Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8](O)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[C:1]1([CH:7]([CH3:11])[C:8]([Cl:19])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C(O)=S)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CC(C(=S)Cl)c1ccccc1

Procedure:
In a 500 ml. three-necked reaction flask containing 45 g (247 mmol) of 2-phenylthiopropionic acid (as prepared in example 21) in 280 ml. of anhydrous benzene equipped with a magnetic stirrer, a reflux condenser connected with a wash-bottle containing H2SO4 there are added carefully by a cock-funnel with pressure compensation, 32 g (270 mmol) of thionyl chloride. The mixture is gradually heated until reflux with vigorous stirring. When gas evolution is completed, the solvent is evaporated and the residue is purified by distillation under reduced pressure (106° C/4 mm) to yield 2-phenylthiopropionic acid chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH3:9].CC1(C)C(C)(C)OB([C:18]2[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])O1.C1(C)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:18]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(Cl)ccc1Br
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1-c1ccc(Cl)cc1C
Temperature: 25 °C
Yield: 99 %

Procedure:
Under an argon atmosphere, a mixture of 2-bromo-5-chloro-toluene (20.55 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (55.23 g), toluene (200 ml), water (125 ml), tripotassium phosphate (53.07 g) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (1.633 g) was stirred with heating under reflux for 1 hr. The reaction mixture was cooled to room temperature, activated carbon (1 g) was added and the mixture was stirred for 10 min at room temperature. The insoluble material was filtered off, and the filtrate was partitioned in a separatory funnel. The organic layer was washed twice with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=98/2) to give the title compound (27.20 g, 99%).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:31][CH3:32])=[C:7]([NH:19][C:20](=[O:30])[C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)[CH:8]=[C:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CO.[Pd]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([NH:19][C:7]2[CH:8]=[C:9]([C:11]3[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]=2[O:31][CH3:32])=[O:30])=[CH:22][CH:23]=1
Reactant: COc1ncccc1-c1cc(NC(=O)c2ccc([N+](=O)[O-])cc2)c(OC)c(C(C)(C)C)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ncccc1-c1cc(NC(=O)c2ccc(N)cc2)c(OC)c(C(C)(C)C)c1

Procedure:
step 4—To a solution of 102 (0.36 g, 0.82 mmol) in EtOAc/MeOH (2:1, 15 mL) was added 10% Pd/C (0.035 g). A stream of hydrogen gas was bubbled through the solution for 20 min, and the white solid precipitate that formed was recovered by filtration to afford 4-amino-N-[3-tert-butyl-2-methoxy-5-(2-methoxypyridin-3-yl)phenyl]benzamide (104).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]1[C:23](=[O:24])[CH2:22][S:21][C:20]1=[S:25]>>[CH3:4][C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[C:22]2[S:21][C:20](=[S:25])[N:19]([CH3:18])[C:23]2=[O:24])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CN1C(=O)CSC1=S
Product: CN1C(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)SC1=S
Yield: 76 %

Procedure:
The title compound was prepared in 76% yield from 3,5-di-tert-butyl-4-hydroxybenzaldehyde and N-methylrhodanine following the procedure of Example 1, m.p. >230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].C(S)CC.Br[C:21]([F:30])([F:29])[C:22]([F:28])([Br:27])[C:23]([F:26])([F:25])[F:24]>CN(C)C=O>[Br:27][C:22]([F:28])([C:23]([F:26])([F:25])[F:24])[C:21]([F:30])([F:29])[O:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8]
Reactant: FC(F)(F)C(F)(Br)C(F)(F)Br
Reactant: Oc1c(Cl)cccc1Cl
Agent: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)C(F)(Br)C(F)(F)Oc1c(Cl)cccc1Cl
Yield: 84.2 %

Procedure:
In a manner similar to Step A of Example 1, the reaction of 16.3 g (0.10 mole) 2,6-dichlorophenol, 13.8 g (0.10 mole) potassium carbonate, 1.0 g (0.013 mole) propanethiol, 62.0 g (0.20 mole) 1,2-dibromohexafluoropropane, and 125 ml of N,N-dimethylformamide produced 33.0 g of 2-(2-bromo-1,1,2,3,3,3-hexafluoropropanoxy)-1,3-dichlorobenzene as an oil. The ir spectra was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=[C:7]([Br:16])[C:3]=1[C:4]([OH:6])=[O:5].[C:17]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[C:10]([O:11][CH3:17])=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH:8]=[C:7]([Br:16])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)c1cc(Br)c(C(=O)O)c(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(C(C)(C)C)cc(Br)c(C(=O)O)c1Br
Temperature: 60 °C
Yield: 34.8 %

Procedure:
step 4—To a solution of 122 (1.0 eq, 2.18 mmol, 767 mg) in acetone (15 mL) was added K2CO3 (3.0 eq, 6.54 mmol, 903 mg) and MeI (5.0 eq, 10.89 mmol, 680 μL). The mixture was heated at 60° C. for 2 h before it was cooled to RT and the organic volatiles were removed under reduced pressure. The residue was partitioned between in EtOAc and water. The organic layer was separated, washed with brine, dried and concentrated. The crude was purified by SiO2 chromatography eluting with a EtOAc/hexane gradient (5 to 30% EtOAc) to afford 278 mg of 2,6-dibromo-4-tert-butyl-3-methoxybenzoic acid (124).
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.[C:19]([O:23][C:24](=[O:31])[CH:25]([NH2:30])[C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:22])([CH3:21])[CH3:20]>>[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]([NH:30][CH:25]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:31])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: CC(C)(C)OC(=O)C(N)C(C)(C)C
Product: CC(C)(C)OC(=O)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-Amino-3,3-dimethyl-butyric acid tert-butyl ester (CAN 99285-38-8) as starting materials and isolated (490 mg, 92%); MS (ESI, m/z): 431.6 (M+H+).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1[S:20](=[O:28])(=[O:27])[NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25].[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH2:29]([NH:36][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1[S:20](=[O:28])(=[O:27])[NH:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)CCNS(=O)(=O)c1cc(C(=O)NC2CCc3ccccc32)ccc1F
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)CCNS(=O)(=O)c1cc(C(=O)NC2CCc3ccccc32)ccc1NCc1ccccc1
Yield: 27.2 %

Procedure:
A solution of 100 mg of 4-fluoro-N-indan-1-yl-3-(3-methylbutylsulfamoyl)benzamide (Example 41), 29 mg of benzylamine, and 100 mg of potassium carbonate in 4 ml of N,N-dimethylacetamide was heated to 100° C. for 6 h. After the addition of water, extraction with EA, and chromatographic separation, 33 mg of 4-benzylamino-N-indan-1-yl-3-(3-methylbutylsulfamoyl)benzamide were obtained.
Reaction SMILES: [F:1][C:2]([F:16])([C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[Cl-].[Cl-].[NH3+:19][C@@H:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:24][NH+:23]=1)[CH3:21].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:16][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)([F:1])[C:3](=[O:5])[NH:19][C@@H:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:31])[F:32])=[CH:24][N:23]=1)[CH3:21]
Reactant: COC(=O)c1ccc(C(F)(F)C(=O)O)cc1
Reactant: C[C@@H]([NH3+])c1ccc(OCC(F)(F)F)c[nH+]1
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)c1ccc(C(F)(F)C(=O)N[C@H](C)c2ccc(OCC(F)(F)F)cn2)cc1
Reaction time: 24 h
Yield: 65.2 %

Procedure:
To a solution of 0.400 g (1.72 mmol) difluoro[4-(methoxycarbonyl)phenyl]acetic acid in 3.50 ml CH2Cl2 was added 0.560 g (1.90 mmol) 2-[(1R)-1-ammonioethyl]-5-(2,2,2-trifluoroethoxy)pyridinium dichloride, 0.308 g (2.26 mmol) HOAT, 0.433 g (2.26 mmol) EDC, and 0.91 mL (5.21 mmol) DIEA. After 24.0 h at room temperature, the reaction mixture was diluted with CH2Cl2, washed three times with water, and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 0-30% EtOAc:hexane) afforded 0.485 g (65%) Methyl 4-[1,1-difluoro-2-oxo-2-({(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}amino)ethyl]-benzoate. 1H NMR (CDCl3, 400 MHz) 8.32 (d, 1H, J=2.84 Hz); 8.10 (d, 2H, J=8.05 Hz); 7.93 (br d, 1H, J=5.95 Hz); 7.71 (d, 2H, J=8.25 Hz); 7.28 (d, 1H, J=2.75 Hz); 7.23 (d, 1H, J=17.12 Hz); 5.19 (m, 1H); 4.41 (q, 2H, J=7.87 Hz); 3.93 (d, 3H, J=0.55 Hz); 1.49 (d, 3H, J=6.68). ESMS+1 for C19H17F5N2O4: 433.1.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]3[CH:17]=[CH:16][N:15]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[C:11]=3[N:12]=[CH:13][N:14]=2)[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH:1]1([C:7]([C:9]2[C:10]3[CH:17]=[CH:16][N:15]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:25]([CH3:27])[CH3:26])[CH:19]([CH3:20])[CH3:21])[C:11]=3[N:12]=[CH:13][N:14]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C3CCCCC3)ncnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(=O)C3CCCCC3)ncnc21
Yield: 56.2 %

Procedure:
Cyclohexyl[7-(triisopropylsilyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]methanol (211 mg, 0.540 mmol) in dichloromethane (7 mL) was stirred with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (347 mg, 0.820 mmol) at room temperature for 2.5 hours. After addition of a mixture (1/1 (v/v)) of saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium thiosulfate, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=30/1 (v/v)) to give the title compound as a colorless solid (117 mg, yield 55%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]1[N:32]=[N:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=1.CO>CC#N>[F:40][C:37]([F:38])([F:39])[C:34]1[N:33]=[N:32][C:31]([CH2:30][NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH:9]3[N:19]4[C:20]5[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=5[N:16]=[CH:17][C:18]4=[O:21])[CH2:10]3)[CH2:4][CH2:3]2)=[CH:36][CH:35]=1
Reactant: NC1CCN(CC2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Reactant: FC(F)(F)c1ccc(CBr)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: O=c1ccc2ncc(=O)n3c2n1CC3CN1CCC(NCc2ccc(C(F)(F)F)nn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A mixture of 2-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (for a synthesis see Example 2(j)) (56.3 mg, 0.187 mmol), K2CO3 (34.4 mg, 0.249 mmol) and 3-(bromomethyl)-6-(trifluoromethyl)pyridazine (for a synthesis see Preparation 1 below) (30 mg, 0.124 mmol) in CH3CN (1 ml) and MeOH (0.1 ml) was stirred at room temperature overnight. LCMS showed amine derivative remaining. An excess of 3-(bromomethyl)-6-(trifluoromethyl)pyridazine (25 mg) was added. The mixture was stirred at room temperature for 1 h. The solid was filtered off and the solvent evaporated. Purification by flash chromatography using Flashmaster II and mixtures of DCM and MeOH as eluent afforded 2-{[4-({[6-(trifluoromethyl)-3-pyridazinyl]methyl}amino)-1-piperidinyl]methyl}-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (17 mg, 30%).
Reaction SMILES: [Si]([O:18][CH:19]([C:21]1[N:25]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[O:23][N:22]=1)[CH3:20])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.F.C([O-])(O)=O.[Na+]>C1COCC1.N1C=CC=CC=1>[OH:18][CH:19]([C:21]1[N:25]=[C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[O:23][N:22]=1)[CH3:20]
Reactant: CCOC(=O)c1nc(C(C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)no1
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C(C)O)no1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Ethyl 3-(1-((tert-butyldiphenylsilyl)oxy)ethyl)-1,2,4-oxadiazole-5-carboxylate (5.90 mmol, 2.5 g) was dissolved in THF and cooled to 0° C. with an ice bath. 70% Hydrogen fluoride in pyridine (1.5 ml) was added slowly. After addition, the reaction mixture was stirred at ambient temperature for overnight. The reaction mixture was basified by aqueous NaHCO3 solution and extracted with DCM. The organic layers were washed with water, dried, filtered and evaporated. The product was purified by flash-chromatography. Yield 897 mg. 1H-NMR (400 MHz; CDCl3): δ 1.46 (t, 3H), 1.66 (d, 3H), 4.53 (q, 2H), 5.11 (q, 1H).
Reaction SMILES: C([O:5][C:6](=[O:45])[CH2:7][O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)=[CH:13][C:12]([C:22](=[O:37])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:11][C:10]=1[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[CH:39]=1)(C)(C)C>C(O)=O>[CH3:21][C:17]1[CH:16]=[C:15]([C:14]2[CH:13]=[C:12]([C:22](=[O:37])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:11]=[C:10]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[CH:39]=3)[C:9]=2[O:8][CH2:7][C:6]([OH:45])=[O:5])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(-c2cc(C(=O)NCCCCCCCc3ccccc3)cc(-c3cccc(C)c3)c2OCC(=O)OC(C)(C)C)c1
Solvent: O=CO
Product: Cc1cccc(-c2cc(C(=O)NCCCCCCCc3ccccc3)cc(-c3cccc(C)c3)c2OCC(=O)O)c1
Yield: 99.4 %

Procedure:
A solution of [3,3″-Dimethyl-5′-(7-phenyl-heptylcarbamoyl) [1,1′:3′,1″]terphenyl-2′-yloxy]acetic acid tert-butyl ester (180 mg, 0.311 mmol) in 3.5 mL HCOOH was stirred at room temperature until all of the ester was consumed by TLC (1:1 EtOAc:Hexanes). The excess HCOOH was removed in vacuo (first on a rotoevaporator then pumping under high vacuum) then crystallized from CH2Cl2/Hexanes to yield 170 mg, 100% of the acid as a yellow foam. mp 58-62 ° C.; 1H NMR (DMSO-d6) δ 1.21-1.28 (m, 6H); 1.44-1.57 (m, 4H); 2.35 (s, 6H); 2.53 (t, J=7.69 Hz, 2H); 3.23 (quartet, J=6.37 Hz, 2H); 3.82 (s, 2H); 7.10-7.24 (m, 7H); 7.30-7.41 (m, 6H); 7.80 (s, 2H); 8.51 (t, J=5.49 Hz, 1H); 12.60 (bs, 1H); IR 3375, 3025, 2925, 2865, 1730, 1630, 1600, 1550, 1450, 1350, 1210, 1195, 1080, and 700cm−1; mass spectrum [(−)ESI], m/z 548 [M−H]−; Anal Calcd. for C36H39NO4: C, 78.66; H, 7.15; N, 2.55; Found: C, 77.39; H, 7.42; N, 2.37.
Reaction SMILES: [C:1](#[N:5])/[CH:2]=[CH:3]/[CH3:4].[NH:6]1[CH:10]=[CH:9][N:8]=[CH:7]1>>[N:6]1([CH:3]([CH3:4])[CH2:2][CH2:1][NH2:5])[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: C/C=C/C#N
Reactant: c1c[nH]cn1
Product: CC(CCN)n1ccnc1

Procedure:
When crotononitrile is reacted with imidazole by the procedure of Example 113, 3-(1H-imidazol-1-yl)butanamine is obtained as an oil. By reaction of this diamine with the appropriate benzoyl chloride by the procedure of Example 27, the products set forth in Table XVIII below are obtained.
Reaction SMILES: [C:1]([C:3]1[N:7]2[C@@H:8]([CH3:15])[CH2:9][N:10]([CH2:13][CH3:14])[C:11](=[O:12])[C:6]2=[C:5]([O:16][CH3:17])[C:4]=1[C:18]([O:20]CC)=O)#[N:2].[NH2:23][NH2:24]>C(O)C.C(O)(=O)C>[NH2:2][C:1]1[C:3]2[N:7]3[C@@H:8]([CH3:15])[CH2:9][N:10]([CH2:13][CH3:14])[C:11](=[O:12])[C:6]3=[C:5]([O:16][CH3:17])[C:4]=2[C:18](=[O:20])[NH:24][N:23]=1
Reactant: CCOC(=O)c1c(OC)c2n(c1C#N)[C@@H](C)CN(CC)C2=O
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Product: CCN1C[C@H](C)n2c(c(OC)c3c(=O)[nH]nc(N)c32)C1=O
Temperature: 110 °C

Procedure:
A solution of ethyl (4S)-6-cyano-2-ethyl-8-methoxy-4-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-carboxylate (1.10 g, 3.60 mmol) in absolute ethanol (25 mL) was purged with argon gas for 15 minutes. The mixture was treated with hydrazine (1.16 g, 36.02 mmol) and 20 drops glacial acetic acid, and heated in a sealed tube in an oil bath at 110° C. overnight. The product mixture was cooled to 0° C. The solid precipitated collected by filtration, washed with cold ethanol and diethyl ether to afford the title compound. The filtrate was concentrated under vacuum, and the residue was subjected to preparative high pressure reverse phase column chromatography. Collection and lyophilization of appropriate fractions provided additional product, which was concentrated from its solution in acetonitrile and anhydrous DMF prior to the following benzylation. ES MS M+1=292.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][C:10]([OH:12])=O)=[O:6])[CH3:3].[F:23][C:24]([F:35])([F:34])[C:25]1[N:29]2[CH2:30][CH2:31][NH:32][CH2:33][C:28]2=[N:27][N:26]=1>>[CH3:22][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][C:10]([N:32]1[CH2:31][CH2:30][N:29]2[C:25]([C:24]([F:35])([F:23])[F:34])=[N:26][N:27]=[C:28]2[CH2:33]1)=[O:12])=[O:6])[CH3:3]
Reactant: FC(F)(F)c1nnc2n1CCNC2
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)ccc1F
Yield: 48.7 %

Procedure:
The title compound was prepared from (3R)-3-[(1,1-dimethylethoxycarbonyl)-amino](2,5-difluorophenyl)butanoic acid (Intermediate 1, 50 mg, 0.16 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-α]pyrazine (30 mg, 0.16 mmol) using a procedure analogous to that described for Example 1, Step C. The crude product was purified by preparative TLC (silica gel, 100% ethyl acetate, then 10% methanol/dichloromethane (2×)) to afford the title compound (38.1 mg) as a solid. 1H NMR (500 MHz, CDCl3) δ 1.38 (s, 9H), 2.57˜3.05 (m, 4H),3.85˜4.30 (m, 5H), 4.90 (s, 1H), 4.95˜5.15 (m, 1H), 5.22˜5.40 (br, 1H), 6.86˜7.24 (m, 3). LC/MS (M+1-t-Boc) 390.
Reaction SMILES: [C:1]1([S:7]([NH:10][NH:11][C:12](=[O:29])[C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH:21]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[OH:22])=[CH:15][CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>CC#N.O>[C:1]1([S:7]([NH:10][NH:11][C:12](=[O:29])[C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH:21]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[OH:22])=[CH:17][CH:18]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NNS(=O)(=O)c1ccccc1)c1ccc(C#CC(O)C2CCCCC2)cc1
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NNS(=O)(=O)c1ccccc1)c1ccc(CCC(O)C2CCCCC2)cc1

Procedure:
Example 36 was synthesized in accordance with the methods of Example 33, except that 4-(3-cyclohexyl-3-hydroxy-1-propynyl)-benzoic acid, 2-(phenylsulfonyl)hydrazide (Example 35) was used instead of 4phenacetylenyl-benzoic acid, 2-(phenylsulfonyl)hydrazide. MS: 403 (M+1 for C21H26N2O4S1); mp 158-159° C.; TLC (SiO2) Rf=0.3 (50% EtOAc/hexanes); HPLC (C18 column, 7:3 CH3CN/H2O+0.1%TFA) 95%, RT=5.0 min. 1H NMR (DMSO-d6) δ 1.10-1.65 (m, 12H), 2.46-2.61 (m, 2H), 4.00 (s, 1H), 7.20 (d, 2 H, J=8.1 Hz), 7.46-7.57 (m, 5H), 7.78 (d, 2H, J=7.3 Hz), 9.93 (s, 1H, 10.56 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si](C)(C)C)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:11]([C:8]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([CH:7]=1)[C:4]([NH2:6])=[O:5])#[CH:12]
Reactant: Cc1ccc(C#C[Si](C)(C)C)cc1C(N)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(C)c(C(N)=O)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
To a solution of 2-methyl-5-((trimethylsilyl)ethynyl)benzamide (I70) (0.190 g, 0.819 mmol) in THF (4 mL) at 0° C. was added 1.0 M solution TBAF in THF (0.5 mL). The mixture was then stirred under N2 at 0° C. for 10 minutes and then at room temperature for 3 hours. The resulting mixture was concentrated under reduced pressure then diluted with water. The resulting precipitate was collected by vacuum filtration to give the title compound (I71) (0.087 g, 67%); 1H NMR (400 MHz, d6-DMSO) δ 7.80 (s, 1H), 7.41 (m, 3H), 7.25 (d, J=7.7 Hz, 1H), 4.17 (s, 1H), 2.36 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([CH2:13]/[C:14](/[CH3:23])=[CH:15]/[CH2:16][CH2:17]/[C:18](/[CH3:22])=[CH:19]/[CH2:20][OH:21])/[CH:4]=[C:5](/[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])\[CH3:6].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]=[C:31]=[S:32])[CH:25]=1>C1COCC1>[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31](=[S:32])[O:21][CH2:20]/[CH:19]=[C:18](\[CH3:22])/[CH2:17][CH2:16]/[CH:15]=[C:14](\[CH3:23])/[CH2:13][CH2:3]/[CH:4]=[C:5](\[CH3:6])/[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH:25]=1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Reactant: S=C=Nc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/COC(=S)Nc1cccnc1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a solution of NaH (60% dispersed in oil, 32 mg, 0.81 mmo) in THF (4 mL) at 0° C. was added alcohol 1 (180 mg, 0.62 mmol) in THF (1 mL) and the reaction mixture was stirred for 30 min at this temperature. Then 3-pyridyl isothiocyanate (169 mg, 124 mmol) in THF (1 mL) was added and stirred at rt. After stirring for 12 h, the reaction mixture was quenched water and extracted with EtOAc (3×). The organic layer was dried and concentrated to get a residue, which was purified by column chromatography (Hexane/EtOAc) to yield thiocarbamate 38a as a viscous liquid (179 mg, 70%). TLC Rf: 0.23 (20% EtOAc/hexanes); 1H NMR (300 MHz, CDCl3): δ 8.55 (d, 1H), 8.40 (d, 1H), 7.95 (m, 1H), 7.30 (m, 2H), 5.49 (t, 1H), 5.11 (m, 3H), 4.70 (d, 2H), 2.16-1.19 (m, 12H), 1.76 (s, 3H), 1.68 (s, 3H), 1.60 (s, 9H); LCMS: MS (m/z): 427 (M+H).