Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28]>C(Cl)Cl>[C:1]12([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][N:17]([CH2:18][CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=4)[C:27]3=[O:28])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: c1cc(CCCNCCCNCCC23CC4CC(CC(C4)C2)C3)ccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C1N(CCCc2ccncc2)CCCN1CCC12CC3CC(CC(C3)C1)C2
Reaction time: 0.33 h
Yield: 9.1 %

Procedure:
A solution of the obtained N-[2-(1-adamantyl)ethyl]-N′-[3-(4-pyridyl)propyl]-1,3-propanediamine (80 mg, 0.23 mmol) in anhydrous methylene chloride (10 ml) and a solution of 1,1′-carbonyldiimidazole (40 mg, 0.26 mmol) in anhydrous methylene chloride (10 ml) were simultaneously added dropwise to anhydrous methylene chloride (60 ml) at room temperature with stirring over 20 minutes. The mixture was stirred overnight, then the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the target compound (8.0 mg, 9.4%).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[NH2:11][CH2:12][CH:13]([OH:15])[CH3:14].C(N(CC)CC)C>ClCCl>[OH:15][CH:13]([CH3:14])[CH2:12][NH:11][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: CC(O)CN
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O)CNC(=O)c1ccncc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
289 g isonicotinoyl chloride hydrochloride was added to 128 g 1-amino-propan-2-ol and 549 mL triethylamine in 2 L dichlormethane at 0° C. The reaction was stirred for 30 min. at 0° C. and then the solvent was removed. The residue was suspended in ethyl acetate and the precipitate was filtered. The filtrate was recrystallized from ethyl acetate to give 154 g of the desired product. Rf: 0.4 (DCM/MeOH=20/1), (M+H)+: 181
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:5]=[C:6]([F:14])[C:7]([N+:11]([O-:13])=[O:12])=[C:8](F)[CH:9]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]([F:14])[C:7]([N+:11]([O-:13])=[O:12])=[C:8]([NH:2][CH3:1])[CH:9]=1
Reactant: O=[N+]([O-])c1c(F)cc(Br)cc1F
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CNc1cc(Br)cc(F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2 M MeNH2 in THF (82 mL) was added dropwise to a solution of 5-bromo-1,3-difluoro-2-nitrobenzene (164 mmol) and Cs2CO3 (197 mmol) in THF (1 L). The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 1 h. The solvent was removed under reduced pressure. The residue was partitioned between EtOAc and H2O. The two phases were separated and the organic layer was dried (Na2SO4) and concentrated to afford the desired product.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([CH3:27])=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]=2[CH3:21])[NH:12][C:11]1=[O:28].[CH2:29]([N:31]([CH2:36][CH3:37])[C:32](=[O:35])[CH2:33]Cl)[CH3:30]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([CH3:27])=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]=2[CH3:21])[N:12]([CH2:33][C:32]([N:31]([CH2:36][CH3:37])[CH2:29][CH3:30])=[O:35])[C:11]1=[O:28]
Reactant: CCN(CC)C(=O)CCl
Reactant: CCOC(=O)c1c(C)cc2[nH]c(=O)n(-c3ccccc3Cl)c(=O)c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)cc2c(c1C)c(=O)n(-c1ccccc1Cl)c(=O)n2CC(=O)N(CC)CC
Temperature: 80 °C
Reaction time: 3 h
Yield: 56.6 %

Procedure:
A portion (30 mg) of sodium hydride suspension (50%) in mineral oil was added to a stirred solution of 3-(2-chlorophenyl)-6-ethoxycarbonyl-5,7-dimethyl-2,4-(1H, 3H)-quinazolinedione (187 mg) in dimethylformamide (10 ml). After addition of N,N-diethyl-chloroacetamide (80 mg), the mixture was stirred at 80° C. for 3 hours. The solvent was evaporated off at reduced pressure, and the residue was extracted with CHCl3. The CHCl3 extract was washed with water, dried over NaSO4 and concentrated. The residue was recrystallized from methanol to give 3-(2-chlorophenyl)-6-ethoxycarbonyl-5,7-dimethyl-1-(N,N-diethyl)aminocarbonylmethyl-2,4(1H, 3H)-quinazolinedione (138 mg, 57%) melting at 228°-229° C. MS: M/e, 485(M+), 450. NMR: δ (ppm, CDCl3), 1.38 (9H, m), 2.39 (3H, s), 2.72 (3H, s), 3.45 (4H, q), 4.40 (2H, q), 4.95 (2H, d), 6.75 (1H, s), 7.40 (4H, m).
Reaction SMILES: C(OC(N1C[C@H](OC2C=CC=CC=2)C[C@H]1C(O)=O)=O)(C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.NC1C=C(Br)SC=1C(N)=O.[Br:66][C:67]1[S:71][C:70]([C:72](=[O:74])[NH2:73])=[C:69]([NH:75][C:76]([C@@H:78]2[CH2:82][C@@H:81]([O:83][C:84]3[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=3)[CH2:80][N:79]2[C:90]([O:92][C:93]([CH3:96])([CH3:95])[CH3:94])=[O:91])=O)[CH:68]=1.[OH-].[Na+].Cl>CN(C)C=O.C(O)C>[Br:66][C:67]1[S:71][C:70]2[C:72](=[O:74])[NH:73][C:76]([C@@H:78]3[CH2:82][C@@H:81]([O:83][C:84]4[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=4)[CH2:80][N:79]3[C:90]([O:92][C:93]([CH3:96])([CH3:95])[CH3:94])=[O:91])=[N:75][C:69]=2[CH:68]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2ccccc2)C[C@H]1C(=O)Nc1cc(Br)sc1C(N)=O
Agent: CC(C)(C)OC(=O)N1C[C@H](Oc2ccccc2)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2ccccc2)C[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
A solution of (4R)-1-(tert-butoxycarbonyl)-4-phenoxy-L-proline (1.04 g), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.29 g) and N-ethyl-N-(1-methylethyl)propan-2-amine (0.692 mL) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 30 min. To the reaction mixture was added 3-amino-5-bromothiophene-2-carboxamide (250 mg) produced in Example 1, step D, and the mixture was stirred at 90° C. for 1.5 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate (20 mL) and aqueous sodium hydrogen carbonate (10 mL) were added to the obtained residue, and the separated aqueous layer was extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give an inseparable mixture of tert-butyl (2S,4R)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]-4-phenoxypyrrolidine-1-carboxylate and impurity having an undetermined structure as a pale-yellow solid. To a solution of the inseparable mixture of tert-butyl (2S,4R)-2-[(5-bromo-2-carbamoylthiophen-3-yl)carbamoyl]-4-phenoxypyrrolidine-1-carboxylate produced above and impurity having an undetermined structure in ethanol (5 mL) was added 2M aqueous sodium hydroxide solution (1.70 mL), and the mixture was stirred at 70° C. for 2 hr. 6M Hydrochloric acid (0.60 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration, and washed successively with water (5 mL), ethanol (5 mL) and diethyl ether (5 mL) to give the title compound (440 mg) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@@H:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C@H:8]([C:36](OCC)=[O:37])[CH2:7]1)=[O:5])[CH3:2].C(OC(N1CCC(N)CC1)=O)(C)(C)C.N(C(C)C)=C=O.[BH4-].[Li+]>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@@H:9]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[C@H:8]([CH2:36][OH:37])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OCC)CC[C@H]1NS(=O)(=O)c1ccc(NC(=O)c2ccccc2C)c2ccccc12
Agent: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(C)N=C=O
Agent: [BH4-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CC[C@@H](NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C)c3ccccc23)[C@H](CO)C1

Procedure:
(±)-(trans)-4-[4-(2-Methyl-benzoylamino)-naphthalene-1-sulfonylamino]-piperidine-1,3-dicarboxylic acid diethyl ester was made following general procedure in Scheme 5, substituting (±)-4-amino-1-benzyl-piperidine-3-carboxylic acid ethyl ester (5) for 4-amino-piperidine-1-carboxylic acid tert-butyl ester and substituting ethyl chloroformate for 2-isocyanato-propane. To the solution of (±)-(trans)-4-[4-(2-methyl-benzoylamino)-naphthalene-1-sulfonylamino]-piperidine-1,3-dicarboxylic acid diethyl ester (57 mg, 0.1 mmol) in THF (5 mL), was added lithium borohydride in THF solution (0.5 mL, 0.25 mmol) and the resultant solution was stired at 0 ° C. for 2 h. The solvent was removed in vacuo and the crude material was purified by HPLC to give the title compound. 1H NMR (300 MHz, MeOD) δ 8.73 (d, 1H), 8.30 (d, 1H), 8.22 (d, 1H), 7.93 (d, 1H), 7.68 (m, 3H), 7.36 (m, 3H), 4.15 (d, 1H), 4.05 (q, 2H), 3.85 (d, 1H), 3.55 (d, 1H), 3.25 (m, 1H), 3.10 (m, 1H), 2.60 (m, 2H), 2.56 (s, 3H), 1.40 (m, 3H), 1.20 (t, 3H); LC/MS m/z 526 (M+H)+
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][CH:15]=[C:14]([C:21](O)=[O:22])[CH:13]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][CH:15]=[C:14]([C:21]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[O:22])[CH:13]=4)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccccn1
Reactant: O=C(O)c1ccc2[nH]c(=O)c3cnc(C4CCCCC4)n3c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1ccccn1)c1ccc2[nH]c(=O)c3cnc(C4CCCCC4)n3c2c1
Reaction time: 23 h

Procedure:
1-Cyclohexyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylic acid as synthesized in above Example 103, 405 mg, 2-aminopyridine 184 mg, 1-hydroxybenzotriazole monohydrate 299 mg, 4-dimethylaminopyridine 31 mg, pyridine 8.5 mL and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 375 mg were mixed and stirred for 23 hours. After distilling the solvent off, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the residue and stirred. The crystals were recovered by filtration and washed successively with water and ethyl acetate. The crystals were heat-suspended in 20 mL of acetone, recovered by filtration and washed with acetone. Drying the crystals, 213 mg of the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:14]=1[CH2:15][NH2:16].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:14]=1[CH2:15][NH:16][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)=[O:10]
Reactant: O=C(O)c1cccc(Br)n1
Reactant: COc1ccc(OC)c(CN)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(CNC(=O)c2cccc(Br)n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
To a mixture of 6-bromopicolinic acid (1.01 g, 5.0 mmol) and 2,5-dimethoxybenzylamine (753 μL, 5.0 mmol) in DMF (10 mL) was added TBTU (1.77 g, 5.5 mmol), followed by N,N-diisopropylethylamine (871 μL, 5.0 mmol). The mixture was stirred at room temperature for 2 hours. After addition of saturated NaHCO3, the mixture was extracted with ethyl acetate. The organic phase was washed with brine (×3), dried (MgSO4), filtered and concentrated. It was triturated with CH3CN to provide the titled compound as white solid (1.05 g, 57%).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][CH2:6][CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)C.[OH-].[Na+]>C1COCC1>[CH:9]1([NH:8][CH2:7][CH2:6][CH2:5][C:4]([OH:15])=[O:3])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOC(=O)CCCNC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCCNC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7 g of 4-bromobutyric acid ethyl ester and 20 g of cyclohexylamine were added to 50 mL of ethanol, and the mixture was stirred at a room temperature for one week. The stirred mixture was concentrated under reduced pressure and extracted with 200 mL of ethyl acetate. The extracted material was washed with purified water, dried with magnesium sulfate, and then concentrated. The obtained residue was distilled under reduced pressure to give 8.2 g of N-cyclohexyl-gamma-aminobutyric acid ethyl ester. The obtained N-cyclohexyl-gamma-aminobutyric acid ethyl ester was added to sodium hydroxide solution (1.68 g of sodium hydroxide/100 mL of purified water), and THF was added thereto till the mixture became homogeneous. After stirring at room temperature for 3 hours, the mixture was neutralized with DOWEX50W [H+ form] and concentrated under reduced pressure. The obtained residue was recrystallized to give 4.1 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26]O)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>C(Cl)Cl>[Br:48][CH2:26][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:19][CH2:18]2)[N:11]=3)=[C:2]([F:1])[CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cc(CBr)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Temperature: 25 °C

Procedure:
To a slurry of (3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methanol (2.05 g, 5.45 mmol), triphenylphosphine (1.64 mL, 7.08 mmol) in DCM (25 mL) at 0° C. under N2, carbon tetrabromide (0.634 mL, 6.53 mmol) was added. The reaction mixture was allowed to warm up to ambient temperature. The crude reaction mixture after 1 h, was concentrate in vacuo and purified by silica gel chromatography to afford 2-(4-(bromomethyl)-2-fluorophenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine. MS (ESI) m/z; calculated: 438.0; Observed: 438.9 (M++1).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(#N)C>O>[N:13]1([C:2]2[N:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc(N2CCOCC2)nc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Ethyl 6-chloronicotinate (5.0 g) and morpholine (10 ml) were mixed and then heated to 100° C. In less than 5 minutes at this temperature, a thick paste formed. Acetonitrile (15 ml) was added and heating was continued overnight at 90° C. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo to give ethyl 6-morpholin-4-ylpyridine-3-carboxylate as a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:15]([C:16]3[CH:17]=[N:18][C:19](S(C4C=CC=CC=4)(=O)=O)=[CH:20][CH:21]=3)=[C:10]3[CH:11]=[N:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][O-:32].[Na+]>CO.O1CCOCC1>[CH3:31][O:32][C:19]1[N:18]=[CH:17][C:16]([C:15]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][N:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=23)=[CH:21][CH:20]=1
Reactant: C[O-]
Reactant: O=S(=O)(c1ccccc1)c1ccc(-c2c(-c3ccccc3)nn3ccncc23)cn1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(-c2c(-c3ccccc3)nn3ccncc23)cn1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of 2-phenyl-3-[6-(phenylsulfonyl)-3-pyridinyl]pyrazolo[1,5-a]pyrazine (3.93 g) and sodium methoxide (5.2M MeOH solution, 10 mL) in MeOH (60 mL) and 1,4-dioxane (60 mL) was stirred at 85° C. for 1 h. The reaction mixture was concentrated in vacuo, and ice water was added, extracted, with EtOAc, washed with water and brine, dried over sodium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane-EtOAc 2:3) to give 3-(6-methoxy-3-pyridinyl)-2-phenylpyrazolo[1,5-a]pyrazine (2.37 g) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]([CH3:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[NH3:17]>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([N:9]([CH3:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=[C:2]([NH2:17])[N:7]=1
Reactant: N
Reactant: CN(c1ccccc1)c1nc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Product: CN(c1ccccc1)c1nc(N)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110 %

Procedure:
To a stirred solution of (4,6-dichloro-[1,3,5]triazin-2-yl)-methyl-phenyl-amine (Intermediate 42, 2.7 g, 10.58 mmol) in THF (45 ml) was added a solution of conc. aqueous ammonia (3 ml, 52.91 mmol). The reaction was allowed to stir at room temperature for 1 h, the reaction was then diluted with THF (50 ml), treated with conc. aqueous ammonia (1 ml, 17.64 mmol) and stirred for 18 h. The reaction was concentrated under vacuum and taken up in DCM (150 ml); the solution was then extracted with 2M aq. HCl (2×50 mL), and saturated brine (20 mL) and dried further over anhydrous sodium sulfate. The organic phase was evaporated to dryness to furnish the product as an off white solid (2.743 g, 110%). Method B HPLC-MS: MH+ requires m/z=236. Found: m/z=236, Rt=1.76 min (88%). 1H NMR (500 MHz, CDCl3) δ ppm 7.09-7.44 (5H, m), 5.21-5.65 (2H, m), 3.40 (3H, s).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[F:21][C:22]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:23]=1[NH2:24].F[C:31]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:32]=1[C:33]([OH:35])=[O:34].Cl.O1CCOCC1>O1CCCC1>[F:21][C:22]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:23]=1[NH:24][C:31]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:32]=1[C:33]([OH:35])=[O:34]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(F)c(F)cc1Nc1ccc(F)cc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Lithium diisopropylamide is generated at −5° C. by combining diisopropylamine (7.2 mL, 51 mmol) and n-butyllithium (33 mL, 53 mmol) in anhydrous tetrahydrofuran (150 mL) under an inert atmosphere. After 0.5 hour, the solution is cooled to −78° C. and 2,4-difluoroaniline (3.46 mL, 34 mmol) is added and stirred for 2 hours. 2,4,5-Trifluorobenzoic acid (3.0 g, 17 mmol) is added, and the mixture is subsequently allowed to warm to room temperature over 18 hours. A saturated solution of hydrogen chloride/dioxane (10 mL) is added, and after 1 hour, the mixture is concentrated to a solid. The solid is dissolved in chloroform and washed with 1.0 M hydrochloric acid, water, and brine. The solution is dried, concentrated in vacuo, and purified by column chromatography (3:1 ethyl acetate/hexanes) to give 2-(2,4-difluoroanilino)-4,5-difluorobenzoic acid as a solid (2.18 g). 1H NMR (CDCl3): δ 8.95 (bs, 1H), 7.80-7.75 (m, 2H), 7.50-6.85 (m, 3H), 6.62-6.40 (m, 1H). MS EI: m/z 286 (M+).
Reaction SMILES: C(N1CCC(=O)CC1)C1C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.FC1C=CC(N2[C:35]3([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:34](=[O:41])[NH:33][CH2:32]2)=CC=1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:35]3([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:34](=[O:41])[NH:33][CH2:32]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C1NCN(c2ccc(F)cc2)C12CCNCC2
Agent: O=C1CCN(Cc2ccccc2)CC1
Product: COc1ccc(N2CNC(=O)C23CCNCC3)cc1

Procedure:
This compound was prepared from 1-benzyl-4-piperidone and 4-methoxy-phenyl amine in analogy of the procedure described for the synthesis of 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one. 1-(4-Methoxy-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one was obtained as colorless solid: MS (ISP): 262.1 MH+.
Reaction SMILES: N#N.C(OC(=O)[N:9]([C:22]([C:24]1[N:25]=[CH:26][S:27][C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)=[O:23])[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:21]=[C:19]([CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][C:12]1[O:13][CH:14]=[C:10]([NH:9][C:22]([C:24]2[N:25]=[CH:26][S:27][C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)=[O:23])[N:11]=1
Reactant: CC(=O)CCCCc1nc(N(C(=O)OC(C)(C)C)C(=O)c2ncsc2-c2cccc(F)c2)co1
Agent: N#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)CCCCc1nc(NC(=O)c2ncsc2-c2cccc(F)c2)co1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(3-fluoro-phenyl)-thiazole-4-carbonyl]-[2-(5-oxo-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (30 mg, 0.06 mmol) in dry CH2Cl2 (1.0 mL) was treated at 0° C. with trifluoroacetic acid (0.05 mL, 0.64 mmol). After stirring at rt for 3 h, the reaction mixture was quenched with sat. aq. NaHCO3, extracted with CH2Cl2 (3×10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by HPLC gave the title compound as a colorless oil. LC-MS-conditions 01: tR=0.99 min, [M+H]+=388.04.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][N:14]([CH2:16][CH2:17][C@@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:28])[CH:24]=2)[CH2:19]1)[CH3:15].[CH3:29][O:30][C:31]1[CH:47]=[CH:46][C:34]([C:35]([O:37][C:38]2[CH:43]=[CH:42][C:41]([CH2:44]O)=[CH:40][CH:39]=2)=[O:36])=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:13][N:14]([CH2:16][CH2:17][C@@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH2:44][C:41]3[CH:40]=[CH:39][C:38]([O:37][C:35]([C:34]4[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:47][CH:46]=4)=[O:36])=[CH:43][CH:42]=3)[CH:24]=2)[CH2:19]1)[CH3:15]
Reactant: CN(C)CC[C@@H]1CCc2cc(O)ccc2C1
Reactant: COc1ccc(C(=O)Oc2ccc(CO)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Oc2ccc(COc3ccc4c(c3)CC[C@@H](CCN(C)C)C4)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
Diethyl azodicarboxylate (40% toluene solution, 0.95 g) was added dropwise to THF solution (6 ml) of 2-(R)-[2-(N,N-dimethylamino)ethyl]-6-hydroxytetralin (300 mg), 4-(hydroxymethyl)phenyl 4-methoxybenzoate (530 mg), and triphenylphosphine (430 mg) under ice-cooling. After stirring for 2 hours at room temperature, the reaction mixture was concentrated. The residue was purified using alumina column chromatography (development solvent; hexane˜hexane:ethyl acetate=10:1), and the titled compound (320 mg) was obtained after recrystallization (ethyl acetate-hexane).