Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:15][CH:14]2[CH2:16][CH2:17][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([N+:18]([O-])=O)=[CH:10][CH:9]=3)[CH2:6]1)=[O:4]>CO.C(O)(=O)C.[Pd]>[NH2:18][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]1[CH2:17][CH2:16][CH:14]2[CH2:15][N:5]([C:3](=[O:4])[C:2]([F:22])([F:1])[F:21])[CH2:6]1
Reactant: O=C(N1CC2CCC(C1)c1cc([N+](=O)[O-])ccc12)C(F)(F)F
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc2c(c1)C1CCC2CN(C(=O)C(F)(F)F)C1
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
2,2,2-Trifluoro-1-(4-nitro-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-ethanone (1.227 g, 3.91 mmol) was placed in methanol (100 mL) and acetic acid (1 mL). 10% Palladium on carbon (6.8 mg) was then added. The reaction was hydrogenated at 20 psi for 30 minutes. The mixture was then filtered through celite and concentrated under reduced pressure to obtain 1-(4-amino-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-2,2,2-trifluoro-ethanone as a brown oil (1.110 g, 100%). LCMS (m/e) 285 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 6.92 (dd, 1H, J=8.0 and 10.9 Hz), 6.60-6.50 (m, 2H), 4.23-4.10 (m, 1H), 3.90-3.75 (m, 1H), 3.46-3.25 (m, 2H), 3.15-3.00 (m, 2H), 2.03-1.91 (m, 2H), 1.80-1.70 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:2].[H-].[Na+].Br[CH2:17][CH2:18]Cl>CS(C)=O>[C:1]([C:3]1([C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:18][CH2:17]1)#[N:2]
Reactant: ClCCBr
Reactant: COC(=O)c1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc(C2(C#N)CC2)c1
Reaction time: 18 h
Yield: 68 %

Procedure:
To a solution of methyl 3-(cyanomethyl)benzoate 1 (2 g, 11.4 mmol) in DMSO (30 mL) was added NaH (60%, 913 mg, 23 mmol) in one portion. 1-bromo-2-chloroethane (1.164 mL, 11.4 mmol) was added slowly at 0° C. and stirring continued for 18 h at 25° C. The reaction was quenched with water, extracted with EtOAc, dried, and evaporated. Compound dissolved again in EtOAc and washed with NaHCO3 solution, brine, dried and concentrated to affording methyl 3-(1-cyanocyclopropyl)benzoate 33 (1.56 g, 68%). NMR (400 MHz, CDCl3) 1.47 (m, 2H), 1.78 (m, 2H), 3.93 (s, 3H), 7.45 (t, J=7.8 Hz, 1H), 7.59 (m, 1H), 7.88 (t, J=1.6 Hz, 1H), 7.97 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[C:12](Cl)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1.Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[C:13]1([C:12]2[O:1][C:2]3[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=3)[N:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1c(O)cccc1C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(O)c1cccc2oc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
To a suspension of 3-hydroxyanthranilic acid (0.300 g, 1.96 mmol) in toluene (10 mL) was added benzoyl chloride (0.830 g, 5.90 mmol) followed by pyridine (0.545 g, 6.92 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 min then heated to 80° C. for 1 hr. After this time the reaction was cooled and poured into a mixture of ethyl acetate (50 mL) and 5% aqueous hydrochloric acid (50 mL). Subsequent separation of the layers, drying the organic over MgSO4 and filtration afforded an orange solution. This solution was concentrated to an orange solid which was directly re-dissolved in xylenes (20 mL) and the solution treated with p-toluenesulfonic acid (0.800 g, 4.20 mmol). The reaction mixture was then heated to reflux for 6 hrs. After this time the reaction was cooled and poured into water (50 mL), the organic layer separated then washed with water (3×50 mL). The organic was dried over MgSO4, filtered and concentrated to an orange/brown solid. Re-crystallization of this solid from ethyl acetate afforded 0.412 g (88% yield) of 2-phenylbenzoxazole-4-carboxylic acid as a light yellow solid: 1H NMR (300 MHz, CD3OD) δ 11.58 (br s, 1H), 8.30 (m, 2H), 8.17 (dd, J=7.8, 0.8 Hz, 1H), 7.83 (dd, J=8.2, 0.8 Hz, 1H), 7.69-7.45 (m, 4H); MS (APCI) m/z 240 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1)[CH3:2].[CH2:15](O)[CH2:16][OH:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.CCCCCC>C1(C)C=CC=CC=1>[CH2:16]1[O:17][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])=[CH:6][CH:7]=2)([CH3:12])[O:13][CH2:15]1
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(C2(C)OCCO2)cc1
Temperature: 25 °C

Procedure:
9.61 g of 4-acetylbenzoic acid ethyl ester (supplied from the firm Wako Pure Chem. Ind.) were dissolved in 200 ml of toluene and thereto were added 20 ml of ethylene glycol and 200 mg of p-toluenesulfonic acid hydrate under argon atmosphere, whereupon the mixture was heated under reflux for 24 hours on Dean-Stark apparatus while removing water. The reaction mixture was then cooled down to room temperature and the toluene layer was washed with water (twice with each 100 ml) and, then, with saturated aqueous sodium chloride solution (100 ml), followed by drying and evaporation to dryness under a reduced pressure, whereby the above-identified compound (12.76 g ) was obtained. Rf=0.58 (ethyl acetate/n-hexane of 1/2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH2:25]([O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH3:26].COC(=O)C(OC)C(C1C=CC=C(OCC2C=CC=CC=2)C=1)O>>[CH2:32]([O:31][C:29](=[O:30])[CH:28]([O:27][CH2:25][CH3:26])[CH:13]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)[OH:14])[CH3:33]
Reactant: CCOCC(=O)OCC
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: COC(=O)C(OC)C(O)c1cccc(OCc2ccccc2)c1
Agent: [Li+]
Product: CCOC(=O)C(OCC)C(O)c1ccc(OCc2ccccc2)cc1

Procedure:
The title compound was prepared from 4-benzyloxybenzaldehyde, lithium diisopropylamide and ethyl 2-ethoxyacetate via the same procedure used for the preparation of 3-(3-benzyloxy-phenyl)-3-hydroxy-2-methoxy propionic acid methyl ester (example 9, step 1). MS (ES) for C20H24O5 [M+H2O—H]+: 327, [M+Na]+: 367.4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[CH:19][CH:18]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:16]=1>>[C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:21]([C:17]2[CH:16]=[C:15]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:23])=[O:22])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1cccc(-c2ccccc2)c1
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2cccc(-c3ccccc3)c2)c1

Procedure:
Starting from (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1) and art-known 3-biphenylsulphonylchloride the title compound can be obtained analogously or similarly as described for compound C1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:7]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]([OH:35])[CH2:25][N:26]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=3)=[O:15])[C:6]=2[CH:36]=1.N1C=CC=CC=1.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[CH2:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:36][C:6]=2[C:7]=1[C:14](=[O:15])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]([OH:35])[CH2:25][N:26]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:18][CH:17]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1oc2ccc(N)cc2c1C(=O)c1ccc(OCC(O)CN(CCCC)CCCC)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCC(O)CN(CCCC)CCCC)cc1
Temperature: 32.5 °C
Reaction time: 2 h

Procedure:
0.3 g of (5-amino-2-butyl-1-benzofuran-3-yl) {4-[3-(dibutylamino)-2-hydroxy-propoxy]-phenyl}methanone (III) was dissolved in 10 ml of dichloromethane. The solution was warmed to 30-35° C. and 0.06 g of pyridine was added at this temperature. After this 0.093 g of methanesulfonyl chloride was added and the mixture was stirred at 30-35° C. for 2 hours. The mixture was cooled to 20-25° C., washed with 2×15 ml of water, 2×15 ml of sodium hydrogencarbonate solution of 5%, 1×15 ml of water. The phases were sepatated and the dichloromethane phase was evaporated.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([NH2:6])=[O:5])[CH2:2]1.[C:10](OC([O-])=O)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>>[C:13]([O:12][C:10]([N:1]1[CH2:9][CH2:8][CH2:7][C@@H:3]([C:4]([NH2:6])=[O:5])[CH2:2]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: NC(=O)C1CCCNC1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
To the reaction mixture obtained in Example 4, tert-butyl dicarbonate (16.1 g, 1.0 equivalent) was added. The pH of the reaction mixture was kept from 7.0 to 8.0. The reaction mixture was stirred for 3 hours at room temperature to obtain a solution containing (R)-1-(tert-butoxycarbonyl)nipecotamide (6.6 g, yield: 39%).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:29][CH2:28][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:27])[CH2:14][CH2:13]2)=[O:8])=[C:5]([N+:32]([O-])=O)[CH:4]=1.CO.[H][H]>[Ni].O>[OH2:8].[ClH:1].[NH2:32][C:5]1[CH:4]=[C:3]([F:2])[CH:31]=[CH:30][C:6]=1[C:7]([NH:9][CH2:10][CH2:11][N:12]1[CH2:29][CH2:28][C:15]2([N:19]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH2:18][NH:17][C:16]2=[O:27])[CH2:14][CH2:13]1)=[O:8]
Reactant: O=C(NCCN1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1)c1ccc(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: O
Product: Nc1cc(F)ccc1C(=O)NCCN1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1

Procedure:
A mixture of 8 parts of 4-fluoro-N-{2-[1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4,5]dec-8-yl]ethyl}-2-nitrobenzamide hydrochloride, 120 parts of methanol and 25 parts of water is hydrogenated at normal pressure and at room temperature with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from methanol. The product is filtered off and recrystallized from ethanol, yielding 1 part of 2-amino-4-fluoro-N-{2-[1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4,5]dec-8-yl]ethyl}benzamide hydrochloride hydrate; mp. 223.5° C.
Reaction SMILES: ClCC([NH:5][C:6]1[CH:28]=[CH:27][CH:26]=[CH:25][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)=[O:9])=O.ClCC(Cl)=O>>[NH2:5][C:6]1[CH:28]=[CH:27][CH:26]=[CH:25][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: O=C(CCl)Nc1ccccc1C(=O)N1CCN(CCc2ccc(Cl)cc2)CC1
Agent: O=C(Cl)CCl
Product: Nc1ccccc1C(=O)N1CCN(CCc2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to that described in Example 22, 1-[2-(N-chloroacetylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine having a melting point of 108°-109° is obtained from 2 g of 1-(2-aminobenzoyl)-4-[2-(4-chlorophenyl)ethyl]-piperazine by reaction with chloroacetyl chloride.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[N:8]=[N:7]1)C.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Cl:17][C:14]1[N:13]=[CH:12][C:11]([C:9]2[N:8]=[N:7][N:6]([CH2:5][CH2:4][OH:3])[CH:10]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)Cn1cc(-c2ccc(Cl)nc2)nn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCCn1cc(-c2ccc(Cl)nc2)nn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl[4-(6-chloropyridin-3-yl)-1H-1,2,3-triazol-1-yl]acetate (150 mg, 0.56 mmol) (Example 413, Step 2) was taken up in THF (2.8 ml) and cooled to 0° C. Diisobutyl aluminum hydride (1.7 ml of 1.0M in hexanes, 1.7 mmol) was added dropwise over 15 minutes, and the reaction was maintained at 0° C. for 30 minutes. The reaction was allowed to warm to room temperature and maintained at room temperature for 20 hours. The mixture was then quenched with saturated aqueous potassium sodium tartrate and stirred for 2 hours. Ethyl acetate (10 mL) was added, and the mixture was stirred for 1 hour, after which product was extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography (0-5% methanol/ethyl acetate) to afford the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:7]2[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:4]([CH:5]=[CH:6]2)[CH:3]1[C:16]([O:18][CH3:19])=[O:17]>[Pd].CO>[O:1]=[C:2]1[CH:7]2[N:8]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH:4]([CH2:5][CH2:6]2)[CH:3]1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1C(=O)C2C=CC1N2C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1C(=O)C2CCC1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 7-tert-butyl 2-methyl 3-oxo-7-azabicyclo[2.2.1]hept-5-ene-2,7-dicarboxylate (50 g, 187.07 mmol, 1.00 equiv), MeOH (500 mL), and Pd/C (5 g, 10%) was stirred overnight at room temperature under a hydrogen atmosphere. The reaction was filtered, and the filtrate was concentrated under vacuum to afford 7-tert-butyl 2-methyl 3-oxo-7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[F:25][C:26]([F:38])([F:37])[O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:25][C:26]([F:37])([F:38])[O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[N:4][C:5]([NH:8][C:9]3[CH:24]=[CH:23][C:12]([CH2:13][N:14]4[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]4)=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:30][CH:29]=1
Reactant: O=C(O)C1CCN(Cc2ccc(Nc3ncc(Br)cn3)cc2)CC1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)C1CCN(Cc2ccc(Nc3ncc(-c4ccc(OC(F)(F)F)cc4)cn3)cc2)CC1
Temperature: 150 °C

Procedure:
To a solution of 1-(4-(5-bromopyrimidin-2-ylamino)benzyl)piperidine-4-carboxylic acid 17 (0.05 mmol) in 1,4-dioxane (1.0 mL) is added 4-(trifluoromethoxy)phenylboronic acid (0.05 mmol), 3M Na2CO3 (0.15 mmol) and Pd(PPh3)4 (0.0025 mmol). The reaction is evacuated and backfilled with nitrogen twice then heated at 150° C. for 10 min. Purification by preparative HPLC (ACN gradient 10-70%) affords 1-(4-(5-(4-(trifluoromethoxy)phenyl)pyrimidin-2-ylamino)benzyl)piperidine-4-carboxylic acid A5. 1H NMR (400 MHz, d6-DMSO) δ 10.06 (s, 1H), 8.89 (s, 2H), 7.88 (M, 4H), 7.48 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 4.23 (s, 2H), 2.95 (m, 1H), 2.51 (m, 4H), 2.09 (m, 2H), 1.71 (m, 2H). MS (m/z) (M+1)+: 473.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])([O-:3])=[O:2].[H-].[Na+].[CH2:22](Br)[C:23]#[CH:24].C1(C)C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:24][C:23]#[CH:22])([O-:3])=[O:2]
Reactant: C#CCBr
Reactant: O=[N+]([O-])c1ccc(NCCOCCO)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCOCCOCCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
2-(2-(2,4-dinitrophenylamino)ethoxy)ethanol (s-1b) (100 mg, 0.369 mmol, 1.0 equiv.) was dissolved in 0.81 mL of DMF and slowly added to a slurry of NaH (17.71 mg, 0.738 mmol, 2.0 equiv.) in 0.81 mL of DMF in a flame dried flask pre-cooled to 0° C. An 80% solution of propargyl bromide in toluene (0.049 □L, 0.443 mmol, 1.2 equiv.) was added slowly. The ice bath was then removed and the reaction was allowed to stir at room temperature for an additional 2 hours. The reaction was then re-cooled to 0° C., quenched with saturated NH4Cl, and then extracted with diethyl ether (3×50 mL). The organic layers were combined, dried with Na2SO4, concentrated under reduced pressure, and chromatographed (silica gel, 3×25 cm, 0% EtOAc in hexanes, then 10% EtOAc in hexanes, then 20% EtOAc in hexanes, then 30% EtOAc in hexanes) to yield 2,4-dinitro-N-(2-(2-(prop-2-ynyloxy)ethoxy)ethyl)aniline (s-2b) as a dark yellow solid (50 mg, 45% yield). IR (thin film) 3360 (m), 3285 (m), 3107 (w), 2872 (m), 1621 (s), 1588 (m), 1524 (m), 1425 (w), 1335 (s), 1305 (m), 1133 (m), 1101 (m), 920 (w), 832 (w); 1H NMR (500 MHz, CDCl3) δ 9.15 (d, J=2.6 Hz, 1H), 8.81 (bs, 1H), 8.27 (dd, J=9.4, 2.3 Hz, 1H), 6.96 (d, J=9.5 Hz, 1H), 4.21 (d, J=2.3 Hz, 2H), 3.84 (t, J=5.2 Hz, 2H), 3.74 (m, 4H), 3.61 (q, J=5.2 Hz, 2H), 2.44 (t, J=2.3 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 148.6, 136.3, 130.7, 130.4, 124.4, 114.2, 79.6, 74.9, 70.7, 69.3, 68.9, 58.7, 43.4. HRMS (ES+) calc'd for C13H15N3O6 (M+H) m/z 310.0994 Found 310.1033.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.C(C(CCCC)COC(=O)CC[SH:28])C.C(C(CCCC)COC(=S)CCC1C=CC=C(C(=O)C)C=1)C.[O-]CC.[Na+]>O1CCOCC1.O1CCCC1.C(O)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O>[SH:28][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: CCCCC(CC)COC(=O)CCS
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: CCCCC(CC)COC(=S)CCc1cccc(C(C)=O)c1
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)c1cccc(S)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A solution of 3′-bromoacetophenone (10 g, 50 mmol), N,N-diisopropylethylamine (18 mL, 0.10 mol), 3-mercaptopropionic acid 2-ethylhexyl ester (11 mL, 48 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.29 g, 0.50 mmol) and tris(dibenzylideneacetone)palladium(0) (0.46 g, 0.50 mmol) in 1,4-dioxane (250 mL) was stirred at 100° C. for 2 days. After the reaction solution was filtered with celite, the filtrate was concentrated in vacuo until the volume became one third approximately. Water (200 mL) was added thereto, extracted with ethyl acetate (200 mL). The organic layer was washed with brine (200 mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give a mixture including 3-(3-acetylphenyl)thiopropionic acid 2-ethylhexyl ester (19 g). This mixture (17 g) was dissolved in tetrahydrofuran (200 mL), sodium ethoxide (7.0 g, 0.10 mol) in ethanol (40 mL) was added thereto, and then the whole was stirred at 50° C. for 2 hours. Water (200 mL) was added to the reaction solution and washed with ethyl acetate (200 mL). 1N Hydrochloric acid (100 mL) was added to the aqueous layer and extracted with ethyl acetate (300 mL), then the organic layer was washed with brine (100 mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title reference compound (6.2 g) as a brown oil (Yield 81%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:46]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(Cl)c(CBr)c1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cc(F)ccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1-chloro-4-fluorobenzene and isolated as light-yellow gum. MS (m/e): 425.3 (MH+).
Reaction SMILES: [OH-].[K+].C([O:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[N:15]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][N:30]2[C:35]([CH3:37])([CH3:36])[CH2:34][CH:33]([O:38]C(=O)C3C=CC=CC=3)[CH2:32][C:31]2([CH3:48])[CH3:47])[C:14]([CH3:50])([CH3:49])[CH2:13]1)(=O)C1C=CC=CC=1>C(O)C>[OH:38][CH:33]1[CH2:34][C:35]([CH3:37])([CH3:36])[N:30]([O:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][N:15]2[C:14]([CH3:50])([CH3:49])[CH2:13][CH:12]([OH:11])[CH2:17][C:16]2([CH3:19])[CH3:18])[C:31]([CH3:48])([CH3:47])[CH2:32]1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OCCCCCCCCON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(O)CC(C)(C)N1OCCCCCCCCON1C(C)(C)CC(O)CC1(C)C

Procedure:
The title compound is prepared by basic hydrolysis (potassium hydroxide in ethanol) of the compound prepared in Example 23A.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1([CH3:25])[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[C:15]([CH3:25])([CH3:14])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1(C)Cc2ccccc2CN1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1(C)Cc2ccccc2CN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3,3-dimethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C([O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[C:7]([OH:19])[CH:6]=1)C=C.Cl[C:21]1[CH:26]=CC=C[C:22]=1Cl>>[OH:19][C:7]1[C:6]([CH2:26][CH:21]=[CH2:22])=[C:5]([OH:4])[CH:18]=[CH:17][C:8]=1[C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: C=CCOc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: Clc1ccccc1Cl
Product: C=CCc1c(O)ccc(C(=O)c2ccccc2)c1O

Procedure:
Commercially available 4-allyloxy-2-hydroxybenzophenone (15 g) was rearranged by heating under reflux in ortho-dichlorobenzene (60 mL) for 26 hours. The product was isolated by dilution of the reaction mixture with 5 volumes hexanes to give a crystalline product as fine needles.