Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[C:2]([NH:5][CH:6]([C:12]([CH3:14])=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]>C(O)C>[C:2]([NH:5][C:6](=[C:12]([NH2:1])[CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: CCOC(=O)C(NC(C)=O)C(C)=O
Reactant: N
Solvent: CCO
Product: CCOC(=O)C(NC(C)=O)=C(C)N
Temperature: 23 °C
Reaction time: 8 h

Procedure:
A solution of 0.054 mmol of ammonia in ethanol was added dropwise to 0.054 mol of ethyl 2-acetamidoacetoacetate in 40 ml of ice cold ethanol over a period of 10 minutes. The reaction vessel was tightly capped and allowed to stir overnight at 23° C., after which the solvent was removed at reduced pressure to provide ethyl 2-acetamido-3-aminobut-2-enoate in a 3/1 ratio of two geometrical isomers.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: Fc1cccc(Br)c1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Product: N#Cc1ccccc1-c1cccc(-n2cnc(C(=O)c3cccc(F)c3)c2)c1

Procedure:
This compound is prepared by method C using compound 12d and 1-bromo-3-fluorobenzene.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[CH2:15]([O:22][CH2:23][CH2:24][CH2:25][O:26][NH2:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:15]([O:22][CH2:23][CH2:24][CH2:25][O:26][NH:27][C:2]1[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=[C:6]([Cl:11])[C:7]=1[NH:8][CH:9]=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NOCCCOCc1ccccc1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=CNc1nc(Cl)c(NC=O)c(NOCCCOCc2ccccc2)n1
Yield: 50.1 %

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (5.4 g, 23.0 mmol), 3-benzyloxyprop-1-oxyamine (4.14, 23.0 mmol), triethylamine (10 ml) and dioxan (50 ml) was stirred at reflux temperature for 3 hours, cooled, filtered and evaporated to dryness. Column chromatography on silica gel (eluted with chloroform-ethanol, 25:1) gave the title compound (4.38 g, 50%). IR: υmax (KBr) 3248, 1692, 1589, 1570, 1473, 1420 cm-1. 1H NMR: δH [(CD3)2SO] 1.88 (2H, quintet, J=6.3 Hz, CH2CH2CH2) 3.57 (2H, t, J=6.3 Hz, CH2OCH2Ph), 3.95 (2H, t, 6.3 Hz, CH2ONH), 4.47 (2H, s, CH2Ph), 7.32 (5H, m, Ph), 8.14 (1H, s, CHONH), 9.26 (1H, s, CHONH), 9.42 (1H, br.s, D2O exchangeable, NHOCH2), 10.83 (2H, br.s, 2×NHCHO).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH2:12][F:13].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][CH2:12][F:13]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: FCCOc1ccc(Cl)cc1Br
Yield: 88.8 %

Procedure:
A stirred suspension of 2-bromo-4-chlorophenol (2.07 g, 10 mmol), 1-bromo-2-fluoroethane (1.52 g, 12 mmol) and potassium carbonate (1.65 g, 12 mmol) in 2-butanone (10 mL) was heated at reflux temperature for 16 hours. The suspension was allowed to cool and then filtered. The filtrate was concentrated in vacuo and then distilled in vacuo to afford the titled compound as a colorless oil (2.25 g, 89%): bp 80-82° C. @ 0.1 torr
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.O[NH:29][C:30](=[NH:37])[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[O:12][N:37]=[C:30]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[N:29]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N=C(NO)c1ccncc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCc1nc(-c2ccncc2)no1

Procedure:
A solution of tert-butoxycarbonylaminoacetic acid (11.0 g, 5.71 mmol) and triethylamine (802 μl, 5.71 mmol) in toluene (30 ml) was cooled to 0° C. and isobutylchloroformate (740 μl, 5.71 mmol) introduced dropwise. The reaction mixture was stirred at 0° C. for 10 min and at rt for 30 min, whereupon N-hydroxyisonicotinamidine (652 mg, 4.76 mmol) and powdered 3 Å molecular sieves (4 g) were added. After heating under reflux for 12 h the reaction was cooled, filtered through celite and the solvent removed in vacuo. The residue was dissolved in EtOAc (200 ml) and washed with water (30 ml) and saturated aqueous NaHCO3 (30 ml), then dried (MgSO4). The solvent was removed and the residue purified by flash chromatography (IH-EtOAc, 2:3) to afford the title compound: RT=2.97 min; m/z (ES+)=277.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[OH:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:6]([O:5][C:3]([CH2:2][N:23]1[CH:24]=[CH:25][C:20](=[O:19])[CH:21]=[CH:22]1)=[O:4])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Oc1ccncc1
Reactant: O=C(CCl)OC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cn1ccc(=O)cc1)OC(c1ccccc1)c1ccccc1

Procedure:
The 1-benzhydryloxycarbonylmethyl-4-pyridothione represented by the formula V is produced in accordance with a method disclosed in J. Chem. Soc., p. 3610 (1958). For example, it is produced by reacting benzhydryl α-chloroacetate with 4-hydroxypyridine in a solvent of N,N-dimethylformamide in the presence of potassium carbonate at a temperature of from 40° to 80° C. to obtain 1-benzhydryloxycarbonylmethyl-4-pyridone, followed by reacting phosphorus pentasulfide with the compound thereby obtained in a solvent of tetrahydrofuran at a temperature of from 40° to 80° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8].[F:15][C:16]([F:30])([F:29])[CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:17][C:16]([F:30])([F:29])[F:15])[C:7]([O:9][CH3:10])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: COC(=O)c1ccc(O)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(F)(F)F)c(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 33.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 520 mg, 13.0 mmol) was added to a stirred, cooled (0° C.) solution of methyl 3-bromo-4-hydroxybenzoate (Description 64, 3.0 g, 13.0 mmol) in N,N'-dimethylformamide (100 ml) and the mixture was stirred at 0° C. for 15 min. 2,2,2-Trifluoroethyltosylate (6.61 g, 26.0 mmol) in N,N'-dimethylformamide (50 ml) was added and the mixture was stirred at 100° C. for 16 h. The mixture was concentrated under reduced pressure to half volume and poured into aqueous sodium hydroxide solution (1 M, 300 ml). The mixture was extracted with ethyl acetate (2×350 ml) and the combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/EtOAc to give the title compound as a colorless oil (1.37 g, 34%). 1H NMR (250 MHz, CDCl3) δ8.27 (1 H, d, J 2.1 Hz), 7.99 (1 H, dd, J 2.1, 8.6 Hz), 6.92 (1 H, d, J 8.6 Hz), 4.42-4.52 (2 H, quartet, J 7.9 Hz), and 3.91 (3 H, s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[C:11]2[C:20]3[N:16]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][N:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]=3[N:13]([CH2:31][C:32]([N:34]([CH:41]([CH3:43])[CH3:42])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:33])[C:12]2=[O:44])=[CH:2]1.C([O-])=O.[NH4+]>[Pd].CCO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[C:20]3[N:16]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][N:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]=3[N:13]([CH2:31][C:32]([N:34]([CH:41]([CH3:42])[CH3:43])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:33])[C:12]2=[O:44])=[CH:2]1
Reactant: CC(C)N(C(=O)CN1C(=O)C(=Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Temperature: 80 °C
Yield: 18.4 %

Procedure:
To 10% Pd/C and EtOH was added 2-[4-(1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide (0.71 g, 1.2 mmol). An additional 25 mL of EtOH was added followed by ammonium formate (0.77 g, 12.2 mmol). The reaction mixture was heated to 80° C. for 6 hours. The catalyst was removed by filtration through Celite® and the filtrate was concentrated. The residue was dissolved in ethyl acetate and the organic solution was washed with saturated NaHCO3. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by chromatography (0% to 18% acetone/methylene chloride) to give 128 mg of 2-[4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide as a racemic mixture. 1H NMR (CD2Cl2) δ 8.18 (s, 1H), 7.64 (dd, 2H), 7.55 (dd, 1H), 7.510-7.41 (m, 8H), 7.36 (dd, 1H), 7.25 (m, 3H), 7.09 (m, 2H), 7.027 (m, 1H), 6.85 (dd, 1H), 4.86 (m, 1H), 4.40 (br d, 1H), 4.04 (dd, 1H), 3.79 (m, 3H), 103 (dd, 6H); MS 581.4 (M+1).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@:9]2([OH:23])[CH2:14][CH2:13][N:12]([C:15](=[O:20])[C@H:16]([NH3+:19])[CH2:17][CH3:18])[CH2:11][C:10]2([CH3:22])[CH3:21])=[CH:5][CH:4]=1.Cl[C:25]([C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31])=[O:26]>C1COCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C@@:9]2([OH:23])[CH2:14][CH2:13][N:12]([C:15](=[O:20])[C@H:16]([NH:19][C:25]([C:27]3[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=3)[C:30]([O:32][CH3:33])=[O:31])=[O:26])[CH2:17][CH3:18])[CH2:11][C:10]2([CH3:22])[CH3:21])=[CH:7][CH:8]=1
Reactant: CC[C@@H]([NH3+])C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC[C@@H](NC(=O)c1cccc(C(=O)OC)c1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1

Procedure:
(R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-1-oxobutan-2-aminium chloride (52.4 mg, 0.14 mmol), methyl 3-(chlorocarbonyl)benzoate (33 mg, 0.17 mmol), THF (5 mL), and diispropylethylamine (135 mg, 1.1 mmol) were stirred overnight at rt. The reaction was concentrated and the product isolated as a white solid using preparative reverse-phase HPLC.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:12][CH2:11]2)[C:5]([C:37]#[N:38])=[C:4]([SH:39])[N:3]=1.Cl[CH2:41][C:42]1[N:43]=[C:44]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=2)[S:45][CH:46]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][CH2:18][O:19][Si:20]([C:33]([CH3:35])([CH3:36])[CH3:34])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:12][CH2:11]2)[C:5]([C:37]#[N:38])=[C:4]([S:39][CH2:41][C:42]2[N:43]=[C:44]([C:47]3[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=3)[S:45][CH:46]=2)[N:3]=1
Reactant: CC(C)(C)[Si](OCCOC1CCC(c2c(C#N)c(N)nc(S)c2C#N)CC1)(c1ccccc1)c1ccccc1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCOC1CCC(c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
300 mg (0.32 mmol) of the compound from Example 6A (isomer mixture) are dissolved in 2.4 ml of dry DMF, 95 mg (0.39 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 109 mg of sodium bicarbonate are added and the mixture is stirred at RT for 8 h. The mixture is then directly purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5), the cis/trans isomers being separated in the process.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N([CH2:20][CH3:21])CC)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.CN(C)C=O>[C:2]1([C:20]#[C:21][C:2]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH:11]=[CH:10][CH:9]=[CH:8][CH:3]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 2-bromo-5-nitrobenzoate (10 g) phenyl acetylene (4.2 ml), triethylamine (100 ml), cuprous iodide(0.4 g),dimethylformamide (200 ml) and bis-(triphenylphosphine)-palladium(II)chloride (1.35 g) was stirred at ambient temperature for 1 hour under an argon atmosphere. The solvents were removed under reduced pressure and the residue treated with 1N, hydrochloric acid (2 L) and then extracted with ethyl acetate (2×300 ml). The combined organic extracts were washed with saturated aequeous sodium bicarbonate solution (100 ml), water (3×100 ml) and brine (100 ml) filtered through phase separating paper and evaporated to dryness. The residue was purified by flash column chromatography on silica using ethyl acetate/hexane(gradient: 0 to 10%) as eluant to give methyl 2-(2-phenylethynyl)-5-nitrobenzoate (compound 76) as a yellow solid (9.98 g).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O>[CH2:6]([NH:13][CH2:3][CH:2]([F:5])[F:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: FC(F)CCl
Reactant: NCc1ccccc1
Solvent: O
Product: FC(F)CNCc1ccccc1
Yield: 48.1 %

Procedure:
An amount of 768.1 g (7.39 mol) of 2,2-difluoro-1-chloroethane and 400 g of benzylamine (3.695 mol) are heated in an autoclave at an internal temperature of 120° C. for 16 hours. Subsequently, 700 g of water are added and the aqueous phase is separated. The organic phase is distilled at standard pressure and the excess 2,2-difluoro-1-chloroethane is distilled off. Remaining traces of 2,2-difluoro-1-chloroethane are distilled off under vacuum (200 mbar). An amount of 304 g of N-benzyl-2,2-difluoroethanamine is obtained as residue with a purity of 97.2%. This corresponds to a yield of 93.4%, based on reacted benzylamine. The benzylamine hydrochloride in the aqueous phase can be rereleased by addition of sodium hydroxide solution and be used once again.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9](N)[S:10][C:6]=2[CH:5]=1)[CH2:2][CH3:3].C([CH2:16][O:17][C:18]1[C:19]([F:28])=[C:20]([C:25]([NH2:27])=[O:26])[C:21]([F:24])=[CH:22][CH:23]=1)#N>>[F:28][C:19]1[C:18]([O:17][CH2:16][C:9]2[S:10][C:6]3[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:13]=[CH:12][C:7]=3[N:8]=2)=[CH:23][CH:22]=[C:21]([F:24])[C:20]=1[C:25]([NH2:27])=[O:26]
Reactant: N#CCOc1ccc(F)c(C(N)=O)c1F
Reactant: CCCc1ccc2nc(N)sc2c1
Product: CCCc1ccc2nc(COc3ccc(F)c(C(N)=O)c3F)sc2c1
Yield: 18 %

Procedure:
Synthesised from 6-propyl-1,3-benzothiazol-2-amine and 3-(cyanomethoxy)-2,6-difluorobenzenecarboxamide, according to Method K, scheme 26. Yield 18% (second step), mp 173-175° C. HPLC-MS (method 1): m/z 363 [M+H]+, Rt=4.35 min.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[N:3]=1.Cl.[NH:22]1[CH2:27][CH2:26][CH2:25][CH:24]([NH:28][C:29]2[N:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)[CH2:23]1>>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:4]1[N:3]=[C:2]([N:22]2[CH2:27][CH2:26][CH2:25][CH:24]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]#[N:36])=[CH:33][N:34]=3)[CH2:23]2)[C:7]([C:8]#[N:9])=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1
Reactant: N#Cc1ccc(NC2CCCNC2)nc1
Reactant: N#Cc1c(C(F)(F)F)cc(-c2ccccc2Cl)nc1Cl
Agent: Cl
Product: N#Cc1ccc(NC2CCCN(c3nc(-c4ccccc4Cl)cc(C(F)(F)F)c3C#N)C2)nc1

Procedure:
Analogously to the preparation of Example 20, 60 mg (0.19 mmol) of 2-chloro-6-(2-chlorophenyl)-4-(trifluoromethyl)pyridine-3-carbonitrile and 47 mg (0.19 mmol) of 6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 10A) were used to obtain, after separation by means of preparative HPLC (method 13), 61 mg (67% of theory) of the product in solid form.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[C:17]1([S:23]([C:26]2[S:30][CH:29]=[N:28][C:27]=2[CH:31]=O)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:31][C:27]2[N:28]=[CH:29][S:30][C:26]=2[S:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:24])=[O:25])=[C:6]1[CH3:15]
Reactant: O=Cc1ncsc1S(=O)(=O)c1ccccc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Solvent: ClCCl
Product: COC(=O)Cn1c(C)c(Cc2ncsc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and 5-benzenesulfonylthiazole-4-carbaldehyde in dichloromethane.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.O[C:17]1[CH:32]=[CH:31][C:20]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:19][CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][C:17]3[CH:32]=[CH:31][C:20]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[CH:19][CH:18]=3)=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2ccc(C(=O)O)cc21
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)CCSc2ccc(C(=O)Oc3ccc(C(=O)OCc4ccccc4)cc3)cc21

Procedure:
A solution of 786 mg (3.54 mmol) of 4,4-dimethyl-6-carboxythiochroman, 804 mg (3.53 mmol) of benzyl 4-hydroxybenzoate, 800 mg (3.88 mmol) of 1, 3-dicyclohexylcarbodiimide and 60 mg (0.49 mmol) of 4-dimethylaminopyridine in 50 ml of methylene chloride was stirred at room temperature for 2 hours. The reaction mixture was then filtered and the residue washed with 20 ml of methylene chloride. The filtrate was concentrated in-vacuo and the resultant crude product was purified by flash chromatography (silica, 20% ethyl acetate in hexanes) followed by recrystallization from a mixture of hexanes and ethyl acetate to give the title compound as a white, crystalline solid. PMR (CDCl3): δ1.39 (6H, s), 1.98 (2H, m), 3.08 (2H, m), 5.37 (2H, s), 7.20 (1H, d, J~8.3 Hz), 7.28 (2H, d, J~8.0 Hz), 7.34-7.48 (5 H, m), 7.82 (1H, dd, J~8.3, 2.0 Hz), 8.14 (2H, d, J~8.0 Hz), 8.16 (1H, d, J~2.0 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])=[C:8]([CH:9]=1)[O:10][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(O)c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(OCCN2CCCC2)c1
Temperature: 70 °C

Procedure:
A flask was charged with 5-nitro-2-pentafluoroethylphenol (3.67 g, 14.2 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (9.71 g, 57.1 mmol), DMF (20 mL) and combined with K2CO3 (5.9 g, 42.1 mmol) and heated to 70° C. for 24 h. The reaction was cooled to RT, taken up in to EtOAc and washed with 2N NaOH, and brine. The organic layer was dried with MgSO4, filtered and concentrated in vacuo. The aqueous layer was acidified, extracted with EtOAc and dried with MgSO4, filtered, concentrated in vacuo and combined with the other portion. The title compound was purified by column chromatography using 0-10% MeOH in CH2Cl2.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[CH3:14][O:15][C:16](=[O:43])[C@@H:17]([O:21][C:22]1[CH:23]=[C:24]([CH:40]=[CH:41][CH:42]=1)[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[C:28]([CH3:38])=[C:27]1[CH3:39])[CH:18]([CH3:20])[CH3:19]>>[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:35]([C:31]2[CH:30]=[C:29]3[C:34](=[CH:33][CH:32]=2)[N:26]([CH2:25][C:24]2[CH:23]=[C:22]([CH:42]=[CH:41][CH:40]=2)[O:21][C@@H:17]([CH:18]([CH3:20])[CH3:19])[C:16]([O:15][CH3:14])=[O:43])[C:27]([CH3:39])=[C:28]3[CH3:38])=[O:36])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: COC(=O)[C@@H](Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1)C(C)C
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)[C@@H](Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1)C(C)C

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(3-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH2:33][CH2:34][C:35]([OH:37])=O)=[CH:20][CH:19]=3)[N:15]=2)=[CH:5][CH:4]=1.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.P(C#N)(OCC)(OCC)=O>C(N(CC)CC)C>[F:38][C:2]([F:1])([F:39])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH2:33][CH2:34][C:35]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[O:37])=[CH:22][CH:23]=3)[N:15]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: C1COCCN1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: O=C(CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1)N1CCOCC1

Procedure:
Using 3-[1-[4-[4-[(2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl)methoxy]phenyl]butyl]-1H-imidazol-2-yl]propionic acid (200 mg), morpholine (97.1 μl), diethyl cyanophosphate (84.5 μl) and triethylamine (77.6 μl), the same reaction as Example 5-(ii) was carried out to yield the titled compound (217 mg).