Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]([C:32]1[CH:33]=[C:34](OS(C(F)(F)F)(=O)=O)[CH:35]=[CH:36][CH:37]=1)[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH3:13])=[N:7]2.C(N(CC)CC)C.[CH3:54][Si:55]([C:58]#[CH:59])([CH3:57])[CH3:56]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:59]#[C:58][Si:55]([CH3:57])([CH3:56])[CH3:54])[CH:33]=1)[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH3:13])=[N:7]2
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C#C[Si](C)(C)C)c3)c(=O)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A 5-mL reaction vial equipped with a magnetic stirrer was purged with nitrogen and charged with compound 138 (220 mg, 0.33 mmol), dichlorobis(triphenylphosphine)palladium(II) (27.1 mg, 0.039 mmol), and anhydrous DMF (1 mL). Triethylamine (146 mg, 1.44 mmol) and (trimethylsilyl)acetylene (102 mg, 1.04 mmol) were added, and the reaction mixture was stirred for 10 h at 90° C. and an additional 8 h at 100° C. Evaporation of the reaction mixture to dryness followed by column chromatography purification afforded 63% yield of compound 139 as an off-white solid. 1H NMR (CD3OΔ) δ (ppm) 7.43-8.33 (m, 8H), 7.30 (d, 1H, J=6.6 Hz), 5-0.64 (s, 2H), 5.14 (bs, 1H), 3.68 (t, 2H, J=8:0 Hz), 2.81 (s, 3H), 1.59-1.64 (m, 3H), 0.94 (m, 2H), 0.32 (s, 9H), −0.09 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13]2[C:18]([C:19]3[N:27]=[CH:26][N:25]=[C:24]4[C:20]=3[N:21]=[CH:22][N:23]4C3CCCCO3)=[CH:17][CH:16]=[CH:15][N:14]=2)=[C:10]2[C:5]([C:6](SC)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1>C(O)(C(F)(F)F)=O.O1CCOCC1>[N:27]1[C:19]([C:18]2[C:13]([NH:12][C:11]3[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]4[C:10]=3[N:9]=[CH:8][N:7]=[C:6]4[NH:43][C:40]3[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=3)=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CSc1ncnc2c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c(C)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1ccc2c(Nc3ccc(Cl)cc3)ncnc2c1Nc1ncccc1-c1ncnc2[nH]cnc12
Temperature: 160 °C

Procedure:
A clear microwave vial was charged with 7-methyl-4-(methylthio)-N-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)quinazolin-8-amine (0.200 g, 0.413 mmol) and 4-chlorobenzenamine (0.105 g, 0.825 mmol) and 5 ml of dioxane. A few drops of TFA was added to the mixture and the reaction vial was capped. The vial was heated in a microwave reactor at 160° C. for 12 minutes. The solid that crashed out of the reaction mixture was filtered off and washed with ethyl acetate. The solid was dissolved in DMSO (3 ml) and purified by RP-HPLC using a gradient of 5% ACN 0.1% TFA to 95% ACN 0.1% TFA in water 0.1% TFA. The pure fractions were neutralized with ammonium hydroxide and the volatiles were removed under reduced pressure. The solid that crashed out of the aqueous layer was filtered off, washed with water and dried in a vacuum oven at 45 degrees to give N8-(3-(9H-purin-6-yl)pyridin-2-yl)-N4-(4-chlorophenyl)-7-methylquinazoline-4,8-diamine as a yellow solid. MS Found: (ESI pos. ion) m/z 480 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:34]4[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:33]=4[CH3:32])(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: Cc1ccc(C)c(S(=O)(=O)Cl)c1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cc(C)ccc4C)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,5-dimethyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=589.7)=85%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13](OC)[C@:12]1([CH3:30])[OH:29].Br.[Na].[Cl:33][C:34]1[N:39]=[CH:38][NH:37][C:36]2=[N:40][CH:41]=[C:42]([CH3:43])[C:35]=12.C(#N)C>C(Cl)Cl>[Cl:33][C:34]1[C:35]2[C:42]([CH3:43])=[CH:41][N:40]([C@@H:13]3[O:16][C@H:17]([CH2:18][O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@H:11]([O:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[C@@:12]3([CH3:30])[OH:29])[C:36]=2[N:37]=[CH:38][N:39]=1
Reactant: Cc1cnc2[nH]cnc(Cl)c1-2
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@]1(C)O
Agent: Br
Agent: [Na]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2ncnc(Cl)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of the product from Step C of Example 62 (1.06 g, 2.1 mmol) in CH2Cl2 (30 mL) was added HBr (5.7 M in acetic acid; 2.2 mL) dropwise. The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 2 h, concentrated in vacuo and co-evaporated with toluene (2×15 mL). The resulting oil was dissolved in MeCN (10 mL) and added dropwise into a solution of the sodium salt of 4-chloro-5-methyl-1H-pyrrolo[2,3-d]pyrimidine in acetonitrile [generated in situ from 4-chloro-5-methyl-1H-pyrrolo[2,3-d]pyrimidine [for preparation, see J. Med. Chem. 33: 1984 (1990)] (0.62 g, 3.7 mmol) in anhydrous acetonitrile (70 mL), and NaH (60% in mineral oil, 148 mg, 3.7 mmol), after 2 h of vigorous stirring at rt]. The combined mixture was stirred at rt for 24 h and then evaporated to dryness. The residue was suspended in water (100 mL) and extracted with EtOAc (250+100 mL). The combined extracts were washed with brine (50 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified on a silica gel column (5×5 cm) using hexane/ethyl acetate (9/1, 5/1, 3/1) gradient as the eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired product (0.87 g) as a colorless foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:8])[CH:5]=[CH:6][CH:7]=1.[Mg].[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12]1.Cl>C(OCC)C.O>[F:8][C:4]1[CH:3]=[C:2]([C:13]2([OH:17])[CH2:14][CH2:15][CH2:16][CH:11]([CH3:10])[CH2:12]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(Br)c1
Reactant: CC1CCCC(=O)C1
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: CC1CCCC(O)(c2cccc(F)c2)C1
Temperature: 5 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
A solution of 50.0 g (0.28 mole) of 3-bromofluorobenzene in 100 ml of diethyl ether was added dropwise with stirring to a cooled reaction vessel containing 7.0 g (0.29 mole) of freshly dried magnesium turnings. The reaction began after 10-20% of the 3-bromofluorobenzene-ether solution had been added. The remainder of the addition was done at a rate sufficient to promote gentle reflux. Upon complete addition an additional 210 ml of diethyl ether was added and the reaction mixture was heated under reflux for 1 hour. The reaction mixture was cooled to 5° C. and 32.5 g (0.29 mole) of 3-methylcyclohexanone in 100 ml of diethyl ether was added dropwise during 30 minutes. Upon complete addition the reaction mixture was stirred for 1 hour at 5° C., heated to reflux temperature for 30 minutes, then allowed to cool to ambient temperature and stand for 16 hours. The reaction mixture was slurried in 450 ml of water and made acidic with aqueous 10% hydrochloric acid. The two phases were separated and the aqueous phase was extracted with three portions of diethyl ether. The combined ether extracts and organic phase were washed with two portions of a saturated aqueous solution of sodium bicarbonate, then one portion of water. The organic layer was dried with sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 58.0 g of 1-(3-fluorophenyl)-3-methyl-1-cyclohexanol as a solid. The compound was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([CH3:12])[CH:4]=1.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>S(Cl)(Cl)=O.O>[CH2:13]([N:15]([CH2:16][CH3:17])[C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH3:12])[CH3:14]
Reactant: CCNCC
Reactant: COc1ccc(C(=O)O)c(C)c1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1ccc(OC)cc1C
Temperature: 80 °C
Yield: 57.6 %

Procedure:
4-methoxy-2-methylbenzoic acid (3.0 g, 18.05 mmol) was taken in thionyl chloride (20 ml) and refluxed for 1 h at 80° C. The reaction mixture was evaporated under reduced pressure. Under nitrogen the crude was quenched with diethyl amine (1.870 ml, 18.05 mmol) slowly under cooling condition. The reaction mixture was dissolved in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get desired compound (2.3 g, 54.7%) as an oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.06-7.04 (d, J=8 Hz, 1H), 6.79 (s, 1H), 6.78-6.76 (d, J=8 Hz, 1H), 3.75 (s, 3H), 3.43 (br, s, 2H), 3.06-3.05 (m, 2H), 2.16 (s, 3H), 1.14 (d, J=8 Hz, 3H), 0.95 (d, J=8 Hz, 3H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]12([CH2:22][NH2:23])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2>C1COCC1>[C:12]12([CH2:22][NH:23][C:4]([C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[C:1]([OH:6])=[O:11])=[O:5])[CH2:19][CH:18]3[CH2:17][CH:16]([CH2:15][CH:14]([CH2:20]3)[CH2:13]1)[CH2:21]2
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCC12CC3CC(CC(C3)C1)C2
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1C(=O)NCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
Phthalic anhydride (2.65 g, 17.9 mmol) was dissolved in dry THF (50 ml) and a solution of 1-adamantanemethylamine (2.96 g, 17.9 mmol) in THF (50 ml) was added. The mixture was stirred at room temperature for 16 h and the solution evaporated to dryness. The residue was triturated with hexane and the precipitate formed was filtered, washed with hexane and dried to leave the title compound (5.42 g, 97%), 1H NMR (d6 -DMSO) δ 12.9 (1H, s), 8.2 (1H, t), 7.8-7.4 (4H, m), 2.9 (2H, d), 1.9 (3H, s), 1.6 (6H, q), 1.5 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:31][CH3:32])[O:13][C@H:12]([CH:14]=[O:15])[C@@H:11]([O:16][Si](C)(C)C)[C@H:10]([O:21][Si](C)(C)C)[C@H:9]2[O:26][Si](C)(C)C)=[CH:4][C:3]=1[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C=O.C[CH2:44][O-:45].[Na+].S(=O)(=O)(O)[O-].[Na+]>CCO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:31][CH3:32])[C@H:9]([OH:26])[C@@H:10]([OH:21])[C@H:11]([OH:16])[C:12]([CH2:44][OH:45])([CH2:14][OH:15])[O:13]2)=[CH:4][C:3]=1[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(COc3ccccc3)c2)O[C@H](C=O)[C@@H](O[Si](C)(C)C)[C@H](O[Si](C)(C)C)[C@H]1O[Si](C)(C)C
Reactant: CC[O-]
Agent: C=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CO[C@@]1(c2ccc(Cl)c(COc3ccccc3)c2)OC(CO)(CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 55 °C

Procedure:
To a solution of (2S,3R,4S,5R,6S)-6-(4-chloro-3-(phenoxymethyl)phenyl)-6-methoxy-3,4,5-tris((trimethylsilyl)oxy)tetrahydro-2H-pyran-2-carbaldehyde (22.9 g, 36.7 mmol) in EtOH (92 mL) under nitrogen atmosphere, was added para-formaldehyde (33.0 g, 1.1 mol) at 55° C. followed by addition of 21% NaOEt in ethanol (23.12 g NaOEt/110 mL EtOH). The reaction mixture was heated at 55° C. overnight. After the completion of the reaction as confirmed by TLC, ethanol was evaporated. The crude compound was extracted with ethyl acetate (700 mL) followed by washing with sodium bisulphate solution (68.67 g, 660.6 mmol) in water (458.7 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to afford crude compound, which was purified by column chromatography (silica gel, 6:4 MeOH:DCM) to obtain the compound as a white solid (12 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.O[CH2:12][C:13]1[O:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:12]([C:4]1[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[NH:6][CH:5]=1)[C:13]1[O:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1)=[CH:5][NH:6]2
Reactant: Clc1cccc2[nH]ccc12
Reactant: O=Cc1ccc(CO)o1
Product: OCc1ccc(C(c2c[nH]c3cccc(Cl)c23)c2c[nH]c3cccc(Cl)c23)o1

Procedure:
The compound Bis(4-chloroindol-3-yl)-(5-hydroxymethylfuran-2-yl)methane was prepared following procedure A, starting from 4-chloro indole and 5-hydroxymethyl furfural. LC: Tr 2.84 min, MS: 411 (M+H)+
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[F:13][C:14]1[CH:15]=[C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH2:28])[CH:17]=[C:18]([F:21])[C:19]=1[F:20]>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:15]=[C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][C:8]([C:7]2[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=2)=[O:9])[CH:17]=[C:18]([F:21])[C:19]=1[F:20]
Reactant: Nc1ccccc1-c1cc(F)c(F)c(F)c1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)Nc2ccccc2-c2cc(F)c(F)c(F)c2)c(C(F)F)n1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
100.0 g (0.504 mol, 98% pure) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride were dissolved at 25° C. in 257.2 g of toluene. The solution was evacuated to 400 mbar and heated to 85° C. Subsequently, within 3 hours, 492.8 g (0.499 mol, 23% strength) of toluenic 3′,4′,5′-trifluorobiphenyl-2-ylamine solution were metered in, after which stirring was continued for another 1 hour. After venting and cooling to 25° C. with a ramp of 10° C./h, the mixture was stirred overnight. Subsequently, the mixture was cooled to 0° C., and the solid constituents were filtered off, washed with cold toluene and dried at 80° C. under reduced pressure. The yield (without further processing of the mother liquor) was 177.7 g (92%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:35]=[CH:34][C:11]([CH2:12][C:13]2[CH:20]=[C:19]([C@@:21]34[O:28][C@@:25]([CH2:29][OH:30])([CH2:26][O:27]3)[C@@H:24]([OH:31])[C@H:23]([OH:32])[C@H:22]4[OH:33])[CH:18]=[CH:17][C:14]=2[C:15]#[N:16])=[CH:10][CH:9]=1.I[CH2:37][CH3:38]>CC(C)=O.C(OCC)(=O)C>[CH2:37]([O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][C:13]2[CH:20]=[C:19]([C@@:21]34[O:28][C@@:25]([CH2:29][OH:30])([CH2:26][O:27]3)[C@@H:24]([OH:31])[C@H:23]([OH:32])[C@H:22]4[OH:33])[CH:18]=[CH:17][C:14]=2[C:15]#[N:16])=[CH:34][CH:35]=1)[CH3:38]
Reactant: N#Cc1ccc([C@]23OC[C@](CO)(O2)[C@@H](O)[C@H](O)[C@H]3O)cc1Cc1ccc(O)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2C#N)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 25.5 %

Procedure:
Potassium carbonate (8 mg, 0.058 mmol) was added to a solution of intermediate 2-(4-hydroxy-benzyl)-4-((1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]oct-5-yl)-benzonitrile (see example 6; 8.9 mg, 0.022 mmol) in acetone (0.4 mL), followed by iodoethane (4 microL, 0.044 mmol) at room temperature. The mixture was stirred at 45° C. overnight. The mixture was diluted with ethyl acetate (60 mL) and washed with water. The organic layer was dried over sodium sulfate and evaporated to dryness. Purification by preparative Thin Layer Chromatography over silica gel (eluting with methanol in dichloromethane: 1 to 9 in volume) allowed isolation of desired product 7A (2.4 mg; 26% yield).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](=O)[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4]1.C([BH3-])#[N:18].[Na+].C([O-])(=O)C.[NH4+]>CO>[NH2:18][CH:8]1[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH:3]1[O:2][CH3:1]
Reactant: COC1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COC1CN(C(=O)OC(C)(C)C)CCC1N
Reaction time: 4 h

Procedure:
To a solution of 1,1-dimethylethyl 3-(methyloxy)-4-oxo-1-piperidinecarboxylate D18 (2.9 g) in MeOH (100 ml), was added sodium cyanoborohydride (7.9 g, 126 mmol) and ammonium acetate (9.7 g, 126 mmol) at R.T. The reaction mixture was stirred for 4 hours. The resulting mixture was concentrated in vacuo, dissolved in water, basified with sodium hydroxide to pH10 and extracted with DCM. The organic layer was dried over anhydrous MgSO4, concentrated in vacuo to get the desired product D19 in 2.85 g. LCMS [MH+] 231@0.83 min (5 min run)
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:15]([CH3:17])[CH3:16])=[N:7][C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.C1C(=O)N([I:27])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:15]([CH3:16])[CH3:17])=[N:7][C:8]3[C:9]([I:27])=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)c1nc2cc[nH]c(=O)c2c2cc(Br)ccc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1nc2c(I)c[nH]c(=O)c2c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred suspension of 9-bromo-6-isopropylbenzo[c]-1,6-naphthyridin-1(2H)-one (81 mg, 0.26 mmol) in DMF (1.5 ml) was added NIS (86 mg, 0.38 mmol), and stirred for 24 hours at room temperature. The reaction mixture was diluted with EtOAc until a solution was formed, and washed with a mixture of 10% aqueous sodium thiosulfate and 1N NaOH. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was adsorbed on to silica gel and purified by silica gel chromatography using an EtOAc/Hexanes gradient to afford 9-bromo-4-iodo-6-isopropylbenzo[c]-1,6-naphthyridin-1(2H)-one. LRMS (ESI) calc'd for (C15H12BrIN2O) [M+H]+, 442.9; found 442.8.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([Mg]Br)C.[CH3:15][C:16]1([CH3:24])[C:18]([CH3:20])([CH3:19])[CH:17]1[C:21](Cl)=[O:22]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:21]([CH:17]1[C:18]([CH3:20])([CH3:19])[C:16]1([CH3:24])[CH3:15])=[O:22])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2ccccc2[nH]1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: Cc1[nH]c2ccccc2c1C(=O)C1C(C)(C)C1(C)C
Yield: 52.6 %

Procedure:
A mixture of 2-methylindole (0.75 g, 5.7 mmol), ethylmagnesium bromide (1.0 M solution in THF, 6.6 mL, 6.6 mmol), zinc chloride (1.0 M solution in Et2O, 6.6 mL, 6.6 mmol) and the product of Example 1A (6.3 mmol) in 15 mL of dichloromethane was processed as described in Example 1B to provide the title compound (0.76 g, 3.0 mmol, 52% yield). MS (DCI/NH3) m/z 256 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[NH:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[N:8]1.[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18].C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[OH:18][CH2:17][C:16]([NH:15][C:12]([C:10]1[CH:9]=[N:8][NH:7][CH:11]=1)=[O:14])([CH3:20])[CH3:19]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1cn[nH]c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1cn[nH]c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
A solution of DMF (2 drops) and oxalyl chloride (0.88 g, 4.5 mmol) in methylene chloride (4 ml) was added to a suspension of 4-pyrazolecarboxylic acid (0.50 g, 4.5 mmol) in methylene chloride (6 ml) and stirred at room temperature for 1 hour. The reaction mixture was concentrated and dried under a reduced pressure. To a suspension of the obtained solid in methylene chloride (5 ml) cooled in an ice-bath, 2-amino-2-methyl-1-propanol (1.33 g, 15 mmol) was added. The mixture was stirred at room temperature for 1 hour, added saturated aqueous NaHCO3 to, and concentrated and dried under a reduced pressure. The residue was extracted with warm chloroform and the solvent was evaporated under a reduced pressure. The residue was subjected to silica gel chromatography (chloroform/methanol/triethylamine=100/10/1) to give the title compound (0.37 g, 45%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][CH2:23][CH2:24][N:25]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.C(OCC)(=O)C.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[O:22][CH2:23][CH2:24][N:25]=3)=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(C3=NCCO3)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(C3=NCCO3)cc2)CC1

Procedure:
2.4 g (7 mmool) of 1-tert.butoxycarbonyl-4-[4-(2-oxazolin-2-yl)benzylidene]piperidine, dissolved in 70 ml of anhydrous ethanol and 20 ml of ethyl acetate, are catalytically hydrogenated (ambient temperature, 20 minutes, hydrogen pressure 50 psi) in the presence of 2.5 g of palladium-carbon (10%). The catalyst is suction-filtered, the filtrate is evaporated down and the residue is reacted further without purification.
Reaction SMILES: C[O:2][C:3]([C:5]1([OH:15])[CH2:10][C:9]([CH3:12])([CH3:11])[NH:8][C:7]([CH3:14])([CH3:13])[CH2:6]1)=O.O.[NH2:17][NH2:18]>CO>[CH3:11][C:9]1([CH3:12])[CH2:10][C:5]([OH:15])([C:3]([NH:17][NH2:18])=[O:2])[CH2:6][C:7]([CH3:14])([CH3:13])[NH:8]1
Reactant: COC(=O)C1(O)CC(C)(C)NC(C)(C)C1
Reactant: NN
Solvent: CO
Solvent: O
Product: CC1(C)CC(O)(C(=O)NN)CC(C)(C)N1

Procedure:
16.2 parts of 2,2,6,6-tetramethyl-4-hydroxypiperidine-4-carboxylic acid methyl ester (according to German Patent No. 91,122), 5 parts of hydrazine hydrate and 20 parts of methanol are boiled under reflux for 10 hours and the methanol is subsequently distilled off. The residue is recrystallised from cyclohexane. Yield: 15.3 parts of 2,2,6,6-tetramethyl-4-hydroxypiperidine-4-carboxylic acid hydrazide melting at 121° to 123° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH:10]([OH:12])[CH3:11])=[N:6][CH:7]=1.[CH2:13](N(CC)CC)C.CS(Cl)(=O)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH:10]([O:12][CH3:13])[CH3:11])=[N:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CC(O)C#Cc1ccc(Br)cn1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: COC(C)C#Cc1ccc(Br)cn1
Reaction time: 1 h
Yield: 34 %

Procedure:
5-Bromo-2-(3-hydroxy-1-butynyl)pyridine (5.426 g) was dissolved in tetrahydrofuran (60 ml), followed by the sequential addition of triethylamine (10 ml) and methanesulfonyl chloride (2.2 ml) under ice-cooling, and the resulting mixture was stirred for 1 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was dissolved in methanol (16 ml), and under ice-cooling, 28% sodiummethoxide/methanol solution (4.6 ml) was added thereto and the resulting mixture was stirred at room temperature overnight. The reaction mixture was evaporated and partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system) to give the title compound as a brown oil (1.968 g, yield; 34%).