Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:11][C:12]2[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=2)[C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)c1cccc(N)c1
Reactant: COc1ccc(C=O)cc1
Solvent: CO
Product: COc1ccc(CNc2cccc(C(=O)OC(C)(C)C)c2)cc1

Procedure:
253A was prepared from 4-methoxybenzaldehyde and tert-butyl 3-aminobenzoate following the procedure as described in 4A. HPLC: Rt=3.82 min. (PHENOMENEX® Luna C18 4.6×30 mm 3 u, A10-90% aqueous methanol containing 0.1% TFA in 2 min; 4 mL/min flow). MS (ES): m/z=314.0 [M+H]+.
Reaction SMILES: C1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)C=CC=CC=1.[CH2:14]([CH:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)[CH2:15][CH3:16]>>[CH2:14]([C@H:17]1[CH2:18][CH2:19][C@H:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:11][CH2:12][CH2:7][CH2:8][CH2:9][CH2:10][O:13][C:10](=[O:13])[CH:9]=[CH2:8])=[CH:25][CH:24]=2)[CH2:21][CH2:22]1)[CH2:15][CH3:16]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CCCC1CCC(c2ccc(O)cc2)CC1
Product: C=CC(=O)OCCCCCCOc1ccc([C@H]2CC[C@H](CCC)CC2)cc1

Procedure:
With the exception of replacing the 4-phenylphenol from the synthesis example 1 with 4-(4-propylcyclohexyl)phenol, 15 g of a monoacrylate containing a group (h): 1-propyl-4-(4-(6-acryloyloxyhexyloxy)phenyl)trans-cyclohexane was obtained in the same manner as the synthesis example 1. Hereafter this monoacrylate is abbreviated as (A-6).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32]Cl>>[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[CH:2][CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[C:20](=[O:27])[O:19]3)[CH2:15][CH2:14]2)=[O:12])=[CH:7]1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reactant: Fc1cc(F)cc(CCl)c1
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cc(F)cc(F)c4)c4ccccc34)CC2)c2ccccc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 3,5-difluorobenzyl chloride gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[C:31]([CH3:32])=[CH:30][N:29]=[C:28]([CH3:33])[CH:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[C:31]([CH3:32])=[CH:30][N:29]=[C:28]([CH3:33])[CH:27]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(C)cn1
Solvent: Cc1ccccc1C
Product: Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)c(C)cn1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (133 mg, 0.75 mmol) and 3-[3-(2,5-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K17) (244 mg, 0.75 mmol) in xylene (15 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as a light red solid (210 mg, 68%).
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][C:6](=[C:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.Cl.O>O1CCCC1.[Cl-].[Na+].O>[CH:15]1([CH:12]2[CH2:13][CH2:14][C:9](=[C:6]3[CH2:7][CH2:8][C:3](=[O:2])[CH2:4][CH2:5]3)[CH2:10][CH2:11]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COC1(OC)CCC(=C2CCC(C3CCCCC3)CC2)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC(=C2CCC(C3CCCCC3)CC2)CC1
Yield: 107.8 %

Procedure:
A solution of 4-(4'-cyclohexylcyclohexylidene)cyclohexanone dimethyl ketal (0.016 mol) and 1.0 N HCl (100 ml) in tetrahydrofuran (125 ml) was left at room temperature for 2.5 hours at which time TLC indicated hydrolysis to be complete. Water and brine were added to the reaction solution and the mixture was extracted with ether (4×). The pooled ether extracts were washed with brine, dried (Na2SO4), filter and concentrated to give 4.49 g of white solid. This solid was chromatographed (790 g of 40-63 μm silica gel, 4.5 1 of 5% ethyl acetate-hexane followed by 10% ethyl acetate-hexane)with4-(4'-cyclohexylcyclohexylidene)cyclohexanonedimethylketal(0.56 g, 10%) eluted first followed by the title compound. Recrystallization of the title compound from hexane gave colorless crystals, mp 81°-81.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:18]>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][O:19][C:17](=[O:18])[N:5]([CH2:4][C:3]2[CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:2]=2[Br:1])[CH2:6][CH3:7])=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccc(Cl)cc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)OCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 56, Step 2, using the following starting materials: (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine and 4-chlorobenzyl chloroformate.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([OH:22])[C:14]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=[CH:13][CH:12]=2)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:29]1C(OC)=C(C(CSC2C=CC=CC=2)=CC=1)C(OC)=O>>[O:25]1[CH:26]=[CH:27][C:23]([C:14]2[C:15]([O:22][CH3:29])=[C:16]([C:11]([CH2:10][S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:13]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:24]1
Reactant: COC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Product: COC(=O)c1c(CSc2ccccc2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-2-methoxy-6-(phenylthiomethyl)-benzoate (Intermediate 80) and used without further characterization.
Reaction SMILES: C(O[CH:4](OCC)[CH:5]1[C:14]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:13][C:12]2[C:7](=[CH:8][C:9]([F:27])=[CH:10][CH:11]=2)[C:6]1=O)C.[ClH:32].[NH2:33][N:34](C)[C:35](=O)OC(C)(C)C>C(O)C>[ClH:32].[F:27][C:9]1[CH:10]=[CH:11][C:12]2[O:13][C:14]3([C:5]4[CH:4]=[N:33][N:34]([CH3:35])[C:6]=4[C:7]=2[CH:8]=1)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3
Reactant: CCOC(OCC)C1C(=O)c2cc(F)ccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: Cn1ncc2c1-c1cc(F)ccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.2 %

Procedure:
To a solution of tert-butyl 3-(diethoxymethyl)-6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (2.6 g, 6.0 mmol) in ethanol (20 mL) was added hydrochloric acid (22.5 mL of 4 M, 89.8 mmol) (4 M in dioxane). The reaction mixture was allowed to stir at 25° C. for 2 hours. The solvent was removed under vacuum, and the obtained solid was azeotroped with ethanol (3×30 mL). The resulting beige-white solid was fully dissolved in ethanol (21 mL) at 25° C. prior to the addition of tert-butyl N-amino-N-methyl-carbamate (1.1 mL, 7.2 mmol). The solution was allowed to stir overnight. To the thick beige-white slurry that formed was added hydrochloric acid (7.5 mL of 4 M, 29.9 mmol) (4 M in dioxane). The mixture was heated at 60° C. to yield a clear yellow solution. After 1 hour at 60° C., a white thick slurry developed. The slurry was allowed to slowly cool to 25° C. over 4 hours, and solids were collected by vacuum filtration. The cake was rinsed with a 10% solution of ethanol in hexanes (2×). Residual solvents were further removed under reduced pressure providing 8-fluoro-1-methyl-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochloride (1.9 g, 92%). 1H NMR (400 MHz, DMSO) δ 7.59 (dd, J=9.3, 2.8 Hz, 1H), 7.43 (s, 1H), 7.27-7.10 (m, 2H), 4.12 (s, 3H), 3.28-3.11 (m, 4H), 2.59 (s, 1H), 2.22-2.02 (m, 4H). ESI-MS m/z calc. 273.1. found 274.1 (M+1)+. Retention time 0.84 minutes (3 min run).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([CH2:15][NH:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:24]=[N:25][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[N:27][CH:28]=2)[CH:20]=[CH:21][CH:22]=1)=O)(C)(C)C.[OH-].[Na+]>ClCCl>[CH3:15][NH:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[N:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[N:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CCc1ncc(-c2cccc(NCC(=O)OC(C)(C)C)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cccc(-c2cnc(CCC(=O)OC)nc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 187.7 %

Procedure:
0.12 ml (1.6 mmol, 5 eq) of trifluoroacetic acid is added to a solution of 118 mg (0.32 mmol, 1 eq) of methyl 3-{5-[3-(tert-butoxycarbonylmethylamino)phenyl]pyrimidin-2-yl}propanoate in 4 ml of dichloromethane. The reaction mixture is stirred for 16 hours at room temperature. The reaction is stopped by adding 20 mL of 1N sodium hydroxide solution and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (99/1 dichloromethane/methanol). 163 mg of methyl 3-[5-(3-methylaminophenyl)pyrimidin-2-yl]propanoate are obtained in the form of a colorless oil. Yield=99%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][C:8]#[N:9])=[CH:5][CH:4]=1.[CH3:12][C:13]([CH3:15])=O.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](=[C:13]([CH3:15])[CH3:12])[C:8]#[N:9])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC#N)cc1
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(C#N)=C(C)C)cc1

Procedure:
According to the procedure described by Example 1, p-methoxybenzylcyanide (18.6 g, 127 mmol) is condensed with acetone (50 ml) under addition of methanol (6.5 ml) and KOH (3.33 g, 50 mmol) to yield, after workup and distillation at 111-113° C./0.05 mbar, 2-(4-methoxyphenyl)-3-methyl-but-2-ene nitrile (14.3 g, 18%).
Reaction SMILES: [BH3-]C#N.[Na+].[Si:5]([O:12][CH2:13][CH:14]([O:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2)[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]>C(O)(=O)C>[Si:5]([O:12][CH2:13][CH:14]([O:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][CH2:28][NH:29]2)[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])([C:8]([CH3:9])([CH3:10])[CH3:11])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)Oc1cccc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)Oc1cccc2c1CCN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
1-[4-(N-Phthalimido)butanoyl]-4-[1,3-bis(t-butyldimethylsilyloxy)propan-2-yloxy]indoline (15) and related compounds. NaBH3CN (1.79 g, 28.5 mmol) was added portionwise to a solution of the indole 14 (4.13 g, 9.5 mmol) in acetic acid (90 mL) and the mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residue was diluted with water, neutralised with solid NaHCO3 and extracted with EtOAc. The combined organic phases were washed with brine, dried and evaporated to give 4-[1,3-bis(t-butyldimethylsilyloxy)propan-2-yloxy]indoline (3.14 g, 75%) as a viscous oil: 1H NMR (90 MHz) δ 6.82 (t, J=7.2 Hz 1H), 6.04-6.32 (m, 2H), 4.16-4.32 (m, 1H), 3.64-3.88 (m, 4H), 3.46 (t, J=7.2 Hz, 2H), 2.88 (t, J=7.2 Hz, 2H), 2.04 (s, 1H), 0.88 (s, 18H), 0.04 (s, 12H). This material was dissolved in dry MeCN (95 mL) and treated with 4-(N-phthalimido)butanoic acid (2.66 g, 11.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.55 g, 13.3 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was taken up in EtOAc, washed with 0.5 M aq. HCl, aq. NaHCO3 and brine, dried and evaporated. Flash chromatography [EtOAc-hexanes (1:4)→(2:3)→(1:1)] gave four products. The first eluted material was 15 (1.69 g) as white crystals, mp 118-120° C. (MeOH). This material was estimated by 1H NMR to contain ˜20% of 1-[4-(N-phthalimido)butanoyl]-4-[1-(t-butyldimethylsilyloxy)propan-2-yloxy]indoline 16. The second eluted material was 1-[4-(N-phthalimido)butanoyl]-4-[1-(t-butyldimethylsilyloxy)propan-2-yloxy]indoline 16 (0.22 g, 6%) as white crystals, mp 118-120° C. (Et2O-hexanes): 1H NMR (500 MHz) δ 7.81 (dd, J=5.4, 2.9 Hz, 2H), 7.71 (d, J=8.2 Hz, 1H), 7.68 (dd, J=5.4, 2.9 Hz, 2H), 7.07 (t, J=8.2 Hz, 1H), 6.51 (d, J=8.2 Hz, 1H), 4.13-4.19 (m, 1H), 4.02 (t, J=8.5 Hz, 2H), 3.74-3.92 (m, 6H), 3.10 (t, J=8.5 Hz, 2H), 2.47 (t, J=7.1 Hz, 2H), 2.15 (quintet, J=7.1 Hz, 2H), 1.23 (d, J=6.2 Hz, 3H), 0.90 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H). LRMS (ES+); calcd for (C29H38N2O5Si+H)+, 523; found, 523.4. Anal. Calcd for C29H38N2O5Si+H2O: C, 64.64; H, 7.45; N, 5.18. Found: C, 64.70; H, 7.13; N, 5.12.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([S:8]([NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:2]=1.C[Al](C)C.[Si:21]([O:38][C@H:39]1[CH2:43][CH2:42][O:41][C:40]1=[O:44])([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[Si:21]([O:38][C@@H:39]([CH2:43][CH2:42][OH:41])[C:40]([NH:7][C:6]1[CH:1]=[CH:2][C:3]([S:8](=[O:10])(=[O:9])[NH:11][C:12]2[S:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:5]=1)=[O:44])([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: CC(C)(C)[Si](O[C@H]1CCOC1=O)(c1ccccc1)c1ccccc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](O[C@@H](CCO)C(=O)Nc1ccc(S(=O)(=O)Nc2nccs2)cc1)(c1ccccc1)c1ccccc1
Yield: 99.8 %

Procedure:
Synthesized according to General Procedure 5. The reaction was set up with sulfathiazole (11.2 g, 44 mmol), CH2Cl2 (150 mL), trimethylaluminum (2.0 M in hexanes, 22 mL, 44 mmol), and (S)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (12.6 g, 37 mmol) in CH2Cl2 (10 mL). Purification by silica gel chromatography (10% MeOH in DCM) afforded the desired amide as a white solid (22 g, 84% yield). 1H-NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.76 (dd, J=1.8, 7.0 Hz, 1H), 7.74 (s, 1H), 7.59-7.53 (m, 4H), 7.44-7.28 (m, 8H), 7.09 (d, J=4.6 Hz, 1H), 6.46 (d, J=4.6 Hz, 1H), 4.34 (dd, J=4.1, 6.7 Hz, 1H), 3.64-3.59 (m, 1H), 3.54 (dd, J=6.1, 11.4 Hz, 1H), 1.99-1.91 (m, 1H), 1.81-1.70 (m, 1H), 1.10 (s, 9H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=596.5; tR=1.93 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:25](=[O:27])[CH3:26])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COC1=C(OC)C(=O)C(CCCCCCCCCCOC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled, well stirred solution of 2,3-dimethoxy-5-methyl-6-(10'-hydroxydecyl)-1,4-benzoquinone(formula IV-2 wherein R=H3CO, n=8, in the free form) (0.3 part) in pyridine (1 volume part) was added acetic anhydride (0.1 volume part). After stirring at room temperature for 1 hour, the mixture was diluted with water, and the aqueous solution was extracted with diethyl ether. The extract was washed successively with water, dilute hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. The residue upon removal of the solvent was crystallized from aqueous ethanol to give 2,3-dimethoxy-5-methyl-6-(10'-acetoxydecyl)-1,4-benzoquinone (formula IV-2 wherein R=H3CO, n=8, in the form of acetate) (0.31 part) as orange needles melting at 38° C.
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][CH:8]=2)[C:5]([C:32]#[N:33])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:39][S:40]SC>>[Si:15]([O:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:2]([S:40][CH3:39])=[CH:3][CH:4]=[C:5]2[C:32]#[N:33])=[CH:12][CH:11]=1)([C:28]([CH3:29])([CH3:30])[CH3:31])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CSSC
Reactant: CC(C)(C)[Si](OCc1ccc(-n2c(Br)ccc2C#N)cc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Product: CSc1ccc(C#N)n1-c1ccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N,N,N'-N'-tetramethylethylenediamine (1.55 ml) and 5-bromo-1-(4-tert-butyldiphenylsilyloxymethylphenyl)pyrrole-2-carbonitrile (3.80 g) was added dropwise n-butyllithium solution (1.6M solution in n-hexane, 5.2 ml) during a period of 20 minutes at -60° C. under nitrogen atmosphere. The mixture was stirred for one hour at the same temperature and then dimethyldisulfide (1 ml) was added therein in one portion. The reaction mixture was allowed to warm to ambient temperature, stirred overnight at the same temperature and then poured into ice water. The separated oil was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated in vacuo to give the residue, which was purified by column chromatography on silica gel to yield 1-(4-tert-butyldiphenylsilyloxymethylphenyl)-5-methylthiopyrrole-2-carbonitrile (1.94 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N+:13]([CH2:15][C:16]1[N:20]=[C:19]([CH3:21])[O:18][N:17]=1)#[C-:14]>>[CH3:1][C:2]1[C:3]2[N:4]([CH:14]=[N:13][C:15]=2[C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cc1nc2ccccc2nc1O
Reactant: [C-]#[N+]Cc1noc(C)n1
Product: Cc1nc(-c2ncn3c2c(C)nc2ccccc23)no1

Procedure:
M.p. 192°-193° C., from 3-methyl-2-quinoxalinol and 3-isocyanomethyl-5-methyl-1,2,4-oxadiazole. (Compound 8)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:25]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:34][C:35]1[CH:36]=[C:37]([CH:43]=[C:44]([CH2:46][N:47]2[CH:51]=[CH:50][N:49]=[CH:48]2)[CH:45]=1)[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CS(C)=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[N:21]([CH2:34][C:35]4[CH:36]=[C:37]([CH:43]=[C:44]([CH2:46][N:47]5[CH:51]=[CH:50][N:49]=[CH:48]5)[CH:45]=4)[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:25]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(CCl)cc(Cn2ccnc2)c1
Reactant: CCc1ccc2c(c1)C=Cc1oc(C)nc1C2c1c[nH]c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(Cn2ccnc2)cc(Cn2cc(C3c4ccc(CC)cc4C=Cc4oc(C)nc43)c(=O)[nH]c2=O)c1

Procedure:
A solution of the product of example 3 step (vii) (2.5 g) in dry dimethylsulphoxide (30 ml) was treated with cesium carbonate (10 g) with stirring. After 20 min a solution of the product of step (ii) (1.5 g) in dimethylsulphoxide (10 ml) was added dropwise over 2 min. After 1.5 hours the reaction mixture was quenched with saturated brine and the product extracted into ethyl acetate. The organic phase was dried (MgSO4) and the solvent was evaporated under reduced pressure to leave a brown gum. Column chromatography eluting with 10% methanol in ethyl acetate containing 1% triethylamine gave the product as a glass.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:20]1[N:21]=[C:22]([NH2:38])[C:23]2[N:24]=[CH:25][N:26]([C:36]=2[N:37]=1)[C@@H:27]1[O:35][C@H:32]([CH2:33][OH:34])[C@@H:30]([OH:31])[C@H:28]1[OH:29]>>[O:12]([C:10]([N:7]1[CH2:6][CH2:5][CH:4]([CH2:1][C:2]#[C:3][C:20]2[N:21]=[C:22]([NH2:38])[C:23]3[N:24]=[CH:25][N:26]([C:36]=3[N:37]=2)[C@@H:27]2[O:35][C@H:32]([CH2:33][OH:34])[C@@H:30]([OH:31])[C@H:28]2[OH:29])[CH2:9][CH2:8]1)=[O:11])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCC1CCN(C(=O)Oc2ccccc2)CC1
Product: Nc1nc(C#CCC2CCN(C(=O)Oc3ccccc3)CC2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Batch: AB-9-97. Phenyl 4-(prop-2-ynyl)piperidine-1-carboxylate, batch JR28-11 (0.329 g, 1.352 mmol) was added to a solution of 2-iodoadenosine (0.513 g, 1.305 mmol) according to general procedure 2. Yield: 54.5 mg, 82%. 1H NMR (CD3OD) δ 8.30 (s, 1H), 7.38-7.06 (3×m, 5H), 5.94 (d, 1H), 4.71 (m, 1H), 4.32-4.17 (2×m, 7H), 3.92-3.72 (2×d, 2H), 3.10-2.90 (2×bt, 4H), 2.48 (d, 5H), 1.93 (2×m, 5H). m/z MH+=509.18. HPLC rt=5.3 min.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:31]=[CH:30][N:29]=[CH:28][C:13]3=[C:14]([CH2:19][C:20]3[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=3)[CH:15]=2)[N:10]=[CH:9]1.[CH3:32][Mg]Br.[Cl-].[NH4+]>C1COCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]3[CH:31]=[CH:30][N:29]=[CH:28][C:13]3=[C:14]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([CH:24]([OH:25])[CH3:32])=[CH:26][CH:27]=3)[CH:15]=2)[N:10]=[CH:9]1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccncc23)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccncc23)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-({3-[(1S,2S)-2-hydroxycyclohexyl]-4-oxo-3,4-dihydropyrido[3,4-h]quinazolin-6-yl}methyl)benzaldehyde (Example 10, 0.035 g, 0.085 mmol) in 2 mL of THF at −50° C. was added methylmagnesium bromide (0.028 mL, 3.0 M diethyl ether solution, 0.85 mmol). After 3 h, additional methylmagnesium bromide (0.028 mL, 3.0 M diethyl ether solution, 0.85 mmol) was added. After 1 h, the mixture was treated with saturated aqueous ammonium chloride and extracted 2× with ethyl acetate. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 430.0 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.25 (s, 1H), 8.53 (s, 1H), 8.42 (d, J=4.5 Hz, 1H), 8.23 (s, 1H), 8.01 (s, 1H), 7.25 (d, J=9.2 Hz, 2H), 7.18 (d, J=8.1 Hz, 2H), 4.88-4.84 (m, 1H), 4.56 (br s, 1H), 4.47 (s, 2H), 4.14-4.12 (m, 1H), 3.65-3.63 (m, 1H), 2.31-2.28 (m, 1H), 2.05-1.84 (m, 4H), 1.62-1.48 (m, 2H), 1.46 (d, J=6.4 Hz, 3H).