenol (100 mg, 0.44 mmol) and Cs2CO3 (152, 0.44 mmol) in acetone (4.4 mL) was treated with a freshly prepeared solution of 2-furylbromomethane in ether (0.75 mL, 0.44 mmol) at room temperature. Reaction control by TLC showed full conversion after 2 hrs. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 3/1) in 32% yield (43 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)([CH:10]2[CH2:15][CH2:14][N:13](S(C3C=CC=CC=3)(=O)=O)[CH2:12][CH2:11]2)O)=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.[BrH:39]>>[BrH:39].[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:26][CH:27]=1
Reactant: O=S(=O)(c1ccccc1)N1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: Br
Solvent: Oc1ccccc1
Product: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
A mixture of 164 g (0.342 mole) of α,α-bis(4-fluorophenyl)-1-(phenylsulfonyl)-4-piperidinemethanol and 80 g (0.85 mole) of phenol in 700 ml of 48% hydrobromic acid was heated at reflux for 7 hr and then was stirred at room temperature for 9 hr. The hydrobromic acid solution was decanted from a gum in the bottom of the reaction flask. The gum was triturated with ~1 liter of ether, and a tan solid formed. The solid was washed with several portions of ether and was dried under high vacuum to give 9.13 g (73%) of slightly impure title product, mp 211°-215° C. A small sample of this solid was recrystallized from methanol to give an analytically pure sample as a crystalline solid, mp 216°-218° C.