Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:21])=[C:16]([CH2:17][CH2:18][CH2:19][NH2:20])[C:11]=2[O:10][CH:9]1[CH2:22][CH3:23])=O)(C)(C)C.Cl.[CH2:25](Cl)Cl>O1CCOCC1>[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:21])=[C:16]([CH2:17][CH2:18][CH2:19][NH2:20])[C:11]=2[O:10][CH:9]1[CH2:22][CH3:23])(=[O:5])[CH3:25]
Reactant: CCC1Oc2c(ccc(Br)c2CCCN)N1C(=O)OC(C)(C)C
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: CCC1Oc2c(ccc(Br)c2CCCN)N1C(C)=O
Reaction time: 2 h
Yield: 40 %

Procedure:
A solution of N-t-butoxycarbonyl 7-(3-aminopropyl)-6-bromo-2-ethylbenzoxazole (30 mg, 0.078 mmol), in methylene chloride (1 mL) was treated with 4 M HCl in dioxane (1 mL) and stirred for 2 hours. The solvent was evaporated and the residue was taken up in pyridine (2 mL) and treated with acetic anhydride (100 μL). After stirring for 2 hours, the reaction was diluted with EtOAc (5 mL) and washed with saturated aqueous copper (II) sulfate (2×5 mL). The organic layer was dried with magnesium sulfate and evaporated. The product was purified on a silica gel column and eluted with 25% EtOAc/hexanes to give a clear oil (10 mg, 40%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:18]#[N:19].[NH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]([C:3]1[N:4]=[CH:5][C:6]([NH:8][CH:9]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)#[N:19]
Reactant: N#Cc1ncc(NC(CC(F)(F)F)C(N)=O)nc1Cl
Reactant: Nc1ccc2ncccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ncc(NC(CC(F)(F)F)C(N)=O)nc1Nc1ccc2ncccc2c1
Reaction time: 20 h
Yield: 5.5 %

Procedure:
A mixture of 2-(6-chloro-5-cyanopyrazin-2-ylamino)-4,4,4-trifluorobutanamide (67 mg, 0.228 mmol), 6-aminoquinoline (48 mg, 0.333 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-4,4,4-trifluorobutanamide (5 mg).
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([N+:11]([O-])=O)=[CH:5][N:4]=1)#[N:2].[Cl-].[Ca+2].[Cl-]>[Fe]>[NH2:11][C:6]1[C:7]([CH3:10])=[C:8]([CH3:9])[C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: Cc1c([N+](=O)[O-])cnc(C#N)c1C
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Product: Cc1c(N)cnc(C#N)c1C
Yield: 43.2 %

Procedure:
2-Cyano-3,4-dimethyl-5-nitropyridine (0.15 g, 0.85 mmol), calcium chloride (0.05 g, 0.42 mmol), and iron powder (0.44 g, 7.8 mmol, 325 Mesh) were reacted as described in example 772B. Purification of the crude product by silica gel chomatography using 1:1 ether/CH2Cl2 as the eluent gave compound 773B (0.054 g, 50%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]([C:16]([C:18]2[C:19]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:20]3[C:25](=[O:26])[N:24]([CH3:27])[CH2:23][CH2:22][N:21]3[C:28]=2Br)=[O:17])[NH:8][C:9]([O:11]C(C)(C)C)=O)=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+].C(OC1C(C(N(CC2C=CC(F)=CC=2)N)=O)=C(Br)N2CCN(C)C(=O)C=12)C1C=CC=CC=1.C1(C(N)C2CCCCC2)CCCCC1>ClCCl.CN(C=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:31]([O:30][C:19]1[C:18]2[C:16](=[O:17])[N:7]([CH2:6][C:5]3[CH:38]=[CH:39][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]=[C:9]([OH:11])[C:28]=2[N:21]2[CH2:22][CH2:23][N:24]([CH3:27])[C:25](=[O:26])[C:20]=12)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CN1CCn2c(Br)c(C(=O)N(Cc3ccc(F)cc3)NC(=O)OC(C)(C)C)c(OCc3ccccc3)c2C1=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN1CCn2c(Br)c(C(=O)N(N)Cc3ccc(F)cc3)c(OCc3ccccc3)c2C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCn2c(c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)nc(O)c32)C1=O
Temperature: 0 °C

Procedure:
A cold (0° C.) solution of tert-butyl 2-(4-fluorobenzyl)-2-[(8-benzyloxy-6-bromo-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)carbonyl]hydrazine-carboxylate (12.30 g, 20.45 mmol) in dichloromethane (150 mL) was saturated with anhydrous HCl gas. After stirring at 0° C. for half an hour, the mixture was treated with saturated aqueous sodium bicarbonate. The organic layer was separated, and the aqueous phase extracted with dichloromethane. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was dissolved in benzene and concentrated under vacuum. The residual white solid was used without further purification. A solution of the above 8-(benzyloxy)-6-bromo-N-(4-fluorobenzyl)-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carbohydrazide (5.20 g, 10.37 mmol) and dicyclohexylmethylamine (3.03 g, 15.53 mmol) in anhydrous DMF (100 mL) was purged with nitrogen for 10 minutes. Bis-(tri-tert-butylphosphine)palladium (0) (0.74 g, 1.45 mmol) was added and mixture was heated under an atmosphere of carbon monoxide (400 psi) in a stainless vessel in an oil bath at 90° C. overnight. The mixture was filtered through a pad of Celite. The filtrate was concentrated under vacuum to remove˜80 mL of the solvent. The residue was partitioned between dichloromethane (600 mL) and dilute aqueous HCl. The organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. As the solution was concentrated to about 20 mL, the solution was cooled in an ice-water bath. The solid precipitated was filtered, washed with cold (0° C.) dichloromethane, and dried in vacuum to provide the titled compound.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][SH:5].[H-].[Na+].Cl[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[N:11]=1>O1CCCC1>[C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([S:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[N:11]=1)#[N:17]
Reactant: N#Cc1cccc(Cl)n1
Reactant: CN(C)CCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCSc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
2-Dimethylaminoethanethiol (0.71 g, 5.0 mmol) was dissolved in tetrahydrofuran (100 ml) and added dropwise to sodium hydride (60% oil, 0.44 g, 11.0 mmol). The reaction mixture was stirred at room temperature for 1 hr. A solution of 2-chloro-6-cyanopyridine (0.70 g, 5.0 mmol) in tetrahydrofuran (10 ml) was added to the mixture, and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure to give the titled compound (0.49 g, 47%). IR (KBr): 2233, 1576, 1549, 1456, 1425, 1143, 794 cm−1. 1H-NMR (CDCl3) δ: 2.32 (6H, s), 2.63 (2H, t, J=7.0 Hz), 3.33 (2H, t, J=7.1 Hz), 7.33-7.36 (2H, m), 7.55 (1H, t, J=7.9 Hz).
Reaction SMILES: P(=O)(O)(O)O.C(OC([NH:13][CH:14]1[CH2:17][N:16]([C:18]2[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=2)[CH2:15]1)=O)(C)(C)C.O.[OH-].[Na+]>ClCCl>[NH2:13][CH:14]1[CH2:17][N:16]([C:18]2[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=2)[CH2:15]1
Reactant: CCOC(=O)c1sc(N2CC(NC(=O)OC(C)(C)C)C2)nc1C(C)C
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1sc(N2CC(N)C2)nc1C(C)C
Reaction time: 15.5 h
Yield: 75 %

Procedure:
85% phosphoric acid (0.14 mL, 1.18 mmol) was added to a solution of ethyl 2-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl}-4-isopropyl-1,3-thiazole-5-carboxylate obtained in Example (221a) (175 mg, 0.47 mmol) in dichloromethane (1 mL) at room temperature, followed by stirring for 15.5 hours. Water and a 50% aqueous sodium hydroxide solution were added to the reaction solution, and then the mixture was extracted with a chloroform/methanol mixed solvent. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. Thereafter, the solvent was evaporated under reduced pressure to obtain 95 mg of the title compound as a colorless oily substance (74%).
Reaction SMILES: [I-].[Na+].[H-].[Na+].N1(O[CH2:15][CH2:16][CH2:17][CH:18]([C:30]2[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=2)[C:19]([NH:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])C2C=CC=CC=2N=N1.O.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:26]([O:25][C:23](=[O:24])[NH:22][N:21]1[CH2:15][CH2:16][CH2:17][CH:18]([C:30]2[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=2)[C:19]1=[O:20])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NNC(=O)C(CCCOn1nnc2ccccc21)c1cc(F)c(F)c(F)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NN1CCCC(c2cc(F)c(F)c(F)c2)C1=O
Temperature: 100 °C
Reaction time: 19 h
Yield: 44.4 %

Procedure:
Sodium iodide (131 mg) and sodium hydride (containing mineral oil at 40%, 70 mg) were added to a solution of tert-butyl N′-[5-(benzotriazol-1-yloxy)-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate (420 mg) in DMF (3 mL), and the reaction solution was stirred at 100° C. for 19 hours. The reaction solution was left to cool to room temperature. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane->ethyl acetate) to obtain 134 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C@H:19]([CH3:22])[CH2:20][OH:21])[N:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(Cl)Cl.ClC(Cl)(Cl)[C:28]([N:30]=C=O)=[O:29].CO.C(=O)([O-])[O-].[K+].[K+].O>>[C:28](=[O:29])([O:21][CH2:20][C@H:19]([C:14]1[N:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:10]=2)[N:15]=1)[CH3:22])[NH2:30]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCCCCCCOc1ccc2nc([C@H](C)CO)ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCCCCCCOc1ccc2nc([C@H](C)COC(N)=O)ncc2c1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
(S)-2-(6-Heptyloxy-quinazolin-2-yl)-propan-1-ol (13, 950 mg, 0.0031 mol) was dissolved in methylene chloride (100 mL, 2 mol), followed by trichloroacetyl isocyanate (449 μL, 0.00377 mol) dropwise at 0° C. The reaction mixture was then gradually warmed up to 23° C., and stirred for additional for 1 hour. Solvent was removed under vacuum, and the residue was redissolved in methanol (100 mL, 3 mol), followed by potassium carbonate (5000 mg, 0.03 mol) and water (20 mL, 1 mol) at 0° C. The reaction mixture was then warmed up to at 23° C. and stirred for 3 hours. MeOH was removed under vacuum, and the aqueous layer was treated with DCM (10×5 mL). The combined organic layers were then washed with water and brine, and then dried over Na2SO4. The crude mixture was purified via chromatography (SiO2, 4 g, 0-100% ethyl acetate/hexanes) to give 1.05 g, (97%). 1H NMR (400 MHz, CHLOROFORM-d) δ: 9.24 (s, 1H), 7.89 (d, J=9.3 Hz, 1H), 7.53 (dd, J=9.0, 2.8 Hz, 1H), 7.11 (d, J=2.8 Hz, 1H), 4.60 (dd, J=10.5, 8.0 Hz, 1H), 4.51 (br. s., 2H), 4.45 (dd, J=10.5, 6.0 Hz, 1H), 4.09 (t, J=6.5 Hz, 2H), 3.47-3.62 (m, 1H), 1.81-1.92 (m, 2H), 1.40-1.65 (m, 11H), 0.82-0.96 (m, 3H). MS (ES, M+1): 346.30.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.CCN(CC)CC.[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O.Cl.O.P>CN(C=O)C>[C:23]([O:22][C:20]([N:7]([CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[CH2:8][C:9]([OH:11])=[O:10])=[O:19])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C(O)CNC1CCOCC1
Agent: Cl
Agent: P
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC(=O)O)C1CCOCC1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
2-(tetrahydro-2H-pyran-4-ylamino)acetic acid (0.2 g, 1.256 mmol) F44 was dissolved in DMF (22.5 mL) and Et3N (2.5 mL, 17.94 mmol). After 5 minutes BOC2O (0.583 mL, 2.51 mmol) was added and the reaction solution was heated to 60° C. for 1 h. The reaction was concentrated by reduced pressure providing a light yellow oil to which was added 20 mL HCl H2O which was adjusted to PH3 at 0° C. and stirred for 10 minutes. The reaction mixture was extracted by ethyl acetate 3×20 mL, dried (MgSO4), filtered, and concentrated to dryness. Ether was added and the mixture was sonicated and filtered providing a white solid F45 2-(tert-butoxycarbonyl(tetrahydro-2H-pyran-4-yl)amino)acetic acid (0.14 g, 0.540 mmol, 43.0% yield).
Reaction SMILES: [OH-].[CH2:2]([N+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].[P:19](=[O:23])([OH:22])([OH:21])[OH:20].C(#N)C.C1(C)C=CC=CC=1>O>[P:19]([O-:23])([O-:22])([OH:21])=[O:20].[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18].[CH2:15]([N+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: O=P(O)(O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=P([O-])([O-])O

Procedure:
Tetra-n-butylammonium hydroxide (40% aq. w/w, about 150 g) was added dropwise to a solution of phosphoric acid (85% aq, w/w, 18 g, 0.155 mmol) in water (150 mL) until the pH reached 7. Water was then evaporated in vacuo to give a syrup which was co-evaporated with dry acetonitrile (2×400 mL) followed by dry toluene (2×400 mL). The resulting white solid (75 g) was dried in vacuo and stored over phosphorus pentoxide under vacuum until used.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Cl:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26](O)=[O:27])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:25][C:26]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:27])[CH:22]=[CH:23][CH:24]=1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(O)Cc1cccc(Cl)c1
Product: O=C(Cc1cccc(Cl)c1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 39.9 %

Procedure:
Example 8 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and (3-chlorophenyl)acetic acid (0.034 g) to give thetitle compound (0.034 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl.[NH2:16][C@@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([O:25]C)=[O:24])[CH2:19][CH2:18]1.[Cl-].[Na+]>CN(C=O)C.O.C(O)(=O)C>[N:16]1([C@@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCCCCCl
Reactant: COC(=O)[C@H]1CC[C@@H](N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)[C@H]1CC[C@@H](N2CCCC2)CC1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
1,4-Dichlorobutane (2.3 ml, 21 mmol), potassium carbonate (12.6 g, 91 mmol) and potassium iodide (400 mg) are added to a solution of methyl cis-4-aminocyclo-hexanecarboxylate hydrochloride (4 g, 21 mmol) in 32 ml of DMF and the mixture is stirred at 100° C. for 6 h and then at RT for 3 d. The reaction mixture is diluted with 200 ml of water, neutralized with glacial acetic acid, saturated with sodium chloride and extracted with dichloromethane. The organic phases are dried, filtered and evaporated. Yield: 3.8 g of methyl cis-4-(pyrrolidin-1-yl)cyclohexanecarboxylate. The intermediate is then stirred, in 10 ml of methanol, with 25 ml of sodium hydroxide solution (1 N) at RT for 15 h. After the methanol has been removed in vacuo, the reaction mixture is adjusted to pH 6 with hydrochloric acid and evaporated further. The residue is taken up in methanol and purified by filtration through silica gel. Yield: 3.5 g.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][C:6]([OH:8])=O)[CH:2]=[CH2:3].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:19])=[C:14]([N:16]=[C:17]=[S:18])[CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:4]1[CH2:5][C:6](=[O:8])[N:16]([C:14]2[CH:15]=[C:10]([Cl:9])[CH:11]=[CH:12][C:13]=2[CH3:19])[C:17]1=[S:18])[CH:2]=[CH2:3]
Reactant: C=CCNCC(=O)O
Reactant: Cc1ccc(Cl)cc1N=C=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN1CC(=O)N(c2cc(Cl)ccc2C)C1=S
Yield: 15.6 %

Procedure:
A mixture of N-allyl glycine (17.4 g), 5-chloro-2-methylphenyl-isothiocyanate (20.1 g), triethylamine (20.2 g), and methylene chloride (150 mL) was heated at reflux for 2 hours. The reaction mixture was evaporated to dryness. Purification was achieved by flash chromatography on silica gel (methylene chloride). Recrystallization from Hexane-EtOAc afford the title compound (4.8 g) as yellow solid, m.p. 106°-109° C. Anal. Calcd. for. C13H13N2O Cl S: C, 55.61; H, 4.67; N, 9.98. Found: C, 55.45; H, 4.56; N, 9.72. Mass spectrum (EI, M.+) m/z 280.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([C:34]2[N:35]=[N:36][S:37][CH:38]=2)[CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:20])[CH3:21])=[O:24])=[C:28]([C:34]2[N:35]=[N:36][S:37][CH:38]=2)[CH:27]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccc(F)cc1-c1csnn1
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1-c1csnn1)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and (4-fluoro-2-(1,2,3-thiadiazol-4-yl)phenyl)methanamine. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.66 (6H, s, 2×CH3), 4.02 (4H, m, 2×CH2), 4.57 (2H, d, J=6.6 Hz, NCH2), 5.32 (2H, s, OCH2), 7.18 (1H, m, aromatic), 7.27-7.34 (4H, m, aromatics), 7.54 (2H, m, aromatics), 7.74 (1H, dd, J=6.2 Hz and J=8.6 Hz, aromatic), 8.71 (1H, s, CH), 8.80 (1H, broad t, NH). HRMS (ESI+) calculated for C26H25FN5O4S [M+H+]: 522.1611: found: 522.1601.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:8]=2[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(O)cc2)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2ccc(O)cc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 2-(4-fluoroanilino)-4-(4-hydroxyphenyl)benzoate, and it was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 55-90% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(4-fluoroanilino)-4-(4-hydroxyphenyl)benzoic acid 14 mg of pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19]C)=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.Br[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[CH3:31])[CH3:23].C(=O)([O-])[O-].[K+].[K+].[OH-].[Li+]>CN(C)C=O.O1CCCC1.O>[Cl:30][C:26]1[C:25]([CH3:31])=[C:24]([CH:22]([N:3]2[C:4]3[CH:10]=[C:9]([N:11]4[CH2:12][CH2:13][O:14][CH2:15][CH2:16]4)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:5]=3[N:6]=[C:2]2[CH3:1])[CH3:23])[CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Reactant: Cc1c(Cl)cccc1C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1C(C)n1c(C)nc2c(C(=O)O)cc(N3CCOCC3)cc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 12.01 %

Procedure:
To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (0.2 g, 0.726 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(1-bromoethyl)-3-chloro-2-methylbenzene (0.339 g, 1.453 mmol) and potassium carbonate (0.301 g, 2.179 mmol). The resulting reaction mixture was stirred for 3 h at 80° C. The solution was cooled to room temperature and poured into water and was extracted with EtOAc. The combined organic phase was washed with Brine and concentrated. The residue was purified on Biotage Isolera purification system using a Biotage 10 g SNAP silica gel cartridge and eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes. The expected compound was collected and evaporated to yield a tan solid. The tan solid was dissolved in tetrahydrofuran (THF) (10.00 mL) followed by the addition of 1M lithium hydroxide solution (10 mL, 10 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and the organic solvent was removed in vacuo. The solution was diluted with water (20 mL) and acidified with 1 N HCl. The mixture was then filtered and the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (20-50%) over 10 minutes. The appropriate fractions were collected and evaporated to yield the desired product (36.1 mg, 0.087 mmol, 12.01% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.04-2.10 (m, 6H) 2.88 (s, 3H) 2.98-3.17 (m, 4H) 3.87 (s, 4H) 5.95-6.06 (m, 1H) 6.70-6.77 (m, 1H) 7.35-7.42 (m, 1H) 7.51-7.57 (m, 1H) 7.60-7.67 (m, 1H) 7.71-7.77 (m, 1H). MS (ES+) m/e 413.8 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:11])(=[O:10])[NH2:9])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH3:17][N:18](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N>[C:17]([C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:11])(=[O:10])[NH2:9])=[CH:4][CH:3]=1)#[N:18]
Reactant: CN(C)C=O
Reactant: NS(=O)(=O)c1ccc(I)cc1
Agent: O=C([O-])O
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(S(N)(=O)=O)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
The compound 2-2 (58 mg) prepared in Step 1 was dissolved in dimethylformamide (2 ml) and to the solution were added zinc cyanide [Zn(CN)2] (58 mg) and tetrakistriphenylphosphine palladium (10 mg), followed by stirring at 80° C. for 12 hours. The resulting mixture was basified with aqueous sodium bicarbonate solution, diluted with ethyl acetate (30 ml), washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was chromatographed on silica gel column eluting with ethyl acetate/hexane (1/2) to yield the compound 2-3 (30 mg, 80%).
Reaction SMILES: C(O)CCCCC.[CH2:8]1[O:12][C:11]2[CH:13]=[C:14]([CH:17](O)[C:18]([C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)=O)[CH:15]=[CH:16][C:10]=2[O:9]1.[NH2:30][C:31]([NH2:33])=[S:32]>O>[CH2:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[N:30]=[C:31]([SH:32])[NH:33][C:18]=3[C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][O:28][C:22]=4[CH:21]=3)=[CH:13][C:11]=2[O:12]1
Reactant: O=C(c1ccc2c(c1)OCO2)C(O)c1ccc2c(c1)OCO2
Reactant: NC(N)=S
Solvent: CCCCCCO
Solvent: O
Product: Sc1nc(-c2ccc3c(c2)OCO3)c(-c2ccc3c(c2)OCO3)[nH]1
Temperature: 0 °C

Procedure:
A hexanol solution (170 ml.) of 10.9 g. (0.036 mole) of piperoin and 5.5 g. (0.072 mole) of thiourea was refluxed for 4 hours, with continuous azeotropic water removal. The mixture was cooled to 0° C. and the solid collected, washed with ether and dried. Recrystallization from dimethylformamide gave 4,5-bis(3,4-methylenedioxyphenyl)-2-mercaptoimidazole, m.p. 282°-283° C.