Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2](OCC)=O.[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([NH2:22])[C:16]([C:23]([NH2:25])=[O:24])=[CH:15]2>CCCCCC>[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]1[N:22]=[C:2]([C:1]([O:8][CH2:9][CH3:10])=[O:7])[NH:25][C:23](=[O:24])[C:16]1=[CH:15]2
Reactant: NC(=O)c1cc2cc(F)ccc2nc1N
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCCCCC
Product: CCOC(=O)c1nc2nc3ccc(F)cc3cc2c(=O)[nH]1
Temperature: 160 °C

Procedure:
A mixture of diethyl oxalate (57.2 g., 0.392 mole) and 6-fluoro-2-aminoquinoline-3-carboxamide (5.34 g., 0.0261 mole) is heated for 18 hours at 160° C. under a nitrogen atmosphere and then allowed to cool to room temperature. Hexane (300 ml.) is added, the mixture stirred and filtered to provide the desired product. It is washed with hexane and dried. yield = 4.9 g. (71%); m.p. 272° C. (dec.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:15][CH:16]([F:27])[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[OH:26]>C(#N)C>[CH2:7]([O:26][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:18]=1[O:17][CH:16]([F:15])[F:27])[CH:22]=[O:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OC(F)F)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (3.91 g, 28.3 mmol) and benzyl bromide (2.5 mL, 21.1 mmol) were added to a solution of 4-(difluoromethoxy)-3-hydroxybenzaldehyde described in Production Example 19-1 (2.66 g, 14.2 mmol) in acetonitrile (50 mL) at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and then the solvent was evaporated. The resultant residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=9:1-3:2). The target fraction was concentrated under vacuum and then the title compound was quantitatively obtained.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[N:4]([CH2:12][CH3:13])[N:3]=1.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15].C(N(CC)CC)C>O1CCCC1.[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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:12]([N:4]1[C:5]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:6][C:2]([C:15]#[C:14][Si:16]([CH3:19])([CH3:18])[CH3:17])=[N:3]1)[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: CCn1nc(Br)nc1N1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCn1nc(C#C[Si](C)(C)C)nc1N1CCCC1
Temperature: 120 °C
Yield: 47.5 %

Procedure:
A mixture of 3-bromo-1-ethyl-5-(pyrrolidin-1-yl)-1H-1,2,4-triazole (240 mg, 979 μmol, Eq: 1.00), ethynyltrimethylsilane (192 mg, 275 μl, 1.96 mmol, Eq: 2) and triethylamine (149 mg, 205 μl, 1.47 mmol, Eq: 1.5) in tetrahydrofuran (3.65 ml) was purged for 5 minutes with nitrogen. Then copper (I) iodide (1.86 mg, 9.79 μmol, Eq: 0.01), bis(triphenylphosphine)palladium(II) chloride (6.87 mg, 9.79 μmol, Eq: 0.01) and triphenylphosphine (2.57 mg, 9.79 μmol, Eq: 0.01) were added, the vessel was capped and heated to 120° C. for 1 day. Once more copper (I) iodide (1.86 mg, 9.79 μmol, Eq: 0.01), triphenylphosphine (2.57 mg, 9.79 μmol, Eq: 0.01), bis(triphenylphosphine)palladium(II) chloride (6.87 mg, 9.79 μmol, Eq: 0.01) and ethynyltrimethylsilane (192 mg, 275 μl, 1.96 mmol, Eq: 2) were added, the vial was purged with argon, capped again and stirred for one more day at 120° C. The crude material was applied on silica gel and purified by flash chromatography over a 20 g silica gel column using heptane/ethyl acetate 10-30% as eluent affording 1-ethyl-5-pyrrolidin-1-yl-3-trimethylsilanylethynyl-1H-[1,2,4]triazole (122 mg, 47.5%) as an orange oil. MS: m/z=263.4 (M+H+)
Reaction SMILES: [CH:1]([N:4]([CH:9]([CH3:11])[CH3:10])[C:5](=[O:8])[O:6][CH3:7])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]C(CC)C.[CH:25](=[O:29])[CH:26]([CH3:28])[CH3:27].Cl>C1COCC1.CCOCC>[CH:9]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:8])[O:6][CH2:7][CH:25]([OH:29])[CH:26]([CH3:28])[CH3:27])([CH3:11])[CH3:10]
Reactant: CC(C)C=O
Reactant: COC(=O)N(C(C)C)C(C)C
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)C(O)COC(=O)N(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
478 mg (3 mmol) of methyl N,N-diisopropylcarbamate are lithiated with 392 mg (3.3 mmol) of TMEDA in 4 ml of THF at -78° C. using 3.3 mmol of sec-BuLi. After 1 h, the reaction mixture is treated with 144 mg (2 mmol) of isobutyraldehyde and stirred for 21 h. The reaction mixture is then treated at -78° C. with 10 ml of 2N hydrochloric acid and 10 ml of ether and the mixture is warmed to room temperature. The phases are separated, the aqueous phase is extracted twice with ether and the combined organic phases are neutralized with saturated NaHCO3 solution. After drying over magnesium sulphate, the solvent is stripped off and the crude product of 500 mg weight is purified by chromatography on silica gel using ether/petroleum ether (1:3). 299 mg (64.6% of theory) of the title compound are obtained as a colorless liquid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl.[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[O:15])[CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Nc1cnccn1)OCC(Cl)(Cl)Cl
Reactant: Fc1cccc(-c2csc(C3CCNCC3)n2)c1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnccn1)N1CCC(c2nc(-c3cccc(F)c3)cs2)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 70.8 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyrazin-2-ylcarbamate (227 mg, 0.839 mmol), 4-[4-(3-fluorophenyl)-1,3-thiazol-2-yl]piperidine (200 mg, 0.762 mmol) and diisopropylethylamine (0.266 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 6 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and ethyl acetate to give the desired product (207 mg, 70.9%) as a solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)C(C)C)(C)C.[NH2:53][C:54]1[NH:58][N:57]=[N:56][N:55]=1>CN(C)C=O>[CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:53][C:54]2[N:55]=[N:56][NH:57][N:58]=2)=[O:28])=[CH:24][N:23]=1)[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: CC(C)CC(Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)O)cn1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CC(Nc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)Nc2nn[nH]n2)cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
To a solution of 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-ylamino)butyl)nicotinic acid (0.100 g, 0.233 mmol) in N,N-dimethylformamide (1.5 mL) was added 1,1′-carbonyldiimidazole (49.1 mg, 0.303 mmol) and N,N-diisopropylethylamine (45.2 mg, 0.350 mmol). The mixture was stirred for 30 minutes at 80° C. 5-Aminotetrazole (59.5 mg, 0.699 mmol) was then added. The resulting mixture was stirred overnight at 80° C. The reaction was concentrated and purification by preparative HPLC gave 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-ylamino)butyl)-N-(2H-tetrazol-5-yl)nicotinamide (50.0 mg, 43%) as a light yellow solid. 1H NMR (400 MHz, CD3OD, δ): 8.90 (s, 1H), 8.05-8.15 (d, 1H), 7.52-7.69 (m, 5H), 7.35-7.38 (m, 2H), 6.61-6.69 (m, 2H), 4.69 (m, 1H), 1.76-1.88 (m, 2H), 1.60-1.70 (m, 1H), 0.98-1.03 (m, 6H). MS (M+1): 496.3.
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([CH3:14])([CH3:13])[C:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=O)C.[NH:16]([C:18]1[CH:37]=[CH:36][C:21]([C:22]([NH:24][CH:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[N:28]([CH3:33])[C:27]([CH3:35])([CH3:34])[CH2:26]2)=[O:23])=[CH:20][CH:19]=1)[NH2:17]>C(O)(=O)C>[O:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:6]1[C:5]([CH3:13])([CH3:14])[C:4](=[O:15])[N:16]([C:18]2[CH:37]=[CH:36][C:21]([C:22]([NH:24][CH:25]3[CH2:26][C:27]([CH3:34])([CH3:35])[N:28]([CH3:33])[C:29]([CH3:32])([CH3:31])[CH2:30]3)=[O:23])=[CH:20][CH:19]=2)[N:17]=1
Reactant: CN1C(C)(C)CC(NC(=O)c2ccc(NN)cc2)CC1(C)C
Reactant: CCOC(=O)C(C)(C)C(=O)c1ccco1
Solvent: CC(=O)O
Product: CN1C(C)(C)CC(NC(=O)c2ccc(N3N=C(c4ccco4)C(C)(C)C3=O)cc2)CC1(C)C

Procedure:
3-Furan-2-yl-2,2-dimethyl-3-oxo-propionic acid ethyl ester (53 mg) and 4-Hydrazino-N-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-benzamide (85 mg) in 0.5 ml of acetic acid were heated up at 65° C. for 2 h. Concentration in vacuo and purification by HPLC gave the expected product (MH+: 451.4)
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[C:17]1([CH2:16][CH2:15][CH2:14][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: BrCCCc1ccccc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCc2ccccc2)cc1

Procedure:
A mixture of 33 g. of ethyl p-aminobenzoate, 19.9 g. of (3-bromopropyl)benzene and 80 ml. of hexamethylphosphoramide is heated at 110° C. for 20 hours. The mixture is chilled, diluted with 25 ml. of water, chilled, diluted with 50 ml. of ethanol and filtered. The solid is washed with cold ethanol-water (1:1) to give tan crystals, m.p. 80°-83° C. Two recrystallizations from ethanol give tan crystals, m.p. 87°-89° C.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH3:45])[CH:35]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:36]([OH:38])=[O:37])=[CH:30][CH:29]=1.[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48](O)[CH2:47]2>C1COCC1>[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH3:45])[CH:35]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:36]([O:38][C@@H:48]2[CH:49]3[CH2:52][CH2:53][N:46]([CH2:51][CH2:50]3)[CH2:47]2)=[O:37])=[CH:30][CH:29]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CN(c1ccc(F)cc1)C(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN(c1ccc(F)cc1)C(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
PS-DCC (1.02 g, 1.35 mmol, loading: 1.33 mmol/g) was suspended in dry THF (13.5 ml). HOBT (0.21 g, 1.35 mmol), 2-((4-fluorophenyl)(methyl)amino)-2-phenylacetic acid hydrochloride (I6) (0.20 g, 0.68 mmol), and (R)-quinuclidin-3-ol (0.26 g, 2.03 mmol) were added. The mixture was shaken at RT overnight. PS-DCC was removed by filtration, washed with EtOAc and THF. The solution was evaporated, and the residue was partitioned between EtOAc and water. The organic phase was washed with saturated NaHCO3, dried with Na2SO4, and evaporated. The crude was purified by flash chromatography (DCM/MeOH=95/5) to afford the title compound (209 mg, 84% yield, mixture of diastereomers).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:15][N:16]([C:23](=[O:52])[CH2:24][CH2:25][CH2:26][CH2:27][N:28]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:29](=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1.C(Cl)Cl>[CH2:8]([O:15][N:16]([C:23](=[O:52])[CH2:24][CH2:25][CH2:26][CH2:27][N:28]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:29](=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][N:34]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:1](=[O:3])[CH3:2])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#CCCCCN(OCc1ccccc1)C(=O)CCCCN(OCc1ccccc1)C(=O)CCCCNOCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(CCCCC(=O)N(CCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Acetic anhydride (8 mL) was slowly added to a solution of (8) (1.25 g, 2.03 mmol) in pyridine (50 mL) and CH2Cl2 (30 mL) which had been cooled to 0° C. Stirring was continued at 0° C. for 30 minutes and then at room temperature overnight. Solvents were removed under high vacuum, and the residue was dissolved in CHCl3 (120 mL), followed by washing with 0.5N HCl (2×40 mL) and saturated NaHCO3 (2×40 mL). After solvent removal, the crude oil was purified by silica gel column chromatography, eluting with 3:1 EtOAc/hexane, to furnish 0.8 g (60%) of (9) as an oil: NMR δ 1.40-1.80 (m, 12H), 2.05 (s, 3H), 2.20-2.50 (m, 6H), 3.40-3.73 (m, 6H), 4.75 (s, 6H), 7.32 (s, 15H). Anal. (C38H 48 N4O6) C, H, N.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH:27]([C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1)[CH2:28][N:29]1[C:34]2[CH:35]=[CH:36][NH:37][C:33]=2[C:32](=[O:38])[NH:31][C:30]1=[S:39])(C(C)(C)C)(C)C.C(OCC)(=O)C>C1COCC1>[OH:26][CH:27]([C:40]1[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=1)[CH2:28][N:29]1[C:34]2[CH:35]=[CH:36][NH:37][C:33]=2[C:32](=[O:38])[NH:31][C:30]1=[S:39]
Reactant: COc1ccc(C(Cn2c(=S)[nH]c(=O)c3[nH]ccc32)O[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(O)Cn2c(=S)[nH]c(=O)c3[nH]ccc32)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
Tetra-n-butylammonium flouride (1M in THF, 1.27 mL, 1.27 mmol) was added to 1-[2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-methoxyphenyl)ethyl]-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d]pyrimidin-4-one (0.065 g, 0.152 mmol) in THF (8 mL). The mixture was stirred at 50° C. overnight. Ethyl acetate was added, and the organic phase was washed with water and brine, dried (MgSO4), filtered and concentrated. This crude material was purified by preparative HPLC to yield the title compound (0.018 g, 37%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:17][NH:18][C:19]([NH:21][CH3:22])=[S:20].C(O)(=O)C>CC(C)=O>[ClH:1].[CH2:15]([O:14][C:12]([C:11]1[C:2]([S:20][CH:19]([NH:21][CH3:22])[NH:18][CH3:17])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:13])[CH3:16]
Reactant: CNC(=S)NC
Reactant: CCOC(=O)c1nc2ccccc2nc1Cl
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CCOC(=O)c1nc2ccccc2nc1SC(NC)NC
Product: Cl

Procedure:
2-Chloro-3-quinoxalinecarboxylic acid, ethyl ester (4.733 g., 0.02 mole) and 2.084 g., (0.02 mole) of N,N'-dimethylthiourea were dissolved in a solution of 10 ml. of acetic acid and 90 ml. of acetone. The mixture was heated at reflux for 1 hour, cooled in an icebath and filtered. The residue was washed with acetone, triturated with two portions of acetonitrile, washed with ether, and dried to give 4.70 g. of the product, m.p. 162°-163.5° (dec.)
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:11]2[C:6](=[CH:7][C:8]([C:13]([O:15][CH3:16])=[O:14])=[C:9]([F:12])[CH:10]=2)[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>ClCCl>[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH:2][C@H:3]1[C:11]2[C:6](=[CH:7][C:8]([C:13]([O:15][CH3:16])=[O:14])=[C:9]([F:12])[CH:10]=2)[CH2:5][CH2:4]1)=[O:30]
Reactant: COC(=O)c1cc2c(cc1F)[C@H](N)CC2
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc2c(cc1F)[C@H](NC(=O)c1ccccc1Cl)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-Methyl 1-amino-6-fluoro-2,3-dihydro-1H-indene-5-carboxylate hydrochloride (A-05) (0.23 g, 1.18 mmol, 1 eq) was dissolved in dichloromethane and DIPEA (2.5 eq), under nitrogen, and 2-chlorobenzoic acid chloride (0.15 ml, 1.18 mmol, 1 eq) was added at 0° C. The reaction mixture was stirred for 2 h at RT. Then the reaction mixture was concentrated and the residue was taken up in ethyl acetate, washed with 10% ammonium chloride solution and with sat. NaCl solution, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, cyclohexane:ethyl acetate 3:1) and the desired product (R)-methyl 1-(2-chlorobenzamido)-6-fluoro-2,3-dihydro-1H-indene-5-carboxylate (B-28) was thus obtained. Yield: 83%.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:6][C:5](=[O:7])/[C:4](=[CH:8]/[C:9]([O:11][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:10])/[O:3]1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:29])[O:3][C:4](=[CH:8][C:9]([OH:11])=[O:10])[C:5](=[O:7])[O:6]1
Reactant: CC1(C)OC(=O)/C(=C/C(=O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C(=CC(=O)O)O1
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
A solution of pure (Z)-2,2 dimethyl-5-(t-butyldiphenylsilyloxy-carbonylmethylene)-1,3-dioxolan-4-one (2.80 g, 6.82 mmol) in tetrahydrofuran (40 ml) was treated at 22° C. with acetic acid (2 ml) followed by 6.8 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 15 minutes at 22° C., the reaction mixture was diluted with ethyl acetate, washed with water, brine and dried (magnesium sulfate). The solvent was concentrated under reduced pressure and the residue was triturated with toluene to give 1.00 g (85% yield) of the title compound as a white crystalline material: mp 203-204° C. (dec.). IR (KBr) ν max (cm−1): 1805, 1707 and 1662. 1H NMR (400 MHz, CDCl3) δ: 1.78 (s, 6), 5.89 (s, 1). Anal. calcd for C7H8O5: C, 48.84; H, 4.68; Found: C, 48.84; H, 4.65.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:28])[C:5](=[O:27])[CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH3:26].[OH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33].N1C=CN=C1.C1CCC(N=C=NC2CCCCC2)CC1>CC(=O)OCC>[OH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([NH:1][CH2:2][CH2:3][N:4]([CH3:28])[C:5](=[O:27])[CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH3:26])=[O:33]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)N(C)CCN
Reactant: O=C(Cl)c1ccccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)N(C)CCNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.4 %

Procedure:
To a solution of (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-aminoethyl)-N-methyldocosa-4,7,10,13,16,19-hexaenamide (104 mg, 0.27 mmol), 2-hydroxybenzoyl chloride (37 mg, 0.27 mmol) and imidazole (19 mg, 0.27 mmol) in EA (4 mL) at 0° C. was added dropwise a solution of DCC (0.57 g, 0.27 mmol) in EA (4 mL). The mixture was stirred (RT, 16 h), filtered and concentrated under reduced pressure. The crude material was purified by chromatography on silica gel, eluting with EA-PE (1:3) to afford 2-hydroxy-N-(2-((4Z,7Z,10Z,13Z,16Z,19Z)—N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethyl)benzamide (100 mg, 73%) as a colorless oil. Mass calculated for C32H44N2O3=504.70. found: [M+H]+=505.5.
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1[CH:13]=[C:12]([CH3:14])[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]=1[N:15]1[C:19]([C:20]([F:23])([F:22])[F:21])=[N:18][N:17]=[C:16]1[S:24][CH2:25][C:26]([O:28]CC)=[O:27]>C1COCC1.CO.O>[CH3:3][C:4]1[CH:13]=[C:12]([CH3:14])[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]=1[N:15]1[C:19]([C:20]([F:22])([F:21])[F:23])=[N:18][N:17]=[C:16]1[S:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: CCOC(=O)CSc1nnc(C(F)(F)F)n1-c1c(C)cc(C)c2c1CCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(C)c(-n2c(SCC(=O)O)nnc2C(F)(F)F)c2c1CCCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.6 %

Procedure:
Lithium hydroxide solution (1M aqueous, 0.436 mL, 0.436 mmol) was added to a solution of ethyl 2-(4-(2,4-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)acetate (0.09 g, 0.218 mmol) in THF/methanol/water (3/3/1, 1.5 mL) and stirred for 18 h at room temperature. The crude reaction mixture was concentrated, acidified with HCl (1M aqueous, 4 mL), and extracted with ethyl acetate (2×3 mL). The combined organics extracts were concentrated to afford 2-(4-(2,4-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)acetic acid as an off-white foam (0.082 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.N1CCNCC1.C([O-])([O-])=[O:23].[K+].[K+]>CC(=O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:23])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc(C(Cl)c2ccccc2)cc1
Agent: C1CNCCN1
Agent: [K+]
Solvent: CCC(C)=O
Product: OC(c1ccccc1)c1ccc(Cl)cc1
Yield: 57 %

Procedure:
A mixture of 1-chloro-4-(chloro-phenyl-methyl)-benzene (4.12 g, 17.4 mmol) in butanone (20 ml), anhydrous piperazine (5.98 g, 69.6 mmol), anhydrous K2CO3 (2.40 g, 17.4 mmol) and KI (2.88 g, 17.4 mmol) was refluxed under nitrogen for 18 hours. The mixture was then cooled and filtered and the solvent removed in vacuo. The residue was dissolved in CH2Cl2 (100 ml) and washed with water (30 ml). Drying and removal of the solvent followed by chromatography (CH2Cl2:CH3OH:NH4OH 90:10:0.5) afforded desired product in 57% yield. D. Synthesis of 1-{4-[(4-Chloro-phenyl)-phenyl-methyl]-piperazin-1-yl}-3,3-diphenyl-propan-1-one