Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[C:15]C(O)(C)C)[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:14]([C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[C:6]([C:5]1[CH:20]=[CH:21][C:2]([F:1])=[CH:3][CH:4]=1)=[O:7])#[CH:15]
Reactant: CC(C)(O)C#Cc1cccc(C(=O)c2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1cccc(C(=O)c2ccc(F)cc2)c1
Temperature: 120 °C
Yield: 57.2 %

Procedure:
In a 100 ml two-necked flask having a reflux condenser were charged 1.11 g (3.9 mmol) of 4-fluoro-3′-(3-hydroxy-3-methyl-1-butynyl)benzophenone and 165 mg (4.1 mmol) of NaOH (Kishida Chemical Co., Ltd.; 0.7 mm particles, 98%) and air in the flask was replaced by Ar gas. 20 ml of toluene was added to the mixture and the mixture was heated at 120° C. under reflux for 0.5 hour. Toluene was added to the reaction mixture and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure using an evaporator. The resultant crude reaction product was purified by column chromatography (hexane/AcOEt=10/1) using silica gel to obtain 0.5 g of 3-ethynyl-4′-fluorobenzophenone as yellow solid. (Yield: 53%)
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:17]2[N:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]2[CH:22]=[CH:23][CH:24]=[CH:25][C:14]=2[CH2:13][C:12]1=[O:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.CC(C)([O-])C.[K+].[N:40](OCCC(C)C)=[O:41]>O.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][N:11]1[C:17]2[N:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]2[CH:22]=[CH:23][CH:24]=[CH:25][C:14]=2[C:13](=[N:40][OH:41])[C:12]1=[O:26])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)CCON=O
Reactant: CC(C)(C)[Si](C)(C)OCCN1C(=O)Cc2ccccc2-c2cccnc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCn1c(=O)c(=NO)c2ccccc2c2cccnc21
Temperature: 20 °C
Reaction time: 0.38 h
Yield: 89 %

Procedure:
Combine 5-[2-(tert-butyl(dimethyl)silyl)oxyethyl]-7H-pyrido[2,3-d][3]benzazepin-6-one (30.0 g, 0.08 mol) and toluene (300.0 mL), cool the reaction mixture to −10-0° C. Add potassium tert-butoxide (18.2 g, 0.16 mol), isoamyl nitrite (13.34 g, 0.11 mol) and then stir for 3-5 hours. Transfer the reaction mixture to a cool (0-5° C.) biphasic solution of ethyl acetate (210 mL) and water (510 mL) and stir for 15-30 minutes. Warm the reaction mixture to 15-25° C. and separate the layers. Extract the aqueous layer with additional ethyl acetate (120 mL) and methyl tert-butyl ether (120 mL) and combine the organic layers. Concentrate the organic under reduced pressure to a solution volume of approximately 60-90 mL and then add toluene (240 mL) and ethyl acetate (75 mL). Filter the solution through silica gel (45.0 g), rinse the silica gel with a mixture of toluene (210 mL) and ethyl acetate (60 mL), and concentrate the filtrate under reduced pressure to a volume of approximately 75 mL. Add heptane (120 mL) and concentrate the mixture to a volume of approximately 60 mL and filter the resulting solids. Wash the filter cake with heptane (25 mL) and dry under vacuum to provide the title compound (28.3 g, 72.5%) as a yellow solid.
Reaction SMILES: CO[C:3]1[C:8]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=CN=CN=1.BrC1[N:23]([CH:24]([CH3:26])[CH3:25])[C:22]2[CH:27]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)[N:28]([C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:29](=[O:30])[C:21]=2C=1.COCCOC.BrC1C(OC)=NC=NC=1>CS(C)=O>[Cl:37][C:35]1[CH:34]=[CH:33][C:32]([CH3:38])=[C:31]([N:28]2[C:29](=[O:30])[C:21]3[CH:3]=[C:8]([B:9]4[O:10][C:11]([CH3:16])([CH3:17])[C:12]([CH3:14])([CH3:15])[O:13]4)[N:23]([CH:24]([CH3:26])[CH3:25])[C:22]=3[CH:27]2[C:39]2[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=2)[CH:36]=1
Reactant: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Reactant: COc1ncncc1B1OC(C)(C)C(C)(C)O1
Agent: COc1ncncc1Br
Solvent: CS(C)=O
Solvent: COCCOC
Product: Cc1ccc(Cl)cc1N1C(=O)c2cc(B3OC(C)(C)C(C)(C)O3)n(C(C)C)c2C1c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 20 %

Procedure:
The title compound was prepared in analogy to the procedure described for Intermediate T, but 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate B) and DME were used instead of 5-bromo-4-methoxy-pyrimidine and DMSO respectively. The reaction was performed at 100° C. for 16 h to afford the title compound (20% purity) as a dark brown solid. tR: 8.52 min (HPLC 2); ESI-MS: tR=1.46 min; [M+H]+ 525/527 (LC-MS 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][N:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=O)[C:12]3=[O:21])[C:6]=2[CH:22]=1.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[C:7]([CH2:10][N:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[N:28][C:27]4[CH:29]=[CH:30][CH:31]=[C:25]([C:24]([F:23])([F:32])[F:33])[CH:26]=4)[C:12]3=[O:21])[C:6]=2[CH:22]=1
Reactant: O=C1C(=O)N(Cc2csc3ccc(Cl)cc23)c2ccccc21
Reactant: Nc1cccc(C(F)(F)F)c1
Product: O=C1C(=Nc2cccc(C(F)(F)F)c2)c2ccccc2N1Cc1csc2ccc(Cl)cc12
Temperature: 140 °C
Yield: 20 %

Procedure:
A mixture of 1-[(5-chloro-1-benzothien-3-yl)methyl]-2H-indole-2,3-dione (50 mg, 0.15 mmol) (prepared as described below) and 3-trifluoromethylaniline (0.020 mL, 0.15 mmol) was heated neat at 140° C. for 2 h. The crude material was purified by preparative TLC using a mixture of 1:3 ethyl acetate and hexane as the eluent giving the desired product as a yellow solid (13 mg, 0.030 mmol, 18%). 1H NMR (400 MHz): δ 7.98 (d, J=2.0, 1H), 7.80 (d, J=8.6, 1H), 7.58 (t, J=7.7, 1H), 7.52 (d, J=8.1, 1H), 7.43 (s, 1H), 7.38 (dd, J=8.6, 1.9, 1H), 7.31 (overlapping singlet and dt, J=1.2, 7.8, 2H), 7.24 (d, J=7.8, 1H), 6.87 (d, J=7.9, 1H), 6.77 (t, J=7.7, 1H), 6.59 (d, J=7.7, 1H), 5.20 (s, 2H). ESI-MS m/z found 471 (MH+ with 35Cl), 473 (MH+ with 37Cl).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[NH:6][C:5]=1[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1.[F:19][C:20]([F:27])([F:26])[C:21](OCC)=[O:22]>C(Cl)(Cl)Cl>[F:19][C:20]([F:27])([F:26])[C:21]([NH:1][CH2:2][CH2:3][C:4]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[NH:6][C:5]=1[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:22]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCc1cc(-c2cccs2)[nH]c1-c1cccs1
Solvent: ClC(Cl)Cl
Product: O=C(NCCc1cc(-c2cccs2)[nH]c1-c1cccs1)C(F)(F)F
Reaction time: 8 h
Yield: 45 %

Procedure:
A solution containing 100 mg (0.36 mmol) of 3-(2-aminoethyl)-2,5-dithienylpyrrole (XXII), 2 mL of ethyl trifluoroacetate, and 5 mL of CHCl3 was allowed to stand at ambient temperature overnight. The CHCl3 solvent was removed in vacuo, and the product XXIII isolated by preparative SiO2 -TLV plates (20×20×1000u) eluted with a 9:1 toluene-dioxane solvent mixture. Sixty mg of compound XXIII was obtained (45% yield).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[N:6][C:7](Cl)=[CH:8][CH:9]=1.[F:11][CH2:12][CH2:13][CH2:14][OH:15]>>[F:11][CH2:12][CH2:13][CH2:14][O:15][C:7]1[N:6]=[N:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: OCCCF
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Product: FCCCOc1ccc(Cl)nn1
Yield: 87 %

Procedure:
3-(3-Fluoropropoxy)-6-chloropyridazine (108c, 557 mg, 87%) was prepared in the same manner as in Example 26 as a white solid using sodium hydride (NaH 60%, 202 mg, 5.04 mmol), 3,6-dichloropyridazine (107, 500 mg, 3.36 mmol) and 3-fluoro-1-propanol (393 mg, 5.04 mmol).
Reaction SMILES: C[O-].[Na+].[CH2:4]([NH:11][C:12]([NH2:14])=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:15][C:16]([CH3:27])([C:22](OCC)=[O:23])[C:17](OCC)=[O:18]>CO>[CH2:4]([N:11]1[C:17](=[O:18])[C:16]([CH3:27])([CH3:15])[C:22](=[O:23])[NH:14][C:12]1=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(C)(C)C(=O)OCC
Reactant: NC(=O)NCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)C(=O)NC(=O)N(Cc2ccccc2)C1=O
Temperature: 5 °C

Procedure:
A mixture of-sodium methoxide (0.343 g, 14.9 mmol), benzylurea (1.6 g, 10.6 mmol), diethyl dimethylmalonate (1.9 g, 10 mmol) and methanol (15 mL) was heated 6 hours at reflux. The reaction mixture was concentrated and the residue was stirred with water (30 mL) at 5° C. and then hydrochloric acid was added. The solids were collected, washed with water and dried to give 1-benzyl-5,5-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione, m.p 136°-137° C.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1)(=[O:6])=[O:5])[CH3:2].O1CC[CH2:19]OO1>CS(O)(=O)=O.FC(F)(F)C(O)=O>[CH2:1]([N:3]1[CH2:19][C:15]2[C:8]3[C:7](=[CH:11][S:10][C:9]=3[CH:12]=[CH:13][CH:14]=2)[S:4]1(=[O:5])=[O:6])[CH3:2]
Reactant: C1COOOC1
Reactant: CCNS(=O)(=O)c1csc2ccccc12
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCN1Cc2cccc3scc(c23)S1(=O)=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1.90 g of N-ethyl-benzo[b]thiophene-3-sulphonamide are dissolved in 25 ml methanesulphonic acid at 35° C. and combined with a solution of 0.29 g of trioxane in 8 ml of trifluoroacetic acid. After 2.5 h stirring at ambient temperature the reaction mixture is poured onto 400 ml of ice water. The solid formed is separated off by filtration, washed with 200 ml of water and then dissolved while hot in 400 ml of ethanol/isopropanol (1:1) and separated from solid residues by filtering again. The residue remaining after the concentration of the filtrate is purified by chromatography. Yield: 0.82 g. M.p.: 156° C.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[S:18][C:17]2[C:16]([F:19])=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28])=[O:9])=C>CO.C(Cl)Cl>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[S:18][C:17]2[C:16]([F:19])=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28])=[O:9]
Reactant: C=COCCONC(=O)c1sc2c(F)cncc2c1Nc1ccc(I)cc1F
Solvent: CO
Solvent: ClCCl
Product: O=C(NOCCO)c1sc2c(F)cncc2c1Nc1ccc(I)cc1F
Yield: 53.6 %

Procedure:
A solution of 7-fluoro-3-(2-fluoro-4-iodo-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid (2-vinyloxy-ethoxy)-amide (100 mg, 0.19 mmol) in a mixture of methanol and DCM was loaded onto a 5 g SCX-2 cartridge, which was eluted with methanol followed by a 2M solution of ammonia in methanol. Appropriate fractions were combined and concentrated under reduced pressure. The residual solid was purified by column chromatography (Si-SPE, gradient 0-40% tert-butyl dimethyl ether in DCM then 10% methanol in DCM) to afford the title compound as a yellow solid (50 mg, 53%). LCMS (method A): RT=9.60 min, M+H+=492. 1H NMR (CD3OD, 400 MHz) 3.58 (2H, t, J=4.89 Hz), 3.84 (2H, t, J=4.91 Hz), 6.89 (1H, t, J=8.76 Hz), 6.98 (1H, dd, J=8.41, 2.15 Hz), 7.21-7.26 (1H, m), 8.02 (1H, d, J=5.61 Hz), 8.45 (1H, dd, J=8.25, 5.61 Hz), 8.53-8.59 (1H, m).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[NH:17][N:16]=[N:15][N:14]=3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cnc(-c2ccccc2)nc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: c1ccc(-c2ncc(-c3nnn[nH]3)cn2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 49.9 %

Procedure:
A mixture consisting of 2-phenylpyrimidine-5-carbonitrile (200 mg, 1.10 mmol), sodium azide (80 mg, 1.2 mmol) and ammonium chloride (66 mg, 1.2 mmol) in DMF (3 mL) was stirred at 100° C. for 24 hours. The reaction mixture was allowed to cool to room temperature. Upon addition of 1N hydrochloric acid (3 mL), a white solid precipitated. The precipitate was isolated by filtration and recrystallized from ethanol to afford the title compound as a white solid (123 mg, 50% yield); melting point 237° C.; 1H-NMR (400 MHz; DMSO-d6) δ 9.51 (s, 2H), 8.51-8.53 (m, 2H), 7.61-7.65 (m, 3H); LC/MS (ESI+) m/z 225; H-PGDS FPBA IC50: 2.5 μM.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[CH:9][N:8]([CH2:11][C:12]2[O:16][C:15]([CH2:17][OH:18])=[CH:14][CH:13]=2)[N:7]=1)([O-:5])=[O:4]>C(C#N)(C)=O.O=[Mn]=O>[N+:3]([C:6]1[CH:10]=[CH:9][N:8]([CH2:11][C:12]2[O:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=2)[N:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccn(Cc2ccc(CO)o2)n1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: O=Cc1ccc(Cn2ccc([N+](=O)[O-])n2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(3-nitro-pyrazol-1-ylmethyl)-furan-2-yl]-methanol (13.80 g, 61.83 mmol) in AcCN (631.0 mL) was treated at rt with MnO2 (35.84 g, 370.98 mmol). The reaction mixture was stirred at rt for 16 h before being filtered through Celite and the solvent was removed under reduced pressure. Purification of the residue by FC (40:60 hept-EA) gave the title compound. TLC: rf (60:40 hept-EA)=0.16. LC-MS-conditions 02: tR=0.81 min. 1H NMR (400 MHz, CDCl3) δ 5.48 (s, 2H), 6.67 (d, J=3.5 Hz, 1H), 6.96 (d, J=2.5 Hz, 1H), 7.24 (d, J=3.8 Hz, 1H), 7.64 (d, J=2.5 Hz, 1H), 9.65 (s, 1H).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]1([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[C:14]([CH3:24])[O+:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:25]1([C:31]2[O:32][C:33]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:34][C:35](=O)[CH:36]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OC(=O)C)(=O)C>>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]1([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[C:14]([CH:24]=[C:35]3[CH:36]=[C:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:32][C:33]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:34]3)[O+:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cc(-c2ccccc2)cc(-c2ccccc2)[o+]1
Reactant: O=c1cc(-c2ccccc2)oc(-c2ccccc2)c1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: C(=C1C=C(c2ccccc2)OC(c2ccccc2)=C1)c1cc(-c2ccccc2)cc(-c2ccccc2)[o+]1

Procedure:
A mixture of 3.5 g. of 2,4-diphenyl-6-methylpyrylium perchlorate, 2.5 g. of 2,6-diphenyl-4-pyrone and 40 ml. of acetic anhydride is refluxed for 15 minutes, cooled, and the solid is collected, washed with ether, and recrystallized from acetic anhydride. A product having a m.p. of 258° C. is obtained. The theoretical values for C35H25ClO6 and the actual values are as follows:
Reaction SMILES: CS[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[N:8][CH:9]=[N:10]2)=[C:5]2[NH:13][CH:14]=[N:15][C:4]=12.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].Cl.BrC1C=C(C=CC=1)N.N>>[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[N:8][CH:9]=[N:10]2)=[C:5]2[NH:13][CH:14]=[N:15][C:4]=12
Reactant: CSc1cc2ncncc2c2[nH]cnc12
Reactant: Nc1cccc(Br)c1
Agent: Cl
Agent: N
Product: Brc1cccc(Nc2cc3ncncc3c3[nH]cnc23)c1
Yield: 76.4 %

Procedure:
A solution of 4-methylthioimidazo[4,5-f]quinazoline (0.43 g, 2 mmol), 3-bromoaniline (0.5 g, 3 mmol), and 3-bromoaniline hydrochloride (0.63 g, 3 mmol) is heated under reflux for 16 h. The precipitate of hydrochloride salt is converted directly to the free base with aqueous NH3, and recrystallized from EtOH to give 4-(3-bromoanilino)imidazo[4,5-f]quinazoline (0.52 g, 77%). 1H NMR (DMSO) δ11.53 (1H, brs), 8.79 (1H, s), 8.68 (1H, s), 8.53 (1H, dd, J=1.8, 1.9 Hz), 8.15 (1H, d, J=8.8 Hz), 7.81 (1H, brd, J=8.6 Hz), 7.71 (1H, d, J=8.9 Hz, 1 H), 7.41 (1H, t, J=8.0 Hz), 7.32 (1H, brd, J=7.8 Hz).
Reaction SMILES: [Cl-].[O:2]([C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=1)[CH2:12][N+]1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:22]([CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25]([O-:27])=[O:26])[CH3:23]>CN(C)C=O>[CH2:22]([CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25]([O:27][CH2:12][C:11]1[CH:19]=[CH:20][CH:21]=[C:9]([O:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]=1)=[O:26])[CH3:23]
Reactant: CCC(C(=O)[O-])c1ccccc1
Reactant: c1ccc(Oc2cccc(C[n+]3ccccc3)c2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCC(C(=O)OCc1cccc(Oc2ccccc2)c1)c1ccccc1
Yield: 156.5 %

Procedure:
4.5 g of 3-phenoxybenzyl pyridinium chloride, 1.4 g of α-ethylphenyl-acetate and 50 ml of dimethylformamide were treated in the same manner as described in Example 1 to obtain 4.65 g of 3-phenoxybenzyl α-ethylphenyl-acetate (nD25 1.5715).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:18]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:10][C:8]1[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:18]=[C:2]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]=2[N:9]=1
Reactant: C1COCCN1
Reactant: Cc1nc2c([N+](=O)[O-])cc(Br)cc2n1Cc1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc2c([N+](=O)[O-])cc(N3CCOCC3)cc2n1Cc1ccccc1
Temperature: 82 °C
Reaction time: 4 h
Yield: 59.6 %

Procedure:
A mixture of 6-bromo-2-methyl-4-nitro-1-(phenylmethyl)-1H-benzimidazole (28 g), morpholine (21 g), Pd(dba)2 (4.6 g), Cs2CO3 (52.8 g) and X-Phos (3.9 g) in dioxane (250 mL) was degassed with nitrogen and then stirred at 82° C. for 4 h. The mixture was cooled to room temperature and the solvent was removed in-vacuo. The residue was then purified by silica gel chromatography eluted with EtOAc:petroleum ether=1:1 to afford the desired product as a yellow solid (17 g, 60%). 1H NMR (300 MHz, DMSO-d6): δ ppm 2.51 (s, 3H), 3.17 (t, 4H, J=4.8 Hz). 3.76 (t, 4H, J=4.8 Hz), 5.55 (s, 2H), 7.10-7.13 (m, 2H), 7.28-7.37 (m, 3H), 7.57-7.61 (m, 2H); LC-MS: m/e=353 [M+1]+.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:25]I.[CH3:27][O:28][C:29](=[O:40])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=1>ClCCl>[CH3:27][O:28][C:29](=[O:40])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][I:25])[CH:33]=1
Reactant: II
Reactant: COC(=O)COc1cccc(CO)c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)COc1cccc(CI)c1
Reaction time: 0.08 h
Yield: 92.7 %

Procedure:
Dichloromethane (85 mL) was added to Ph3P (4.942 g, 18.8 mmol), imidazole (1.311 g, 19.3 mmol) and I2 (4.735 g, 18.7 mmol). The mixture was stirred for 5 min. and then a solution of 12-2 (2.937 g, 15.0 mmol) in 15 mL dichloromethane was added by cannula. The reaction was stirred for 3 h, silica gel was added and the mixture evaporated. The residue was purified by flash chromatography on silica gel (10%→20%→30% ethyl acetate/hexanes) to give 12-3 (4.246 g, 13.9 mmol, 93%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH:5]=[N+]=[N-])[CH3:2].C(OC(OCC)CNC(N)=O)C.[Cl:23][CH2:24][C:25](=[O:50])[C@:26]1([OH:49])[C@:43]2([CH3:44])[C@H:29]([C@H:30]3[C@:40]([F:46])([C@@H:41]([OH:45])[CH2:42]2)[C@:38]2([CH3:39])[C:33](=[CH:34][C:35](=[O:47])[CH:36]=[CH:37]2)[CH2:32][CH2:31]3)[CH2:28][C@H:27]1[OH:48]>CO>[Cl:23][CH2:24][C:25](=[O:50])[C@:26]1([OH:49])[C@:43]2([CH3:44])[C@H:29]([C@H:30]3[C@:40]([F:46])([C@@H:41]([OH:45])[CH2:42]2)[C@:38]2([CH3:39])[C:33](=[CH:34][C:35](=[O:47])[CH:36]=[CH:37]2)[CH2:32][CH2:31]3)[CH2:28][C@H:27]1[O:48][CH2:5][CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](O)[C@](O)(C(=O)CCl)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: CCOC(C=[N+]=[N-])OCC
Agent: CCOC(CNC(N)=O)OCC
Solvent: CO
Product: CCOC(CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CCl)OCC
Temperature: 0 °C

Procedure:
A solution of 2,2-diethoxy-1-diazoethane (prepared from 0.0935 mole of N-2,2-diethoxyethyl urea by the method of W. Kirmse and M. Buschhoff, Chem. Ber., 100, 1491 (1967)) in 300 ml of 3:2 ether-pentane is diluted with 100 ml of methanol and cooled to 0°C. A total of 2.5 g of 21-chloro-9-fluoro-11β,16α,17-trihydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate is added in portions until nitrogen evolution ceases. The solvent is removed in vacuo and the residue is dissolved in chloroform and chromatographed on an 80 g -- silica gel column. Elution with chloroform gives 2.16 g of TLC pure material that is recrystallized from acetone-hexane to give 1.75 g of 21-chloro-16α-(2,2-diethoxyethoxy)-9-fluoro-11β,17-dihydroxypregna-1,4-diene-3,20-dione, melting point 200°-202°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]=O)[C:6]#[N:7].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1)([O-:16])=[O:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH2:11][CH2:12][N:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][C:20]2[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=2)[CH2:26][CH2:27]1)[C:6]#[N:7]
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Reactant: COc1cc(C#N)ccc1CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C#N)ccc1CCN1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1

Procedure:
A solution of 3-methoxy-4-(2-oxoethyl)benzonitrile (91 mg, 0.56 mmol), 1-[2-(4-nitrophenyl)ethyl]piperazine (110 mg, 0.56 mmol) and NaBH(OAc)3 (393 mg, 1.87 mmol) in anhydrous DCM (15 mL) was stirred at ambient temperature overnight. The reaction was completed according to TLC. The reaction mixture was added 15 mL of DCM, washed with brine, separated the organic layer, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC to give the product. 1H-NMR (400 MHz, CDCl3) δ 8.15 (d, J=8.5 Hz, 3H), 7.37 (d, J=8.5 Hz, 3H), 7.05 (s, 1H), 3.85 (s, 3H), 2.85˜2.96 (m, 5H), 2.49˜2.75 (m, 11H). MS m/z: 395 (M+1)+. (0.30 μM)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:17](=[O:20])(=[O:19])[NH2:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6].[CH:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[CH2:22].C(O)(=O)C>CO.O>[C:11]1([C:10]2[C:9]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[NH:1][CH2:22][CH2:21][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1
Reactant: C=Cc1ccncc1
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCCc2ccncc2)c1-c1ccccc1

Procedure:
A solution of 3-amino-4-phenyl-5-sulfamylbenzoic acid (1.46 g), 4-vinylpyridine (1.0 ml) and acetic acid (0.5 ml) in methanol (7.5 ml) is refluxed for 5-6 hours. After cooling, the resulting solution is diluted with water (16 ml) to precipitate crude 4-phenyl-3-(4-pyridylethylamino)-5-sulfamylbenzoic acid, which is collected by filtration, washed with water and dried. After recrystallization twice from aqueous ethanol, the acid is obtained with a melting point of 216.5°-217.5° C.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:27][CH3:28])[C:10]1=[O:29])C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:27]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([F:20])=[C:14]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:13]=2)[C:18](=[O:19])[N:9]([OH:8])[C:10]1=[O:29])[CH3:28]
Reactant: [H][H]
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCOCC3)cc21
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Solvent: C1CCOC1
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCOCC3)cc21
Yield: 94.8 %

Procedure:
Five percent Pd/BaSO4 (50 mg) was added to a solution of 3-benzyloxy-1-ethyl-6-fluoro-7-morpholino-1H-quinazoline-2,4-dione (Example G, 0.23 g, 0.58 mmol) in 70 mL of THF and 5 mL methanol. The mixture was shaken under 50 PSI of hydrogen for 16 hours, filtered, and concentrated to afford 0.17 g of the title compound as a solid, mp 162-163° C.