Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].C([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:16]2[O:17][C:18]([CH3:21])([CH3:20])[CH2:19][C:15]=2[CH:14]=[CH:13][CH:12]=1)(=O)C.O.Cl>CO>[CH3:20][C:18]1([CH3:21])[O:17][C:16]2[C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][OH:5])=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:19]1
Reactant: CC(=O)OCCCCOc1cccc2c1OC(C)(C)C2
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cccc(OCCCCO)c2O1
Yield: 84.6 %

Procedure:
With stirring, a solution of 2.24 grams (0.056 mole) of sodium ydroxide in 125 mL of methanol was added 8.0 grams (0.028 mole) of 4-(2,2-dimethyl-2,3-dihydrobenzo[2,3-b]furan-7-yloxy)butyl acetate. Upon completion of addition the reaction mixture was stirred at ambient temperature during a three-hour period. After this time 150 mL of water was added to the reaction mixture, and the mixture was acidified to a pH of 6 with concentrated hydrochloric acid. The mixture was then extracted with four 50 mL portions of diethyl ether. The combined extracts were washed with one 50 mL portion of water, dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, yielding 5.6 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([C:15]2[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=2)[NH2:18])=[N:11][CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:22]([O:26][C:27]([NH:29][C:30]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=S)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl.C(OCC)(=O)C>[C:36]([O:35][C:33]([NH:32][C:30]([NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])=[N:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([C:10]2[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:16]=1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Oc1cccnc1-c1cccc(N)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2O[Si](C)(C)C(C)(C)C)c1)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 88.8 %

Procedure:
To a suspension of 3-(3-tert-butyldimethylsilyloxypyridin-2-yl)-aniline (303 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (335 mg) and diisopropylethylamine (0.405 ml) in dichloromethane (10 ml) was added 1-methyl-2-chloropyridinium iodide (335 mg), and the mixture was stirred for 18 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, 35 g, 20% ethyl acetate in n-hexane) to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-tert-butyldimethylsilyloxypyridin-2-yl)phenyl)guanidine (486 mg).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])([CH3:22])[CH3:21].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:15][CH2:14][CH2:13][O:12][C:8]1[CH:7]=[C:6]([CH2:5][CH:4]([O:17][CH3:18])[C:3]([OH:2])=[O:19])[CH:11]=[CH:10][CH:9]=1)([CH3:22])[CH3:21]
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Reactant: CC(C)c1ccccc1O
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCCOc2ccccc2C(C)C)c1)C(=O)O

Procedure:
The title compound-was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 323, Step 1) and 2-isopropylphenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C22H28O5 [M+Na]+: 395.4.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH3:21])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19]>[Pt](=O)=O.FC(F)(F)C(O)=O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:20][CH3:21])[N:8]=[C:9]2[C:18]=1[C:17]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:11]=[C:10]2[NH2:19]
Reactant: CCn1nc2c(N)nc3ccccc3c2c1CCCCCl
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc2c(N)nc3c(c2c1CCCCCl)CCCC3
Yield: 57.6 %

Procedure:
A mixture of 1-(4-chlorobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine (3 g, prepared as described in Example 19), platinum (IV) oxide (3 g), and trifluoroacetic acid (50 mL) was placed under hydrogen pressure (50 psi, 3.4×105 Pa) on a Parr shaker for 2 days. The reaction mixture was filtered through a layer of CELITE filter agent and the filter cake was rinsed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was made basic (pH 14) by the addition of 50% sodium hydroxide and then extracted with chloroform. The extract was dried over sodium sulfate and then purified by chromatography on a HORIZON HPFC system (eluting with chloroform/CMA in a gradient from 100:0 to 70:30) to provide 1.75 g of 1-(4-chlorobutyl)-2-ethyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8](O)=[O:9]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][OH:9]
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1Cl
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(F)cc2)cc1Cl
Reaction time: 18 h

Procedure:
A solution of 3.1 g (12.4 mmol) of 3-chloro-4′-fluoro-1,1′-biphenyl-4-carboxylic acid, prepared in step 5.1., in 50 ml of tetrahydrofuran is admixed dropwise at ambient temperature with 9.3 ml (18.56 mmol) of a solution (2M) of borane-dimethyl sulphide complex in tetrahydrofuran. Stirring is continued at ambient temperature for 18 hours.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]([CH3:18])([S:7]([CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)(=[O:9])=[O:8])[CH3:6])C.C[Si](C)(C)[O-].[K+]>C1COCC1>[CH3:18][C:5]([S:7]([CH2:10][CH2:11][CH:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)(=[O:9])=[O:8])([CH3:6])[C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)CCC1CCOCC1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)S(=O)(=O)CCC1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a solution of 1.34 g (4.6 mmol) of 2-methyl-2-[2-(tetrahydro-pyran-4-yl)-ethanesulfonyl]-propionic acid ethyl ester in THF (40 mL) are added 1.17 g (9.2 mmol) of potassium trimethylsilanolate. The reaction is stirred at room temperature for 2 h. The solvent is removed under reduced pressure. The residue is partitioned between DCM (50 mL) and 1M aqueous HCl solution (10 mL). The aqueous layer is extracted with DCM (2×50 mL). The combined organic extracts are dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure to afford 1.02 g of 2-methyl-2-[2-(tetrahydro-pyran-4-yl)-ethanesulfonyl]-propionic acid. Yield: 84%, ES-MS: m/z 263 [M−H]
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2].[OH-:16].[Na+].OO>O>[C:1]([C:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)([CH3:5])[CH3:4])(=[O:16])[NH2:2]
Reactant: [OH-]
Reactant: COC(=O)c1ccc(C(C)(C)C#N)cc1
Agent: OO
Agent: [Na+]
Solvent: O
Product: CC(C)(C(N)=O)c1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 4-(1-cyano-1-methylethyl)benzoate (1.0 g), sodium hydroxide (0.4 g), water (2 ml) and IMS (5 ml) was heated to 50° C. with stirring. Hydrogen peroxide (60% w/v, 1.23 ml) was added dropwise and the reaction mixture was stirred at 50° C. for 1 hour. and then at ambient temperature for 3 hours. The reaction mixture was evaporated to dryness under reduced pressure. Water (10 ml) was added to the residue and this mixture was heated at 95° C. for 1 hour. The mixture was cooled, washed with dichloromethane, acidified with 5M hydrochloric acid and filtered to give 4-(1-carbamoyl-1-methylethyl)benzoic acid, m.p. 218°-219° C.
Reaction SMILES: S1CCCSC1.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][C:8]1([CH3:7])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14]
Reactant: CC1CCCCC1=O
Reactant: O=C1CCC(=O)N1Br
Agent: C1CSCSC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(Br)CCCCC1=O

Procedure:
Aldehydes 4B and 4C were synthesized by a modification of the procedure reported by Corey and Erickson (Corey, E. J. and Erickson, B. W. (1971) "Oxidative hydrolysis of 1,3-dithiane derivatives to carbonyl compounds using N-halosuccimide reagent," J. Org. Chem. 36(3):553-560) which is depicted in Scheme 4. Bromination of 2-methylcyclohexanone (7) with 1 equivalent of N-bromosuccinimide (Rinne, W. W. et al., "New methods of preparation of 2-methylcyclohexen-1-one," J. Am. Chem. Soc. (1950) 72:5759-5760) in refluxing CCl4 for 12 hours gave quantitative yield of 2-bromo-2-methylcyclohexanone. Dehydrobromination of this bromide with three equivalents of Li2CO3 and three equivalents of LiBr in N,N-dimethylformamide (DMF) (Stotter, P. L. and Hill, K. A., "α Halocarbonyl Compounds. E. A Position-Specific Preparation of α-Bromo Ketones by Bromination of Lithium Enolates. A Position-Specific Introduction of α, β-Unsaturation into Unsymmetrical Ketones,"J. Org. Chem. (1973) 38:2576-2578) at 130° C. for 3 h provided a 72% yield of 2-methyl-2-cyclohexen-1-one (8). A 1,2-addition reaction of 8 with 1.5 equivalents of lithiated 1,3-dithiane [generated from 1,3-dithiane (9) with n-BuLi in THF] in THF at -10° C. to give a 96% yield of the 1,2-adduct 10. Rearrangement of 10 with 1 % sulfuric acid in p-dioxane (52% yield) followed by removal of the dithiane protecting group of the resulting alcohol, 11, with N-chlorosuccinimide (NCS) and silver nitrate in acetonitrile-water gave aldehyde 4B (50% yield). Alcohol 4B is not a stable compound and decomposes upon standing at room temperature in a few days. A more stable material, 4C, was synthesized in a better yield from the rearrangement reaction of 10 in formic acid-THF in the presence of catalytic amount of p-toluenesulfonic acid (70% yield) followed by removal of the dithiane moiety with NCS-AgNO3 (59% yield) (Scheme 4). In the formic acid rearrangement reaction, besides the desired product, 1-[2-(1,3-dithianyl)]-3-formyloxy-2-methyl-1-cyclohexene, 9% yield of 3-[2-(1,3-dithianyl)]-2-methyl-2-cyclohexen-1-ol (11) was also isolated.
Reaction SMILES: [CH3:1][P:2](=[O:13])([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][CH:4]=1>CO.[Pd]>[CH3:12][P:2]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)([CH3:1])=[O:13]
Reactant: CP(C)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CP(C)(=O)c1ccc(N)cc1
Yield: 86 %

Procedure:
The dimethyl(4-nitrophenyl)phosphane oxide) produced as described above was hydrogenated in the presence of 10% Pd/C (15 mg) in MeOH (5 mL) for 2 h. The mixture was then filtered and the filtrate concentrated in vacuo to yield 19 mg of the desired 4-(dimethylphosphoryl)aniline (yield: 86%) which was used directly in further chemistries without purification. 1H-NMR (CDCl3, 400 MHz): δ=1.67 (d, J=12.8 Hz, 6 H), 4.11 (s, br, 2 H), 6.73 (dd, J=2.0, 8.4 Hz, 2 H), 7.48 (dd, J=8.4, 11.2 Hz, 2 H). MS (ES+): m/z 170.04 (MH+). HPLC: tR=1.23 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1)#[N:2].C([O-])([O-])=O.[K+].[K+].Br[C:25]1[C:26]([N:45]2[CH2:49][C@H:48]([OH:50])[C@@H:47]([OH:51])[CH2:46]2)=[N:27][CH:28]=[C:29]([CH:44]=1)[C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]([Cl:43])([F:42])[F:41])=[CH:35][CH:34]=1)=[O:31]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:43][C:40]([F:41])([F:42])[O:39][C:36]1[CH:37]=[CH:38][C:33]([NH:32][C:30]([C:29]2[CH:44]=[C:25]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])[C:26]([N:45]3[CH2:46][C@H:47]([OH:51])[C@@H:48]([OH:50])[CH2:49]3)=[N:27][CH:28]=2)=[O:31])=[CH:34][CH:35]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2cnccc2C#N)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccncc1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cnc1N1C[C@H](O)[C@@H](O)C1
Temperature: 130 °C
Reaction time: 0.25 h

Procedure:
4-Cyanopyridine-3-boronic acid pinacol ester (192 mg, 0.836 mmol), K2CO3 (0.418 mL, 0.836 mmol) and Pd(PPh3)4 (24.14 mg, 0.021 mmol) were added to a solution of 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)nicotinamide (Stage 248.1, 200 mg, 0.418 mmol) in DMF (2.5 mL) in a vial at RT. The vial was evacuated/purged with argon, sealed and heated at 130° C. for 18 h. The RM was diluted with EtOAc (60 mL) and washed with an aq. sat. solution of NaHCO3 (20 mL) and brine (2×20 mL). The organic phase was dried over Na2SO4, filtered and the solvent was evaporated off under reduced pressure. The resulting residue was suspended in MeOH (3 mL), stirred for at RT 15 min, filtered and washed with MeOH (2 mL). The filtrate was filtered through a SPE PL-Thiol cartridge (StratoSpheres™, 500 mg, nominal:1.5 mmol) and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative SFC (Column 2-EP, from 21% to 26% in 6 min) to afford the title product as a yellow solid. HPLC (Condition 10) tR=5.90 min, UPLC-MS (Condition 3) tR=0.94 min, m/z=502.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.95 (d, J=11.34 Hz, 2H) 3.14-3.39 (m, 2H) 3.86 (br. s, 2H) 5.02-5.07 (m, 1H) 5.09-5.14 (m, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.86 (d, J=8.60 Hz, 2H) 7.96-8.06 (m, 1H) 8.12 (d, J=17.60 Hz, 1H) 8.76-8.88 (m, 2H) 9.08 (br. s, 1H) 10.21 (d, J=4.69 Hz, 1H).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[NH:9][CH2:8][C@H:7]([O:10][C:11]2[CH:16]=[N:15][C:14]([CH:17]3[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[CH2:6]1)=[N+:2]=[N-:3].C(N(CC)CC)C.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CO>[N:1]([CH2:4][C@@H:5]1[CH2:6][C@@H:7]([O:10][C:11]2[CH:16]=[N:15][C:14]([CH:17]3[CH2:18][CH2:19]3)=[CH:13][N:12]=2)[CH2:8][N:9]1[CH2:28][C:29]([O:31][CH3:32])=[O:30])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC[C@@H]1C[C@@H](Oc2cnc(C3CC3)cn2)CN1
Reactant: COC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CN1C[C@H](Oc2cnc(C3CC3)cn2)C[C@H]1CN=[N+]=[N-]
Temperature: 65 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
To a solution of the product from Example 201A (290 mg, 1.114 mmol) in triethylamine (388 μl, 2.79 mmol) and methanol (0.3 mL) was added methyl bromoacetate (175 μL, 1.894 mmol), and the resulting mixture was stirred at 65° C. for 18 hours. The cooled mixture was concentrated in vacuo and partitioned between 1 N sodium bicarbonate and ethyl acetate. The organic extract was dried over Na2SO4, filtered and concentrated. The crude product was purified by chromatography on a 12 g silica gel column eluting with 5% ethyl acetate/hexanes for 3 minutes then a gradient to 100% ethyl acetate over 20 minutes to give the title compound as an oil (203 mg, 54.8%). 1H NMR (500 MHz, pyridine-d5) δ ppm 6.74 (s, 1H), 4.63 (s, 1H), 4.36 (d, J=61.9 Hz, 1H), 4.08 (dt, J=14.2, 6.0 Hz, 1H), 3.81 (dd, J=42.1, 9.2 Hz, 1H), 3.62 (dd, J=11.3, 4.3 Hz, 1H), 3.46-3.27 (m, 1H), 2.23 (dd, J=21.4, 10.3 Hz, 1H), 2.17-2.04 (m, 1H), 1.49 (d, J=8.4 Hz, 11H); MS (ESI) m/z 333 (M+H)+.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:21]=[C:20]2[C:15]([C:16](=[O:22])[NH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1>CN(C)C=O>[CH2:1]([O:8][C:12]1[CH:21]=[C:20]2[C:15]([C:16](=[O:22])[NH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
A solution of benzyl alcohol (5.27 g, 48.7 mmol) in N,N-dimethylformamide (12 mL) was cooled to 0° C. prior to the portion-wise addition of sodium hydride (60% dispersion in mineral oil, 1.95 g, 48.7 mmol). This mixture was warmed to room temperature and stirred for 30 minutes before being cooled to 0° C. followed by the addition of a solution of the product from Step 1 (2.0 g, 12 mmol) in N,N-dimethylformamide (12 mL). After the addition, the reaction was warmed to 95° C. for 16 hours. After cooling to room temperature, the reaction was partitioned between EtOAc and H2O. The layers were separated and the precipitated solids in the organic layer were collected by filtration, washed with EtOAc and air dried. A second crop of solids was collected and the filtrate washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to provide a third crop of solids. Combination of the solids and drying to constant weight afforded 2.82 g (93%) of 7-(benzyloxy)quinazolin-4(3H)-one as a tan solid. MS 253.3 (ES+).
Reaction SMILES: [NH2:1][C:2]1[CH2:6][S:5][C:4](=[O:7])[CH:3]=1.COC1C=C2C(=C(OC)C=1)N(CC1C=CC(Cl)=CC=1)C=C2.C(=O)([O-])[O-].[K+].[K+].[Cl:35][C:36]1[CH:56]=[CH:55][C:39]([CH2:40][N:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43]([C:50](=[O:54])[C:51](Cl)=[O:52])=[CH:42]2)=[CH:38][CH:37]=1>COCCOC.O>[Cl:35][C:36]1[CH:56]=[CH:55][C:39]([CH2:40][N:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43]([C:50](=[O:54])[C:51]([NH:1][C:2]3[CH2:6][S:5][C:4](=[O:7])[CH:3]=3)=[O:52])=[CH:42]2)=[CH:38][CH:37]=1
Reactant: NC1=CC(=O)SC1
Reactant: O=C(Cl)C(=O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Agent: COc1cc(OC)c2c(ccn2Cc2ccc(Cl)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=C1C=C(NC(=O)C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)CS1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 4-amino-5H-thiophen-2-one of Preparation 5 (103 mg), powdered potassium carbonate (138 mg) and 2-(1-(4-chlorobenzyl)-1H-indol-3-yl)-2-oxo-acetyl chloride of Example 1 (334 mg) in 1,2-dimethoxyethane (5 ml) is stirred at room temperature for 2 h. After this time the reaction mixture is poured in water (50 ml) and the obtained precipitate is collected by filtration and thoroughly washed with water. The still wet solid is suspended in methanol and stirred for 30′. Filtration followed by drying at 40° C. under vacuum gives 2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-(5-oxo-2,5-dihydro-3-thienyl)acetamide (280 mg).
Reaction SMILES: [N:1]1(CCCC2N=[N+]([O-])C3C=C4C(CCC4)=CC=3[N+]=2[O-])[CH2:6]COC[CH2:2]1.N1(C[CH2:32][CH2:33][NH:34][C:35]2[N:36]=[N+:37]([O-:49])[C:38]3[CH:48]=[C:47]4[C:43]([CH2:44][CH2:45][CH2:46]4)=[CH:42][C:39]=3[N+:40]=2[O-:41])CCOCC1>>[CH2:33]([NH:34][C:35]1[N:36]=[N+:37]([O-:49])[C:38]2[CH:48]=[C:47]3[C:43]([CH2:44][CH:45]([N:1]([CH3:6])[CH3:2])[CH2:46]3)=[CH:42][C:39]=2[N+:40]=1[O-:41])[CH3:32]
Reactant: [O-][n+]1nc(CCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)CCC3
Reactant: [O-][n+]1nc(NCCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)CCC3
Product: CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CC(N(C)C)C3

Procedure:
More preferably, the compound of Formula I is 3-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1,4-Dioxide or N-[3-(4-Morpholinyl)propyl]-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazin-3-amine 1,4-dioxide.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][C:30](O)=[O:31])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[NH2:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][C:48]([OH:50])=O>>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([O:28][CH2:29][C:30]([CH:48]([OH:50])[CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][NH2:33])=[O:31])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: NCCOCCOCCOCCOCCC(=O)O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCC(=O)C(O)CCOCCOCCOCCOCCN)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.9 %

Procedure:
The mixture of pentafluorophenyl ester of Cholest-5-en-3β-yloxyacetic acid (175 mg, 0.29 mmol) and 15-amino-4,7,10,13-tetraoxapentadecanoic acid (160 mg, 0.60 mmol) was dried in an apparatus equipped with septum for 4 h at room temperature and 0.1 Pa. The apparatus was flushed with argon (2×) and then dry N,N-dimethylformamide (6 ml) and N-ethyldiisopropylamine (2 ml) were added through the septum and the mixture was stirred at room temperature for 16 h. Flash chromatography of the crude reaction mixture on silica gel column (200 ml) in toluene-ethyl acetate (gradient: 0-80% ethyl acetate, 10 ml/min, 160 min) gave (cholest-5-en-3β-yloxy)acetyl-15-amino-4,7,10,13-tetraoxapentadecanol acid (general formula X, where n3=1 and n4=3; 167 mg, 84%). For C40H69NO8Na HR-MS, calculated: m/z: 714.4915. found: m/z: 714.4916; 1H NMR (400 MHz, CDCl3) δ ppm: 5.34-5.38 m, 1H (CH2-5′); 4.00 s, 2H (CH2COO); 3.78 t, J=6.06 Hz, 2H (CH2-3); 3.59-3.68 m, 14H (7×CH2O); 3.52 q, J=5.47 Hz, 2H (CH2-14); 3.23 tt, J=11.24, 4.36 Hz, 1H (CH-3′); 2.61 t, J=6.00 Hz, 2H (CH2-2); 2.36 ddd, J=13.20, 4.70 (CH-4′a); 2.19-2.29 m, 1H (CH-4′b); 1.77-2.06 m, 5H (cholesteryl); 1.00 s, 3H (CH3-19′); 1.29 d, J=3.66 Hz, 24H (cholesteryl); 0.92 d, J=6.57 Hz, 3H (CH3-21′); 0.88 d, J=1.89 Hz, 3H (CH3-26′); 0.86 d, J=1.77 Hz, 3H (CH3-27′); 0.68 s, 3H (CH3-18′).
Reaction SMILES: C1C=CN2CC3C=CC=CC=3NCC=12.ClC1C=CC(OCC(Cl)=O)=CC=1.[Cl:27][C:28]1[CH:51]=[CH:50][C:31]([O:32][CH2:33][C:34]([N:36]2[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[CH2:40][N:39]3[CH:47]=[CH:48][CH:49]=[C:38]3[CH2:37]2)=[O:35])=[C:30](C)[CH:29]=1>>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][C:34]([N:36]2[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[CH2:40][N:39]3[CH:47]=[CH:48][CH:49]=[C:38]3[CH2:37]2)=[O:35])=[CH:50][CH:51]=1
Reactant: Cc1cc(Cl)ccc1OCC(=O)N1Cc2cccn2Cc2ccccc21
Agent: O=C(Cl)COc1ccc(Cl)cc1
Agent: c1ccc2c(c1)Cn1cccc1CN2
Product: O=C(COc1ccc(Cl)cc1)N1Cc2cccn2Cc2ccccc21

Procedure:
This compound was prepared from 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 4-chlorophenoxyacetyl chloride in the same manner as the preparation of 10-[(4-chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Example 139, Step B, m.p. 120-122° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=O.[BH4-].[Li+]>CCO>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]2[O:8][N:7]=[C:6]([CH3:17])[C:5]=2[CH2:3][OH:2])=[CH:15][CH:14]=1
Reactant: COC(=O)c1c(C)noc1-c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Product: Cc1noc(-c2ccc(Br)cc2)c1CO
Temperature: 60 °C

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester (5 g, 16.8 mmol) and lithium borohydride (1.85 g, 84.1 mmol) were combined in EtOH and stirred at 60° C. After aqueous workup, the crude material was purified by silica gel chromatography to give the title compound.