Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:16][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(OC2CCNCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 118.6 %

Procedure:
A solution of 4-(6-chloro-pyridin-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (5.68 g, 18.16 mmol) in DCM (2 mL) was treated with TFA (25 mL) and stirred at room temperature for 1 hour. The mixture was concentrated under vacuum, dissolved in 1 N aqueous HCl and washed with EtOAc. The aqueous a phase was basified with ammonium hydroxide and extracted into EtOAc. The combined extracts were dried over Na2SO4 and concentrated under vacuum to give 2-chloro-5-(piperidin-4-yloxy)-pyridine (4.58 g) as a yellow solid. 1H NMR (300 MHz, DMSO) δ 8.54 (br s, 1H), 8.18 (d, J=3.1 Hz, 1H), 7.60-7.53 (m, 1H), 7.45 (d, J=8.8 Hz, 1H), 4.76-4.65 (m, 1H), 3.30-3.19 (m, 2H), 3.11-3.00 (m, 2H), 2.15-2.03 (m, 2H), 1.89-1.74 (m, 2H). LCMS (m/z, Method A) ES+ 213.1 [M+1]+.
Reaction SMILES: [CH:1]1[C:2]2[N:3]([C:7]([CH2:10][OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:5][N:6]=1>CCOC(C)=O>[CH:1]1[C:2]2[N:3]([C:7]([CH:10]=[O:11])=[CH:8][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: OCc1ccc2cnccn12
Solvent: CCOC(C)=O
Product: O=Cc1ccc2cnccn12
Temperature: 80 °C
Yield: 100.1 %

Procedure:
Pyrrolo[1,2-a]pyrazin-6-yl-methanol (0.06 g, 0.41 mmol) is dissolved in EtOAc (3 mL), treated with IBX (0.34 g, 1.2 mmol) and heated to 80° C. for 3 h. The solution was allowed to cool to RT and filtered with a syringe filter frit. The solution was concentrated under a nitrogen stream to yield the title compound (0.06 g), which was used without further purification. 1H NMR (CDCl3) δ 9.87 (s, 1H), 9.34 (d, 1H), 9.02 (s, 1H), 7.93 (d, 1H), 7.47 (d, 1H), 6.82 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[S:30][C:15]3([CH2:20][CH2:19][N:18](C(OC4C=CC=CC=4)=O)[CH2:17][CH2:16]3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37]>C(O)CO.CCOCC>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37].[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[S:30][C:15]3([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccccc1)N1CCC2(CC1)SC(c1cccc(F)c1)c1ccccc12
Agent: O=C(O)/C=C\C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CCOCC
Product: Fc1cccc(C2SC3(CCNCC3)c3ccccc32)c1
Temperature: 160 °C
Reaction time: 0.75 h

Procedure:
To 6.97 g of 3-(3-fluorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine] of Example 57 in 100 ml of ethylene glycol, under nitrogen, at 150° C. is added 16 g of 85% potassium hydroxide pellets. The reaction is stirred in a 160° C. bath for 45 minutes. The solution is then poured into 225 ml of ice-water, diluted to 500 ml and extracted with three 175 ml portions of dichloromethane. The combined dichloromethane extracts are washed with 200 ml portions of water and one 50 ml portion of saturated aqueous sodium chloride solution, and dried over magnesium sulfate to give a solid free base. The free base in ether is treated with ethereal maleic acid to give a salt. The salt is washed with ether and recrystallized from methanol-acetone-ether to give a white powder of 3-(3-fluorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine] maleate, m.p. 188°-188.5° C.
Reaction SMILES: [CH3:1][O:2][B:3]([O:13][CH3:14])[C:4]1[CH:5]=[N:6][C:7]([CH2:10][CH2:11][CH3:12])=[N:8][CH:9]=1.O[CH2:16][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]C)CO>CO>[CH2:10]([C:7]1[N:6]=[CH:5][C:4]([B:3]2[O:2][CH2:1][CH:16]([CH2:17][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][O:13]2)=[CH:9][N:8]=1)[CH2:11][CH3:12]
Reactant: CCCc1ncc(B(OC)OC)cn1
Reactant: CCCCCCCC(CO)CO
Solvent: CO
Product: CCCCCCCC1COB(c2cnc(CCC)nc2)OC1

Procedure:
20 g of dimethoxy-(2-propylpyrimidin-5-yl)-borane (obtained from 2-propylpyrimidin-5-ylmagnesium chloride and trimethoxyborane) and 30 g of 2-hydroxymethylnonan-1-ol are heated at 100° for 12 hours, the methanol formed being removed continuously by distillation. When the reaction is complete, excess nonanol is removed under reduced pressure, and 2-(2-propylpyrimidin-5-yl)-5-heptyl-1,3,2-dioxaborinane is obtained.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([C@H:9]2OC(=O)N[C@@H:10]2C2C=CC=C(C#CC3C=CC=CC=3)C=2)[CH:6]=[CH:7][CH:8]=1.Br[C:30]1[CH:31]=[C:32]([C@@H:37]2[C@@H:41]([C:42]3[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=3[F:49])[O:40][C:39](=[O:50])[NH:38]2)[C:33]([F:36])=[N:34][CH:35]=1.C1(C#C)C=CC=CC=1>>[F:49][C:43]1[CH:44]=[CH:45][C:46]([F:48])=[CH:47][C:42]=1[C@H:41]1[O:40][C:39](=[O:50])[NH:38][C@@H:37]1[C:32]1[C:33]([F:36])=[N:34][CH:35]=[C:30]([C:10]#[C:9][C:5]2[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=2)[CH:31]=1
Reactant: O=C1N[C@H](c2cc(Br)cnc2F)[C@@H](c2cc(F)ccc2F)O1
Reactant: COc1cccc([C@H]2OC(=O)N[C@@H]2c2cccc(C#Cc3ccccc3)c2)c1
Solvent: C#Cc1ccccc1
Product: O=C1N[C@H](c2cc(C#Cc3ccccc3)cnc2F)[C@@H](c2cc(F)ccc2F)O1

Procedure:
Prepared according to the same procedure as (+)-(4R,5R)-5-(3-methoxyphenyl)-4-(3-(phenylethynyl)phenyl)oxazolidin-2-one, starting with (4R,5R)-4-(5-bromo-2-fluoropyridin-3-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one and phenylacetylene. 1H NMR (CDCl3) δ: 8.37 (d, J=1.2 Hz, 1H), 8.11 (dd, J=8.9, 2.1 Hz, 1H), 7.56 (dd, J=7.6, 1.8 Hz, 2H), 7.35-7.42 (m, 3H), 7.21-7.26 (m, 1H), 7.07-7.14 (m, 2H), 6.99 (s, 1H), 5.57 (d, J=5.8 Hz, 1H), 5.07 (d, J=5.8 Hz, 1H). 19F NMR (CDCl3) δ: −71.32 (br. s., 1F), −117.12 (br. s., 1F), −123.54 (d, J=8.7 Hz, 1F). Mass spec.: 395.1 (MH)+.
Reaction SMILES: C1([Si](OC)(OC)OC)C=CC=CC=1.C(O[Si](OCC)(OCC)OCC)C.C[Si](OCC)(OCC)OCC.[F:38][C:39]([F:45])([F:44])[S:40]([O-:43])(=[O:42])=[O:41].CO[Si](CC[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][N+:56]=1C)(OC)OC.Cl.C(OCC(O)C)C>O.CC(C)=O.CO.C(O)C>[F:38][C:39]([F:45])([F:44])[S:40]([O-:43])(=[O:42])=[O:41].[NH+:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:55]=1
Reactant: CO[Si](CCc1cccc[n+]1C)(OC)OC
Agent: CCOCC(C)O
Agent: CCO[Si](C)(OCC)OCC
Agent: CCO[Si](OCC)(OCC)OCC
Solvent: O
Solvent: CC(C)=O
Solvent: CO
Product: c1cc[nH+]cc1
Temperature: 25 °C

Procedure:
4.92 g of phenyltrimethoxysilane, 72.39 g of tetraethoxysilane, 22.04 g of methyltriethoxysilane, 0.56 g of the 30% methanol solution of trimethoxysilylethylmethylpyridinium trifluoromethanesulfonate, and 150 g of acetone were charged into a 500 mL flask to be dissolved and the resultant mixed solution was warmed while stirring the mixed solution with a magnetic stirrer to reflux. Next, 33.13 g of 0.01 M hydrochloric acid was added to the mixed solution. The mixed solution was subjected to the reaction for 240 minutes and then the resultant reaction solution was cooled down to room temperature. Then, 200 g of propylene glycol monoethyl ether was added to the reaction solution, and ethanol and methanol as reaction by-products, acetone, water, and hydrochloric acid were distilled off under reduced pressure to obtain a hydrolysis-condensation product. The polymer thus obtained corresponded to Formula (VII-22):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][C:7]([C:14]([NH:16][C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[C:19]([O:21]C)=[O:20])=[O:15])=[CH:6]2.[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][C:7]([C:14]([NH:16][C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[C:19]([OH:21])=[O:20])=[O:15])=[CH:6]2
Reactant: COC(=O)c1ccccc1NC(=O)C1=Cc2cc(OC)c(OC)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c(cc1OC)CC(C(=O)Nc1ccccc1C(=O)O)=C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a stirred solution of methyl 2-(5,6-dimethoxy-1H-indene-2-carboxamido)benzoate (120 mg, 0.34 mmol) in THF (6 mL) and MeOH (3 mL) was added 2 N NaOH solution (0.85 mL) dropwise. The resulting mixture was stirred at room temperature for 2 h, then quenched with 1N HCl solution and extracted with DCM. The organic extracts were washed with a saturated aqueous NaCl solution and dried over sodium sulfate. The solvent was then removed under reduced pressure to give 2-(5,6-dimethoxy-1H-indene-2-carboxamido)benzoic acid (100 mg, 87%). 1H-NMR (400 MHz, DMSO-d6) δ 3.72 (br s, 2H), 3.79 (s, 3H), 3.81 (s, 3H), 7.15 (m, 1H), 7.24 (s, 1H), 7.26 (s, 1H), 7.55-7.66 (m, 2H), 8.04 (dd, J=8.0, 1.6 Hz, 1H), 8.70 (dd, J=8.4, 1.2 Hz, 1H), 11.91 (s, 1H); LC-MS (ES-API); rt 9.23 min; m/z calculated for C19H17NO5 [M−H]− 338.1, found 338.1.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16].C1(C)C=CC=CC=1>ClCCl.CO>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:17])=[O:16]
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1NC1CCCCC1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
Cyclohexylamine (8.1 ml) was added dropwise to 1-fluoro-2-nitrobenzene (4) (3.7 mg) under a nitrogen atmosphere at 0°. To the resulting orange solid, dry toluene (10 ml) was added and the mixture was stirred at 23 ° C. for 30 min. then diluted with dichloromethane/methanol 1/1 (100 ml) and the organic layer was washed with brine (50 ml), 10 % solution sodium hydroxide (50 ml) and brine (50 ml), dried and concentrated in vacuo to give the title compound as an orange solid (7.45 g). Mp 105°-7° T.l.c. CH-EA (7:3). Rf 0.78
Reaction SMILES: I[Si](C)(C)C.C(OC([NH:13][C:14]1[N:15]=[C:16]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[NH:17][C:18]=1[C:19]#[N:20])=O)(C)(C)C>C(#N)C>[NH2:13][C:14]1[N:15]=[C:16]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[NH:17][C:18]=1[C:19]#[N:20]
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccc(Cl)cc2Cl)[nH]c1C#N
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: N#Cc1[nH]c(-c2ccc(Cl)cc2Cl)nc1N
Temperature: 0 °C
Reaction time: 48 h
Yield: 38.1 %

Procedure:
A solution of iodotrimethylsilane (2.83 g, 0.014 mol) in acetonitrile (5 ml) was added dropwise with stirring to a suspension of 4-(tert.butoxycarbonylamino)-5-cyano-2-(2,4-dichlorophenyl)imidazole (5.0 g, 0.014 mol) in acetonitrile (250 ml) whilst maintaining the temperature at about 0° C. The mixture was stirred at room temperature for 48 hours and the precipitated beige solid filtered off. The solid was purified by mplc on silica eluting with a mixture of ethyl acetate and hexane (1:2) to give an off-white solid which was recrystallized from ethanol to give 4-amino-5-cyano-2-(2,4-dichlorophenyl)imidazole (1.35 g) m.p. 223°-225° C. as an off-white solid.
Reaction SMILES: [I-].C([N+:5]1[CH:9]=[CH:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=2)[CH:6]=1)(=O)C.[ClH:24].C>>[ClH:24].[N:7]1([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)[CH:8]=[CH:9][N:5]=[CH:6]1
Reactant: CCOC(=O)c1ccc(OCCn2cc[n+](C(C)=O)c2)cc1
Agent: Cl
Agent: [I-]
Product: O=C(O)c1ccc(OCCn2ccnc2)cc1
Temperature: 80 °C
Yield: 79 %

Procedure:
A mixture of 1.3 g of 1-acetyl-3-[2-(4-ethoxycarbonylphenoxy)ethyl]imidazolium iodide in 100 ml of 2N-hydrochloric acid was heated at 80° C. for 2 hours. After cooling, the solution was treated with an activated charcoal and concentrated under reduced pressure. The residue were triturated with acetone and the resulting crystals were filtered and dried to obtain 0.64 g of 4-[2-(1-imidazolyl)ethoxy]benzoic acid hydrochloride (79.0% yield). Colorless granules.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[Na].[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[CH3:22])CCl>C(O)C.C(OCC)C>[CH3:13][C:14]1[CH:15]=[C:16]([CH2:3][CH2:2][C:1]([OH:9])=[O:8])[CH:19]=[CH:20][C:21]=1[CH3:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(CCl)cc1C
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccc(CCC(=O)O)cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 70.0 ml of diethyl malonate dissolved in 400 ml of dry ethanol was added 10.0 g of metalic sodium. The reaction mixture was stirred for 30 minutes and cooled to 0° C; and 66.5 g of 3,4-dimethylbenzyl chloride was added thereto. This reaction mixture was stirred for 1 hour at room temperature, heated at the boiling temperature for 4 hours and concentrated under reduced pressure to produce residues, which were dissolved in ethyl ether. This ethereal solution was washed with water. To the residues obtained after a further concentration of the organic phase were added 500 ml of water and 170 g of KOH; and this mixture was heated at the boiling temperature for 24 hours. This mixture was concentrated under reduced pressure until about a half of the amount remained, and 200 ml of sulfuric acid was then slowly added thereto. The resultant solution was heated at the boiling temperature for 24 hours, extracted twice with 300 ml of ethyl ether and evaporated under reduced pressure to obtain solids, which were recrystallized from boiling hexane to provide 42.1 g of 3-(3,4-dimethylphenyl)propanoic acid as a white solid (yield 55%), having the characteristics of: m.p. 82° C.; NMR(CDCl3, 300 MHz) δ2.22(s, 3H, CH3), 2.24(s, 3H, CH3), 2.66(t, J=8 Hz, 2H, ArCH2), 2.89(t, J=8 Hz, 2H, CH2CO), 6.93~7.70(m, 3H, ArH).
Reaction SMILES: C([NH:4][C:5]1[NH:6][C:7](=O)[C:8]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH3:22])[CH:16]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1)(=O)C.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+].C[Si](C)(C)N[Si](C)(C)C.[O-]CC.[Na+]>C1(C)C=CC=CC=1.ClCCl.C(O)C>[NH2:4][C:5]1[N:6]=[C:7]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:8]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH3:22])[CH:16]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: C1COCCN1
Reactant: CC(=O)Nc1nc2ccc(-c3ccc(F)c(C)c3)nc2c(=O)[nH]1
Agent: CC[O-]
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc3nc(N)nc(N4CCOCC4)c3n2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
to a suspension of 2-acetamido-6-(3-methyl-4-fluorophenyl)-pyrido[3,2-d]pyrimidin-4(3H)-one (312 mg, 1 mmol) in toluene (10 ml) was added morpholine (4 mmol, 0.23 ml), p-toluene sulfonic acid (0.1 mmol, 19 mg), ammonium sulfate (13 mg, 0.1 mmol) and 1,1,1,3,3,3-hexamethyldisilazane (2 ml, 8 mmol). The reaction mixture was refluxed for 48 hours till a brown solution was formed. The solvents were evaporated in vacuo, yielding crude 2-acetamido-4-(morpholino)-6-(4-methyl-3-fluoro-phenyl)-pyrido[3,2-d]pyrimidine. The residue was redissolved in a mixture of dichloromethane and ethanol (in a ratio of 80/20, 10 ml). A sodium ethoxide solution (0.2 N solution) was added till pH 12 and the resulting mixture was stirred overnight at room temperature. The solvents were evaporated in vacuo. The crude residue was purified by preparative TLC on silica, using a methanol/dichloromethane mixture in a ratio of 10:90 as mobile phase, yielding pure 2-amino-4-(morpholino)-6-(3-methyl-4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine (80 mg, yield: 25%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][CH:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[CH:5]([C:7]([OH:9])=[O:8])[NH2:6].[OH-].[Na+].[Cl:19][C:20]1[S:24][C:23]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][CH:21]=1>O.C1COCC1.CCOC(C)=O>[Cl:19][C:20]1[S:24][C:23]([S:25]([NH:6][CH:5]([C:7]([OH:9])=[O:8])[CH:4]([CH2:10][C:11]([F:12])([F:13])[F:14])[CH2:3][C:2]([F:15])([F:16])[F:1])(=[O:27])=[O:26])=[CH:22][CH:21]=1
Reactant: NC(C(=O)O)C(CC(F)(F)F)CC(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(NS(=O)(=O)c1ccc(Cl)s1)C(CC(F)(F)F)CC(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
The crude 5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-dl-norvaline (0.92 g, 3.56 mmol) and NaOH mixture was dissolved in water (10 ml). The mixture was cooled to 0° C. in an ice bath. 5-Chlorothiophene-2-sulfonyl chloride (0.852 g, 3.9 mmol) was dissolved in THF (10 mL) and added dropwise to the reaction mixture over 10 min. After 60 min, the reaction mixture was allowed to warm gradually to 25° C. and stirred for 16 h. THF was removed in vacuo and the mixture was acidified to pH<2 with 1N HCl. After 15 min, a precipitate began to crash out of the milky white mixture. After 60 min, the mixture was cooled in a refrigerator for 45 min and then filtered. The precipitate was washed with 1N HCl (10 mL) to provide a white solid which gummed out. It was dissolved in EtOAc (100 mL). The aqueous layer was washed with EtOAc (3×50 mL) and the organic layers were washed with saturated aqueous NaCl (50 mL). The organic layer was dried over MgSO4, filtered and concentrated to afford N-[(5-chlorothien-2-yl)sulfonyl]-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-dl-norvaline as a brown oil (1.3 g, 86.3%).
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]([CH3:7])=[O:6])=O.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:26]=[CH:25][N+:24]([O-])=[C:23]3C[CH2:29][C@@H:30](C)[C:22]=23)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:5]([O:4][CH:2]1[C:23]2[N:24]=[CH:25][N:26]=[C:21]([N:18]3[CH2:19][CH2:20][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:16][CH2:17]3)[C:22]=2[C@H:30]([CH3:29])[CH2:1]1)(=[O:6])[CH3:7]
Reactant: C[C@@H]1CCc2c1c(N1CCN(C(=O)OC(C)(C)C)CC1)nc[n+]2[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Reaction time: 1.67 h
Yield: 99.8 %

Procedure:
Ac2O (77.0 mL, 816 mmol) was added to (R)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine 1-oxide (21.0 g, 62.8 mmol). The reaction mixture was heated under nitrogen in a 90° C. sand bath and stirred for 100 minutes. The reaction mixture was cooled to room temperature, and excess acetic anhydride was removed by rotary evaporation. The resulting oil was dissolved in DCM, which was then poured carefully into ice saturated Na2CO3. The mixture was extracted with DCM, and the combined extracts were dried (Na2SO4), filtered and concentrated to give (5R)-tert-butyl 4-(7-acetoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (23.6 g, 100%) as a foam. LC/MS (APCI+) m/z 377.1 [M+H]+.
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([C:4]([NH:6][CH2:7][C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[O:5])[CH3:3]>C(O)(=O)C.[Pd]>[NH:1]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[C@H:2]([C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Yield: 87.5 %

Procedure:
VII (16.97 g, 50 mmol) was taken in glacial acetic acid (170 ml) and hydrogenated overnight in the presence of 10% Pd/C (1.7 g) as catalyst at 40 psi. The catalyst was filtered with the aid of celite and solvent removed under reduced pressure. The residue was taken in satd. NaHCO3 solution, extracted with EtOAC (3×), cooled, acidified to pH 2.0 and re-extracted with EtOAC (3×). The combined EtOAC extracts were washed with satd. NaCl, and concentrated under reduced pressure. The residue was triturated with EtOAC: Pet. ether (1:1) and the precipitate obtained was filtered, washed with pet. ether and dried (10.9 g, yield: 87.5%), Rf4 0 52. Anal Calcd. for C10H18N2O5 .1/2H2O: C 46.50, H 7.41, N 10.84%. Found: C 46.64, H 7.41, N 10.84%.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[C@H:6]([CH3:9])[NH:7][CH3:8])[CH3:3].[H-].[Na+].[C:13]([S:16][CH2:17][CH2:18][C:19](Cl)=[O:20])(=[O:15])[CH3:14].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:2]([O:4][C:5](=[O:10])[CH:6]([N:7]([C:19](=[O:20])[CH2:18][CH2:17][S:16][C:13](=[O:15])[CH3:14])[CH3:8])[CH3:9])[CH3:3]
Reactant: CC(=O)SCCC(=O)Cl
Reactant: CCOC(=O)[C@H](C)NC
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)N(C)C(=O)CCSC(C)=O
Yield: 75.2 %

Procedure:
The solution of 15 g (89.5 mmol) of N-methylalanine ethyl ester-hydrochloride in 850 ml of anhydrous tetrahydrofuran is mixed at 23° C. with 4.1 g of an approximately 60% sodium hydride dispersion and, after 3 hours, with 23.5 g of 3-acetylsulfanyl-propanoic acid chloride. It is allowed to react for two days, mixed with saturated sodium bicarbonate solution, and extracted several times with ethyl acetate. The combined organic extracts are washed with saturated sodium chloride solution, dried over sodium sulfate, and the residue that is obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel. 17.6 g (67.3 mmol, 75%) of the title compound is isolated as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:3]([NH:9][C:15]2[CH:16]=[N:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1ncc(Cl)nc1Br
Reactant: COc1ccc(B(O)O)cn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2ncc(Cl)nc2Br)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 17.5 %

Procedure:
A mixture of 3-bromo-5-chloropyrazin-2-amine (624 mg, 2.99 mmol, Ark Phar. Inc), 6-methoxypyridin-3-ylboronic acid (1374 mg, 8.98 mmol, Combi. Blocks), copper (II) acetate (896 mg, 4.49 mmol, Aldrich, St. Louis, Mo.), and N,N-diisopropylethylamine (2.083 mL, 11.97 mmol, Aldrich, St. Louis, Mo.) in dichloromethane (20 mL) was stirred at room temperature for 48 h. The mixture was filtered through a pad of Celite® (diatomaceous earth) and washed with EtOAc. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 10% EtOAc/hexanes to give 3-bromo-5-chloro-N-(6-methoxypyridin-3-yl)pyrazin-2-amine (165 mg, 0.523 mmol, 17.47% yield). 1H NMR (300 MHz, CDCl3) δ 3.95 (s, 3H) 6.79 (d, J=8.77 Hz, 1H) 6.92 (s, 1H) 7.77 (dd, J=8.84, 2.41 Hz, 1H) 8.01 (s, 1H) 8.29 (d, J=2.05 Hz, 1H). m/z (ESI, +ve ion) 316.9 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].Cl[CH2:12][C:13]1[O:17][N:16]=[C:15]([CH2:18][S:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:14]=1>C[O-].[Na+].CO>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([S:19][CH2:18][C:15]2[N:14]=[C:13]([CH2:12][S:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[N:2]([CH3:10])[CH3:1])[O:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: CN(C)c1ccccc1S
Reactant: ClCc1nc(CSc2ccc(Cl)cc2)no1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)c1ccccc1SCc1nc(CSc2ccc(Cl)cc2)no1

Procedure:
2-Dimethylaminobenzenethiol (1.67 g, 0.011 mol) was dissolved in a solution of sodium methoxide (0.59 g) in methanol (50 ml) and 5-chloromethyl-3-(4-chlorophenylthiomethyl)-1,2,4-oxadiazole (3.0 g 0.011 mol) was added dropwise with stirring. After a further 10 min. stirring the solution was filtered and evaporated to leave a brown oil, which was purified by chromatography on silica gel elution with hexane/ether (3:2) giving 3-(4-chlorophenylthiomethyl)-5-(2-dimethylaminophenylthiomethyl)-1,2,4-oxadiazole as a colourless oil, mass spectrum M+1 392; refractive index 1.6263.