Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]1[CH:22]=[C:21]([C:23](O)=[O:24])[NH:20][N:19]=1.N>>[ClH:1].[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:23]([C:21]3[CH:22]=[C:18]([C:14]4[S:13][CH:17]=[CH:16][CH:15]=4)[NH:19][N:20]=3)=[O:24])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1cc(-c2cccs2)n[nH]1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc(-c2cccs2)[nH]n1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 3-(2-thienyl)-1H-pyrazole-5-carboxylic acid (Specs) according to methods A and C; yield 34 mg, 0.08 mmol (33%): 1H NMR (300 MHz, methanol-d4) δ 2.09-2.29 (m, 6H), 2.45 (s, 2H), 3.49 (d, J=13 Hz, 2H), 3.56 (s, 2H), 3.83 (d, J=13 Hz, 2H), 4.29 (s, 1H), 7.02 (s, 1H), 7.12 (dd, J=5, 4 Hz, 1H), 7.43 (dd, J=4, 1 Hz, 1H), 7.48 (dd, J=5, 1 Hz, 1H); MS (DCI/NH3) m/z 329 (M+H)+; Anal. C17H20N4OS.2HCl.0.15H2O.0.05C4H8O2: C, H, N.
Reaction SMILES: [C:1]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22].[OH2:29].[OH-].[Na+].OO>C1COCC1.C(OCC)(=O)C>[OH:29][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: C#CCCCCCCCCCCCCCCCCCCCC(=O)OC(C)(C)C
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCCCCO
Reaction time: 1 h
Yield: 54 %

Procedure:
A solution of the acetylene (33) (0.4 g, 1.02 mmol) in dry THF (5 ml) at room temperature under nitrogen was treated with borane-dimethyl sulphide complex (1.04 ml of a 2M solution in THF, 2.08 mmol) and the resulting solution stirred for 1 hour, after which time no starting material was present on tlc. The reaction was then treated sequentially with water (2 ml), 2N aqueous sodium hydroxide (1 ml) and 30% hydrogen peroxide (1 ml). The resulting solution was left a further 15 minutes, then ethyl acetate added and the organic layer separated. The aqueous layer was re-extracted with ethyl acetate, the organic layers combined, dried (MgSO4) and evaporated. The crude product obtained in this manner was purified on silica (5 g). Elution with 10% ethyl acetate in petrol gave tert.-butyl 22-hydroxydocosanoate (34) as a white solid (0.23 g, 54%).
Reaction SMILES: C1([O:7][S:8](=O)(=[O:10])[NH2:9])C=CC=CC=1.[CH3:12][O:13][C:14]([C:16]1([OH:19])[CH2:18][CH2:17]1)=[O:15]>>[CH3:12][O:13][C:14]([C:16]1([O:19][S:8](=[O:10])(=[O:7])[NH2:9])[CH2:18][CH2:17]1)=[O:15]
Reactant: NS(=O)(=O)Oc1ccccc1
Reactant: COC(=O)C1(O)CC1
Product: COC(=O)C1(OS(N)(=O)=O)CC1

Procedure:
1-Sulfamoyloxy-cyclopropanecarboxylic acid methyl ester was synthesized according to the method presented in the synthesis of sulfamic acid phenyl ester in Example 1 with the exception of utilizing 1-hydroxy-cyclopropanecarboxylic acid methyl ester to obtain 1-Sulfamoyloxy-cyclopropanecarboxylic acid methyl ester.
Reaction SMILES: C([C:3]1([C:16]([O-:18])=O)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)C.O.[NH2:20][NH2:21]>C(O)C>[NH:20]([C:16]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:18])[NH2:21]
Reactant: NN
Reactant: CCC1(C(=O)[O-])CCN(C(=O)OC(C)(C)C)CC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reaction time: 1 h

Procedure:
A mixture of 1-tert-butyl 4-ethylpiperidine-1,4-dicarboxylate (21 g), hydrazine monohydrate (40 mL), and ethanol (200 mL) was heated and refluxed for 22 hours. After leaving to be cooled, the solvent was evaporated under reduced pressure, to the residue were added saturated brine and ethyl acetate, and the organic phase was separated. The organic phase was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. To the residue was added diisopropyl ether, followed by stirring for 1 hour, and the resulting solid was collected by filtration and dried under reduced pressure to obtain tert-butyl 4-(hydrazinocarbonyl)piperidine-1-carboxylate (17.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:5]([C:7]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=O.C(=O)([O-])[O-].[K+].[K+].Br[CH:34](C(OCC)=O)[C:35]([O:37]CC)=[O:36]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[C:8](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=3)[C:9](=[O:10])[O:11][C:34]=2[C:35]([OH:37])=[O:36])[CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: COc1cc(C(=O)O)c(C(=O)c2cc(Br)c(OC)c(OC)c2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(-c3cc(Br)c(OC)c(OC)c3)c(C(=O)O)oc(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
To a solution of 2-(3-bromo-4,5-dimethoxybenzoyl)-4,5-dimethoxy-benzoic acid (6 g) in dimethylformamide (110 ml) are added potassium carbonate (4.29 g) and diethyl bromomalonate (3.71 g), and the mixture is stirred at room temperature overnight. The reaction mixture is evaporated to remove dimethylformamide, and to the residue are added ethyl acetate and water. The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure. To the residue are added dioxane (35 ml) and conc. hydrochloric acid (35 ml), and the mixture is heated under reflux for five hours. The reaction mixture is cooled, and thereto are added chloroform and water. The chloroform layer is separated, washed, dried, and concentrated under reduced pressure. The residue is crystallized from ether to give 4-(3-bromo-4,5-dimethoxyphenyl)-6,7-dimethoxyisocoumarin-3-carboxylic acid (2.54 g) as listed in Table 58.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH3:21])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: COc1ccccc1O
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COc1ccccc1OCCCOc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 2-methoxy-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil. MS (ES) for C20H24O6 [M+NH4]+: 378.4.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.I[CH3:10]>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[C:3]([O:8][CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Oc1ncccc1Br
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: COc1ncccc1Br
Reaction time: 24 h
Yield: 62.5 %

Procedure:
Under an argon atmosphere, a mixture of 3-bromo-2-hydroxypyridine (3.49 g, 20 mmol), silver carbonate (3.67 g, 13.31 mmol), and iodomethane (1.5 mL, 24.1 mmol) in benzene (30 mL) was stirred in the dark at 40° C. to 50° C. for 24 hours, cooled in an ice bath, and filtered. The filtrate was washed once with 2% aqueous sodium bicarbonate and twice with water, dried (MgSO4), the benzene was evaporated at atmospheric pressure, and the residue was purified by flash chromatography (eluting with hexane/ethyl acetate, 2:1) to obtain the title compound (2.35 g, 12.5 mmol, 62%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH:11]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH3:26])[CH:17]=1)[CH2:12][C:13](O)=[O:14].C(N1C=CN=C1)([N:29]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH:11]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH3:26])[CH:17]=1)[CH2:12][C:13]([NH2:29])=[O:14]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(N)=O)N2Cc3ccccc3C2=O)ccc1OC
Reaction time: 0.33 h
Yield: 76.6 %

Procedure:
A mixture of 3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionic acid (12.6 g, 35.4 mmol) and 1,1′-carbonyldiimidazole (5.97 g, 36.8 mmol), in tetrahydrofuran (100 mL) was stirred for 1.5 hours at room temperature. To the solution was added ammonium hydroxide (7.5 mL, 112.5 mmol, 28-30%) and stirring was continued for 20 minutes. The tetrahydrofuran was removed in vaciio and the remaining residue was slurried in 100 mL of water for 30 minutes. The mixture was filtered and the white solid was washed with water (150 mL), air dried and dried in vaczio (60° C., <1 mm). The resulting solid was recrystallized form ethyl acetate (1.1 L) and was then dried in vacuo (60° C., <1 mm) to afford 9.61 g (77%) of 3-(1-oxoisoindolin2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionamide as a white solid: mp 169-171.5; 1H NMR (DMSO-d6) δ7.75-7.40 (m, 5H), 7.05-6.80 (m, 4H), 5.75 (m, 1H), 4.56 (d, J=17.6 Hz, 1H), 4.14 (d, J=17.6 Hz, 1H), 3.98 (m, 2H), 3.72 (s, 3H), 2.93 (m, 2H), 1.30 (t, J=6.9 Hz, 3H); 13C NMR (DMSO-d6) δ171.2, 166.8, 148.3, 147.8, 141.6, 132.2, 132.1, 131.2, 127.8, 123.4, 122.7, 119.1, 112.1, 111.7, 63.6, 55.4, 51.3, 46.2, 37.8, 14.6; Anal. Calcd. for C20H22N2O5. Theoretical: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.89; H, 6.31; N, 7.83.
Reaction SMILES: [Mg].Br[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][N:10]2[CH3:13])=[CH:5][CH:4]=1.[CH:16](=[O:18])[CH3:17]>O1CCCC1>[CH3:17][CH:16]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][N:10]2[CH3:13])=[CH:5][CH:4]=1)[OH:18]
Reactant: CC=O
Reactant: CN1CCC(C)(C)c2ccc(Br)cc21
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)N(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
2 g of Magnesium shavings were covered with 20 ml of tetrahydrofuran. A solution of 20.8 g of 7-bromo-1,2,3,4-tetrahydro-1,4,4-trimethylquinoline in 80 ml of tetrahydrofuran was added dropwise thereto at 55°-60° C. using an ultrasonics bath. Thereafter, the mixture was boiled at reflux for an additional 2 hours, cooled to 0° C. and a solution of 10 g of acetaldehyde in 80 ml of tetrahydrofuran was added dropwise thereto. After stirring at room temperature for 1 hour, the mixture was poured on to ice/saturated ammonium chloride solution and extracted with ether. The oil obtained after drying and evaporation of the solvent was filtered over a silica gel column (eluting agent hexane/ethyl acetate 9:1) and gave 14.5 g of 1,2,3,4-tetrahydro-α,1,4,4-tetramethyl-7-quinolinemethanol as a yellowish oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[N:2]1.[NH2:8][C:9]([CH3:31])([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[C:10]([NH:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])=[O:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>N1C=CC=CC=1>[NH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([CH2:21][C:9]([CH3:31])([NH:8][CH2:6][C:3]2[NH:2][N:1]=[CH:5][CH:4]=2)[C:10]([NH:12][CH:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])=[O:11])=[CH:23]1
Reactant: CC(NC(=O)C(C)(N)Cc1c[nH]c2ccccc12)c1ccccc1
Reactant: O=Cc1cc[nH]n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(NC(=O)C(C)(Cc1c[nH]c2ccccc12)NCc1ccn[nH]1)c1ccccc1
Yield: 10 %

Procedure:
To a stirred solution of pyrazole-3-carboxaldehyde (96 mg, 1 mmol, supplied as dimer) in pyridine (10 mL) was added 2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide (161 mg, 0.5 mmol) followed by sodium triacetoxyborohydride (848 mg, 4 mmol). After stirring over night at room temperature another portion of sodium triacetoxyborohydride (424 mg, 2 mmol) was added. After stirring over night at room temperature the pyridine was removed under reduced pressure. The residue was taken up in CH2Cl2 (100 mL) and saturated NaHCO3. The aqueous phase was extracted with CH2Cl2 (100 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO4), and the solvent was removed under reduced pressure. The residue was initially purified by chromatography on normal phase silica using 95% EtOAc in heptane as eluent. The solvent was removed under reduced pressure and the residue was dissolved in aqueous acetonitrile and acidified using formic acid. Purification by chromatography on reverse phase silica using 25% CH3CN in H2O (0.1% formic acid in mobile phases) as eluent gave pure product. The solvent was removed under reduced pressure and the residue was suspended between EtOAc and saturated NaHCO3. The EtOAc was dried (MgSO4) and the solvent was removed under reduced pressure to give pure product as a glass (20 mg, 10%); IR (film): 3260, 3059, 2979, 2927, 1651, 1515, 1456, 1374, 1266, 1105, 1048, 1011, 932, 741 cm−1; NMR (DMSO-d6): δ1.22 (3H, s); 1.35 (3H, d, J=6.8 Hz); 2.26 (1H, s); 2.96-3.05 (2H, m); 3.50-3.75 (2H, m); 4.93 (1H, s); 6.10 (1H, s); 6.89-6.93 (2H, m); 7.00-7,04 (1H, m); 7.18-7.32 (6H, m); 7.35 (0.5H, s); 7.52 (1H, d, J=7.8 Hz); 7.60 (0.5H, s); 8.05-8.20 (1H, m); 10.82 (1H, s); 12.52 (0.5H, s); 12.73 (0.5H, s); MS m/e (ES+): 424.1 (27%); 402.1 (100%, M++H).
Reaction SMILES: [CH2:1]([N:3]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C@@H:30]([CH3:46])[C:31](N2[C@H](C)[C@H](C3C=CC=CC=3)OC2=O)=[O:32])[CH:21]=1)[C:4]([CH:6]1[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH-:47].[Li+].OO.Cl>O>[CH:6]1([C:4]([N:3]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[C:22]([C@@H:30]([CH3:46])[C:31]([OH:32])=[O:47])[CH:21]=2)[CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]1
Reactant: [OH-]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)N2C(=O)O[C@@H](c3ccccc3)[C@H]2C)cc(C(F)(F)F)c1)C(=O)C1CC1
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: O
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)O)cc(C(F)(F)F)c1)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of cyclopropanecarboxylic acid ethyl-{3′-[(R)-1-methyl-2-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-2-oxo-ethyl]-4,5′-bis-trifluoromethyl-biphenyl-2-ylmethyl}-amide (0.036 g, 0.06 mmol) in THE (1 mL) and H2O (1 mL) was added lithium hydroxide (0.005 g, 0.11 mmol) and hydrogen peroxide (29%; 0.01 mL, 0.11 mmol), and the reaction was stirred at room temperature overnight. The mixture was acidified to pH 5 with 10% aqueous HCl and extracted with EtOAc. The crude material was purified by preparative HPLC to give the title compound. M+H is 488.
Reaction SMILES: FC(F)(F)C(C(O)=O)=O.[NH2:10][CH:11]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)[CH2:16][CH2:15]1)=[O:13].[CH:40]([N:43]1[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]1[CH2:52][C:53](O)=[O:54])([CH3:42])[CH3:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][CH:11]([NH:10][C:53](=[O:54])[CH2:52][C@@H:44]2[C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:51][N:43]2[CH:40]([CH3:41])[CH3:42])[C:12](=[O:13])[N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH2:26][N:27]3[CH:31]=[N:30][CH:29]=[N:28]3)[CH2:16][CH2:15]2)=[CH:38][CH:37]=1
Reactant: NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2Cn2cncn2)CC1
Reactant: CC(C)N1Cc2ccccc2C1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)C(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N1Cc2ccccc2[C@H]1CC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2Cn2cncn2)CC1
Reaction time: 3 h
Yield: 17.4 %

Procedure:
To a solution of 2-amino-3-(4-chloro-phenyl)-1-[4-(2-[1,2,4]triazol-1-ylmethyl-phenyl)-piperazin-1-yl]-propan-1-one trifluoroacetyl carboxylate salt(0.30 g, 0.55 mmol), (2-isopropyl-2,3-dihydro-1H-isoindol-1-yl)-acetic acid (0.12 g, 0.55 mmol), HATU (0.21 g, 0.55 mmol) in DCM was added DIPEA (0.19 mL, 1.13 mmol). After about 3 hours, the solution was purified by silica gel chromatography (eluent: 3% 2.0M NH3 in MeOH/DCM). The purified fractions were combined and concentrated under reduced pressure to give the final compound as white foam (0.06 g, 18%). ES MS 626.3 (M+H)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](SC)[N:5]2[N:10]=[C:11]([CH2:13][CH3:14])[N:12]=[C:4]2[CH:3]=1.[OH-:15].[K+]>>[Cl:1][C:2]1[N:7]=[C:6]([OH:15])[N:5]2[N:10]=[C:11]([CH2:13][CH3:14])[N:12]=[C:4]2[CH:3]=1
Reactant: CCc1nc2cc(Cl)nc(SC)n2n1
Reactant: [OH-]
Agent: [K+]
Product: CCc1nc2cc(Cl)nc(O)n2n1

Procedure:
In analogy to Example 33A, 242 mg (99% of theory) of the product are obtained from 280 mg (1.22 mmol) of 7-chloro-2-ethyl-5-(methylsulphanyl)[1,2,4]triazolo[1,5-c]pyrimidine (Example 101A) by heating in methanolic potassium hydroxide solution.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[C:12](=O)([O-])[O-].[K+].[K+].IC>CC(=O)CC>[CH3:12][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:9])([F:10])[F:11]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccccc1C(F)(F)F
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CI
Product: COc1ccccc1C(F)(F)F
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A stirred solution of 2-hydroxybenzotrifluoride (23.0 g, 142 mmol) in 2-butanone (107 mL) was treated with potassium carbonate (25.51 g, 185 mmol) and iodomethane (13.3 mL, 213 mmol). The mixture was heated at reflux overnight under argon until the thin-layer chromatography showed a completed reaction. The mixture was cooled to room temperature and filtered through diatomaceous earth. The filtered solid was washed with acetone and the filtrate concentrated carefully in vacuo without heating. The resulting crude liquid was purified by vacuum distillation to yield the title compound (21.79 g, 0.124 mol, 87%) as a colorless liquid.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1.ClC1NC2C=CC=CC=2N=1.[CH:24]([C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH2:29])([CH3:26])[CH3:25]>CN1C(=O)CCC1.O>[CH:24]([C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH:29][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1)([CH3:26])[CH3:25]
Reactant: CC(C)c1ccccc1N
Reactant: O=[N+]([O-])c1ccc2[nH]c(Cl)nc2c1
Agent: Clc1nc2ccccc2[nH]1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)c1ccccc1Nc1nc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-5-nitro-1H-benzimidazole (1.5 mmol; prepared from nitration of 2-chloro-1H-benzimidazole; Galy et al, J. Heterocycl. Chem. 1997, 34, 6, 1781-1788) in dry NMP (3 mL) was added 2-isopropylaniline (4 mmol). The resulting solution was subjected to microwave irradiation at 150° C. for 1 h. The contents were cooled to room temperature, diluted with water (20 mL) and extracted with EtOAc (2×15 mL). The combined extracts were then washed with water (20 mL) and brine (20 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue obtained was purified by silica gel chromatography using EtOAc/hexane as eluent to obtain (2-isopropylphenyl)-(5-nitro-1H-benzimidazol-2-yl)-amine as light yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[O:30][CH2:31][CH3:32])=[CH:11][CH:10]=1)#[N:2].C[Sn]([N:37]=[N+:38]=[N-:39])(C)C>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:17]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:39][N:38]=[N:37][N:2]=3)=[CH:14][CH:13]=2)[C:20]2[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1)[CH3:32]
Reactant: CCOC(=O)c1cccc2nc(OCC)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc2nc(OCC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylate (0.7 g) and trimethyltin azide (0.7 g) in toluene (15 ml) was heated under reflux for 4 days. The reaction mixture was concentrated to dryness and to the residue were added methanol (20 ml) and 1N-HCl (10 ml). The mixture was stirred at room temperature for 30 minutes and adjusted to pH 3 to 4 with 1N NaOH. After removal of the solvent, the residue was partitioned between chloroform and water. The organic layer was washed with water and dried, and the solvent was evaporated to dryness to give a syrup. The syrup was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals (0.35 g, 45%), m.p. 158°-159° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[O:18])=[CH:16][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:20]=1)=O.[C:21]1([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.CC(O)=O>[C:21]1([CH:27]2[CH2:31][CH2:30][N:29]([CH2:1][C:3]3[CH:4]=[CH:5][C:6]4[O:12][C:11]5[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[O:18])=[CH:16][C:10]=5[CH2:9][CH2:8][C:7]=4[CH:20]=3)[CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)c1ccc2c(c1)CCc1cc(C=O)ccc1O2
Reactant: c1ccc(C2CCNC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NC(=O)c1ccc2c(c1)CCc1cc(CN3CCC(c4ccccc4)C3)ccc1O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of aldehyde intermediate obtained in step 4, Example 1 (92 mg, 0.34 mmol) in THF/AcOH (6.5 mL/30 μL) add 3-phenylpyrrolidine (0.34 mmol). Stir the mixture at room temperature overnight. Add NaBH(OAc)3 (0.52 mmol) and stir at room temperature overnight. Eliminate the solvent and purify by ISCO chromatography (eluent: CHCl3/B 0-10%; B: EtOH/NH4OH 10%).
Reaction SMILES: Br[C:2]1[C:3]([O:32][CH3:33])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:14]4[C:15](=[O:26])[N:16]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:13]=4[C:12]([C:27]4[S:31][CH:30]=[N:29][CH:28]=4)=[C:9]3[C:10]=2[CH:11]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1.C([O-])([O-])=O.[K+].[K+].C(COC)OC>O>[C:22]([N:16]1[C:15](=[O:26])[C:14]2[N:8]3[CH2:7][CH2:6][C:5]4[CH:4]=[C:3]([O:32][CH3:33])[C:2]([C:36]5[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=5)=[CH:11][C:10]=4[C:9]3=[C:12]([C:27]3[S:31][CH:30]=[N:29][CH:28]=3)[C:13]=2[CH2:21][O:20][CH2:19][CH2:18][CH2:17]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: OB(O)c1cccnc1
Reactant: COc1cc2c(cc1Br)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCOC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1cc2c(cc1-c1cccnc1)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCOC3
Yield: 93.7 %

Procedure:
A solution of 75 mg of 8e, 35 mg of pyridine-3-boronic acid, 60 mg of K2CO3 in 2 ml of degassed 90% aq. dimethoxyethane was heated at 90° C. for 16 h The reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The organic layer was once washed with 1M K2CO3, once with water, dried and concentrated. The crude material was chromatographed over silica gel using a gradient of toluene/acetone. The isolated material was treated with diethyl ether and provided 70 mg of 8f; Mp 200-201° C.; Rf 0.15 (toluene/acetone 7/3). MS-ESI: [M+1] 529.3.