Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:30][CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=1[Cl:26])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: NCc1ccccc1Cl
Solvent: c1ccccc1
Product: O=C(NCc1ccccc1Cl)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (0.500 g, 1.37 mmol), 2-chlorobenzylamine (0.240 g, 1.69 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-chlorobenzyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.590 g, 85.4% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:17][CH2:16][C:9]2([O:13][CH:12]([CH3:14])[C:11](=O)[CH2:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.Cl.[NH2:26][OH:27]>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:17][CH2:16][C:9]2([O:13][CH:12]([CH3:14])[C:11](=[N:26][OH:27])[CH2:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC2(CC1)CC(=O)C(C)O2
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC2(CC1)CC(=NO)C(C)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-Ethoxycarbonyl-2-methyl-1-oxa-8-azaspiro [4.5 ]decan-3-one (20 g, 0.083 mol) was dissolved in absolute ethanol (1 L) and combined with triethylamine (11.5 ml) and hydroxylamine hydrochloride (5.7 g). The mixture was stirred at room temperature overnight. The ethanol was evaporated in vacuo and the residue was stirred with ether. The insoluble solids were filtered and the ether filtrate was evaporated. The residual oxime was purified by chomatography on silica gel and elution with ammoniated 2-10% MeOH/CHCl3. Evaporation of the solvents afforded the oxime, 11.5 g.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:10]=[C:11]1[N:16]2[CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH:15]2[CH2:14][NH:13][CH2:12]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]1([C:7]([N:13]2[CH2:12][C:11](=[O:10])[N:16]3[CH2:17][CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH:15]3[CH2:14]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: O=C1CNCC2c3ccccc3CCCN12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(C1CCCCC1)N1CC(=O)N2CCCc3ccccc3C2C1
Temperature: 0 °C
Reaction time: 5 h
Yield: 63.6 %

Procedure:
Cyclohexanoyl chloride (0.34 g) was added to a solution of 4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepine (0.5 g) in chloroform (20 ml, ethanol-free) maintained at 0° C. and triethylamine (0.26 g) added. The mixture was maintained at 0° C. for 30 min then at room temperature for 5 h. The solution was washed with, first, dilute hydrochloric acid and secondly with sodium bicarbonate solution. The chloroform solution was dried (MgSO4) and evaporated. The residue was recrystallised from chloroform/40°-60° C. petroleum ether to give white crystals of the title compound (0.48 g, 64%) m.p. 187°-90° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:32])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:30][CH3:31])=[C:17]([CH2:20][N:21]([CH3:29])[C:22]4([C:26]([NH2:28])=[O:27])[CH2:25][NH:24][CH2:23]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:33][C:34]([CH3:36])=O>>[Cl:2][C:3]1[C:4]([F:32])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:30][CH3:31])=[C:17]([CH2:20][N:21]([CH3:29])[C:22]4([C:26]([NH2:28])=[O:27])[CH2:25][N:24]([CH:34]([CH3:36])[CH3:33])[CH2:23]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CNC1
Agent: Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CN(C(C)C)C1
Yield: 50 %

Procedure:
3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]azetidine-3-carboxamide hydrochloride salt Example 74 was coupled with acetone using the same method as for the equivalent step in Example 76 to give the title product (50 mg, 50%) as a white powder; 1H NMR Spectrum: (CDCl3) 0.95 (d, 6H), 2.42 (s, 3H), 2.49 (brs, 1H), 3.24 (brs, 2H), 3.63 (d, 2H), 3.97 (m, 5H), 5.32 (brs, 1H), 7.14 (m, 2H), 7.24 (s, 1H), 7.65 (brs, 1H), 7.75 (brs, 1H), 7.99 (s, 1H), 8.54 (brs, 1H), 8.73 (s, 1H); Mass Spectrum: (M+H)+ 487.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[N:22][C:17]=1[NH:15][CH:9]1[C:10]2[NH:11][C:12]3[C:4](=[CH:3][CH:2]=[CH:14][CH:13]=3)[C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: Clc1ncccn1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: c1cnc(NC2CCCc3c2[nH]c2ccccc32)nc1

Procedure:
N-Pyrimidin-2-yl-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (150 mg, 0.81 mmol) and 2-chloropyrimidine (184 mg, 1.62 mmol) in a similar manner as described in Example 22 to give 16 mg (8%) of a yellow solid. 1H-NMR (DMSO-d6): δ 10.63 (s, 1H), 8.32 (d, 2H), 7.43 (d, 1H), 7.36 (d, 1H), 7.25 (d, 1H), 7.01-6.97 (m, 1H), 6.93-6.89 (m, 1H), 6.60 (t, 1H), 5.32-5.28 (m, 1H), 2.68-2.57 (m, 2H), 2.041.97 (m, 2H), 1.87-1.75 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][NH2:8])[CH2:3][CH2:2]1.[C:9]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=O)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C(O)C>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][C:19](=[N:8][O:7][CH:4]2[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]2)[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: NOC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(=NOC2CCNCC2)CC1
Temperature: 70 °C

Procedure:
1.16 g (10 mmol) of crude 70b in 20 mL of ethanol was treated with boc-piperidinone (1.99 g, 10 mmol) and NaOAc.3H2O (2.04 g, 15 mmol). The reaction was heated up to 70° C. overnight. The ethanol was evaporated to 3 mL and the solution was diluted with water and a fine precipitate was filtered. The solid was dissolved in DCM, dried and concentrated to give 0.65 g of solid. The filtrate was extracted with ethyl acetate 3 times, dried and combined with the solid to give 1.1 g of crude 70c.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](O)=[O:31]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[O:31])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(O)c1ccccn1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1ccccn1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and pyridine-2-carboxylic acid to yield (3aR,4S,7aR)-4-(pyridine-2-carbonyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=296 (ester eliminated ion); RT=3.433 min; HPLC Method III
Reaction SMILES: C([N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]=[C:9]1[C:15]1[C:16]([CH:26]2[CH2:28][CH2:27]2)=[CH:17][C:18]([CH3:25])=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21])C1C=CC=CC=1.Cl.[H][H]>[Pd].CO>[CH:26]1([C:16]2[C:15]([C:9]3[NH:8][C:12]([O:13][CH3:14])=[N:11][N:10]=3)=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:25])[CH:17]=2)[CH2:28][CH2:27]1
Reactant: COC(=O)c1cc(-c2nnc(OC)n2Cc2ccccc2)c(C2CC2)cc1C
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(-c2nnc(OC)[nH]2)c(C2CC2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
A flask containing methyl 5-(4-benzyl-5-methoxy-4H-1,2,4-triazol-3-yl)-4-cyclopropyl-2-methylbenzoate (compound 91.4, 0.55 g, 1.46 mmol) and Pd/C (10%, 0.25 g) was purged with nitrogen, then MeOH (10 mL) and HCl (4 M in dioxane, 37 μL, 0.15 mmol) were carefully added. The system was then charged with hydrogen and the mixture was stirred at room temperature for 3 hours. Upon completion, the system was purged with nitrogen, then the mixture was neutralized with a few drops of NH4OH and filtered through Celite®. The filtrate was concentrated under reduced pressure and the residue was purified using prep-TLC (hexanes:EtOAc 1:1) to yield 0.3 g (71%) of the title compound as a clear oil. m/z (ES+) 288 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8](=[O:17])[NH:9][CH:10]1[CH2:15][CH2:14][CH:13](C)[CH2:12][CH2:11]1)=[O:4].[OH-].[Na+].CO.O1CCOC[CH2:23]1>>[CH3:23][C@@H:15]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:9][C:8]([C@@H:6]1[CH2:7][C@H:5]1[C:3]([OH:2])=[O:4])=[O:17]
Reactant: COC(=O)[C@@H]1C[C@H]1C(=O)NC1CCC(C)CC1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CCCC[C@H]1NC(=O)[C@@H]1C[C@H]1C(=O)O
Yield: 87 %

Procedure:
Stir a solution of trans-2-(4-methyl-cyclohexylcarbamoyl)-cyclopropane-carboxylic acid monomethyl ester (Example 11a) (4.5 g, 19.8 mmol), 5N NaOH (40 mL) and MeOH/dioxane overnight. Concentrate the reaction mixture under vacuum, cool the resulting solution and acidify to pH 5. Collect the precipitate, wash (H2O) and dry under vacuum at 40° C. to obtain 3.7 g (87%) of solid.
Reaction SMILES: O=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[N:10]2[C:6](=[N:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[S:5][N:4]=1.N1C=CC=CC=1.Cl.[NH2:28][OH:29]>C(O)C>[OH:29][N:28]=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[N:10]2[C:6](=[N:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[S:5][N:4]=1
Reactant: NO
Reactant: O=C(c1ccccc1)c1nsc2nc3ccccc3n12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C(c1ccccc1)c1nsc2nc3ccccc3n12
Yield: 89.2 %

Procedure:
To a solution of 0.5 g (1.79 mmol) of 3-(oxophenylmethyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole in 7 mL of ethanol was added 0.5 mL (6.46 mmol) of pyridine and 0.5 g (7.20 mmol) of hydroxylamine hydrochloride. The mixture was refluxed for overnight. The precipitate was collected by filtration, and washed with methanol and dichloromethane to give the crude product, which was recrystallized from methanol to yield 0.47 g (89%) of the title compound as white crystals. mp 247° C.; 1H NMR (DMSO-d6) δ11.89 (s, 1H), 7.81 (d, 1H), 7.73 (dd, 2H), 7.45-7.53 (m, 5H), 7.32 (t, 1H) ppm; 13C NMR (CDCl3) δ168.25, 155.24, 150.52, 147.95, 136.94, 135.67, 134.30(2C), 133.03, 131.52(2C), 130.35, 127.26, 124.28, 116.91 ppm; IR (KBr) δ2731, 1549, 1475, 1450, 1251, 1194, 983, 753, 736 cm-1. HRMS calcd for C15H10N4OS 294.0575, found 294.0583.
Reaction SMILES: C(N1C=C([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)C=N1)C.Br[C:18]1[CH:19]=[N:20][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH:22]=1>>[CH3:15][C:10]1([CH3:16])[C:11]([CH3:14])([CH3:13])[O:12][B:8]([C:18]2[CH:19]=[N:20][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH:22]=2)[O:9]1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: FC(F)(F)Cn1cc(Br)cn1
Product: CC1(C)OB(c2cnn(CC(F)(F)F)c2)OC1(C)C

Procedure:
The title compound was prepared in the same manner as 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole starting with 4-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazole.
Reaction SMILES: [Br:1][CH:2]([Br:16])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[CH3:17][Si:18]([CH3:22])([CH3:21])[CH2:19][NH2:20].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(OC)(C)(C)C>[Br:1][CH:2]([Br:16])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:20][CH2:19][Si:18]([CH3:22])([CH3:21])[CH3:17])=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]
Reactant: C[Si](C)(C)CN
Reactant: O=C(O)c1ccc(C(Br)Br)c(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CNC(=O)c1ccc(C(Br)Br)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
4-(dibromomethyl)-3-(trifluoromethyl)benzoic acid (18.0 g, 49.7 mmol) was suspended in CH2Cl2. 1-(Trimethylsilyl)methanamine (5.1 g, 49.7 mmol) and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.5 g, 54.7 mmol) were added to the solution at 0° C. The reaction mixture was stirred at room temperature over night. The reaction mixture was diluted with t-BuOMe and washed with 2M HCl, H2O, and brine. After drying over MgSO4 and evaporation, the product was found to be 22.0 g (99%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.FC(F)(F)S([O-])(=O)=O.[N:17]1([S:22](N2C=C[NH+](C)C2)(=[O:24])=[O:23])[CH:21]=[CH:20][N:19]=[CH:18]1>>[N:17]1([S:22]([N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]2)(=[O:24])=[O:23])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: OCC1CCNCC1
Reactant: C[NH+]1C=CN(S(=O)(=O)n2ccnc2)C1
Agent: O=S(=O)([O-])C(F)(F)F
Product: O=S(=O)(N1CCC(CO)CC1)n1ccnc1

Procedure:
[1-(Imidazole-1-sulfonyl)-piperidin-4-yl]-methanol was prepared in accordance with step A of the general method described in example 76 from 4-(hydroxymethyl)-piperidine and 3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium trifluoromethanesulfonate; MS: m/e=246.5 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:14]([C:16]([O:20]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6]([C:16]([NH2:14])=[O:20])=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: c1ccc(-c2ccccc2)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1-c1ccccc1
Reaction time: 2 h
Yield: 45 %

Procedure:
Biphenyl acid 50 (40 mg, 0.064 mmol, 1 eq) and HBTU (49 mg, 0.13 mmol, 2 eq) were dissolved in DMF (1 mL) followed by the addition of amine (S)—N1,N1-dimethyl-3-phenylpropane-1,2-diamine (23 mg, 0.13 mmol, 2 eq). The reaction mixture was stirred for 2 h, diluted with EtOAc and quenched with a saturated aqueous NaHCO3 solution. The reaction mixture was extracted with EtOAc (3×100 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford an oil. The crude oil was purified by silica gel chromatography (2-5% MeOH/DCM) to afford 23 mg of biphenyl amide 51. Yield 45%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)#[CH:2].[F:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)=[CH:4][CH:5]=1
Reactant: Fc1ccc(I)cc1
Reactant: C#Cc1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Fc1ccc(C#Cc2ccc(F)cc2)cc1
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A 2-Liter 4-neck round-bottom flask, equipped with an overhead mechanical stirrer, a nitrogen inlet, a condenser, placed inside a heating mantle, was charged with 1-ethynyl-4-fluorobenzene (500 g, 4.165 Mol), 1-fluoro-4-iodobenzene (715 g, 3.23 Mol), 22.5 g of dichlorobis(triphenylphosphine)palladium[II] catalyst, 6 g of copper[I] iodide, 8 g of triphenylphosphine, and 800 mL of anhydrous triethylamine. This was heated to reflux (~88° C. ) with stirring. Heating continued for 1 hour after which a gas chromatograph sample showed <1% starting material remained. The reaction mixture was cooled and the copious precipitate was filtered. The solids were washed with dry triethylamine. The combined triethylamine solutions were concentrated on the rotary evaporator and the brown residue was taken up in a minimum of dichloromethane. This was placed on a silica gel plug (about 1.5 kg) and eluted with hexanes (8L). The hexane fractions were concentrated on the rotary evaporator. The solid was recrystallized from methanol. The recrystallized solid, now a pale yellow material, was taken up in portions with hexane and the solution run through another silica gel plug (about 2 kg). The first 8L were clear, the next 16L (using recycled hexane) were yellow. The clear solutions were combined and stripped of solvent to yield a white solid. The yellow solutions were run through another clean silica gel plug to give a clear solution. This was stripped of solvent to give a white solid. The white solids were combined and dried to constant weight in a vacuum oven giving 648 g of the final product. (73% yield, m.p. 95°-97° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:17][C:11]=2[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH2:35]Br.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH2:35][C:34]1[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:32]([Cl:31])[CH:33]=1)[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)(=[O:20])=[O:21])[CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CBr)cc1Cl
Reactant: CC(C)(C)OC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(F)cc3)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2nc3ccc(OS(=O)(=O)c4ccc(F)cc4)cc3[nH]2)cc1Cl
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
A stirred solution of 4-fluoro-benzenesulfonic acid 2-tert-butoxycarbonylamino-3H-benzoimidazol-5-yl ester (Example 55 (step 3), 200 mg) in dry dimethylformamide (3 ml) was treated with sodium hydride (12 mg, 60% dispersion in mineral oil). After stirring for 30 minutes the mixture was treated with a solution of 3-chloro-4-methoxy-benzyl bromide (94 mg) in dimethylformamide (1 ml) and stirring was continued for a further 3 hours. The reaction mixture was poured into water (10 ml) and then extracted three times with ethyl acetate (10 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane (1:2, v/v) to give 4-fluoro-benzenesulfonic acid 2-[tert-butoxycarbonyl-(3-chloro-4-methoxy-benzyl)-amino]-3H-benzoimidazol-5-yl ester (70 mg) as a beige solid.
Reaction SMILES: [F:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[C:9]1=[O:25].FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[C:9]1=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(F)C(=O)OC1)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OCC(N2CCC3(CCNCC3)C2=O)=C1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(4-fluoro-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (109 mg, 0.308 mmol) in methylene chloride (1 mL) was added trifluoroacetic acid (1.896 mL, 24.61 mmol) and the resulting solution was stirred at rt for 1 h. After removing the volatiles, the residue was dissolved in methanol and loaded onto an ion exchange column. After washing with methanol, the product was eluted with 2N ammonia in methanol solution which was concentrated to give the title compound. LC/MS: (M+1)+: 255.09.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]2[N:20]=[CH:19][CH:18]=[CH:17][C:11]=2[C:12]([O:14][CH2:15]C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:29])C>>[C:1]1([CH2:7][CH2:8][N:9]2[C:10]3[N:20]=[CH:19][CH:18]=[CH:17][C:11]=3[C:12](=[O:13])[O:14][C:15]2=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Reactant: CCOC(=O)c1cccnc1NCCC1=CCCCC1
Product: O=c1oc(=O)n(CCC2=CCCCC2)c2ncccc12

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 45A for the product of Example 3A (0.493 g, 91%). MS (DCI) m/z 290 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:30]([F:33])([F:32])[F:31])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH:34]1[CH2:38][C:37](=[O:39])[NH:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:30]([F:31])([F:32])[F:33])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:34]4[CH2:38][C:37](=[O:39])[NH:36][CH2:35]4)=[O:22])=[C:19]([C:26]([F:27])([F:28])[F:29])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Reactant: O=C1CNCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)benzoic acid (100 mg, 0.20 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL), imidazolidin-4-one (34 mg, 0.39 mmol, 2.00 equiv), HATU (150 mg, 0.39 mmol, 2.00 equiv), DIEA (51 mg, 0.39 mmol, 2.00 equiv). The resulting solution was stirred for 1 h at rt. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:0). This resulted in 100 mg (88%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl)carbonyl]imidazolidin-4-one as yellow oil.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:33]=[CH2:34])=[C:19]([CH:32]=1)[O:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:33]=[CH2:34])=[C:19]([O:20][CH2:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH2:1])[CH:32]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: C=Cc1ccc(OCc2ccccc2)cc1OCC(=O)c1ccc(OC)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc(OCc2ccccc2)cc1OCC(=C)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
A suspension of MTPPB (2.29 g, 6.41 mmol) in anhydrous THF (20 mL) was cooled in an ice bath and added with t-BuOK (0.72 g, 6.42 mmol) in portions under nitrogen. After stirring at 0° C. for 15 min, the suspension was added with compound 2a (2.0 g, 5.34 mmol) as obtained above. The resultant mixture was stirred at 0° C. for 2 hrs, followed by quenching with a saturated NH4Cl solution. After removal of most of the THF in vacuo, the resultant residue was extracted six times with EtOAc (20 mL). The organic layers were combined, washed with a saturated NaCl solution, and dried with anhydrous MgSO4. After filtration, the filtrate was concentrated in vacuo, followed by purification via silica gel column chromatography (ethyl acetate/n-hexane=1:15), thus giving the title compound 2 as a colorless liquid (1.89 g, 95% yield).