Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4[C:22]5[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][C:23]=5[S:29][C:20]=4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.Cl.[CH3:34][N:35]([CH:42]([CH3:44])[CH3:43])[CH2:36]/[CH:37]=[CH:38]/[C:39](O)=[O:40]>>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4[C:22]5[CH2:28][CH2:27][CH2:26][N:25]([C:39](=[O:40])/[CH:38]=[CH:37]/[CH2:36][N:35]([CH3:34])[CH:42]([CH3:44])[CH3:43])[CH2:24][C:23]=5[S:29][C:20]=4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: Fc1cccc(Cn2ncc3cc(Nc4ncnc5sc6c(c45)CCCNC6)ccc32)c1
Reactant: CC(C)N(C)C/C=C/C(=O)O
Agent: Cl
Product: CC(C)N(C)C/C=C/C(=O)N1CCCc2c(sc3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)C1

Procedure:
The title compound was synthesized in analogy to Example 89 from N-[1-(3-fluorobenzyl)-1H-indazol-5-yl]-6,7,8,9-tetrahydro-5H-pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-4-amine from Example 83A (100 mg, 0.23 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (61 mg, 0.32 mmol) to yield 39 mg (29%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:16](Cl)(=[O:18])[CH3:17].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:18])[CH3:17])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2ccccc2)cc1F
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(-c2ccc(C(C)=O)cc2)cc1F
Yield: 82 %

Procedure:
3-Fluoro-4-methoxybiphenyl was acetylated with acetyl chloride/AlCl3 in carbon disulfide in the usual way. The product was twice recrystallized from toluene to obtain 3'-fluoro-4'-methoxy-4-acetylbiphenyl (yield: 82%), m.p. 149°~149.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH:13][CH2:14][C:15]3[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=3[CH3:21])=[O:12])[CH:10]=1)[N:7]([CH3:24])[CH:6]=[C:5]2[CH:25]([CH3:27])[CH3:26].Cl.[CH3:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(Cl)Cl.O>[CH3:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH:13][CH2:14][C:15]4[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=4[CH3:21])=[O:12])[CH:10]=2)[N:7]([CH3:24])[CH:6]=[C:5]3[CH:25]([CH3:26])[CH3:27])=[CH:35][CH:34]=1)[CH3:31]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c(C(C)C)cn(C)c23)c(=O)[nH]1
Reactant: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)cc3)cc3c(C(C)C)cn(C)c23)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
In a glass pressure tube was added 5-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxamide (225 mg, 0.523 mmol), 4-(N,N-dimethylaminomethyl)phenylboronic acid pinacol ester hydrochloride (200 mg, 0.672 mmol), potassium phosphate (340 mg, 1.602 mmol), dioxane (12 mL) and water (3 mL). The reaction was stirred and purged with N2 then PdCl2 (dppf)-CH2Cl2 adduct (40 mg, 0.049 mmol) was added. The reaction was capped and stirred at 110° C. for 4 h LCMS indicated that the reaction was complete. The dark black reaction was transferred to a round bottom flask and evaporated to dryness. The crude material was purified by silica gel chromatography (Analogix, SF25-40 g, 0 to 70% CH2Cl2/20% (5% NH4OH in MeOH) in CH2Cl2). A short DASi column was used and the compound loaded as a suspension in CH2Cl2. The pure fractions were combined and evaporated to dryness to give the product as a very dark brown-black solid. The solid was taken up in CH2Cl2 and treated with Silicycle Si-Thiol derivatized silica gel (2 g, 1.46 mMol/g, cat. no. R51030B). After swirling for ˜30 minutes the mixture was filtered through a pad of Celite, washed with CH2Cl2, and evaporated to dryness. The now light yellow colored solid was dissolved in a small amount of CH2Cl2, triturated with hexanes, filtered and dried under vacuum to give 5-{4-[(dimethylamino)methyl]phenyl}-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxamide (95 mg, 0.196 mmol, 37.5% yield) as a light tan solid. 1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.50 (t, J=4.93 Hz, 1H), 7.83 (d, J=1.52 Hz, 1H), 7.68 (s, 1H), 7.66 (s, 1H), 7.40 (s, 1H), 7.38 (s, 1H), 7.33 (d, J=1.52 Hz, 1H), 7.10 (s, 1H), 5.87 (s, 1H), 4.36 (d, J=5.05 Hz, 2H), 3.69 (s, 3H), 3.34 (br. s., 3H), 3.22 (dt, J=6.73, 13.58 Hz, 1H), 2.26 (br. s., 6H), 2.24 (s, 2H), 2.11 (s, 3H), 1.31 (d, J=6.82 Hz, 6H). MS (ES)+m/e 485.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[NH:4][CH:5]=[N:6][CH:7]=1.P(Cl)(Cl)([Cl:11])=O>>[ClH:11].[Cl:11][C:3]1[C:2]([CH3:1])=[CH:7][N:6]=[CH:5][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cnc[nH]c1=O
Product: Cc1cncnc1Cl
Product: Cl
Temperature: 90 °C

Procedure:
A mixture of 5-methyl-3H-pyrimidin-4-one (0.60 g, 3.6 mmol) and phosphorous oxychloride (2.0 mL) was heated at 90° C. for 2.5 h. The mixture was evaporated to dryness under reduced pressure and the resultant solid was purified by sublimation under reduced pressure to furnish the title compound as a white solid. This compound was unstable to air and was used immediately in the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].CCN(C(C)C)C(C)C.[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CCCCO>[CH:27]1([NH:33][C:2]2[CH:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:11]([O:10][CH3:9])[CH:12]=3)[N:5]=[CH:4][N:3]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCCCC1
Reactant: COc1cccc(N)c1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(Nc2cc(NC3CCCCC3)ncn2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
100 mg of 4,6-dichloropyrimidine, 83 mg of 3-methoxyaniline and 103 mg of DIPEA were dissolved in 1 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was kept in a heating block at 120° C. for 6 hours. The reaction was monitored by TLC and was completed after 6 hours. The mixture obtained was cooled to r.t., 100 mg of cyclohexylamine and 139 mg of DIPEA were added and the mixture obtained was heated under microwave irradiation for an hour at 200° C. The reaction was finished and pure product was purified by column chromatography using PE:EtOAc 2:1. Pure N4-Cyclohexyl-N6-(3-methoxyphenyl)pyrimidine-4,6-diamine in the form of a colorless solid was obtained.
Reaction SMILES: ClC1N=[C:4]([NH:18][C:19]2[C:24]([C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][C:22]([CH3:31])=[CH:21][N:20]=2)[C:5](=[O:17])[N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:7]=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:6]2[CH:7]=[C:26]([Si:27]([CH3:30])([CH3:29])[CH3:28])[C:25]3[C:24]4[C:19]([NH:18][C:4]=3[C:5]2=[O:17])=[N:20][CH:21]=[C:22]([CH3:31])[CH:23]=4)=[CH:10][CH:11]=1
Reactant: COc1ccc(Cn2cc(Cl)nc(Nc3ncc(C)cc3C#C[Si](C)(C)C)c2=O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cc([Si](C)(C)C)c3c([nH]c4ncc(C)cc43)c2=O)cc1
Temperature: 130 °C
Reaction time: 94 h
Yield: 89 %

Procedure:
In a 2 L round bottom flask, 5-chloro-1-(4-methoxybenzyl)-3-(5-methyl-3-((trimethylsilyl)ethynyl)pyridin-2-ylamino)pyrazin-2(1H)-one (35.2 g, 77.85 mmol) was taken up with anhydrous toluene (880 mL), attached a reflux condenser and transferred to an oil bath that was heated to 130° C. The reaction was stirred in the oil bath for 94 h and concentrated in vacuo to afford a brown solid. The crude was suspended in ethyl acetate (200 mL) and heated to a mild boil. The product (pale yellow powder, 27.4 g, 89% yield) was collected by filtration, washed with additional ethyl acetate, diethyl ether and dried under high vacuum. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.43 (s, 9 H) 2.56 (s, 3 H) 3.80 (s, 3 H) 5.30 (s, 2 H) 6.89 (d, J=8.59 Hz, 2 H) 7.11 (s, 1 H) 7.35 (d, J=8.84 Hz, 2 H) 8.22 (s, 1 H) 8.52 (d, J=1.52 Hz, 1 H). ESI-MS: m/z 392.4 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11](/[C:14](=[N:19]\[S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])/[CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al]([C:31]#[N:32])(CC)CC.CC(O)C>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C@@:14]([NH:19][S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])([C:31]#[N:32])[CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Al](C#N)CC
Reactant: C=CCC/C(=N/[S@](=O)C(C)(C)C)C1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C=CCC[C@@](C#N)(N[S@](=O)C(C)(C)C)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
A solution of (R,Z)—N-(1-(1-benzylpiperidin-4-yl)pent-4-enylidene)-2-methylpropane-2-sulfinamide (2.74 g, 7.6 mmol) in THF (130 mL, 0.06 M) was cooled to −78° C. Separately, a 1 M solution of Et2AlCN (11.4 mmol, 11.4 mL) was dissolved in THF (20 mL) and cooled to −78° C. iPrOH (0.64 mL, 8.26 mmol) was added dropwise and the solution was warmed to RT over 20 min, then added dropwise to the sulfinamide solution. The reaction was allowed to warm gradually to RT and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride (50 mL) and filtered through Celite. The Celite pad was washed with ethyl acetate (3×) and the combined organics were washed saturated aqueous sodium chloride, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel (1-9% methanol in dichloromethane and again with 2-5% methanol in ethyl acetate) to afford the desired product (1.99 g, 67%) along with its undesired diastereoisomer (0.46 g, 15%). Rf 0.26 (10% MeOH/CH2Cl2). 1H NMR (CDCl3, 300 MHz) δ 7.31-7.25 (m, 5H), 5.83-5.78 (m, 1H), 5.13-5.03 (m, 2H), 3.51 (d, J=1.5 Hz, 2H), 3.41 (s, 1H), 3.00 (d, J=11.0 Hz, 2H), 2.34-2.29 (m, 2H), 2.05-1.83 (m, 6H), 1.60-1.44 (m, 3H), 1.25 (s, 9H). ESI MS found for C22H33N3OS m/z [388.4 (M+1)].
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.C([O-])(=O)C.[NH4+:17].O>C(O)CO>[NH2:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: OCCO
Solvent: O
Product: Nc1cc(=O)oc2ccccc12
Temperature: 60 °C
Reaction time: 6 h
Yield: 99.4 %

Procedure:
97.2 g of 4-hydroxycoumarin and 69.3 g of ammonium acetate in 300 ml of ethylene glycol are heated to 70° C. for 3 hours, whilst stirring, and to 160° C. for 6 hours, the mixture is cooled to 60° C., 1 liter of water is added, whilst stirring, and the mixture is cooled to room temperature. The colourless crystalline precipitate is filtered off, washed with water and dried in vacuo at 60° C. 96 g of 4-aminocoumarin in an almost pure form are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:14])[C:12]#N)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[O:16]1CCOC[CH2:17]1.CC[O:24]CC>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:14])[C:12]([O:16][CH3:17])=[O:24])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(O)C#N)cc1OC
Reactant: CCOCC
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)C(O)c1ccc(OC)c(OC)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To 2-(3,4-dimethoxyphenyl)-2-hydroxyacetonitrile (1.25 g, 6.48 mmol) in ether (20 mL) and MeOH (1.5 mL) at −10° C. was added 4N HCl in dioxane (6 mL, 24 mmol). The reaction was stirred at −10° C. for 1 h, then stored at 4° C. for 2 days. The reaction was filtered, and washed with ether. The solid was dissolved in water (15 mL) and CH2Cl2 (15 mL) and stirred for 1 h. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×20 mL), dried (Na2SO4), filtered and concentrated. The resulting residue was purified via silica gel chromatography (0-60% ethyl acetate/hexanes) to provide 6B (1.35 g, 92%). LC-MS: 249.16 (M+Na)+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.Cl[CH2:26][C:27]#[N:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[C:27]([CH2:26][N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3][C:2]3=[O:1])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17]1)#[N:28]
Reactant: N#CCCl
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(CC#N)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 150 mg), chloroacetonitrile (31 μL) and anhydrous potassium carbonate (124 mg) in dry acetonitrile (4 mL) under N2 was stirred at ambient temperature for 20 hours, diluted with methylene chloride (20 mL), washed with water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is recrystallized from methylene chloride/diethyl ether to give the title compound, mp 165-167° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([Br:17])[C:14]=1[O:15][CH3:16])[CH:6]=[C:7]([C:10]#[N:11])[C:8]#[N:9].[C:18]1([CH:25]=[CH:24][CH:23]=[C:21]([OH:22])[CH:20]=1)[OH:19].N1CCCCC1>C(O)C>[NH2:9][C:8]1[O:19][C:18]2[C:25]([CH:6]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:14]([O:15][CH3:16])=[C:13]([Br:17])[CH:12]=3)[C:7]=1[C:10]#[N:11])=[CH:24][CH:23]=[C:21]([OH:22])[CH:20]=2
Reactant: COc1cc(C=C(C#N)C#N)cc(Br)c1OC
Reactant: Oc1cccc(O)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(C2C(C#N)=C(N)Oc3cc(O)ccc32)cc(Br)c1OC
Yield: 59.5 %

Procedure:
To a mixture of 3,4-dimethoxy-5-bromobenzylidenemalononitrile (293 mg, 1 mmol) and resorcinol (110 mg, 1 mmol) in ethanol (2 mL) was added piperidine (0.1 mL, 1 mmol). The mixture was refluxed for 2 h. The solvent was evaporated, the residue was purified by chromatography on silica gel with EtOAc and hexane (1:2) as eluant, yielding 240 mg (59.5%) of the title compound. 1H NMR (DMSO-d6): 9.77 (brs, 1H), 6.96–6.86 (m, 5H), 6.52 (d, J=8.1, 1H), 6.41 (s, 1H), 4.65 (s, 1H), 3.80 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [O:1]1[CH2:10][CH:2]1[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C.O>[N:11]([CH2:10][CH:2]([OH:1])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[N+:12]=[N-:13]
Reactant: c1ccc(CC2CO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC(O)Cc1ccccc1
Temperature: 90 °C

Procedure:
To the stirring solution of (2,3-epoxypropyl)benzene (1.0 g, 7.5 mmol) in 4 mL DMF was added a solution of sodium azide (0.97 g, 15 mmol) in 4 mL water. The solution was heated to 90° C. for 1 h. The solvent was removed under reduced pressure. The solid residue was partitioned between ethyl acetate and near saturated sodium chloride. The aqueous layer was washed three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and purified on 10 g of silica eluting with 0 to 50% ethyl acetate/hexanes to give a clear oil. NMR (CDCL3) d (1H, 1.97 ppm), m (2H, 2.73-2.82 ppm), m (1H, 3.22-3.30 ppm), dd (1H, 3.36 ppm), m (1H, 3.92-4.02 ppm), m (3H, 7.13-7.28 ppm), m (2H, 7.28-7.34 ppm).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][N:19]=4)[CH:14]=[C:13]([C:21]([O:23]CC)=[O:22])[C:12]3=[O:26])[CH:9]=[CH:10][C:2]1=2.O.[OH-].[Li+].O>O1CCOCC1>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][N:19]=4)[CH:14]=[C:13]([C:21]([OH:23])=[O:22])[C:12]3=[O:26])[CH:9]=[CH:10][C:2]1=2
Reactant: CCOC(=O)c1cc2cccnc2n(-c2ccc3c(c2)OCCO3)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc2cccnc2n(-c2ccc3c(c2)OCCO3)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
4.3 g (12 mmol) of ethyl 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in 1,4-dioxane (100 mL), and 1.0 g (24 mmol) of lithium hydroxide monohydrate and 50 mL of water were added thereto at room temperature. The resulting mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and a solid precipitated therefrom was dissolved in chloroform. This solution was washed with an aqueous solution of citric acid and water in this order, and was dried and concentrated. The solid thus obtained was washed with diisopropyl ether, and thus 3.96 g of the title compound was obtained as pale yellow crystals (yield: quantitative).
Reaction SMILES: C(OC(=O)C)(=[O:3])C.[CH3:8][C:9]1([CH3:27])[O:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[C:22]([CH3:23])=[CH:21][N+:20]([O-])=[C:19]([CH3:25])[C:18]=2[CH3:26])[CH2:11][O:10]1.C([O-])(=[O:30])C.[Na+].C(OC(C)C)(C)C>>[OH2:3].[CH3:8][C:9]1([CH3:27])[O:14][CH2:13][CH:12]([CH2:15][O:16][C:17]2[C:22]([CH3:23])=[CH:21][N:20]=[C:19]([CH2:25][OH:30])[C:18]=2[CH3:26])[CH2:11][O:10]1
Reactant: CC(=O)[O-]
Reactant: Cc1c[n+]([O-])c(C)c(C)c1OCC1COC(C)(C)OC1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Solvent: CC(C)OC(C)C
Product: Cc1cnc(CO)c(C)c1OCC1COC(C)(C)OC1
Product: O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 105 %

Procedure:
Acetic anhydride (1.10 kg) was added dropwise over 1.5 hours to a mixture heated to 50 to 60° C. of 4-(2,2-dimethyl-1,3-dioxan-5-yl)methoxy-2,3,5-trimethylpyridine 1-oxide (1.20 kg) and sodium acetate (0.18 kg). After 0.5 hours had passed, the mixture was heated for 4.5 hours at 80° C. The mixture was then cooled so that its internal temperature was not greater than 30° C., and left to stand. The mixture was then concentrated under reduced pressure. The resulting residue was dissolved in methanol (1.0 L), and the resultant solution was then charged over 1 hour into a mixture of 48% aqueous sodium hydroxide (0.71 kg) and chilled water (2.85 L). The solution was stirred at room temperature for 5 hours and 45 minutes, and then concentrated under reduced pressure. The concentrated residue was charged with water (3.0 L), and the resultant mixture was extracted with toluene (2.3 L×4). The combined toluene layers were washed with water (1.2 L). The resultant organic layer was filtered with Celite and then concentrated. The resulting residue was charged with diisopropyl ether (1.15 L) at room temperature, and this solution was further charged with warm water (45° C., 74 mL). Once crystal precipitation had been confirmed, the solution was stirred for 1 hour at 25° C. and then charged with heptane (3.6 L). The stirring was continued overnight. After stirring for a further 5 hours under ice cooling, the solution was filtered to obtain yellow crystals. The obtained yellow crystals were charged with diisopropyl ether (3.5 L) and dissolved at 50° C. Insoluble matter was removed by filtration, and the solution was then slowly cooled and allowed to age overnight at 5° C. The obtained crystals were filtered, washed with heptane (0.5 L) and wind-dried to obtain 0.69 kg of the title compound.
Reaction SMILES: CO.[SH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].C[O-].[CH3:20][O:21][C:22]1[CH:42]=[CH:41][C:25]([CH2:26][S: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]Br)=[CH:24][CH:23]=1>CCOC(C)=O.C(O)(=O)C>[CH3:20][O:21][C:22]1[CH:42]=[CH:41][C:25]([CH2:26][S: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][S:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:24][CH:23]=1
Reactant: O=C(O)CCCCCCCCCCCS
Reactant: COc1ccc(CSCCCCCCCCCCCCBr)cc1
Agent: C[O-]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(CSCCCCCCCCCCCCSCCCCCCCCCCCC(=O)O)cc1
Reaction time: 0.08 h
Yield: 48.7 %

Procedure:
Na (116 mg, 5 mmol) was dissolved it dry MeOH. 12-mercapto-1-dodecanoic acid (340 mg, 1.46 mmol) --synthesized according to JACS 115, 3458-3474, 1993--was added to the methoxide solution. After stirring with some heating for 5 min, (2) (497 mg, 1.24 mmol) was added to the reaction. The reaction became very viscous and an additional 1.75 mL of MeOH was introduced. The reaction was then left overnight. The reaction was quenched with 10% acetic acid. The paste-like reaction mixture was transferred to a 500 mL separatory funnel dissolved in equal volumes of EtOAc/Hex (1:1) and the acetic acid solution. The organic layer was separated. The aqueous layer was then extracted two more times. The combine extracts were concentrated yielding 740.3 mg (1.34 mmol) of crude product. The excess acetic acid was removed as a toluene azeotrope. The solid was crystallized from isopropyl ether giving 483 mg (71%). TLC and NMR show an impurity believed to be a disulfide side product. The material was further purified by flash chromatography eluting with CHCl3 /MeOH/AA (99:0.5:0.5) yielding 334 mg (0.604 mmol, 49%) of pure product. 1H NMR (CDCl3): d 9.45 (brs, 1H, COOH), 7.23 (d, J=8.8 Hz, 2H, AA' of AA' BB' aromatic system), 6.85 (d, J=8.7 Hz, 2H, BB' of AA' BB' aromatic system), 3.80 (s, 3H, methoxy), 3.66 (s, 2H, benzyl), 2.50 (t, J=7.3 Hz, 4H, RCH2SCH2R), 2.40 (t, J=7.3 Hz, 2H, RSCH2R), 2.35 (t, J=7.5 Hz, 2H, RCH2COOH), 1.5-1.7 (cm, 8H, CH2 b to heteroatoms), 1.15-1.45 (cm, 30H, bulk methylenes). 13C NMR (CDCl3): d 179.5 (COOH), 129.9 (aromatic, 2C), 113.9 (aromatic, 2C), 55.2 (MeOR), 35.6 (CH2), 33.7 (CH2), 32.2 (CH2), 31.3 (CH2), 29.7 (CH2), 29.4 (CH2), 29.2 (CH2), 28.9 (CH2), 24.6 (CH2).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[C:12](/[C:14]2[CH:23]=[CH:22][C:21]3[C:20]([CH3:25])([CH3:24])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=3[CH:15]=2)\[CH3:13])=[CH:7][CH:6]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>CCOCC.O1CCCC1>[CH3:24][C:20]1([CH3:25])[CH2:19][CH2:18][C:17]([CH3:26])([CH3:27])[C:16]2[CH:15]=[C:14](/[C:12](/[CH3:13])=[CH:11]/[C:8]3[CH:9]=[CH:10][C:5]([CH2:4][OH:3])=[CH:6][CH:7]=3)[CH:23]=[CH:22][C:21]1=2
Reactant: CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: C/C(=C\c1ccc(CO)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-naphthalene is reacted with acetyl chloride and aluminium chloride in nitrobenzene to give (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) methyl ketone. Reduction of this ketone with lithium aluminium hydride in ether yields 5,6,7,8-tetrahydro-α-5,5,8,8-pentamethyl-2-naphthalene-methanol which is converted by treatment with phosphorus tribromide in ether/hexane in the presence of a small amount of pyridine into 2-bromoethyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene. This bromoethyl compound is converted by treatment with triphenylphosphine in xylene while heating for 12 hours into [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-ethyl]-triphenylphosphonium bromide which, in a Wittig reaction with 4-ethoxycarbonyl-benzaldehyde, yields p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzoic acid ethyl ester of melting point 90°-91° C. This ester is reduced with lithium aluminum hydride in ether/tetrahydrofuran to give p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzyl alcohol of melting point 123°-124° C. (from methanol).