Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=2[CH:4]=1)#[CH:2].C([Li])CCC.CCCCCC.[CH2:28]([O:30][C:31](Cl)=[O:32])[CH3:29]>CCOCC>[CH3:13][C:9]1([CH3:14])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]2[CH:4]=[C:3]([C:1]#[C:2][C:31]([O:30][CH2:28][CH3:29])=[O:32])[CH:12]=[CH:11][C:10]1=2
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
To a cold solution (-78° C.) of 2-ethynyl,5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (900 mgs, 4.3 mmols) in ether (20 ml) was added n-butyllithium in hexane (5.6 mmols). The mixture was stirred for 45 mins, and ethylchloroformate (1.3 g, 12 mmols) was added via syringe. Stirring was continued for 45 mins then the mixture was warmed gradually to -10° C. and quenched by adding sodium bicarbonate (NaHCO3) solution (10 ml). Diethyl ether (100 ml) was added, the organic phase washed with water (10 ml), brine (10 ml), and dried (MgSO4). The solvent was removed in vacuo. Purification of the residue over silicagel (5% ethylacetate in hexane) gave the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[CH2:10][C@@H:11]([NH2:26])[C:12]([NH:14][C@H:15]([C:20](=[O:25])[N:21]([O:23][CH3:24])[CH3:22])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:33]=[CH:32][C:31]([CH:34]2[CH2:38][CH:37](OC)O[CH:35]2OC)=[CH:30][CH:29]=1.FC(F)(F)C(O)=O>ClCCCl>[CH2:1]([O:8][C:9](=[O:27])[CH2:10][C@@H:11]([N:26]1[CH:37]=[CH:38][C:34]([C:31]2[CH:32]=[CH:33][C:28]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:29][CH:30]=2)=[CH:35]1)[C:12]([NH:14][C@H:15]([C:20](=[O:25])[N:21]([O:23][CH3:24])[CH3:22])[CH2:16][CH:17]([CH3:18])[CH3:19])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Reactant: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](N)CC(=O)OCc1ccccc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CON(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Yield: 48 %

Procedure:
As described in Example 1(c) for the preparation of N-(8-oxo-4-oxa-1,7-diaza-tricyclo-[9.6.1.012,17 ]-octadeca-11(18),12,14,16-tetraen-9-yl)-3-(3-phenyl-1H-pyrrol-1-yl acid benzyl ester, 3(R)-amino-N-(1(S)-(N-methoxy-N-methylcarbamoyl)-3-methylbutyl)succinamic acid benzyl ester was deprotected. The crude amine salt and 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1(a)) were condensed in anhydrous 1,2-dichloroethane with trifluoroacetic acid to provide in 48% yield 3(R)-(3-biphenyl-4-yl-1H-pyrrol-1-yl)-N-[1(S)-(N-methoxy-N-methylcarbamoyl)-3-methyl-butyl]succinamic acid benzyl ester as an amorphous solid. 1H NMR (CDCl3): δ 7.62 (d, 2H, J=7.4 Hz), 7.58 (s, 3H), 7.44 (t, 2H, J=7.7 Hz), 7.35-7.21 (m, 7H), 7.10 (s, 1H), 6.80 (t, 1H, J=2.2 Hz), 6.60 (bs, 1H), 5.17-1.13 (m, 1H), 5.10 (s, 2H), 4.97-4.92 (m, 1H), 3.77 (s, 3H), 3.44 (dd, 1H, J=5.7, 17.1 Hz), 3.17 (s, 3H), 3.03 (dd, 1H, J=8.8, 16.5 Hz), 1.67-1.36 (m, 3H), 0.92 (d, 3H, J=6.25 Hz), 0.87 (d, 3H, J=6.3 Hz). Anal. Calculated for C35H39N3O5 : C, 72.27; H, 6.76; N, 7.22. Found: C, 72.19; H, 6.78; N, 7.16.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=CC=CC=1C.[H][H]>[Ni].CO>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: Cc1ccccc1Cl
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.76 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml), Raney Nickel (0.15 g wet basis) and o-chlorotoluene (50 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml methanol. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>95%, trans<5%, dehalogenation product<0.1%, yield 0.76%].
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[NH:7][C:6]=2[CH:5]=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH3:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:12])([F:13])[F:14])[N:7]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[CH3:27])[C:6]=2[CH:5]=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1
Reactant: Cc1c(Cl)cccc1CBr
Reactant: O=[N+]([O-])c1cc(Br)c2nc(C(F)(F)F)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1Cn1c(C(F)(F)F)nc2c(Br)cc([N+](=O)[O-])cc21
Temperature: 90 °C
Reaction time: 6 h
Yield: 56.2 %

Procedure:
Charged a 100 mL round bottom flask containing 4-bromo-6-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole (4.3 g, 13.87 mmol) dissolved in N,N-Dimethylformamide (DMF) (30 mL) with 1-(bromomethyl)-3-chloro-2-methylbenzene (3.81 g, 17.34 mmol) then added potassium carbonate (4.79 g, 34.7 mmol). The resulting reaction suspension was stirred for 6 h at 90° C., then cooled to RT, and filtered to remove potassium carbonate. The resulting filtrate was concentrated to a small volume (˜10 mL), and diluted with water. The aqueous suspension was extracted with chloroform (3×), the organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and finally concentrated in vacuo. The crude solid was slurried in hexane to provide 4-bromo-1-(3-chloro-2-methylbenzyl)-6-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole (3.5 g, 7.80 mmol, 56.2% yield). The material was carried onto the nitro reduction without further purification. MS (ES+) m/e: 449.0, 450.8 [M+H]+(bromine pattern). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.55 (d, J=2.02 Hz, 1H) 8.08 (d, J=1.77 Hz, 1H) 7.40 (d, J=8.08 Hz, 1H) 7.04 (t, J=7.96 Hz, 1H) 6.23 (d, J=7.83 Hz, 1H) 5.63 (s, 2H) 2.52 (s, 3H)
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([O:13][CH3:14])[CH:4]=1.[CH:15]([NH:18][CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:15]([N:18]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([O:13][CH3:14])[CH:4]=1)[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]
Reactant: COC(=O)c1ccc(CBr)cc1OC
Reactant: CC(C)NC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CN(C(C)C)C(C)C)ccc1C(=O)O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 4-bromomethyl-2-methoxybenzoate (2.59 g), diisopropylamine (3.92 ml), potassium carbonate (1.38 g) and dimethylformamide (30 ml) was stirred at 80° C. for 2 hours, to which was added water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated. The residue was dissolved in THF-EtOH (1:1, 30 ml), to which was added 1 N sodium hydroxide solution (15 ml) and the solution was stirred at 80° C. for 20 minutes. To the solution was added water and the solution was washed with ether, made acidic with 1 N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated. The residue was dissolved in THF and insoluble materials were filtered off. The filtrate was concentrated and crystallized with isopropylether to give the title compound (0.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Cl)[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[Na+].[SH:31][CH2:32][CH2:33][S:34]([O-:37])(=[O:36])=[O:35].COC1C=C(C=CC=1OC)C(Cl)=O>C(Cl)Cl>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][S:31][CH2:32][CH2:33][S:34]([OH:37])(=[O:36])=[O:35])[CH:15]=1
Reactant: O=S(=O)([O-])CCS
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(CCl)c1
Agent: COc1ccc(C(=O)Cl)cc1OC
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(CSCCS(=O)(=O)O)c1
Temperature: 40 °C
Reaction time: 96 h
Yield: 46.1 %

Procedure:
Subsequently, methyl 5-chloro-2-[3-(chloromethyl)benzoyl]aminobenzoate (1.8 g) was dissolved in anhydrous methylene chloride. Triethylamine (1.5 ml) and 2-mercaptoethanesulfonic acid sodium salt (compound B′) (1.3 g) were added to the solution at room temperature, and the mixture was stirred at 40° C. for 4 days. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, was dried over sodium sulfate, and was then concentrated. The residue was purified by column chromatography on silica gel to give 5-chloro-2-[3-(2-sulfo-ethylsulfanylmethyl)-benzoylamino]-benzoic acid methyl ester (1.08 go yield 46.1%) as a useful intermediate.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[CH2:17][CH2:16][CH:15]([C:18](OC)=[O:19])[C:14]1=O.CO>O>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[C:14]2[N:1]=[C:2]([OH:3])[N:4]=[C:18]([OH:19])[C:15]=2[CH2:16][CH2:17]1
Reactant: COC(=O)C1CCC(c2ccccc2OC)C1=O
Reactant: NC(N)=O
Solvent: CO
Solvent: O
Product: COc1ccccc1C1CCc2c(O)nc(O)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a melt of urea (6.07 g, 101 mmol) (bath temp 150° C.) was added methyl 3-(2-methoxyphenyl)-2-oxocyclopentanecarboxylate (5.3 g, 20.21 mmol) dropwise. After stirring overnight, the reaction was cooled to rt. Added MeOH (30 ml), and broke up the solid mass with a spatula and stirred for 1 h. Added water (600 ml), and stirred for 3 hr. The mixture was added to a Buchner funnel, and washed with water. Dried overnight in the vacuum oven (45° C.) to obtain 7-(2-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diol (4.03 g, 15.60 mmol, 77% yield) as a tan solid. LC-MS (M+H)+=259.1.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:5][CH2:4]1.CO.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[OH-].[Na+]>C1(C)C=CC=CC=1>[N:3]1([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:5][CH2:4]1
Reactant: C1CC(C2CCNCC2)CCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCC(C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
4,4′-Bipiperidine dihydrochloride (2.95 g) was mixed with MeOH (25 ml), and a mixture of benzyl chloroformate (2.2 g) and toluene (5 ml) was added dropwise thereto over 1 hour while keeping the solution neutral by adding a 6 M aqueous NaOH solution at the same time. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. CHCl3, and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain benzyl 4,4′-bipiperidine-1-carboxylate (1.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[F:34][C:35]([F:39])([F:38])[CH2:36]I.O>CN(C)C=O>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:3][C:2]=1[O:1][CH2:36][C:35]([F:39])([F:38])[F:34]
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC)c(O)c2)n1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC)c(OCC(F)(F)F)c2)n1
Temperature: 50 °C

Procedure:
A 0.3 g quantity of the N-[2-(3-hydroxy-4-methoxy phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide obtained in Example 2 and 0.22 g of potassium carbonate were dissolved in 10 ml of dimethylformamide, and 0.34 g of 1,1,1-trifluoro-2-iodoethane was added thereto. The mixture was stirred with heating at 50° C. overnight. The reaction mixture was allowed to cool, water was then added thereto, and extraction was performed with ethyl acetate. After washing with water twice, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give 0.14 g of white powdery N-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-2-ethoxybenzamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:25])[CH:5]=[CH:6][C:7]=1[CH:8]1[S:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]([CH3:24])[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:9]1=2.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]O)[CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:24][N:15]1[C:10]2[NH:11][CH2:12][CH2:13][S:14][CH:8]([C:7]3[CH:6]=[CH:5][C:4]([O:25][CH2:32][C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[CH:3][C:2]=3[CH3:1])[C:9]=2[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:16]1
Reactant: OCc1cccnc1
Reactant: Cc1cc(O)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCc2cccnc2)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C
Temperature: 0 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
To a degassed solution of 3-methyl-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]phenol (0.071 g, 0.2 mmol, Ex. #D.42) in anhydrous THF (10 mL) was added 3-pyridinemethanol (0.033 g, 0.3 mmol) and triphenylphosphine (0.131 g, 0.5 mmol), at rt. After 30 min the mixture was cooled to about 0° C. and diisopropyl azodicarboxylate (0.1 mL, 0.5 mmol) was added dropwise. The resulting mixture was stirred for about 16 h at rt, and then concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/methanol 95:5) followed by trituration with diethyl ether to give 1-methyl-4-[2-methyl-4-(3-pyridylmethoxy)phenyl]-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.012 g, 0.03 mmol, 14%) as a pale yellow solid: LC-MS (Table 1, Method e) Rt=5.09 min; m/z 444 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.59 (3 H, s) 2.70 (1 H, ddd, J=14.9, 6.1, 2.3 Hz) 2.88 (1 H, ddd, J=14.9, 8.8, 2.5 Hz) 3.19-3.29 (1 H, m) 3.53-3.62 (1 H, m) 3.78 (1 H, br s) 3.84 (3 H, s) 5.01 (2 H, s) 6.62 (1 H, s) 6.63 (1 H, dd, J=8.4, 2.6 Hz) 6.82 (1 H, d, J=2.6 Hz) 7.07 (1 H, ddd, J=7.4, 4.9, 1.2 Hz) 7.16 (1 H, d, J=8.4 Hz) 7.30 (1 H, dd, J=7.8, 4.9 Hz) 7.58 (1 H, td, J=7.8, 1.9 Hz) 7.71-7.79 (2 H, m) 8.48 (1 H, d, J=4.9 Hz) 8.56 (1 H, dd, J=4.8, 1.5 Hz) 8.65 (1 H, d, J=1.9 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:19]=[CH:18][C:17]4[N:16]([CH2:20][CH2:21][CH:22]([NH:27]C(=O)OC(C)(C)C)[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][C@@H:14]5[CH2:35][O:36][CH2:37][CH2:38][N:13]5[C:12]=4[N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1>C(Cl)Cl.FC(F)(F)C(O)=O>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:19]=[CH:18][C:17]4[N:16]([CH2:20][CH2:21][CH:22]([NH2:27])[C:23]([CH3:26])([CH3:24])[CH3:25])[CH2:15][C@@H:14]5[CH2:35][O:36][CH2:37][CH2:38][N:13]5[C:12]=4[N:11]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)NC(CCN1C[C@@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(N)CCN1C[C@@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 193 using tert-butyl (1-((R)-2-(1H-indol-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-4,4-dimethylpentan-3-yl)carbamate (PREPARATION x78) in CH2Cl2 (0.5 mL) and trifluoroacetic acid (0.5 mL) (11.7 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (s, 9 H), 1.51-1.75 (m, 1 H), 1.91-2.08 (m, 1 H), 3.02-3.39 (m, 4 H), 3.53-3.65 (m, 6 H), 3.80-3.96 (m, 1 H), 3.97-4.16 (m, 2 H), 4.60-4.76 (m, 1 H), 6.96-7.12 (m, 1 H), 7.20-7.33 (m, 1 H), 7.47-7.88 (m, 4 H), 11.33-11.59 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C24H32N6O, 421.27 found 421.4.
Reaction SMILES: FC1C=CC(CBr)=CC=1.[CH3:10][S:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH3:22][C:23]1[CH:27]=[C:26]([N:28]2[C:32](=[O:33])[NH:31][N:30]=[CH:29]2)[S:25][C:24]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH3:22][C:23]1[CH:27]=[C:26]([N:28]2[C:32](=[O:33])[N:31]([CH2:18][C:17]3[CH:20]=[CH:21][C:14]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:15][CH:16]=3)[N:30]=[CH:29]2)[S:25][C:24]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)cc1C
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: Fc1ccc(CBr)cc1
Product: CCOC(=O)c1sc(-n2cnn(Cc3ccc(S(C)(=O)=O)cc3)c2=O)cc1C
Yield: 81 %

Procedure:
Following the procedure as described in Example 29, making variations as required to replace 4-fluorobenzyl bromide with 4-methylsulfonylbenzyl bromide to react with ethyl 3-methyl-5-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiophene-2-carboxylate, the title compound was obtained as a yellowish solid in 81% yield: 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J=7.9 Hz, 2H), 7.76 (s, 1H), 7.59 (d, J=7.9 Hz, 2H), 6.95 (s, 1H), 5.10 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 3.04 (s, 3H), 2.55 (s, 3H), 1.36 (t, J=7.1 Hz, 3H); MS (ES+) m/z 444.3 (M+23).
Reaction SMILES: [CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][OH:65])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.[C:72]1([CH3:82])[CH:77]=[CH:76][C:75]([S:78](Cl)(=[O:80])=[O:79])=[CH:74][CH:73]=1>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[S:78]([C:75]1[CH:76]=[CH:77][C:72]([CH3:82])=[CH:73][CH:74]=1)([O:65][CH2:64][CH:22]1[CH2:21][CH:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23]1)(=[O:80])=[O:79]
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(CO)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC1CC(COS(=O)(=O)c2ccc(C)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reaction time: 120 h
Yield: 96.1 %

Procedure:
3,4,5-Tris(octadecyloxy)cyclohexylmethyl alcohol (68.5 g, 74.5 mmol) was dissolved in chloroform (700 ml), pyridine (26.9 ml, 0.33 mol), DMAP (903 mg, 7.39 mmol) and p-toluenesulfonyl chloride (44.9 g, 0.236 mol) were added, and the mixture was stirred for 5 days. The solvent was evaporated, and the residue was precipitated with acetonitrile (700 ml) and washed with acetonitrile (700 ml) to give 3,4,5-tris(octadecyloxy)cyclohexylmethyl tosylate (76.9 g, 71.6 mmol, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]([O:7][CH3:8])=[CH2:6])=[CH2:4].CC(O[Na])=O.C(=O)=O.CC(C)=O.[Se:21](Cl)Cl>CCCCCC>[CH3:1][O:2][C:3]1[C:5]([O:7][CH3:8])=[CH:6][Se:21][CH:4]=1
Reactant: Cl[Se]Cl
Reactant: C=C(OC)C(=C)OC
Agent: CC(=O)O[Na]
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COc1c[se]cc1OC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a well stirred solution of 2,3-dimethoxy-1,3-butadiene (1.47 g, 12.9 mmol, (11)) and CH3COONa (2.64 g, 32.25 mmol) in dry hexane (80 mL) at −78° C. (dry ice/acetone bath), under an inert atmosphere, was added a solution of freshly prepared SeCl2 in hexane over a period of 15 min. The resulting yellowish solution was further stirred for 1 h at −78° C. and then removed from the cooling bath and the reaction mixture was brought to room temperature over a period of 2 h and further stirred for 5 h. The reaction mixture was filtered through neutral alumina and washed with hexane. The residue was concentrated to give brown yellow oil. The crude product was purified by flash column chromatography on TLC grade silica gel (Hexane:Ethyl acetate—95:5) to provide DMOS (0.85 g, 35%, (12)) as a white crystalline solid. mp. 43-45° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]2[C:5]([C:6]([Cl:17])=[C:7]([O:13][CH2:14][CH2:15][CH3:16])[O:8][C:9]2=[O:10])=[CH:4][CH:3]=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>C1COCC1>[CH2:18]([NH:20][C:21]([NH:1][C:2]1[CH:12]=[C:11]2[C:5]([C:6]([Cl:17])=[C:7]([O:13][CH2:14][CH2:15][CH3:16])[O:8][C:9]2=[O:10])=[CH:4][CH:3]=1)=[O:22])[CH3:19]
Reactant: CCCOc1oc(=O)c2cc(N)ccc2c1Cl
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCCOc1oc(=O)c2cc(NC(=O)NCC)ccc2c1Cl
Yield: 45 %

Procedure:
This compound was synthesized by the reaction of an equimolar amount of 7-amino-4-chloro-3-propoxyisocoumarin and ethyl isocyanate in small amount of dry THF. The reaction mixture was stirred at r. t. for a few days. During this time the yellow crystals slowly crystallized out. After filtration, the compoumds were recrystallized once more from THF-pentane, yield 45%; mp 189°-191° C.; TLC, Rf =0.43 (CH3Cl:MeOH=9:1); MS, m/e 324 (M+). Anal. Calc. for C15H17O4N2Cl: C, 55.42; H, 5.23. Found: C, 55.31; H, 5.28.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Cl-].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][Zn+])=[CH:17][CH:16]=1.C(Cl)Cl>C1COCC1>[F:13][C:14]([F:23])([F:24])[C:15]1[CH:22]=[CH:21][C:18]([CH2:19][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: FC(F)(F)c1ccc(C[Zn+])cc1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2ccc(C(F)(F)F)cc2)cc1
Temperature: 70 °C
Yield: 54.8 %

Procedure:
Argon was bubbled through a mixture of methyl 4-bromobenzoate 42a (9.3 mmol, 2.0 g), 2 mL of THF, and 4-trifluoromethylbenzylzinc chloride (0.5 M in THF, 46.5 mmol, 93 mL) for 5 min. Pd(dffp)Cl2.CH2Cl2(0.5 mol, 409 mg) was added and the reaction tube was capped and heated at 70° C. for 16 h. The mixture was cooled and filtered through Celite. Water was added to the filtrate and the resulting solid was filtered off. The organic solution was dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (silica gel, 0-10% EtOAc in heptane) to give 1.5 g (55%) of methyl 4-(4-(trifluoromethyl)benzyl)benzoate, 42b.