Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[C:12](C)[C:5]=2[O:4]1.[CH2:17]1COCC1.[C:22]1([C@H:32]([NH2:34])[CH3:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC>O.CCOCC>[C:22]1([CH:32]([NH:34][C:14]([C:11]2[CH:10]=[CH:9][C:6]3[O:7][CH2:8][C:3]([CH2:2][OH:1])([CH3:17])[O:4][C:5]=3[CH:12]=2)=[O:16])[CH3:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: C1CCOC1
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: Cc1c(C(=O)O)ccc2c1OC(CO)CO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CC(NC(=O)c1ccc2c(c1)OC(C)(CO)CO2)c1cccc2ccccc12

Procedure:
To a round bottom flask equipped with magnetic stirring and a nitrogen inlet was added 3-hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid (2.00 g, 8.92 mmol), THF (45 mL), (R)-(+)-1-(1-naphthyl)ethylamine (2.23 mL, 8.92 mmol), and finally 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.53 g, 9.81 mmol). This mixture was stirred at room temperature for 36 hours. A few drops of water were added and the mixture stirred for 5 minutes. The reaction was diluted with ether and washed once with 1N HCl, once with saturated sodium bicarbonate(aq), once again with 1N HCl, dried over magnesium sulfate, filtered and evaporated to provide 3-hydroxymethyl-3-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid (1-naphthalen-1-yl-ethyl)-amide. Crystals of acceptable purity for x-ray crystallography were obtained by subliming the material twice under vacuum at 60° C. This x-ray analysis established the regiochemistry and the absolute stereochemistry of the compounds as shown, since the configuration of the naphthylethylamine stereocenter is known and not subject to racemization under the conditions of synthesis. 1H NMR (300 MHz, CD3COCD3) δ (ppm): 1.71 (d, 3H), 2.22 (s, 3H), 3.80 (m, 2H), 4.06 (m, 1H), 4.23 (m, 2H), 4.32 (m, 1H), 6.09 (m, 1H), 6.65 (d, 1H), 6.87 (d, 1H), 7.55 (m, 3H), 7.69 (m, 2H), 7.83 (d, 1H), 7.94 (d, 1H), 8.35 (d, 1H); TLC Rf=0.12 (1:1 ethyl acetate/hexane).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[C:14]1([C:13]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:10][NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=C(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NN=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A four neck flask (1 liter) equipped with a thermometer, a reflux condenser and a stirrer was charged with 68.0 g (0.5 mol) of benzohydrazide, 700 ml of methanol and 3.5 ml of acetic acid. Added thereto was 109.2 g (0.6 mol) of benzophenone while stirring at room temperature, and heating under reflux was continued for 12 hours. The reaction liquid was cooled down to 5° C. or lower, and then crystal was filtered off and dried under reduced pressure, whereby white crystal was obtained.
Reaction SMILES: CC(C)(OC([NH:7][CH:8]([CH:12]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:13]=[CH2:14])[C:9]([OH:11])=[O:10])=O)C.S(Cl)(Cl)=O.[Br:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.[CH3:39]O>C(Cl)Cl.C(N(CC)CC)C>[Br:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:7][CH:8]([CH:12]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:13]=[CH2:14])[C:9]([O:11][CH3:39])=[O:10])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: C=CC(OCc1ccccc1)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CO
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CC(OCc1ccccc1)C(NS(=O)(=O)c1ccc(Br)cc1)C(=O)OC
Temperature: 25 °C

Procedure:
The 2-[[1,1-dimethylethoxy)carbonyl]amino-3-phenylmethoxy-4-pentenoic acid 63b (1.8 g, 5.37 mmol) is dissolved in methanol (54 mL) and thionyl chloride (8.3 mL) is added dropwise to the mixture. The resulting mixture is stirred at room temperature until the reaction is complete by tlc. The crude reaction is dried and re-evaporated from methanol (3 times). The dried reaction mixture is taken up in methylene chloride (30 mL) and triethylamine (7 mL). 4-Bromophenylsulfonyl chloride (1.23 g, 4.83 mmol) is added and the reaction is stirred overnight. The solvent is removed in vacuo and the oil is taken up in ethyl acetate, and then washed consecutively with 1N HCl, saturated sodium bicarbonate solution, and finally with brine, then dried over magnesium sulfate and the solvent removed in vacuo. The crude material is adsorbed onto silica gel and purified over a silica column eluting with hexane followed with hexane:ethyl acetate (8:2). Product fractions are combined and dried to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH3:13])[C:11]([S:14][CH3:15])=[N:10][N:9]=1.ClC1C=C(C=CC=1)C(OO)=[O:21]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH3:13])[C:11]([S:14]([CH3:15])=[O:21])=[N:10][N:9]=1
Reactant: CSc1nnc(-c2ccccc2F)n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1c(-c2ccccc2F)nnc1S(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, 0° C., solution of 3-(2-fluorophenyl)-4-methyl-5-methylthio-4H-1,2,4-triazole (5.0 g, 2.2×10-2 mole) and CH2Cl2 (125 ml) was added portionwise m-chloroperoxybenzoic acid (4.83 g, 2.24×10-2 mole, 80% active MCPBA). After stirring overnight at room temperature, the reaction was diluted with CH2Cl2 until homogeneous and was then washed in turn twice with saturated aqueous NaHCO3 and once with saturated aqueous NaCl. After drying over anhydrous Na2SO4, the CH2Cl2 was evaporated leaving an oil which slowly crystallized. Crystallization from EtOAc/hexane gave a colorless solid: 3.7 g (68%), mp 95°-97° C.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:3]=1.[H-].[Na+].I[CH3:27]>CN(C)C=O>[NH2:1][C:2]1[N:7]([CH3:27])[C:6](=[O:8])[C:5]([C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:3]=1
Reactant: COc1ccc(-c2c(-c3cccc(F)c3)nc(N)[nH]c2=O)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(-c3cccc(F)c3)nc(N)n(C)c2=O)cn1
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
To a solution of 2-amino-6-(3-fluorophenyl)-5-(6-methoxy-3-pyridyl)-3,4-dihydro-4-pyrimidinone (1.0 g, 3.2 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (77 mg, 3.2 mmol). After stirring for 10 minutes, iodomethane (454 mg, 0.2 mL, 3.2 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. After removing the solvent from the reaction mixture, the residue was washed with water, to give the title compound (600 mg).
Reaction SMILES: N1C=CC=CC=1.ClC(Cl)(O[C:11](=[O:17])OC(Cl)(Cl)Cl)Cl.[CH3:19][C@H:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([CH3:26])[NH:21]1.C[C@H]1CCC[C@@H](C)N1.C(Cl)(=O)N.CCN(C(C)C)C(C)C.[F:48][C:49]1[CH:50]=[CH:51][C:52]([NH:55][NH2:56])=[N:53][CH:54]=1>C(Cl)Cl>[F:48][C:49]1[CH:50]=[CH:51][C:52]([N:55]([C:11]([N:21]2[C@H:22]([CH3:26])[CH2:23][CH2:24][CH2:25][C@@H:20]2[CH3:19])=[O:17])[NH2:56])=[N:53][CH:54]=1
Reactant: NNc1ccc(F)cn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@@H]1CCC[C@H](C)N1
Agent: NC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@H](C)N1C(=O)N(N)c1ccc(F)cn1
Temperature: 45 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
Pyridine (2.40 mL, 29.7 mmol) was added dropwise to an ice cold suspension of triphosgene (4.42 g, 14.9 mmol) in DCM (30.0 mL). cis-2,6-Dimethylpiperidine (2.00 mL, 14.9 mmol) was added and the reaction stirred for 3 hours, then quenched by dropwise addition of HCl (1M aqueous, 30 mL). The mixture was extracted into DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The product was used in the next reaction without purification. cis-2,6-Dimethylpiperidine-carbamoylchloride (1.79 g, 10.2 mmol) was dissolved in DCM (90.0 mL) and DIPEA (2.42 mL, 13.9 mmol) was added followed by (5-fluoro-pyridin-2-yl)-hydrazine (WO 2010 022076, which is incorporated herein by reference in its entirety, 1.18 g, 9.30 mmol) and the reaction heated to 45° C. overnight. The reaction was cooled and quenched into water. The mixture was extracted into DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC using 0-6% [2M NH3 in MeOH] in DCM to give the title compound (1.38 g, 56%). 1H NMR (300 MHz, CDCl3): 1.29 (6H, d, J 7.1 Hz), 1.48-1.90 (6H m), 4.26 (2H, qn, J 6.9 Hz), 6.39 (1H, d, J 2.3 Hz), 6.50 (1H, d, J 2.3 Hz), 6.74 (1H, dd, J 9.0, 3.6 Hz), 7.27 (1H, ddd, J 8.9, 8.0, 2.9 Hz), 8.03 (1H, d, J 2.9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)=[CH:9]\[CH2:10][OH:11])=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:57][O:58][C:59](=[O:70])[CH2:60][O:61][C:62]1[CH:67]=[CH:66][C:65](O)=[CH:64][C:63]=1[CH3:69]>O1CCCC1>[CH3:57][O:58][C:59](=[O:70])[CH2:60][O:61][C:62]1[CH:67]=[CH:66][C:65]([O:11][CH2:10]/[CH:9]=[C:8](\[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)/[C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:13]=2)=[CH:64][C:63]=1[CH3:69]
Reactant: OC/C=C(\c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Reactant: COC(=O)COc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(F)cc2)c2ccc(C#Cc3ccccc3)cc2)cc1C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of the above alcohol (100 mg, 0.305 mmol) in dry tetrahydrofuran (20 ml), was added tributylphosphine (0.11 ml, 0.61 mmol). The mixture was cooled to 0° C. and added 1,1′-(azodicarbonyl)dipiperidine (153 mg, 0.61 mmol), and after 10 min. (4-hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (65 mg, 0.34 mmol) were added. The reaction mixture was stirred for 1.5 hours at 0° C. and then allowed to warm up to ambient temperature overnight. To the reaction mixture was added silica gel Fluka 60 (10 g) and the reaction mixture was evaporated in vacuo. The residue was purified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) giving {4-[(Z)-3-(4-fluoro-phenyl)-3-(4-phenylethynyl-phenyl)allyloxy]-2-methyl-phenoxy}-acetic acid methyl ester as an oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7](C(O)=O)=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:14].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18]C1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH:38]1CC[O:41][CH2:40][CH2:39]1.NC(N)=O>C(Cl)Cl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:14].[NH:38]1[CH2:18][CH:19]([C:20]([NH2:16])=[O:21])[O:41][CH2:40][CH2:39]1
Reactant: C1COCCN1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C1CCc2cc(C(=O)O)ccc2C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(N)=O
Solvent: ClCCl
Product: NC(=O)C1CNCCO1
Product: O=C1CCc2ccccc2C1
Temperature: 25 °C
Yield: 51 %

Procedure:
2-Tetralone-6-carboxylic acid, ethylene ketal (395 mg, 2.07 mmol) was codissolved in CH2Cl2 (50 mL) with N-hydroxysuccinimide (260 mg, 2.76 mmol) at 0° C. and treated with a slight excess of 1,3-dicyclohexylcarbodiimide (502 mg, 2.50 mmol). The mixture was allowed to warm to ambient temperature over 30 minutes, during which time a fine white precipitate formed. Morpholine (0.91 mL, 10.4 mmol, d=0.998) was added and the solution stirred at ambient temperature for 16 hours The suspended urea was filtered away and the solution concentrated in vacuo to a colorless oil. The oil was applied to a silica flash chromatography column and eluted with 50-100% EtOAc in hexanes to yield 323 mg (51%) of 2-tetralone-6-morpholinamide, ethylene ketal as a slowly crystallizing solid, clean by NMR, TLC.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=2[CH3:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][N:28]([CH3:32])[C:29](Cl)=[S:30]>O1CCOCC1.CN(C)C1C=CN=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([CH3:19])=[CH:13][C:14]([O:18][C:29](=[S:30])[N:28]([CH3:32])[CH3:27])=[CH:15][C:16]=2[CH3:17])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(O)cc(C)c1-c1ccc(C(C)(C)C)cc1
Reactant: CN(C)C(=S)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cc(OC(=S)N(C)C)cc(C)c1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
To a solution of 4′-tert-butyl-2,6-dimethyl-biphenyl-4-ol (10 g, 37.3 mmol) in dioxane (157 ml) is added 4-dimethylaminopyridine (476 mg, 3.9 mmol), triethylamine (10 mL, 78.6 mmol), and dimethylthiocarbamoyl chloride (6.1 g, 49.1 mmol). The reaction mixture is heated to reflux overnight. After cooling to rt, the reaction mixture is partitioned between ethyl acetate and water. The aqueous layer is back-extracted with ethyl acetate, and the combined organic layers are dried and concentrated. The resulting residue is applied to silica gel and eluted using 20% ethyl acetate in hexanes to give dimethyl-thiocarbamic acid O-(4′-tert-butyl-2,6-dimethyl-biphenyl-4-yl)ester (12.2 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[N:3]=1.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]1>>[ClH:1].[ClH:1].[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH:39][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=3)[N:3]=2)[CH2:35][CH2:34]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1ccc(C(F)(F)F)cc1
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(NCCNC(=O)c3ccc(C(F)(F)F)cc3)c3ncn(C4CCCC4)c3n2)CC1
Temperature: 140 °C

Procedure:
342 mg of the product obtained in Stage 1 above and 428 mg of trans-1,4-diaminocyclohexane are mixed together and the reaction medium is heated to approximately 140° C. for 4 hours and 30 minutes. After evaporating the solvent, chromatography on silica is carried out eluting with methylene chloride/methanol/ammonium hydroxide in a proportion of 85/15/1.5, followed by taking up in an ethanolic solution of hydrochloric acid, leaving to crystallize, separating, drying under reduced pressure and 281.6 mg of expected product is recovered.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH:6]1[CH2:10][N:9]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[C:8](=[O:21])[NH:7]1)[CH3:5].Cl[CH2:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=1)=[O:25].C(=O)([O-])O.[Na+]>CN(C=O)C.O>[O:21]=[C:8]1[N:9]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:15][CH:16]=2)[CH2:10][CH:6]([CH:4]([CH3:3])[CH3:5])[N:7]1[CH2:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=1)=[O:25]
Reactant: CC(C)C1CN(c2ccc(C(F)(F)F)nc2)C(=O)N1
Reactant: O=C(CCl)Nc1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C1CN(c2ccc(C(F)(F)F)nc2)C(=O)N1CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
Sodium hydride (60%, 22 mg) was added to a solution of 4-(propan-2-yl)-1-[6-(trifluoromethyl)pyridin-3-yl]imidazolidin-2-one (50 mg) in DMF (1.5 mL), and the mixture was stirred at room temperature for 15 min. After 2-chloro-N-[3-(trifluoromethyl)phenyl]acetamide (52 mg) was added thereto, the resulting mixture was stirred at room temperature for 21 hr. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, followed by extraction with chloroform. The organic layer was separated out by phase separation cartridge and concentrated under reduced pressure. The residue was purified by column chromatography (NH cartridge, and silica gel cartridge, hexane/ethyl acetate) and preparative HPLC to afford the title compound (79 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[S:12])[N:8]([CH2:13][CH2:14][O:15][CH3:16])[C:7]2=[O:17].[C:18]([O-])([O-])=O.[K+].[K+].CI>C1COCC1>[I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH3:18])[N:8]([CH2:13][CH2:14][O:15][CH3:16])[C:7]2=[O:17]
Reactant: COCCn1c(=S)[nH]c2c(I)cccc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COCCn1c(SC)nc2c(I)cccc2c1=O
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
A sealable flask was charged with 2-amino-3-iodobenzoic acid (5.02 g, 19.09 mmol) and 2-methoxyethyl isothiocyanate (3.35 g, 28.6 mmol) in tBuOH (30 mL) followed by TEA (3.98 mL, 28.6 mmol). The flask was sealed and heated in an oil bath at 100° C. for 4 h with a blast shield. The reaction mixture was cooled to RT and the off white solid was filtered, rinsed with 2×25 mL of ether and dried to give 8-iodo-3-(2-methoxyethyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (6.21 g, 17.15 mmol, 90% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.99 (1H, s), 8.26 (1H, dd, J=7.6, 1.2 Hz), 8.00 (1H, dd, J=7.9, 1.3 Hz), 7.17 (1H, t, J=7.7 Hz), 4.60 (2H, t, J=6.5 Hz), 3.65 (2H, t, J=6.6 Hz), 3.31 (3H, s). m/z (ESI, +ve) 362.8 (M+H)+. To a 500-mL round-bottomed flask was added sequentially 8-iodo-3-(2-methoxyethyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (6.01 g, 16.59 mmol), THF (75 mL K2CO3 (5.73 g, 41.5 mmol), and MeI (2.06 mL, 33.2 mmol). The reaction mixture was heated in an oil bath at 65° C. for 6 h. The mixture was concentrated to half of its volume, poured into ice/water (100 mL) and stirred for 10 min. The suspension was filtered and the solid was washed with cold water (20 mL) and cold ether (20 mL). The off-white solid was dried to give 8-iodo-3-(2-methoxyethyl)-2-(methylthio)quinazolin-4(3H)-one (715a; 4.91 g). The filtrate was extracted with 50 mL of EtOAc. The EtOAc layer was concentrated and the brown solid was stirred in 5 mL of ether and 5 mL of hexanes. The solid was filtered and dried to give 8-iodo-3-(2-methoxyethyl)-2-(methylthio)quinazolin-4(3H)-one (715a; 1.1 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.34 (1H, dd, J=7.6, 1.4 Hz), 8.09 (1H, dd, J=7.9, 1.3 Hz), 7.22 (1H, t, J=7.7 Hz), 4.25 (2H, t, J=6.2 Hz), 3.65 (2H, t, J=6.2 Hz), 3.30 (3H, s), 2.75 (3H, s). m/z (ESI, +ve) 376.7 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:7]([Li])CCC.[C:12]([NH:15][C:16]1[C:17]([CH3:30])=[C:18]([CH3:29])[C:19]2[O:23][C:22]([CH:25]=O)([CH3:24])[CH2:21][C:20]=2[C:27]=1[CH3:28])(=[O:14])[CH3:13].O>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:12]([NH:15][C:16]1[C:17]([CH3:30])=[C:18]([CH3:29])[C:19]2[O:23][C:22]([CH3:24])(/[CH:25]=[CH:7]\[C:3]3[CH:2]=[CH:1][CH:6]=[CH:5][CH:4]=3)[CH2:21][C:20]=2[C:27]=1[CH3:28])(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1c(C)c(C)c2c(c1C)CC(C)(C=O)O2
Reactant: [Li]CCCC
Reactant: CCCCCC
Agent: [Cl-]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1c(C)c(C)c2c(c1C)CC(C)(/C=C\c1ccccc1)O2
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
A suspension of benzyltriphenylphosphonium chloride (0.7 g, 1.8 mmol) in tetrahydrofuran (10 ml) was cooled to -20° C. and n-butyllithium hexane solution (1.6M, 1.12 ml, 1.8 mmol) was added dropwise. The reaction mixture was stirred for 30 minutes and then a solution of 5-acetylamino-2-formyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran (0.45 g, 1.7 mmol) in tetrahydrofuran (5 ml) was added. The reaction mixture was stirred at room temperature for additional 30 minutes. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The extract was washed with water, dried and then concentrated. The residue was purified by column chromatography on silica gel (isopropyl ether-ethyl acetate, 1:1) to obtain the desired compound (0.44 g, yield: 76.2%) as oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.Br[CH2:17][CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:20]([O:19][CH2:18][CH2:17][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCCOCc1ccccc1
Reactant: Nc1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Product: c1ccc(COCCNc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
In a round bottom flask aniline (2.0 g, 21.5 mmol, 2.0 mL), 2,6-lutidine (2.30 g, 21.5 mmol) and benzyl 2-bromoethyl ether (4.6 g, 21.5 mmol, 3.4 mL) were combined in DMF (10 mL) and stirred at 100° C. overnight. The reaction was allowed to cool and then diluted with ethyl acetate (50 mL). This was washed with water (3×20 mL) and the organics were dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (0-50% B, 100 g, 19.5 CV, 85 mL/min) to afford 2.22 g (37%) of (2-benzyloxy-ethyl)-phenyl-amine (21) as a yellow oil. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 43.6, 68.6, 73.2, 113.1, 117.5, 127.5, 127.7, 128.4, 129.1, 138.2, 148.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C@H:10]3[C:16](=O)[N:15](COCC[Si](C)(C)C)[C:14]4[CH:26]=[C:27]([O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]5[C:38]([O:68][CH3:69])=[CH:39][C:40]6[C:46](=[O:47])[N:45]7[CH:48]=[C:49]([C:51]8[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][CH:52]=8)[CH2:50][C@H:44]7[C:43](=O)[N:42](COCC[Si](C)(C)C)[C:41]=6[CH:67]=5)[C:28]([O:30][CH3:31])=[CH:29][C:13]=4[C:12](=[O:70])[N:11]3[CH:71]=2)=[CH:4][CH:3]=1.C([BH-](CC)CC)C.[Li+]>O1CCCC1.ClCCl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C@H:10]3[CH:16]=[N:15][C:14]4[CH:26]=[C:27]([O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]5[C:38]([O:68][CH3:69])=[CH:39][C:40]6[C:46](=[O:47])[N:45]7[CH:48]=[C:49]([C:51]8[CH:52]=[CH:53][C:54]([OH:57])=[CH:55][CH:56]=8)[CH2:50][C@H:44]7[CH:43]=[N:42][C:41]=6[CH:67]=5)[C:28]([O:30][CH3:31])=[CH:29][C:13]=4[C:12](=[O:70])[N:11]3[CH:71]=2)=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(O)cc4)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(c3ccc(N)cc3)=CN1C2=O
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(O)cc4)C[C@H]1C=N3)N=C[C@@H]1CC(c3ccc(N)cc3)=CN1C2=O
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 40 %

Procedure:
A flame-dried flask was charged with SEM dilactam 13 (109 mg, 109 μmol, 1 eq) dissolved in anhydrous tetrahydrofuran (2.2 mL), and cooled to −78° C. Lithium triethylborohydride (0.33 mL of a 1 M solution in THF, 330 μmol, 3 eq) was added dropwise and the reaction was stirred under nitrogen for 2.5 hours, at which time LC revealed incomplete conversion to product. An additional 0.66 mL of reductant was added and the reaction was stirred for one more hour. The reaction was quenched through the addition of water (1 mL) and allowed to warm to room temperature, then diluted brine (25 mL) and extracted three times with dichloromethane (25 mL). The combined organics were washed with brine (25 mL), dried over sodium sulfate, and evaporated to dryness. The residue was dissolved in a mixture of dichloromethane (2.8 mL), ethanol (7.4 mL), and water (1.0 mL), and silica gel (2.7 g) was added. The resulting slurry was stirred at room temperature for 4 days. TLC analysis revealed conversion to imine dimer 14, at which time the slurry was filtered over a sintered glass funnel and the silica gel cake was washed with 10% methanol in chloroform until no further PBD absorbance was observed in the filtrate. Concentration of the filtrate provided crude imine dimer 14. The material was dissolved in minimal dichloromethane and purified by radial chromatography on a 1 mm chromatotron plate eluted with CH2Cl2/MeOH mixtures (100:0 to 80:20) to provide 14 (31 mg, 40%). LC-MS: tR 8.48 min, m/z (ES+) found 712.2 (M+H)+.