Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[CH:7]=[C:6](C)[CH:5]=[C:4]([CH3:9])[C:3]=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[C:19]([F:21])[C:18]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][C:16]=1[NH2:26].C(Cl)(=O)C1C=CC=CC=1>N1C=CC=CC=1>[F:21][C:19]1[C:18]([C:22]([O:24][CH3:25])=[O:23])=[CH:17][C:16]2[N:15]([N:14]=[C:9]([C:4]3[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=3)[N:26]=2)[CH:20]=1
Reactant: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Reactant: COC(=O)c1cc(N)[n+](N)cc1F
Solvent: c1ccncc1
Solvent: O=C(Cl)c1ccccc1
Product: COC(=O)c1cc2nc(-c3ccccc3)nn2cc1F
Temperature: 100 °C
Reaction time: 20 h
Yield: 49.8 %

Procedure:
A mixture of 1,2-diamino-5-fluoro-4-(methoxycarbonyl)pyridinium 2,4,6-trimethylbenzenesulfonate (1.719 g, 4.46 mmol) and benzoyl chloride (1.03 ml, 8.92 mmol) in pyridine (12 ml) is stirred for 20 hours at 100° C. The solvent is evaporated and the residue stirred for 2.5 hours with sat. aqueous ammoniumchloride solution while neutralizing to pH 6-7 with sat. aqueous sodium bicarbonate solution. The solid is collected by filtration, washed with water and dried affording methyl 6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (603 mg, 49.8%) as a light brown solid. Mp.: 162-8° C. MS: m/z=272.2 (M+H+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.[CH3:28][O:29][CH2:30][CH2:31]O.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[I:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:31][CH2:30][O:29][CH3:28])=[CH:23][CH:22]=1
Reactant: COCCO
Reactant: Oc1ccc(I)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.9 %

Procedure:
Triphenylphosphine (2.8 g, 10.7 mmol) was added to an ice-cold solution of 4-iodophenol (2.2 g, 10.0 mmol) and 2-methoxyethanol (0.79 ml, 10.0 mmol) in tetrahydrofuran (10 ml). A solution of diethyl azodicarboxylate (1.88 ml, 11.5 mmol) in tetrahydrofuran (10 ml) was then added dropwise, and the reaction stirred at room temperature for 18 hours. The mixture was evaporated under reduced pressure, the residue partitioned between dichloromethane and hydrochloric acid (2N) and the phases separated. The organic layer was washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue was triturated with diethyl ether, the resulting suspension filtered and the filtrate concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using pentane:dichloromethane (75:25) as eluant to give the title compound, (2.0 g, 71%) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([OH:23])=O)=[CH:15][CH:16]=2)[NH:11][N:10]=1.Cl.[CH:29]([O:32][NH2:33])([CH3:31])[CH3:30].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:29]([O:32][NH:33][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1)([CH3:31])[CH3:30]
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Reactant: CC(C)ON
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)ONC(=O)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 50.1 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), O-isopropyl-hydroxylamine hydrochloride (18.7 mg, 0.17 mmol), triethylamine(58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 17.4 mg (50%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 9.23 (1H, s), 8.69 (H, d, J=2.1), 8.03 (4H, m), 7.50 (5H, m), 7.23 (1H, s), 7.04 (1H, d, J=6.7 Hz), 6.92 (1H, m), 5.98 (1H, m), 4.13 (1H, m), 1.29 (6H, d, J=8.1). ESIMS (M+H+): 414.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[C:12](/[CH3:23])=[CH:13]/[C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1.[CH2:25]([NH2:28])[CH2:26][CH3:27]>C(Cl)(Cl)Cl.C(OCC)C.[OH-].[Na+]>[CH2:25]([NH:28][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14](/[CH:13]=[C:12](/[C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[O:5][CH2:4][CH2:3][C:2]3([CH3:24])[CH3:1])\[CH3:23])=[CH:15][CH:16]=1)[CH2:26][CH3:27]
Reactant: CCCN
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCO3)cc1

Procedure:
A 15 ml aliquot of the chloroform solution of the mixed anhydride of 4-[(E)-2-(4,4-dimethyl-6-chromanyl)-2-methylvinyl]benzoic acid from Preparation 13 was added to a solution of 0.1 g (1.71 mmole) of n-propylamine in ca. 25 ml of chloroform at 0° C. The reaction mixture was filtered and then it was extracted twice with 1N hydrochloric acid. The resulting chloroform solution was dried (MgSO4) and evaporated in vacuo to give an oily solid. This solid was dissolved in diethyl ether and 2N sodium hydroxide. The layers were separated and the ether layer was filtered, dried (MgSO4) and evaporated in vacuo. The residue was recrystallized from diethyl ether-hexane, to give 0.127 g of the title compound, mp 138°-139° C.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.II.[C:23](O)(=[O:25])C>[Cu](Cl)Cl>[CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[C:11]([CH2:12][CH2:13]1)=[CH:10][C:9]([OH:20])=[C:8]([O:25][CH3:23])[CH:7]=3)[CH2:4][CH2:3]2
Reactant: CC(=O)O
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: Cl[Cu]Cl
Agent: II
Product: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 2 h
Yield: 75 %

Procedure:
To this end, 2-iodo-estrone 49 was prepared by treating oestrone with mercuric acetate and iodine in acetic acid.40 The selective halogenation at position 2 was complete within 2 hours at room temperature with an overall yield of 56% after successive recrystallizations. 2-Iodo-estrone then reacted with a large excess of a freshly prepared solution of sodium methoxyde, in presence of copper chloride in refluxing pyridine41 and gave 2-methoxy-estrone 50 with a yield of 75%. This method has the advantage of not involving any protecting group and gives good overall yield (42%) for the synthesis of 2-methoxy-estrone in two steps from oestrone.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+]([O-])=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Hydroxy-4-nitro-benzonitrile (11.2 g, 68 mmole) was dissolved in DMF (200 ml). Potassium carbonate (11 g. 80 mmole) and benzyl bromide (9 ml, 75 mmole) were added. The reaction was stirred at room temperature overnight. The DMF was removed in vacuo and the residue taken up in ethyl acetate and water. The organic layer was separated, washed with 1 N NaOH, then with water, and dried over sodium sulfate. The crude product (5 g) was dissolved in ethyl acetate (75 ml) and added to a flask containing 5% Pt/C (500 mg). The reaction was placed under a hydrogen atmosphere (balloon) and stirred vigorously for several hours until the reaction was done (TLC). The catalyst was filtered off and the solvent removed. The product was purified by flash chromatography to yield 4.12 g of 4-amino, 2-benzyloxybenzonitrile.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:20]([CH3:21])=[CH:19][C:8]2[N:9]3[CH2:14][CH2:13][CH:12](CC([O-])=O)[C:10]3=[N:11][C:7]=2[C:6]=1[N+:22]([O-:24])=[O:23])(=[O:3])[CH3:2].C([O-])([O-])=[O:26].[K+].[K+]>CO>[C:1]([NH:4][C:5]1[C:20]([CH3:21])=[CH:19][C:8]2[N:9]3[CH2:14][CH2:13][CH:12]([OH:26])[C:10]3=[N:11][C:7]=2[C:6]=1[N+:22]([O-:24])=[O:23])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1c(C)cc2c(nc3n2CCC3CC(=O)[O-])c1[N+](=O)[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)Nc1c(C)cc2c(nc3n2CCC3O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 205 mg (0.61 mmol) of 15b in 10 mL of dry methanol was added 88 mg of K2CO3. The reaction was stirred at room temperature for 20 min and then concentrated in vacuo. The black residue was flash chromatographed on silica gel using a chloroform/methanol (98:2) mixture as the eluant. The yellow-colored product was recrystallized by dissolving it in a minimum amount of (4:1) chloroform/methanol, adding hexane, and then chilling: 141 mg (78%) yield: dec pt 259° C.; TLC (chloroform:methanol[20:80]) Rf =0.35, IR(KBr pellet) 3237, 3181, 3065, 1741, 1700, 1667, 1632, 1574, 1532, 1404 cm-1 ; 1H NMR (dimethyl sulfoxide-d6) δ9.67 (1 H, s, amide proton), 7.66 (1 H, s, C(8) proton), 5.97 (1 H, d, J= 5.3 Hz, hydroxyl proton), 5.09 (1 H, m, C(3) proton), 4.22 and 4.05 (2 H, 2×m, C(1) diastereomeric methylene), 2.90 and 2.37 (2 H, 2×m, C(2) diastereomeric methylene), 2.27 (3 H, s, 7-methyl proton), 1.97 (3 H, s, acetamido methyl); mass spectrum (EI mode) m/z, 290(P+), 272(P+ -H2O), 248 (P+ -ketene) 244 (P+ -NO2) Anal. Calcd for C13H14N4O4.0.75H2O: C, 51.39; H, 5.13; N, 18.44. Found: C, 51.75; H, 4.77; N, 18.45.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][OH:11])=[NH:9])=[CH:4][N:3]=1.[F:12][C:13]([F:34])([F:33])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22]([C:30](O)=O)[N:21]=2)=[CH:16][CH:15]=1>>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:25]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:34])([F:33])[F:12])=[CH:15][CH:16]=2)[N:21]=[C:22]([C:30]2[O:11][N:10]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([NH2:1])=[N:3][CH:4]=3)[N:9]=2)[N:23]=1
Reactant: N=C(NO)c1cnc(N)nc1
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Product: Nc1ncc(-c2noc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)n2)cn1

Procedure:
The title compound was prepared from 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example C.4) (0.115 g, 0.75 mmol) and 4-(4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.2) (0.17 g, 0.5 mmol) according to the general procedure V. Obtained as a white solid (0.14 g, 62%). MS (EI) 453.1 [(M)+]; mp 216° C.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu][C:12]#[N:13].C(N)CN>CN(C=O)C>[O:10]1[C:6]2=[CH:5][CH:4]=[CH:3][C:2]([C:12]#[N:13])=[C:7]2[CH:8]=[CH:9]1
Reactant: N#C[Cu]
Reactant: Brc1cccc2occc12
Solvent: NCCN
Solvent: CN(C)C=O
Product: N#Cc1cccc2occc12
Temperature: 25 °C
Yield: 41.3 %

Procedure:
Combine 4-bromo-benzofuran (1.0 g, 5.07 mmol), copper(I) cyanide (0.9 g, 10.2 mmol), anhydrous DMF (16 ml) and reflux for 17 h. Cool the reaction mixture to ambient temperature, treat with 50% (v/v) aqueous ethylenediamine (25 mL). Extract the reaction mixture with diethyl ether (3×15 mL), combine the organic extracts, wash with brine (15 mL) and dry over anhydrous Na2SO4. Evaporate the solvent and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1 and 4:1) to obtain the desired intermediate as a colorless oil (0.3 g, 39%).
Reaction SMILES: BrCCCC1C=CC=[C:7]2[C:8]([NH:10]C(=O)[C:6]=12)=O.[CH3:16][O:17][C:18]1[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][CH2:6][CH2:7][CH2:8][NH2:10]
Reactant: COc1ccccc1N
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Product: COc1ccccc1NCCCN
Yield: 33.5 %

Procedure:
By using 3-bromopropylphthalimide (25.0 g) and o-anisidine (10 g) as starting materials, the title compound (4.9 g) was obtained in the same manners as those of Reference Example 57, (1) and Reference Example 54, (4).
Reaction SMILES: C(C1N=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24]C2)[C:8]2N=NN(CC3C=CC=CC=3Cl)[C:9]=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].C(O)(=O)C(O)=O.C1C2(CCCN2)CO1>>[C:28]([C:32]1[N:33]=[C:34]([N:22]2[CH2:7][CH2:8][CH2:9][C:27]32[CH2:24][O:25][CH2:26]3)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: C1CNC2(C1)COC2
Agent: O=C(O)C(=O)O
Product: CC(C)(C)c1nc(N2CCCC23COC3)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-oxa-5-azaspiro[3.4]octane oxalate and isolated as white solid (8.4 mg, 43%). MS (m/e): 413.4 (MH+).
Reaction SMILES: [CH3:1][S:2][CH:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.[ClH:16]>CO.O1CCOCC1>[ClH:16].[CH3:1][S:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: CSC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CSC1CCNCC1

Procedure:
A solution of tert-butyl 4-(methylthio)piperidine-1-carboxylate (63 mg, 0.27 mmol) in methanol (1 mL) and 4 N hydrogen chloride in dioxane (4 mL) was refluxed for 2 min and then concentrated and dried to provide 4-(methylthio)piperidine hydrochloride as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].C(N(CC)CC)C.[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>O1CCCC1>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[O:13][C:27](=[O:30])[CH2:28][CH3:29])=[CH:5][C:4]=1[C:16]([F:19])([F:17])[F:18])#[N:2]
Reactant: CCC(=O)Cl
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)On1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(C#N)cc21
Yield: 95 %

Procedure:
A solution of 0.4 g (1.48 mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline -2,3(1H,4H)-dione in 50 ml dry tetrahydrofuran was added 0.25 ml (1.82 mmol) dry triethylamine and 0.15 ml (1.72 mmol) propionyl chloride. The mixture was refluxed for 30 min., and then evaporated in vacuo. The residue was stirred with water to give 0.46 g (95%) 7-cyano-1-propionyloxy-6-trifluoromethyl-quinoxaline-2,3(1H,4H)-dione. M.p. 227° C. 1H-NMR (DMSO-d6): 8.37 (1H, s), 7.73 (1H, s), 4.5 (2H, q), 1.35 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([C:19]([OH:21])=[O:20])=[CH:18][C:12]=3[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:30])=[CH:25][CH:24]=3)[C:10](=[O:36])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:39](O)[CH3:40].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([C:19]([O:21][CH2:39][CH3:40])=[O:20])=[CH:18][C:12]=3[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[O:30])=[CH:25][CH:24]=3)[C:10](=[O:36])[CH2:9]2)=[O:7])=[CH:37][CH:38]=1
Reactant: O=C(O)c1ccc2c(c1)N(Cc1ccc(C(=O)N3CCCC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Reactant: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)N(Cc1ccc(C(=O)N3CCCC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Reaction time: 8 h

Procedure:
5 mg (0.009 mmol) of 4-(4-chlorobenzoyl)-2-oxo-1-[4-(1-pyrrolidinecarbonyl)benzyl]-2,3,4,5-tetrahydro-1H-benzo[e][1,4]-diazepine-8-carboxylic acid was dissolved in 5 ml of dichloromethane. 0.001 ml (0.018 mmol) of ethanol, 2 mg (0.011 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.003 ml (0.018 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].Cl[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH:14]2[CH2:17][N:16]([C:18]([C:20]3[O:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:23][N:24]=3)=[O:19])[CH2:15]2)=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:2][N:3]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([S:13][CH:14]2[CH2:17][N:16]([C:18]([C:20]3[O:21][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:23][N:24]=3)=[O:19])[CH2:15]2)=[CH:11][CH:12]=1)[CH3:4]
Reactant: O=C(c1nnc(-c2ccccc2)o1)N1CC(Sc2ccc(CCl)cc2)C1
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc(SC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.6 %

Procedure:
Dimethylamine hydrochloride (0.10 g, 1.24 mmol) and 60B (0.16 g, 0.41 mmol) were mixed in DCM (5 ml). Triethylamine (0.290 ml, 2.07 mmol) was added and the mixture was stirred at RT for 2.5 h. More of triethylamine (0.290 ml, 2.07 mmol) and dimethylamine hydrochloride (0.10 g, 1.24 mmol) were added. The mixture was stirred overnight at RT and then diluted with DCM (10 ml). The mixture was washed with water, filtered through a phase separator and then evaporated. The residue was purified by column chromatography eluting with NH3 in MeOH (2M)/DCM (1:99, 2:98). There was obtained 0.14 g (84%) of 60 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.20 (s, 6H), 3.38 (s, 2H), 4.16 (m, 2H), 4.61 (m, 2H), 5.07 (m, 1H), 7.50 (t, 2H), 7.56 (t, 1H), 8.12 (d, 2H), MS (APCI+) m/z 395 [M+H]+, LC purity: 97%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.O1C[CH2:27][CH2:26][CH2:25]1.CN1CCCC1=O.C([Mg]Cl)(C)C>C(OCC)(=O)C.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[CH:26]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1)([CH3:27])[CH3:25]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc(C)c(-c2ccc3c(Cl)nncc3c2)c1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC(C)[Mg]Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C)c(-c2ccc3c(C(C)C)nncc3c2)c1
Reaction time: 0.17 h

Procedure:
A 50-mL round-bottom flask under argon was charged with ethyl 3-(1-chlorophthalazin-6-yl)-4-methylbenzoate (106 mg, 0.32 mmol), iron(III) acetylacetonate (5.7 mg, 0.032 mmol), tetrahydrofuran (2.2 mL), and 1-methyl-2-pyrrolidinone (0.22 mL). Isopropylmagnesium chloride (0.24 mL, 0.49 mmol) was added via a syringe to the resulting red solution, causing an immediate color change to brown, and then finally to dark brown. The resulting mixture was stirred for 10 min, and the reaction was diluted with ethyl acetate and carefully quenched with 10% HCl solution. The mixture was washed with saturated aqueous NaHCO3 solution and the organic layer was dried (MgSO4) and concentrated in vacuo. CombiFlash purification (20% to 50% ethyl acetate in hexanes) afforded the title compound as a cream amorphous solid. MS (ES+): 335.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:54]=[CH:53][C:16]([C:17]([N:19]([CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][N:30]=[C:29]([C:32]5[CH:37]=[CH:36][C:35]([C:38]6[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=6)=[CH:34][CH:33]=5)[N:28]=4)=[CH:23][CH:22]=3)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[C:5]([C:55]([F:58])([F:57])[F:56])[CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:19]([CH2:45][C:46]([OH:48])=[O:47])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][N:30]=[C:29]([C:32]5[CH:37]=[CH:36][C:35]([C:38]6[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=6)=[CH:34][CH:33]=5)[N:28]=4)=[CH:23][CH:22]=3)=[O:18])=[CH:53][CH:54]=2)=[O:11])=[C:5]([C:55]([F:58])([F:57])[F:56])[CH:4]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(-c4nc(-c5ccc(-c6ccc(C)cc6)cc5)no4)cc3)cc2)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4nc(-c5ccc(-c6ccc(C)cc6)cc5)no4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirring solution of tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetate INT-41 (77.0 mg, 0.097 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 1 h. The solvent was concentrated and the residue re-slurried from DCM (4 mL), then washed successively with DCM (2 mL) and isohexanes (2 mL) to afford 56 mg (78%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetic acid 362. LCMS-ESI (m/z) calculated for C41H33F3N4O6: 734; no ion observed, tR=8.91 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.82 (s, 1H), 10.34 (s, 1H), 8.35-8.04 (m, 4H), 8.04-7.81 (m, 2H), 7.75-7.52 (m, 6H), 7.49-7.30 (m, 5H), 7.26-7.15 (m, 2H), 4.79 (s, 1H), 4.72 (s, 1H), 4.06 (s, 1H), 4.01 (s, 1H), 3.90-3.78 (m, 5H), 2.38 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.NC[C:24]1[CH:25]=[C:26]([N:30]2[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]2)[CH:27]=[CH:28][CH:29]=1>C1(O)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][C:28]4[CH:29]=[CH:24][CH:25]=[C:26]([N:30]5[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]5)[CH:27]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NCc1cccc(N2CC[C@@H](O)C2)c1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Solvent: Oc1ccccc1
Product: O=c1c2sc(-c3ccc(Cl)cc3)cc2ncn1Cc1cccc(N2CC[C@@H](O)C2)c1
Temperature: 150 °C
Yield: 579.6 %

Procedure:
Methyl 5-(4-chlorophenyl)-3-{[(1E)-(dimethylamino)methylene]amino}thiophene-2-carboxylate (0.131 g, 0.41 mmol) and (3R)-1-[3-(aminomethyl)phenyl]pyrrolidin-3-ol (0.062 g, 0.26 mmol, purity 80%) in phenol (0.5 g) were subjected to microwave heating at 150° C. for 1 h. The product was precipitated with ether and decanted. The solid residue was washed with MeOH and CH2Cl2 to give 0.66 g (57%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.90 (s, 1H), 7.88 (d, 2H, J=8.7 Hz), 7.56 (d, 2H, J=8.7 Hz), 7.11 (t, 1H, J=7.9 Hz), 6.56-6.52 (m, 2H), 6.43 (d, 1H, J=7.5 Hz), 5.15 (s, 2H), 4.92 (d, 1H, J=7.5 Hz), 3.40-3.18 (m, 3H), 3.03 (bd, 1H, J=9-7 Hz), 2.07-1.95 (m, 1H), 1.91-1.82 (m, 1H). 13C NMR (100 MHz, DMSO-d6) δ 157.6, 156.1, 149.8, 149.6, 147.8, 137.4, 134.3, 131.3, 129.4, 127.9, 121.8, 121.7, 114.1, 110.9, 110.7, 69.2, 55.9, 48.9, 45.4, 33.6. MS (ESI+) 438.1 (M+1H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].F[B-](F)(F)F.[CH2:17]([O+](CC)CC)[CH3:18]>>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](=[NH:7])[O:6][CH2:17][CH3:18]
Reactant: CC[O+](CC)CC
Reactant: NC(=O)c1cccc(Cl)c1F
Agent: F[B-](F)(F)F
Product: CCOC(=N)c1cccc(Cl)c1F

Procedure:
starting from 3-chloro-2-fluorobenzamide and triethyloxonium tetrafluoroborate there is obtained ethyl 3-chloro-2-fluorobenzimidate as an oil; mass spectrum: 200 (10), 173 (25), 166 (15), 157 (100), 156 (73);