Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([NH:24][C:25]1[CH:26]=[C:27]2[C:40](=[CH:41][CH:42]=1)[CH2:39][C@:29]1([C:37]3[C:32](=[N:33][CH:34]=[CH:35][CH:36]=3)[NH:31][C:30]1=[O:38])[CH2:28]2)[CH2:3][NH:4][C@H:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][CH2:7][NH:8][C:9]1([C:14]([O:16]C)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.O([Si](C)(C)C)[K:44]>C1COCC1>[O:1]=[C:2]([NH:24][C:25]1[CH:26]=[C:27]2[C:40](=[CH:41][CH:42]=1)[CH2:39][C@:29]1([C:37]3[C:32](=[N:33][CH:34]=[CH:35][CH:36]=3)[NH:31][C:30]1=[O:38])[CH2:28]2)[CH2:3][NH:4][C@H:5]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:6][CH2:7][NH:8][C:9]1([C:14]([O-:16])=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13]1.[K+:44]
Reactant: COC(=O)C1(NCC[C@H](NCC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)c2ccccc2)CCCC1
Reactant: C[Si](C)(C)O[K]
Solvent: C1CCOC1
Product: O=C(CN[C@@H](CCNC1(C(=O)[O-])CCCC1)c1ccccc1)Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Product: [K+]

Procedure:
To a stirred solution of methyl 1-({(3S)-3-[(2-oxo-2-{[(2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]amino}ethyl)amino]-3-phenylpropyl}amino)cyclopentanecarboxylate from Step A (0.141 g, 0.249 mmol) in dry THF (5 mL) was added KOTMS (64.0 mg, 0.498 mmol) and the reaction mixture was heated to 40° C., at which point the desired product began to precipitate. Two additional quantities of KOTMS (˜60 mg×2) were added over the next 2 h resulting in a complete consumption of starting material. The mixture was then allowed to cool to ambient temperature. The THF, which contained only traces of product, was then decanted away from the precipitated product. This solid was then washed with two additional quantities of anhydrous THF (5 mL×2), to provide the title compound. MS: m/z=554 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:24]([O-:26])=[O:25])=[CH:19][CH:18]=1>CN(C=O)C>[CH2:3]([C:7]1[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[C:24]([O:26][C:17]([CH3:22])([CH3:18])[CH3:16])=[O:25])=[CH:19][CH:18]=2)[C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: O=C([O-])C(c1ccc(CBr)cc1)C1CCCC1
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1.6 g (0.053 mol) of sodium hydride (80% strength) are suspended in 50 ml of DMF under protective gas, 10 g (0.053 mol) of 2-butyl-5-formyl-4-chloroimidazole (preparation according to EP 324,377) in 100 ml of DMF are added dropwise at 0° C., the mixture is then stirred at 0° C. for 15 min and 18.9 g (0.053 mol) of tert-butyl 2-(4-bromomethylphenyl-2-cyclopentylacetate in 100 ml of DMF are added dropwise. The mixture is stirred at 0° C. for 2 h, the solvent is evaporated, the residue is taken up in diethyl ether and filtered and, after concentration, chromatographed on silica gel 60 using dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][O:15]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][O:15]2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: BrCC1CCCO1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Product: O=[N+]([O-])c1cc(OCC2CCCO2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 2-Bromomethyl-tetrahydro-furan using the conditions described in Example 10C to provide 2-(4-Chloro-3-nitro-phenoxymethyl)-tetrahydro-furan which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][C:18](=[O:24])[CH2:19][Si](C)(C)C)([CH3:16])([CH3:15])[CH3:14].[CH3:25][C:26]1([C:29](N2C=CN=C2)=[O:30])[CH2:28][CH2:27]1.Cl>O1CCCC1>[CH3:25][C:26]1([C:29](=[O:30])[CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:24])[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)C[Si](C)(C)C
Reactant: CC1(C(=O)n2ccnc2)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC(=O)C1(C)CC1
Reaction time: 0.25 h

Procedure:
A solution of n-butyllithium (2.5M in hexane, 36 ml) was added dropwise with stirring to a cooled solution of diisopropylamine (9.09 g) in dry tetrahydrofuran (i.e. tetrahydofuran) in an atmosphere of nitrogen, whilst maintaining the temperature below -70° C. The mixture was stirred for 0.25 hour and t-butyltrimethylsilylacetate (16.9 g) was added dropwise with stirring whilst maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 1 hour. A suspension of 1-(1-methylcyclopropylcarbonyl)-imidazole (13.5 g) in dry tetrahydrofuran (120 ml) was added dropwise whilst maintaining the temperature below -60° C. The mixture was stirred at -78° C. for 3 hours and the temperature was allowed to rise to room temperature. Hydrochloric acid (2M, 100 ml) was added cautiously and the mixture was extracted with ether (2×100 ml). The combined extracts were washed with hydrochloric acid (2M, 3×50 ml) and water (3×50 ml), dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated to dryness to give t-butyl 3-(1-methylcyclopropyl)-3-oxopropionate as an orange oil NMR (CDCl3) 0.65(m,2H), 1.1(m,2H), 1.25(s,3H), 1.4(s,9H), 3.2(s,2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([F:18])[CH:10]=1.CN(C)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[O:28]1C[CH2:31][CH2:30][CH2:29]1.C(Cl)(=O)C=C>C(C1C(O)=C(CCCC)C=C(C)C=1)CCC.O>[C:29]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:21][O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([F:18])[CH:10]=1)(=[O:28])[CH:30]=[CH2:31]
Reactant: O=C(O)c1ccc(OCCCCCCO)cc1F
Reactant: CN(C)c1ccccc1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Agent: CCCCc1cc(C)cc(CCCC)c1O
Solvent: O
Product: C=CC(=O)CCCCCCOCCCCCCOc1ccc(C(=O)O)c(F)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, 4-(6-hydroxyhexyloxy)-2-fluorobenzoic acid (189 g), N,N-dimethylaniline (133 g) and 2,6-dibutyl-p-cresol (0.80 g) were added to tetrahydrofuran (500 mL). Acrylic acid chloride (100 g) was added dropwise thereto, followed by agitating at 60° C. for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with hydrochloric acid, a saturated sodium hydrogencarbonate aqueous solution and water, and after drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from ethanol to obtain 4-(6-acryloylhexyloxyhexyloxy)-2-fluorobenzoic acid (141 g).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:31])[CH2:18][CH2:19][C:20]2[CH:21]=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:12][CH:11]=1)([O:6]CC)=[O:5])[CH3:2].C[Si](Br)(C)C>C(#N)C>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:31])[CH2:18][CH2:19][C:20]2[CH:21]=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:12][CH:11]=1)([OH:6])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(NC(=O)CCc2cnoc2-c2ccccc2)cc1)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: CCOP(=O)(O)Cc1ccc(NC(=O)CCc2cnoc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
A mixture of N-[4-(diethylphosphonomethyl)phenyl]-3-(5-phenyl-4-isoxazolyl)propionamide (221 mg), trimethylsilyl bromide (0.17 ml) and acetonitrile (10 ml) was stirred at room temperature for 16 hr. The reaction mixture was purified by preparative HPLC to give N-[4-(ethylphosphonomethyl)phenyl]-3-(5-phenyl-4-isoxazolyl)propionamide (139 mg, 67%). melting point: 80–82° C.
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:3]=1[CH2:4][N:5]([CH3:14])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].N[C:22](=NO)[C:23]1C=CC(CN(C)CC(OC(C)(C)C)=O)=C(Br)C=1.C(B1OC(C)(C)C(C)(C)O1)=C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.O>[C:19]([C:17]1[CH:16]=[CH:15][C:3]([CH2:4][N:5]([CH3:14])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:2]([CH:22]=[CH2:23])[CH:18]=1)#[N:20]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)cc1Br
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1Br
Agent: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=Cc1cc(C#N)ccc1CN(C)CC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 92 %

Procedure:
A mixture of tert-butyl N-(2-bromo-4-cyanobenzyl)-N-methylglycinate (Intermediate 33 Step 1, 658 mg, 1.94 mmol), vinyl boronic acid pinacol ester (597 mg, 3.88 mmol), K2CO3 (536 mg, 3.88 mmol) and tetrakis-triphenylphosphine palladium(0) (224 mg, 0.19 mmol) was prepared in a mixture of dioxane/water (5:1; 6 mL) and heated at 100° C. for 18 hours. The reaction mixture was diluted with DCM/water and separated. The organic phase was passed through a hydrophobic frit and the solvents evaporated in vacuo. The residue was purified by flash chromatography (silica, iso-hexane/EtOAc) to afford the title compound (508 mg, 92%). 1H NMR (CDCl3, 400 MHz) δ 7.77 (1H, s), 7.58-7.43 (2H, m), 7.13 (1H, dd, J=17.4, 11.0 Hz), 5.69 (1H, d, J=17.4 Hz), 5.42 (1H, d, J=11.0 Hz), 3.80 (2H, s), 3.18 (2H, s), 2.36 (3H, s), 1.50 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:20]([O:27][C:28]1[C:33](F)=[CH:32][C:31]([NH:35][C:36]([C:38]2[CH:43]=[N:42][CH:41]=[CH:40][N:39]=2)=[O:37])=[C:30]([N+:44]([O-:46])=[O:45])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[CH2:20]([O:27][C:28]1[C:33]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:32][C:31]([NH:35][C:36]([C:38]2[CH:43]=[N:42][CH:41]=[CH:40][N:39]=2)=[O:37])=[C:30]([N+:44]([O-:46])=[O:45])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccccc1F
Reactant: O=C(Nc1cc(F)c(OCc2ccccc2)cc1[N+](=O)[O-])c1cnccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cc(Oc2ccccc2F)c(OCc2ccccc2)cc1[N+](=O)[O-])c1cnccn1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
0.54 ml of 2-fluorophenol and 2.53 g of potassium carbonate were added to a dimethylformamide (16 ml) solution of 2.14 g of N-(4-benzyloxy-5-fluoro-2-nitrophenyl)pyrazinecarboxamide, and the reaction liquid was stirred at 90° C. for 5 hours, and then water was added to it. The resulting deposit was taken out through filtration to obtain the entitled compound as a yellow solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([OH:14])=[CH:9][C:8]=1[N:15]1[C:20](=[O:21])[N:19]([CH3:22])[C:18](=[O:23])[CH:17]=[N:16]1.C(N(CC)CC)C>O1CCCC1.O>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:9][C:8]=1[N:15]1[C:20](=[O:21])[N:19]([CH3:22])[C:18](=[O:23])[CH:17]=[N:16]1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(=O)cnn(-c2cc(O)c(Cl)cc2Cl)c1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1c(=O)cnn(-c2cc(OS(C)(=O)=O)c(Cl)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
A solution of 0.35 g (0.0031 mole) of methanesulfonyl chloride in 5 mL of tetrahydrofuran was added to a stirred solution of 0.8 g (0.0028 mole) of 2-(2,4-dichloro-5-hydroxyphenyl)-4-methyl-1,2,4-triazine-3,5-(2H,4H)-dione (Compound 9, Example III H) and 0.30 g (0.0031 mole) of triethylamine in 10 mL of tetrahydrofuran. The reaction mixture was stirred at room temperature for approximately 18 hours, then diluted with water. The resultant mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The dried extract was filtered, and the filtrate was evaporated under reduced pressure to give 0.81 g of 2-(2,4-dichloro-5-methylsulfonyloxyphenyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione as a solid, Compound 23 in the tables.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][S:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:25]=[CH:24][C:22]=2[N:23]=1)=[O:17])=[O:7])(C)(C)C.NC1SC2C=C(OS(C3C=CC(F)=CC=3)(=O)=O)C=CC=2N=1.C(C(CCCCCCN)C(O)=O)([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=O>>[C:63]([O:62][CH:9]([N:8]=[C:6]=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][S:29]([C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)(=[O:30])=[O:31])[CH:25]=[CH:24][C:22]=2[N:23]=1)=[O:17])([CH3:66])([CH3:65])[CH3:64]
Reactant: CC(C)(C)OC(=O)C(CCCCCCN)C(=O)O
Reactant: CC(C)(C)OC(=O)NCCCCCCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Agent: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Product: CC(C)(C)OC(CCCCCCC(=O)Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)N=C=O

Procedure:
According to the method of intermediate 17, 4-fluorobenzenesulfonic acid 2-(8-tert-butoxycarbonylaminooctanoylamino)benzothiazol-6-yl ester is pre-pared by combining 4-fluorobenzenesulfonic acid 2-aminobenzothiazol-6-yl ester (intermediate 16) with Boc-8-aminocaprylic acid.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4](=[O:11])[C:5]1C=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[S:14]1C=CC=C1CC(Cl)=O.C(NCC)C>>[CH2:1]([N:3]([CH2:12][CH3:13])[C:4](=[O:11])[CH2:5][C:6]1[S:14][CH:9]=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCN(CC)C(=O)c1ccccc1
Reactant: O=C(Cl)Cc1cccs1
Solvent: CCNCC
Product: CCN(CC)C(=O)Cc1cccs1

Procedure:
The product of Example 42 was followed using 2-thiopheneacetyl chloride and diethylamine giving the desired product as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[N:7]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH2:16])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[O:18]=[C:19]1[NH:23][C:22](=[O:24])[CH:21]([CH2:25][C:26]2[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](O)=[O:33])=[CH:28][CH:27]=2)[S:20]1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>O1CCCC1>[C:1]([O:5][C:6](=[O:17])[N:7]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:32](=[O:33])[CH2:31][O:30][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH:21]2[S:20][C:19](=[O:18])[NH:23][C:22]2=[O:24])=[CH:36][CH:35]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 64.4 %

Procedure:
To a mixture of N-(2-amino-5-chlorophenyl)-N-methylcarbamic acid t-butyl ester (2.50 g) (obtained in Reference Example 2), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (3.01 g) (obtained in Reference Example 6), triethylamine (1.49 ml) and anhydrous tetrahydrofuran (50 ml) was added diethyl cyanophosphonate (1.75 g) and the resulting mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was chromatographed on a silica gel column using n-hexane/ethyl acetate (2/1) as the eluant to give the desired product (3.26 g). Rf=0.41 (thin-layer chromatography on a silica gel plate using n-hexane/ethyl acetate (2/3) as the eluant).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[CH3:21][C:22]1[CH:38]=[CH:37][CH:36]=[CH:35][C:23]=1[C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)=[O:25].CO[C:41](=O)[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH3:48])[CH:43]=1>C1COCC1.CCCCCC>[CH3:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:26]2[C:41]([C:42]3[CH:43]=[C:44]([CH3:48])[CH:45]=[CH:46][CH:47]=3)=[CH:21][C:22]3[C:23](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:24]2=[O:25])=[CH:33][CH:32]=1
Reactant: Cc1ccc(CNC(=O)c2ccccc2C)cc1
Reactant: COC(=O)c1cccc(C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(Cn2c(-c3cccc(C)c3)cc3ccccc3c2=O)cc1
Temperature: 0 °C
Reaction time: 0.92 h
Yield: 46.8 %

Procedure:
To a solution of diisopropylamine (1.2 mL, 8.56 mmol) in THF (15 mL) at 0° C. was added n-butyllithium (5.2 mL of a 1.6 M solution in hexane, 8.32 mmol). After stirring at 0° C. for 10 minutes the resulting lithium diisopropylamide solution was treated with a solution of 2-methyl-N-(4-methylbenzyl)benzamide (616 mg, 2.57 mmol) in THF (20 mL) over 15 min. The resulting deep brown-red solution was stirred at 0° C. for 55 minutes at which time it was treated with a solution of 3-methylbenzoic acid methyl ester (0.39 mL, 2.76 mmol) in THF (20 mL) over 20 minutes. After an additional 1 hour at 0° C. the reaction was quenched by the addition of 3N HCl (25 mL). The biphasic mixture was then heated to reflux with vigorous stirring. After 75 minutes at reflux the reaction mixture was allowed to cool to ambient temperature overnight. After cooling overnight, the reaction was concentrated to remove most of the THF. The resulting residue was diluted with ether (100 mL), and water (50 mL), and then basified by careful addition of solid Na2CO3. The basic aqueous was extracted with ether (3×40 mL), combined organics were washed with brine (50 mL), dried over Na2CO3, filtered, and concentrated to afford a yellow oil. The crude product was purified by silica gel column chromatography on a Jones Flashmaster instrument eluting with a gradient from 0% to 6% ethyl acetate/hexane on a 50 g silica column. The product peak was collected to afford 2-(4-methylbenzyl)-3-m-tolyl-2H-isoquinolin-1-one (408 mg, 47% yield) as a yellow oil that slowly solidified to a waxy solid:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH:23]1[CH:27]=[C:26]([CH2:28][C:29]([NH:31][NH2:32])=[O:30])[N:25]=[CH:24]1.Cl>C(O)C.O1CCOCC1>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[CH:19]=[N:32]/[NH:31][C:29](=[O:30])[CH2:28][C:26]2[N:25]=[CH:24][NH:23][CH:27]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=Cc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: NNC(=O)Cc1c[nH]cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(Cc1c[nH]cn1)N/N=C/c1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-formylphenyl 4-(trifluoromethyl)benzenesulfonate (6.5 g, 19.7 mmol) in ethanol (100 ml) is added to a solution of 4-imidazoleacetic acid hydrazide (18 mmol) in ethanol (200 mL). A catalytic amount of HCl in dioxane (3 mL) is added and the mixture is stirred at room temperature overnight. The precipitate that forms is removed by filtration. The filtrate is concentrated and chromatographed on silica eluting with 5% (2M ammonia in methanol)/CH2Cl2 to give 2-((E)-{2-[2-(1H-imidazol-4-yl)acetyl]hydrazono}methyl)phenyl 4-(trifluoromethyl)benzenesulfonate as a white solid. The yield is 3.1 g, 38%. 1H NMR (400 MHz, DMSO) d 11.94 (s, 1H), 11.48 (2s, 1H), 8.02 (m, 6H), 7.21 (m, 5H), 3.64 (2 s, 2H). ESI+ for C19H15F3N4O4S, m/z 453, (M+H)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[N:12][CH:13]=2)=[O:7])[CH2:2]1.CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[CH3:32][C:31]([CH3:34])([CH3:33])[C:30]([N:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[CH:13]=[N:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[N:10][CH:9]=2)=[O:7])[CH2:2]1)=[O:35]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(NC1CNC1)c1cnc(-c2cccc(F)c2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)N1CC(NC(=O)c2cnc(-c3cccc(F)c3)nc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a solution of N-azetidin-3-yl-2-(3-fluorophenyl)pyrimidine-5-carboxamide (50 mg, 0.16 mmol) in DMF (1.0 mL) was added DIPEA (0.06 mL, 0.32 mmol) and pivaloyl chloride (30 mg, 0.24 mmol). The mixtures were stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and brine. The organic layer was dried (MgSO4), filtered and concentrated to give a solid, which was purified by chromatography (silica, 80% EtOAc/Hex) to give the product, N-[1-(2,2-dimethylpropanoyl)azetidin-3-yl]-2-(3-fluorophenyl)pyrimidine-5-carboxamide (50 mg, 86%). HRMS (M+H)=357.1727 expected, observed=357.1799.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1.[C:26]([O:33][CH3:34])(=[O:32])[CH2:27][C:28]([O:30][CH3:31])=[O:29].CC(C)([O-])C.[K+].O1CCCC1>Cl.C(OCC)C>[C:14]1([C:12]2[N:13]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH:27]([C:26]([O:33][CH3:34])=[O:32])[C:28]([O:30][CH3:31])=[O:29])[O:10][C:11]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CC(=O)OC
Reactant: BrCCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C(CCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1)C(=O)OC
Reaction time: 17.5 h
Yield: 84.3 %

Procedure:
A mixture of 2-(7-bromoheptyl)-4,5-diphenyloxazole (10.00 g, 25 mmol), dimethyl malonate (9.95 g, 8.60 mL, 75 mmol), potassium tert-butoxide (8.44 g, 75 mmol), Eighteen Crown 6 ether (catalytic amount) and tetrahydrofuran (200 mL) was heated to reflux under an atmosphere of nitrogen. After 17.5 hours, the mixture was cooled, diluted with 2N hydrochloric acid solution and extracted with CH2Cl2. The combined extracts were dried over sodium sulfate and concentrated in vacuo to leave an oil. Chromatography on a column of silica gel using a mixture of hexanes and diethyl ether (9:1) as eluent afforded dimethyl 2-[7-(4,5-diphenyl-2-oxazolyl)heptyl]propanedioate (9.47 g, 83%) as an oil. An analytical sample (hydrated) was prepared by rechromatographing a 3.28 g sample on silica gel using a mixture of hexane and diethyl ether (4:1) as the mobile phase.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][NH:15]2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[C:38]([O-:41])(O)=O.[Na+].C(Cl)(Cl)=O.[NH2:47][CH:48]([C:62]([CH3:65])([CH3:64])[CH3:63])[C:49]([NH:51][CH:52]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH2:54][CH:53]1[OH:61])=[O:50]>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=3)[CH2:16][N:15]2[C:38](=[O:41])[NH:47][CH:48]([C:49](=[O:50])[NH:51][CH:52]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH2:54][CH:53]2[OH:61])[C:62]([CH3:65])([CH3:63])[CH3:64])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: O=C([O-])O
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1)C(=O)OCC
Reactant: CC(C)(C)C(N)C(=O)NC1c2ccccc2CC1O
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 32 h

Procedure:
To a solution of compound 12 (0.13 mmol) in THF (2 mL), was added a large excess of NaHCO3 (s) and a solution of phosgene in toluene (1.6 M, 600 μL). After 10 min of agitation the slurry was filtered and concentrated to dryness. The solid was redissolved in dichloromethane and a large excess of NaHCO3 (s) and 2-Amino-N-(2-hydroxy-indan-1-yl)-3,3-dimethyl-butyramide (0.65 mmol) was added. The slurry was agitated for 24-40 hrs at RT. The slurry was filtered, concentrated and subjected to silica column chromatography (gradient elution from 100% DCM to MeOH/DCM 2:98) to give the title compound (89.6 mg, 0.11 mmol). Purity by HPLC>95%. M+H+790.3.