Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([CH:15]2[CH2:17][CH2:16]2)[C:13]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:15]1([N:14]2[C:13]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:12]=3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH2:17][CH2:16]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2ccc(F)cc2n1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a solution of [(S)-1-(1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (414 mg, 1.3 mmol) in DCM (7 mL) was added TFA (3 mL) and the mixture stirred at RT for 1 h. The volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The two phase system was stirred for 10 min and then the organic layer was dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound as a yellow oil (166 mg, 58%). LCMS (Method C): RT 1.66 min [M+H]+ 220.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[S:5][C:6]=1[CH3:7].[CH3:25][N:26](C=O)C>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.[C-]#N.[C-]#N.[Zn+2]>[Cl:24][C:19]1[CH:18]=[C:17]([C:11]2([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=[C:8]([C:4]3[S:5][C:6]([CH3:7])=[C:2]([C:25]#[N:26])[CH:3]=3)[CH2:12]2)[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: Cc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C#N
Reaction time: 1 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (1.2 g) is added to a solution of Zn(CN)2 (1.2 g) and 3-(4-bromo-5-methyl-thiophen-2-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (4.6 g) in DMF (12 ml). After 1 h at 120° C. in the microwave, the reaction is quenched with water (150 ml) and ethyl acetate (100 ml) and filtered over celite. The aqueous phase is separated and further extracted two times with ethyl acetate. The organic phases are combined, washed with a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-thiophene-3-carbonitrile (2.2 g) as a beige crystal.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[CH:23]=[CH:24][C:25]([NH2:27])=[CH:26][C:19]=3[S:18]2(=[O:29])=[O:28])[CH2:9][CH2:8]1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:21](=[O:22])[C:20]3[CH:23]=[CH:24][C:25]([NH:27][C:30](=[O:32])[CH3:31])=[CH:26][C:19]=3[S:18]2(=[O:28])=[O:29])[CH2:9][CH2:8]1
Reactant: Nc1ccc2c(c1)S(=O)(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c(c1)S(=O)(=O)N(CCCCN1CCN(c3ncccn3)CC1)C2=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
200 ml of acetic anhydride are added to 0.06 mol of 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-6-amino-1,2-benzoisothiazol-3(2H)one 1,1-dioxide, and the mixture is stirred at room temperature for 12 hours. It is then evaporated to dryness, isopropyl ether is added and the mixture is stirred for 1 hour. It is then filtered and the colourless crystals are dried in vacuo.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]=[N:19][C:20](Cl)=[C:21]([CH3:24])[C:22]=3[CH3:23])[CH2:13][C@H:12]2[CH3:26])=[N:9][CH:10]=1)=[O:4].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([NH:27][C:3]([C:5]2[N:6]=[CH:7][C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:18]=[N:19][C:20]([NH:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[C:21]([CH3:24])[C:22]=4[CH3:23])[CH2:13][C@H:12]3[CH3:26])=[N:9][CH:10]=2)=[O:4])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1cnc(N2CCN(c3nnc(Cl)c(C)c3C)C[C@H]2C)cn1
Product: Cc1c(Nc2ccccc2)nnc(N2CCN(c3cnc(C(=O)Nc4ccccc4)cn3)[C@H](C)C2)c1C
Temperature: 190 °C

Procedure:
To (R)-4-(6-chloro-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′-carboxylic acid methyl ester (compound 54, 250 mg, 0.663 mmol) is added aniline (2.4 mL, 26.5 mmol) in a microwave tube. The reaction mixture is heated at 190° C. for 30 min in a microwave reactor. The reaction mixture is loaded on silica gel and purified by flash chromatography, eluting with 50%-100% EtOAc: heptane for six column volumes, followed with 3%-10% MeOH in DCM. Both example 3 and 4 are collected and concentrated to afford white solids.
Reaction SMILES: Cl.[C:2]1([NH:8]N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:11]([N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1)[CH3:12]>C(O)C>[CH2:11]([N:13]1[CH2:18][CH2:17][C:16]2[NH:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:15]=2[CH2:14]1)[CH3:12]
Reactant: NNc1ccccc1
Reactant: CCN1CCC(=O)CC1
Agent: Cl
Solvent: CCO
Product: CCN1CCc2[nH]c3ccccc3c2C1
Temperature: 80 °C

Procedure:
To a solution of phenylhydrazine hydrochloride (1 equiv) in ethanol was added 1-ethylpiperidin-4-one hydrochloride (1 equiv) and heated at 80° C. for 16 h. After completion of the reaction (monitored by LCMS). The reaction mixture was concentrated under vacuum and basified with aq. saturated NaHCO3, extracted with EtOAc, the organic layer was separated dried over sodium sulfate and concentrated under reduced pressure to obtain 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, free base) δ (ppm) 7.8 (bs, 1H), 7.4 (d, 1H), 7.2-7.0 (m, 3H), 3.7 (s, 2H), 2.9 (s, 4H), 2.7-2.6 (q, 2H), 1.2 (t, 3H).
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][C:2]2=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[H][H]>C(O)C.[Pt]=O>[CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH:2]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CCCC=C1CCC2CCC1C2
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: O=C(O)CCCCC1CCC2CCC1C2

Procedure:
A solution of 3.4 g (16.3 mmol) of 5-(bicyclo[3.2.1]oct-2-ylidene)pentanoic acid in 100 ml of absolute ethanol was hydrogenated at 50 psi over 300 mg of platinum oxide in a Parr apparatus. After 1.5 hr hydrogen uptake became slow. After 4 hr the system was flushed with nitrogen, and the catalyst was removed by filtration through diatomaceous earth filter aid (Celite). The filtrate was evaporated in vacuo to yield 3.25 g (96%) of quite pure 5-(bicyclo[3.2.1]oct-2-yl)pentanoic acid as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.[CH2:17]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH2:34])[CH2:29]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:17]([O:24][C:25](=[O:35])[NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:13]([C:12]2[C:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][O:10][C:11]=2[CH3:16])=[O:15])[CH2:29]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2cnccc2Cl)c1C(=O)O
Reactant: NC1CCCC(CNC(=O)OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2cnccc2Cl)c1C(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Yield: 66.1 %

Procedure:
Combine 3-(4-chloro-pyridin-3-yl)-5-methyl-isoxazole-4-carboxylic acid (0.50 g, 0.0021 mol) with (3-amino-cyclohexylmethyl)-carbamic acid benzyl ester (0.63 g, 0.0021 mol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.40, 0.0021 mol), 1-hydroxy-7-azabenzo-triazole (0.29 g, 0.0021 mol), and N,N-diisopropylethyl amine (1.10 mL, 0.0063 mol), in N,N-dimethylformamide (10 mL) and stir overnight at ambient temperature. Concentrate in vacuo and take up in water and extract with ethyl acetate. Wash the combined extracts with water and dry over sodium sulfate. Concentrate and elute over silica gel using methanol/dichloromethane to give 0.67 g (66%) of the desired amide. MS(ES): (M+1)+ 483.2, 485.2 m/z.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(N[C:42]1[CH:47]=[CH:46][C:45]([C:48](=[O:53])NCCC)=[CH:44][CH:43]=1)=O)C2>>[C:48]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)(=[O:53])[C:45]1[CH:46]=[CH:47][CH:42]=[CH:43][CH:44]=1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccncc2C1
Solvent: CC(=O)Cl
Product: O=C(Nc1ccc(C2=CCN(C(=O)c3ccccc3)CC2)cc1)N1Cc2ccncc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting benzoyl chloride for acetyl chloride and N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.61 (s, 1H), 8.50 (d, J=5.0 Hz, 1H), 8.46 (s, 1H), 7.55-7.58 (m, 2H), 7.42-7.49 (m, 6H), 7.35-7.41 (m, 2H), 5.98-6.21 (m, 1H), 4.79-4.82 (m, 4H), 3.95-4.39 (m, 2H), 3.79-3.93 (m, 1H), 3.51-3.61 (m, 1H), 2.46-2.60 (m, 2H); MS (ESI(+)) m/e 425 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11]([CH2:13][N:14]3C(=O)C4C(=CC=CC=4)C3=O)[CH:10]=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[N:8]=2)[CH:2]=1.O.NN>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11]([CH2:13][NH2:14])[CH:10]=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=3)[N:8]=2)[CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccnc2)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccnc2)n1
Temperature: 90 °C

Procedure:
To a solution of 2-[2-pyridin-3-yl-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-ylmethyl]-isoindole-1,3-dione (0.1 g, 0.217 mmol) in ethanol (5 mL) was added hydrazine mono-hydrate (14 μl, 0.434 mmol) at rt. The resulting mixture was heated to 90° C. for 12 h then cooled to rt. The resulting mixture was concentrated and taken on crude to the next step. MS (ESI): mass calcd. for C17H13F3N4, 330.1; m/z found, 331.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:26]=[CH:25][C:16]([C:17]([N:19]4[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]4)=[O:18])=[CH:15][CH:14]=3)[C:10]3[CH:27]=[CH:28][CH:29]=[CH:30][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:26]=[CH:25][C:16]([C:17]([N:19]4[CH2:23][CH2:22][CH:21]([O:24][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:20]4)=[O:18])=[CH:15][CH:14]=3)[C:10]3[CH:27]=[CH:28][CH:29]=[CH:30][C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1ccc(Cn2c(-c3ccccc3)nc3ccccc32)cc1)N1CCC(O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(C(=O)c2ccc(Cn3c(-c4ccccc4)nc4ccccc43)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
A solution of 1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]benzoyl}pyrrolidin-3-ol (0.85 g, 3 mmol) in DCM at 0° C. is treated with and triethylamine (0.91 mL, 6.6 mmol) followed by methylsulfonyl chloride (0.25 mL, 3.3 mmol), stirred at room temperature overnight and concentrated to give methanesulfonic acid 1-[4-(2-phenyl-benzoimidazol-1-ylmethyl)-benzoyl]-pyrrolidin-3-yl ester as a white powder (1.4 g) identified by HPLC and MS [476.3 m/e (M+H)].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[F:12][C:13]([F:40])([F:39])[C:14]([CH2:34][NH:35][CH2:36][CH2:37]C)([OH:33])[CH2:15][NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[N:20][N:21]2[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:35]([CH2:36][CH3:37])[CH2:34][C:14]([CH2:15][NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[N:20][N:21]2[C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)([OH:33])[C:13]([F:12])([F:40])[F:39])=[O:5]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1c(F)cccc1Cl

Procedure:
Prepared similarly to Example 48 from 2-chloro-6-fluorobenzoylchloride and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[CH:11]=1)[C:7](=O)[CH3:8]>C(O)C>[Cl:16][C:12]1[CH:11]=[C:10]([C:6]2[S:3][C:2]([NH2:4])=[N:1][C:7]=2[CH3:8])[CH:15]=[CH:14][N:13]=1
Reactant: NC(N)=S
Reactant: CC(=O)C(Br)c1ccnc(Cl)c1
Solvent: CCO
Product: Cc1nc(N)sc1-c1ccnc(Cl)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Thiourea (1.8 g, 29.4 mmol) is added to a stirred solution of 1-bromo-1-(2-chloro-pyridin-4-yl)-propan-2-one (7.3 g, 29.4 mmol) in ethanol (150 ml). The mixture is heated at 60° C. for 3 hours then allowed to cool to room temperature and stand for 18 h. The hydrobromide salt of the titled compound precipitates during this time and is removed by filtration and washed with diethyl ether.
Reaction SMILES: [O-]CC.[Na+].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C1C=CC=CC=1.Cl[CH:31]([C:37]([CH3:39])=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(Cl)(Cl)(Cl)Cl>[CH2:35]([O:34][C:32]([C:31]1[O:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=3)=[CH:10][C:11]=2[C:37]=1[CH3:39])=[O:33])[CH3:36]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CCOC(=O)Cc1ccc(-c2ccc(O)cc2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)Cc1ccc(-c2ccc3oc(C(=O)OCC)c(C)c3c2)cc1
Reaction time: 2 h

Procedure:
To a solution of 0.25 mole of sodium ethoxide is added 64 g. (0.25 mole) of ethyl 4-(4-hydroxyphenyl)phenylacetate. After stirring two hours the solution is evaporated, benzene is added, and the solution is further evaporated. The residue is dissolved in 800 ml. of benzene, 0.25 mole of ethyl α-chloroacetoacetate is added, and the mixture is stirred at room temperature, then heated at its reflux temperature for 16 hours and filtered hot. Evaporation provides a residue which is dissolved in carbon tetrachloride and filtered through silica gel. This intermediate is treated with concentrated sulfuric acid at 0° C. After stirring one hour, ice is added and the mixture is extracted with benzene. The benzene layer is dried, then evaporated. The residue is recrystallized from a dichloromethanehexane mixture, then carbon tetrachloride, to provide ethyl 4-(2-ethoxycarbonyl 3-methylbenzofuran-5-yl)phenylacetate, m.p. 110°-112° C.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([O:27][P:28]([CH:38]([NH:42][C:43](=[O:53])[CH2:44][CH2:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH:39]([CH3:41])[CH3:40])([O:30]CC1C=CC=CC=1)=[O:29])[C:17]([O:19]CC1C=CC=CC=1)=[O:18])=O)C1C=CC=CC=1>O1CCOCC1.O.[OH-].[Pd+2].[OH-]>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([O:27][P:28]([CH:38]([NH:42][C:43](=[O:53])[CH2:44][CH2:45][CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[CH:39]([CH3:41])[CH3:40])([OH:30])=[O:29])[C:17]([OH:19])=[O:18]
Reactant: CC(C)C(NC(=O)CCCc1ccccc1)P(=O)(OCc1ccccc1)O[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C(NC(=O)CCCc1ccccc1)P(=O)(O)O[C@@H](CCCCN)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The benzyl (S)-6-benzyloxycarbonylamino-2-((2-methyl-1-(4-phenylbutanoylamino)propyl)(benzyloxyphosphinoyl)oxy)hexanoate (43.9 mg) obtained in the above step (f) was dissolved in a mixed solvent of dioxane and water (3:1) (439 ml), and the solution was added with palladium hydroxide (8.8 mg) and stirred under a hydrogen atmosphere at room temperature for 18 hours. The reaction mixture was filtered with celite, and the filtrate was concentrated under reduced pressure. The residue was purified by HP-20 (Diaion, 5 g, water to methanol) to obtain the title compound: (S)-6-amino-2-(2-methyl-1-(4-phenylbutanoylamino)propyl(hydroxyphosphinoyl)oxy)hexanoic acid (17.5 mg, 70%, a diastereoisomeric mixture of 1:1).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][C@H:12]([OH:20])[CH2:13][CH2:14][CH2:15][C@@H:16]([CH3:19])[CH2:17][CH3:18])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(OCC)C>[C:1]1([CH3:21])[CH:2]=[CH:3][C:4]([S:7]([O:10][CH2:11][C@H:12]([O:20][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][O:22]2)[CH2:13][CH2:14][CH2:15][C@@H:16]([CH3:19])[CH2:17][CH3:18])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: C1=COCCC1
Reactant: CC[C@H](C)CCC[C@@H](O)COS(=O)(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC[C@H](C)CCC[C@H](COS(=O)(=O)c1ccc(C)cc1)OC1CCCCO1
Yield: 59 %

Procedure:
A mixture of 2.85 g of (2R,6S)-2-hydroxy-6-methyloctyl p-toluenesulfonate obtained in Step 5, 0.8 g of 3,4-dihydro-2H-pyran, 28 ml of diethyl ether, and 0.28 g of p-toluenesulfonic acid was allowed to react in a flask for 6 hours. The resulting solution was poured into 100 ml of a 1% sodium hydrogencarbonate aqueous solution, extracted with diethyl ether, washed with water, and concentrated to obtain 3.58 g of a crude product, which was then purified by HPLC to obtain 2.13 g (99%) of the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.Cl[CH2:11][C:12]([CH3:14])=[CH2:13].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:12]([CH3:14])=[CH2:11])=[C:4]([F:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=C(C)COc1ccc(Br)cc1F
Temperature: 70 °C
Reaction time: 15 h

Procedure:
To a solution of 4-bromo-2-fluorophenol (26.8 g) and 3-chloro-2-methylprop-1-ene (13.7 mL) in acetone (420 mL) was added potassium carbonate (29 g), and the mixture was stirred at 70° C. for 15 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (29.9 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C1(C)C=CC=CC=1>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.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
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: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=Cc2cc(Cl)cc(-c3ccc(Cl)cc3)c2OC1C(F)(F)F
Temperature: 25 °C
Yield: 62.7 %

Procedure:
Ethyl 6-chloro-8-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 73, Step 2)(1.3 g, 3.02 mmol), potassium carbonate (1.25 g, 9.06 mmol), 4-chorophenylboronic acid (0.52 g, 3.33 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.174 g, 0,151 mmol) were added to toluene (30 mL) and the resulting solution was heated to reflux for 18 hours. After cooling to room temperature the reaction mixture was poured into ethyl acetate (50 mL). It was washed with 1 N HCl (2×25 mL), saturated aqueous sodium bicarbonate (2×25 mL), and water (2×25 mL). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to yield a brown oil. The crude material was purified by flash chromatography using 1% ethyl acetate in hexane yielding a white solid. Recrystallization from hexane afforded the ester as a white solid (0.79 g, 64%): mp 114.2–115.9° C. 1H NMR (CDCl3/300 MHz) 7.69 (s, 1H), 7.41 (s, 4H), 7.30 (d, 1H, J=2.4 Hz), 7.22 (d, 1H, J=2.6 Hz), 5.70 (q, 1H, J=6.9 Hz), 4.37–4.29 (m, 2H), 1.35 (t, 3H, J=7.1 Hz). ESLRMS m/z 434 (M+NH4+). FABHRMS m/z 434.0574 (M+NH4+, Calc'd. 434.0538). Anal. Calc'd. for C19H13Cl2F3O3: C, 54.70; H, 3.14; Cl, 17.00. Found: C, 54.79; H, 3.18; Cl, 16.65.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C1C(=O)N([Br:22])C(=O)C1>C1COCC1.CN1C(=O)CCC1>[Br:22][C:12]1[N:4]2[C:5]3[C:10]([N:11]=[C:2]([Cl:1])[C:3]2=[N:14][CH:13]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: Clc1nc2ccccc2n2ccnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Clc1nc2ccccc2n2c(Br)cnc12
Reaction time: 18 h
Yield: 87.4 %

Procedure:
To a stirred suspension of 4-chloro-imidazo[1,2-a]quinoxaline (28.9 g, 141.8 mmol) in THF/NMP 2:1 (300 mL) was added NBS (25.2 g, 141.8 mmol) in one portion at rt. After 18 h stirring, additional 12.6 g (70.9 mmol) NBS were added and the mixture was stirred for additional 2 h at rt. After removal of the THF portion of the organic phase by vacuum evaporation, water was added (500 mL). The precipitate was filtered and the residue was washed with water and dried to give 1-bromo-4-chloro-imidazo[1,2-a]quinoxaline as an off-white solid (35 g, 78.6%): 1H-NMR (300 MHz, d6-DMSO): δ=12.42 (1H, s), 8.19 (1H, s), 7.75 (1H, d), 7.44 (2H, m) ppm. UPLC-MS: RT=1.14 min; m/z 284.6 [MH+]; required MW=283.5.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]=O>CC(O)=O.CC(N(C)C)=O>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(Nc2nccc(-c3ccc(N)s3)n2)c1
Reactant: O=Cc1ccccn1
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: Cc1cccc(Nc2nccc(-c3ccc(NCc4ccccn4)s3)n2)c1
Reaction time: 18 h

Procedure:
A solution of [4-(5-aminothiophen-2-yl)-pyrimidin-2-yl]-m-tolyl-amine (prepared according to Method 4) (15 mg, 0.053 mmol) and pyridine-2-carbaldehyde (4.5 uL, 0.048 mmol) were dissolved in a 25% solution of HOAc in DMA (0.5 mL). MP-CNBH3 resin (2.5 eq.) was added after 2 h and the reaction was shaken for 18 h. The reaction was filtered and the resin washed with DMA. The crude mixture was purified by preparative LCMS to afford 11.1 mg, 61.2%). MS: m/z 374 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ2.26 (s, 3H), 4.42 (d, J=6.5 Hz, 2H), 5.96 (d, J=4.5 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 6.986 (d, J=5.5 Hz, 1H), 7.10 (t, J=7.5 Hz, 1H), 7.27 (m, 1H), 7.38 (d, J=7.5 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.56 (d, J=4.0 Hz, 1H), 7.73 (br s, 1H), 7.76 (m, 1H), 7.81 (t, J=5.5 Hz, 1H), 8.16 (d, J=6.0 Hz, 1H), 8.53 (br dd, J=4.5 Hz, 1H), 9.24 (s, 1H).