Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([S:14]([N:17]([C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28])[C:18]3[C:23]([O:24][CH3:25])=[N:22][C:21]([CH3:26])=[CH:20][N:19]=3)(=[O:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:34](O)(=O)[CH3:35].[C:38]([BH3-])#N.[Na+].Cl>CC(C)=O.O>[CH2:30]([O:29][C:27]([N:17]([C:18]1[C:23]([O:24][CH3:25])=[N:22][C:21]([CH3:26])=[CH:20][N:19]=1)[S:14]([C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH:34]([CH3:35])[CH3:38])=[CH:3][CH:4]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:16])=[O:15])=[O:28])[CH:31]([CH3:33])[CH3:32]
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(N)cc1
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(NC(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(4-aminophenyl)-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.17 g) in acetone (3 ml) and water (3 ml) was acidified to pH 4 with glacial acetic acid. Sodium cyanotrihydridoborate (0.045 g) was added and the mixture was stirred at ambient temperature for 16 hours. The mixture was then poured into 2M hydrochloric acid (10 ml) and extracted with ethyl acetate (2×25 ml). The aqueous layer was basified to pH 10 with 2M sodium hydroxide and re-extracted with ethyl acetate (2×25 ml). All of the organic extracts were combined, washed with brine and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 35-50% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)-2-[4-(isopropylamino)phenyl]pyridine-3-sulphonamide (0.11 g) as a gum; 1H NMR (d6-DMSO): 0.6 (d, 6H), 1.2 (d, 6H), 1.6 (m, 1H), 3.6 (m, 1H), 3.8 (d, 2H), 4.0 (s, 3H), 5.8 (d, 1H), 6.6 (d, 2H), 7.35 (d, 2H), 7.6 (m, 1H), 8.2 (s, 1H), 8.8 (m, 2H); mass spectrum (+ve ESP): 514 (M+H)+.
Reaction SMILES: I.[Cl:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]([CH3:15])[NH:6][C:7](SC)=[N:8]2.[OH-].[NH4+:17]>C(#N)C.C(O)(C(F)(F)F)=O>[Cl:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]([CH3:15])[NH:6][C:7]([NH2:17])=[N:8]2
Reactant: [NH4+]
Reactant: CSC1=Nc2cccc(Cl)c2C(C)N1
Agent: I
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC1NC(N)=Nc2cccc(Cl)c21
Temperature: 130 °C
Yield: 62 %

Procedure:
5-Chloro-4-methyl-2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (100 mg, 0.28 mmol) was suspended in a mixture of ammonium hydroxide (1 ml, 25% in H2O) and acetonitrile (1 ml) and heated in a microwave oven to 130° C. (15 min) and subsequently to 170° C. (30 min). The title compound (35 mg, 62%) was isolated from the reaction mixture by preparative, reverse-phase HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min) as a white solid.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:11][C:12]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:13]=1[NH2:14].F[C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[C:23]([F:29])[C:22]=1[N+:30]([O-:32])=[O:31].C(OCC)(=O)C>C1COCC1>[F:11][C:12]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:13]=1[NH:14][C:21]1[C:22]([N+:30]([O-:32])=[O:31])=[C:23]([F:29])[CH:24]=[C:25]([F:28])[C:26]=1[F:27]
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1F
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.24 %

Procedure:
A solution of 1.0 M lithium hexa methyl disilazide (LiN(SiMe3)2) “LHMDS” (15.37 mL, 15.37 mmol) was slowly added to a stirred solution of 2-fluoro-4-iodoaniline (3.64 g, 15.37 mmol) in dry THF (100 mL) under nitrogen at −78° C. and stirring continued at −78° C. for another hour. 2,3,4,6-Tetrafluoronitrobenzene was added, and the reaction mixture was allowed to warm to room temperature and stirring continued for another 16 hours. Ethyl acetate (200 mL) was added and the organic phase was washed with water, dried over sodium sulfate and further purified by column chromatography to provide the product as a yellow solid (3.75 g, 59.24%). M−H+: 410.9. 1H NMR (DMSO, 300 MHz): 6.85 (t, 1H); 7.38 (d, 1H); 7.62 (m, 2H); 8.78 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[C:13]([C:17]1[C:25]([Cl:26])=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([O:27][CH3:28])[CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>>[ClH:26].[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:21](=[O:22])[C:20]2[CH:24]=[C:25]([Cl:26])[C:17]([C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:18][C:19]=2[O:27][CH3:28])[CH2:7]1
Reactant: COc1cc(C(C)(C)C)c(Cl)cc1C(=O)O
Reactant: CN1CCc2c(N)cccc2C1
Product: COc1cc(C(C)(C)C)c(Cl)cc1C(=O)Nc1cccc2c1CCN(C)C2
Product: Cl

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 4-tert-butyl-2-methoxy-5-chlorobenzoic acid.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=O)[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>CCO>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:1][N:7]1[C:11](=[O:12])[C:10]2[C:9](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]1=[O:13]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCc1ccco1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1Cc1ccco1
Temperature: 25 °C

Procedure:
Furfurylamine (5.70 mL, 61.8 mmol) and phthalic anhydride (10.0 g, 90.9 mmol) were heated to 120° C. for approximately 45 min. The reaction mixture was cooled to rt and then suspended in EtOH. The resulting suspension was filtered to afford the title compound i-1a. 1HNMR (500 MHz, CDCl3): δ 7.88 (dd, 2H, J=3.2, 5.3 Hz), 7.73 (dd, 2H, J=3.0, 5.5 Hz), 6.38 (d, 1H, J=3.2 Hz), 6.32 (m, 1H), 4.88 (s, 2H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([Cl:17])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)[CH2:3][CH2:2]1.[CH2:28]([NH2:30])[CH3:29].N1C=CC=CC=1>C(Cl)Cl.C(OCC)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([NH:30][CH2:28][CH3:29])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)[CH2:3][CH2:2]1.[ClH:17]
Reactant: CCOc1ccc(Cc2nc3cc(S(=O)(=O)Cl)ccc3n2CC2CC2)cc1
Reactant: CCN
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCNS(=O)(=O)c1ccc2c(c1)nc(Cc1ccc(OCC)cc1)n2CC1CC1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following general procedure 36B: Used 1-(cyclopropylmethyl)-2-(4-ethoxybenzyl)-1H-benzimidazole-5-sulfonyl chloride (from 0.2 mmol of aniline precursor), ethyl amine (2M solution in THF, 0.4 mmol) and pyridine (0.5 mL) in CH2Cl2 (4 mL). The resulting mixture was stirred at room temperature overnight. Isolated the desired product as the HCl salt after column chromatography and treatment with 1 M HCl solution in diethyl ether (61 mg, 87%). 1H NMR (400 MHz, CD3OD): δ 8.28 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 4.32 (s, 2H), 4.02–3.93 (m, 4H), 3.06–2.98 (m, 2H), 1.38 (t, J=7.6 Hz, 3H), 1.10 (t, J=8.0 Hz, 3H), 1.07–1.00 (m, 1H), 0.55–0.52 (m, 2H), 0.30–0.24 (m, 2H). MS (ESI) (M+H)+=414. Anal. Calcd for C12H27N3O3S.1.1HCl: C, 58.25; H, 6.24; N, 9.26. Found: C, 58.19; H, 6.73; N, 8.62.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:36]([N:38]([CH2:54][CH3:55])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=1)[CH3:37]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)(Cl)Cl.O.COCCOC>[CH2:54]([N:38]([CH2:36][CH3:37])[C:39]1[CH:40]=[C:41]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7])=[C:4]([NH:15][C:16]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:23]=3)=[O:17])[CH:3]=2)[CH:42]=[CH:43][CH:44]=1)[CH3:55]
Reactant: CCN(CC)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cncc(-c2ccccc2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Solvent: O
Product: CCN(CC)c1cccc(-c2ccc(C(=O)OC(C)(C)C)c(NC(=O)c3cncc(-c4ccccc4)c3)c2)c1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
Tert-butyl 4-bromo-2-(5-phenylpyridine-3-carboxamido)benzoate (0.11 g), sodium carbonate (64 mg), water (0.30 mL), and bis(triphenylphosphine)palladium(II) dichloride (3.5 mg) were added to an ethylene glycol dimethyl ether (1.0 mL) solution of N,N-diethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (83 mg), followed by heating to reflux under a nitrogen atmosphere for 2 hours and 40 minutes. The reaction mixture was cooled to room temperature, and then water and chloroform were added thereto. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 90-70% hexane/ethyl acetate] to obtain 0.12 g of tert-butyl 4-(3-(diethylamino)phenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:30][CH2:31][C:32](Cl)=[O:33]>>[F:30][CH2:31][C:32]([NH:21][C@@H:19]([CH3:20])[C@H:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[O:33]
Reactant: O=C(Cl)CF
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)CF)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 19 mg, 50 μmol) and fluoroacetyl chloride (14 mg, 150 μmol). Yield 16 mg (71%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([OH:14])=O)=[N:10][C:9]2[NH:8][C:7](=[O:15])[CH2:6][S:5][C:4]=2[CH:3]=1.[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([N:22]=[CH:23][C:24]([S:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]3)=[N:25]2)=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([N:22]=[CH:23][C:24]([S:28][CH2:29][CH2:30][N:31]3[CH2:32][CH2:33][CH:34]([NH:37][C:12]([C:11]4[C:2]([Cl:1])=[CH:3][C:4]5[S:5][CH2:6][C:7](=[O:15])[NH:8][C:9]=5[N:10]=4)=[O:14])[CH2:35][CH2:36]3)=[N:25]2)=[CH:20][CH:19]=1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Reactant: O=C1CSc2cc(Cl)c(C(=O)O)nc2N1
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4nc5c(cc4Cl)SCC(=O)N5)CC3)nc2c1

Procedure:
The title compound is prepared as a yellow solid (9 mg, 12% yield) following Scheme 3 and in analogy to Example 35 using 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (31 mg, 0.12 mmol, 1.0 eq) and 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (40 mg, 0.12 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [CH3:1][N:2]([CH2:4]Cl)[CH3:3].CN(CCCCl)C.C([N:21]1[C:26](=[O:27])[C:25]2[CH:28]=[N:29][C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:33]=[CH:32][C:31]=3[C:24]=2[N:23]2[N:41]=[C:42]([CH3:44])[CH:43]=[C:22]12)(=O)C1C=CC=CC=1>>[CH3:1][N:2]([CH2:4][N:21]1[C:26](=[O:27])[C:25]2[CH:28]=[N:29][C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:33]=[CH:32][C:31]=3[C:24]=2[N:23]2[N:41]=[C:42]([CH3:44])[CH:43]=[C:22]12)[CH3:3]
Reactant: Cc1cc2n(C(=O)c3ccccc3)c(=O)c3cnc4c(cnn4-c4ccccc4)c3n2n1
Reactant: CN(C)CCl
Agent: CN(C)CCCCl
Product: Cc1cc2n(CN(C)C)c(=O)c3cnc4c(cnn4-c4ccccc4)c3n2n1

Procedure:
By substituting dimethylaminomethyl chloride for the dimethylaminopropyl chloride in the procedure of Example 4 and utilizing 2-methyl-8-phenyl-4H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one product of Example 15 instead of 8-ethyl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one, 4-dimethylaminomethyl-2-methyl-8-phenyl-4H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is obtained.
Reaction SMILES: [CH:1]12[CH:12]=[CH:11][CH:7]([CH:8]3[CH:10]1[CH2:9]3)[CH:6]1[CH:2]2[C:3](=[O:14])[O:4][C:5]1=[O:13].[CH3:15][OH:16]>>[CH3:15][O:16][C:3]([CH:2]1[CH:1]2[CH:12]=[CH:11][CH:7]([CH:8]3[CH:10]2[CH2:9]3)[CH:6]1[C:5]([OH:4])=[O:13])=[O:14]
Reactant: CO
Reactant: O=C1OC(=O)C2C3C=CC(C4CC34)C12
Product: COC(=O)C1C2C=CC(C3CC23)C1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 94 %

Procedure:
rac-(1R,2S,6R,7S,8S,10R)-4-Oxatetracyclo[5.3.2.02,6.08,10]dodec-11-ene-3,5-dione (prepared as described in Example 51a, 0.86 g, 4.50 mmol) was dissolved in methanol (20 mL). The reaction was stirred at 25° C. for 72 h. The mixture was concentrated to afford a clear oil. Purification by flash column chromatography (Teledyne Isco RediSep column; 0 to 60% ethyl acetate in hexanes) afforded the desired product, rac-(1S,2S,4R,5R,6S,7R)-7-(Methoxycarbonyl)tricyclo[3.2.2.02,4]non-8-ene-6-carboxylic acid (0.94 g, 4.23 mmol, 94%) as a white solid. 1H NMR (400 MHz, CDCl3) δ: 0.06-0.17 (2H, m), 1.26-1.38 (2H, m), 2.74-2.85 (2H, m), 3.15-3.19 (2H, m), 3.67 (3H, s), 5.85-5.86 (2H, m). LC-MS (ESI) calcd for C12H14O4 222.24, found 223.5 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.Cl.C(O)=[O:12]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:9])=[O:12])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccnc(Cl)n1
Reactant: O=CO
Agent: Cl
Product: NC(=O)c1ccnc(Cl)n1
Reaction time: 8 h

Procedure:
338 g of 98% strength formic acid are introduced into a 1--1 round bottom flask fitted with magnetic stirring and containing 131.9 g (946 mmol) of 2-chloropyrimidine-4-carbonitrile, and a stream of gaseous hydrochloric acid is passed through slowly for 1 h 30 min. The mixture is allowed to stand overnight, the solid is isolated on sintered glass and is then purified by recrystallisation with filtration while hot, from a mixture of nitromethane and ethyl acetate. In this way, 107.03 g of grey solid are isolated as three crops, after drying under vacuum and with heating. Melting point: 152.5°-154° C.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]3([CH3:19])[CH2:18][O:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[C:47]1([C:53]2[O:57][C:56]([C:58]([NH2:61])([CH3:60])[CH3:59])=[N:55][N:54]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]3([CH3:19])[CH2:18][O:17][CH2:16]3)=[CH:6][C:7]([C:10]([NH:61][C:58]([C:56]3[O:57][C:53]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[N:54][N:55]=3)([CH3:60])[CH3:59])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC1(COc2cc(C(=O)O)ncc2C2CC2)COC1
Reactant: CC(C)(N)c1nnc(-c2ccccc2)o1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(COc2cc(C(=O)NC(C)(C)c3nnc(-c4ccccc4)o3)ncc2C2CC2)COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To a solution of the acid 5-cyclopropyl-4-((3-methyloxetan-3-yl)methoxy)picolinic acid (20 mg, 76.0 μmol) in dichloromethane (1 ml) was added DIPEA (24.5 mg, 33.2 μl, 190 μmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (23.1 mg, 83.6 μmol). The reaction is stirred for 30 minutes at room temperature followed by addition of 2-(5-phenyl-1,3,4-oxadiazol-2-yl)propan-2-amine (CAN 68176-04-5, 15.4 mg, 76.0 μmol) and the reaction mixture was stirred overnight at room temperature. The reaction was diluted with dichloromethane (5 mL) and washed with a 0.2M aqueous solution of hydrochloric acid (3×10 mL) and brine (15 mL). The organic phase is dried over magnesium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a gradient of heptane and ethyl acetate to yield the title compound (24.3 mg, 71%). MS (ESI, m/z): 449.7 (M+H+).
Reaction SMILES: Cl.[N:2]1([C:7](=[NH:9])[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:10][C:11]([SH:14])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:10][C:11]1[S:14][N:8]=[C:7]([N:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)[N:9]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)N1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Clc1nc(N2CCCC2)ns1
Temperature: 25 °C
Yield: 31.1 %

Procedure:
To a solution of pyrrolidine-1-carboximidamide hydrochloride (1.50 g, 10.0 mmol) and perchloromethyl mercaptan (1.08 ml, 10.0 mmol) in dichloromethane (20 ml) was added dropwise a solution of sodium hydroxide (1.60 g, 40.0 mmol) in water (4 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 590 mg (31.0%) of the desired product as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][C:10]=1Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CN(C)[CH:31]=[O:32].CCOCC>O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][C:10]=1[CH:31]=[O:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OC(C)(C)C)c(Br)c1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OC(C)(C)C)c(C=O)c1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
3.3 g (0.01 mol) 2,5-bis-tert.-butyloxycarbonylamino-bromobenzene from step A are dissolved in 100 ml of water-free tetrahydrofuran under argon. Gradually 17 ml of a 1.6 molar methyl lithium ether solution (0.03 mol) are added. The reaction mixture is cooled to −20° C. Subsequently 7 ml of 1.5 molar t-butyl lithium solution (0.01 mol) are added gradually. After ending the addition the solution is stirred for 30 minutes at −20° C. Subsequently 1.2 g of dimethylformamide (0.02 mol) are added and the reaction mixture is stirred for an hour at −20° C. After slow heating to room temperature the reaction mixture is hydrolyzed with water and then poured into ether, the aqueous phase is extracted with ether and then the organic phase is dried with magnesium sulfate. The solvent is distilled off in a rotary evaporator and the residue is purified on silica gel with petroleum ether/ethyl acetate (9:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH:35]1(CO)[CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH:35]2[CH2:37][CH2:36]2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCC4CC4)cc3)c2cc1OC
Yield: 37.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cyclopropylmethanol (19 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (25 mg, yield 34%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:20][C:21]([C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27])([F:23])[F:22].CCOC(C)=O>C(Cl)Cl>[N:9]1[CH:10]=[CH:11][N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:26]([C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[C:21]([F:20])([F:22])[F:23])=[O:27])[CH2:3][CH2:2]2)[N:8]=1
Reactant: c1cnc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2nccnn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
Compound 3 is prepared according to synthesis method 2: 0.4 g (2.42 mmoles) of derivative 5a is placed in 10 ml of CH2Cl2. 0.5 ml (3.63 mmoles) of triethylamine is added. At 0° C., 0.4 ml (2.66 mmoles) of trifluoromethylbenzoyl chloride is added drop by drop, the reaction medium is stirred at ambient temperature for 18 hours. After concentrating the reaction medium to dryness, the residue obtained is taken up with AcOEt and washed with water. After drying on MgSO4, the organic phase is concentrated. The residue obtained is purified by silica flash chromatography (CH2Cl2,100%). 0.72 g of yellow powder is isolated (yield: 95%).
Reaction SMILES: [Na].[F:2][C:3]([F:7])([F:6])[CH2:4][OH:5].Cl[C:9]1[N:10]=[C:11]([CH3:19])[C:12]([C:15]([O:17]C)=[O:16])=[N:13][CH:14]=1.[OH-].[Na+]>>[CH3:19][C:11]1[C:12]([C:15]([OH:17])=[O:16])=[N:13][CH:14]=[C:9]([O:5][CH2:4][C:3]([F:7])([F:6])[F:2])[N:10]=1
Reactant: COC(=O)c1ncc(Cl)nc1C
Reactant: OCC(F)(F)F
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Product: Cc1nc(OCC(F)(F)F)cnc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
Sodium, which had been stored in mineral oil, was rinsed in hexane and cut into approximately 70-mg slivers. Those slivers of sodium (0.37 g, 16.08 mmol) were loaded into a 150-mL resealable vessel. The vessel was purged with argon, placed in a water bath, and 2,2,2-trifluoroethanol (31.2 mL, 429 mmol) was added. Bubbling ensued immediately. Bubbling had ceased and sodium had disappeared around 30 minutes. The mixture was stirred at room temperature for another 30 minutes. To this mixture was added methyl 5-chloro-3-methylpyrazine-2-carboxylate (1.00 g, 5.36 mmol). The vial was sealed and heated at 45° C. overnight. After addition of 1 M sodium hydroxide (5.90 mL, 5.90 mmol), the mixture was stirred at 45° C. overnight. The reaction mixture was concentrated to remove most of the trifluoroethanol. The residue was dissolved in the minimum amount of water (300 mL), and the aqueous phase was washed with diethyl ether (2×30 mL). The aqueous phase was acidified with 5 M HCl (5 mL). The aqueous phase was extracted with DCM until TLC (15% MeOH-DCM) showed product wasn't coming out any more. The organics were combined, dried over MgSO4 and concentrated to give 3-methyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid (1.28 g, 100% yield). 1H NMR (300 MHz, CDCl3) δ ppm 10.57 (br, 1H), 8.15 (s, 1H), 4.87 (qt, 2H, J=8.2), 2.93 (s, 3H).