Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].O1CCCC1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1.Cl[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][C:23]=1[CH:28]=[O:29]>O>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:18][C:22]2[N:26]([CH3:27])[N:25]=[CH:24][C:23]=2[CH:28]=[O:29])=[CH:15][CH:14]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: Cn1ncc(C=O)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc(C=O)c1OCc1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 36.6 %

Procedure:
Under cooling in an ice bath, potassium tert-butoxide (217 mg) was added to a tetrahydrofuran (2.8 mL) solution of 4-chlorobenzyl alcohol (217 mg), and the obtained solution was then stirred for 20 minutes. Under cooling in an ice bath, 5-chloro-1-methyl-1H-pyrazol-4-carbaldehyde (200 mg) was added to the reaction solution, and the obtained solution was then stirred for 3 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=80:20 to 60:40), so as to obtain the title compound (127 mg) in the form of a colorless oily substance.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C.CCOC(C)=O>[CH2:14]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(COC2CCC3(CC2)OCCO3)cc1
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a mixture of 1,4-dioxaspiro[4.5]decan -8-ol (1.18 g, 7.46 mmol) and NaH (0.358 g, 8.96 mmol) in DMF (5 mL) at 0° C. was added benzyl bromide (1.06 mL, 8.95 mmol). After being stirred overnight under N2, water and EtOAc were added. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), concentrated and flash chromatographed using 10% EtOAc/hexane to give 1.524 g of the title compound. MS (EI) calcd: (M+1)+=249.1; found: 249.2. 1H NMR (300 MHz, CDCl3) δ (ppm) 7.35 (5H, m), 4.52 (2H, s), 3.95 (4H, m), 3.5 (1H, m), 1.95-1.50 (8H, m).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[N:22]=[CH:23][N:24]=[C:25]4[C:32]=3[C:31]3[C@@H:30]([CH2:33][C:34]#[N:35])[CH2:29][CH2:28][C:27]=3[S:26]4)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:36][Li].O.OO>CO>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[N:22]=[CH:23][N:24]=[C:25]4[C:32]=3[C:31]3[C@@H:30]([CH2:33][C:34]([NH2:35])=[O:36])[CH2:29][CH2:28][C:27]=3[S:26]4)[CH2:16][CH2:15]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]O
Reactant: N#CC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCN(Cc6ccccc6)CC5)CC4)c3c21
Agent: OO
Solvent: O
Solvent: CO
Product: NC(=O)C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCN(Cc6ccccc6)CC5)CC4)c3c21
Temperature: 0 °C
Reaction time: 4 h
Yield: 32.4 %

Procedure:
To a solution of 2-[(3R)-12-[[4-(4-benzylpiperazin-1-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetonitrile (270 mg, 0.55 mmol, 1.00 equiv) in methanol (25 mL) were added LiOH.H2O (70 mg) and H2O2 (30%) (1.2 mL). The resulting solution was stirred for 4 h at 0° C. in a water/ice bath. The reaction was then quenched by the addition of 100 mL of Na2SO3 (sat.). The resulting solution was extracted with 6×50 mL of dichloromethane and the organic layers combined. After evaporation, the residue was purified by silica gel column with dichloromethane/methanol (4:1). This resulted in 90 mg (32%) of Compound I-122 as a white solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH:14]1([OH:18])[CH2:17][CH2:16][CH2:15]1.N1C=CC=CC=1.O>ClCCl>[N+:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][C:2](=[O:3])[O:18][CH:14]2[CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([O-:13])=[O:12]
Reactant: OC1CCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCC1
Temperature: 25 °C

Procedure:
A solution of 4-nitrophenyl chloroformate (6.00 g) in dichloromethane (12 mL) is added dropwise to an ice-cooled mixture of cyclobutanol (2.00 g), and pyridine (2.4 mL) in dichloromethane (10 mL). The resulting mixture is stirred over night at room temperature. Water and dichloromethane are added and the organic phase is separated, washed with brine and dried over MgSO4. The solvent is evaporated leaving the title compound as an oil, which is used without further purification. Yield: 6.61 g (crude); LC (method 2): tR=1.30 min; Mass spectrum (ESI+): m/z=260 [M+Na]+.
Reaction SMILES: [I:1]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.O[CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[I:1][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: II
Reactant: CC(C)(C)OC(=O)NCCO
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCI
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.5 %

Procedure:
Iodine (30.46 g, 0.120 mol) was added in three portions to a solution of triphenylphosphine (28.85 g, 0.110 mol) and imidazole (7.49 g, 0.110 mol) in dichloromethane (654 mL), and the reaction was stirred until the iodine dissolved. A solution of tert-butyl 2-hydroxyethylcarbamate (17.7 g, 0.110 mol) in dichloromethane (150 mL) was added over a period of 45 minutes, and the reaction was stirred for 16 hours at ambient temperature. The reaction mixture was poured into saturated aqueous sodium thiosulfate and stirred until the solution became colorless. The organic layer was washed sequentially with saturated aqueous sodium thiosulfate, water, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure. The resulting pale yellow oil was purified by column chromatography on silica gel (eluting with 80:20 hexanes:ethyl acetate) to provide a pale yellow oil which slowly crystallized to afford 24.6 g of tert-butyl 2-iodoethylcarbamate as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25].CCOC(C)=O.C(Cl)(Cl)Cl>CN(C=O)C.[I-].[Na+]>[CH2:3]([O:10][N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CCCCCCl
Reactant: CC(C)(C)OC(=O)NOCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(CCCCC#N)OCc1ccccc1
Reaction time: 0.25 h
Yield: 86.8 %

Procedure:
Sodium iodide (84 mg, 0.56 mmol) and then sodium hydride (80% oil dispersion, 0.49 g, 16.3 mmol) were added to (A) (2.68 g, 12.0 mmol) in dry DMF (40 mL). After stirring 15 min, 5-chlorovaleronitrile (1.5 mL, 13.3 mmol) was added, and the suspension heated at 80°-85° C. for 4 h under argon. After cooling, the reaction was quenched with H2O (100 mL), then extracted with ether (4×75 mL). The combined organic layers were washed with 100 mL each of 1% aqueous Na2SO3, H2O and brine and then concentrated to give 4.39 g crude product. Column chromatography with 4.5% EtOAc/CHCl3 produced 3.17 g of (B) (87% yield): NMR δ 1.5-1.75 (s+m, 13 H), 2.3 (t, 2 H), 3.4 (t, 2 H), 4.77 (s, 2 H), 7.3 (s, 5 H). Anal. Calcd for C17H24N2O3 : C, 67.08; H, 7.95; N, 9.20. Found: C, 67.19; H, 7.99; N, 9.11.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[CH2:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)(=[O:10])=[O:9])[CH3:12]
Reactant: NCC1CCOCC1
Reactant: CCS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: CCS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 1-chloro-4-(ethylsulfonyl)-2-nitrobenzene (Step C of Example 2) and 4-aminomethyltetrahydropyran (Apollo Scientific Ltd.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12].O.O.[Sn](Cl)Cl.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C.C(O)C>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[CH3:1])[NH2:8]
Reactant: COc1cc([N+](=O)[O-])ccc1C
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(N)ccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a solution of 2-methyl-5-nitroanisole (11.56 g, 69.2 mmol) in a mixture of ethyl acetate (200 mL) and ethanol (70 mL) was added portionwise tin (II) chloride dihydrate (109 g, 0.483 mol) and the mixture was stirred at room temperature overnight. The reaction mixture was basified with aq. K2CO3 and filtered over celite. The layers were separated. The aqueous layer was further extracted with ethyl acetate and the combined organics washed successively with water and brine, dried over MgSO4, filtered and evaporated to give 8.02 g of 3-methoxy-4-methyl-aniline (86% yield). 1H NMR (300 MHz; CDCl3): 2.09 (s, 3 H), 3.76(s, 3 H), 4.01 (br s, 1 H), 6.20 (m, 2 H), 6.90 (d, J=8.4 Hz, 1 H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][C:18]3[C:22](=[O:25])[CH2:23][CH2:24][C:17]=3[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2.[Al+3].[Cl-].[Cl-].[Cl-].[C:30](Cl)([CH3:32])=[O:31].C([O-])(O)=O.[Na+]>C1([N+]([O-])=O)C=CC=CC=1.O>[C:30]([C:13]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:8][CH2:7][CH:3]3[CH2:4][CH2:5][CH2:6][N:2]3[CH3:1])[C:21]3[CH:20]=[CH:19][C:18]4[C:22](=[O:25])[CH2:23][CH2:24][C:17]=4[C:16]=3[C:15]=2[CH:14]=1)(=[O:31])[CH3:32]
Reactant: CN1CCCC1CCn1c2ccccc2c2c3c(ccc21)C(=O)CC3
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: CC(=O)c1ccc2c(c1)c1c3c(ccc1n2CCC1CCCN1C)C(=O)CC3
Reaction time: 0.67 h

Procedure:
Compound 65 (0.336 g, 1.00 mmol) was dissolved in PhNO2 (7 mL). The solution was cooled down in an ice bath. Then, AlCl3 (0.67 g, 5.02 mmol) and after that, AcCl (0.36 mL, 5.04 mmol) were added. The resulting mixture was kept for 40 min (LC/MS monitoring), diluted with water, neutralized with aqueous NaHCO3 solution, extracted with CHCl3, and evaporated. The product was purified on a short thick column, eluent: 100:0→90:10. Yield of product: 0.307 g (82%) (R); S-isomer was obtained similarly (77%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([O:40][CH3:41])=[C:35](B(O)O)[CH:36]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:10])[C:5]([Cl:9])=[C:6]([C:33]2[CH:32]=[C:31]([Cl:30])[CH:36]=[CH:35][C:34]=2[O:40][CH3:41])[N:7]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: Clc1nc(Cl)c(Cl)c(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: COc1ccc(Cl)cc1-c1nc(Cl)nc(Cl)c1Cl
Reaction time: 2 h
Yield: 68.8 %

Procedure:
In a 250 mL three-neck flask fitted with a degassing tube and temperature probe, acetonitrile (100 mL) and water (25 mL) were degassed with N2 for 30 min while stirring. 2,4,5,6-Tetrachloropyrimidine (8.77 g, 0.0402 mol, 1.5 equiv) and triphenylphosphine (0.70 g, 2.6 mmol, 0.1 equiv) were added and the resulting mixture was degassed for 15 min. 5-Chloro-2-methoxy-phenylboronic acid (5.00 g, 0.0268 mol, 1.0 equiv), K3PO4 (11.39 g, 0.0536 mol, 2.0 equiv) and palladium acetate (301 mg, 1.3 mmol, 0.05 equiv) were added and the resulting mixture was degassed for 5 min. After 2 h at rt, the reaction mixture was poured into CH2Cl2 (250 mL) and washed twice with water (125 mL). The organic layer was dried and concentrated. The crude product was purified by FCC to give a white solid (5.97 g, 69%). MS (ESI+): mass calcd. for C11H7Cl4N2O, 322.9; m/z found, 323.0 [M+H+]. 1H NMR (CDCl3): 7.45 (dd, J=8.9, 2.6 Hz, 1H), 7.31 (d, J=2.6 Hz, 1H), 6.94 (d, J=8.9 Hz, 1H), 3.82 (s, 3H).
Reaction SMILES: [C:1]([N:8]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])(C)C)=[O:2].C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)(OCC1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=O>O1CCOCC1.O>[C:1]([N:8]1[CH2:15][C:14]([F:16])([F:17])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][CH2:4][CH:7]1[C:37]2[C:38](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:39]2[C:44]1=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: O
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1CC(F)(F)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 113.8 %

Procedure:
A solution of 652 mg (2 mmol) of N-Boc-4,4-difluoroproline in 10 mL of 1;1 TFA/CH2Cl2 was stirred at 0° C. for 45 min, and concentrated in vacuo. The residue was taken up in 3 mL of dioxane, and 5 mL of 10% aqueous sodium carbonate was added, followed by a solution of 675 mg (1 eq) of Fmoc-Cl in 5 mL of dioxane. The mixture was stirred at room temperature for 16 h, diluted with 20 mL of water, extracted with 2 20-mL portions of diethyl ether, acidified to pH 2, and extracted with three 30-mL portions of ethyl acetate. The combined organic extracts were washed with 50 mL of brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography over silica gel (eluted with CH2Cl2/CH3OH 10:1), to afford 850 mg (88%) of N-Fmoc-4,4-difluoroproline as a brownish solid. 1H NMR (500 MHz, CDCl3) δ 2.55 (m, 1H) 2.95 (m, 1H), 3.80 (m, 2H), 4.20 (m, 1H), 4.30 (m, 2H), 4.55 (m, 1H), 7.32 (m, 2H), 7.45 (m, 2H), 7.70 (m, 2H), 7.90 (m, 2H). Exact mass calculated for C20H17F2NO4 m/e 373.11, found m/e 374.4.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C(N(CC)CC)C.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2cc(N3CCN(c4ccccc4)CC3)ncn2)cc1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared as in Example 59: 0.12 mmol) in 2 mL of ethanol is added 50 μL of triethylamine and 1-Phenylpiperazine (19 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture can then be filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.[NH2:13]C1C=CC=C(Br)C=1C(N)=O.[N-]=C=O.[Na+]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[NH:13][C:5](=[O:11])[NH:6]2
Reactant: NC(=O)c1c(N)cccc1Br
Reactant: O=C1Nc2cccc(Br)c2C1=O
Agent: [N-]=C=O
Agent: [Na+]
Product: O=c1[nH]c(=O)c2c(Br)cccc2[nH]1

Procedure:
Compounds of formula I may be synthesized according to Scheme 1. Commercially available 4-bromoindoline-2,3-dione may be hydrolyzed to 2-amino-6-bromobenzamide followed by condensation with sodium isocyanate to form 5-bromoquinazoline-2,4(1H,3H)-dione. The protocols include, but are not limited to, palladium mediated cross coupling between 5-bromoquinazoline-2,4(1H,3H)-dione and the aryl boronic acid or ester to form the intermediate 5-substituted quinazoline-2,4(1H, 3H)-dione. Conversion to the corresponding dichloro quinazoline and sequential displacement at the 4-position followed by transition metal mediated cross coupling or displacement of the C2 chloride forms compounds I as described.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].CI.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C(C)=O)cc1C
Yield: 96.9 %

Procedure:
A mixture of 1 (4 hydroxy-3-methylphenyl)-ethanone 5.0 g, methyl iodide 5.70 g, potassium carbonate 20.0 g and acetone 200 ml was stirred with heating under reflux for six hours. The reaction mixture was filtered and was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure to give 1-(4-methoxy-3-methylphenyl)-ethanone 5.3 g.
Reaction SMILES: [NH2:1][C@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([CH2:27][CH3:28])[CH:20]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].C(Cl)Cl.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:44][CH2:43][C:42]3[CH:45]=[CH:46][CH:47]=[CH:48][C:41]=3[NH:40][C:39]2=[O:49])[CH2:34][CH2:33]1>C(#N)C>[CH2:27]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[CH2:25][CH3:26])[CH2:18][C@@H:2]([NH:1]/[C:35](=[N:38]/[C:39]#[N:40])/[N:32]1[CH2:33][CH2:34][CH:35]([N:38]2[CH2:44][CH2:43][C:42]3[CH:45]=[CH:46][CH:47]=[CH:48][C:41]=3[NH:40][C:39]2=[O:49])[CH2:36][CH2:37]1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4])[CH3:28]
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: CCc1ccc(C[C@@H](N)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC
Solvent: ClCCl
Solvent: CC#N
Product: CCc1ccc(C[C@@H](N/C(=N/C#N)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 390 mg (1.01 mmol) (R)-2-amino-3-(3,4-diethyl-phenyl)-1-[4-(1-methylpiperidin-4-yl)-piperazin-1-yl]-propan-1-one, 270 mg (1.01 mmol) diphenylcyano-carbonimidate and 50 mL DCM was stirred for 4 h at RT and then evaporated down under reduced pressure. The residue was combined with 30 mL acetonitrile and 270 mg (1.10 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and refluxed for 14 h. The reaction mixture was evaporated down under reduced pressure and the residue was purified by chromatography. The product fractions were evaporated down, the residue was triturated with PE and suction filtered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:24])([CH3:23])[C:9](=O)[CH2:10][NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[S:13])=[CH:4][C:3]=1[O:25][CH3:26].C(OCC)C>CC(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:12]([SH:13])=[N:11][CH:10]=2)([CH3:24])[CH3:23])=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: COc1cc(C(C)(C)C(=O)CNC(=S)Nc2ccc(F)cc2)ccc1Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1cc(C(C)(C)c2cnc(S)n2-c2ccc(F)cc2)ccc1Cl
Yield: 94698.8 %

Procedure:
A solution of 1-(3-(4-chloro-3-methoxyphenyl)-3-methyl-2-oxobutyl)-3-(4-fluorophenyl)-thiourea (21) (230 g, 0.58 mmol) in HOAc (1 L) was heated to reflux for 4 h with mechanical stirring. The reaction mixture was cooled and evaporated to give a residue which was treated with diethyl ether to give 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-thiol (22) (207 g, 95%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 6.91-7.19 (d, 1H), 6.86-6.88 (t, 2H), 6.81 (s, 1H), 6.86-6.91 (t, 2H), 6.81 (s, 1H), 6.59-6.63 (m, 2H), 6.50-6.53 (d, 2H), 6.45 (s, 1H), 3.74 (s, 3H), 1.46 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.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.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:31]#[C:30][CH2:29][OH:32])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Clc1cc(Cl)cc(I)c1
Reactant: C#CCO
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: OCC#Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3,5-dichloroiodobenzene (2.50 g), copper(I) iodide (34.9 mg), triphenylphosphine (120 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (189 mg), propargyl alcohol (0.596 ml), diisopropylethylamine (6.38 ml) and tetrahydrofuran (50 ml) was stirred at room temperature for 4 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-80:20) to give the object product (1.73 g) as a brown solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([CH3:24])([CH3:23])[C:14]([N:16]3[CH:20]4[CH2:21][CH2:22][CH:17]3[CH2:18][CH2:19]4)=[O:15])[CH:11]=2)[NH:6][C:5]=1[C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=1.S([O-])([O-])(=O)=O.[Mg+2].[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([C:45]2[S:49][C:48]([CH:50]=O)=[CH:47][CH:46]=2)[CH:40]=1.C([BH3-])#N.[Na+]>C(Cl)(Cl)Cl.CO.C(O)(=O)C>[CH:17]12[N:16]([C:14](=[O:15])[C:13]([C:10]3[CH:11]=[C:12]4[C:7](=[CH:8][CH:9]=3)[NH:6][C:5]([C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([CH3:32])[CH:26]=3)=[C:4]4[CH2:3][CH2:2][NH:1][CH2:50][C:48]3[S:49][C:45]([C:41]4[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=4)=[CH:46][CH:47]=3)([CH3:24])[CH3:23])[CH:20]([CH2:19][CH2:18]1)[CH2:21][CH2:22]2
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCN)c1
Reactant: O=Cc1ccc(-c2cccnc2)s1
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCNCc2ccc(-c3cccnc3)s2)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1-(7-azabicyclo [2.2.1]hept-7-yl)-2-methyl-propan-1-one (15 mg in a mixture of 1.0 mL dry chloroform and 0.10 mL methanol) at 0° C. was added 25 mg magnesium sulfate followed by 5-pyridin-3-yl-thiophene-2-carbaldehyde (9.3 mg) and the mixture stirred at low temperature. After 40 minutes, 0.070 mL of acetic acid were added followed by a solution of sodium cyanoborohydride (4.4 mg in 0.10 mL methanol) and the mixture allowed to warm to room temperature. After 20 hours, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate, extracted with methylene chloride and the combined organics washed sequentially with water and brine. Purification of the concentrate by preparative tlc on silica gel (ethyl acetate) followed by preparative reverse phase HPLC (water:acetonitrile, 60:40) gave the title compound (3.2 mg). MASS: 602 (M+H)