Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[N:13]=[C:14]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[NH:15][C:16]=2[CH3:17])=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[NH:24]1[CH2:27][CH:26]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:25]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[N:13]=[C:14]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[NH:15][C:16]=2[CH3:17])=[CH:7][C:3]=1[C:4]([N:24]1[CH2:27][CH:26]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:25]1)=[O:5]
Reactant: Cc1cc(C)c(-c2nc(C3CCOC3)[nH]c2C)cc1C(=O)O
Reactant: N#Cc1ccc(C2CNC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2nc(C3CCOC3)[nH]c2C)cc1C(=O)N1CC(c2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.1 %

Procedure:
The mixture of 2,4-dimethyl-5-(5-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazol-4-yl)benzoic acid (compound 171.2, 100 mg, 0.30 mmol), 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 71 mg, 0.37 mmol), EDCI (95 mg, 0.50 mmol), HOBt (20 mg, 0.10 mmol) and DIEA (207 μL, 1.20 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure, diluted with saturated NaHCO3 (10 mL) and extracted with EtOAc (30 mL). The organic phase was washed with brine (3×10 mL), dried over MgSO4 and concentrated under reduce pressure. The residue was purified by preparative TLC with 6% methanol in dichloromethane and lyophilized to give 16 mg (12%) of the title compound as a white solid. m/z (ES+) 441 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH:15]([CH3:19])[CH2:16][CH:17]=[CH2:18])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:7])=[O:6])C=C>C(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH3:19][CH:15]1[CH2:16][CH:17]=[CH:18][CH2:1][N:4]([S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)(=[O:6])=[O:7])[CH2:14]1
Reactant: C=CCC(C)CN(CC=C)S(=O)(=O)c1ccccn1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: CC1CC=CCN(S(=O)(=O)c2ccccn2)C1
Yield: 82.9 %

Procedure:
Pyridine-2-sulfonic acid allyl-(2-methyl-pent-4-enyl)-amide (1.2 g, 4.3 mmol) was diluted in CH2Cl2 (100 ml). After carefully degass by Ar, Grubbs catalyst (0.35 g, 0.43 mmol) was added under Ar protection. The mixture was then refluxed for 2 h before the reaction mixture was concentrated by rotary evaporation. The product was purified by column chromatography (5%-20% EtOAc/hexanes) to give the title compound (0.9 g, 83% yield): MS (M+H+):253.2; 1H-NMR (400 Hz, CDCl3): d=8.70(d, 1H), 8.0-7.75(m, 2H), 7.5 (m, 1H) 5.79-5.60(m, 2H), 4.00(d, 2H), 3.65(dd, 1H), 3.22(dd, 1H), 2.30-2.05(m, 3H), 0.96(d, 3H)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[CH:11](=O)C>>[CH3:11][NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: NCCCN1CCOCC1
Reactant: CC=O
Product: CNCCCN1CCOCC1

Procedure:
By using N-(3-aminopropyl)morpholine (1.0 g) as a starting material, the title compound (57 mg) was obtained in the same manners as those of Reference Example 51, (1), Reference Example 8, (2) and Reference Example 19, (3).
Reaction SMILES: [CH3:1][Mg]Br.[CH:4]([C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:5].[Cl-].[NH4+]>>[OH:5][CH:4]([C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)[CH3:1]
Reactant: O=Cc1nc2ccccc2s1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CC(O)c1nc2ccccc2s1
Reaction time: 3.5 h
Yield: 66 %

Procedure:
5.0 ml of methylmagnesium bromide were added dropwise to a solution of 0.61 g of 2-formylbenzothiazole [prepared as described in step (a) above] which was cooled in an acetone-dry ice bath. The reaction vessel was transferred to an ice-water bath and the reaction mixture was stirred for 3.5 hours. At the end of this time, a saturated aqueous ammonium chloride solution was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.44 g (yield 66%) of the title compound as a solid having a melting point of 59° to 60° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1.[N-:14]=[N+:15]=[N-:16].[Na+].S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[OH-].[Na+]>C(#N)C>[CH3:1][N:2]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=2)=[N:16][N:15]=[N:14]1
Reactant: [N-]=[N+]=[N-]
Reactant: CNC(=O)c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cn1nnnc1-c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 17.7 %

Procedure:
In a dry flask N-methyl-3-nitro-benzamide (30.0 g, 167 mmol) was dissolved in acetonitrile (835 mL) and sodium azide (10.9 g, 167 mmol) was added and the reaction cooled in an ice bath. Triflic anhydride (29 mL, 172 mmol) was added dropwise to maintain the internal temperature below 3° C. The reaction mixture was stirred for 3.5 hours at 0° C. The reaction mixture was poured into IN aqueous sodium hydroxide (100 mL). The organic layer was separated dried with sodium sulfate, filtered, and concentrated in vacuo to 50 mL. The solution was diluted with dichloromethane and added water to precipitate a yellow solid (18.46 g, 54%). A second crop of crystals was obtained by concentrated the filtrate in vacuo and adding it to boiling ethyl acetate. Upon cooling to 0° C., 6.07 g (18%) of additional material was isolated upon filtration. further purification. 1H NMR (300 MHz, CDCl3), δ: 3.67 (m, 1H), 8.49 (dd, J=8, J′=2, 1H), 8.31 (d, J=8, 1H), 7.94 (dd, J=8, J′=8, 1H), 4.22 (s, 3H).
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:35](I)[CH3:36]>O>[CH2:35]([O:22][C:21]([C:19]1[O:20][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][CH:18]=1)=[O:23])[CH3:36]
Reactant: CCI
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCC)o1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 10.0 g (0.031 mole) of 5-tetradecyloxy-2-furoic acid, 4.3 g (0.034 mole) of potassium carbonate, and dimethyl formamide is stirred at room temperature after which 15.6 g (0.10 mole) of ethyl iodide is added. The mixture is heated to 50° C with stirring overnight then poured into water and extracted with ether. The ether layer is washed with water and salt water then dried over sodium sulfate, filtered, and the ether is distilled off and replaced by ethanol. Upon cooling the ethanol solution a solid is obtained which is 5-tetradecyloxy-2-furoic acid ethyl eseter, M.P. 39°-40° C.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1N)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.Cl.CCCCCC.[OH-:32].[Na+]>CCOCC>[CH3:1][C:2]1[C:3](=[O:32])[C:4](=[O:5])[C:6]2[C@@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C@@:14]3([O:21][CH3:22])[C@H:13]4[NH:23][C@H:12]4[CH2:11][N:10]3[C:7]=2[C:8]=1[OH:9]
Reactant: CO[C@@]12[C@H](COC(N)=O)C3=C(C(=O)C(C)=C(N)C3=O)N1C[C@@H]1N[C@@H]12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CO[C@@]12[C@H](COC(N)=O)C3=C(C(O)=C(C)C(=O)C3=O)N1C[C@@H]1N[C@@H]12
Temperature: 25 °C
Reaction time: 30 h
Yield: 63 %

Procedure:
Mitomycin C (2.2 g, 6.6 mmoles) was dissolved in 140 ml 0.1N methanolic NaOH (50%) and the reaction mixture was stirred at room temperature for 30 hours. The solution was then adjusted to ca. pH 4.0 with 1N HCl and extracted with ethyl acetate (4×500 ml). The combined ethyl acetate extracts were dried (Na2SO4) and evaporated under reduced pressure at about 30° to 35° C. to obtain a solid residue, which upon dissolving in ether and treating with excess hexane afforded a purple precipitate. The precipitate was collected and air dried to afford the title compound as a fine purple powder (1.4 g, 63%).
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=1)[C:3](O)=[O:4].Cl.[F:21][C:22]1[CH:23]=[C:24]([C:28]2([NH2:35])[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][CH:2]([C:6]1[CH:11]=[C:10]([C:12]([F:13])([F:15])[F:14])[CH:9]=[C:8]([C:16]([F:17])([F:18])[F:19])[CH:7]=1)[C:3]([NH:35][C:28]1([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[CH:23]=2)[CH2:29][CH2:30][C:31](=[O:34])[CH2:32][CH2:33]1)=[O:4]
Reactant: NC1(c2cccc(F)c2)CCC(=O)CC1
Reactant: CC(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: CC(C(=O)NC1(c2cccc(F)c2)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Prepared from (RS)-α-methyl-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 4) and 1-(3-fluorophenyl)-4-oxocyclohexylamine hydrochloride (Description 181) according to the method of Example 1. 1H NMR (360 MHz, CDCl3) δ 7.81 (1H, s), 7.73 (2H, s), 7.29–7.24 (1H, m), 7.06–7.03 (1H, m), 6.97–6.94 (2H, m), 5.78 (1H, s), 3.72 (1H, q, J 7.0 Hz), 2.81–2.75 (1H, m), 2.63–2.57 (1×, m), 2.44–2.24 (6H, m), and 1.53 (3H, d, J 7.0 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.B(F)(F)F.[CH3:15]O>>[Br:1][C:2]1[C:3]([C:8]([O:10][CH3:15])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1Br
Reactant: CO
Agent: FB(F)F
Product: COC(=O)c1ncccc1Br

Procedure:
3-Bromopicolinic acid (5 g.) is stirred and refluxed under nitrogen with 40 ml. of 14% boron trifluoride in methanol. the solution is cooled and the methanol is evaporated. The residue is dissolved in chloroform. The chloroform extracts are washed with 5% aqueous sodium bicarbonate solution and water, then the organic solution is dried and evaporated. The residue is recrystallized from cyclohexane to give methyl 3-bromopicolinate, m.p. 34°-36°C.
Reaction SMILES: FC1C=CC(CC2C=C3C(C(O)=C(C(OCC)=O)C(=[O:24])N3CCCSC)=NC=2)=CC=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]2[CH:48]=[C:47]3[C:42]([C:43]([OH:61])=[C:44]([C:56]([O:58][CH2:59][CH3:60])=[O:57])[C:45](=[O:55])[N:46]3[CH2:49][CH2:50][CH2:51][S:52]([CH3:54])=[O:53])=[N:41][CH:40]=2)=[CH:34][CH:33]=1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]2[CH:48]=[C:47]3[C:42]([C:43]([OH:61])=[C:44]([C:56]([O:58][CH2:59][CH3:60])=[O:57])[C:45](=[O:55])[N:46]3[CH2:49][CH2:50][CH2:51][S:52]([CH3:54])(=[O:24])=[O:53])=[N:41][CH:40]=2)=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(C)=O)c1=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCSC)c1=O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(C)(=O)=O)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cold (0° C.) solution of 30% ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methylthio)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 70% ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methylsulfinyl)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (269 mg, 0.611 mmol) in dichloromethane (10 mL) was added m-chloroperoxybenzoic acid (158 mg, 0.915 mmol). The reaction mixture was warmed to room temperature and stirred 3 hours. The reaction mixture was diluted with dichloromethane and washed with water and brine, then dried over sodium sulfate. Filtration and concentration provided ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methylsulfonyl)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1 H), 7.66 (s, 1 H), 7.22 (dd, J=8.5, 5.5 Hz, 2 H), 7.03 (t, J=8.5 Hz, 2 H), 4.52 (q, J=7.1 Hz, 2 H), 4.39 (t, J=7.8 Hz, 2 H), 4.13 (s, 2 H), 3.16 (t, J=6.9 Hz, 2 H), 2.95 (s, 3 H), 2.22 (m, 2 H), 1.48 (t, J=7.0 Hz, 3 H); MS m/z 461 (M−H)−.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:6]=[C:7]([NH2:23])[C:8]2[N:9]=[CH:10][N:11]([C:21]=2[N:22]=1)[C@@H:12]1[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[C@H:13]1[OH:14]>O>[NH:2]([C:5]1[N:6]=[C:7]([NH2:23])[C:8]2[N:9]=[CH:10][N:11]([C:21]=2[N:22]=1)[C@@H:12]1[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[C@H:13]1[OH:14])[NH2:3]
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NN
Solvent: O
Product: NNc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 62 °C

Procedure:
A reaction vessel is charged with hydrazine hydrate (1285 g). The solution is heated to approximately 62° C., and 2-chloroadenosine (500 g) is added while maintaining the temperature of approximately 62° C. The mixture is maintained at a target of 62° C. for at least 2 hours, until the level of residual 2-chloroadenosine in the mixture is not more than 0.10%. The mixture is cooled to approximately 40° C. and the mixture is checked to verify the presence of solids. Water (2275 g) is slowly added while maintaining the temperature at approximately 40° C. The mixture is cooled to approximately 10° C. and held for not less than 1 hour. The product is isolated by filtration, washed with water (1195 g) and then with absolute ethanol (1885 g). The product is dried under vacuum at up to 30° C. for not less than 12 hours, to give 2-hydrazinoadenosine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:25])=[C:12]([O:14]C(=O)C2C=CC(F)=C(Cl)C=2)[CH:13]=1)=[O:6].[OH-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:25])=[C:12]([OH:14])[CH:13]=1)=[O:6]
Reactant: Cc1ccc(NC(=O)c2ccc(F)c(Cl)c2)cc1OC(=O)c1ccc(F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccc(F)c(Cl)c2)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Chloro-4-fluoro-benzoic acid 5-(3-chloro-4-fluoro-benzoylamino)-2-methyl-phenyl ester (3.93 g, 9 mmol) was dissolved in a mixture of tetrahydrofuran (25 mL), methanol (50 mL) and aqueous 1N sodium hydroxide (9 mL, 9 mmol). The mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure to remove most of the organic solvent. The resulting suspension was diluted with water (45 mL) and saturated aqueous sodium bicarbonate solution (5 mL). After standing for 30 minutes, the precipitate was collected and washed with water and dried to give crude 3-chloro-4-fluoro-N-(3-hydroxy-4-methyl-phenyl)-benzamide as a white powder. (Yield 2.59 g, 103%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])=[S:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[S:13][C:12]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])=[N:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(NC(=S)NCCCO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2sc(NCCCO)nc2c1
Yield: 72.2 %

Procedure:
A mixture of 21 parts of N-(2-chloro-5-nitrophenyl)-N'-(3-hydroxypropyl)thiourea, 10 parts of potassium carbonate and 180 parts of N,N-dimethylformamide is stirred and refluxed for 30 minutes. After cooling, 300 parts of water are added and the product is allowed to crystallize. It is filtered off and washed with water, yielding 13.3 parts (72.2%) of 3-[(5-nitro-2-benzothiazolyl)amino]-1-propanol; mp. 140°-144° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1.[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[O:22][C:21]2=[O:28].ClCCl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Br:17][C:18]1[CH:26]=[CH:25][C:24]([C:23]([C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[C:4](=[CH:3][C:2]([Br:1])=[CH:14][CH:13]=4)[C:5]([CH3:16])([CH3:15])[C:6]=3[CH:7]=2)=[O:27])=[C:20]([CH:19]=1)[C:21]([OH:28])=[O:22]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: CC1(C)c2ccccc2-c2ccc(Br)cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)c2cc(Br)ccc2-c2ccc(C(=O)c3ccc(Br)cc3C(=O)O)cc21
Temperature: 25 °C
Yield: 60.6 %

Procedure:
2-bromo-9,9-dimethyl-9H-fluorene (25.0 g, 0.092 mol) and 5-bromoisobenzofuran-1,3-dione (26.89 g, 0.119 mol) were placed in a reaction vessel, and added with dichloromethane (700 ml). At 0° C., aluminum chloride (18.5 g, 0.138 mol) was gradually added thereto, and the temperature was raised up to room temperature. Then, the resultant mixture was stirred for 12 hours. After the reaction was completed, the resultant product was gradually added with distilled water. The resultant product was extracted with an excess of dichloromethane, and washed several times with distilled water. After solvent removal, the produced solid was placed in a Hexane 2 l-containing vessel, washed, filtered, and dried, 5-bromo-2-(7-bromo-9,9-dimethyl-9H-fluorene-2-carbonyl)benzoic acid (27.9 g, yield 61%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:25]2=[O:28])=[CH:20][C:19]=1F>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][C:18]=2[Br:17])[C:25](=[O:28])[N:24]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[CH:23]=[CH:22]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cn2ccc3cc(F)c(Br)cc3c2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2ccc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)c(Br)cc3c2=O)cc1

Procedure:
126 mg (0.625 mmol) of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 2.5 mL of dimethylacteamide and 30 mg (0.75 mmol) of NaH (60% purity) were added at room temperature. After 15 minutes 181 mg (0.5 mmol) of 7-bromo-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (313) were added and stirring was continued at room temperature. After 5.5 h the solvent was removed i. vac. After adding saturated sodium bicarbonatesodium bicarbonate solution, the mixture was extracted twice with dichloromethane. The organic layers were dried with MgSO4 and evaporated. After final purification by preparative HPLC, 182 mg of the product could be isolated. Rt=1.93 min (Method C). Detected mass: 543.5/545.5 (M+H+).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([C:12]1[CH:25]=[CH:24][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=2)=[C:14]([CH2:26][CH2:27][CH3:28])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].ClC1C=CC=[C:34]([C:38]([O:40]O)=[O:39])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[C:38]([O:40][CH2:23][C:19]1[CH:18]=[C:17]([O:16][C:15]2[CH:24]=[CH:25][C:12]([C:3]([O:8][CH2:9][O:10][CH3:11])([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:29])[F:30])=[CH:13][C:14]=2[CH2:26][CH2:27][CH3:28])[CH:22]=[CH:21][N:20]=1)(=[O:39])[CH3:34]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccnc(C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccnc(COC(C)=O)c1
Temperature: 140 °C
Yield: 55.6 %

Procedure:
To a solution of 4-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)-2-methylpyridine (780 mg, 1.78 mmol) in chloroform (2 mL), m-chloroperbenzoic acid (2.05 g) was added at room temperature and the resultant mixture was stirred. After completion of the reaction, the reaction solution was added with an aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and then dried using sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The obtained residue was added with acetic anhydride and heated at a surrounding temperature of 140° C. After completion of the reaction, the reaction solution was added with methanol (4 mL) at room temperature, then neutralized by adding a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (490 mg, yield 56%) was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.CCN(CC)CC.[C:18]([O:22][C:23]([N:25]1[CH2:32][CH2:31][NH:30][CH2:29][C:26]21[CH2:28][CH2:27]2)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:32][CH2:31][N:30]([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:29][C:26]21[CH2:27][CH2:28]2)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC12CC2
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 110 °C

Procedure:
To commercially available 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 6.5 mmol) dissolved in DMF (5 ml) was added Et3N (1.3 ml, 9.8 mmol) followed by commercially available 4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester (1.5 g, 7.2 mmol). The reaction mixture was heated for 16 hours at 110° C. After evaporation of the solvent in vacuo the crude mixture was treated with water (25 mL) and extracted with EtOAc (4×30 mL) the combined organic phases were washed with brine (2×20 mL), dried over Na2SO4, filtered and concentrated in vacuo to provide 1.5 g crude. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=S)[CH:8](C)[CH2:9][NH:10][C:4]=2[CH:3]=1.[C:15]([NH:18][NH2:19])(=O)C>C(O)CCC>[CH:15]1[N:6]2[C:5]3[CH:13]=[CH:14][CH:2]=[CH:3][C:4]=3[N:10]=[CH:9][CH2:8][C:7]2=[N:19][N:18]=1
Reactant: CC(=O)NN
Reactant: CC1CNc2cc(Br)ccc2NC1=S
Solvent: CCCCO
Product: C1=Nc2ccccc2-n2cnnc2C1

Procedure:
A solution of 7-bromo-3-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione (1.5 g, 5.5 mmol) and acetohydrazide (693 mg, 9.36 mmol) in n-butanol (20 mL) was heated at 130° C. for 12 hours. The reaction mixture was concentrated in vacuo, diluted with water (20 mL), extracted with ethyl acetate (15 mL×3) and washed with brine (10 mL×3). The combined organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to give a crude product, which was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to afford 4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine, 5,6-dihydro-1,4-dimethyl-8-bromo as a white solid (1 g, 62%). 1H NMR (300 MHz, CDC13): δ 7.19-7.14 (m, 2H), 7.01 (d, J=8.1 Hz, 1H), 3.74-3.64 (m, 1H), 3.43-3.36 (m, 1H), 3.13-3.05 (m, 1H), 2.49 (s, 3H), 1.50 (d, J=6.9 Hz, 3H). LRMS (M+H)+: calcd 292.03. found 292.