Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][C:15]=1[OH:16])[CH2:7][C@@H:8]([C:10]([OH:12])=[O:11])[NH2:9])([O-:3])=[O:2].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O.C(O)CCC>[OH-].[Na+]>[C:18]([NH:9][C@H:8]([C:10]([OH:12])=[O:11])[CH2:7][C:6]1[CH:13]=[CH:14][C:15]([OH:16])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:17]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N[C@@H](Cc1ccc(O)c([N+](=O)[O-])c1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c([N+](=O)[O-])c1)C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a solution of 1.36 g (6.00 mmol) of 3-nitro-L-tyrosine in 30 mL of 1N NaOH, 1.74 g (8.00 mmol) of (BOC)2O in 8 mL of tent-butanol was added. The stiffing was continued overnight and the tert-butanol was removed in vacuo. Ethyl acetate (25 mL) was added to the residual aqueous layer and the resulting solution was cooled to 0° C. A solution of 1N KHSO4 was used to acidify the solution to pH 2 and the aqueous layer was separated and extracted with 25 mL of ethyl acetate (2×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 0.265 g (13%) of the title compound as yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[C:14]([O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O.O>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([C:23]3[CH:24]=[CH:25][C:20]([C:19]([O:18][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:27])=[CH:21][CH:22]=3)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Reactant: c1cc(CN2CCNCC2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1ccc(N2CCN(Cc3ccncc3)CC2)cc1
Temperature: 130 °C
Reaction time: 21 h
Yield: 70.2 %

Procedure:
To a solution of 1-[(4-Pyridyl)methyl]piperazine (1.00 g, 5.6 mmol) in DMSO (4.5 mL) in a pressure vessel was added t-butyl-4-fluorobenzoate (1.05 g, 5.4 mmol) followed by potassium carbonate (0.74 g, 5.4 mmol). The pressure vessel was closed and the mixture was stirred at 130° C. for 21 h. The mixture was diluted with EtOAc (300 mL) and water (50 mL). The organic layer was separated, washed with a saturated NaHCO3 solution, brine, dried over MgSO4, and concentrated in vacuo. The residue obtained was purified by flash chromatography using 0-5% MeOH in DCM to afford the title compound 338 as a pink solid (1.34 g, 71% yield).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[CH3:6][CH:7]([C@H:9]([CH:11]=[CH:12][C@H:13]([C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH:23]=C(CC([O-])=O)C=[CH:26]2)=[CH:21][CH:20]=3)[CH2:17][CH2:16]1)[CH3:14])[CH3:10])[CH3:8].[C:38]([OH:41])(=O)[CH3:39]>CO.C(O)C.C(OCC)C>[CH3:8][CH:7]([C@H:9]([CH:11]=[CH:12][C@H:13]([C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22]([CH2:23][C@@H:38]([OH:41])[CH:39]=[CH:26]2)=[CH:21][CH:20]=3)[CH2:17][CH2:16]1)[CH3:14])[CH3:10])[CH3:6]
Reactant: CC(=O)O
Reactant: CC(C)[C@@H](C)C=C[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C=C(CC(=O)[O-])C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CO
Solvent: CCO
Solvent: CCOCC
Product: CC(C)[C@@H](C)C=C[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C=C[C@]4(C)[C@H]3CC[C@]12C
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Calcium chloride (15.0 g) was dissolved in methanol (150 ml) and cooled to -10° C . To a cooled solution was added dropwise while keeping at -10° C. a solution of sodium borohydride (7.5 g) in ethyl alcohol (150 ml) and the solution was stirred at the same temperature for 30 minutes. A solution of ergosta-1,3,5,7,22-pentaen-3-ylacetate (III) (5.0 g) from Example 1 in diethyl ether (100 ml) was added dropwise at a temperature between -5° and -10° C. The reaction mixture was stirred at a temperature between 0° and -5° C. for 3 hrs. and then at room temperature for 3 hrs. 50% Acetic acid was added to prepare a uniform solution and the solution was extracted with ethyl acetate. The extract was washed with water, then an aqueous sodium bicarbonate solution and dried. Ethyl acetate was concentrated and the residue was purified by silica gel chromatography (eluted with chloroform) followed by crystallization with acetone to give 4.2 g (90% yield) of ergosta-1,5,7,22-tetraen-3β-ol (I), m.p. 156°-157° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:39])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C@@H:23]([N:31]3[CH2:36][C@@H:35]([CH3:37])[NH:34][CH2:33][C@@H:32]3[CH3:38])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=3)[CH:18]=2)[CH2:12][CH2:11]1)[CH3:2].[CH:41]1([CH:44]=O)[CH2:43][CH2:42]1>>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:39])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C@@H:23]([N:31]3[CH2:36][C@@H:35]([CH3:37])[N:34]([CH2:44][CH:41]4[CH2:43][CH2:42]4)[CH2:33][C@@H:32]3[CH3:38])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=3)[CH:18]=2)[CH2:14][CH2:15]1)[CH3:2]
Reactant: CCOC(=O)CCCCCN1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)NC[C@@H]3C)c2)CC1
Reactant: O=CC1CC1
Product: CCOC(=O)CCCCCN1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(CC4CC4)C[C@@H]3C)c2)CC1
Yield: 38.3 %

Procedure:
The title compound was made by a procedure identical to that of Example 96 with 1.50 g of 6-(4-{3-[(R)-((2S,5 R)-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperazin-1-yl)-hexanoic acid ethyl ester (2.72 mmol) and 0.38 g of cyclopropanecarboxaldehyde (5.5 mmol) to give 0.63 g of desired compound as a white solid. 1H NMR (300 MHz, d6-DMSO): □ 0.02-0.03 (m, 2H); 0.38-0.41 (d, J=7.7 Hz, 2H); 0.73-0.75 (m, 1H); 0.86-0.88 (d, J=5.7 Hz, 3H); 1.08-1.10 (d, J=6.0 Hz, 3H); 1.12-1.17 (t, 3H), 1.21-1.28 (m, 2H); 1.37-1.55 (m, 4H); 1.73-1.80 (m, 1H); 2.07-2.33 (m, 8H); 2.48-2.62 (m, 5H); 2.86-2.89 (dd, 1H); 3.27-3.33 (m, 4H); 3.53-3.56 (m, 1H); 3.98-4.05 (q, 2H); 5.04 (s, 1H); 6.62-6.66 (m, 3H); 7.10-7.15 (t, 1H); 7.18-7.20 (dd, 1H); 7.32-7.40 (m, 3H); 9.34 (s, 1H). MS: 604.9 (M+1, 70%), 437.1 (50%), 209.1 (75%), 167.1 (100%). Calculated for C36H52N4O4 0.08 CH2Cl2: C, 70.85; H, 8.60; N, 9.16. Found: C, 70.89; H, 8.65; N, 8.86.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:28](O)=[O:29])[N:18]([CH3:27])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1>>[CH2:1]([NH:7][C:28]([C:17]1[N:18]([CH3:27])[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[N:16]=1)=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Cn1c(C(=O)O)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reactant: CCCCCCN
Product: CCCCCCNC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)n1C

Procedure:
Using essentially the same procedure as Example 20, Step B, but using hexylamine (0.020 mL, 0.12 mmol), 4,5-di-(4-chlorophenyl)-1-methylimidazole-2-carboxylic acid (20 mg, 0.060 mmol) from Example 20, Step A was converted to the title compound. HPLC/MS: 430 (M+1), 432 (M+3); Rt=4.91 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([O:31]C)=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN(CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
A solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(diethylamino)-3-methyl-2-oxopiperidin-3-yl)acetate (Example 429, step C) in water/methanol (1:1) was treated with lithium hydroxide (1N, 5 eq) at room temperature for 15 h. The mixture was concentrated and purified by reversed phase HPLC (Sunfire™ Prep C18 OBD 10 μm column; Waters, Milford, Mass.; 40-90% water/acetonitrile gradient with 0.1% TFA). Desired fractions were then pooled and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][C:17]#[N:18])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:19][CH2:20][CH3:21])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:22])[CH:5]=1.C(O)C.Cl.[OH-].[Na+].[Cl-].[NH4+:30]>C(Cl)(Cl)Cl.O>[ClH:1].[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][C:17](=[NH:30])[NH2:18])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:19][CH2:20][CH3:21])([CH2:10]2)[CH2:8][CH2:7][C:6](=[O:22])[CH:5]=1
Reactant: CCCC12CCC(=O)C=C1c1c(cc(CC#N)c(Cl)c1Cl)C2
Reactant: [NH4+]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: CCCC12CCC(=O)C=C1c1c(cc(CC(=N)N)c(Cl)c1Cl)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(5,6-Dichloro-2,3,9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluoren-7-yl)-acetonitrile (3.34 g, 10 mMole) is dissolved in chloroform (40 ml) and ethanol (650 mg, 10.9 mMole) and the mixture cooled to 0° C. The mixture is stirred and saturated with hydrogen chloride gas. After standing for 16 hours, the mixture is basified by the dropwise addition of 10 normal sodium hydroxide. The resultant chloroform solution of the imino ester free base is washed with water, dried over K2CO3 and the chloroform removed by evaporation in vacuo. The residue consisting of the imino ether is dissolved in ethanol (30 ml) and water (5 ml) then ammonium chloride (700 ml, 13 mMole) is added and the mixture stirred at room temperature for 4 hours. The mixture is filtered to remove the excess ammonium chloride and the filtrate evaporated in vacuo. Treatment with acetone gave the product which was recrystallized from a mixture of ethanol and diethyl ether.
Reaction SMILES: [ClH:1].N[CH2:3][CH:4]([CH3:9])[C:5]([O:7][CH3:8])=[O:6].[NH2:10][CH2:11][CH:12]1CC(C(O)=O)C1>>[ClH:1].[NH2:10][CH2:11][CH:12]1[CH2:9][CH:4]([C:5]([O:7][CH3:8])=[O:6])[CH2:3]1
Reactant: COC(=O)C(C)CN
Reactant: NCC1CC(C(=O)O)C1
Agent: Cl
Product: COC(=O)C1CC(CN)C1

Procedure:
Compound 81-B was prepared in analogy to compound W in Example 20 by using 3-(aminomethyl)cyclobutanecarboxylic acid (PharmaBlock (Nanjing) R&D Co. Ltd, CAS: 1310729-95-3) instead of DL-3-aminoisobutyric acid.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][CH2:6][C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]1)=[O:8].[Cl-].[NH4+]>CN(C)C(=O)C>[O:8]=[C:7]1[CH2:6][CH2:5][CH2:4][N:9]1[C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]1
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)CCCCl)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@H]1CC[C@H](N2CCCC2=O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sixty % sodium hydride in oil (9.60 g) is suspended in N,N-dimethyacetamide (500 ml), to this mixture is added methyl trans-4-(4-chlorobutyrylamino)-cyclohexanecarboxylate (52.32 g) obtained in Reference Example 113(2) gradually under ice-cooling. The reaction solution is warmed to room temperature, stirred for 24 hours, and thereto are poured saturated aqueous ammonium chloride solution and ice-water, and the mixture is extracted with chloroform. The organic layer is washed with saturated brine, dried over magnesium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: ethyl acetate) and the obtained solid is suspended in n-hexane-diisopropyl ether. The resulting crystals are collected by filtration and dried to give methyl trans-4-(2-oxo-pyrrolidin-1-yl)cyclohexanecarboxylate (39.20 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:8])[N:5]=[N:6][CH:7]=1.[CH3:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:8][C:4]1[N:5]=[N:6][CH:7]=[C:2]([C:11]2[CH:12]=[C:13]([NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=3)[CH:14]=[N:15][C:10]=2[CH3:9])[CH:3]=1
Reactant: Clc1cc(Br)cnn1
Reactant: Cc1ncc(NC(=O)c2cccc(C(F)(F)F)c2)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1ncc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cnnc(Cl)c1
Temperature: 108 °C

Procedure:
A mixture of 5-bromo-3-chloropyridazine (1.0 equiv.), N-(6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-3-(trifluoromethyl)benzamide (1.2 equiv.), sodium carbonate (2 M, 8 equiv.) and PdCl2(dppf) (0.5 equiv.) in DME (0.1 M) were heated to 108° C. for 13 min in the microwave. After removing the DME soluble portion and concentrating, the resulting solid was partitioned between EtOAc and water. The organic phase was washed with brine and then dried over sodium sulfate. After concentration, the crude material was purified via preparative reverse phase HPLC. Volatiles were removed by rotary evaporation and the remaining aqueous solution was basified with sodium bicarbonate. This solution was extracted with EtOAc, washed with brine and dried over sodium sulfate. The solution was concentrated and dried under vacuo to give crude N-(5-(6-chloropyridazin-4-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide and was used in the next step without further purification. LCMS (m/z) (M+H)=393.1, Rt=0.73 min.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:19]1([C:22]([NH2:30])([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)[CH3:23])[CH2:21][CH2:20]1>>[CH:19]1([C:22]([NH:30][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)[CH3:23])[CH2:21][CH2:20]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 1-Cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (CAN 1155536-64-3) as starting materials and isolated (190 mg, 27%) as alight yellow oil; MS (ESI, m/z): 411.0 (M+H+).
Reaction SMILES: [CH2:1]([C@H:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:5]([OH:7])=O)[CH2:2]C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:45][C:46]([NH2:57])=[N:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH2:55][NH2:56])[CH:50]=1.Cl.Cl.C(O)(C(F)(F)F)=O>CN(C=O)C.CO>[C:46]([NH:47][CH2:48][C:49]1[CH:50]=[C:51]([CH:52]=[CH:53][CH:54]=1)[CH2:55][NH:56][C:5](=[O:7])[C@H:4]([CH2:1][CH3:2])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[NH:57])[CH3:45]
Reactant: CCCCCC[C@@H](CCC)C(=O)O
Reactant: CC(N)=NCc1cccc(CN)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCCC[C@@H](CC)C(=O)NCc1cccc(CNC(C)=N)c1
Reaction time: 0.08 h

Procedure:
(R)-2-propyloctanoic acid (100 mg, 0.48 mmol) was dissolved in 1 mL DMF. HATU (201 mg, 0.53 mmol) and NMM (192 μL, 1.73 mmol) were added and the solution was stirred for 5 min. 1400-W (94 mg, 0.528 mmol) was added and the solution was stirred for 2 h at rt. The reaction was quenched with TFA (142 μL, 1.87 mmol) TFA and MeOH (1 mL) and purified by preparative HPLC (5% to 100%, ACN/water) to give the product (Example 6) as a white solid. 1H-NMR (500 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.22 (s, 1H), 8.76 (s, 1H), 8.37 (t, 1H), 7.34-7.37 (m, 1H), 7.22-7.29 (m, 3H), 4.47 (d, 2H), 4.42 (d, 2H), 2.18-2.24 (m, 4H), 1.46-1.50 (m, 2H), 1.20-1.31 (m, 12H), 0.84-0.87 (m, 6H). MS (ESI) 346 (M+H).
Reaction SMILES: [CH2:1]([CH:3]1[C:7](=[O:8])[C:6]([S:9]CC2C=CC=CC=2)=[C:5]([CH2:17][CH3:18])[O:4]1)[CH3:2].[Na].N>CCOCC>[CH2:1]([CH:3]1[C:7](=[O:8])[CH:6]([SH:9])[CH:5]([CH2:17][CH3:18])[O:4]1)[CH3:2]
Reactant: CCC1=C(SCc2ccccc2)C(=O)C(CC)O1
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: CCC1OC(CC)C(S)C1=O

Procedure:
A solution of 1.4 g of 2,5-diethyl-4-benzylthio-2,3-dihydrofuran-3-one in 50 ml anhydrous ether was treated with 0.88 g of sodium in liquid ammonia as described in Example A7. After working up the reaction mixture the title compound could be isolated by preparative gaschromatography. Relative retention time as compared with 43.1 minutes for dodecane was 51.9 minutes.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][CH:20]=[C:21]([C:23]([O:25]C)=[O:24])[N:22]=3)=[CH:14][C:13]=2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][CH:20]=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)=[CH:14][C:13]=2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)co3)cc2OC)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)O)co3)cc2OC)nc1Cl
Yield: 62.4 %

Procedure:
The same operation as in Example (91d) was performed using methyl 2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxyphenyl)-1,3-oxazole-4-carboxylate obtained in Example (102e) (0.26 g, 0.64 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (3 mL) and tetrahydrofuran (5 mL), to obtain 156 mg of the title compound as a colorless solid (62%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:7]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[CH2:8]>>[N:12]1[CH:13]=[CH:14][C:9]([CH2:7][CH2:8][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:10][CH:11]=1
Reactant: C=Cc1ccncc1
Reactant: C1CNCCN1
Product: c1cc(CCN2CCNCC2)ccn1
Temperature: 25 °C
Yield: 40.1 %

Procedure:
To a melt of piperazine (15 g, 0.17 mol) heated to 105° C. was added dropwise 4-vinylpyridine (1.25 mL, 0.012 mol). After refluxing the reaction for 5.5 hours, it was cooled to room temperature and chromatographed to provide 0.92 g of the title compound.
Reaction SMILES: [C:1](Br)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:45])=[C:11]([N:13]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[S:32](=[O:39])(=[O:38])[NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:22][C:21]=3[F:40])[C:15]([CH2:41][CH2:42][CH2:43][CH3:44])=[N:14]2)[CH:12]=1>CN(C1C=CN=CC=1)C>[CH2:41]([C:15]1[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32](=[O:39])(=[O:38])[NH:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:22][C:21]=2[F:40])[C:17](=[O:18])[N:13]([C:11]2[CH:12]=[C:7]([NH:6][C:1](=[O:4])[CH2:2][CH3:3])[CH:8]=[CH:9][C:10]=2[Cl:45])[N:14]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCC(=O)Br
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Agent: CN(C)c1ccncc1
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Yield: 84 %

Procedure:
Propionyl bromide was reacted with 2(5-amino-2-chlorophenyl)-5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step C) in the presence of DMAP according to the procedure of Example 69. Flash chromatography of the crude product on silica gel (gradient elution with 3:1 to 1:1 hexane-EtOAc) gave an 84% yield of the title compound as a white solid, mp 103°-105° C.; homogeneous by TLC (1:1 hexane-EtOAc); mass spectrum (FAB) m/e 648 (M+Li)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:22]([O-])=O)=[C:7]([CH:21]=1)[NH:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]2[N:14]=[C:15]([S:17][CH3:18])[O:16][C:12]=2[CH:11]=1.CC(O)=O.CO>C(Cl)Cl.[Zn]>[CH3:1][O:2][C:3]1[CH:21]=[C:7]([NH:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]3[N:14]=[C:15]([S:17][CH3:18])[O:16][C:12]=3[CH:11]=2)[C:6]([NH2:22])=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(NCc2ccc3nc(SC)oc3c2)c1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(N)c(NCc2ccc3nc(SC)oc3c2)c1
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a stirred solution of 5-methoxy-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline (1.05 g, 3.05 mmol), HOAc (3.6 mL) and methanol (3.6 mL) in DCM (40 mL) at 0° C. was added zinc dust (1.98 g, 30.5 mmol) portionwise. After stirring for 2 h, the mixture was filtered. The filtrate was washed with aq NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure to give 5-methoxy-N1-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamine as a light yellow solid (920 mg, 95.7%). 1H NMR (300 MHz, DMSO-d6) δ 7.55-7.60 (m, 2H), 7.35 (d, J=7.8 Hz, 1H), 6.47 (d, J=8.1 Hz, 1H), 5.93-5.99 (m, 2H), 5.32 (t, 1H), 4.38 (d, J=5.7 Hz, 2H), 4.13 (s, 2H), 3.50 (s, 3H), 2.74 (s, 3H). LCMS (ESI) m/z 316 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]1[N:26]=[C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[S:28][CH:29]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]1[N:26]=[C:27]([N:30]2[CH2:31][CH2:32][N:33]([C:9]([NH:8][C:5]3[O:4][N:3]=[C:2]([CH3:1])[C:6]=3[CH3:7])=[O:16])[CH2:34][CH2:35]2)[S:28][CH:29]=1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: Fc1ccc(-c2csc(N3CCNCC3)n2)c(F)c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4ccc(F)cc4F)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 15 h
Yield: 34.5 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (225 mg, 0.782 mmol), 1-[4-(2,4-difluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.711 mmol) and diisopropylethylamine (0.248 ml, 1.42 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, 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 (hexane:ethyl acetate=1:1), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 103 mg (34.4%) of the desired product as a solid. mp 166-167° C.