Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=2)[CH:36]=[C:35](CO)[CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1.O>[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([F:43])[CH:41]=2)[CH:36]=[C:35]([CH2:20][Cl:24])[CH:34]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1cc(OCc2ccccc2)c2cc(F)ccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc2cc(CCl)cc(OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.5 %

Procedure:
To a solution of triphenylphosphine (2.8 g, 10.6 mmol) in anhydrous tetrahydrofuran (16 mL) was added carbon tetrachloride (5 mL). After the mixture was stirred at room temperature for 10 minutes, (4-benzyloxy-6-fluoro-naphthalen-2-yl)-methanol (1.5 g, 5.3 mmol) was added as a solid under a nitrogen atmosphere. After being stirred at reflux for 2 hours, the resulting mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL×2). The combined aqueous layers were extracted with ethyl acetate (100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (elution with 5% ethyl acetate in petroleum ether) to afford 1-benzyloxy-3-chloromethyl-7-fluoro-naphthalene (1.4 g, 87.5%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([O:5][CH2:6][CH:7]=[N:8][OH:9])([CH3:4])[CH3:3].ClN1C(=O)CCC1=O.[CH:18]1([C:22](=O)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][CH2:20][CH2:19]1.[O-]CC.[Na+]>CN(C)C=O.O1CCCC1>[CH:18]1([C:22]2[O:9][N:8]=[C:7]([CH2:6][O:5][C:2]([CH3:4])([CH3:3])[CH3:1])[C:23]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OCC=NO
Reactant: CCOC(=O)CC(=O)C1CCC1
Agent: CC[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(COC(C)(C)C)noc1C1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of (1,1-dimethylethyl)oxyethanal oxime (1.71 g, 13.0 mmol) in N,N-dimethylformamide (10 mL) was added N-chlorosuccinimide (1.74 g, 13.0 mmol) while the flask was in a water bath. After approximately 10 minutes the flask was removed from the water bath and the solution was stirred for approximately 1 hour. The solution, containing the crude imidoyl chloride, was then poured into ether and washed twice with water followed by brine, and then was dried over magnesium sulfate and concentrated. Then to a separate solution of ethyl 3-cyclobutyl-3-oxopropanoate (2.66 g, 15.6 mmol) in tetrahydrofuran (8 mL) at 0° C. was added sodium ethoxide (21 wt % solution in ethanol, 5.82 mL, 15.6 mmol). The above imidoyl chloride was diluted with tetrahydrofuran (6 mL) then added to the solution containing the ketoester. A solid was seen to precipitate. After the addition the solution was allowed to warm to ambient temperature and stirred overnight. The mixture was then poured into ether and washed twice with water followed by brine, dried over magnesium sulfate and concentrated to afford ethyl 5-cyclobutyl-3-{[(1,1-dimethylethyl)oxy]methyl}-4-isoxazolecarboxylate (3.13 g, 87%). 1H-NMR (400 MHz, DMSO-d6) δ 4.53 (s, 2H), 4.22 (q, J=7 Hz, 2H), 4.17-4.05 (m, 1H), 2.33-2.27 (m, 4H), 2.09-2.03 (m, 1H), 1.95-1.86 (m, 1H), 1.26 (t, J=7 Hz, 3H), 1.17 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][C:5]([F:21])=[CH:4][N:3]=1.O1CCCC1.[OH-].[Na+].Cl[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=1>CN(C)C=O>[F:21][C:5]1[CH:6]=[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=4)=[CH:16][CH:15]=3)[CH:9]=2)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(F)cc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: Fc1ccc(CCl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ncc(F)cc1-c1cc(Cc2ccc(OCc3ccc(F)cn3)cc2)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To 4-(5-(2-amino-5-fluoro-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (20.0 mg, 0.07 mmol) described in Manufacturing Example 174-1-1 were added tetrahydrofuran (3 mL) and a 5 N sodium hydroxide aqueous solution (14.0 μL, 0.07 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. Next, the reaction solution was concentrated under a reduced pressure, which gave a white solid. To a mixture of this solid and N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of 2-chloromethyl-5-fluoro-pyridine (11.2 mg, 0.08 mmol) described in manufacturing Example 41-1-2, which was stirred for 1 hour at 60° C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (24.7 mg, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH:22]([CH2:23][O:24][CH2:25][C:26]([O-:28])=[O:27])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1.[OH-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[C@H:22]([CH2:23][O:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)(=[O:12])=[O:11])=[C:5]([CH3:29])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2Cc3ccccc3CC2COCC(=O)[O-])c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N2Cc3ccccc3C[C@H]2COCC(=O)O)c(C)c1
Temperature: 25 °C

Procedure:
(S)-tert-butyl 2-((2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)methoxyacetate (1.58 g, 3.32 mmol) was dissolved in tetrahydrofuran (10 ml), and sodium hydroxide solution (531 mg, 13.28 mmol in water (0.5 ml)) was added. The reaction mixture was refluxed for 2 h, then cooled to room temperature again, and water (20 ml) was added. The pH value of the aqueous phase was adjusted to pH 2 with 2 M hydrochloric acid, and extraction with ethyl acetate (3×20 ml) was carried out. The crude product was used in the next stage without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([NH2:12])=[N:9][CH:8]=2)=[CH:5][C:4]([C:13]([F:16])([F:15])[F:14])=[N:3]1.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20](Cl)=[O:21].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:19]=1[C:20]([NH:12][C:10]1[S:11][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:13]([F:16])([F:14])[F:15])[CH:5]=2)=[CH:8][N:9]=1)=[O:21]
Reactant: Cn1nc(C(F)(F)F)cc1-c1cnc(N)s1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(C(F)(F)F)cc1-c1cnc(NC(=O)c2c(F)cccc2F)s1
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a mixture of 5-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl]-1,3-thiazole-2-ylamine (63, 4.6 mg, 0.019 mmol) in 0.5 ml DCM were added 2,6-difluorobenzoyl chloride (5 μl, 2 eq), DIEA (17 μl, 3 eq) and DMAP (2 mg). After stirred at r.t for overnight, the reaction mixture was worked up with DCM/aq. NaCO3, the DCM phase was concentrated to dryness. The solid residue was dissolved in 1 ml THF/MeOH/H2O (5:4:1). 0.1 ml of 1N NaOH were added and mixture was stirred at r.t for 1 h before worked up DCM//aq. NaCO3. DCM phase was concentrated and subjected to silica gel flash column to give 5.6 mg of (2,6-difluorophenyl)-N-{5-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl] (1,3-thiazol-2-yl)}carboxamide (64) as white solid (yield: 75.9%; purity>95%). LC-MS: calcd. for C15H9F5N4OS: 389 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:18])=[C:12]2[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)([CH3:7])[CH3:6])[CH3:2].[Na].[H-].[Na+].[CH2:32](Br)[CH:33]=[CH2:34]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:28])[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:34][CH:33]=[CH2:32])[C:13]([CH3:18])=[C:12]2[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc2[nH]c(C)c(CCc3ccc(Cl)cc3)c2c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: C=CCn1c(C)c(CCc2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
Two grams (5 m mole) of 2-{3-[2-(4-chloro-phenyl)-ethyl]-2-methyl-1H-indole-5-yloxy}-2-methyl-propanoic acid ethylester in 20 ml of absolute dimethylformamide were converted to the sodium salt in the present of 0.24 g (~5 m mole) of 55% sodium hydride immersion in oil, and the mixture was alkylated with 1.2 g (10 m mole) of allylbromide at room temperature. After the solvent was distilled off in vacuo, the evaporation residue was dissolved in toluene, filtered, and purified over a silicagel column (solvent: toluene).
Reaction SMILES: Br.[C:2]1([N:8]=[N:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21](=[O:27])[C@@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33]([NH:35][CH2:36][C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].C1(N=C=NC2CCCCC2)CCCCC1>>[C:2]1([N:8]=[N:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21](=[O:27])[C@@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:37](=[O:38])[CH2:36][NH:35][C:33]([O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:34])=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(N=Nc2ccccc2)c2ccccc12)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)Nc1ccc(N=Nc2ccccc2)c2ccccc12

Procedure:
The L-proline 4-phenylazo-1-naphthylamide hydrobromide thus obtained and t-butyloxycarbonyl glycine (1.36 g, 0.0077 mole) were coupled by N, N'dicyclohexylcarbodimide and the reaction mixture was worked up as in Example 6. The crude product was then purified by column chromatography, and the final product was obtained as crystals. Yield 1.1 g.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([OH:25])([CH3:24])[CH3:23])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:26])=[CH:10][CH:11]=3)[N:6]=1.CO.[CH3:29]S(O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([O:25][CH3:29])([CH3:23])[CH3:24])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:26])=[CH:10][CH:11]=3)[N:6]=1
Reactant: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(O)ccc1O2
Reactant: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(O)ccc1O2

Procedure:
A vessel was charged with (S)-2′-amino-3-(3-hydroxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (0.512 g, 1.457 mmol) in methanol (17.73 mL, 437 mmol). Methane sulfonic acid (0.945 mL, 14.57 mmol) was added, and the vial was sealed and placed in a 55° C. oil bath overnight. Potassium carbonate was added to quench the acid, and the mixture was filtered with the aid of DCM. The filtrate was evaporated, and the residue was soluble in MeOH/DCM, but some potassium carbonate still came through. The residue was purified by chromatography on a 50-g SNAP column, eluting with 0-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM. The material thus obtained was rechromatographed to under the same conditions to give (S)-2′-amino-3-(3-methoxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol as a pale-yellow solid.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([O:39][C:40](=[O:52])[NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:24][O:25][C:26](=[O:38])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O)C1C=CC=CC=1.C([O-])=O.[NH4+].CO.O>CO.[Pd]>[NH2:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([O:39][C:40](=[O:52])[NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:24][O:25][C:26](=[O:38])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14]
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](N)C(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Temperature: 40 °C

Procedure:
A solution of (R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio)propanoate (14) in MeOH (0.1 M) was stirred under nitrogen at room temperature. A small scoop (catalytic) of Pd/C was then added and stirred. A solution of ammonium formate (8 eq) in 9:1 MeOH/water was then added, the reaction vessel purged with nitrogen and heated to 40° C. for 4 hours. The reaction was then cooled to room temperature and diluted with EtOAc. The reaction mixture was filtered through celite then Na2SO4 and concentrated. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-60% EtOAc/Hex to afford the title compound as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)#[N:18]>O1CCCC1>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([NH:8][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([C:17]#[N:18])=[CH:20][CH:21]=2)=[CH:10][CH:11]=1)#[N:14]
Reactant: N#Cc1ccc(N)cc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1

Procedure:
13.1 g (0.13 moles) of triethylamine were added to a solution of 14.2 g (0.12 moles) of 4-aminobenzonitrile in 100 ml of tetrahydrofuran and the temperature was then kept at about 5° C. and 20 g (0.12 moles) of 4-cyanobenzoyl chloride were added dropwise. The mixture was left to react for 12 h under agitation. The solvent was evaporated, the residue was taken up with H2O and the precipitate formed was filtered. The precipitate was washed with dilute HC1, a 10% solution of bicarbonate and again with H2O.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]([O:13]CC)=O.[C-:16]#[N:17].[Na+].CN>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]([NH:17][CH3:16])=[O:13]
Reactant: [C-]#N
Reactant: CCOC(=O)CCc1c(Cl)cccc1Br
Agent: CN
Agent: [Na+]
Product: CNC(=O)CCc1c(Cl)cccc1Br

Procedure:
Ethyl 3-(2-bromo-6-chlorophenyl)propanoate (Example 1f), 5.0 g, 17.1 mmol) and sodium cyanide (0.168 g, 3.43 mmol) were stirred in methanamine (8 M in ethanol, 30 mL, 240 mmol) at rt overnight. The solvent was evaporated, the residue was taken up in ethyl acetate and the mixture was washed with saturated aqueous sodium carbonate and brine. The organic phase was separated and the solvent was removed by rotary evaporation. The crude product was added to a silica gel column and was eluted with 0-100% ethyl acetate in heptane. The collected fractions were combined and the solvent was removed by rotary evaporation to give the title product. Yield 2.98 g, 63%. 1H NMR (500 MHz, CDCl3) δ ppm 2.40-2.47 (m, 2H) 2.85 (d, 3H) 3.28-3.35 (m, 2H) 5.44 (br. s., 1H) 7.02 (t, 1H) 7.33 (dd, Hz, 1H) 7.47 (dd, Hz, 1H). MS m/z 277.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]([OH:12])[CH2:10][NH2:11])=[CH:7][C:6]([CH2:13][CH3:14])=[C:5]([CH3:15])[N:4]=1.C(N1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])(OCC)=O>C(O)C>[CH3:1][O:2][C:3]1[C:8]([CH:9]([OH:12])[CH2:10][N:11]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])=[CH:7][C:6]([CH2:13][CH3:14])=[C:5]([CH3:15])[N:4]=1
Reactant: CCc1cc(C(O)CN)c(OC)nc1C
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: CCc1cc(C(O)CN2C(=O)c3ccccc3C2=O)c(OC)nc1C
Reaction time: 6 h
Yield: 14.9 %

Procedure:
To a suspension of 2-methoxy-3-(2-amino-1-(R/S)hydroxyethyl)-5-ethyl-6-methylpyridine (345 mg, 1.64 mmol) in ethanol (5 mL) was added N-(carbethoxy)-phthalimide (373 mg, 1.70 mmol). The reaction was stirred for six hours as suspension dissolved. The solvent was evaporated and the viscous residue triturated with ethyl acetate/diethyl ether as product crystallized. By filtration 273 mg (49%) of pure product was collected, m.p. 134°-135° C. These mother liquors were flash chromatographed on silica gel and eluted with 20% ethyl acetate/80% hexane to give an additional 83 mg (15%) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:23])[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][C:10](C(OC)=O)=[C:9]2[OH:22])=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].[Cl-].[Na+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:23])[C:9](=[O:22])[CH2:10][CH2:11][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:13]2)=[CH:4][C:3]=1[C:24]([F:25])([F:26])[F:27]
Reactant: COC(=O)C1=C(O)C(C)(c2ccc(Cl)c(C(F)(F)F)c2)CC(C(=O)OC)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C1CCC(=O)C(C)(c2ccc(Cl)c(C(F)(F)F)c2)C1
Temperature: 155 °C
Yield: 45.2 %

Procedure:
A solution of dimethyl 5-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxy-5-methylcyclohex-3-ene-1,3-dicarboxylate (mixture of diastereomers, 485 mg, 1.192 mmol) in DMSO (5 mL) was treated with sodium chloride (139 mg, 2.385 mmol) and water (0.107 mL, 5.96 mmol). The resulting mixture was bubbled with nitrogen for 15 min, and then heated under nitrogen on an oil bath at 150-160° C. for 4.5 h. After this time, the mixture was cooled to rt, diluted with water and then extracted three times with ethyl acetate. The combined organic layers were washed with water followed by saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under vacuum to yield a residue. The residue was purified by column chromatography on silica gel, eluting with 20-35% ethyl acetate-hexanes, to provide methyl (1RS,3RS)-3-(4-chloro-3-(trifluoromethyl)-phenyl)-3-methyl-4-oxocyclohexanecarboxylate (137 mg, 33%) and methyl (1SR,3RS)-3-(4-chloro-3-(trifluoro-methyl)phenyl)-3-methyl-4-oxocyclohexanecarboxylate (188 mg, 45%). The (1SR, 3RS) diastereomer could be partially converted to the (1RS, 3RS) diastereomer as described in the procedure of Example 7, Part 3.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][NH2:12])=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[Br:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=O)=[CH:17][CH:16]=1.BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:8][C:5]1[N:4]=[C:3]([C:9]2[O:10][C:19]([C:18]3[CH:22]=[CH:23][C:15]([CH2:14][Br:13])=[CH:16][CH:17]=3)=[N:12][N:11]=2)[C:2]([NH2:1])=[N:7][CH:6]=1
Reactant: NNC(=O)c1nc(Br)cnc1N
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1ncc(Br)nc1-c1nnc(-c2ccc(CBr)cc2)o1
Yield: 77.1 %

Procedure:
A 1 L 3 neck round bottom flask was fitted with a mechanical stirrer, a cooling bath used as secondary containment, an addition funnel, a J-Kem temperature probe and a nitrogen inlet/outlet. The vessel was charged under nitrogen with 3-amino-6-bromopyrazine-2-carbohydrazide (12 g, 51.72 mmol), 4-(bromomethyl)benzoic acid (11.12 g, 51.72 mmol) and acetonitrile (460 ml, 20 ml/g based on the mass of the two reagents). Stirring was commenced and the pot temperature was recorded at 21° C. The suspension was then treated with dibromo(triphenyl)phosphorane (98.22 g, 232.7 mmol) added as a solid in one portion. The suspension was continued to stir at ambient temperature for 1 hour. The addition funnel was then charged with diisopropylethylamine (54 ml, 310.3 mmol) which was added neat drop wise over 1 hour, which resulted in an exotherm to 30° C. The resulting light brown suspension was continued to stir at ambient temperature for 20 hours. The reaction mixture was vacuum filtered through a glass frit buchner funnel and the filter cake was displacement washed with acetonitrile (2×150 ml) followed by hexane (250 ml). The material was further dried under vacuum to provide the product 5-bromo-3-(5-(4-(bromomethyl)phenyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-amine as a yellow solid (16.4 g, 39.89 mmol, 77% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 4.82 (s, 2H), 7.72 (d, J=8.2 Hz, 2H), 7.80 (s, 2H), 8.11 (d, J=8.1 Hz, 2H), 8.45 (s, 1H)
Reaction SMILES: N1CCCCC1.[CH2:7]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=O)[CH2:8][CH2:9][CH2:10][C:11]#[CH:12].C([CH2:27][C:28]([NH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34])=[O:29])(O)=O.Cl>C1(C)C=CC=CC=1>[CH2:7]([O:13][C:14]1[CH:15]=[C:16](/[CH:17]=[CH:27]/[C:28]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([OH:35])=[O:34])=[O:29])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:8][CH2:9][CH2:10][C:11]#[CH:12]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: C#CCCCCOc1cc(C=O)ccc1OC
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: C#CCCCCOc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC
Yield: 67.8 %

Procedure:
Piperidine (0.26 mL, 2.6 mmol) was added to a suspension of 3-(hex-5-ynyloxy)-4-methoxybenzaldehyde (0.60 g, 2.6 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.52 g, 2.4 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1M HCl. The crude product was recrystallised from EtOH/water providing (E)-2-[[3-(3-(hex-5-ynyloxy)-4-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.64 g, 70%) as a pale yellow crystalline solid; mp 135-137° C.; δH (400 MHz, DMSO-d6) 1.62 (p, J=7.2 Hz, 2H, CH2), 1.82 (p, J=7.2 Hz, 2H, CH2), 2.25 (dt, J=7.2, 2.4 Hz, 2H, CH2CCH), 2.78 (t, J=2.4 Hz, 1H, CCH), 3.80 (s, 3H, OCH3), 4.05 (t, J=7.2 Hz, 2H, OCH2), 6.77 (d, J=15.6 Hz, 1H, CH═CHCO), 6.99 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.23 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.37 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.61 (d, J5,6=8.0 Hz, 1H, H6), 11.27 (s, 1H, NH), 13.58 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 18.1, 25.3, 28.5, 56.3, 68.4, 72.1, 85.0, 112.3, 112.5, 117.3, 120.5, 121.0, 123.3, 127.9, 131.8, 134.7, 141.7, 142.3, 149.0, 151.5, 164.8, 170.1; HRMS (ESI) calculated for C23H23NO5 [M+H]+ 394.1649. found 394.1650; vmax 753, 1257, 1512, 1586, 1675, 2941, 3242, 3536 cm−1.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:12])[O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[N+:13]([O-])=O.[BH4-].[Na+]>CO.O.Cl[Ni]Cl>[NH2:13][C:3]1[CH:4]=[CH:5][C:6]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[N:7][C:2]=1[Br:1]
Reactant: COC(=O)Nc1ccc([N+](=O)[O-])c(Br)n1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)Nc1ccc(N)c(Br)n1
Reaction time: 0.01 h
Yield: 97.5 %

Procedure:
To a solution of methyl 6-bromo-5-nitropyridin-2-ylcarbamate (700 mg, 2.5 mmol) in CH3OH (20 mL) was added NiCl2 (1.2 g, 5.1 mmol) and NaBH4 (300 mg, 7.6 mmol) successively at 0° C. The mixture was stirred for 20 seconds. The reaction mixture was diluted with water and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give methyl 5-amino-6-bromopyridin-2-ylcarbamate (600 mg, 96%). 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J=8.4 Hz, 1H), 7.13 (brs, 1H), 7.09 (d, J=8.8 Hz, 1H), 3.81 (s, 3H).