Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].[C:18]([O:21][C:22]1[CH:27]=[C:26](I)[CH:25]=[CH:24][C:23]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:20])[CH3:19]>>[C:18]([O:21][C:22]1[CH:27]=[C:26]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)[CH:25]=[CH:24][C:23]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Oc1cc(I)ccc1OCc1ccccc1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Product: CC(=O)Oc1cc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)ccc1OCc1ccccc1

Procedure:
This compound was obtained by coupling rac-3,4-dihydro2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 5-iodo-2-(phenylmethoxy)phenyl acetate under the conditions described in Example 26. The crude product was chromatographed over the 50 fold amount of silica gel using methylene chloride. The combined fractions were evaporated and the residue was crystallized from methanol after treatment with charcoal and was recrystallized from ether/hexane for analysis to give colorless crystals with m.p. 117°-120°.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O-:10])=O.[NH3:11].CN([CH:15]=[O:16])C>CO>[NH2:11][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:16][CH3:15])=[O:10]
Reactant: N
Reactant: O=C([O-])c1sccc1CBr
Reactant: CN(C)C=O
Solvent: CO
Product: COC(=O)c1sccc1CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 3-(bromomethyl)thiophene-2-carboxylate (9.3 g, 39.6 mmol) in DMF (150 mL) was added 7.0 N NH3 in MeOH (150 mL). After stirring at room temperature for 1 h, the reaction was concentrated and purified by flash chromatography over silica gel (5%-10% MeOH/DCM) to provide methyl 3-(aminomethyl)thiophene-2-carboxylate (4.86 g, 72% yield) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.83 (d, J=5.0 Hz, 1H), 7.28 (d, J=5.0 Hz, 1H), 4.45 (s, 2H), 3.94 (s, 3H); MS (EI) m/z=172.2 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])([OH:17])[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25]N1C(=O)CCC1=O.C(O)(=O)C.C1(C)C=CC=CC=1>O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:25])=[CH:14][CH:15]=2)[C:10]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])([OH:17])[C:9]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN(C)C(=O)CC1(O)C(=O)N(Cc2ccccc2)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CN(C)C(=O)CC1(O)C(=O)N(Cc2ccccc2)c2ccc(Cl)cc21
Yield: 88.2 %

Procedure:
A flask is charged with 2-(1-benzyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide (Example 18) (10 g, 30.83 mmol), N-chloro succinimide (NCS) (4.12 g, 30.83 mmol), acetic acid (40 and toluene (20 mL). The orange suspension is then stirred over night and becomes a homogeneous solution. After the addition of about 5 mL of water, the solvent is removed on the rotavapor. To the residue, water is added, and the product is extracted with chloroform. After drying and removal of solvent 11 g of crude product is obtained which after chromatography on silica (toluene:ethyl acetate 1:1) gives the title product (9.76 g, 88%) as yellow foam. 1H-NMR (CDCl3, 300 MHz) δ 2.74, 3.08 (AB, 2H, 2J=16.3 Hz, CH2CONMe2); 4.85 (s, 2H, NCH2Ph); 6.32 (br s, 1H, OH); 6.58 (d, 1H, 3J=8.2 Hz, H-7); 7.10 (dd, 1H, 4J=2.0 Hz, H-6); 7.13-7.32 (m, 5H, Ph); 7.46 (d, 1H, H-4). 13C-NMR (CDCl3, 75 MHz) δ 35.77, 37.77 (N(CH3)2); 38.80 (CH2CONMe2); 44.27 (CH2Ph); 74.65 (C-3); 110.72 (C-7); 125.10 (C-4); 127.33 (Ph ortho-C); 127.90 (Ph para-C); 128.54 (C-5); 129.00 (Ph meta-C); 129.49 (C-6); 132.80 (C-9); 135.26 (C-15); 141.08 (C-8); 170.31 (C-11); 175.96 (C-2).
Reaction SMILES: [BH4-].[Na+].[C:3](O)(C(F)(F)F)=O.[C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[C:30]#N)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C=O.[C:34]([BH3-])#[N:35].[Na+]>C1COCC1.C(#N)C>[C:10]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[CH2:30][N:35]([CH3:34])[CH3:3])[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Cl)c2C#N)CC1
Reactant: O=C(O)C(F)(F)F
Reactant: [BH3-]C#N
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CN(C)Cc1c(Cl)cccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.1 %

Procedure:
Sodium borohydride (1.2 g, 31.4 mmol) was dissolved in THF (20 mL) and TFA (2.42 mL, 31.4 mmol) in THF (20 mL) was added dropwise at 0° C., and the reaction was stirred for about 30 minutes. 1-Boc-4-(3-Chloro-2-cyano-phenyl)-piperazine (2.0 g, 6.3 mmol) was dissolved in ThF (20 mL) and added dropwise to the solution at 0° C., and the reaction was stirred for about 24 hours. The reaction was carefully quenched with H2O and ethyl acetate (200 mL) was added. The mixture was washed with H2O (3×25 mL), brine (25 mL) and dried over MgSO4. The solvents were removed in vacuo and the crude reaction mixture was dissolved into acetonitrile (7 mL). Formalin (1.6 mL, 59.2 mmol) was added, followed by sodium cyanoborohydride (0.26 g, 7.4 mmol) at 0° C. The reaction was warmed to r.t. and stirred for about one hour. The reaction was quenched with H2O and ethyl acetate (100 mL) was added. The solution was washed with saturated NaHCO3 (2×10 mL) and dried over MgSO4. Purification by silica gel chromatography (1:1 hexanes/ethyl acetate) gave the title compound as a yellow oil (180 mg, 13%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][CH2:26][C@@H:27]([OH:30])[CH2:28][OH:29]>>[OH:30][C@@H:27]([CH2:28][OH:29])[CH2:26][NH:25][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[CH:5]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: NC[C@@H](O)CO
Product: COc1ccc(C(=O)NC[C@@H](O)CO)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzoic acid obtained in step B of Example 2-2-1 and (R)-3-amino-1,2-propanediol (produced by Wako Pure Chemical Industries) in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25].[CH3:27][NH:28][CH3:29].CO>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][N:28]([CH3:29])[CH3:27])[CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CNC
Reactant: O=C(Cl)CCCCl
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)CCCC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reaction time: 24 h
Yield: 36 %

Procedure:
Reaction of N4-(3-bromophenyl)-4,6-quinazolinediamine (10) (1.76 g, 5.58 mmol) with 4-chlorobutanoyl chloride (0.75 mL, 6.70 mmol) and then aqueous dimethylamine according to the general procedure A, with the exception that the first step was performed in dioxane and the second at 50° C. for 24 hours, gave N-[4-(3-bromoanilino)-6-quinazolinyl]-4-(dimethylamino)butanamide (16) (36%) as a white solid, m.p. (MeOH) 180-182° C. 1H NMR [(CD3)2SO] δ 10.23 (s, 1H), 9.87 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.57 (s, 1H), 8.17 (dd, J=1.9, 1.9 Hz, 1H), 7.88-7.84 (m, 2H), 7.77 (d, J=8.9 Hz, 1H), 7.37-7.27 (m, 2H), 2.43 (t, J=7.2 Hz, 2H), 2.29 (t, J=7.2 Hz, 2H), 2.16 (s, 6H), 1.78 (quintet, J=7.2 Hz, 2H). Analysis found: C, 55.46; H, 5.33; N, 15.96. C20H22BrN5O.¼H2O requires: C, 55.50; H, 5.24; N, 16.18.
Reaction SMILES: Cl.Cl.[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)[CH3:4].CCN(C(C)C)C(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C1COCC1>[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([OH:26])[CH2:25][CH2:24][CH2:23][N:22]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)[CH3:4]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCNC3)n(C)c2n1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCN(S(C)(=O)=O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.3 %

Procedure:
A mixture of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-3-ol dihydrochloride from Example 746 (150 mg, 0.28 mmol) and DIPEA (192 μL, 1.12 mmol) in THF (3 mL) was stirred for 5 min before the addition of methanesulfonyl chloride (22 μL, 0.28 mmol). The resulting mixture was stirred at r.t. for 4 h then partitioned between H2O and DCM. The organic phase was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) affording 765 (67 mg, 44%). LCMS (method I): RT 3.30 min, [M+H]+ 541.2. 1H NMR (DMSO, 400 MHz): δ 8.02-8.01 (1 H, m), 7.64-7.64 (1 H, m), 7.25-7.24 (2 H, m), 6.05 (1 H, s), 4.26 (4 H, brd s), 3.96 (3 H, s), 3.78 (4 H, t, J=4.60 Hz), 3.61 (2 H, s), 3.44-3.41 (1 H, m), 3.28-3.26 (2 H, m), 3.06-3.03 (1 H, m), 2.95 (3 H, s), 2.17-2.14 (1 H, m), 2.09-1.92 (2 H, m), 1.80-1.70 (1 H, m), 1.33 (3 H, t, J=7.43 Hz)
Reaction SMILES: [Br:1][C:2](=[CH2:6])[CH2:3][CH2:4][OH:5].[CH:7]([O:9][CH2:10][CH3:11])=[CH2:8]>C(OCC)C.C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]([CH2:3][CH2:4][O:5][CH:7]([O:9][CH2:10][CH3:11])[CH3:8])=[CH2:6]
Reactant: C=C(Br)CCO
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(Br)CCOC(C)OCC
Reaction time: 1 h
Yield: 91.6 %

Procedure:
While cooling a solution of 10.38 g (0.0687 mol) of 3-bromo-3-buten-1-ol in 20 ml of diethyl ether with 50 mg (0.000263 mol) p-toluene sulfonic acid monohydrate in an ice water bath, 19 ml (0.199 mol) of ethyl vinyl ether was added slowly dropwise to maintain an internal temperature of <10° C. After 1 hour at 0° C., a few drops of triethylamine was added. The reaction mixture was poured onto water. The resulting mixture was transferred to a separatory funnel and the phases were separated. The isolated organic layer was washed with brine then dried over potassium carbonate and filtered. The solvent was removed from the filtrate in vacuo to yield 14.04 g of 2-bromo-4-(1-ethoxy-ethoxy)-but-1-ene as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(OC(C)(C)C)=O)[N:6]=[CH:5]2.[CH:18]1([CH2:21][NH:22][C:23](=[O:39])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:20]C1.[C:40](=O)([O-])[O-].[Na+].[Na+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:21]1([NH:22][C:23](=[O:39])[C:24]2[CH:25]=[CH:26][C:27]([CH3:40])=[C:28]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[NH:7][N:6]=[CH:5]4)[CH:29]=2)[CH2:18][CH2:20]1
Reactant: CC1(C)OB(c2cccc(C(=O)NCC3CC3)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Br)ccc21
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2[nH]ncc2c1

Procedure:
To a solution of tert-butyl 5-bromo-1H-indazole-1-carboxylate (Intermediate 3, 2.0 g) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 5, 2.04 g) in DME (125 ml) was added tetrakis (triphenylphosphine) palladium (0.78 g) and aqueous sodium carbonate (1M, 80 ml). The mixture was heated at reflux under nitrogen for 16 h. The solvent was evaporated and the residue was purified by column chromatography on silica, eluting with cyclohexane:ethyl acetate (2:1 to 1:1) to give the title compound (1.38 g).
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]\[C:4]1[CH:15]=[C:12]([O:13][CH3:14])[C:9]([O:10][CH3:11])=[CH:8][C:5]=1[O:6][CH3:7].CO[C:18]1C(CC=C)=CC(OC)=C(OC)[CH:19]=1.C(C1C(=O)C(Cl)=C(Cl)C(=[O:36])C=1C#N)#N.C/C=C/C1C=C(OC)C(OC)=CC=1OC>>[CH3:7][O:6][C:5]1[CH:8]=[C:9]([O:10][CH3:11])[C:12]([O:13][CH3:14])=[CH:15][C:4]=1[CH2:3][CH2:2][C:1](=[O:36])[CH2:18][CH3:19]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: C=CCc1cc(OC)c(OC)cc1OC
Reactant: C/C=C\c1cc(OC)c(OC)cc1OC
Agent: C/C=C/c1cc(OC)c(OC)cc1OC
Product: CCC(=O)CCc1cc(OC)c(OC)cc1OC

Procedure:
The present invention relates to a process for the preparation of high purity and yield α-asarone, trans 2,4,5-trimethoxy cinnamaldehyde, 2,4,5-trimethoxy-phenyl propionone, from β-asarone or β-asarone rich Acorus calamus oil containing α and γ-asarone by hydrogenating, followed by treatment with DDQ with or without solid support of silica gel or alumina in dry organic solvent and α-asarone can also be obtained by treating the hydrogenated product of β-asarone or β-asarone rich Acorus calamus with DDQ in an aqueous organic solvent to obtain an intermediate 2,4,5-trimethoxy phenyl propionone, which in turn is reduced with sodiumborohydride to obtain the corresponding 2,4,5-trimethoxy-phenyl propanol and followed by final treatment with a dehydrating agent.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[N:3]=1.[CH2:10]([NH2:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:10]([NH:28][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH2:1])[N:7]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: Nc1nc(N)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCNc1nc(N)nc(N)n1
Temperature: 100 °C
Yield: 18.1 %

Procedure:
2,6-Diamino-4-chloro-s-triazine (100 g., 0.7 mole), octadecyl amine (207 g., 0.7 mole), and sodium carbonate (100 g) were dissolved in 1000 mls of dimethyl formamide and heated at 100° C. for 4 hours. While still hot, the contents of the reactor was filtered to remove the inorganic salts. When the hot filtrate was allowed to cool, the crude octadecyl melamine precipitated. With filtration, 208 grams (M.P. 78°-82° C.) of a pale yellow solid was recovered. Addition of the second filtrate to cold water yielded an additional 48 grams of solid (M.P. 60°-80° C.).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH:7]1[CH:12]=CC=C[CH:8]=1>CC(C)=O>[CH3:8][C:7]1([CH3:12])[NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][O:4]1
Reactant: CC(C)(N)CO
Reactant: c1ccccc1
Solvent: CC(C)=O
Product: CC1(C)COC(C)(C)N1
Yield: 57 %

Procedure:
Firstly, the precursor compound (2,2,4,4-tetramethyl-1,3-oxazolidine was prepared. To 237 g (3.0 mole) of 2-amino-2-methyl-1-propanol, there was added approximately 750 ml of dry benzene containing 174 g (3.0 mole) of acetone.
Reaction SMILES: O=[C:2]1[CH2:6]N(CC([O-])=O)C(=O)N1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[CH2:18][N:19]1[C:23](=[O:24])[C:22](=[O:25])[N:21]([CH2:26][C:27]([OH:29])=[O:28])[C:20]1=C)([O-:14])=[O:13].[N+](C1C=C(C=CC=1)CBr)([O-])=[O:35].[N+](C1C=C(C=CC=1)CN1C(=O)C(=O)N(CC(O)=O)C1=S)([O-])=O>>[OH:25][CH:22]1[N:21]([CH2:26][C:27]([O:29][CH2:2][CH3:6])=[O:28])[C:20](=[O:35])[N:19]([CH2:18][C:17]2[CH:31]=[CH:32][CH:33]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:23]1=[O:24]
Reactant: C=C1N(CC(=O)O)C(=O)C(=O)N1Cc1cccc([N+](=O)[O-])c1
Reactant: O=C([O-])CN1CC(=O)NC1=O
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C(O)CN1C(=O)C(=O)N(Cc2cccc([N+](=O)[O-])c2)C1=S
Product: CCOC(=O)CN1C(=O)N(Cc2cccc([N+](=O)[O-])c2)C(=O)C1O

Procedure:
The above-prepared dioxoimidazolidine-1-acetate product of paragraph (1) was condensed with 3-nitrobenzyl bromide in the same manner as mentioned in Example 8 paragraph (2) to give ethyl 5-hydroxy-3-(3-nitrobenzyl)-2,4-dioxoimidazolidine-1-acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[S:39])(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=S)Nc2ccccc2)cc1NS(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
A mixture of 3-(3,5-dichloro-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide from Example 118 (3.61 g, 8.0 mmol) and Lawesson's reagent (3.57 g, 8.8 mmol) was stirred at room temperature overnight in tetrahydrofuran (250 mL). The reaction mixture was warmed to 50° C. for about one hour, then to 65° C. for about 4 hours then stirred at room temperature overnight. The mixture was concentrated to dryness and the residue dissolved in ethyl acetate and filtered through silica gel. Concentration of the eluant followed by trituration in hexanes/ethyl acetate (1:1) afforded the crude product (3.06 g). A portion (0.8 g) of this was chromatographed on silica gel in hexanes/ethyl acetate (1:1) to afford a pure sample (0.324 g); m.p. 206-208° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([N+:16]([O-])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:19]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)([O-])=O.[NH:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](O)=[O:36]>>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]3[N:13]=[C:26]([C:25]4[CH:28]=[CH:29][C:22]([NH:19][C:35]([C:31]5[NH:30][CH:34]=[CH:33][CH:32]=5)=[O:36])=[CH:23][CH:24]=4)[NH:16][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)c1ccc[nH]1
Product: O=C(Nc1ccc(-c2nc3ccc(-c4ccccc4)cc3[nH]2)cc1)c1ccc[nH]1

Procedure:
Compound 644 was prepared according to the procedure similar to that described in Scheme III from 1-phenyl-3,4-dinitrobenzene, 4-nitrobenzaldehyde, and 2-pyrrolecarboxylic acid. [M+H]+ calcd for C24H18N4O: 379.15; found: 378.96.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].O.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO>[CH3:13][O:12][C:11]1[C:2]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(OC)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OC)c(-c2ccccc2)c1
Temperature: 95 °C
Yield: 95 %

Procedure:
To a solution of methyl 3-bromo-4-methoxybenzoate (13 g, 53 mmol) in toluene (500 mL), methanol (65 mL), and water (106 mL) was added phenyl boronic acid (7.8 g, 63.6 mmol) and potassium carbonate (14.6 g, 106 mmol) and bubbled with argon for 6 min. Tetrakis(triphenylphosphine)palladium(0) (370 mg) was added and bubbled with argon for another 2 min. The reaction mixture was then heated to 95° C. for 20 h with stirring. After cooling to RT, the two phases were separated and the aqueous layer was extracted with ether, dried with magnesium sulfate, and concentrated. Purification by MPLC (5% ethyl acetate in hexanes) gave 12.2 g of the desired product as an off white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:7][CH2:8][CH2:9][CH2:10][Cl:11])[CH2:3][C:4](O)=[O:5].[CH:13](Cl)(Cl)Cl.S(Cl)(Cl)=O.CN(C)[CH:23]=[O:24]>>[CH3:1][C:2]([CH3:12])([CH2:7][CH2:8][CH2:9][CH2:10][Cl:11])[CH2:3][C:4]([O:24][CH2:23][CH3:13])=[O:5]
Reactant: CN(C)C=O
Reactant: ClC(Cl)Cl
Reactant: CC(C)(CCCCCl)CC(=O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CC(C)(C)CCCCCl

Procedure:
To a solution of 3,3-dimethyl-7-chloroheptanoic acid (428 g., 2.21 moles) in 3 l. of chloroform containing 3 ml. of N,N-dimethylformamide is added 500 ml. of thionyl chloride and the resulting solution is tested under reflux for 3 hours. The reaction solution then is concentrated in vacuo and the residual acid chloride is dissolved in a minimum amount of benzene and added slowly to a solution containing 1260 ml. of 95% ethanol and 2520 ml. of benzene and 390 ml. of collidine. After heating under reflux for 1 hour, the solution is concentrated and the residue is dissolved in ether washed with water, dilute sodium bicarbonate solution and saline solution, dried over magnesium sulfate and concentrated to give 415 g. of crude oil, which is distilled under vacuum to yield two fractions: 46.6 g. boiling at 75°C. (0.3 mm.) and 236.7 g. boiling at 75° - 80°C. (0.3 mm). The total yield is 283.3 g. (60%) and the product is indicated to be 95% pure by g.l.c.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].Cl[CH2:17][CH:18]([OH:41])[CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH:26]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1>CS(C)=O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH:26]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[N:23]2[CH2:22][CH2:21][N:20]([CH2:19][CH:18]([OH:41])[CH2:17][N:3]3[C:14](=[O:15])[C:13]4[N:11]([CH3:12])[CH:10]=[N:9][C:8]=4[N:6]([CH3:7])[C:4]3=[O:5])[CH2:25][CH2:24]2)=[CH:28][CH:29]=1
Reactant: OC(CCl)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1cnc2c1c(=O)n(CC(O)CN1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)c(=O)n2C
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.9 %

Procedure:
To sodium hydride (0.3 g, 6.25 mmol of 50% with oil, prewashed with pentane) was added dry dimethyl sulfoxide (12 mL) and theobromine (0.9 g, 5 mmol). A fine suspension was formed to which was added 1-(1-chloro-2-hydroxy-3-propanyl)-4-(4, 4'-difluorobenzhydryl)piperazine (1.9 g, 5 mmol) dissolved in dry DMSO (10 mL) over 5 minutes. The mixture was stirred at room temperature under nitrogen for 24 hours and then heated to 70° C. for 20 hours. The DMSO was evaporated in vacuo (1 mmHg) at 75° C. and the residue was triturated in methylene chloride and filtered through Celite®. The filtrate was evaporated in vacuo to give a tacky solid (2.62 g) which was purified by flash chromatography over silica gel using 10% methanol/methylene chloride to give the desired product which was further purified with ether. The ether insoluble material was pure product (0.6 g, 25%), mp 138° -140° C.; DCI/MS: 525; 100 MHz 1H NMR (CDCl3)δ: 7.85 (s, 1H), 7.32 (m, 4H), 6.95 (m, 4H), 4.2 (s, IH), 4.1-4.22 (m, 3H), 3.97 (s, 3H), 3.57 (s, 3H), 2.3-2.5 (m, 10H).