Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH:17]1([NH:20][C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24](I)[CH:23]=2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:17]1([NH:20][C:21]([C:22]2[CH:27]=[C:26]([C:6]3[CH:5]=[CH:4][C:3]([C:9](=[O:10])[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[C:2]([NH2:1])[CH:7]=3)[C:25]([CH3:28])=[CH:24][CH:23]=2)=[O:30])[CH2:18][CH2:19]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1I
Reactant: Nc1cc(Br)ccc1C(=O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)c2ccccc2)c(N)c1
Temperature: 95 °C
Reaction time: 4 h
Yield: 48.6 %

Procedure:
To a solution the (2-Amino-4-bromo-phenyl)-phenyl-methanone (276 mg, 1.0 mmol) and N-Cyclopropyl-3-iodo-4-methyl-benzamide (301 mg, 1.0 mmol) in 5 mL of methyl sulfoxide was added potassium carbonate (276 mg, 2.0 mmol) and followed by Pd(PPh3)4 (58 mg, 0.05 mmol). After the reaction mixture was stirred at 95° C. for 4 hours, the reaction mixture was allowed to cool to room temperature and 10 mL of water was added to the mixture. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers washed with water (10 mL) and brine (10 mL), dried over MgSO4, and the solvents were evaporated. The residue was purified by chromatography (hexanes:ethyl acetate=1:1) to give the desired compound as a colorless solid (180 mg, 49%).
Reaction SMILES: Br[C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(CC(=O)C)(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[NH3:26]>O.[Cu+2].C(CC(=O)C)(=O)C.CN1C(=O)CCC1>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:7]=[C:2]([NH2:26])[C:3]([NH2:12])=[N:4][CH:5]=1
Reactant: Nc1ncc(C(F)(F)F)cc1Br
Reactant: N
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)CC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1cc(C(F)(F)F)cnc1N
Temperature: 110 °C

Procedure:
To an autoclave reactor, 3-bromo-5-trifluoromethyl-pyridine-2-ylamine (40 g), acetylacetone copper(II) (2.2 g), acetylacetone (6.6 g), cesium carbonate (59 g), and NMP (105 ml) were added, and then 28% of aqueous ammonia solution (25 mL) was added under ice-cooling. After the reactor was sealed, the mixture heated to 110° C., and stirred with heating for 12 hours. The mixture was ice-cooled to room temperature, then diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 15 g 5-trifluoromethyl-pyridine-2,3-diamine (Compound (1F)-22).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.Cl.[NH2:35][CH2:36][CH:37]1[CH2:39][CH2:38]1>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:35][CH2:36][CH:37]3[CH2:39][CH2:38]3)=[O:22])(=[O:16])=[O:15])[CH2:10]2)=[CH:6][CH:7]=1
Reactant: NCC1CC1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(NCC1CC1)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Yield: 62.7 %

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 110 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (121 μM), 0.026 cm3 of triethylamine and 21 mg of aminomethylcyclopropane hydrochloride. 68 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-cyclopropylmethylbenzamide are thus obtained in the form of a yellow foam [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 0.24 (mt, 2H), 0.44 (mt, 2H), 1.03 (mt, 1H), 2.98 (s, 3H), 3.15 (t, J=6 Hz, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.86 (broad s, 1H), 7.89 (broad d, J=8 Hz, 1H), 8.64 (t, J=6 Hz, 1H)].
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:15]=[C:16]1[O:20][C@H:19]([C:21]([Cl:24])([Cl:23])[Cl:22])[N:18]2[CH2:25][CH2:26][CH2:27][C@@:17]12[CH:28]=O.[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH2:35].C(O)(=O)C>ClCCCl>[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH:35][CH2:28][C@@:17]12[CH2:27][CH2:26][CH2:25][N:18]1[C@@H:19]([C:21]([Cl:24])([Cl:23])[Cl:22])[O:20][C:16]2=[O:15]
Reactant: NCc1cccc(F)c1
Reactant: O=C[C@@]12CCCN1[C@@H](C(Cl)(Cl)Cl)OC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@]12CNCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium triacetoxyborohydride (544 mg, 2.57 mmol) was added to (3R,7aR)-1-oxo-3-trichloromethyl-dihydro-pyrrolo[1,2-c]oxazole-7a-carbaldehyde (obtained as described in J. Org. Chem. 2006, 71(1), 97-102, 500 mg, 1.835 mmol), 3-fluorobenzylamine (0.251 mL, 2.20 mmol) and acetic acid (0.263 mL, 4.59 mmol) in DCE (4 mL) under an argon atm. The RM was stirred at rt for 3 h, then partitioned between water and DCM, the combined organic dried over Na2SO4 and evaporated to give the title compound as a pale yellow oil which was used without further purification.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[NH:12]C(=O)C(F)(F)F.Br[CH2:20][CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]2[O:2][CH2:20][CH:21]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[NH:12][C:4]=2[CH:5]=1)([O-:11])=[O:10]
Reactant: CCOC(=O)C=CCBr
Reactant: O=C(Nc1cc([N+](=O)[O-])ccc1O)C(F)(F)F
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC1COc2ccc([N+](=O)[O-])cc2N1
Temperature: 0 °C

Procedure:
220 ml of ethanol are introduced into a 1 l three-necked flask, with magnetic stirring, cooled to 0° C., and 3 g (0.133 mol) of sodium are added slowly, in small portions, followed by successive dropwise addition of 22.29 g (0.088 mol) of N-(2-hydroxy-5-nitrophenyl)trifluoroacetamide and 22.65 g (0.088 mol) of 75% pure ethyl 4-bromo-2-butenoate, and the mixture is heated at reflux for 3 h.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([C:26]1[N:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[NH2:25]>CCCCCCC.C(O)C.CC(O)C>[CH3:21][CH:22]([CH3:32])[CH2:23][C@@H:24]([NH:25][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:26]1[N:27]=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)CC(N)c1cccnn1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Solvent: CC(C)O
Solvent: CCCCCCC
Solvent: CCO
Product: CC(C)C[C@@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1cccnn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 3-methyl-1-(pyridazin-3-yl)butan-1-amine (Example 321 a) as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using a mixture of heptane, ethanol and 2-propanol as eluent. The (+)-enantiomer was isolated. MS (EI): m/e=432.5 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10](=O)[CH:11]=O.C(O)(=O)C.C(O)C>O>[I:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:11][CH:10]=[N:9]2
Reactant: Nc1ccc(I)cc1N
Reactant: O=CC=O
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Ic1ccc2nccnc2c1
Temperature: 25 °C
Yield: 64 %

Procedure:
A solution of 4-iodo-benzene-1,2-diamine (0.46 g, 1.96 mmol), ethanedial [40% in water] (2.25 mL), acetic acid (1 mL) and ethanol (20 mL) were heated to 100° C. for several hours and then cooled to room temperature. Water was added and the crude product was extracted with ethyl acetate. The product was purified via silica gel column chromatography with hexane:ethyl acetate (1:1) to give 0.323 g (64%) of 6-iodo-quinoxaline.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[C:17]3[CH2:21][CH2:20][N:19]([C:22]4[CH:23]=N[CH:25]=[CH:26][CH:27]=4)[C:18]3=[O:28])[CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]2)=[CH:4][CH:3]=1.[C:29]1(C)C=CC=CC=1>C(N(CC)CC)C.Cl[Pd]Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[C:17]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:29][CH:23]=4)[C:18]3=[O:28])[CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CC(=C2CCN(c3cccnc3)C2=O)c2ccc(Cl)cc2N1
Reactant: Cc1ccccc1
Agent: Cl[Pd]Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(=C2CCN(c3ccccc3)C2=O)c2ccc(Cl)cc2N1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of intermediate 4b (370 g) in toluene (5.2 lit), Triethylamine (248 ml), Triphenilphosphine (7.4 g) and PdCl2 (2.52 g) were added. The resulting solution was warmed to 100° C. and stirred for 2 h. The suspension was chilled to 20-25° C. and toluene (2.6 ml) was added. The reaction mixture was washed with NH4Cl 8% (3×5.2 lit) and water (5.2 lit). The organic layer was filtered over a celite pad and it was washed with toluene (1 lit); then it was distilled under vacuum (T=50° C.; P=60 mbar) to reach 6.3 lit. After cooling to T=20-25° C., isooctane (5.2 lit) was dropped over 30 min. The precipitate was stirred for 2 h 30 min then it was filtered and washed with a mixture toluene/isooctane 1/1 (1.85 lit). The yellow solid was dried in vacuum at T=40° C. for 18 h to obtain the title compound as a yellow solid 210 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]4)[CH2:12][CH2:11]2)[CH:7]=1.[C:28]([NH2:31])(=[O:30])[CH3:29]>>[F:27][C:5]1[CH:4]=[CH:3][C:2]([NH:31][C:28](=[O:30])[CH3:29])=[CH:7][C:6]=1[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]3)[CH2:12][CH2:11]1
Reactant: CC(N)=O
Reactant: Cc1ccc2c(N3CCN(CCc4cc(Br)ccc4F)CC3)cccc2n1
Product: CC(=O)Nc1ccc(F)c(CCN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Yield: 66 %

Procedure:
The title compound was prepared in 66% yield according to the general procedure for the preparation of the amides, ureas and carbamates (Method A) starting from 5-{4-[2-(5-bromo-2-fluorophenyl)ethyl]-1-piperazinyl}-2-methylquinoline and acetamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:24])[C:5]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:7]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:6]=2[N:23]=1.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>ClC(Cl)C>[C:25]([N:24]([C:25](=[O:28])[CH2:26][CH3:27])[C:4]1[C:5]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:7]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:6]=2[N:23]=[C:2]([CH3:1])[CH:3]=1)(=[O:28])[CH2:26][CH3:27]
Reactant: CCC(=O)Cl
Reactant: Cc1cc(C)c(-n2c3c(c4c(N)cc(C)nc42)CCCC3)c(C)c1
Solvent: CC(Cl)Cl
Product: CCC(=O)N(C(=O)CC)c1cc(C)nc2c1c1c(n2-c2c(C)cc(C)cc2C)CCCC1

Procedure:
2-Methyl-6,7,8,9-tetrahydro-9-(2,4,6-trimethylphenyl)-5H-pyrido[2,3-b]indol-4-amine (1b) (470 mg) dissolved in 10 mL dichloroethane is refluxed for 3 hours with propionyl chloride (0.5 mL). The. residual reagents are evaporated under reduced pressure. The crude product is partitioned between aqueous sodium carbonate solution and dichloromethane. The organic extract is dried over sodium sulfate and concentrated. The solid, diacylated product is triturated with hexanes and collected by filtration to afford N,N-Dipropionyl-2-methyl-6,7,8,9-tetrahydro-9-(2,4,6-trimethyl phenyl)-5H-pyrido[2,3-b]indol-4-amine 1c as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])[CH:7]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O.C(O)(C)(C)C>[CH3:29][C:28]1[C:23]([N:20]2[CH2:21][CH2:22][N:17]([C:15]([C:5]3[CH:4]=[CH:3][C:2]([N:31]4[CH2:35][CH2:34][CH2:33][C:32]4=[O:36])=[CH:7][C:6]=3[N:8]3[CH2:12][CH2:11][N:10]([CH3:13])[C:9]3=[O:14])=[O:16])[CH2:18][CH2:19]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: O=C1CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCN(C)C3=O)CC2)c(C)c1
Agent: [Pd]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3N3CCN(C)C3=O)CC2)c(C)c1
Yield: 48 %

Procedure:
To a mixture of 1-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-methylimidazolidin-2-one (116 mg) described in Preparation Example 241, pyrrolidin-2-one (35 mg), tripotassium phosphate (81 mg), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (28 mg) and 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (13 mg) was added tert-butanol (1.5 mL), and the mixture was stirred with heating under reflux for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was evaporated, and the residue was purified by column chromatography (ethyl acetate:methanol) to give the title compound (62 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2C(=O)C(F)(F)F)=[O:11])=[CH:5][C:4]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)=[O:25].[OH-].[K+]>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C@@H:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)=[O:11])=[CH:5][C:4]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)=[O:25]
Reactant: COc1ccc(NC(=O)[C@@H]2CCCN2C(=O)C(F)(F)F)cc1NC(=O)Nc1cnccn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(NC(=O)[C@@H]2CCCN2)cc1NC(=O)Nc1cnccn1
Reaction time: 0.17 h

Procedure:
A suspension of (S)-1-(2,2,2-trifluoro-ethanoyl)-pyrrolidine-2-carboxylic acid [4-methoxy-3-(3-pyrazin-2-yl-ureido)-phenyl]-amide (Compound 36, Example 6) (22 mg, 0.05 mmol) in a mixture of methanol (MeOH, 5 mL) and water (about 0.25 mL) was treated with KOH (100 mg, large excess). Within 10 minutes, all ingredients were in solution. The reaction mixture was treated with water (20 mL) and extracted with ethyl acetate (2×20 mL). The organic layers were combined and washed with water (10 mL) and brine (10 mL), dried with sodium sulfate, and concentrated to a tan solid (13 mg, 75%). 1H NMR (300 MHz, d6-DMSO) δ: 10.13 (s, 1H), 10.03 (s, 1H), 9.85 (s, 1H), 8.90 (s, 1H), 8.38-8.28 (m, 2H), 8.25 (d, J=2.6 Hz, 1H), 7.41 (dd, J=8.8, 2.6 Hz), 6.98 (d, J=8.8 Hz, 1H), 3.88 (s, 3H, 3.69 (dd, J=8.7, 5.6 Hz, 1H), 2.94-2.87 (m, 2H), 2.10-1.97 (m, 1H), 1.81-1.60 (m, 3H). LRMS (ESI, positive) m/e 357.1 (M+1).
Reaction SMILES: [Li].C(CC(O)=O)(CCC=C(C)C)(C=C)C.[C:16]([O:19][C:20]([CH3:29])([CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH:21]=[CH2:22])(=[O:18])[CH3:17].[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40](Cl)=[O:41]>C1COCC1>[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40](=[O:41])[CH2:17][C:16]([O:19][C:20]([CH3:29])([CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH:21]=[CH2:22])=[O:18]
Reactant: C=CC(C)(CCC=C(C)C)OC(C)=O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: C=CC(C)(CCC=C(C)C)CC(=O)O
Agent: [Li]
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1ccc2ccccc2c1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamnide (101.0 mL of a 2.0 M solution, 0.202 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition fiunel. The flask is placed in a dry ice-acetone bath. 3,7-Dimethyl-1,6-octadien-3-yl acetate (linalyl acetate) in the amount of (18.66 g, 0.095 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min before being treated with a solution of 2-naphthoyl chloride in the amount of (17.43 g, 0.090 mol) dissolved in THF (25 mL) over 30 min. The mixture is warmed to −20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (53 mL). The mixture is poured into a separatory fumnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 5% ethyl acetate dissolved in petroleum ether) to give an oil. Purity of the product is determined by thin layer chromatography and GC analysis and the structure confirmed by mass spectrometry, 1H and 13C NMR.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9](B3OCCCO3)[CH:10]=[CH:11][CH:12]=2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1.Br[C:24]1[C:25]([CH3:31])=[N:26][N:27]([CH3:30])[C:28]=1[CH3:29].C(=O)([O-])O.[Na+].[OH-].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:24]3[C:25]([CH3:31])=[N:26][N:27]([CH3:30])[C:28]=3[CH3:29])[CH:8]=2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1
Reactant: Cc1nn(C)c(C)c1Br
Reactant: Nc1nc2ccccc2n1-c1cccc(B2OCCCO2)c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1nn(C)c(C)c1-c1cccc(-n2c(N)nc3ccccc32)c1

Procedure:
A mixture of 2-(3-(2-amino-1-benzimidazolyl)phenyl)-1,3,2-dioxaborinane (2.0 g, 6.82 mmol), 4-bromo-1,3,5-trimethylpyrazole (1.29 g, 6.82 mmol), tetrakis(triphenylphosphine)-palladium(0) (0.24 g, 0.20 mmol), sodium hydrogen carbonate (2.29 g, 27.3 mmol), water (27 ml) and 1,2-dimethoxyethane (54 ml) was stirred at reflux overnight. Aqueous sodium hydroxide (50 ml) was added and the mixture was extracted twice with ethyl acetate (50 ml). The crude extract was purified by chromatography using silica gel and a mixture of ethanol (4%) and dichloromethane as eluent. The product was isolated as the free base. Yield 0.60 g, 28%. M.p. 198-200° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:18][N:17]=[C:16]([C:19]([O:21]CC)=O)[N:15]=1.Cl.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[CH2:35][CH2:36][NH2:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[CH2:35][CH2:36][NH:37][C:19]([C:16]1[N:15]=[C:14]([CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])[O:18][N:17]=1)=[O:21]
Reactant: CCOC(=O)c1noc(Cc2nc(-c3ccccc3)oc2C)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1Cc1nc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)no1

Procedure:
This compound was prepared according to method F with ethyl 5-((5-methyl-2-phenyloxazol-4-yl)methyl)-1,2,4-oxadiazole-3-carboxylate (0.075 g; 0.238 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL); 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.055 g; 0.238 mmol), HATU (0.090 g; 0.238 mmol), N,N diisopropylethylamine (0.102 mL; 0.594 mmol), in DMF (3 mL). The crude mixture was purified by flash column chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.042 (39%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:11][C@H:10]([N:22]([C:27](=[O:31])[C:28](O)=[O:29])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:54][C:55]1[CH:61]=[CH:60][C:58]([NH2:59])=[C:57]([NH:62][CH2:63][CH2:64][CH2:65][CH2:66][O:67][CH3:68])[CH:56]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:54][C:55]1[CH:61]=[CH:60][C:58]([NH:59][C:28](=[O:29])[C:27]([N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C@H:10]2[CH2:11][C@@H:12]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]2)=[O:31])=[C:57]([NH:62][CH2:63][CH2:64][CH2:65][CH2:66][O:67][CH3:68])[CH:56]=1
Reactant: COCCCCNc1cc(F)ccc1N
Reactant: CC(C)CN(C(=O)C(=O)O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCCCNc1cc(F)ccc1NC(=O)C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 2.9 %

Procedure:
{[(3S,5R)-1-(tert-Butoxycarbonyl)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl](2-methylpropyl)amino}(oxo) acetic acid (221 mg), HOBt (95 mg) and WSC.HCl (144 mg) were dissolved in DMF (5 ml), 4-fluoro-2-(4-methoxybutylamino)aniline (106 mg) and diisopropylethylamine (97 μl) were added, and the mixture was stirred at room temperature for 15 hr and at 60° C. for 2 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (9.11 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([C:8]2[S:9][CH2:10][C:11]([C:14]([F:17])([F:16])[F:15])(O)[N:12]=2)[CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([C:8]2[S:9][CH:10]=[C:11]([C:14]([F:15])([F:16])[F:17])[N:12]=2)[CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(C2=NC(O)(C(F)(F)F)CS2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])c(-c2nc(C(F)(F)F)cs2)c1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
The tertiary alcohol (3.9 g, 0.013 mol) obtained in Step C was refluxed for 3 h in toluene (60 mL) in the presence of a catalytic amount of p-toluenesulfonic acid (0.2 g). Azeotropic removal of water was achieved by employing a Dean-Starke trap. After cooling to room temperature, the toluene was removed under vacuum. The residue was taken up in ethyl acetate (200 mL) and washed with 10% aqueous sodium carbonate and brine (100 mL each). The dried (MgSO4) solution was concentrated to give 2.5 g (68% yield) of the title compound as white solid melting at 98°-104° C. 1H NMR (300 MHz, CDCl3) δ 7.91-7.94 (m,2H), 7.53 (s,1H), 7.43-7.46 (m,1H), 2.51 (s,3H).