Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)=[O:4].[N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][CH:13]=1>O1CCOCC1>[N:12]1([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=2)=[O:4])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: c1ccc2[nH]cnc2c1
Solvent: C1COCCO1
Product: O=C(Cn1cnc2ccccc21)c1cccc(Br)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 2-bromo-1-(3-bromophenyl)ethanone (120 mg, 0.432 mmol) in dioxane (2 mL) was added benzoimidazole (102.0 mg, 0.864 mmol) and the reaction mixture was stirred for 1 h at 80° C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using MeOH:CH2Cl2 (4:96) as eluent to give the sub-title compound in 53% yield (71.8 mg, 0.227 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17]([N:19]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:20]3=[O:30])=[O:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[CH:40][N:39]=1>O1CCOCC1.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>[CH3:15][C:14]1[N:13]=[C:12]([NH:16][C:17]([N:19]2[CH2:23][CH2:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:20]2=[O:30])=[O:18])[CH:11]=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:42]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:37])[CH:43]=2)[CH:7]=1
Reactant: Cc1nc(NC(=O)N2CCN(C3CCOCC3)C2=O)ccc1Oc1ccnc(Cl)c1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
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: C1COCCO1
Solvent: O
Product: Cc1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)nc3C)ccn2)ccn1
Temperature: 80 °C
Yield: 35.4 %

Procedure:
A mixture of Example C3 (0.377 g, 0.873 mmol) and K2CO3 (0.362 g, 2.62 mmol) in dioxane (4 mL) and water (1 mL) was sparged with Ar, treated with 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.201 g, 0.917 mmol) and Pd(Ph3P)4 (0.101 g, 0.087 mmol), sparged again with Ar and heated at 80° C. overnight. The mixture was cooled to RT, diluted with EtOAc, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc). The material was treated with Et2O, stirred at RT and the resulting solid collected via filtration and dried to afford N-(6-methyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (151 mg, 35%). 1H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1 H), 8.56 (d, J=5.6 Hz, 1 H), 8.52 (d, J=5.2 Hz, 1 H), 7.93-7.88 (m, 2 H), 7.79 (dd, J=5.3, 1.6 Hz, 1 H), 7.66-7.63 (m, 2 H), 6.86 (dd, J=5.6, 2.4 Hz, 1 H), 3.93-3.77 (m, 5 H), 3.49-3.34 (m, 4 H), 2.52 (s, 3 H), 2.26 (s, 3 H), 1.78-1.66 (m, 2 H), 1.63-1.57 (m, 2H); MS (ESI) m/z: 489.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:22]([F:25])([F:24])[F:23])=[CH:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[O:26]1[CH:30]=[CH:29][CH2:28][CH2:27]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:22]([F:25])([F:23])[F:24])=[CH:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:19][CH:27]3[CH2:28][CH2:29][CH2:30][O:26]3)=[O:18])=[CH:15][CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C1=COCC1
Reactant: NC(=O)c1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(C(=O)NC2CCCO2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
To a solution of 0.25 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)benzoic acid amide that was synthesized under Synthetic Example 9 in 3 mL of dichloromethane, 68 mg of 2,3-dihydrofuran and a catalytic amount of p-toluenesulfonic acid monohydrate were added and the mixture was stirred for 18 hours at room temperature. The solvent was distilled off from the reaction solution under reduced pressure, and the resulting residue was purified using silica gel column chromatography that was eluted with ethyl acetate-hexane (2:3) followed by crystallization from a mixed solvent of hexane and a small amount of ethyl acetate to obtain 0.12 g of aimed product as yellow solid.
Reaction SMILES: [C:1]1(=[O:28])[N:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12.CO.[ClH:31].C[CH2:33][O:34]CC>C(Cl)(Cl)Cl>[ClH:31].[C:4]1(=[O:23])[N:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]=[CH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19](=[NH:20])[O:34][CH3:33])=[CH:17][CH:16]=3)=[CH:11][CH:12]=2)[C:1](=[O:28])[C:2]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:3]12
Reactant: CCOCC
Reactant: N#Cc1ccc(C=Cc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)cc1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=N)c1ccc(C=Cc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1.7 g of 4-[2-(4-phthalimidomethylphenyl)ethenyl]benzonitrile in 100 ml of chloroform was added at room temperature slowly dropwise 30 ml of anhydrous methanol saturated with anhydrous hydrogen chloride. The mixture was stirred at room temperature for 15 hours. The reaction mixture was stripped of the solvent under reduced pressure. Ether was added to the residue and the precipitated crystals were collected by filtration to yield 1.6 g of methyl 4-[2-(4-phthalimidomethylphenyl)ethenyl]benzimidate hydrochloride; m.p. 230°-234° C. (decomp.).
Reaction SMILES: [CH2:1]([S:3]([C@@H:6]1[N:9]([C:10](=[O:12])[CH3:11])[C:8](=[O:13])[C@H:7]1[CH2:14][CH2:15][CH2:16][N:17](C(OCC1C=CC=CC=1)=O)[C:18]([NH:20]C(OCC1C=CC=CC=1)=O)=[NH:19])(=[O:5])=[O:4])[CH3:2].[ClH:41]>[Pd].CO.C(OCC)(=O)C>[ClH:41].[CH2:1]([S:3]([C@@H:6]1[N:9]([C:10](=[O:12])[CH3:11])[C:8](=[O:13])[C@H:7]1[CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH2:20])=[NH:19])(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)[C@H]1[C@H](CCCN(C(=N)NC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)C(=O)N1C(C)=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)[C@H]1[C@H](CCCNC(=N)N)C(=O)N1C(C)=O
Yield: 62 %

Procedure:
A methanol/ethyl acetate (2.5 mL/2.5 mL) solution of compound 22 (380 mg, 0.66 mmol) and lN HCl (0.66 mL), containing 10% palladium on carbon, was stirred under a hydrogen atmosphere until TLC indicated the disappearance of the starting material. The suspension was filtered through a pad of Celite, and the solution was concentrated to afford 140 mg (62%) of the product as a yellow foam.
Reaction SMILES: [SH:1][C@H:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH2:5][O:4][CH2:3]1.ClOC(C)(C)C.[Cl:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH2:22].S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Cl:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH:22][S:1][C@H:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH2:5][O:4][CH2:3]1
Reactant: Nc1ccc(F)cc1Cl
Reactant: CCOC(=O)C1=CCOC[C@H]1S
Agent: CC(C)(C)OCl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1=CCOC[C@H]1SNc1ccc(F)cc1Cl
Reaction time: 0.5 h

Procedure:
To a solution (400 mL) of ethyl (3S)-3-sulfanyl-3,6-dihydro-2H-pyran-4-carboxylate (14.5 g) in dichloromethane was added dropwise tert-butyl hypochlorite (10 mL) at −78° C. After stirring for 30 min, 2-chloro-4-fluoroaniline (23 mL) was added dropwise at −78° C. The reaction mixture was stirred for 1 hr, and the reaction was discontinued with 5% aqueous sodium sulfite solution (300 mL). After extraction with dichloromethane (300 mL), the extract was washed with water, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=15:1→5:1) to give the title compound as a crude product (20.0 g, 96.3% ee). This product was crystallized from diisopropyl ether/hexane (120 mL, 1:5) to give the title compound (12.3 g, 62%) as white crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:22])[N:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3.[OH-].[Na+].[CH2:25]([OH:29])[CH2:26][CH2:27][OH:28]>O>[OH:28][CH2:27][CH2:26][CH2:25][O:29][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:22])[N:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3
Reactant: OCCCO
Reactant: O=C1c2cccc3c(Br)ccc(c23)C(=O)N1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C1c2cccc3c(OCCCO)ccc(c23)C(=O)N1c1ccccc1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
A mixture of 6-bromo-2-phenyl-benzo[de]isoquinoline-1,3-dione (4.0 g), sodium hydroxide (0.67 g) and 1,3-propane diol (50 ml) was maintained with stirring at 120° C. for 10 hrs. The reaction mixture was cooled to room temperature. Water (100 ml) was added to the mixture and solid separated out. The solid was filtered, washed with water, and dried at 100° C. for 8 hours to provide a crude product in a yield of 1.90 g. The crude product was purified using mono chloro benzene (60 ml) and activated charcoal (0.20 g). The weight of the of the purified product obtained was 1.15 g. 1H-NMR: 3.93 δ (m, 2 protons); 4.35 δ (m, 1 proton); 2.25 δ (m, 2 protons); 3.96 δ (m, 2 protons); 4.47 δ (m, 2 proton); 7.13 δ (m, 2 protons); 5.14 δ (m, 1 proton); 7.36 δ (m, 3 protons); 7.51 δ (m, 3 protons); 7.84 δ (m, 1 proton); 8.46 δ (m, 2 protons); 8.69 δ (m, 1 proton).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1.N1C=CC=CC=1.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>ClCCl>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH:19][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cccc(C2CC(C)(C)c3cc(C)ccc3N2)c1
Yield: 37.4 %

Procedure:
To a stirred mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.56 mmol) in dichloromethane (3 mL) was added pyridine (79 mg, 1.01 mmol) in dichloromethane (2 mL) and ethanesulfonyl chloride (108 mg, 0.84 mmol) under nitrogen. The resultant mixture was stirred for 18 h. The reaction mixture was diluted with dichloromethane, washed with water (twice), saturated brine, and dried over Magnesium sulfate. Magnesium sulfate was removed by filtration, and after evaporation, the residue was purified on chromatography column (silica gel, petroleum ether: ethyl acetate=10:1) to afford 75 mg of ethanesulfonic acid [3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide yellow solid (Yield: 37%). MS (ESI+APCI) M+1=359.2.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.Cl.[CH3:8][N:9]1[C:18]2[NH:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[N:14]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)=[C:27]([CH3:41])[CH:26]=3)=[O:24])[CH2:13][C:12]=2[CH:11]=[N:10]1>ClCCl.C(N(CC)CC)C>[CH3:1][S:2]([N:38]1[CH2:37][CH2:36][N:35]([CH2:34][CH2:33][CH2:32][O:31][C:28]2[CH:29]=[CH:30][C:25]([C:23]([N:14]3[CH2:13][C:12]4[CH:11]=[N:10][N:9]([CH3:8])[C:18]=4[NH:17][C:16]4[CH:19]=[CH:20][CH:21]=[CH:22][C:15]3=4)=[O:24])=[CH:26][C:27]=2[CH3:41])[CH2:40][CH2:39]1)(=[O:4])=[O:3]
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCN1CCNCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCN1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methanesulfonyl chloride (0.57 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of (3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-[3-methyl-4-(3-piperazin-1-yl-propoxy)-phenyl]-methanone dihydrochloride (Compound number 408) (2.67 mg, 0.005 mmol) in dichloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 1 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=539.2
Reaction SMILES: F[C:2](F)(F)C(O)=O.C([Zn]CC)C.ICI.[C:16]([NH:19][C@@:20]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][C:24](=[CH2:26])[C@@H:23]2[C@H:21]1[C@H:22]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])(=[O:18])[CH3:17]>ClCCl>[C:16]([NH:19][C@@:20]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][C:24]2([CH2:2][CH2:26]2)[C@@H:23]2[C@H:21]1[C@H:22]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])(=[O:18])[CH3:17]
Reactant: C=C1C[C@@](NC(C)=O)(C(=O)OCC)[C@H]2[C@@H]1[C@@H]2C(=O)OCC
Reactant: O=C(O)C(F)(F)F
Agent: CC[Zn]CC
Solvent: ClCCl
Solvent: ICI
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(C)=O)(C(=O)OCC)CC21CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under nitrogen, add a solution of trifluoroacetic acid (1.9 mL, 25 mmol) in dichloromethane (12.5 mL) dropwise very slowly to a cooled (ice bath) stirred solution of diethylzinc (1M in heptanes) (25 mL, 25 mmol) in dichloromethane (12.5 mL). After 10 minutes, add a solution of diiodomethane (2.01 mL, 25 mmol) in dichloromethane (12.5 mL). After 10 minutes, add a solution of diethyl (1S,2S,5R,6S)-2-acetamido-4-methylene-bicyclo[3.1.0]hexane-2,6-dicarboxylate (2.46 g, 8.3 mmol) in dichloromethane (12.5 mL). After 60 minutes remove the ice bath and leave the reaction mixture to stir overnight at room temperature. Quench the clear reaction solution by dropwise addition of the reaction mixture to 0.2M aqueous hydrochloric acid (200 mL) under vigorous stirring. After 1 hour separate the dichloromethane layer, wash with brine, dry over magnesium sulfate, filter and concentrate in vacuum to yield the required product contaminated with unreacted starting material (4.4 g). Purify by flash chromatography eluting with ethyl acetate:cyclohexane (50:50 to 100:0) to give a colorless oil (3.1 g). Purify by SFC(RT=2.48 minutes (UV, 200 nm); HPLC Column: AD-H 30 mm×250 mm 5 μm; CO2 gradient: 5% iso-propyl alcohol w/0.2% dimethylethylamine for 0.5 minutes, then 5%-27% in 2.2 minutes. Column temperature: 35° C.; pressure: 100000 kPa; flow rate: 210 mL/minute) to yield unreacted diethyl (1S,2S,5R,6S)-2-acetamido-4-methylene-bicyclo[3.1.0]hexane-2,6-dicarboxylate. (580 mg, 2.0 mmol) and title compound (1.82 g, 5.9 mmol). MS (m/z): 310 (M+1), 332 (M+23).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1
Yield: 95.8 %

Procedure:
4-(5-Bromopyrirnidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1.01 g), 4-fluorophenylboronic acid (0.45 g), tetrakis(triphenylphosphine)palladium(0) (0.12 g) and potassium phosphate (1.25 g) were dissolved in a mixture of 1,2-dimethoxyethane (40 ml) and water (10 ml), degassed and heated to reflux under nitrogen. After 16 h. the reaction was cooled, reduced in vacuo, dissolved in diethyl ether (100 ml) and washed with water (3×20 ml), saturated brine (20 ml), dried (Na2SO4) and evaporated. The black residue was then chromatographed on silica, with 2% methanol/dichloromethane to provide the title compound as a pale yellow solid (1.01 g, 96%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:15][CH2:14][CH2:13][C:4]=2[N:5]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:7]=1.[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][OH:23])=[CH:19][CH:18]=1>CN1C(=O)CCC1.O>[CH:8]1([C:6]2[N:7]=[C:2]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([CH2:21][CH2:22][OH:23])=[CH:19][CH:18]=3)[C:3]3[CH2:15][CH2:14][CH2:13][C:4]=3[N:5]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Nc1ccc(CCO)cc1
Reactant: Clc1nc(C2CCCC2)nc2c1CCC2
Solvent: CN1CCCC1=O
Solvent: O
Product: OCCc1ccc(Nc2nc(C3CCCC3)nc3c2CCC3)cc1
Temperature: 120 °C
Yield: 51.4 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-cyclopentyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.132 g, 0.59 mmol) and 4-aminophenethyl alcohol (0.162 g, 1.18 mmol) in NMP (4 mL). The resulting mixture was heated at 120° C. under microwave irradiation for 2 h. The reaction mixture was cooled, diluted with water (40 mL) to afford a solid. The solid was isolated by filtration then purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford the title compound (0.098 g, 51%) as a light brown solid. MW=323.43. M.p. 178-180° C. 1H NMR (DMSO-d6, 500 MHz) δ 8.47 (s, 1H), 7.70 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H), 4.59 (t, J=5.0 Hz, 1H), 3.61-3.55 (m, 2H), 3.09 (quin, J=8.0 Hz, 1H), 2.77 (q, J=7.5 Hz, 4H), 2.67 (t, J=7.0 Hz, 2H), 2.01 (quin; J=7.5 Hz, 2H), 1.97-1.90 (m, 2H), 1.87-1.78 (m, 2H), 1.78-1.68 (m, 2H), 1.65-1.55 (m, 2H); APCI MS m/z 324 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][N:31]3[CH2:30][CH2:29][N:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[O:21][CH3:20])[CH2:33][CH2:32]3)[O:13][N:12]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1ccc(-c2cc(CCC=O)on2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccccc4OC)CC3)on2)cc1OC
Yield: 108 %

Procedure:
About 2 min after dissolving 3-[3-(3,4-dimethoxyphenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-(2-methoxyphenyl)piperazine (7.4 mg, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (24 mg, 0.12 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 22.6 hr and followed the same processes as in Example 1 to obtain 18.9 mg (100%) of the target compound.
Reaction SMILES: [C:1]1([S:7]([CH:10]([NH2:30])[C:11]2[N:16]([CH3:17])[C:15]([C:18](O)=[O:19])=[C:14]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13](=[O:29])[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:31][NH:32][C:18]([C:15]1[N:16]([CH3:17])[C:11]([CH:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[NH2:30])=[CH:12][C:13](=[O:29])[C:14]=1[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:19]
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(C(N)S(=O)(=O)c2ccccc2)n1C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
To a stirred solution of 6-(benzene sulfonyl amino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-01) (400.0 mg, 0.935 mmol) in dimethylformamide (10 mL) were added HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (426.17 mg, 1.12 mmol) and diisopropylethylamine (1.08 mL, 6.54 mmol). The mixture was stirred for 30 min., thenmethylamine hydrochloride salt (189.31 mg, 2.80 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, it was quenched with ice cold water and the reaction mixture was extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. It was then purified using normal column chromatography to get 6-(benzene sulfonyl amino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methyl amide (15-01) (180.0 mg, 43.62%) as a white solid.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@H:9]([CH2:28][F:29])[C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:27])(=[N:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[O:19])=[CH:14][CH:13]=1)[OH:11].C([O:32][C:33](=O)[CH:34]([Cl:36])[Cl:35])C>CO>[Cl:35][CH:34]([Cl:36])[C:33]([NH:8][C@H:9]([CH2:28][F:29])[C@H:10]([OH:11])[C:12]1[CH:13]=[CH:14][C:15]([S:18]([CH3:27])(=[N:20][C:21](=[O:26])[C:22]([F:24])([F:25])[F:23])=[O:19])=[CH:16][CH:17]=1)=[O:32]
Reactant: CS(=O)(=NC(=O)C(F)(F)F)c1ccc([C@@H](O)[C@H](N)CF)cc1
Reactant: CCOC(=O)C(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CS(=O)(=NC(=O)C(F)(F)F)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
To a solution of (1R,2S)-2-Amino-3-fluoro-1-(4-(methyl-N-(2,2,2-trifluoroacetyl)sulfonimidoyl)phenyl)-propan-1-ol TFA salt (426 mg, 1.479 mmol) in Methanol (5 mL) is added TEA (0.299 mL, 2.95 mmol) followed by addition of ethyldichloroacetate (0.279 mL, 1.775 mmol) The resulting reaction mixture is stirred at room temperature for 16 h. Solvent is evaporated in vacuo to get crude which is purified by combi-flash chromatography using 10.3% MeOH in DCM as an eluent to afford title compound (212 mg) as yellow oil. 1H-NMR (400 MHz, DMSO) δ: 3.02 (s, 3H), 4.19-4.13 (m, 1H), 4.15 (bs, 1H), 4.36-4.41 (m, 1.5H), 4.44-4.56 (m, 1H), 4.66-4.69 (m, 0.5H), 4.93 (t, J=4.56 Hz, 1H), 6.0 (d, J=4.64 Hz, 1H), 7.54 (d, J=8.28 Hz, 2H), 7.87 (d, J=8.36 Hz, 2H), 9.49 (d, J=8.36 Hz, 1H). LC-MS (m/z): M+H=343.1 (fragment).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][N:17]1[CH2:43][CH2:42][C:20]2[N:21]([CH2:29][CH:30](OS(C)(=O)=O)[C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][C:27]=3[C:19]=2[CH2:18]1>CN(C=O)C.O>[CH3:16][N:17]1[CH2:43][CH2:42][C:20]2[N:21]([CH2:29][CH:30]([O:8][C:1](=[O:9])[C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[C:31]3[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=3)[C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][C:27]=3[C:19]=2[CH2:18]1
Reactant: O=C(O)c1ccncc1
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccncc2)CCN(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(OC(=O)c2ccncc2)c2ccncc2)CCN(C)C1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 6.2 %

Procedure:
To a solution of isonicotinic acid (200 mg, 1.626 mmol) in DMF (10 mL) was added potassium carbonate (560 mg, 4.065 mmol) and stirred the solution at 80° C. for 30 min. Methanesulfonic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl ester (455 mg, 1.138 mmol) was added portionwise into the reaction mixture, which was stirred at 80° C. 30 min. The progress of reaction was monitored by LCMS and TLC. The reaction mixture was cooled to RT, diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (4×50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield isonicotinic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylester (30 mg). 1H NMR (CDCl3, freebase) δ (ppm): 8.79 (d, 2H), 8.58 (d, 2H), 7.77 (d, 2H), 7.23 (d, 1H), 7.18 (s 1H), 7.12 (d, 2H), 7.0 (d, 1H), 6.24 (t, 1H), 4.54 (dd, 1H), 4.35 (dd, 1H), 3.68 (s, 2H), 2.76 (t, 2H), 2.61 (m, 1H), 2.51 (s, 3H), 2.43 (s, 3H), 2.43 (m, 1H). Separation by chiral HPLC provided enantiomers 147a and 147b.