Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:14]=[C:13]([O:15][CH:16]([CH3:18])[CH3:17])[NH:12][N:11]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[F:20][C:21]1[CH:22]=[N:23][C:24]([C@@H:27]([NH2:29])[CH3:28])=[N:25][CH:26]=1.CCN(C(C)C)C(C)C>CCCCO>[Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:14]=[C:13]([O:15][CH:16]([CH3:18])[CH3:17])[NH:12][N:11]=2)=[N:4][C:5]([NH:29][C@H:27]([C:24]2[N:25]=[CH:26][C:21]([F:20])=[CH:22][N:23]=2)[CH3:28])=[N:6][CH:7]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2Br)n[nH]1
Temperature: 165 °C
Yield: 60 %

Procedure:
A mixture of 5-bromo-2-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 13, 150 mg, 0.45 mmol), (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 88 mg, 0.5 mmol) and DIPEA (0.12 ml) in n-BuOH (2 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated in microwave reactor at 165° C. for 4 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (20-60% EtOAc in hexanes) to give the titled compound as solid (118 mg, 60%). NMR: 11.98 (s, 1H), 9.36 (s, 1H), 8.82 (s, 2H), 8.10 (s, 1H), 7.96 (s, 1H), 5.56 (s, 1H), 5.13 (s, 1H), 4.66 (m, 1H), 1.48 (m, 3H), 1.26 (m, 6H); m/z 437.
Reaction SMILES: [F:1][C:2](=[C:13]([F:15])[F:14])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17]>C1COCC1>[F:1][C:2](=[C:13]([F:15])[F:14])[CH2:3][C:4](=[S:17])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CC(F)=C(F)F)Nc1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Product: FC(F)=C(F)CC(=S)Nc1ccccc1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
A mixture of 3,4,4-trifluoro-N-phenyl-3-butenamide (1.0 g, 4.65 mmol) and phosphorus pentasulfide (2.07 g, 4.65 mmol) in anhyd. THF (100 mL) was heated at reflux under nitrogen for 1 hour. The reaction mixture was cooled to r.t. and filtered. The filtrate was concentrated and the residue was chromatographed over silica gel (dichloromethane/hexanes, 80/20) to give 0.65 g (60%) of the desired compound as a pale yellow solid. m.p. 65-67° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15](SC)=[CH:16][N+:17]([O-:19])=[O:18])[N:9]=1)[CH3:3].[CH3:22][O:23][CH2:24][CH2:25][NH2:26]>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:26][CH2:25][CH2:24][O:23][CH3:22])=[CH:16][N+:17]([O-:19])=[O:18])[N:9]=1)[CH3:1]
Reactant: COCCN
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1csc(CN(C)C)n1
Solvent: CCO
Product: COCCNC(=C[N+](=O)[O-])NCCSCc1csc(CN(C)C)n1

Procedure:
A reaction mixture, prepared from 1.25 g of 1-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-1-methylthio-2-nitroethylene, 0.27 g of 2-methoxyethylamine and 20 ml of ethanol, was heated to refluxing temperature for about three hours. The solvent was then removed by evaporation and the resulting residue was chromatographed over silica using a gradient elution technique. The desired compound was eluted with a 5:95 methanol:ethyl acetate solvent mixture. Removal of the solvent yielded N-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-(2-methoxy)ethyl 2-nitro-1,1-ethenediamine as an oil.
Reaction SMILES: Cl.[OH:2][C@@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[S:8][C:7]2[C:18]3[C:23]([CH:24]=[CH:25][C:6]=2[N:5]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:4]1=[O:31])=[CH:22][CH:21]=[CH:20][CH:19]=3.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([O:2][C@@H:3]1[C@H:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[S:8][C:7]2[C:18]3[C:23]([CH:24]=[CH:25][C:6]=2[N:5]([CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])[C:4]1=[O:31])=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:34])[CH3:33]
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Reaction time: 7 h
Yield: 98 %

Procedure:
A mixture of 3.6 g of (+)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[1,2-b]-1,4-thiazepin-4(5H)-one hydrochloride and 6 mL acetic anhydride was stirred at 100° for 7 hours. The excess reagent was removed under reduced pressure and to the residue ice-water was added. The resulting suspension was made basic with concentrated ammonium hydroxide and extracted with methylene chloride. The combined methylene chloride solutions were washed with water (15 mL) and dried (magnesium sulfate). Removal of the solvent at reduced pressure gave 3.6 g (98%) of (+)-cis-3-(acetyloxy)-2,3-dihydro-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[1,2-b]-1,4-thiazepin-4(5H)-one as an amorphous compound, [α]D25 +11.02° (C 0.56, MeOH).
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:15])[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:5][CH2:4]1.[CH2:16](Br)[CH2:17][CH3:18].O>CN(C)C=O>[CH2:16]([CH:12]1[CH2:13][CH2:14][CH:9]([CH:6]2[CH2:5][CH2:4][CH:3]([OH:15])[CH2:8][CH2:7]2)[CH2:10][CH2:11]1)[CH2:17][CH3:18]
Reactant: OC1CCC(C2CCCCC2)CC1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC1CCC(C2CCC(O)CC2)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
60% Sodium hydride (1.01 g) was added slowly to a suspension of 4,4′-bicyclohexanol (5 g) in N,N-dimethylformamide (50 ml) at ambient temperature, and the mixture was stirred for 6 hours at 80° C. To the mixture was added dropwise n-propylbromide (2.29 ml) at 0-5° C., and the reaction mixture was stirred for 18.5 hours at 80° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methyl alcohol (50:1) to give 4′-propyl-4-hydroxy-1,1′-bicyclohexane (1.21 g).
Reaction SMILES: [NH2:1][C@H:2]1C[CH2:5][C@H:4](O)[CH2:3]1.[CH3:8][C@@H:9]([C@@H:15]1[C@@:19]2([CH3:35])[C@@H:20]([OH:34])[CH2:21][C@@H:22]3[C@@:27]4([CH3:33])[CH2:28][CH2:29][C@@H:30]([OH:32])[CH2:31][C@H:26]4[CH2:25][CH2:24][C@H:23]3[C@@H:18]2[CH2:17][CH2:16]1)[CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH3:36][OH:37]>>[NH2:1][C@H:2]1[C@H:36]([OH:37])[CH2:5][CH:4]=[CH:3]1.[CH3:8][C@@H:9]([C@@H:15]1[C@@:19]2([CH3:35])[C@@H:20]([OH:34])[CH2:21][C@@H:22]3[C@@:27]4([CH3:33])[CH2:28][CH2:29][C@@H:30]([OH:32])[CH2:31][C@H:26]4[CH2:25][CH2:24][C@H:23]3[C@@H:18]2[CH2:17][CH2:16]1)[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CO
Reactant: N[C@H]1CC[C@H](O)C1
Agent: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Product: N[C@@H]1C=CC[C@H]1O

Procedure:
A 49.5 g (0.50 M) quantity of dl trans-3-amino-hydroxycyclopentane dissolved in about 100-200 ml of methanol and 98 g (0.25M) of deoxycholic acid dissolved in about 200-300 ml of methanol are mixed and allowed to crystallize for several hours. The crystals of trans-3-amino-4-hydroxycyclopentene are collected by filtration and washed three times with some portions of methanol. There is obtained 105 g of trans-3-amino-4-hydroxycyclopentene deoxycholate as light beige crystals, m.p. 195°-197° (dec). The mother liquors are saved for Step 2.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([O:17][C@H:18]3[CH2:22][N:21](C(OC(C)(C)C)=O)[C@H:20]([C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])[CH2:19]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH:39]=[CH2:40])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1.[CH2:48]([O:51][C:52]([NH:54][C@H:55]([C:60](O)=[O:61])[CH2:56][CH2:57][CH2:58][CH3:59])=[O:53])[CH:49]=[CH2:50].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH2:48]([O:51][C:52]([NH:54][C@H:55]([C:60]([N:21]1[CH2:22][C@H:18]([O:17][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH:39]=[CH2:40])[CH:13]=3)[N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:16]=2)[CH2:19][C@H:20]1[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])=[O:61])[CH2:56][CH2:57][CH2:58][CH3:59])=[O:53])[CH:49]=[CH2:50]
Reactant: C=CCOC(=O)N[C@@H](CCCC)C(=O)O
Reactant: C=Cc1ccc2nc(-c3ccccc3)cc(O[C@@H]3C[C@@H](C(=O)OCC[Si](C)(C)C)N(C(=O)OC(C)(C)C)C3)c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N[C@@H](CCCC)C(=O)N1C[C@H](Oc2cc(-c3ccccc3)nc3ccc(C=C)cc23)C[C@H]1C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a flask containing 1-tert-butyl 2-[2-(trimethylsilyl)ethyl] (2S,4R)-4-[(2-phenyl-6-vinylquinolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylate 5 (45 mg, 0.08 mmol) was added a 4 M solution of HCl in dioxane (1.4 mL, 5.6 mmol). After 1 h, LC-MS analysis indicated complete consumption of the starting material (5) and formation of the desired -Boc product. The volatile components were then removed in vacuo, and the crude material was taken up in DMF (1 mL). To this mixture was added alloc-Nle-OH (4) (26 mg, 0.12 mmol), DIPEA (0.144 mL, 0.8 mmol), and TBTU (39 mg, 0.12 mmol). After stirring at RT for 30 min, complete consumption of the amine was evidenced via LC-MS. The reaction mixture was then worked-up with 1N HCl and EtOAc. The organic layer was washed with brine and dried over MgSO4. The solvent was then removed in vacuo and the crude product was purified on silica (10-50% EtOAc/hexanes) to yield 50 mg (95% yield) of 2-(trimethylsilyl)ethyl N-[(allyloxy)carbonyl]-L-norleucyl-(4R)-4-[(2-phenyl-6-vinylquinolin-4-yl)oxy]-L-prolinate 6. 1H NMR (500 MHz, CDCl3) ppm: mixture of amide rotamers: 8.07 (m, 3H), 7.97 (br s, 1H), 7.88 (m, 1H), 7.54-7.47 (m, 3H), 7.07 (s, 1H), 6.92 (dd, J=17.5 Hz, 10.5 Hz, 1H), 5.90 (d, J=17.5 Hz, 1H), 5.83 (m, 1H), 5.43-5.63 (m, 3H), 5.25-5.13 (m, 2H), 4.79 (app t, J=8 Hz, 1H), 4.65-4.37 (m, 4H), 4.26 (m, 2H), 4.10 and 4.08 (2 d, J=4.0 Hz and 4.5 Hz, 1H), 2.78 (m, 1H), 2.42 (m, 1H), 1.83 (m, 1H), 1.63 (m, 1H), 1.44-1.33 (m, 4H), 1.05-0.98 (m, 2H), 0.92 (m, 3H), 0.05 (s, 9H). LRMS (CI, [M+H]) Calc'd=658.4. Found=658.4. HRMS (APCI, [M+H]+) Calc'd for C37H48N3O6Si: 658.3307. found: 658.3348.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:13][C:14]3[C:19]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH3:27])[N:21]=4)=[CH:18][CH:17]=[CH:16][N:15]=3)[C:8]([CH3:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:28][C:29]([F:39])([F:38])[O:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34].Cl.N>O1CCOCC1.CO>[CH3:12][C:8]1[C:7]([O:13][C:14]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH3:27])[N:21]=3)=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([NH:34][C:33]1[CH:35]=[CH:36][CH:37]=[C:31]([O:30][C:29]([F:28])([F:38])[F:39])[CH:32]=1)=[N:3][CH:4]=[CH:5]2
Reactant: CNc1nccc(-c2cccnc2Oc2c(C)ccc3c(Cl)nccc23)n1
Reactant: Nc1cccc(OC(F)(F)F)c1
Agent: Cl
Agent: N
Solvent: CO
Solvent: C1COCCO1
Product: CNc1nccc(-c2cccnc2Oc2c(C)ccc3c(Nc4cccc(OC(F)(F)F)c4)nccc23)n1
Temperature: 170 °C

Procedure:
4-(2-(1-Chloro-6-methylisoquinolin-5-yloxy)pyridin-3-yl)-N-methylpyrimidin-2-amine (0.150 g, 0.40 mmol) was suspended in dioxane (1.00 mL) to which mixture was added 3-(trifluoromethoxy)aniline (0.12 ml, 0.79 mmol). 4N HCl in dioxane (1.00 mL) was added and the mixture was stirred. The vessel was sealed and heated to 170° C. in microwave for 15 minutes. The reaction mixture was treated with 2M ammonia in methanol and concentrated directly onto silica gel. The material was chromatographed eluting with a gradient of EtOAc/hexanes (15-100%) followed by trituration of the pure material in EtOAc to afforded 6-methyl-5-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)-N-(3-(trifluoromethoxy)phenyl)isoquinolin-1-amine. MS (M+H)+ 519.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12](Cl)=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:15][C:16]1[CH:25]=[CH:24][C:19]2=[N:20][C:21](=[O:23])[N:22]=[C:18]2[CH:17]=1.O.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([C:12]([NH:15][C:16]2[CH:25]=[CH:24][C:19]3=[N:20][C:21](=[O:23])[N:22]=[C:18]3[CH:17]=2)=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(Cl)c1cc2ccccc2cc1O
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1N=c2ccc(NC(=O)c3cc4ccccc4cc3O)cc2=N1
Yield: 86 %

Procedure:
CS 178560 describes the reaction of a solution of 3-hydroxy-2-naphthoyl chloride in toluene with 5-aminobenzimidazolone in the 30-fold amount of water in the presence of sodium acetate to give 3-hydroxy-N-benzimida-zolon-5-yl-2-naphthamide in 86% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9][CH3:10])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:19])C=1.CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([CH3:10])=[O:19])=[CH:4][N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1ccc(Cl)nc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CS(=O)Cc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of 2-chloro-5-[(methylthio)methyl]pyridine (A) (7.60 g, 40 mmol) in chloroform (100 mL) cooled in ice-water bath was added a solution of 70-75% m-chloroperbenzoic acid (mCPBA, 10.51 g, ca 44 mmol) in chloroform (110 mL) over a period of 1.5 h under stirring. The stirring was continued for another 1 h at 0° C. Methanol (12 mL) was added to the mixture, which was then bubbled with ammonia gas to precipitate the benzoic acid and the extra mCPBA if any. TLC showed there was small amount of unreacted starting material in the reaction mixture. Most of the ammonium salt was removed by filtration. The filtrate was concentrated before it was loaded onto a Et3N-treated silica gel plug, which was eluted with 10% MeOH in CH2Cl2 to give 7.6 g of 2-chloro-5-[(methylsulfinyl)methyl]pyridine (B) in 92% yield as a colorless oil that turned into a white solid upon drying in vacuo (m.p. 72-74° C.). LC-MS (ELSD): mass calcd for C7H8CINOS [M+H]+ 190.67. Found: 190.21.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([OH:23])[CH2:8][C:9]1([OH:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:26]([O:23][CH:7]([CH2:6][O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:8][C:9]1([OH:22])[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OCC(O)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OCC(CC1(O)CCN(C(=O)OC(C)(C)C)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97 %

Procedure:
2.59 g of tert-butyl 4-[3-(tert-butoxy)-2-hydroxypropyl]-4-hydroxy-1-piperidinecarboxylate was dissolved in 10 ml dimethylformamide, 400 mg of sodium hydride and 823 mg of benzyl chloride were added thereto, and the mixture was stirred at room temperature for 20 min. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with water and brine, and dried over magnesium sulfate. After filtration, the solvent was evaporated, and the resulting residue was-purified by silica gel column chromatography (hexane/ethyl acetate) to give 2.66 g of tert-butyl 4-(2-(benzyloxy)-3-(tert-butoxy)propyl]-4-hydroxy-1-piperidinecarboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH3:10].C1COCC1.C([Li])CCC.C(O[B:25]1[O:33][C:30]([CH3:32])([CH3:31])[C:27]([CH3:29])([CH3:28])[O:26]1)(C)C>O>[CH2:9]([S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:25]1[O:33][C:30]([CH3:32])([CH3:31])[C:27]([CH3:29])([CH3:28])[O:26]1)[CH3:10]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CCSc1ccccc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCSc1ccccc1B1OC(C)(C)C(C)(C)O1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A mixture of 14.1 g of 1-bromo-2-ethylsulfanylbenzene and 65 mL of THF was cooled to −70° C., and 44.7 ml of n-butyl lithium (1.63M hexane solvent) was added at a rate such that the internal temperature of the mixture was kept at −60° C. or less, and the mixture was stirred at −50° C. for 30 minutes. A mixture of 14 g of isopropoxyboronic acid pinacol ester and 5 mL of THF was added at a rate such that the internal temperature of the mixture was kept at −60° C. or less, and the mixture was heated to the room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 7.9 g of 2-ethylsulfanylphenylboronic acid pinacol ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.O.[NH2:24][NH2:25]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:24][NH:25]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCCCC3)nc(N)n2)cc1F
Solvent: CCO
Solvent: O
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCCCC2)n1
Temperature: 95 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
In a 25 mL sealable tube under argon were combined 4-[2-amino-6-(1-piperidinyl)-4-pyrimidinyl]-2-fluorobenzonitrile (0.106 g, 0.258 mmol), hydrazine monohydrate (0.51 mL, 10.3 mmol) and EtOH (5 mL). The vial was sealed and the reaction mixture was stirred overnight at 95° C. The reaction was cooled to room temperature and concentrated. The resulting solid was sonicated on a mixture of EtOH (1 mL) and water (9 mL). The mixture was filtered and the solid was washed with water and dried under vacuum at 40° C. to afford the title compound (66 mg, 80%) as a white solid. LC-MS (ES) m/z=310 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.53 (m, 4H), 1.64 (m, 2H), 3.47-3.79 (m, 4H), 5.37 (s, 2H), 6.03 (s, 2H), 6.58 (s, 1H), 7.57 (dd, J=8.3, 1.3 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.94 (s, 1H), 11.49 (s, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:24]([O:25][CH3:26])=[CH:23][C:8]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)=[O:10])=[CH:7][C:6]=1[O:27][CH3:28])(=[O:3])[CH3:2].CC(C1C=C(C=C(C(C)(C)C)C=1O)C(NCC1C=CC([N+]([O-])=O)=CC=1)=O)(C)C>>[C:1]([O:4][C:5]1[C:24]([O:25][CH3:26])=[CH:23][C:8]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)=[O:10])=[CH:7][C:6]=1[O:27][CH3:28])(=[O:3])[CH3:2]
Reactant: COc1cc(C(=O)NCCc2ccc([N+](=O)[O-])cc2)cc(OC)c1OC(C)=O
Agent: CC(C)(C)c1cc(C(=O)NCc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Product: COc1cc(C(=O)NCCc2ccc(N)cc2)cc(OC)c1OC(C)=O

Procedure:
The experimental protocol used is the same as that described for intermediate 2-2, with 4-acetoxy-3,5-dimethoxy-N-[2-(4-nitrophenyl)ethyl]-benzamide replacing the 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide. A colourless oil is obtained with a quantitative yield. The product is used directly in the following stage without additional purification.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]([CH3:23])[NH:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][CH:11]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]([CH3:23])[NH:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1NC(=O)NN=C1c1ccc(NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
Benzaldehyde (0.25 g) was added to a solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.48 g) in methanol (45 ml), and the mixture was stirred for 1.5 hours at room temperature. Acetic acid (0.13 ml) was added thereto and then a solution of sodium cyanoborohydride (0.1 g) in methanol (0.7 ml) was added dropwise with stirring. After adding, the reaction mixture was warmed at 50° C. for 2 hours under stirring and evaporated in vacuo. An aqueous solution of sodium bicarbonate was added to the residue and the mixture was triturated to give 6-(4-benzylaminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.68 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6](O)=[O:7].C(Cl)(=O)C(Cl)=O.[CH3:18][NH2:19]>CN(C=O)C.C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][CH3:18])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: CN
Reactant: O=C(O)c1ccc(F)cc1O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(F)cc1O
Reaction time: 2 h

Procedure:
DMF (2 drops) was added to a mixture of 4-fluorosalicylic acid (2 g, 12.8 mmol) and oxalyl chloride (2.85 mL, 32.0 mmol) in THF (15 mL). The reaction was stirred for 2 hours then reduced in vacuo. The residue was dissolved in THF (10 mL) and added dropwise to 2M methylamine in THF (32 mL) at 0° C. The reaction was stirred at RT for 72 hours and the THF removed in vacuo. The residue was partitioned between ethyl acetate (80 mL) and water (80 mL). The aqueous layer was further extracted into ethyl acetate (80 mL) and the combined organics washed with brine (50 mL), dried (MgSO4), and reduced in vacuo to give a white solid. The material was chromatographed on silica, eluting with 5-40% ethyl acetate in isohexane, to give the desired compound as a white solid (1.43 g).
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[NH2:32][C:33]1[CH:50]=[CH:49][C:36]([C:37]([N:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][CH2:41][CH2:40]2)=[O:38])=[CH:35][CH:34]=1.C(N(CC)CC)C>O1CCCC1>[N:1]1([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH:32][C:33]2[CH:50]=[CH:49][C:36]([C:37]([N:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][CH2:41][CH2:40]3)=[O:38])=[CH:35][CH:34]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Reactant: O=C(O)c1ccccc1-n1cccc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2CCCc3ccccc32)cc1)c1ccccc1-n1cccc1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
To a solution of 2-(1-pyrrolyl)benzoic acid (206 mg), diphenyl chlorophosphate (325 mg), 1-(4-aminobenzoyl}-1,2,3,4-tetrahydroquinoline (277 mg) in tetrahydrofuran (10 ml) was added triethylamine (333 mg) at 0° C. The resulting mixture was allowed to warm to ambient temperature where it was maintained for 5 hours. The solvent was evaporated and diluted with ethyl acetate and washed with water, saturated sodium bicarbonate aqueous solution and brine. The organic layer was dried over sodium sulfate and concentrated to give 1-{4-[2-(1-pyrrolyl)benzoylamino]benzoyl}-1,2,3,4tetrahydroquinoline (280 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(Cn2cccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A mixture of 4-nitrobenzyl bromide (0.500 g, 2.31 mmol), 1H-pyrazole (0.362 g, 5.23 mmol), and potassium carbonate (0.704 g, 5.09 mmol) in acetonitrile (30 mL) was stirred at rt overnight. After this time, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.380 g, 76%) as a white solid. MW=203.20. 1H NMR (CDCl3, 500 MHz) δ 8.21-8.19 (m, 1H), 8.19-8.16 (m, 1H), 7.61-7.57 (m, 1H), 7.48-7.44 (m, 1H), 7.32-7.28 (m, 2H), 6.35 (t, J=2.1 Hz, 1H), 5.44 (s, 2H); APCI MS m/z 204 [M+H]+.