Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)C=CC=CC=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3ccc(Cl)c(C(F)(F)F)c3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (100 mg, 0.38 mmol) and 4-chloro-3-trifluoromethyl-phenylboronic acid (150 mg, 0.45 mmol) were coupled to yield 2-(4-chloro-3-trifluoromethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 121 mg (88%) as a pale yellow solid: m.p. 118.5-119° C.; 1H NMR (300 MHz, d6-DMSO) δ 3.06 (m, 2H), 3.41 (m, 2H), 7.27 (app t, J=7.8 Hz, 1H), 7.60 (dd, J=7.8, 0.9 Hz, 1H), 7.73 (dd, J=7.2, 0.9 Hz, 1H), 7.89 (m, 2H), 8.08 (d, J=1.5 Hz, 1H), 8.14 (br t, 1H), 11.82 (br s, 1H). MS (FAB, MH+) 365. Anal. (C18H12ClF3N2O.0.45 H2O.0.2 CHCl3) C, H, N.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([N:22]=[CH:23][N:24]([CH2:26][CH3:27])[CH3:25])=[C:17]([CH3:28])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC.C1CCCCC1.CC(C)=O.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[CH:16]=[C:17]([CH3:28])[C:18]([N:22]=[CH:23][N:24]([CH2:26][CH3:27])[CH3:25])=[CH:19][C:20]=2[CH3:21])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CCN(C)C=Nc1cc(C)c(Br)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCCCC1
Solvent: O
Solvent: COCCOC
Product: CCN(C)C=Nc1cc(C)c(-c2ccc(C(C)(C)C)cc2)cc1C
Temperature: 80 °C
Reaction time: 16 h
Yield: 46.7 %

Procedure:
The reaction is carried out using inert conditions (argon or nitrogen atmosphere, dry solvents). A suspension of 0.3 g (1.8 mmol) of (4-tert-butylphenyl)boronic acid, 0.4 g (1.5 mmol) of N′-(4-bromo-2,5-dimethylphenyl)-N-ethyl-N-methylimidoformamide, 1.5 g (4.5 mmol) caesium carbonate and 0.03 g (0.03 mmol) tetrakis(triphenylphosphin)palladium in 3.5 ml of 1,2-dimethoxyethan was stirred for 16 hrs at 80° C. At room temperature 5 ml of water and 15 ml of toluene were added. The organic layer was separated, the watery layer was again extracted using 15 ml of toluene. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Column chromatographic (cyclohexane/aceton:4/1) yielded 0.23 g (0.7 mmol) 47% of N′-(4′-tert-butyl-2,5-dimethylbiphenyl-4-yl)-N-ethyl-N-methylimidoformamide; log P (pH 2.3)=2.67.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[C@@H:21]([C:22]4[C:23](=[O:29])[NH:24][CH:25]=[C:26]([F:28])[CH:27]=4)[CH2:20][O:19][C:18]3=[O:30])=[N:13][C:12]=12)=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:28][C:26]1[CH:25]=[N:24][C:23]2[O:29][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:7])[C:8]3=[C:12]4[N:13]=[C:14]([CH:15]=[CH:16][N:11]4[N:10]=[CH:9]3)[N:17]3[C@H:21]([CH2:20][O:19][C:18]3=[O:30])[C:22]=2[CH:27]=1
Reactant: O=C(NCCCCl)c1cnn2ccc(N3C(=O)OC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCCOc2ncc(F)cc2[C@H]2COC(=O)N2c2ccn3ncc1c3n2
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
To a solution of (S)-N-(3-chloropropyl)-5-(4-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (35 mg, 0.08 mmol) in DMF (3 mL) was added cesium carbonate (79 mg, 0.24 mmol). The mixture was stirred at 65° C. for 30 minutes then at ambient temperature for 48 hours. The mixture was treated with water (30 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were washed with water (5×10 mL) and brine (10 mL), then dried over Na2SO4, filtered and concentrated. The residue was purified via flash column chromatography eluting with 2% MeOH/DCM to afford the title compound (13 mg, 41% yield) as an amorphous white solid. MS (apci) m/z=399.2 (M+H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=2)[NH:11][CH:10]=1)(=O)=O.[CH3:20][O:21][C:22]1[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:24][CH:25]=[N:26][CH:27]=1.C(N(CC)C(C)C)(C)C>C(#N)C.C(Cl)(Cl)Cl>[C:18]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:8][CH2:7][CH2:6][N:31]1[CH2:32][CH2:33][N:28]([C:23]2[C:22]([O:21][CH3:20])=[CH:27][N:26]=[CH:25][N:24]=2)[CH2:29][CH2:30]1)#[N:19]
Reactant: CS(=O)(=O)OCCCc1c[nH]c2ccc(C#N)cc12
Reactant: COc1cncnc1N1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(C#N)cc23)CC1
Yield: 42.4 %

Procedure:
To a solution of 3-(5-cyano-1H-indol-3-yl)propyl methanesulfonate (2.35 mmol, 1.0 equiv.) in 25 mL of anhydrous acetonitrile was added 0.874 g (4.5 mmol, 1.5 equiv.) of (5-methoxy-4-pyrimidinyl)piperazine and 1.0 mL of N,N-diisopropylethylamine. The mixture was heated to reflux for thirteen hours. The solution was cooled, diluted with 100 mL of chloroform and washed once with 20 mL of 10% aqueous sodium carbonate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel using 5% methanol in methylene chloride containing 0.5% concentrated aqueous ammonium hydroxide to yield 0.375 g (42%, two steps) of 1-[3-(5-cyano-1H-indol-3-yl) propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine pure by 1H NMR analysis.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2].F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].[F-].[K+]>O>[CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1N
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [F-]
Agent: [K+]
Solvent: O
Product: CC(C)c1ccccc1Nc1ccccc1[N+](=O)[O-]
Temperature: 180 °C
Yield: 87.8 %

Procedure:
2-isopropylaniline (27 g, 200 mmol), 2-fluoronitrobenzene (14 g, 100 mmol), and potassium fluoride (8.6 g, 150 mmol) were mixed in a one-neck flask. The mixture was heated up to 180° C. under nitrogen for 48 hours. After cooled to room temperature, water (200 mL) was added. The mixture was then extracted with dichloromethane (200 mL) for three times. The solvent was evaporated and the residue was purified by column chromatography using 20% of dichloromethane in hexanes. 22.5 g of desired product was obtained.
Reaction SMILES: C(I)C.[C:4]([O:7][C@@H:8]1[C@@H:13]([O:14][C:15](=O)[CH3:16])[C@H:12]([CH3:18])[O:11][CH:10]=[CH:9]1)(=O)[CH3:5].[OH-].[Na+].CS(C)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:4]([O:7][C@@H:8]1[C@@H:13]([O:14][CH2:15][CH3:16])[C@H:12]([CH3:18])[O:11][CH:10]=[CH:9]1)[CH3:5]
Reactant: CC(=O)O[C@H]1[C@H](C)OC=C[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCI
Product: CCO[C@H]1[C@H](C)OC=C[C@@H]1OCC
Reaction time: 66 h
Yield: 8.6 %

Procedure:
Ethyl iodide (32 mL, 0.40 mol), 3,4-di-O-acetyl-6-deoxy-L-glucal (4.28 g, 0.20 mol), 50% aqueous NaOH (43 mL, 0.81 mol) and DMSO (11.4 mL, 0.16 mol) were added sequentially to a 300-mL round-bottom, three-neck flask equipped with an overhead stirrer. Stirring was begun and tetrabutylammonium hydrogen sulfate (2.04 g, 0.006 mol) added in a single portion. Stirring was continued for 66 h. The mixture was partitioned between water and Et2O. The aqueous layer was extracted twice with Et2O (20 mL) and a final time with 1:1 Et2O-CH2Cl2 (20 mL). The organic layers were combined, washed successively with water, dilute aqueous sodium thiosulfate, water and brine and dried over sodium sulfate and potassium carbonate and concentrated under reduced pressure. A white solid precipitated during evaporation. The mixture was diluted with pentane and the solid removed by filtration. The solvent was removed from the filtrate under reduced pressure to yield a pale yellow oil (3.2 g, 87%) which was sufficiently homogeneous to use in subsequent reactions without additional purification. 1H NMR d 6.32 (dd, J=6.1, 0.6, 1 H), 4.78 (dd, J=6.1, 1.2, 1 H), 1.36 (d, J=6.4, 3 H), 1.22 (t, J=7.0, 6 H).
Reaction SMILES: [Cs+].[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:4]=1[C:5]([O-:7])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:20][N:21]1[C:25](=[O:26])[CH:24]([CH2:27][CH2:28][CH3:29])[N:23]([CH2:30][CH3:31])[S:22]1(=[O:33])=[O:32]>CO.CN(C=O)C>[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:4]=1[C:5]([O:7][CH2:20][N:21]1[C:25](=[O:26])[CH:24]([CH2:27][CH2:28][CH3:29])[N:23]([CH2:30][CH3:31])[S:22]1(=[O:32])=[O:33])=[O:6]
Reactant: CCCC1C(=O)N(CCl)S(=O)(=O)N1CC
Reactant: O=C([O-])c1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCC1C(=O)N(COC(=O)c2c(Cl)cccc2Cl)S(=O)(=O)N1CC
Temperature: 0 °C
Yield: 80 %

Procedure:
A mixture of 2,6-dichlorobenzoic acid cesium salt (prepared from 0.42 g of the acid and cesium carbonate (0.36 g) in methanol followed by removal of methanol and drying in vacuo) and 2-chloromethyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.5 g) in DMF was allowed to react at 90°-100° C. for 2 hours, and then cooled. The mixture was diluted with ice/water, extracted with ether/ethyl acetate, and the organic layer was washed with water, brine, and dried. The organic solution was concentrated in vacuo and the residue was purified by flash chromatography to afford 0.64 g (80%) of 2-(2,6-dichloro-phenylcarbonyloxymethyl)-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: Ar=2,6-Cl2 -phenyl; R1 =H; R2 =propyl; R3 =ethyl) as an oil.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:9]2=[C:10]3[C:15](=[CH:16][CH:17]=[C:8]2[NH:7][C:6]1=[O:18])[N:14]=[CH:13][CH:12]=[CH:11]3)[CH3:3].[CH3:19][N:20]([CH2:22][C:23]1[CH:29]=[CH:28]C(N)=[CH:25][CH:24]=1)[CH3:21].Cl>C(O)C>[CH3:19][N:20]([CH2:22][C:23]1[CH:29]=[CH:28][C:3]([NH:2]/[CH:4]=[C:5]2\[C:6](=[O:18])[NH:7][C:8]3[C:9]\2=[C:10]2[C:15](=[CH:16][CH:17]=3)[N:14]=[CH:13][CH:12]=[CH:11]2)=[CH:25][CH:24]=1)[CH3:21]
Reactant: CN(C)C=C1C(=O)Nc2ccc3ncccc3c21
Reactant: CN(C)Cc1ccc(N)cc1
Agent: Cl
Solvent: CCO
Product: CN(C)Cc1ccc(N/C=C2\C(=O)Nc3ccc4ncccc4c32)cc1
Temperature: 25 °C

Procedure:
A mixture of dimethylaminomethylidene-1,3-dihydro-2H-pyrrolo[3,2-f]quinoline-2-one (0.1 mmol), 4-dimethylaminomethylaniline (0.1 mmol) and conc. hydrochloric acid (0.02 mL) in ethanol (1 mL) was heated at reflux until the reaction was complete as determined by tic analysis. The reaction mixture was allowed to cool to room temperature. The solvent was evaporated and the residue purified using silica gel chromatography to give the title compound as an orange-brown solid, 15 mg. (42%). 1H NMR (DMSO-d6): δ 2.17 (s, 6H), 3.17 (s, 2H), 7.31-7.51 (m, 6H), 7.74 (d, J=8.7 Hz, 1H), 8.74 (d, J=3.3 Hz, 1H), 8.83 (d, J=6.0 Hz, 1H), 8.86 (d, J=12 Hz, 1H), 10.95 (s, 1H), 11.80 (d, J=12 Hz, 1H); APESI+MS m/z 345 (M+1)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[CH3:47][C:48]1[CH:49]=[C:50]([C:65]2[CH:66]=[CH:67][C:68]([C:71](O)=[O:72])=[N:69][CH:70]=2)[CH:51]=[C:52]([NH:54][C:55]2[N:60]=[C:59]([C:61]([F:64])([F:63])[F:62])[CH:58]=[CH:57][N:56]=2)[CH:53]=1>O.CN(C=O)C>[CH3:47][C:48]1[CH:49]=[C:50]([C:65]2[CH:66]=[CH:67][C:68]([C:71]([N:3]3[CH2:4][CH2:5][O:1][C:2]3=[O:6])=[O:72])=[N:69][CH:70]=2)[CH:51]=[C:52]([NH:54][C:55]2[N:60]=[C:59]([C:61]([F:64])([F:63])[F:62])[CH:58]=[CH:57][N:56]=2)[CH:53]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(=O)O)nc2)c1
Reactant: O=C1NCCO1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(=O)N3CCOC3=O)nc2)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
DMF (800 μL), 1,3-oxazolidin-2-one (28 mg, 0.32 mmol), triethylamine (67 μL, 0.48 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (100 mg, 0.19 mmol) were added to 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridine-2-carboxylic acid (60 mg, 0.16 mmol) and the reaction was stirred for 60 hours at room temperature. The reaction mixture was then diluted with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (10-80% acetonitrile/water with 0.1% TFA) and then chromatography on silica gel (10-100% acetone gradient in hexanes) to afford 3-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]carbonyl}-1,3-oxazolidin-2-one. MS ESI calc'd for C21H17F3N5O3 [M+H]+ 444. found 444. 1H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.87-8.77 (m, 2H), 8.13 (dd, J=2.2 Hz, 8.1, 1H), 8.02 (s, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.60 (s, 1H), 7.31-7.21 (m, 2H), 4.49 (t, J=7.8 Hz, 2H), 4.11 (t, J=7.8 Hz, 2H), 2.37 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[C:58]([NH2:63])(=[O:62])[CH:59]([CH3:61])[CH3:60]>O1CCOCC1.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.[Pd].[Pd]>[N+:15]([C:12]1[N:11]=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:63][C:58](=[O:62])[CH:59]([CH3:61])[CH3:60])[CH:7]=2)=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: CC(C)C(N)=O
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)C(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccn1
Temperature: 25 °C
Yield: 44.9 %

Procedure:
A suspension of Example A1 (2.00 g, 7.95 mmol), Cs2CO3 (5.00 g, 15.35 mmol), X-Phos (0.200 g, 0.420 mmol), Pd2(dba)3 (0.200 g, 0.218 mmol) and isobutyramide (1.00 g, 11.48 mmol) in dioxane (20 mL), under Ar, was heated at 90° C. overnight. The mixture was cooled to RT, the solids removed via filtration, washed with DCM and THF and the filtrate concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)isobutyramide (1.08 g, 45%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 8.58 (m, 1H), 8.41 (dd, J=8.9, 0.5 Hz, 1H), 8.31 (d, J=5.7 Hz, 1H), 7.99 (dd, J=8.9, 2.8 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 6.89 (dd, J=5.7, 2.4 Hz, 1H), 2.72 (m, 1H), 1.03 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 303.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:24][C:25]([C@H:29]1[CH2:34][CH2:33][C@H:32](O)[CH2:31][CH2:30]1)([CH3:28])[CH2:26][CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:25]([C@@H:29]1[CH2:30][CH2:31][C@H:32]([O:23][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([CH2:12][N:9]2[CH2:10][CH2:11][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]2)[CH:22]=[CH:21]3)[CH2:33][CH2:34]1)([CH2:26][CH3:27])([CH3:24])[CH3:28]
Reactant: CCC(C)(C)[C@H]1CC[C@H](O)CC1
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O)ccc3c2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(Cc2ccc3cc(O[C@H]4CC[C@@H](C(C)(C)CC)CC4)ccc3c2)CC1
Reaction time: 0.33 h
Yield: 100.7 %

Procedure:
A mixture of 1-(6-hydroxy-naphthalen-2-ylmethyl)-piperidine-4-carboxylic acid ethyl ester (0.400 g, 1.28 mmol), trans-4-(1,1-dimethyl-propyl)-cyclohexanol (0.2395 g, 1.406 mmol) and triphenylphosphine (0.6695 g, 2.553 mmol) in toluene (5 mL, 40 mmol) was stirred for 20 min, then, diisopropyl azodicarboxylate (0.32 mL, 1.5 mmol) was added drop wise at 0° C. The solution was stirred at reflux overnight. The reaction was added to silica gel and the solvent was concentrated. The residue was purified with silica gel eluted with EtOAc in hexanes from 0 to 20% to give product as oil (0.6 g, 100%). LCMS: Rt=1.95 min, m/z=466.49 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([N:33]2[C:37](=[O:38])[CH2:36][CH2:35][C@@H:34]2[CH2:39][OH:40])[CH:3]=1.[C:41](Cl)(=[O:43])[CH3:42].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>O1CCCC1>[C:41]([O:40][CH2:39][C@H:34]1[CH2:35][CH2:36][C:37](=[O:38])[N:33]1[C:4]1[CH:3]=[C:2]([F:1])[CH:32]=[CH:31][C:5]=1[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:28])[C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:30])[CH3:29])=[O:9])(=[O:43])[CH3:42]
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CO)c(OCc1ccccc1)c2=O
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC[C@H]1CCC(=O)N1c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 23 °C
Reaction time: 4 h
Yield: 65.9 %

Procedure:
To a solution of intermediate 192, (R)-N-(4-fluoro-2-(2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)benzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.045 g, 0.082 mmol) in tetrahydrofuran (5 mL) was added acetyl chloride (12.8 μL, 0.180 mmol) and diisopropylethylamine (31.4 μL, 0.180 mmol). The reaction mixture was stirred at 23° C. for 4 h. NaHCO3 (1N in H2O, 30 mL) was then added and the organic material was extracted with ethyl acetate (2×25 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on a Biotage system using a silica gel column with ethyl acetate/Hexanes (1:1) to ethyl acetate 100% as eluent to afford the title compound (0.032 g, 67% yield): 1HNMR 400 MHz (MeOD) δ ppm: 7.48 (3H, m), 7.33 (3H, m), 7.16 (1H, m), 7.03 (1H, m), 5.24 (2H, s), 4.60 (1H, m), 4.55 (1H, m), 4.22 (1H, dd, J=12.0, 4.5 Hz), 4.08 (2H, t, J=5.0 Hz), 3.99 (3H, m), 2.62 (2H, m), 2.44 (1H, m), 2.09–1.92 (5H, m), 1.62 (3H, s), 1.61 (3H, s). LCMS (M+H)+ m/z 593.
Reaction SMILES: [I:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16](C(OCC)=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5].[OH-].[K+]>>[I:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[CH:11][CH:12]=1)=[O:5]
Reactant: CCOC(=O)N1CCN(c2ccc(NC(=O)c3ccccc3I)cc2)CC1
Agent: [K+]
Agent: [OH-]
Product: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1I

Procedure:
A mixture of intermediate (27) (0.041 mol) and potassium hydroxide (0.41 mol) in ispropanol (200 ml) was stirred and refluxed for 3 hours and the solvent was evaporated till dryness. Water was added. The mixture was extracted with DCM and the solvent was evaporated, yielding 2-iodo-N-[4-(1-piperazinyl)phenyl]benzamide (intermediate 28).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH3:7])[C@:5]([CH2:14][OH:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:16])[N:3]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1.[CH3:29][C:30]([CH3:43])([O:32][C:33]([NH:35][C@@H:36]([CH:40]([CH3:42])[CH3:41])[C:37](O)=[O:38])=[O:34])[CH3:31].Cl.CN(C)CCCN=C=NCC.O>CN(C)C1C=CN=CC=1.ClCCl>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([N:3]2[C:4](=[O:16])[C@@:5]([CH2:14][O:15][C:37](=[O:38])[C@@H:36]([NH:35][C:33]([O:32][C:30]([CH3:29])([CH3:43])[CH3:31])=[O:34])[CH:40]([CH3:42])[CH3:41])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:6]([CH3:7])[C:2]2=[O:1])=[CH:18][C:19]=1[C:25]([F:28])([F:26])[F:27])#[N:22]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)[C@@]1(CO)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC[C@@]1(c2ccccc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C

Procedure:
A solution of 0.45 g of (S)-4-[2,5-dioxo-4-(hydroxymethyl)-3-methyl-4-phenylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile, 0.33 g of (2S)-2-[(1,1-dimethylethoxy)carbonylamino]-3-methylbutanoic acid, 0.185 g of 4-dimethylamino pyridine and 0.45 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 70 mL of dichloromethane is stirred for 1 hour then poured into water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography over silica gel while eluting with 70/30 heptane/ethyl acetate mixture to provide the desired compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:11]1[CH:30]=[CH:29][C:14]([O:15][C:16]([C:18]2[S:22][C:21]([CH2:23][CH2:24][C:25]([OH:27])=O)=[C:20]([CH3:28])[CH:19]=2)=[O:17])=[CH:13][CH:12]=1)(=[NH:10])[NH2:9].CCN=C=N[CH2:36][CH2:37][CH2:38][N:39]([CH3:41])C.Cl>N1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:38]([N:39]([C:25](=[O:27])[CH2:24][CH2:23][C:21]1[S:22][C:18]([C:16]([O:15][C:14]2[CH:13]=[CH:12][C:11]([C:8](=[NH:10])[NH2:9])=[CH:30][CH:29]=2)=[O:17])=[CH:19][C:20]=1[CH3:28])[CH2:41][C:3]([OH:5])=[O:4])[CH:37]=[CH2:36]
Reactant: Cc1cc(C(=O)Oc2ccc(C(=N)N)cc2)sc1CCC(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Product: C=CCN(CC(=O)O)C(=O)CCc1sc(C(=O)Oc2ccc(C(=N)N)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 242.4 %

Procedure:
The compound (100 mg, 0.224 mmol) obtained in step 1, M-5 (49.9 mg, 0.291 mmol), and WSC hydrochloride (64.4 mg, 0.336 mmol) were dissolved in pyridine (0.5 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, trifluoroacetic acid (1.0 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by high performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to give the title compound (98.5 mg, 0.181 mmol, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.N1C=CN=C1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([O:12][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:8]=[CH:7]2
Reactant: Nc1cccc2ccc(O)cc12
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](Oc1ccc2cccc(N)c2c1)(c1ccccc1)c1ccccc1
Reaction time: 48 h
Yield: 360.5 %

Procedure:
To a solution of 8-amino-2-naphthol (5.0 g, 31.4 mmol) in 200 mL of dimethylformamide was added imidazole (2.4 g, 34 mmol) and tert-butyldiphenylsilyl chloride (8.6 mL, 33 mmol). After 48 hours, water was added and the reaction was stirred overnight. The solution was partitioned between EtOAc and water, washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to provide the titled product (45.0 g). The crude product was purified by silica gel chromatography (10% EtOAc/hexane) to provide the pure titled product.