Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[NH:48]1[CH2:53][CH2:52][CH2:51][CH:50]([C:54]([OH:57])([CH3:56])[CH3:55])[CH2:49]1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:48]2[CH2:53][CH2:52][CH2:51][CH:50]([C:54]([OH:57])([CH3:56])[CH3:55])[CH2:49]2)=[O:15])=[CH:6][CH:7]=1
Reactant: CC(C)(O)C1CCCNC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2oncc2C(=O)N2CCCC(C(C)(C)O)C2)cc1
Reaction time: 2 h
Yield: 54.8 %

Procedure:
A solution of 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10 mg, 0.05 mmol), TBTU (19 mg, 0.06 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (17 μL, 0.10 mmol, 2 equ) in DMF (0.3 mL) was added to 2-piperidin-3-ylpropan-2-ol hydrochloride (9 mg, 0.05 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (9 mg). MS (ESI, pos. ion) m/z calcd for C19H24N2O3: 328.1787, found 328.1787.
Reaction SMILES: [C:1]1([C:7]2([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:16]=[N+:17]([O-])[CH:18]=[CH:19][CH:20]=4)[N:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C1C=CC=CC=1.[CH2:31]([N:33](CC)CC)C.C[Si](C#N)(C)C>CC#N.C(Cl)Cl.CCOC(C)=O.C(Cl)Cl>[C:1]1([C:7]2([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([C:31]#[N:33])=[N:17][CH:16]=4)[N:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: [O-][n+]1cccc(-c2csc(C3(c4ccccc4)CC3)n2)c1
Agent: C[Si](C)(C)C#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(Cl)c1ccccc1
Product: N#Cc1ccc(-c2csc(C3(c4ccccc4)CC3)n2)cn1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
3-[2-(1-phenylcyclopropyl)-1,3-thiazol-4-yl]pyridine 1-oxide (2-1, 0.156 g, 01.53 mmol) in anhydrous CH3CN (10.0 mL) was treated with benzoyl chloride (0.073 mL, 0.089 mmol) and triethylamine (0.088 mL, 0.636 mmol) and the mixture was cooled to 0° C. Trimethylsilyl cyanide (0.136 mL, 1.06 mmol) was added and the reaction stirred 48 h at 25° C. The reaction was directly subjected to flash chromatography (SiO2, ISCO 10 g Redi-sep, 1% EtOAc/CH2Cl2) followed by preparative TLC (100% CH2Cl2) and provided 5-[2-(1-phenylcyclopropyl)-1,3-thiazol-4-yl]pyridine-2-carbonitrile (2-2). 1H NMR (300 MHz, CDCl3) δ 9.82 (d, J=1.5 Hz, 1H), 8.31 (dd, J=8.2, 2.2 Hz, 1H), 7.72 (dd, J=8.2, 0.7 Hz, 1H), 7.52 (m, 2H), 7.47 (s, 1H), 7.40 (m, 3H), 1.86 (dd, J=6.9, 3.9 Hz, 2H), 1.50 (dd, J=6.9, 3.9 Hz, 2H); MS 304.0 found 304.4 (M+H+) required.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[F:12][C:13]1[C:14]([C:19]2([CH2:23][NH2:24])[CH2:22][CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][CH:18]=1.CCN(C(C)C)C(C)C.CN1C(=O)CCC1>O.C(OCC)(=O)C>[F:12][C:13]1[C:14]([C:19]2([CH2:23][NH:24][C:2]3[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=3)[CH2:22][CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCC1(c2ncccc2F)CCC1
Reactant: COC(=O)c1ccc(Cl)nn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NCC2(c3ncccc3F)CCC2)nn1
Temperature: 120 °C
Yield: 51.5 %

Procedure:
To a 20 dram vial was added methyl 6-chloropyridazine-3-carboxylate (510 mg, 2.7 mmol, 1.0 equiv), (1-(3-fluoropyridin-2-yl)cyclobutyl)methanamine (738 mg, 4 mmol, 1.5 equiv), DIPEA (0.7 mL, 4 mmol, 1.5 equiv), and NMP (2 mL). The reaction was heated at 120° C. for 40 min and then diluted with water (20 mL) and ethyl acetate (50 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (1×20 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (20-100% EtOAc/hexanes) to give 440 mg (48%) of methyl 6-((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazine-3-carboxylate as a white solid. m/z=331.1 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([NH:6][C:7]2[C:12](=[O:13])[NH:11][CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[C:25]([CH3:32])[CH:24]=4)=[O:21])[CH:15]=3)[CH:8]=2)[CH2:3]1.[C:33]([Cl:37])(=[O:36])[CH:34]=[CH2:35]>C(Cl)Cl>[ClH:37].[C:33]([N:2]1[CH2:5][CH:4]([NH:6][C:7]2[C:12](=[O:13])[NH:11][CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:30])[CH3:31])=[C:25]([CH3:32])[CH:24]=4)=[O:21])[CH:15]=3)[CH:8]=2)[CH2:3]1)(=[O:36])[CH:34]=[CH2:35]
Reactant: Cc1cc(NC(=O)c2cc(-c3c[nH]c(=O)c(NC4CNC4)c3)ccn2)ccc1C(C)C
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: C=CC(=O)N1CC(Nc2cc(-c3ccnc(C(=O)Nc4ccc(C(C)C)c(C)c4)c3)c[nH]c2=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
To a solution of 5-(azetidin-3-ylamino)-N-(4-isopropyl-3-methylphenyl)-6-oxo-1,6-dihydro-[3,4′-bipyridine]-2′-carboxamide hydrochloride (60 mg, 0.14 mmol) in DCM (20 mL) was added acryloyl chloride (0.14 mL, 0.17 mmol) and TEA (0.1 mL, 0.7 mmol)). The mixture was stirred overnight at RT. The reaction was quenched by addition of MeOH (2 mL) and 4M HCl in 1,4-dioxane (2 mL). Water was added, the mixture extracted several times with ethyl acetate, the organic layers dried (MgSO4), filtered and concentrated. The residue was purified by Prep. HPLC (pH<7) and converted to the HCl salt to afford 5-((1-acryloylazetidin-3-yl)amino)-N-(4-isopropyl-3-methylphenyl)-6-oxo-1,6-dihydro-[3,4′-bipyridine]-2′-carboxamide hydrochloride (16 mg, 24% yield) as a yellow solid: 1H NMR (400 MHz, MeOD) δ 8.70 (d, J=4.8 Hz, 1H), 8.37 (d, J=1.2 Hz, 1H), 7.81 (dd, J=1.6, 5.2 Hz, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 7.41 (d, J=1.6 Hz, 1H), 6.92 (s, 1H), 6.74 (d, J=2.4 Hz, 1H), 6.41 (dd, J=10.0, 16.8 Hz, 1H), 6.28 (dd, J=2.0, 16.8 Hz, 1H), 5.78 (dd, J=2.0, 10 Hz, 1H), 4.78-4.81 (m, 1H), 4.52-4.59 (m, 2H), 4.23-4.27 (m, 1H), 4.02-4.04 (m, 1H), 2.90-2.94 (m, 1H), 2.38 (s, 3H), 1.29 (d, J=6.8 Hz, 6H); MS (ES) m/z 472 (M+H).
Reaction SMILES: Br[C:2]1[C:3](=[O:13])[N:4]([CH2:8][CH2:9][CH2:10][CH2:11][Cl:12])[CH:5]=[CH:6][CH:7]=1.[F:14][C:15]1[N:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:12][CH2:11][CH2:10][CH2:9][CH2:8][N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:16]2[C:15]([F:14])=[N:20][CH:19]=[CH:18][CH:17]=2)[C:3]1=[O:13]
Reactant: O=c1c(Br)cccn1CCCCCl
Reactant: OB(O)c1ccc(F)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=c1c(-c2cccnc2F)cccn1CCCCCl
Yield: 79 %

Procedure:
The title compound was prepared in 79% yield using a similar procedure as set out earlier in Prep8 starting from 3-bromo-1-(4-chlorobutyl)-2(1H)-pyridinone (Prep7) (400 mg, 1.51 mmol), (6-fluoro-3-pyridinyl)boronic acid (commercial Alfa Aesar) (426 mg, 3.02 mmol), K2CO3 (627 mg, 4.54 mmol), triphenylphosphine (200 mg, 0.75 mmol) and palladium(II)acetate (68 mg, 0.30 mmol) dissolved in dioxane (5 ml).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:40])[O:15][CH2:16][C@@H:17]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=3[Cl:38])=[O:28])[CH2:18][C:19]([F:25])([F:24])[CH2:20][N:21]=[N+]=[N-])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:40])[O:15][CH2:16][C@@H:17]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=3[Cl:38])=[O:28])[CH2:18][C:19]([F:24])([F:25])[CH2:20][NH2:21])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc(-c2cccc(F)c2)no1)CC(F)(F)CN=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc(-c2cccc(F)c2)no1)CC(F)(F)CN
Yield: 53.8 %

Procedure:
To a mixture of (S)-5-azido-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4,4-difluoropentyl 3-(3-fluorophenyl)isoxazol-5-ylcarbamate (0.35 g, 0.6 mmol) in MeOH (2 mL), was added 10% Pd/C (0.1 g). The mixture was transferred to an autoclave reactor, charged with 10 psi of hydrogen, and stirred for 10 mM. The catalyst was filtered off and the filtrate was concentrated. The residue was purified on RP-HPLC using a mixture of acetonitrile and H2O with 0.1% TFA. The elute was washed with saturated NaHCO3. The organic layer was concentrated to give (S)-5-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4,4-difluoropentyl 3-(3-fluorophenyl)isoxazol-5-ylcarbamate (0.18 g, 54%) as a white solid. LRMS (M+H+) m/z 558.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:10].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[F:29]>N1C=CC=CC=1>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[O:10])(=[O:27])=[O:26])=[CH:21][C:20]=1[F:29]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(Br)c(F)c2)cn1

Procedure:
The title compound was prepared according to the general procedures for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone 2.4 g (8.77 mmol) and 4-bromo-3-fluoro-benzenesulfonyl chloride 2.16 g (8.77 mmol) stirred in 14 ml pyridine. Purification on silica gel with flash column chromatography gave a light orange solid.
Reaction SMILES: [C:1]([CH:6]([CH2:10]C#C)[C:7](=O)[CH3:8])([O:3][CH2:4][CH3:5])=O.C(=O)(O)O.[NH2:17][C:18]([NH2:20])=[NH:19].CC(C)=O>CS(C)=O>[CH3:8][C:7]1[C:6]2[CH:10]=[C:4]([CH3:5])[O:3][C:1]=2[N:17]=[C:18]([NH2:20])[N:19]=1
Reactant: N=C(N)N
Reactant: C#CCC(C(C)=O)C(=O)OCC
Agent: O=C(O)O
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: Cc1cc2c(C)nc(N)nc2o1
Yield: 8.3 %

Procedure:
A mixture of 4.0 g 3-carbethoxy-5-hexyn-2-one and 2.4 g guanidine carbonate was heated in 6 ml dimethylsulfoxide under a nitrogen atmosphere at 110°-120° for 2 hours. The solution was then cooled, acetone added and the solid collected then rinsed with water to afford 0.27 g of 4,6-dimethylfuro[2,3-d]pyrimidin-2-amine: m.p. 263°-265°. The above filtrates were diluted further with water and the deposited solid was collected and dried to give 0.44 g of 2-amino-6-methyl-5-(2-propynyl)-4(3H)pyrimidinone, m.p. 245°-249°. Absorptions at 2.1 (triplet), 2.55 (singlet), and 3.45 (doublet) ppm in the nuclear magnetic resonance spectrum (60 MHz) indicated the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:22]1([C:28](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:1]([O:3][C:4]([CH:6]1[C:14]2[N:13]=[CH:12][N:11]([C:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C1CCCc2[nH]cnc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C1CCCc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of 4,5,6,7-tetrahydro-1H-benzimidazole-4-carboxylic acid ethyl ester (18.9 g, 97 mmol, J. Am. Chem. Soc., 1996, 98, 984) in acetonitrile (250 ml) were added triethylamine (27 ml, 194 mmol) and a solution of triphenylmethyl chloride (40.6 g, 146 mmol) in acetonitrile (500 ml). The resulting mixture was stirred at 20° C. overnight. The mixture was concentrated under reduced pressure and the residue was re-dissolved in ethyl acetate, washed with water (2×) and brine (1×), and concentrated under reduced pressure. The residue was recrystallised from ethyl acetate/heptane, to yield 20.8 g (49%) of 1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole-4-carboxylic acid ethyl ester as colourless solid. From the mother liquor more product (10.3 g, 24%) was isolated by column chromatography (silica gel, gradient elution with heptane/ethyl acetate 9:1 to 1:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[C:11]([NH2:13])[N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](I)[CH:15]=2)[N:9]=1.[C:21]([NH2:26])(=[O:25])[C:22]([CH3:24])=[CH2:23].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:13][C:11]1[N:10]([C:14]2[CH:15]=[C:16](/[CH:23]=[C:22](\[CH3:24])/[C:21]([NH2:26])=[O:25])[CH:17]=[CH:18][CH:19]=2)[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:12]=1
Reactant: C=C(C)C(N)=O
Reactant: Nc1cc(-c2ccccc2F)nn1-c1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C/C(=C\c1cccc(-n2nc(-c3ccccc3F)cc2N)c1)C(N)=O
Temperature: 80 °C
Yield: 94.4 %

Procedure:
3-(2-Fluorophenyl)-1-(3-iodophenyl)-1H-pyrazol-5-amine (0.500 g, 1.32 mmol, 1.00 eq), methacrylamide (0.281 g, 3.30 mmol, 2.50 eq), Pd(OAc)2 (0.0118 g, 0.0527 mmol, 0.04 eq), Ph3P (0.0346 g, 0.132 mmol, 0.10 eq) and Et3N (0.919 ml, 6.59 (mmol, 5.00 eq) were combined in DMF (3 ml) and heated at 80° C. overnight. The reaction was cooled to RT, diluted with H2O and extracted with EtOAc (2×). The combined organics were washed with 5% citric acid (2×), brine (1×) and dried (MgSO4). Filtration and evaporation gave crude product which was purified by flash chromatography to afford 0.4192 g (95%) of pure (E)-3-(3-(5-amino-3-(2-fluorophenyl)-1H-pyrazol-1-yl)phenyl)-2-methylacrylamide. MS (ESI) m/z: 337.2 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:25])[NH:10][C@H:11]([CH2:19]OS(C)(=O)=O)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:26]=[N+:27]=[N-:28].[Na+].O.C(OCC)(=O)C>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9](=[O:25])[NH:10][C@H:11]([CH2:19][N:26]=[N+:27]=[N-:28])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 88.5 %

Procedure:
A solution of (S)-[1-[[(methylsulphonyl)oxy]methyl]-2-phenylethyl]carbamic acid phenylmethyl ester (2.0 g, 5.5 mmol) in dimethylformamide (35 ml) was heated with sodium azide (0.43 g, 6.6 mmol) at 80° C. for 4.5 h. The reaction was then cooled and poured into iced water (100 ml) and ethyl acetate (70 ml). The aqueous phase was extracted with ethyl acetate (2×70 ml) and the combined extract was washed with water (50 ml), dried (MgSO4) and evaporated to leave an oil which was purified by flash chromatography eluting with 20% ethyl acetate in cyclohexane to give the title compound (1.51 g) as an oil, MH+ =312.
Reaction SMILES: C([Li])(CC)C.[CH2:6]([N:8]([CH2:18][CH3:19])[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[CH3:7].CN([CH:23]=[O:24])C.Cl>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH2:18]([N:8]([CH2:6][CH3:7])[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[CH:23]=[O:24])[CH3:19]
Reactant: CCN(CC)C(=O)c1ccc(C)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C)cc1C=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Tetramethylethyleneamine (6.20 g, 5336 mmol, 8.05 mL) was dissolved in anhydrous THF (100 mL) under argon and cooled to minus 78EC. s-Butyl lithium (1.30M, 53.36 mmol, 41.04 mL) was added to the solution slowly via syringe. The solution was stirred for 10 min at minus 78EC, then N,N-diethyl-4-methyl-benzamide (9.28 g, 48.51 mmol), dissolved in 50 mL of anhydrous THF was added to the reaction mixture over 15 min. The reaction was stirred for 1 h at minus 78EC, the DMF (7.09 g, 97.02 mol, 7.51 mL) was added to the solution rapidly. The reaction mixture was allowed to slowly warm to room temp and stir for 12 h. The reaction mixture was poured into 1N HCl and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (3:1 hexane/ethyl acetate) Yield 7.98 g. 1H NMR (CDCl3, 300 MHz): δ 1.08 (t, 3H), 1.32 (t, 3H), 2.46 (s, 3H), 3.13 (q, 2H), 3.42 (a, 2H), 7.28 (d, J=8, 1H), 7.45 (d, J=7, 1H), 7.77 (s, 1H), 10.01 (s, 1H).
Reaction SMILES: O.[I-:2].[I-].[I-].[I-].[CH2:6]([C:8]1[C:21]2[C:12](=[S+:13][C:14]3[C:19]([N:20]=2)=[C:18]([CH3:22])[CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)[CH3:7].C(C1[C:38]2[C:29](=[S+][C:31]3[C:36]([N:37]=2)=C(C)C=CC=3)C=CC=1)C.C(C1C2C(=[S+]C3[C:53]([N:54]=2)=C(C)C=CC=3)C=CC=1)C.C(C1C2C(=[S+]C3C(N=2)=C(C)C=CC=3)C=CC=1)C.[CH3:74][N:75]1[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]1>CO>[I-:2].[CH3:74][N:75]1[CH2:80][CH2:79][N:78]([C:10]2[C:9]([N:37]3[CH2:36][CH2:31][N:54]([CH3:53])[CH2:29][CH2:38]3)=[C:8]([CH2:6][CH3:7])[C:21]3[C:12]([CH:11]=2)=[S+:13][C:14]2[C:19](=[C:18]([CH3:22])[CH:17]=[CH:16][CH:15]=2)[N:20]=3)[CH2:77][CH2:76]1
Reactant: CCc1cccc2[s+]c3cccc(C)c3nc12
Reactant: CN1CCNCC1
Agent: [I-]
Solvent: CO
Solvent: O
Product: CCc1c(N2CCN(C)CC2)c(N2CCN(C)CC2)cc2[s+]c3cccc(C)c3nc12

Procedure:
A solution of 1-ethyl-9-methylphenothiazin-5-ium tetraiodide hydrate (50 mg, 0.07 mmol) in methanol (10 mL) and 1-methylpiperazine (30 mg, 0.3 mmol) was stirred for 2 h at room temperature. The resulting mixture was concentrated to dryness and purified by flash chromatography using the methanol-chloroform gradient to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CC(=O)c1cnc(OCC(F)(F)F)c(Cl)c1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCC(F)(F)F)c(Cl)c1
Yield: 57 %

Procedure:
The title compound is prepared in 57% yield (0.65 g, a white solid) from 1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (0.8 g, 3.15 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[CH:15]=[C:16]([OH:19])[CH:17]=2)[CH2:12][NH:11][C:10]1=[O:27].C(=O)([O-])[O-].[K+].[K+].[CH2:34](Cl)[CH:35]=[CH2:36].[I-].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[CH:15]=[C:16]([O:19][CH2:36][CH:35]=[CH2:34])[CH:17]=2)[CH2:12][NH:11][C:10]1=[O:27]
Reactant: O=C1NCc2c(-c3ccccc3Cl)cc(O)cc2N1c1c(Cl)cccc1Cl
Reactant: C=CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2

Procedure:
A solution containing 1-(2,6 dichlorophenyl)-5-(2-chlorophenyl)-7-hydroxy-3,4-dihydro-2(1H)-quinazolinone (259 mg, 0.617 mmol) (INTERMEDIATE 49), potassium carbonate (300 mg, 2.2 mmol), allyl chloride (0.45 mL, 5.53 mmol) and sodium iodide (87 mg, 0.58 mmol) in 15 mL acetone was refluxed for seven hours. The solution was concentrated and the residue partitioned between EtOAc and water. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography using 2% acetone in DCM to give 1-(2,6-dichlorophenyl)-5-(2chlorophenyl)-7-allyloxy-3,4-dihydro-2(1H)-quinazolinone. 1H NMR(CDCl3, 500 MHz): δ 4.18 (d, 1H, 14.2 Hz), 4.34 (d, 1H, J=14.2 Hz), 4.40 (app d, 2H, J=5.5 Hz), 5.20-5.32(m, 2H), 5.77 (d, 1H, J=2.3 Hz), 5.82 (s, 1H), 5.90-6.00 (m, 1H), 6.44 (d, 1H, J=2.3 Hz), 7.27-7.31 (m, 1H), 7.32-7.38 (m, 3H), 7.48-7.52 (m, 3H). MS(ES) 459 (M+H); LC 1: 3.30 min.
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][NH2:17].[C:18]([C:21]([N:27]([CH3:37])[C:28]([C:30]1[CH:35]=[CH:34][C:33]([I:36])=[CH:32][CH:31]=1)=[O:29])([CH3:26])[C:22]([NH:24][CH3:25])=[O:23])(O)=[O:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[I:36][C:33]1[CH:32]=[CH:31][C:30]([C:28]([N:27]([CH3:37])[C:21]([CH3:26])([C:18]([NH:17][O:16][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)=[O:19])[C:22]([NH:24][CH3:25])=[O:23])=[O:29])=[CH:35][CH:34]=1
Reactant: NOC1CCCCO1
Reactant: CNC(=O)C(C)(C(=O)O)N(C)C(=O)c1ccc(I)cc1
Agent: 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
Solvent: O
Product: CNC(=O)C(C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DIPEA (0.11 mL) and O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (24 mg) were added to a DMF (5.0 mL) solution of 1-{[2-carboxy-1-(methylamino)-1-oxopropan-2-yl](methyl)carbamoyl}-4-iodobenzene (Intermediate 11, 81 mg) and HATU (120 mg) under ice cooling, and the mixture was stirred for 2 hours at room temperature. Water was added, and the mixture was extracted with chloroform. Then, the organic layer was washed with brine, and dried over magnesium sulfate. The desiccant was filtered out, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by NH type silica gel column chromatography (gradient elution with chloroform/methanol=100/0→95/5) to obtain 2-[(4-iodobenzoyl)(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (Intermediate 12, light yellow oil) (59 mg, 57%).