Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[Li+].[Li+].[Br-].[Li+]>CN(C=O)C.C(OCC)(=O)C>[C:2]1([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(C2(Br)CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C2=CCCCC2)cc1
Temperature: 20 °C
Yield: 88.8 %

Procedure:
1-(Bromocyclohexyl)-4-nitrobenzene (18.4 g, 64.8 mmol), lithium carbonate (5.3 g, 71.2 mmol), and lithium bromide (6.2 g, 71.2 mmol) were reacted together in DMF (100 mL) for 2 hours at 160° C. The reaction mixture was cooled to 20° C., diluted with ethyl acetate (500 mL), and washed with water (300 mL). The aqueous phase was extracted with ethyl acetate (200 mL) and the combined organic phases were washed with water (3×150 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified on silica (350 g) using ethyl acetate and heptane (1:9) as eluent to give 11.7 g of 1-cyclohex-1-enyl-4-nitrobenzene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>COCCOC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(OCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: O=C(O)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Yield: 97.7 %

Procedure:
A solution of methyl 3-benzyloxybenzoate (38.0 g) and 5N NaOH solution (207 ml) in 1,2-dimethoxyethane (207 ml) was stirred at room temperature for 3 hours 30 minutes and at 100° C. for 1 hour 20 minutes. The reaction mixture was cooled with ice water, mixed with 6N HCl (1.1 mole), and extracted with diethyl ether. The extract was washed with brine, dried over MgSO4, and evaporated in vacuo to afford 3-benzyloxybenzoic acid (34.96 g) as a colorless powder.
Reaction SMILES: [C:1]([C:4]1[CH:36]=[CH:35][C:7]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([N:16]([C:25]([NH:27][CH2:28][CH:29](OC)OC)=[O:26])[N:17]=CC3C=CC=CC=3)=[CH:11][C:10]=2[Cl:34])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl>C(OCC)(=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([N:16]3[C:25](=[O:26])[NH:27][CH2:28][CH:29]=[N:17]3)=[CH:11][C:10]=2[Cl:34])=[CH:35][CH:36]=1)(=[O:3])[CH3:2]
Reactant: COC(CNC(=O)N(N=Cc1ccccc1)c1cc(Cl)c(Cc2ccc(C(C)=O)cc2)c(Cl)c1)OC
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(Cc2c(Cl)cc(N3N=CCNC3=O)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
In 7 ml of ethyl acetate was dissolved 0.7 g of 2-[4-(4-acetylbenzyl)-3,5-dichlorophenyl]-1-benzylidene-4-(2,2-dimethoxyethyl)semicarbazide. To the solution was added 0.27 g of 35% hydrochloric acid. The mixture was stirred for one hour at room temperature. The reaction mixture was washed with water, dried and concentrated. The residue was purified by column chromatography (Merck Silica Gel 60; normalhexane-ethylacetate=1:3) to provide 0.24 g of the title compound. m.p. 189-190° C.
Reaction SMILES: C[Si](OP(=O)=O)(C)C.[NH2:9][C:10]1[C:11]([OH:16])=[N:12][CH:13]=[CH:14][CH:15]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:22](O)=O>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:22]2[O:16][C:11]3[C:10]([N:9]=2)=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:25]=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: COc1cc(C(=O)O)ccc1-c1ccccn1
Reactant: Nc1cccnc1O
Agent: C[Si](C)(C)OP(=O)=O
Product: COc1cc(-c2nc3cccnc3o2)ccc1-c1ccccn1
Temperature: 200 °C

Procedure:
To 5 mL of trimethylsilyl polyphosphate was added 3-aminopyridin-2-ol (150 mg, 1.59 mmol) and 3-methoxy-4-pyridin-2-ylbenzoic acid (229 mg, 1.0 mmol). The mixture was heated at 200° C. for 2 h, quenched over ice, and made basic (pH 14) with 1N NaOH. The aqueous phase was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resultant oil was taken up in a minimum of EtOAc and purified by prep TLC (1:1 EtOAc/hexanes) to give 2-(3-methoxy-4-pyridin-2-ylphenyl)[1,3]oxazolo[5,4-b]pyridine as a light yellow solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.73 (dq, 1H), 8.43 (dd, 1H), 8.32 (dd, 1H), 8.02 (d, 1H), 7.99–7.93 (m, 2H), 7.92–7.85 (m, 2H), 7.55 (dd, 1H), 7.40 (ddd, 1H), 4.01 (s, 3H); MS (ESI) 304 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7](O)=[O:8].Cl>O1CCCC1.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[S:3][C:4]([CH3:10])=[CH:5][C:6]=1[CH:7]=[O:8]
Reactant: Cc1cc(C(=O)O)c(C)s1
Agent: [Mn+4]
Agent: Cl
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1cc(C=O)c(C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a solution (20 mL) of 2,5-dimethylthiophene-3-carboxylic acid (920 mg) in tetrahydrofuran was added 1.0M borane-tetrahydrofuran complex in tetrahydrofuran solution (7.07 mL) at 0° C., and the mixture was stirred at room temperature overnight. 1.0M Borane-tetrahydrofuran complex in tetrahydrofuran solution (14.1 mL) was added, and the mixture was further stirred at room temperature for 3 hr. 1N Hydrochloric acid was added to quench the reaction, tetrahydrofuran was evaporated using evaporator, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (ethyl acetate:hexane=2:3, volume ratio) to give a yellow oil. To a solution of the obtained oil in tetrahydrofuran (10 mL) was added activated manganese dioxide (3.32 g), and the mixture was stirred at room temperature overnight. Manganese dioxide was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (562 mg, 68%) as a yellow oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][CH2:22][N:23]1[C:27](=[O:28])[CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[S:25][CH:24]1[C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1.C(Cl)(Cl)(Cl)[Cl:45]>>[Cl:45][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[S:25][CH:24]1[C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1
Reactant: CCCCCCCCCC1SC(c2cccnc2)N(CCO)C1=O
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCCCC1SC(c2cccnc2)N(CCCl)C1=O
Temperature: 25 °C
Yield: 80 %

Procedure:
Triphenylphosphine (3.44 g, 13 mmol) was added to a mixture of 3-(2-hydroxyethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one (3.49 g, 10 mmol) and carbon tetrachloride (20 ml) with stirring at room temperature. Then the mixture was refluxed with stirring for 2.5 hours. The product mixture was cooled and filtered to remove the formed crystals. The filtrate was concentrated and chromatographed, giving the cis-isomer (0.55 g) and trans-isomer (1.46 g) of the title compound and a mixture of two isomers (0.94 g) (total 2.95 g, 80% yield).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[CH2:7][C@H:8]1[N:15]([S:16]([C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:28]=2[N:27]=[CH:26][CH:25]=[CH:24]3)(=[O:18])=[O:17])[CH2:14][C:13]2[CH:29]=[CH:30][CH:31]=[CH:32][C:12]=2[CH2:11][O:10][CH2:9]1)(=[O:3])[CH3:2].O=P(Cl)(Cl)Cl>O>[CH3:2][C:1]1[O:3][C:6]([CH2:7][C@H:8]2[N:15]([S:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)(=[O:18])=[O:17])[CH2:14][C:13]3[CH:29]=[CH:30][CH:31]=[CH:32][C:12]=3[CH2:11][O:10][CH2:9]2)=[N:5][N:4]=1
Reactant: CC(=O)NNC(=O)C[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nnc(C[C@@H]2COCc3ccccc3CN2S(=O)(=O)c2cccc3cccnc23)o1
Temperature: 110 °C
Reaction time: 3 h
Yield: 42.3 %

Procedure:
A mixture of compound 27a (100 mg, 0.21 mmol) and POCl3 (3 mL) was stirred at 110° C. for 3 h. The mixture was taken up in H2O (10 mL) and extracted with DCM (30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by Prep-TLC to give the pure compound 27 (40 mg, 42% yield). LCMS (m/z): 451.1 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22](C4C=NC=NC=4)[CH2:21][CH2:20]3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:31]=1)[CH3:2].C(N(CC)C(C)C)(C)C.[O:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[C:46](Cl)=[O:47].O>ClCCl>[CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([C:46]([C:42]4[O:41][CH:45]=[CH:44][CH:43]=4)=[O:47])[CH2:23][CH2:24]3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:31]=1)[CH3:2]
Reactant: O=C(Cl)c1ccco1
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCN(c3cncnc3)CC1)C2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(CC1CCN(C(=O)c3ccco3)CC1)C2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.4 %

Procedure:
Compound 32 (800 mg, 1.92 mmol) obtained in Example 32 was suspended in dichloromethane (15 mL), and the mixture was stirred at room temperature for 4 hours after adding N,N-diisopropylethylamine (1.16 mL, 6.71 mmol) and 2-furoyl chloride (226 μL, 2.30 mmol). Thereafter, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography, and crystallized from diethyl ether to give the title compound (Compound 35) (601 mg, 71%).
Reaction SMILES: [NH3:1].CO.O=[C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH2:14]([O:13][C:11]([C:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=1[NH2:1])=[O:12])[CH3:15]
Reactant: N
Reactant: CCOC(=O)C1CCCCC1=O
Solvent: CO
Product: CCOC(=O)C1=C(N)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To 7N-ammonia-methanol solution, 170 g of ethyl 2-oxocyclohexanecarboxylate was added and stirred for an overnight at room temperature. Concentrating the solvent under reduced pressure, crude crystals were obtained, which were recrystallized from ethyl acetate-n-hexane to provide 152 g (90%) of 2-aminocyclohex-1-enecarboxylic acid ethyl ester.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:11]=[CH:10][C:9](OC)=[CH:8][C:7]=2[N+:14]([O-])=O)[CH2:3][CH2:2]1.[CH2:17]([OH:19])C>>[CH:1]1([CH2:4][NH:5][C:6]2[C:7]([NH2:14])=[CH:8][CH:9]=[C:10]([O:19][CH3:17])[CH:11]=2)[CH2:2][CH2:3]1
Reactant: CCO
Reactant: COc1ccc(NCC2CC2)c([N+](=O)[O-])c1
Product: COc1ccc(N)c(NCC2CC2)c1
Temperature: 10 °C
Reaction time: 2.5 h

Procedure:
N-(Cyclopropylmethyl)-4-methoxy-2-nitroaniline (175 g) was dissolved in ethanol (1750 mL) and was added to a 4.0 L Hast ‘C” Shaker can. The mixture was cooled to 10° C. and treated with 3% Pt/0.6% VG/C, deGussa (4.5 g). The vessel was sparged under nitrogen and then sparged three times with hydrogen at a setting of 40 psi and agitated for 2.5 hours. To a pre-washed solka-flok with ethanol, the mixture was filtered through solka-flok through a sintered glass funnel to have about a ½ inch depth of solka-flok. The solka-flok was then washed with 1 L ethanol and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:10]=2[C:11](OC)=[O:12])=[C:4]([N+:20]([O-])=O)[CH:3]=1.O.O.Cl[Sn]Cl>Cl.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:10]=3[C:11](=[O:12])[NH:20][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(Cl)cc1Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: O=C1Nc2cc(Br)ccc2Nc2cc(Cl)ccc21
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A mixture of Example 2A (6.0 g, 15.6 mmol) and SnCl2.2H2O (10.54 g, 46.8 mmol) in 37% HCl (200 mL) and methanol (300 mL) was heated to reflux for 20 hours, cooled to room temperature, and filtered. The filter cake was washed with 1:1H2O/methanol and dried in a vacuum oven at 65° C. to provide 4.6 g (91%) of the desired product. MS (DCI) m/e 324 (M+H)+, 341 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.18 (s, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.12-7.16 (m, 2H), 7.05 (d, J=2 Hz, 1H), 6.95 (dd, J=8.4, 2 Hz, 1H), 6.91 (d, J=9.1 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][OH:23].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:23][CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CN(C)CCO
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)CCOc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, 2-dimethylaminoethanol and DBU in DME. ES-MS m/e (%): 274 (M+H+, 100).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C@:7]12[CH2:24][CH2:23][C@@:21]3([CH3:22])[C@@H:17]([CH2:18][CH2:19][C:20]3=[O:25])[C@@H:16]1[CH2:15][CH2:14][C:13]1[C@:8]2([CH3:27])[CH2:9][CH2:10][C:11](=[O:26])[CH:12]=1.[C-:28]#[N:29].[K+].O>CO>[CH3:22][C@@:21]12[C:20]([OH:25])([C:28]#[N:29])[CH2:19][CH2:18][C@H:17]1[C@@H:16]1[CH2:15][CH2:14][C:13]3[C@@:8]([CH3:27])([C:7]1([OH:6])[CH2:24][CH2:23]2)[CH2:9][CH2:10][C:11](=[O:26])[CH:12]=3
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Reactant: [C-]#N
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(O)(C#N)[C@@]3(C)CCC12O
Reaction time: 2.5 h

Procedure:
Sulfuric acid (2.07 ml) is added to 9α-hydroxyandrost-4-ene-3,17-dione (I, 21.14 g) and potassium cyanide (6.70 g) slurried in methanol (71.5 ml) and water (6.8 ml) at <5°. The mixture is allowed to warm to 15° over 0.5 hr, then warmed to 30° over 1 hr. The mixture is stirred at 30° for 2.5 hr, then cooled to 2° and sulfuric acid (0.32 ml) is added. The mixture is then stirred at 30° for 2 hr and water (13 ml) is added. Next, water (52 ml) is added over 12 hr, maintaining the mixture at 30°. The mixture is stirred 5 hr at 30°, then cooled to 0° and quenched with sulfuric acid (1 ml). Methanol (89 ml) is added and the mixture is heated to 55°. The solvent is then removed by reduced pressure until the boiling point begins to rise rapidly. The mixture is then cooled to 32° and water (105 ml) is added over 12 min. The mixture is further cooled to 0° and the the solids are collected by vacuum filtration and washed with water to give the title compound, mp 230°-233° (with decomposition). ##STR1##
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3].[CH:18]1([CH2:24][C:25](=O)[C:26]([OH:28])=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([BH3-])#N.[Na+]>>[C:26]([CH:25]([NH:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3])[CH2:24][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([OH:28])=[O:27]
Reactant: C[C@H](N)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Reactant: O=C(O)C(=O)CC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NC(CC1CCCCC1)C(=O)O)C(=O)N1C2CCCCC2C[C@H]1C(=O)O

Procedure:
Condense 1-[(S)-alanyl]octahydroindole-2(S)-carboxylic acid (prepared as described in Example 1) and 3-cyclohexyl-2-oxopropionic acid with sodium cyanoborohydride as described in Example 5 to obtain the title compound,
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].[NH:62]1[CH2:66][CH2:65][CH2:64][CH2:63]1>O1CCCC1.C(OCC)C.O>[N:62]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH2:66][CH2:65][CH2:64][CH2:63]1
Reactant: C1CCNC1
Reactant: N#Cc1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: N#Cc1cccc(N2CCCC2)c1
Temperature: 80 °C
Yield: 5.2 %

Procedure:
A reaction mixture of 3-bromo-benzonitrile (0.91 g, 5 mmol), tris(dibenzylidenecetone)-dipalladium (229 mg), (S)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (311 mg, 0.5 mmol), sodium tert-butoxide (740 mg, 7.7 mmol), pyrrolidine (0.58 mL, 6.9 mmol) in tetrahydrofuran (10 mL) was heated at 80° C. in a sealed tube for 6 h. The reaction mixture was worked up with water and diethyl ether. The organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 0-5% ethyl acetate in hexanes yielded 3-pyrrolidin-1-yl-benzonitrile (45 mg, 5%).
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[CH2:8]([C:10]1([CH2:16][CH3:17])[CH2:12][CH:11]1[C:13]([NH2:15])=[O:14])[CH3:9]>C1(C)C=CC=CC=1>[CH2:8]([C:10]1([CH2:16][CH3:17])[CH2:12][CH:11]1[C:13]([NH:15]/[C:2](=[CH:6]\[CH3:7])/[C:3]([OH:5])=[O:4])=[O:14])[CH3:9]
Reactant: CCC1(CC)CC1C(N)=O
Reactant: CCC(=O)C(=O)O
Solvent: Cc1ccccc1
Product: C/C=C(\NC(=O)C1CC1(CC)CC)C(=O)O
Yield: 9.7 %

Procedure:
A mixture of 2.3 g of 2-ketobutyric acid, 2.0 g of 2,2-diethylcyclopropanecaboxamide, and 25 ml of toluene was heated under reflux for 16 hrs with removal of H20 by a modified Dean-Stark trap containing molecular sieves (4A). No product precipitated upon cooling. Ether (25 ml) was added and the mixture was extracted with saturated NaHCO3 (3 times). The combined extracts were acidified with concentrated HCl. The gummy precipitate crystallized when triturated with water. Recrystallization from ethyl acetate gave 0.31 g of product, m.p. 129°-30°. The NMR spectrum was consistent with the desired structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][CH:8]([C:12]([OH:14])=O)[CH2:7]1.[CH2:21]([C@@H:28]1[CH2:32][O:31][C:30](=[O:33])[NH:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:21]([C@@H:28]1[CH2:32][O:31][C:30](=[O:33])[N:29]1[C:12]([CH:8]1[CH2:9][C:10](=[O:11])[N:6]([CH2:5][C:4]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:3]=2[O:2][CH3:1])[CH2:7]1)=[O:14])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: COc1ccc(CN2CC(C(=O)O)CC2=O)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN2CC(C(=O)N3C(=O)OC[C@H]3Cc3ccccc3)CC2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.3 %

Procedure:
To a solution of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (31.7 g) in chloroform (300 ml) were sequentially added (R)-4-benzyl-2-oxazolidinone (20.0 g), WSC.HCl (23.8 g) and 4-dimethylaminopyridine (6.90 g) under ice-cooling, the mixture was stirred for 15 minutes, warmed to room temperature and stirred for 18 hours. This reaction mixture was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1 to 1/9) to give the titled compound (low-polarity component 26.4 g, high-polarity component 13.3 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[C:8](=[O:11])[NH:9][N:10]=[C:6]2[C:5]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]([F:43])([F:42])[F:41])=[N:38][CH:39]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]2[C:8](=[O:11])[N:9]([CH2:33][C:34]3[CH:39]=[N:38][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:36][CH:35]=3)[N:10]=[C:6]2[C:5]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:3]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: Nc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2n[nH]c(=O)n12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Temperature: 50 °C
Reaction time: 1.33 h
Yield: 67.2 %

Procedure:
To a mixture of crude 5-amino-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (26 mg, 0.07 mmol), DMF (0.5 mL), and potassium carbonate (45 mg, 0.32 mmol) was added 5-chloromethyl-2-(trifluoromethyl)pyridine (21.2 mg, 0.11 mmol). The resulting reaction mixture was stirred at 50° C. for 80 min. The reaction mixture was purified by preparative reverse phase HPLC without prior workup to obtain 25 mg of the title compound as a light yellow solid. HPLC/MS: retention time=4.14 min, [M+H]30 =531.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[CH3:7][C:8]([C:11]1[CH:12]=[C:13]([S:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2O)[CH:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:16]=1)([CH3:10])[CH3:9].FC(F)(F)C(O)=O.O>C(Cl)Cl>[CH3:10][C:8]([C:11]1[CH:12]=[C:13]([S:21][C@@H:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C@H:27]2[S:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH:14]=[C:15]([C:17]([CH3:18])([CH3:19])[CH3:20])[CH:16]=1)([CH3:7])[CH3:9]
Reactant: COC(=O)CS
Reactant: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2O)cc(C(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COC(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Reaction time: 0.25 h

Procedure:
Methyl thioglycolate (2.65 g, 0.025 moles) was added by syringe to a solution of trans-2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexanol (5.0 g., 0,025 moles) in methylene chloride (10 ml). After stirring the reaction mixture for 15 minutes, trifluoroacetic acid (10 ml) was added by syringe, and the reaction mixture was stirred for 20 hours at room temperature. The reaction mixture was poured into cold water (100 ml). After stirring for 30 minutes, the mixture was extracted with ethyl acetate. The aqueous layer was washed with ethyl acetate (50 ml). The combined ethyl acetate extracts were washed twice with 75 ml of water, dried over sodium sulfate, filtered and concentrated to give the crude product as an oil. The title compound was purified by silica gel chromatography and dried in a vacuum oven at 60° C. for 3 hours. The structure assignment was supported by NMR, infrared spectroscopy, and elemental analysis.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][NH:5][CH:4]=[C:3]1[O:8][CH2:9][C:10]([OH:12])=[O:11].[Cl:13][O-].[Na+].ClCl.Cl>[OH-].[Na+]>[O:1]=[C:2]1[C:7]([Cl:13])=[CH:6][NH:5][CH:4]=[C:3]1[O:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: [O-]Cl
Reactant: O=C(O)COc1c[nH]ccc1=O
Agent: Cl
Agent: ClCl
Agent: [Na+]
Product: O=C(O)COc1c[nH]cc(Cl)c1=O

Procedure:
To a solution of 2-(4-oxo-1,4-dihydropyridin-3-yloxy)acetic acid (16.9 g) in 0.5 N sodium hydroxide aqueous solution (200 ml), was added dropwise under cooling a sodium hypochlorite aqueous solution (70 ml) whose active chlorine is about 10% at 3° to 8° C. with stirring. The mixture was stirred for 30 minutes at the same temperature and adjusted to pH 3 with 10% hydrochloric acid. Precipitated crystals were collected by filtration, recrystallized from 1 N hydrochloric acid and dried at 90° to 95° C. for 4-5 hours in a stream of air to give crystals (16.7 g) of 2-(4-oxo-5-chloro-1,4-dihydropyridin-3-yloxy)acetic acid, mp 253° to 255° C.