Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:43]=[CH:42][C:26]([CH2:27][O:28][C:29](ON=C(C2C=CC=CC=2)C#N)=[O:30])=[CH:25][CH:24]=1.O1CCOCC1>O>[CH3:21][O:22][C:23]1[CH:43]=[CH:42][C:26]([CH2:27][O:28][C:29]([NH:11][CH2:10][CH2:9][C:8]2[C:12]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:13]=3)[NH:6][CH:7]=2)=[O:30])=[CH:25][CH:24]=1
Reactant: COc1ccc(COC(=O)ON=C(C#N)c2ccccc2)cc1
Reactant: NCCc1c[nH]c2ccc(F)cc12
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(COC(=O)NCCc2c[nH]c3ccc(F)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a strirred suspension 1.4 g (7.8 mmol) of 5-fluorotryptamine in 5 mL of water and 1.1 mL (7.8 mmol) of triethylamine was added 2.5 g (7.8 mmol) of 2-(4-methoxybenzyloxycarbonyloxyimino)-2-phenylacetonitrile (MOZ-ON) and 10 mL of dioxane. The reaction mixture was stirred at room temperature for 1 hour under argon, diluted with water, and extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography, over silica gel, using hexane:ethyl acetate (2:1 and later 1:1) as eluents to provide 1.7 g (63%) of N-(p-methoxybenzyloxycarbonyl)-5-fluorotryptamine as an off-white solid. mp 118°-119° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH:6]([PH:10](=[O:14])[O:11][CH2:12][CH3:13])[O:7][CH2:8][CH3:9])[CH3:4].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>O1CCCC1>[CH2:3]([O:5][CH:6]([P:10]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])[O:11][CH2:12][CH3:13])[O:7][CH2:8][CH3:9])[CH3:4]
Reactant: CCOC(OCC)[PH](=O)OCC
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(OCC)P(=O)(Cc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 12 g of oil-free sodium hydride in 300 ml of absoluted tetrahydrofuran under an inert atmosphere is treated with a solution of 103.5 g of 95% ethyl diethoxymethylphosphinate in 100 ml of absolute tetrahydrofuran at such a rate so as to maintain the temperature at or just below 20° C. After the addition is complete, the suspension is stirred for 1 hour at room temperature and then cooled to approximately 10° C. before addition of 85.5 g of benzylbromide, maintaining the temperature below 15° C. Finally, the white suspension is stirred for 20 hours at room temperature. Water is then added and the tetrahydrofuran layer is separated. The aqueous layer is extracted with dichloromethane and the combined organic layers are dried and concentrated in vacuo. Distillation of the residue in high vacuum affords ethyl diethoxymethyl(benzyl)phosphinate as a colourless oil of b.p. 105-125 (10-2 mbar). 'H-NMR (CDCl3): δ (ppm)=7.29 (5 H, m, Ph), 4.48 (1 H d, 5=9 HZ, CHP), 4.08 (2 H, q, CH2OP), 3.83 (2 H, m, CH2OC), 3.66 (2 H, m, CH2OC), 3.21 (2 H, ABq, d, 5=15×6 HZ, CH2P), 1,23 (9 H, m, 3×CH3).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1)(=[O:4])=[O:3].[H-].[Na+].CS(O[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>ClCCl.CO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[N:10]([CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:33])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:27][CH2:26]3)[C:9]=2[CH:15]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(S(C)(=O)=O)cc32)CC1
Yield: 66 %

Procedure:
6-(Methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one (Intermediate 101) (280 mg, 1.23 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (1.62 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (20:1) gave the product in 66% yield as a yellow gum.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([F:10])/[CH:5]=[CH:6]/[C:7]([O-:9])=[O:8].CC1C=CC(S([CH2:22][N+:23]#[C-:24])(=O)=O)=CC=1.[CH3:25]I>CS(C)=O.C(OCC)C.C(O)C.[OH-].[Na+]>[CH3:22][N:23]1[CH:24]=[C:5]([C:4]([F:11])([F:10])[F:3])[C:6]([C:7]([OH:9])=[O:8])=[CH:25]1
Reactant: O=C([O-])/C=C/C(F)(F)F
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: CS(C)=O
Product: Cn1cc(C(=O)O)c(C(F)(F)F)c1

Procedure:
Sodium hydride (8.0 g of a 75% dispersion in oil) is suspended at +5° C. in a mixture of DMSO (300 ml) and diethylether (100 ml). A solution of ethyl 4,4, trifluorocrotonate (20 g) and TOSMIC (23 g) in DMSO (100 ml) is added through a dropping funnel at such a rate that the temperature does not exceed 10° C. After stirring the reaction mixture for an additional hour at room temperature methyl iodide (15.8 ml) is added with cooling. After 2 hours at room temperature the reaction mixture is poured onto crushed ice. Repeated extraction with ether, washing of the combined organic phases with brine and evaporation of the solvent under reduced pressure gives a product mixture in form of a light amber oil. The crude product mixture is heated at 60° C. in a mixture of ethanol (100 ml) and sodium hydroxide (50 ml of a 30% aqueous solution). Washing of the solution with ether, acidifying of the aqueous phase with concentrated hydrochloric acid and filtering gives the 1-methyl4-trifluoromethylpyrrole-3-carboxylic acid in form of a crystalline solid. 1H-NMR (CDCl3): 7.24(d, 1H); 6.88(d, 1H); 3.63(s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]([CH3:17])=[N:15][N:16]=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:18]([N:25]1[C:33]2[C:28](=[CH:29][C:30]([NH2:34])=[CH:31][CH:32]=2)[CH:27]=[N:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[ClH:1].[CH2:18]([N:25]1[C:33]2[C:28](=[CH:29][C:30]([NH:34][C:2]3[C:11]4[C:6](=[CH:7][C:8]([C:12]5[O:13][C:14]([CH3:17])=[N:15][N:16]=5)=[CH:9][CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:31][CH:32]=2)[CH:27]=[N:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1nnc(-c2ccc3c(Cl)ncnc3c2)o1
Reactant: Nc1ccc2c(cnn2Cc2ccccc2)c1
Solvent: CC#N
Product: Cc1nnc(-c2ccc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3c2)o1
Product: Cl

Procedure:
The crude solid 4-Chloro-7-(5-Methyl-[1,3,4]oxadiazol-2-yl)-quinazoline was suspended in dry acetonitrile. 1-Benzyl-1H-indazol-5-ylamine (0.03 g) was added and the mixture heated at reflux for 18 hours under nitrogen (Procedure A). The mixture was cooled and the title compound collected by filtration; δH [2H6]DMSO 11.82(1H, bs), 9.08(1H, s), 8.99(1H, s), 8.47(1H, s), 8.44(1H, d), 8.37(1H, s), 8.17(1H, s), 7.89(1H, d), 7.72(1H, d), 7.35(5H, m), 5.80(2H, s) 2.72 (3H, s); m/z (M+1+) 434.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[OH-].[K+].Cl[C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:13]=1[C:14]#[N:15].C1(C)C=CC=CC=1>CN1CCCC1=O.O>[C:14]([C:13]1[C:16]([C:20]([F:21])([F:22])[F:23])=[CH:17][CH:18]=[CH:19][C:12]=1[O:2][C:1]1[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)#[N:15]
Reactant: Oc1cccc(O)c1
Reactant: N#Cc1c(Cl)cccc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1c(Oc2cccc(O)c2)cccc1C(F)(F)F
Temperature: 62.5 °C
Reaction time: 2.5 h

Procedure:
Resorcinol [44.0 g (0.4 mol)] is partly dissolved in 170 ml of N-methylpyrrolidone, and potassium hydroxide [min. 85% pure; 34.5 g (0.52 mol)] and then 2-chloro-6-(trifluoromethyl)benzonitrile [20.5 g (0.1 mol)] are added. The mixture is stirred at 60-65° C. for 2.5 h. After addition of 300 ml of toluene and 400 ml of water, the aqueous phase is separated off and extracted once more with 300 ml of toluene. The combined organic phases are dried over MgSO4 and, after filtration, concentrated. Digestion of the oily residue with 150 ml of water, filtration and drying affords pale brownish crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][O:20][CH2:21][C:22]([OH:24])=O)(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]1([OH:37])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:37][C:31]1([C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)[CH2:32][CH2:33][N:34]([C:22](=[O:24])[CH2:21][O:20][CH2:19][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][N:13]2[S:10]([C:6]2[C:5]([CH3:25])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=2[CH3:9])(=[O:11])=[O:12])[CH2:35][CH2:36]1
Reactant: OC1(c2cccs2)CCNCC1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)O)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCC(O)(c3cccs3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (68 mg, 0.424 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (acid unit S24) (150 mg, 0.404 mmol) in methylene chloride (5 ml) and the mixture was stirred for 1 h at room temperature. A solution of 4-(thiophen-2-yl)piperidin-4-ol (73 mg, 0.404 mmol) in methylene chloride (2 ml) was subsequently added and the reaction mixture was stirred for 15 h at room temperature. Thereafter, saturated sodium bicarbonate solution (10 ml) was added to the reaction mixture and the aqueous phase was subsequently extracted with methylene chloride (2×10 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried with sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography with ethyl acetate/hexane (20:1).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH:6]([C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([CH3:18])[CH3:17])[C:10]=1[NH2:11])([CH3:8])[CH3:7].C([O-])(=O)C.[Na+]>CC(C)=O.O>[CH3:18][CH:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]([CH:6]([CH3:8])[CH3:7])[C:10]=1[NH:11][C:3](=[O:4])[CH2:2][Br:1])[CH3:17]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(Br)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CBr
Temperature: 25 °C
Yield: 86.2 %

Procedure:
Bromoacetyl bromide (17.0 g, 84.6 mmol) was added dropwise to a well-stirred ice cold solution of 2,6-diisopropylaniline (10.0 g, 56.4 mmol) in acetone (25 mL) and water (25 mL) containing sodium acetate (15.3 g, 112.8 mmol). The reaction mixture was stirred at room temperature for an hour and then diluted with water (100 mL). The product was filtered and washed with cold water, saturated sodium, bicarbonate, again with water, and finally with hexane. It was dried in a vacuum at 40° C. to yield 14.5 g (86%) of title compound as a white solid 1H NMR was consistent with the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][CH2:13][C:14]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=1[O:24][CH3:25]>CN(C)C=O.C(OCC)(=O)C>[BrH:12].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=2[O:24][CH3:25])[CH:9]=1
Reactant: NC(=O)c1cc(Cl)cnc1N
Reactant: COc1ccc(S(C)(=O)=O)cc1CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Br
Product: COc1ccc(S(C)(=O)=O)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Temperature: 100 °C
Reaction time: 4 h
Yield: 27.9 %

Procedure:
To a solution of 2-amino-5-chloronicotinamide (0.15 g) in N,N-dimethylformamide (3 ml) was added 2-(bromomethyl)-1-methoxy-4-(methylsulfonyl)benzene (0.29 g), and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was diluted with ethyl acetate. The precipitate was collected by filtration and washed with ethyl acetate. The obtained precipitate was recrystallized from methanol-ethyl acetate to give the title compound (110 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:11]=[C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:5]=[C:6](C(O)=O)[N:7]=1.[CH3:19][C:20]([OH:23])([CH3:22])[CH3:21].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C[N:42]([CH:44]=[O:45])C>>[C:20]([O:23][C:44](=[O:45])[NH:42][C:6]1[N:7]=[C:2]([NH2:1])[C:3]2[N:4]([N:11]=[C:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:5]=1)([CH3:22])([CH3:21])[CH3:19]
Reactant: CN(C)C=O
Reactant: CC(C)(C)O
Reactant: Nc1nc(C(=O)O)cn2nc(-c3ccco3)nc12
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: CC(C)(C)OC(=O)Nc1cn2nc(-c3ccco3)nc2c(N)n1
Temperature: 80 °C
Yield: 16 %

Procedure:
A mixture containing 8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazine-6-carboxylic acid (100 mg, 0.41 mmol; see Example 8 above), TEA (209 μL, 1.5 mmol), t-BuOH (1.5 mL) and diphenylphosphoryl azide (339 μl, 1.6 mmol) in DMF (1.5 ml) was heated (at around 80° C.) overnight. The solvent was removed in vacuo and the residue was purified by HPLC (C18, H2O:MeCN gradient) to afford the product as a yellow solid (20 mg, 16%). 1H NMR (300 MHz, CDCl3) δ 1.56 (s, 9H), 5.92 (br. s, 2H), 6.58 (dd, J=3.4, 1.8 Hz, 1H), 7.15 (dd, J=3.4, 0.8 Hz, 1H), 7.62 (dd J=1.8, 0.8 Hz, 1H), 8.61 (br. s, 1H). MS: m/z 317 [M+H]+.
Reaction SMILES: O[Li].O.C([O:6][C:7]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=2)=[O:8])C>C1COCC1.CO.O>[N+:18]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:7]([OH:8])=[O:6])=[CH:17]2)([O-:20])=[O:19]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
LiOH.H2O (1.06 g, 46.2 mmol, 2.1 eq.) was added to a suspension of 5-nitro-1H-indole-2-carboxylic acid ethyl ester (II) (5.15 g, 22 mmol, 1 eq.) in THF/MeOH/H2O 1:1:2 (180 ml). The final suspension turned to dark yellow and was stirred at 25° C. After 30 min the solubilization was complete and total conversion was achieved after 6 hours. The reaction mixture was cooled to 0° C. and quenched with HCl 2N until the solution reached pH 5. Organic volatiles were removed under reduced pressure and the white precipitate was filtered and dried to give the compound of formula (III). Yield=4.53 g (quantitative). Same procedure on 50 g scale afforded 42.2 g of the compound of formula (III) (96% yield).
Reaction SMILES: [NH:1]1[C:5]([CH:6]2[CH2:11][CH2:10][CH2:9][N:8](C(OCC3C=CC=CC=3)=O)[CH2:7]2)=[CH:4][CH:3]=[N:2]1.Cl.C(Cl)Cl.CO>O1CCOCC1>[NH:1]1[C:5]([CH:6]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]2)=[CH:4][CH:3]=[N:2]1
Reactant: O=C(OCc1ccccc1)N1CCCC(c2ccn[nH]2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1cc(C2CCCNC2)[nH]n1
Yield: 56.8 %

Procedure:
A 250-mL round-bottom flask was charged with a solution of benzyl 3-(1H-pyrazol-5-yl)piperidine-1-carboxylate (14 g, 46.61 mmol, 1.00 equiv, 95%) in dioxane (100 mL). To the mixture was added conc.HCl (60 mL, 36%). The resulting mixture was refluxed for 2 hours. The progress was monitored by TLC (DCM:MeOH=10:1). Upon completion, the resulting mixture was concentrated on a rotary evaporator. Then, pH was adjusted to 9 with saturated aqueous Na2CO3. The resulting mixture was then extracted with THF (8×200 mL). Combined organic layers were dried over anhydrous magnesium sulfate. After filtration and concentration on a rotary evaporator, the residue was purified by a silica gel column chromatography eluted with EtOAc/MeOH (10:1) affording 3-(1H-pyrazol-5-yl)piperidine as pale yellow oil (4 g, 54%). LCMS: [M+H]+: 152.1; 1H NMR (CDCl3) δ 7.47 (s, 1H), 6.05 (s, 1H), 3.16 (m, 1H), 3.11 (m, 2H), 2.99 (m, 1H), 2.76 (m, 1H), 2.57 (m, 2H), 1.95 (m, 1H), 1.56 (m, 1H), 1.46 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][CH:12]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].COC(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][CH2:12][N:27]3[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH2:25][CH2:26]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=CCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: ClCCCl
Product: CS(=O)(=O)N1CCN(CCc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
To a solution of crude (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-acetaldehyde (300 mg) and 1-methanesulfonyl-piperazine (243 mg) in 1,2-dichloroethane (10 mL) at room temperature was added trimethylorthoformate (0.33 mL). The reaction mixture was stirred at room temperature for 1 h and then sodium triacetoxyborohydride (534 mg) was added. The reaction mixture was stirred at room temperature for 16 h and then quenched with saturated aqueous sodium carbonate solution (20 mL) and extracted into dichloromethane (2×20 mL). The combined organics were washed with aqueous brine solution (2×20 mL), dried (MgSO4), concentrated and purified using column chromatography to give 2-chloro-6-[2-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a white solid (100 mg).
Reaction SMILES: [C:1]([O:6][C:7]1([CH2:17][CH3:18])[CH:14]2[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].C([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[CH2:28])=[CH:25][CH:24]=1)(=O)C.CO.C(O)(=O)C>CN(C)C1C=CN=CC=1.O>[C:1]([O:6][C:7]1([CH2:17][CH3:18])[CH:8]2[CH2:16][CH:12]3[CH2:11][CH:10]([CH2:15][CH:14]1[CH2:13]3)[CH2:9]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[CH2:28])=[CH:25][CH:24]=1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: C=C(C)C(=O)OC1(CC)C2CC3CC(C2)CC1C3
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: C=Cc1ccc(O)cc1
Reaction time: 20 h

Procedure:
Into a flask were charged 250 g of the copolymer of 2-ethyl-2-adamantyl methacrylate and p-acetoxystyrene (20:80) obtained in Synthesis Example 3, 10.3 g (0.084 mol) of 4-dimethylaminopyridine and 202 g of methanol, and aged for 20 hours under reflux. After cooling, the reaction liquid was neutralized with 7.6 g (0.126 mol) of glacial acetic acid and poured into a large amount of water to precipitate a polymer. The deposited polymer was filtrated, dissolved in acetone, then, poured into a large amount of water to cause precipitation, and this operation was repeated three times in total for purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH2:8]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C>ClCCl>[CH2:8]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH:22]([CH3:24])[CH3:23])[C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])[CH2:17][CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C(=O)CCCCl)C1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 34.5 %

Procedure:
A solution of 4-chlorobutyryl chloride (5.3 mL, 47.4 mmol) in dichloromethane (400 mL) was added dropwise to a mixture of 1-benzyl-4-(isopropylamino)piperidine (10 g, 43.07 mmol) and DIPEA (9.0 mL, 51.7 mmol) in dichloromethane (200 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then at room temperature for 2 h. The solution was then washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1) to give 5.0 g of the title intermediate as viscous oil (35% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]([NH2:19])[C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=1)(=[O:3])[CH3:2].[S:20]([O:25]C)([O:23][CH3:24])(=[O:22])=[O:21]>[N+](C1C=CC=CC=1)([O-])=O>[S:20]([O-:25])([O-:23])(=[O:22])=[O:21].[C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]([NH2:19])[C:9]3[C:14]([N+:15]=2[CH3:24])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=1)(=[O:3])[CH3:2].[C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]([NH2:19])[C:9]3[C:14]([N+:15]=2[CH3:24])=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)Nc1ccc2nc3ccccc3c(N)c2c1
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)Nc1ccc2c(c1)c(N)c1ccccc1[n+]2C
Product: O=S(=O)([O-])[O-]
Temperature: 140 °C
Yield: 102.4 %

Procedure:
300 cm3 of nitrobenzene are introduced into a 1-dm3 three-necked flask and then 11.2 g (0.0446 mol) of 2-acetamido-9-aminoacridine and 11 cm3 (0.116 mol) of dimethyl sulphate are successively introduced, with stirring. The mixture is then heated at 140° C. for 20 minutes. After cooling, the precipitate obtained is filtered, washed with 20 cm3 of nitrobenzene and six times 20 cm3 of diethyl ether, air-dried and 14.35 g (85%) of 2-acetamido-9-amino-10-methylacridinium sulphate are obtained.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]1[O:19][C:18]2[CH:17]=[CH:16][C:15]([N:20]=[C:21]=[O:22])=[CH:14][C:13]=2[O:12]1.C([O:25]CC)C>>[CH2:1]([N:8]1[C:9](=[O:25])[S:10][N:20]([C:15]2[CH:16]=[CH:17][C:18]3[O:19][CH2:11][O:12][C:13]=3[CH:14]=2)[C:21]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: O=C=Nc1ccc2c(c1)OCO2
Reactant: S=C=NCc1ccccc1
Product: O=c1sn(-c2ccc3c(c2)OCO3)c(=O)n1Cc1ccccc1

Procedure:
Reagents: Benzylisothiocyanate (6.5 mmol, 0.85 mL), 3,4-(methylendioxy)phenyl-isocyanate (6.5 mmol, 1.06 mL) and SO2Cl2 (6.5 mmol, 0.52 mL) in diethyl ether (25 mL). Isolation: filtration of reaction mixture. Purification: recrystallization from MeOH.
Reaction SMILES: [Si](OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(N3C4=NC=CC=C4C=C3)CCCC2)N=1)=O)(C(C)(C)C)(C)C.[CH2:45]([O:52][C:53]1[C:54]([C:75](O)=[O:76])=[N:55][C:56]([CH2:60][C:61]2([N:66]3[C:70]4=[N:71][CH:72]=[CH:73][CH:74]=[C:69]4[CH:68]=[CH:67]3)[CH2:65][CH2:64][CH2:63][CH2:62]2)=[N:57][C:58]=1[OH:59])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[Si:78]([O:85][CH2:86][CH2:87][NH:88][CH:89]([CH3:91])[CH3:90])([C:81]([CH3:84])([CH3:83])[CH3:82])([CH3:80])[CH3:79]>>[Si:78]([O:85][CH2:86][CH2:87][N:88]([CH:89]([CH3:91])[CH3:90])[C:75]([C:54]1[C:53]([O:52][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[C:58]([OH:59])[N:57]=[C:56]([CH2:60][C:61]2([N:66]3[C:70]4=[N:71][CH:72]=[CH:73][CH:74]=[C:69]4[CH:68]=[CH:67]3)[CH2:62][CH2:63][CH2:64][CH2:65]2)[N:55]=1)=[O:76])([C:81]([CH3:84])([CH3:83])[CH3:82])([CH3:80])[CH3:79]
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (409) was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (405) from 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (404) (250 mg, 0.56 mmol) and [2-(tert-tutyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (367 mg, 1.69 mmol) (8b) to get an off-white sticky solid (220 mg, 61%).