Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Hf:1].P(=O)(O)(O)O.[O:7]=[P:8]12[O:19]P3([O:20][P:10]([O:12]P(O3)([O:15]1)=O)(=[O:11])[O:9]2)=O>O>[O-:15][P:8]([O:9][P:10]([O-:20])([O-:12])=[O:11])(=[O:7])[O-:19].[Hf+4:1]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Reactant: [Hf]
Agent: O=P(O)(O)O
Solvent: O
Product: O=P([O-])([O-])OP(=O)([O-])[O-]
Product: [Hf+4]

Procedure:
By a second method of synthesis, a hafnium compound is reacted with phosphoric acid or P2O5 and water. The second method yields pure hafnium pyrophosphate that is substantially free of residual oxide. Residual oxide is always present as a second phase together with the pyrophosphates when the novel phosphors are prepared by the foregoing first method. In one embodiment of the second method, the synthesis is done by reacting hafnium oxychloride and phosphoric acid (or a solution of P2O5 and water). A mixture of hafnium oxychloride and phosphoric acid is first heated while stirring in a Teflon container on a hot plate. Then the mixture is transferred to a silica container. The container and contents are heated gradually to 1000° C. First, the temperature of the container is raised to 400° , then to 800° , and then to 1000° C, soaking the contents for a few hours at each of the mentioned temperatures. After the heat treatment at 1000° C, the material is cooled to room temperature, crushed and ground. Then, the ground material is heated in air at 1200° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(N(CC)CC)C>[CH3:29][S:30]([NH:1][CH2:2][C@@H:3]1[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][N:4]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CN)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CNS(C)(=O)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1

Procedure:
To a solution of (2S,4R)-2-aminomethyl-4-t-butyldimethylsilyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2 g) were successively added triethylamine (0.82 ml) and methanesulfonyl chloride (0.42 ml) under ice-cooling with stirring, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give (2S,4R)-2-methanesulfonylaminomethyl-4-t-butyldimethylsilyloxy-1-(4nitrobenzyloxycarbonyl)pyrrolidine (2.15 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][F:14])[CH:11]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:33]1[CH:34]=[N:35][C:36]([C:39]#[N:40])=[N:37][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][F:14])[CH:11]([C:15]2[CH:20]=[CH:19][C:18]([C:33]3[CH:34]=[N:35][C:36]([C:39]#[N:40])=[N:37][CH:38]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C(CF)C(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)OC1(C)C
Reactant: N#Cc1ncc(Br)cn1
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: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(CF)C(c2ccc(-c3cnc(C#N)nc3)cc2)OC1(C)C
Yield: 47.8 %

Procedure:
To the solution of 4-Fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-oxazolidine-3-carboxylic acid tert-butyl ester (1 g, 2.298 mmol, 1.0 eq) in toluene/water (3:1-24 mL) is added 5-Bromo-pyrimidine-2-carbonitrile (0.42 g, 2.282 mmol, 1.20 eq), Na2CO3 (0.48 g, 4.528 mmol) and degassed with nitrogen for 15 minutes followed by addition of Tetrakis(triphenylphosphine)palladium(0) (0.132 g, 0.114 mmol) and heated reaction mixture to 80° C. for 16 hours. Solvent is evaporated in vacuo to get the crude which is purified by column chromatography eluting from 10% ethyl acetate/hexane to give title compound (0.45 g): 1H-NMR (400 MHz, DMSO-d6) 1.43 (s, 9H), 1.51 (s, 3H), 1.63 (s, 3H), 3.85-3.92 (m, 1H), 4.47-4.59 (m, 1H), 4.76-4.96 (m, 1H), 5.17 (d, 1H, J=7.16), 7.67 (d, 2H, J=8.24 Hz), 7.96 (d, 2H, J=8.24 Hz), 9.40 (s, 2H).). m/z M−H 410.8.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C1COCC1>[Br:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:1]([CH2:10][C:9]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cc(Br)c2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1cc(N(Cc2ccccc2)Cc2ccccc2)nc2ccccc12
Reaction time: 0.5 h
Yield: 185.2 %

Procedure:
A solution of 2-amino-4-bromoquinoline (244 mg, 1.09 mmol) in THF (5 mL) at 0° C. was treated with NaH (96 mg, 60% dispersion in oil, 2.4 mmol), stirred for 30 min, treated with benzyl bromide (0.335 mL, 2.4 mmol), stirred at room temperature for 3 days, poured into water (30 mL), extracted with EtOAc (2×10 mL), dried (MgSO4), concentrated in vacuo, purified by chromatography [SiO2; heptane-EtOAc (10:1)] and the resulting solid recystallised (MeOH) to give the product (407 mg, 99%) as a white crystalline solid: IR νmax (Nujol)/cm−1 3059, 3020, 2955, 2925, 2854, 1609, 1592, 1542, 1498, 1455, 1426 and 1358; NMR δH (400 MHz, CDCl3) 4.89 (4H, s), 7.15 (1H, s), 7.20-7.68 (11H, m),7.56 (1H, t, J 7.0 Hz), 7.69 (1H, d, J 8.7 Hz) and 7.94 (1H, d, J 8.4 Hz).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=[C:17]2[CH:25]=O)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+](=[C:29](P(=O)(OC)OC)C(=O)C)=[N-].O>CO.C(OCC)(=O)C>[C:25]([C:17]1[N:16]([S:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:15])=[O:14])[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1)#[CH:29]
Reactant: O=Cc1cc2cccnc2n1S(=O)(=O)c1ccccc1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
Potassium carbonate (0.97 g, 6.98 mmol) was added to a suspension of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (1.00 g, 3.49 mmol) in methanol (1.0 mL), followed by the addition of a solution of dimethyl 1-diazo-2-oxopropylphosphonate (0.81 g, 4.19 mmol) in methanol (0.2 mL). The reaction mixture was stirred at room temperature for 2 hours, after which water was added, then ethyl acetate. The layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The crude was purified by flash chromatography to afford 2-ethynyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.40 g, 41%; purity 70%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:24]2[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15](C3C=CC=CC=3Cl)=[O:16])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC([C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[CH:56]=1)=O>>[C:1]([C:5]1[N:6]=[C:7]([N:24]2[CH2:28][CH2:27][C:26]([F:29])([F:30])[CH2:25]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]([C:55]3[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[CH:56]=3)=[O:16])[N:13]=2)[N:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC(=O)c3ccccc3Cl)nc2n1
Reactant: O=C(CBr)c1cccc(Cl)c1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC(=O)c3cccc(Cl)c3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 2-[5-tert-Butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl]-1-(2-chloro-phenyl)-ethanone (example 47), 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-bromo-1-(3-chlorophenyl)ethanone and isolated as yellow solid. MS (m/e): 435.3 (MH+).
Reaction SMILES: [Mg].BrCC[C@H](C)CCCC(C)C.BrC[C@@H](C)CCOC1CCCCO1.[CH3:26][C@H:27]([CH2:37][CH2:38][CH2:39][C@H:40]([CH3:47])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:28][CH2:29][O:30]C1CCCCO1>O1CCCC1>[CH3:26][C@H:27]([CH2:37][CH2:38][CH2:39][C@H:40]([CH3:47])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:28][CH2:29][OH:30]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCOC1CCCCO1
Agent: CC(C)CCC[C@@H](C)CCBr
Agent: C[C@H](CBr)CCOC1CCCCO1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCO
Reaction time: 3 h

Procedure:
A Grignard solution is prepared in the manner described above in Example 10 from 0.3 g (12.4 mmol) of magnesium and 2.54 g (11.5 mmol) of (R)-1-bromo-3,7-dimethyloctane in 10 ml of absolute tetrahydrofuran. To this solution are added dropwise at 0° 1.45 g (5.57 mmol) of 2-[(S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran followed by 0.3 ml of a 0.1 molar solution of Li2CuCl4 in tetrahydrofuran. This reaction mixture is stirred at 0° for 3 hours. The working-up as well as the hydrolysis of the tetrahydro-2-{[(3R,7R)-3,7,11-trimethyldodecyl]-oxy}-2-H-pyran obtained to (3R,7R)-3,7,11-trimethyl-1-dodecanol is effected in the manner described above in Example 10. The yield of (3R,7R)-3,7,11-trimethyl-1-dodecanol amounts, after bulb-tube distillation at 90°-95°/0.05 Torr, to 0.5 g (43% based on 2-[ (S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran); [α]D20 =+3.9° (c=1.05, n-octane).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@H:14]2[C@@H:19]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:21])[CH2:18][CH2:17][NH:16][CH2:15]2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:33]1[CH2:35][C@@H:34]1[CH2:36][O:37][C:38]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:39]=1[CH:40]=[CH:41][CH:42]=[N:43]2>C(O)(C)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@H:14]2[C@@H:19]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:21])[CH2:18][CH2:17][N:16]([CH2:35][C@@H:34]([OH:33])[CH2:36][O:37][C:38]3[CH:47]=[CH:46][CH:45]=[C:44]4[C:39]=3[CH:40]=[CH:41][CH:42]=[N:43]4)[CH2:15]2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Reactant: O=C(NCCCCc1ccccc1)[C@H]1CCNC[C@H]1C(=O)NCCCCc1ccccc1
Solvent: CC(C)O
Product: O=C(NCCCCc1ccccc1)[C@H]1CCN(C[C@@H](O)COc2cccc3ncccc23)C[C@H]1C(=O)NCCCCc1ccccc1
Temperature: 70 °C
Yield: 82.8 %

Procedure:
cis-Piperidine-3,4-dicarboxylic acid bis[(4-phenyl-butyl)-amide] (9) (70.9 mg; 0.163 mmol) is dissolved in isopropanol (10 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (32.8 mg; 0.163 mmol) is added then the mixture is heated to 70° C. and maintained for 18 hours. After cooling to ambient temperature the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (0%→50% methanol in methylene chloride) affording the desired product (86.0 mg) as an oil. ESMS: MH+ 637.4 (base).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1ccc(-c2cc3ccc(O)cc3s2)cc1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Oc1ccc(-c2cc3ccc(OC(=O)c4ccccc4)cc3s2)cc1)c1ccccc1

Procedure:
2-(4-Hydroxyphenyl)-6-hydroxybenzo[b]thiophene and benzoyl chloride were converted to the title compound by the procedure of Example 3 to yield a white crystalline solid. mp 216° C.-218° C.
Reaction SMILES: C(N([CH:7]([CH3:9])[CH3:8])CC)(C)C.CS(O[CH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:19]=[O:20])(=O)=O.[CH3:32][N:33]([CH3:36])C=O>>[C:26]1([CH2:25][O:24][C:23]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][C:16]=2[CH2:15][N:33]2[CH2:36][CH2:19][CH:18]([CH2:21][C:8]3[CH:7]=[CH:9][CH:23]=[CH:16][CH:15]=3)[CH2:17][CH2:32]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CS(=O)(=O)OCc1cc(C=O)ccc1OCc1ccccc1
Reactant: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(CN2CCC(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(phenylmethyl)piperidinyl (200 mg) and diisopropylethylamine (130 mg) in dimethylformamide (1 ml) was added 3-[[(methylsulfonyl)oxy]methyl]-4-phenylmethoxybenzaldehyde (320 mg). After stirring at room temperature for 3 hours the reaction mixture was partially concentrated under reduced pressure and the residue was purified by flash column chromatography using petroleum ether:diethyl ether (1:1) as eluant. The pure fractions were combined and evaporated under reduced pressure to give 4-phenylmethoxy-3-[[4-(phenylmethyl)-1-piperidinyl]-methyl]benzaldehyde (170 mg) as a gum. 1H NMR (CDCl3) δ9.95 (s, 1H, CHO); 5.20 (s, 2H); 3.68 (s, 2H). TLC (silica gel): Rf=0.2 (dichloromethane: diethyl ether, 3:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([NH:17][C:18](=O)[C:19]([F:22])([F:21])[CH3:20])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:45]>>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([N:17]=[C:18]([Cl:45])[C:19]([F:22])([F:21])[CH3:20])[CH:5]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(NC(=O)C(C)(F)F)cc(-c2ccc(C)cn2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1cc(N=C(Cl)C(C)(F)F)cc(-c2ccc(C)cn2)c1
Temperature: 95 °C
Reaction time: 48 h

Procedure:
3-(2,2-Difluoro-propionylamino)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (0.630 g, 1.88 mmol) and triphenyl phosphine (0.989 g, 3.77 mmol) were added to 15 mL of CCl4. The reaction mixture was heated to 95° C. and stirred under nitrogen for 48 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 0.612 g of 3-(1-chloro-2,2-difluoro-propylideneamino)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester, which was used directly in the next step without further purification.
Reaction SMILES: [CH:1]1[N:6]=[C:5]([NH2:7])[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][O:17]P(O)(O)=O)[C@@H:13]([OH:22])[C@H:12]3[OH:23])[C:3]=2[N:2]=1.[NH2:24][C@H:25]([C:36]([OH:38])=[O:37])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1.CO.CC(C)=O>O>[C@@H:11]1([N:10]2[C:3]3[N:2]=[CH:1][N:6]=[C:5]([NH2:7])[C:4]=3[N:8]=[CH:9]2)[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:22])[C@H:12]1[OH:23].[NH2:24][C@H:25]([C:36]([OH:38])=[O:37])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
1 mol adenosine-5'-monophosphoric acid is dissolved in 5 parts water. Separately, 2 mols tryptophane are dissolved in 5 parts water. Thereafter, the solution of the amino acid is poured into 9 parts of a 2:1 mixture of methanol and acetone. To this mixture the solution of the nucleotide is slowly added. A. precipitate forms. This precipitate is filtered off and dried at 60°C. Then the precipitate is suspended in water. To the suspension the exact amount of NaOH is added to neutralize the free carboxylic groups of the tryptophane. The precipitate dissolves. The solution is evaporated under reduced pressure, and a white crystalline powder is obtained, which consists of adenosine-5'-monophosphoric acid-(Na-tryptophanate)2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].[NH4+].[Cl-]>CCOCC.CCCCC>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCC
Product: CCOC(=O)C(=O)c1ccccc1OC
Reaction time: 0.75 h

Procedure:
A solution of 27 g of 1-bromo-2-methoxybenzene in 270 ml of ether is cooled to −70° C. under an argon atmosphere, 90 ml of a 1.6 M solution of n-butyllithium in pentane are added dropwise and the mixture is then left stirring for 45 minutes. 78 ml of diethyl oxalate are added rapidly and the mixture is left stirring, while allowing the temperature to return to RT. After stirring for 1 hour at RT, saturated NH4Cl solution is added to the mixture, the phases are separated after settling has taken place, the aqueous phase is extracted with ether, the combined organic phases are washed with water and then with saturated NaCl solution and dried over Na2SO4, and the solvents are evaporated off under vacuum. The excess diethyl oxalate is removed by distillation under vacuum (b.p.=87° C. at 2 000 Pa). The resulting product is chromatographed on silica gel, eluting with a DCM/hexane mixture (50/50; v/v) and then with DCM. The product obtained is purified by distillation under vacuum. 13 g of the expected product are obtained; b.p.=110° C. at 3 Pa.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:12])=[N:9][C:10]=1[CH3:11])[CH3:2].[F:13][C:14]([F:26])([F:25])[C:15]1[CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>>[CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:12][S:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:25])[F:26])[CH:16]=2)(=[O:23])=[O:22])=[N:9][C:10]=1[CH3:11])[CH3:2]
Reactant: CCOCc1ccc(N)nc1C
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CCOCc1ccc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)nc1C

Procedure:
This material was prepared in analogy to example 1 from 5-Ethoxymethyl-6-methyl-pyridin-2-ylamine (0.066 g) and 3-(trifluoromethyl)-benzenesulfonyl chloride (0.108 g) as a light yellow solid (0.115 g). MS (ESI−): 373.1 ([M−H]−)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([SH:14])[CH:4]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)#[N:16]>N1C=CC=CC=1>[CH3:13][O:12][C:11]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[S:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:16][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: N#Cc1ccccn1
Reactant: COc1cc(S)c(C(=O)O)cc1OC
Solvent: c1ccncc1
Product: COc1cc2sc(-c3ccccn3)nc(=O)c2cc1OC
Yield: 55.5 %

Procedure:
A mixture of 4,5-dimethoxy-2-mercaptobenzoic acid (2.20 g, 10.2 mmol), 2-cyanopyridine (1.10 g, 10.2 mmol) and pyridine (15.0 ml) was refluxed for 20 hrs as described in Example 9. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-chlorobenzene to give the titled compound (1.70 g, 55%).
Reaction SMILES: NC[C:3]([OH:5])=[O:4].N[C@H](C(O)=O)C.[NH2:12][C@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15].N[C@H](C(O)=O)[CH2:22][CH:23]([CH3:25])[CH3:24].N[C@H](C(O)=O)CCCCN>>[C:23]([O:5][C:3]([NH:12][C@@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:4])([CH3:25])([CH3:24])[CH3:22]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: NCC(=O)O
Reactant: CC(C)[C@H](N)C(=O)O
Agent: C[C@H](N)C(=O)O
Agent: NCCCC[C@H](N)C(=O)O
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
2Thr, 1.88; Ser, 1.22; Gly, 1.06; Ala, 1.17; Val, 1.05; Leu, 1.17; 2Phe, 2.24; 2 Lys, 2.00.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C:8]([CH2:17][NH2:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[F:19]C1C=CC=CC=1CC#N>>[C:1]([N:5]1[CH2:6][CH2:7][C:8]([CH2:17][NH2:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:19])[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCc1ccccc1F
Reactant: CC(C)(C)N1CCC(CN)(c2ccccc2)CC1
Product: CC(C)(C)N1CCC(CN)(c2ccccc2F)CC1

Procedure:
The title material was prepared as described in the synthesis of (1-tert-butyl-4-phenylpiperidin-4-yl)methanamine (Synthesis of amines, Example H) using 2-(2-fluorophenyl)acetonitrile.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][O:8][C@H:7]([CH2:11][NH:12][C:13]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][N:21]=3)[CH:16]=[C:15]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[N:14]=2)[CH2:6]1)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].I[CH2:42][CH3:43]>CN(C=O)C.CC(=O)OCC>[CH2:42]([N:32]1[CH2:33][CH2:34][CH:29]([C:26]2[CH:25]=[CH:24][C:23]([C:15]3[N:14]=[C:13]([NH:12][CH2:11][C@H:7]4[O:8][CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6]4)[C:22]4[C:17](=[N:18][CH:19]=[CH:20][N:21]=4)[CH:16]=3)=[CH:28][CH:27]=2)[CH2:30][CH2:31]1)[CH3:43]
Reactant: CS(=O)(=O)N1CCO[C@H](CNc2nc(-c3ccc(C4CCNCC4)cc3)cc3nccnc23)C1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN1CCC(c2ccc(-c3cc4nccnc4c(NC[C@@H]4CN(S(C)(=O)=O)CCO4)n3)cc2)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of (R)—N-((4-(methylsulfonyl)morpholin-2-yl)methyl)-7-(4-(piperidin-4-yl)phenyl)pyrido[4,3-b]pyrazin-5-amine in (39.5 mg, 0.082 mmol) in DMF (5 mL) was added K2CO3 (22.6 mg, 0.164 mmol) and iodoethane (25.5 mg, 0.164 mmol) at room temperature. The reaction was stirred at 100° C. for 18 hours. After that, the reaction was dissolved in 50 mL of EA, washed with H2O (25 mL) and brine (25 mL), dried over Na2SO4 and concentrated, purified on TLC (CH2Cl2:MeOH=20:1) to give yellow solid. MS (m/z): 511 (M+H)+