Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:4]1[N:8]=[N:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:26])[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])=[N:5]1)[CH3:3].[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[C:51]([CH:55]=[CH:56][CH:57]=3)[C:52](O)=[O:53])=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[C:51]([C:52]([N:30]4[CH2:31][CH2:32][CH:27]([N:12]5[C:13](=[O:26])[C:14]6[S:18][C:17]([C:19]7[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=7)=[CH:16][C:15]=6[N:10]([CH2:9][C:6]6[N:7]=[N:8][N:4]([CH2:2][CH3:3])[N:5]=6)[C:11]5=[O:33])[CH2:28][CH2:29]4)=[O:53])[CH:55]=[CH:56][CH:57]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35]
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)O)c1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc(F)cc6)cc5n(Cc5nnn(CC)n5)c4=O)CC3)c1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(4-fluorophenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (108 mg; compound B82) is reacted with 3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (88 mg; compound C8) and HBTU (183 mg) in DCM/DMF (10 ml/1 ml) in the presence of DIPEA (227 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc/DCM, 100/0/0 to 50/40/10 to 30/60/10 to 0/90/10 (v/v/v)] as a solid.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6]Br.Br[C:9]1[CH:10]=[C:11]([CH3:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1.[P:17]([O-:24])(OCC)OCC.Cl>C1COCC1.C1(C)C=CC=CC=1.O>[CH3:15][C:13]1[CH:14]=[C:9]([PH:17](=[O:24])[C:9]2[CH:10]=[C:11]([CH3:16])[CH:12]=[C:5]([CH3:6])[CH:14]=2)[CH:10]=[C:11]([CH3:16])[CH:12]=1
Reactant: BrCCBr
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CCOP([O-])OCC
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)cc([PH](=O)c2cc(C)cc(C)c2)c1
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 78.3 %

Procedure:
Under a nitrogen stream, a solution of magnesium (3.28 g, 4.01 equivalents), a small amount of iodine and 1,2-dibromoethane in THF (10 mL) was stirred at room temperature for 1.5 hrs. A solution of 5-bromo-m-xylene (25.2 g, 4.05 equivalents) in THF (100 mL) was added at 25° C., and the mixture was stirred at 40° C. for 40 min. A solution of diethyl phosphite (4.64 g, 33.6 mmol) in THF (5 mL) was added at −33° C., and the mixture was stirred at 0° C. for 30 min. Water (30 mL) was added at 3° C., and 6M-HCl (20 mL) and toluene (50 mL) were added. The mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned, and the organic layer was washed with 10% aqueous NaHCO3 solution (30 mL), and the organic layer was concentrated under reduced pressure. The residue was recrystallized from heptane and dried (reduced pressure, 50° C.) to give the title compound (6.80 g, white powder). yield 78.3%. melting point: 82.4° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH3:21].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[S:29][CH2:30][CH2:31][C:32](ON2C(=O)CCC2=O)=[O:33])C=CC=CC=1.C(N(CC)CC)C.ClCCl>CO>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH3:21])[N:7]([NH:6][CH2:5][CH2:4][CH2:3][NH:2][C:32](=[O:33])[CH2:31][CH2:30][SH:29])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1NCCCN
Reactant: O=C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1nc2c(N)nc3ccccc3c2n1NCCCNC(=O)CCS

Procedure:
A mixture of N1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinoline-1,4-diamine hydrochloride (1.00 g, 3.26 mmol), succinimido 3-(triphenylmethylthio)propanoate (A. Bray et. al. Aust. J. Chem. 1990, 43, 629-634; 2.22 g, 4.89 mmol), triethylamine (0.45 mL, 3.26 mmol), dichloromethane (33 mL), and methanol (15 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (gradient elution with a solution of 2% ammonium hydroxide in methanol and chloroform). The purified compound was treated with trifluoroacetic acid (3 mL) and triethylsilane (2 mL) in dichloromethane (30 mL) at room temperature overnight. More trifluoroacetic acid was added and after an additional day the reaction was complete. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel (gradient elution with a solution of 2% ammonium hydroxide in methanol and chloroform) to yield 327 mg of N-{3-[(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}-3-mercaptopropanamide. MS (ESI) m/z 359 (M+H)+.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:19][CH:20]([O:23][CH3:24])[O:21][CH3:22]>CN(C=O)C.CCOC(C)=O>[CH3:22][O:21][CH:20]([O:23][CH3:24])[CH2:19][O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(CBr)OC
Reactant: OC1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(COC1CCCCC1)OC
Yield: 30.6 %

Procedure:
Dissolve cyclohexanol (2.00 mL, 19.1 mmol) in DMF (9.6 mL), then add NaHMDS (1 M solution in THF, 21.0 mL, 21.0 mmol), and stir the solution at room temperature for 5 min. Add 2-bromo-1,1-dimethoxyethane (2.26 mL, 19.1 mmol), then stir the mixture at room temperature under a nitrogen atmosphere for three days. Dilute the mixture with EtOAc (250 mL) and wash with saturated aqueous NaCl (2×250 mL). Dry the organic phase over MgSO4, filter, and concentrate the filtrate under reduced pressure. Subject the resulting crude material to silica gel chromatography eluting with a gradient of 0% to 10% EtOAc/hexanes. Concentrate the fractions containing the desired product under reduced pressure to furnish the title compound as a pale yellow oil (1.10 g, 31% yield). 1H NMR (400 MHz, CDCl3): δ 4.47 (t, J=5.3 Hz, 1H), 3.49 (d, J=5.3 Hz, 2H), 3.39 (s, 6H), 3.25 (tt, J=9.2, 3.7 Hz, 1H), 1.94-1.87 (m, 2H), 1.76-1.69 (m, 2H), 1.55-1.49 (m, 1H), 1.34-1.17 (m, 5H).
Reaction SMILES: COC(=O)NC(C(N1CCCC1C1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([B:27]3[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=O)C(C)C.[C:37]([O:41][C:42]([N:44]1[CH2:48][C:47](=[CH2:49])[CH2:46][CH:45]1[C:50](O)=O)=[O:43])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][C:42]([N:44]1[CH2:48][C:47](=[CH2:49])[CH2:46][CH:45]1[C:50]1[NH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([B:27]3[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]3)=[CH:25][CH:26]=2)=[CH:19][N:20]=1)=[O:43])([CH3:38])([CH3:39])[CH3:40]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: C=C1CC(C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=C1CC(c2ncc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1

Procedure:
This compound was made using the same procedure used to make [2-Methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester using 4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester. LCMS-ESI+: calc'd for C25H34BN3O4: 451.26 (M+); Found: 452.33 (M+H+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[N:14]=[CH:13][N:12]([CH3:16])[C:11]=2[C:10](=[O:17])[NH:9][C:8]1=[O:18].[H-].[Na+].[C:21]([O:24][C@H:25]([CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29]I)(=[O:23])[CH3:22]>CS(C)=O>[C:21]([O:24][C@H:25]([CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29][N:9]1[C:10](=[O:17])[C:11]2[N:12]([CH3:16])[CH:13]=[N:14][C:15]=2[N:7]([CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:8]1=[O:18])(=[O:23])[CH3:22]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2Cc1ccco1
Reactant: CC(=O)O[C@H](C)CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2C)n(Cc2ccco2)c1=O
Reaction time: 0.42 h
Yield: 77.9 %

Procedure:
To a stirring suspension 3-(2-furylmethyl)-7-methylxanthine (0.40 g, 1.62 mmol) in dimethylsulfoxide (20 ml) was added sodium hydride (41 mg, 1.71 mmol) in one portion. After stirring for 25 minutes, (R)-5-acetoxy-1-iodohexane (0.46 g, 1.71 mol) was added neat. After stirring at room temperature for 72 hours, the reaction was quenched by the addition of water (75 ml) and extracted with ethyl acetate (3x 35 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (2x 35 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to give (R)-1-(5-acetoxyhexyl)-3-(2-furylmethyl)-7-methylxanthine (0.49 g, 78% yield) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Br[C:15]1[CH:20]=[C:19]([N:21]([CH3:23])[CH3:22])[CH:18]=[C:17](Br)[N:16]=1.[CH3:25][N:26]([CH:28]=[O:29])C>CCCCCC>[C:25]1([NH:26][C:28]([C:15]2[CH:20]=[C:19]([N:21]([CH3:23])[CH3:22])[CH:18]=[C:17]([O:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=3)[N:16]=2)=[O:29])[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CN(C)c1cc(Br)nc(Br)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: CN(C)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)Nc2ccccc2)c1
Temperature: 25 °C

Procedure:
1.4 g (0.0071×1.2 mol) of 3-(trifluoromethyl) phenol was dissolved in about 20 ml of DMF. The solution was further mixed with 0.30 g (ca. 60% in mineral oil; 0.0071-1.06 mol) of NaH and then with 2.00 g (0.0071 mol) of 2,6-dibromo-4-dimethylamino pyridine. After treating the solution under reflux for about 6 hours, the resultant solution was allowed to stand for cooling to room temperature. After the reaction solution was distributed in hexane-saturated sodium bicarbonate water, the organic phase of the obtained solution was washed with saturated brine and dried with anhydrous sodium sulfate, followed by concentration thereof. Thereafter, the concentrated solution was purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane) and the obtained eluate was subjected to recrystallization using hexane, thereby obtaining an aimed product.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:10](=O)([O-])[O-].[K+].[K+].IC>COCCOC>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=c1[nH]cc(Cl)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CI
Product: Cn1cc(Cl)cc(Br)c1=O
Yield: 74.6 %

Procedure:
A mixture of 3-bromo-5-chloro-1H-2-pyridone (930 mg, 4.46 mmol), potassium carbonate (1.25 g, 9.1 mmol) and iodomethane (2.8 mL, 45 mmol) in 10 mL of DME was heated to reflux for 18 hr. The mixture was filtered hot and concentrated. The residue was recrystallized from ethyl acetate to give 3-bromo-5-chloro-1-methyl-2-pyridone (740 mg, 74%), mp 162-163° C. HRMS (C6H5BrClNO): Obs. Mass 220.9249. Calcd. Mass 220.9243 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[CH:41][N:40]=[C:39]2[S:43][CH2:44][O:45][CH3:46])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[CH:41][N:40]=[C:39]2[S:43][CH2:44][O:45][CH3:46])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: COCSc1nccn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: COCSc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(-c3ccccc3F)ccc2NC(=O)OC(C)(C)C)c1
Yield: 93.5 %

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (303 mg, 1.0 mmol) and 3-[3-(2-methoxymethylsulfanyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H12) (512 mg, 1.41 mmol) according to the general procedure K. Obtained as a light yellow solid (552 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([Cl:6])=[O:5].[NH2:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[NH:18][CH2:19][C:20]([CH3:23])([OH:22])[CH3:21])=[CH:15][CH:14]=[CH:13][CH:12]=2>C(#N)C>[ClH:6].[OH:22][C:20]([CH3:23])([CH3:21])[CH2:19][NH:18][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[NH:7][C:4](=[O:5])[CH2:3][O:2][CH3:1]
Reactant: COCC(=O)Cl
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Solvent: CC#N
Product: COCC(=O)Nc1cnc2ccccc2c1NCC(C)(C)O
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methoxyacetyl chloride (2.5 g, 23 mmol) was added dropwise to a solution of 1-[(3-aminoquinolin-4-yl)amino]-2-methylpropan-2-ol (prepared as described in Part A of Example 8, approximately 4.4 g, 19 mmol) in acetonitrile (96 mL). The reaction mixture was stirred for 1 hour at room temperature. A solid formed that was isolated by filtration, washed with acetonitrile, and dried to yield 5.5 g of N-{4-[(2-hydroxy-2-methylpropyl)amino]quinolin-3-yl}-2-methoxyacetamide hydrochloride as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.Br[CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:26]([N:23]1[CH2:22][CH2:21][C@H:20]2[N:15]3[C:16]4[C:11](=[CH:10][C:9]([C:3]5[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=5[Cl:1])=[CH:18][C:17]=4[C@H:19]2[CH2:24]1)[CH2:12][CH2:13][CH2:14]3)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCBr
Reactant: Clc1cccc(-c2cc3c4c(c2)[C@H]2CNCC[C@H]2N4CCC3)c1Cl
Product: CCCCN1CC[C@@H]2[C@H](C1)c1cc(-c3cccc(Cl)c3Cl)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (28 mg, 82%) from (±)-cis-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.083 mmol) and 1-bromobutane (23 mg, 0.17 mmol). 1H NMR (CDCl3, 300 MHz) δ 0.92(t, J=7.3 Hz, 3H), 1.32 (se, J=7.3 Hz, 2H), 1.53-1.65 (br, 2H), 2.02-2.25 (m, 5H), 2.38-2.53 (br, 2H), 2.58-2.68 (m, 1H), 2.75 (t, J=6.4 Hz, 2H), 2.80-2.92 (br, 1H), 2.95-3.07 (br, 1H), 3.31 (dt, J=10.3, 3.6 Hz, 1H), 3.37-3.45 (br, 2H), 6.94 (s, 1H), 6.99 (s, 1H), 7.15-7.21 (m, 2H), 7.35-7.40 (m, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=O)[NH:5][CH:6]=[N:7]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:33]>>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([Cl:33])=[N:5][CH:6]=[N:7]2
Reactant: O=c1[nH]cnc2cccc(F)c12
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Fc1cccc2ncnc(Cl)c12

Procedure:
Thus, 5-fluoro-3,4-dihydroquinazolin-4-one (2 g) was reacted with triphenylphosphine and carbon tetrachloride to give 5-fluoro-4-chloroquinazoline (1.34 g); NMR Spectrum: (CDCl3) 7.47.5 (m, 1H), 7.9-8.0 (m, 2H), 9.1 (s, 1H); and
Reaction SMILES: [OH:1][CH:2]([CH2:19]O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18].[BrH:21].[C:22]([OH:25])(=O)[CH3:23].C(=O)(O)[O-].[Na+].C(=O)=O>ClCCl>[C:22]([O:1][CH:2]([CH2:19][Br:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18])(=[O:25])[CH3:23]
Reactant: CC(=O)O
Reactant: Br
Reactant: O=C1CCCCN1CCCCCCCCCC(O)CO
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC(CBr)CCCCCCCCCN1CCCCC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To N-(10,11-dihydroxyundecyl)-2-piperidone (4.21 g, 14.8 mmol) was added 30% hydrogen bromide-acetic acid (8.7 mL) and the mixture was then stirred for 1 hour. The solution was poured carefully into a mixture of sodium bicarbonate (15 g), ice water (150 mL), and dichloromethane (100 mL). After carbon dioxide evolution has subsided, the organic layer was separated and the aqueous layer extracted with dichloromethane (2×80 mL). The combined organic layers was dried over sodium sulfate and the solvent evaporated under vacuum to give 1-(10-acetoxy-11-bromoundecyl)-2-piperidone (4.9 g, 89% yield) as a viscous oil which dissolves in methanol (10 mL). A 1 M sodium methoxide (15 mL, 15 mmol) in methanol solution was added all at once. After stirring for 1 hour, the solution was treated with water (50 mL) and then extracted with dichloromethane (3×50 mL). The combined extracts were dried over sodium sulfate and the solvent evaporated under vacuum. The residue was purified by chromatography using ethyl acetate to yield 2.40 g (61% yield) N-(10,11-Oxidoundecyl)-2-piperidone as a colorless oil.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2I)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[Na+].[Na+].[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([C:27]([F:38])([F:37])[F:26])[CH:33]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(I)C1=O
Reactant: OB(O)c1cccc(C(F)(F)F)c1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 95 °C
Reaction time: 24 h
Yield: 33.5 %

Procedure:
To a stirred solution of 100 mg of 5-{4-(aminosulfonyl)phenyl}-2,2-dimethyl-4-iodo-3(2H)-furanone dissolved in 15 ml toluene and 5 ml ethanol, were added 30 mg of tetrakis(triphenylphosphine)palladium(0), 5 ml of 2 M aqueous sodium carbonate, and 100 mg of 3-(trifluoromethyl)benzeneboronic acid. Then the mixture was stirred at 95° C. for 24 hours. The reaction mixture was purified according to a procedure similar to Step 4 of Example 22 to yield 35 mg of 5-{4-(aminosulfonyl)phenyl}2,2-dimethyl-4-{3-(trifluoromethyl)phenyl}-3(2H)-furanone. mp: 129-130° C. NMR: δ1.59 (s, 6H), 4.93 (br, s, 2H), 7.48 (m, 2H), 7.59 (m, 2H), 7.76 (d, J=8.7 Hz, 2H), 7.93 (d, J=9.0 Hz, 2H). IR (cm−1): 3343, 3265, 1691, 1593, 1329, 1262.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:16]([O:23][C:24]([NH:26][C@@H:27]([CH3:31])[C:28](O)=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH2:16]([O:23][C:24](=[O:25])[NH:26][C@H:27]([C:28]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[N:8]=1)[CH3:31])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1cccc(N)c1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cccc2nc([C@H](C)NC(=O)OCc3ccccc3)n(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 90.5 %

Procedure:
To a solution of 3-methyl-N2-phenyl-benzene-1,2-diamine (852 mg, 4.3 mmol) in anhydrous DCM (20 mL) were added (S)-2-benzyloxycarbonylaminopropionic acid (1.44 g, 6.45 mmol), HOBt (639 mg, 4.73 mmol), 4-methylmorpholine (1.04 mL, 9.46 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.24 g, 6.45 mmol). The mixture was stirred at RT for 6.5 h and then partitioned between DCM (100 mL) and water. The organic layer was then washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was dissolved in AcOH (10 mL) and heated to 65° C. for 18 h. After cooling to RT, volatiles were removed under reduced pressure and the residue diluted with EtOAc (100 mL). The organic layer was washed with a saturated solution of NaHCO3, followed by brine, then dried (Na2SO4) and concentrated in vacuo affording [(S)-1-(7-Methyl-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid benzyl ester as brown foam (1.5 g, 90%). LCMS: RT 3.07 min [M+H]+ 386.2.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[C:10]3=[N:9][C:8]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:10]3=[N:9][C:8]=2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCCCCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 7-(2,3-diphenyl-7,8-dihydropyrido[3,2-b]pyrazin-5(6H)-yl)heptanoate (step 2)(6.1 g, 13.8 mmol) in THF (300 ml) and MeOH (100 ml) was treated with a solution of lithium hydroxide monohydrate (3.5 g, 83 mmol) in water (100 ml). The reaction mixture was heated at reflux for 5 h and allowed to cool to room temperature. The pH of the mixture was adjusted to <pH5 using 2M HCl. The volatile solvents were removed in vacuo and the remaining residue was diluted with water (50 ml) and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield a greenish grey solid. The crude material was dissolved in MeOH (30 ml) and purified in 2 portions on a cartridge packed with 113 g LiChroprep® RP-18 (40-63 μm, supplier Merck, reverse phase column) eluting with 10-100% MeCN in water. The resulting solid was re-crystallized from a hot mixture of EtOH (120 ml) and water (90 ml). After seeding and stirring for 1 h at 5° C., the crystals were filtered off and the product dried for 2 days at 40° C. in a vacuum oven to afford the title compound;