Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.O1CCCC1.C([Li])CCC.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O.C(O)C>[CH2:22]([C:3]1[CH:4]=[CH:5][S:1][C:2]=1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCBr
Reactant: c1csc(-c2cccs2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCCCCCCCc1ccsc1-c1cccs1
Reaction time: 10 h
Yield: 65.1 %

Procedure:
The process is commenced by placing about 3 g of bithiophene in a round bottom flask with a side arm (for introducing an inert gas), followed by adding an anhydrous tetrahydrofuran to dissolve the bithiophene. The temperature of the solution is then lowered to −78° C. (using liquid nitrogen plus ethanol as coolant). Thereafter, about 5.8 ml of n-butyl lithium (n-BuLi) (2.5 M, dissolved in hexane) is gradually drop-added to the solution. After the temperature of the solution has returned to room temperature, the solution is continuously mixed for about 15 minutes. After this, 2.5 ml of 1-bromooctane (Br—C8H17) is added, and the solution is continuously stirred for about 10 hours. The reaction was carried out under the inert gas all the time. After a predetermined reaction time is reached, deionized water is added to terminate the reaction. An extraction is performed by adding ether to the solution. An organic layer is then collected. Another extraction of the organic layer is performed using a saturated sodium hydrogen carbonate aqueous solution, deionized water and a saturated sodium chloride solution, respectively. The resulting crude product is then purified using column chromatography (eluent is hexane) to obtain an intermediate product octylbithiophene (the yield is about 65.1%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH2:14]([O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26](Cl)=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=[N:29]2)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[C:9]([O:8][C:7](=[O:13])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26]1[C:25]2[C:30](=[CH:31][C:22]([O:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:23][CH:24]=2)[N:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33])([CH3:10])([CH3:12])[CH3:11]
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Reaction time: 18 h
Yield: 79.8 %

Procedure:
tert-Butyl N-(4-aminobutyl)carbamate (28.6 g, 152.0 mmol) was added dropwise to a solution of 7-benzyloxy-4-chloro-3-nitroquinoline (40.7 g, 138 mmol), prepared in Parts A-D of Example 1, and triethylamine (38.5 mL, 276 mmol) in dichloromethane over a period of 1.5 hours. After the reaction was stirred for 18 hours, the reaction mixture was washed twice with water and once with saturated aqueous sodium chloride. The organic was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized from 2-propanol to afford 51.4 g of tert-butyl[4-(7-benzyloxy-3-nitroquinolin-4-ylamino)butyl]carbamate as a golden brown powder.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH:12]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH3:16])=[O:14])[C:7]2[CH:8]=[N:9][N:10]([S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[C:11]=2[CH:12]=1
Reactant: COC(=O)c1cc(Br)cc2[nH]ncc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)cc2c1cnn2S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
Sodium hydride (1.289 g, 32.2 mmol) was added portion wise to a solution of methyl 6-bromo-1H-indazole-4-carboxylate (4.11 g, 16.11 mmol) in N,N-dimethylformamide (50 ml) at 0° C. The dark orange mixture was stirred at 0° C. for 10 mins, then treated with 4-methylbenzenesulfonyl chloride (3.38 g, 17.72 mmol). The resultant pale cream mixture was stirred for 30 mins at 0° C. then poured into water (1000 ml). The cream precipitate was filtered off under vacuum and dried in the vacuum oven at 50° C. for 18 h to give the title compound as a yellow solid (5.51 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:45][C:46]([F:68])([F:67])[O:47][C:48]1[CH:53]=[CH:52][C:51]([NH:54][S:55]([C:58]2[CH:63]=[CH:62][C:61](B(O)O)=[CH:60][CH:59]=2)(=[O:57])=[O:56])=[CH:50][CH:49]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:61]2[CH:62]=[CH:63][C:58]([S:55](=[O:56])(=[O:57])[NH:54][C:51]3[CH:50]=[CH:49][C:48]([O:47][C:46]([F:67])([F:45])[F:68])=[CH:53][CH:52]=3)=[CH:59][CH:60]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1
Reactant: O=S(=O)(Nc1ccc(OC(F)(F)F)cc1)c1ccc(B(O)O)cc1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OS(=O)(=O)C(F)(F)F)c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)Nc3ccc(OC(F)(F)F)cc3)cc2)c1C
Temperature: 25 °C
Yield: 28.1 %

Procedure:
A stirred solution of (6-fluoro-3-methyl-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (0.10 g, 0.26 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Triphenylphosphine (0.016 g, 0.06 mmol), palladium (II) acetate (0.007 g, 0.03 mmol), 4-(N-(4-(trifluoromethoxy)phenyl)sulfamoyl)phenyl-boronic acid (0.128 g, 0.35 mmol) and a 2 M aqueous solution of sodium carbonate (0.5 mL, 1.0 mmol) were added simultaneously to the reaction mixture at room temperature under argon. The reaction mixture was refluxed for 2 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The collected organic extracts were washed with water and then brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (Biotage, 5-10% ethyl acetate-hexane) to provide {6-fluoro-3-methyl-4-[4-(4-trifluoromethoxy-phenylsulfamoyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.040 g, 29%) as a solid. MS calcd. for C27H20F4NO5S [(M−H)−] 546, obsd. 546.0.
Reaction SMILES: I[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]2[S:4][CH2:3][CH2:2][N:14]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:6]=2[CH:7]=1)([O-:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])ccc2SCCI)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCSc3ccc([N+](=O)[O-])cc32)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 42.4 %

Procedure:
To a stirred solution of tert-butyl 4-(2-(2-iodoethylthio)-5-nitrophenylamino)piperidine-1-carboxylate (1.49 g, 2.94 mmol) in DMF (10 mL) was added potassium carbonate (0.812 g, 5.87 mmol). The resulting mixture was stirred at 90° C. for 3 hours. The reaction mixture was then diluted with ethyl acetate and washed sequentially with water and saturated sodium carbonate (2×). The organic phase was dried, filtered, concentrated, and then chromatographed in 1:4 ethyl acetate:hexanes, giving the desired product (473 mg, 42.4%) as an orange foam. 1H NMR (DMSO-d6) δ 7.57 (d, J=2.4 Hz, 1H), 7.41 (dd, J=8.7, 2.4 Hz, 1H), 7.22 (d, J=8.7 Hz, 1H), 4.09-3.88 (m, 3H), 3.47-3.42 (m, 2H), 3.12-3.08 (m, 2H), 3.01-2.85 (m, 2H), 1.72-1.51 (m, 4H), 1.41 (s, 9H); ESI-MS (m/z, %): 402 (M+Na, 95), 380 (MH+, 28), 324 (100), 280 (55).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.S(Cl)(Cl)=O.[CH2:14]([O:16][C:17](=[O:27])[C@H:18]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH2:19])[CH3:15].C(N(CC)CC)C>C1C=CC=CC=1.C(Cl)Cl.CN(C1C=CC=CN=1)C.CN(C)C=O>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:19][C@H:18]([C:17]([O:16][CH2:14][CH3:15])=[O:27])[CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:9])[N:6]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: CN(C)c1ccccn1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCOC(=O)CC[C@H](NC(=O)c1csc(Br)n1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a 100 mL 14/20 round bottom flask under a nitrogen atmosphere was charged 1.7 g (8.17 mmmol) of 2-bromo-4-thiazolecarboxylic acid in 17 mL of benzene, followed by the addition of 2.4 mL (33 mmol) of thionyl chloride, and a catalytic amount of dimethylformamide. The reaction was heated to reflux for 2 hours The volatiles were removed in vacuo, and this residue was then dissolved in 20 mL of methylene chloride and added dropwise to an ice-bath cooled mixture of 2.06 g (8.58 mmol) of L-glutamic acid diethyl ester, 2.39 mL (10.1 mmol) of triethylamine, and 10 mg of dimethylaminopyridine in 30 mL of methylene chloride. After the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 hours The reaction was diluted with methylene chloride, washed with 0.5 N hydrochloric acid, water, 5% sodium bicarbonate, water, dried over sodium sulfate, and removed in vacuo. The crude residue was purified using silica gel flash chromatography eluting with 3:1 chloroform/ether to give 2.7 g (84%) of diethyl N-(2-bromo-4-thiazolylcarbonyl)-L-glutamate as a yellow oil. Rf =0.43 (3:1 chloroform/ether). 1H NMR (300 MHz, DMSO-d6) δ 1.14 (q, J=7.1 Hz, 6H), 1.98-2.18 (m, 2H), 2.35 (t, J=7.3 Hz, 2H), 3.97-4.11 (m, 4H), 4.37-4.50 (m, 1H), 8.28 (d, J=5.9 Hz, 1H), 8.73 (d, J=7.7 Hz, 1H)
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Br:22][C:23]1[C:24](Cl)=[C:25]([C:31](=[O:38])[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[C:26]([CH3:30])=[N:27][C:28]=1[CH3:29]>CC#N>[Br:22][C:23]1[C:24]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[C:25]([C:31](=[O:38])[C:32]([O:34][CH:35]([CH3:36])[CH3:37])=[O:33])[C:26]([CH3:30])=[N:27][C:28]=1[CH3:29]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(Cl)c1Br
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CCC(c3ccccc3)CC2)c1Br
Temperature: 80 °C
Reaction time: 24 h
Yield: 73.9 %

Procedure:
To a solution of 4-phenylpiperidine (1.25 g, 7.75 mmol) and DIEA (4.1 mL, 23.3 mmol) in anhydrous CH3CN (40 mL) was added isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (2.59 g, 7.75 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.) and stirred for 24 h; concentrated, and charged (DCM) to a 80 g ISCO silica gel cartridge and gradient eluted (5-35% EtOAc/hexanes) using an Isolera chromatography station to give isopropyl 2-(5-bromo-2,6-dimethyl-4-(4-phenylpiperidin-1-yl)pyridin-3-yl)-2-oxoacetate 2.63 g (74%). 1H NMR (500 MHz, DMSO-d6) δ 7.34-7.31 (m, 2H), 7.25-7.20 (m, 3H), 5.11-5.06 (m, 1H), 3.50 (br. s, 2H), 2.94 (br. s, 2H), 2.68-2.63 (m, 1H), 2.63 (s, 3H), 2.13 (s, 3H), 1.81-1.78 (m, 2H), 1.60 (br. s, 2H), 1.26 (d, J=6.2 Hz, 6H). UPLC (M+H)=461.05.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]1([C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>N1C=CC=CC=1>[OH:1][CH2:2][CH:3]([OH:4])[CH2:5][O:6][C:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OCC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: OCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 42.7 %

Procedure:
Glycerol (3.02 g, 32.8 mmol) (Wako Pure Chemical Industries, Ltd.) and triphenylchloromethane (1.00 g, 3.50 mmol) (Wako Pure Chemical Industries, Ltd.) were dissolved in pyridine (20 mL) (Wako Pure Chemical Industries, Ltd.), and the mixture was refluxed for 5 hours. The mixture was allowed to cool to room temperature, and then water was added thereto, followed by extraction with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform (Wako Pure Chemical Industries, Ltd.):methanol (Wako Pure Chemical Industries, Ltd.)=97:3), to thereby obtain the title compound (0.50 g, 42% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:14])[C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=O.CC(O)C.[CH3:19][C:20](=[O:25])[CH2:21][C:22](=[O:24])[CH3:23].N1CCCCC1>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:21]([C:20](=[O:25])[CH3:19])[C:22](=[O:24])[CH3:23])[CH:7]=[C:8]([Cl:14])[C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CC(=O)CC(C)=O
Reactant: CS(=O)(=O)c1c(Cl)cc(C=O)cc1Cl
Solvent: C1CCNCC1
Solvent: O=CO
Solvent: CC(C)O
Product: CC(=O)C(=Cc1cc(Cl)c(S(C)(=O)=O)c(Cl)c1)C(C)=O
Temperature: 23.5 °C
Reaction time: 63 h

Procedure:
3,5-Dichloro-4-(methylsulfonyl)benzaldehyde (1.5 g), 2-propanol (20 mL), 2,4-pentanedione (1.6 mL), formic acid (44 mL) and piperidine (114 mL) were mixed and stirred at 22-25° C. for 63 h. The product was filtered, washed with 2-propanol and dried (yield 1.0 g, melting point 134-136° C.). 1H-NMR(400 MHz, DMSO-d6 d=2.29 (s, 3H), 2.46 (s, 3H), 3.48 (s, 3H), 7.67 (s, 2 H), 7.71 (s, 1H).
Reaction SMILES: [Cl-].[NH4+].C(O)C.O.[N+:7]([C:10]1[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=1[O:12][C:13]1[C:14]2[C:21]([CH3:22])=[C:20]([CH3:23])[NH:19][C:15]=2[N:16]=[CH:17][N:18]=1)([O-])=O>[Fe].C(OCC)(=O)C.O1CCCC1>[NH2:7][C:10]1[CH:27]=[CH:26][CH:25]=[CH:24][C:11]=1[O:12][C:13]1[C:14]2[C:21]([CH3:22])=[C:20]([CH3:23])[NH:19][C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: Cc1[nH]c2ncnc(Oc3ccccc3[N+](=O)[O-])c2c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1[nH]c2ncnc(Oc3ccccc3N)c2c1C
Temperature: 78.5 °C
Reaction time: 1.5 h
Yield: 30.7 %

Procedure:
After adding iron powder (0.1 g), ammonium chloride (0.2 g), ethanol (4 ml) and water (1 ml) to the 4-(nitrophenoxy)-5,6-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine (80 mg) synthesized by the intermediate synthesis method described above, the mixture was stirred at 75-82° C. for 1.5 hours. After returning the reaction system to room temperature and adding tetrahydrofuran (3 ml) and ethyl acetate (3 ml), the mixture was filtered with celite, the filtrate was subjected to liquid separation, and the organic layer was washed with water and saturated saline in that order, dried over sodium sulfate, concentrated to dryness under reduced pressure and washed with diethyl ether to obtain the title compound (22 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1ccc(F)cc1F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1cc([N+](=O)[O-])c(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To 500 ml of conc. sulfuric acid was added 151 g of 2,4-difluorobenzoic acid. With ice cooling and stirring, 114 g of potassium nitrate powder was added thereto in portions over 30 minutes. Stirring was continued for a further 1 hour, yielding a sherbet-like precipitate. The reaction solution was poured into 1.5 L of ice water and stirred for 30 minutes. The precipitate was collected by filtration, washed with 1 L of distilled water, air dried, and then dried in vacua over phosphorus pentoxide to give 164.5 g of 2,4-difluoro-5-nitrobenzoic acid as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][CH2:27][C:28]1[NH:29][C:30]([CH3:33])=[CH:31][CH:32]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([NH:26][CH2:27][C:28]1[NH:29][C:30]([CH3:33])=[CH:31][CH:32]=1)=[O:8]
Reactant: Cc1ccc(CN)[nH]1
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1ccc(C(=O)NCc2ccc(C)[nH]2)cc1OC

Procedure:
18.1 g (0.1 mol) of 3,4-dimethoxybenzoic acid are reacted with 17.8 g (0.11 mol) of carbonyldiimidazole and 11.0 g (0.1 mol) of 2-aminomethyl-5-methyl-pyrrole (compare Example 11), as described in Example 15.
Reaction SMILES: [CH3:1][C@@H:2]1[C:28](=[O:29])[C:27]([O:30][C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)=[CH:26][C@@:25]2([CH3:42])[C@H:3]1[CH2:4][C@H:5]1[O:14][C:12](=[O:13])[C@H:11]([O:15][C:16]([CH:18]=[C:19]([CH3:21])C)=[O:17])[C@@H:10]3[C@:6]41[C@@H:24]2[C@@H:23]([OH:43])[C@H:22]([OH:44])[C@@:9]3([C:45]([O:47][CH3:48])=[O:46])[O:8][CH2:7]4.[CH3:49][C:50](C(C)C)=[CH:51]C(Cl)=O.C(Cl)(Cl)Cl.CO.O.O>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1[C@@H:3]2[CH2:4][C@H:5]3[O:14][C:12](=[O:13])[C@H:11]([O:15][C:16](/[CH:18]=[C:19](/[CH:50]([CH3:51])[CH3:49])\[CH3:21])=[O:17])[C@@H:10]4[C@@:6]53[CH2:7][O:8][C@:9]4([C:45]([O:47][CH3:48])=[O:46])[C@@H:22]([OH:44])[C@H:23]([OH:43])[C@@H:24]5[C@@:25]2([CH3:42])[CH2:26][C:27](=[O:30])[C:28]=1[OH:29]
Reactant: CC(=CC(=O)Cl)C(C)C
Reactant: COC(=O)[C@@]12OC[C@]34[C@H]([C@@H](O)[C@@H]1O)[C@@]1(C)C=C(O[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@H]5O)C(=O)[C@@H](C)[C@@H]1C[C@H]3OC(=O)[C@H](OC(=O)C=C(C)C)[C@@H]24
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Product: COC(=O)[C@@]12OC[C@]34[C@H]([C@@H](O)[C@@H]1O)[C@@]1(C)CC(=O)C(O)=C(C)[C@@H]1C[C@H]3OC(=O)[C@H](OC(=O)/C=C(\C)C(C)C)[C@@H]24
Temperature: 25 °C
Reaction time: 96 h
Yield: 58 %

Procedure:
A solution of 15-desenecioyl bruceoside-A (VI, 89.9 mg, 0.15 mmol) in dry pyridine (2 mL) was added dropwise to a solution of 3,4-dimethyl-2-pentenoyl chloride (IX, 330 mg, 2.25 mmol) in dry chloroform (2 mL). The mixture was stirred at room temperature for 20 hours until the thin layer chromatography (chloroform-methanol-water, 50:14:3) showed the disappearance of (VI), water was then added to decompose the unreacted acid chloride. The reaction product without further purification and isolation, was dissolved in dichloromethane (10 mL), and then borontrifluoride etherate (six drops) added. The reaction mixture was stirred at room temperature and examined by thin layer chromatography (chloroform-acetone, 1:1). After 4 days, the product was subjected to preparative thin layer chromatography (chloroform-acetone, 10:1) to yield pure bruceantin (V, 47.7 mg, 58% yield).
Reaction SMILES: [CH:1]1([C:5]#[N:6])[CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[O:15]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16]1.CN(C)P(N(C)C)(N(C)C)=O>C1COCC1>[OH:20][C:17]1([C:1]2([C:5]#[N:6])[CH2:4][CH2:3][CH2:2]2)[CH2:18][CH2:19][O:15][CH2:16]1
Reactant: N#CC1CCC1
Reactant: O=C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: N#CC1(C2(O)CCOC2)CCC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 44.3 %

Procedure:
To a solution of cyclobutanecarbonitrile (405 mg, 5 mmol) in THF (7 ml) was added 2.0M lithium diisopropylamide (2.5 ml, 5 mmol) dropwise at −78° C. The reaction solution was stirred at −78° C. for 40 minutes, followed by the addition of a solution of dihydrofuran-3(2H)-one (473 mg, 5.5 mmol) in hexamethylphosphoramide (268 mg, 1.5 mmol). The mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with 1N aqueous HCl solution and extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (eluted with petroleum ether:EtOAc=20:1) to provide the title compound as a corloless oil (0.37 g, yield 44%). 1H NMR (400 MHz, CDCl3): δ 4.15-4.05 (m, 2H), 3.86 (d, J=10.0 Hz, 1H), 3.74 (d, J=9.6 Hz, 1H), 2.47-2.42 (m, 4H), 2.39-2.31 (m, 3H), 2.01-1.94 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:9])[CH:5]=[C:6]([NH:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: NCc1ccccc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1nc(Cl)cc(NCc2ccccc2)n1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A mixture of 2-amino-4,6-dichloropyrimidine (0.5 g, 3.05 mmol), benzylamine (0.35 ml, 3.2 mmol), potassium carbonate (0.25 g, 1.81 mmol) and ethanol (15 ml) were heated to reflux for 16 h. The reaction mixture was cooled to room temperature and the solvents were removed under reduced pressure. The residue was triturated with ethyl acetate and the white product was collected by filtration. Concentration of the ethyl acetate filtrate also afforded a second crop of product. The combined solids were dried to give the required pyrimidine (0.36 g, 50%), m.p. 136° C.; δH (200 MHz, d6-DMSO) 4.55 (2H, br s, OCH2), 5.87 (1H, br s, C(5)H), 6.54 (2H, br s, NH2), 7.35-7.41 (5H, m, C6H5), 7.72 (1H, m, NH); m/z (+EI) 234 (M+, 85%), 106 (100), 91 (C6H5CH2+, 51%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[CH:23]=[C:22]([C@:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH2:25][CH3:26])[N:21]=[N:20]4)=[CH:15][CH:16]=3)[N:11]=[C:10]([C:32](=[O:34])[CH3:33])[CH:9]=2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.CC(C)=O>[F:30][C:27]([F:28])([F:29])[C@:24]([C:22]1[N:21]=[N:20][N:19]([CH2:18][C:14]2[CH:13]=[C:12]3[C:17]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:9][C:10]([CH:32]([OH:34])[CH3:33])=[N:11]3)=[CH:16][CH:15]=2)[CH:23]=1)([OH:31])[CH2:25][CH3:26]
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(C(C)=O)nc3c2)nn1)C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(C(C)O)nc3c2)nn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-1-[4-(4-fluorophenyl)-7-({4-[1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)quinolin-2-yl]ethanone (100 mg, 0.21 mmol) in dichloromethane (5 mL) at −78° C. was added diisobutylaluminum hydride (79 μL, 0.44 mmole). The solution was stirred 20 minutes after which a few drops of acetone were added. The reaction was warmed up to rt and sodium sulfate decahydrate (205 mg, 0.63 mmol) was added. After stirring for 30 minutes the mixture was filtered on celite and concentrated. Purification on silica gel (eluting with acetone/dichloromethane, 3:7) gave the title compound. MS (+ESI): 475 (M+H)+.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:15][CH2:14][C:13]2[N:16]=[N:17][C:18](C3C=CC=CC=3)=C[C:12]=2[CH2:11][CH2:10]1)=O)(C)(C)C.[O:26]1[CH2:31][CH2:30]OCC1>>[ClH:1].[CH3:18][N:17]1[N:16]=[C:13]2[CH2:14][CH2:15][NH:9][CH2:10][CH2:11][C:12]2=[CH:30][C:31]1=[O:26]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-c3ccccc3)nnc2CC1
Agent: Cl
Product: Cn1nc2c(cc1=O)CCNCC2

Procedure:
40 mL dioxane solution of hydrogen chloride was added to 5.5 g 3-phenyl-5,6,8,9-tetrahydro-1,2,7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester in 40 mL dioxane at 5° C. The reaction was stirred over night. The solvent was removed and co-evaporated with ethyl acetate to yield 3.7 g of the desired product. (M+H)+: 180, Rt: 7.84 min (method AE)