Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([CH3:12])[C:4]=1[Br:13])C.CO.Cl>O1CCCC1>[Br:13][C:4]1[C:5]([CH3:12])=[C:6]([CH2:7][OH:8])[CH:10]=[CH:11][CH:3]=1
Reactant: CCc1ccc(C(=O)O)c(C)c1Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Br)cccc1CO
Yield: 90 %

Procedure:
Ethyl 3-bromo-2-methylbenzoic acid was reduced as follows: Add 5 equivalents of borane tetrahydrofuran complex, via syringe, to 10 mmol ethyl 3-bromo-2-methylbenzoic acid in tetrahydrofuran (5 mL). The mixture was refluxed for two hours, then cooled in an ice bath. Methanol (10 mL) was added dropwise, followed by 1 N HCl (50 mL). The solvent was removed and the mixture partitioned between ethyl acetate and water. The yield was 90%. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ7.5 (d, 1H) 7.2 (d, 1H) 7.1 (t, 1H), 4.6 (s, 2H) 2.3 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.Br[CH2:13][CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:15]([O:11][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[C:8](=[O:10])[CH3:9])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: CC(=O)c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(F)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.1 %

Procedure:
A mixture of 1-(4-fluoro-2-hydroxyphenyl)ethanone (7.50 g, 48.7 mmol), 3-bromoprop-1-ene (6.48 g, 53.5 mmol), and potassium carbonate (13.5 g, 97.0 mmol) in DMF (75 mL) was vigorously stirred at rt for 24 h. The reaction mixture was diluted with water (100 mL) while stirring. The white precipitate was collected by vacuum filtration. The solid was rinsed with water (300 mL). The solid was dried under high vacuum to afford 1-(2-(allyloxy)-4-fluorophenyl)ethanone (7.92 g, 40.0 mmol, 82% yield) as a white solid. LCMS (M+Na)+=217.1. 1H NMR (500 MHz, chloroform-d) δ 7.82 (dd, J=8.7, 7.0 Hz, 1H), 6.71 (ddd, J=8.7, 7.6, 2.3 Hz, 1H), 6.66 (dd, J=10.8, 2.3 Hz, 1H), 6.08 (ddt, J=17.3, 10.6, 5.3 Hz, 1H), 5.55-5.41 (m, 1H), 5.41-5.29 (m, 1H), 4.63 (dt, J=5.4, 1.4 Hz, 2H), 2.62 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH2:12][C:13]#[N:14])=[N:6][C:5]2=[O:15].C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>O1CCOCC1>[CH:30]1[C:31]([Cl:33])=[CH:32][C:24]([Cl:23])=[C:25]([C:26](/[C:12](/[C:13]#[N:14])=[C:7]2/[NH:8][C:9]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]([NH:6]/2)=[O:15])=[O:27])[CH:29]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: N#CCc1nc(=O)c2cc(Cl)ccc2[nH]1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N#C/C(C(=O)c1ccc(Cl)cc1Cl)=C1/NC(=O)c2cc(Cl)ccc2N1
Yield: 6.9 %

Procedure:
To solution of 2-(6-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)acetonitrile (52.0 mg, 237 μmol) and triethylamine (36.3 μL, 260 μmol) in dioxane (4 mL) was added 2,4-dichlorobenzoyl chloride (33.1 μL, 237 μmol) and the resulting mixture was refluxed overnight with stirring. A solid precipitate formed upon cooling of the reaction mixture, which was recovered by vacuum filtration and washed sequentially with methanol, water, methanol, and dichloromethane. The solid was then dried to yield ciliobrevin C (4) (6.4 mg, 7%). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.50 (d, J1=8.3 Hz, 1H), 7.56 (dd, J1=8.3 Hz, J2=1.9 Hz, 1H), 7.77 (d, J=1.9 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.88 (dd, J1=8.9 Hz, J2=2.3 Hz, 1H), 8.00 (d, J2=2.4 Hz, 1H). 13C NMR (500 MHz, DMSO-d6) δ ppm 72.1, 117.52, 118.98, 121.22, 125.61, 127.67, 129.22, 129.66, 129.99, 130.49, 134.88, 135.64, 38.11, 138.58, 155.05, 157.52, 188.76. HRMS (m/z): [M+Na]+ calc. for C17H8N3O2Cl3Na, 413.9580; observed, 413.9583.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH2:7](O)[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][CH2:21][CH3:22].S(=O)(=O)(O)O>C1C=CC=CC=1.O>[CH2:22]([O:5][C:4](=[O:6])[C@H:2]([CH3:3])[NH2:1])[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][CH3:7]
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCOC(=O)[C@H](C)N
Temperature: 25 °C
Reaction time: 7 h
Yield: 86.1 %

Procedure:
4.46 g (0.05 mole) of L-alanine was taken, and 13.3 g (0.055 mole) of cetyl alcohol was taken as an alcohol. After 200 ml of benzene was added thereto as a solvent, these materials were stirred and mixed. After the addition of 4.9 g (0.05 mole) of sulfuric acid as an acid catalyst, the resulting reaction mixture was heated under reflux. In this case, water was formed with the progress of the esterification reaction and released in the form of an azeotropic mixture with benzene, which was continuously removed from the reaction system. Thus, the reaction was completed in about 7 hours (at an internal temperature of 80.5° C.). After being cooled to room temperature, the reaction mixture was poured into a separating funnel and treated with 300 ml of a mixture of 0.2N NaOH and 6% NaCl solutions. This treatment was repeated three times. Thereafter, the benzene layer was isolated and washed thoroughly with water. After washing with water, the benzene layer was isolated and dried overnight over anhydrous sodium sulfate. Thereafter, the benzene layer was filtered and the resulting benzene solution was evaporated to remove the solvent. Thus, there was obtained 13.5 g (86.1% yield) of purified L-alanine cetyl ester in the form of an oily material.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.OC[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[NH:44][C:43](=[O:45])[C:42]3[C:37](=[CH:38][C:39]([O:48][CH3:49])=[CH:40][C:41]=3[O:46][CH3:47])[N:36]=2)=[CH:31][CH:30]=1>CN(C=O)C>[Br:5][CH2:1][CH2:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[NH:44][C:43](=[O:45])[C:42]3[C:37](=[CH:38][C:39]([O:48][CH3:49])=[CH:40][C:41]=3[O:46][CH3:47])[N:36]=2)=[CH:33][CH:34]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCO)cc3)nc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCCBr)cc3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Carbon tetrabromide (0.26 g, 0.77 mmol) was added to a solution of triphenylphosphine (0.24 g, 0.92 mmol) in anhydrous DMF (5 mL) at 0° C. A solution of 2-[4-(2-hydroxy-ethoxy)-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.21 g, 0.61 mmol) in DMF (2 mL) was then added dropwise and stirred at room temperature for 16 hours. Solvent was removed under reduced pressure and the residue was diluted with water (10 mL) and extracted with dichloromethane (4×10 mL). The combined organic phase was washed with brine and dried over anhydrous magnesium sulfate. Solvent was removed and the residual solid was triturated with ether. The resulting slurry was filtered and washed with ether several times (to remove the triphenylphosphine oxide) and finally with a solution of dichloromethane-ether (1:4) to obtain 2-[4-(2-bromo-ethoxy)-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as an off-white solid. Yield: 0.25 g (quantitative).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:7][C:8]=1[CH3:9].CCN(CC)CC.OS([O-])=O.[Na+]>C(Cl)Cl>[Br:1][C:5]1[C:4]([Cl:3])=[C:8]([CH3:9])[NH:7][C:6]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc(Cl)c(C)[nH]1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c(C)c(Cl)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
Bromine (0.56 ml, 11 mmol) was added to a solution of 1 g (5.3 mmol) of ethyl 4-chloro-5-methyl-1H-pyrrole-2-carboxylate (WO2006087543) and 0.8 ml (5.7 mmol) Et3N in CH2Cl2. After stirring at room temperature for 2 h, aqueous NaHSO3 was added and the CH2Cl2 was removed and the aqueous residue was partitioned between water and EtOAc. The EtOAc layer was separated and washed with brine. The EtOAc layer was dried over anhydrous MgSO4, and the solvent was removed to give 1.5 g of the product as a solid. MS (ES) (MH+): 240 for C8H9BrClNO2; NMR (d6-DMSO): 1.3 (t, 3H), 2.2 (s, 3H), 4.2 (q, 2H), 12.3 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][C:3]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]=O.CCO>CCOC(C)=O>[Cl:12][C:5]1[C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]2[N:1]=[C:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[N:13]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=3)[C:3]=2[CH:4]=1
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1Nc1ccc(CCO)cc1
Reactant: O=Cc1ccccn1
Solvent: CCOC(C)=O
Solvent: CCO
Product: OCCc1ccc(-n2c(-c3ccccn3)nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Temperature: 25 °C
Yield: 51.8 %

Procedure:
A mixture of 2-(4-{[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethanol (1.83 g, 5.54 mmol), 2-pyridinecarboxaldehyde (0.53 ml, 5.54 mmol), and EtOH (40 ml) was refluxed for 1 hour. After cooling to room temperature, the solvent was removed. The residue was dissolved with benzene (50 ml) and treated with Pb(OAc)4 (3.38 g, 6.10 mmol) at room temperature for 1 hour. The mixture was diluted with EtOAc and the solution was washed with sat. NaHCO3 aq. and brine. The organic fraction was dried over MgSO4, then filtered. After evaporation in vacuo, the residue was purified by silica-gel column chromatography eluting with hexane/EtOAc=5/2 to afford 1.20 g (52%) of the title compound.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:47][C:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1.CO.[CH2:59]([N:66]1[CH2:70][CH:69]=[C:68]([C:71](=[O:73])[CH3:72])[CH2:67]1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>O>[CH2:59]([N:66]1[CH2:70][C@H:69]([C:51]2[CH:52]=[CH:53][C:48]([Cl:47])=[CH:49][CH:50]=2)[C@@H:68]([C:71](=[O:73])[CH3:72])[CH2:67]1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(=O)C1=CCN(Cc2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: CO
Product: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 55 °C
Yield: 33 %

Procedure:
A two necked flask was charged under argon with rhodium(acac)bis ethylene (45 mg, 0.05 eq.), (R)-BINAP (110 mg, 0.05 eq.) and 4-chloro-phenylboronic acid (1.20 g, 2.2 eq.). 100 mL of MeOH and 10 mL of H2O were added followed by 1-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)-ethanone (0.70 g). The reaction mixture was heated at 55° C. for 8 hours, cooled down to RT and concentrated under vacuo. Purification by flash chromatography (SiO2, EtOAc/Heptane 2/1) afforded 0.36 g (33%) of the title product as a light yellow oil. ES-MS m/e: 314.0 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26]1[S:30][C:29]([C:31](O)=[O:32])=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:31]([C:29]3[S:30][C:26]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:20]=4[CH3:19])=[CH:27][CH:28]=3)=[O:32])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1ccncc1-c1ccc(C(=O)O)s1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccncc1-c1ccc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)s1
Yield: 55.8 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.116 g, 0.446 mmol), 5-(4-methylpyridin-3-yl)thiophene-2-carboxylic acid (0.098 g, 0.446 mmol), DIPEA (0.233 ml, 1.337 mmol), HOBt hydrate (0.102 g, 0.668 mmol) and EDCI (0.128 g, 0.668 mmol) as described in the previous Example affording 0.115 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.19 (d, 3H), 2.41 (s, 3H), 4.32 (m, 2H), 4.43 (m, 1H), 6.95 (d, 1H), 7.33 (d, 1H) 7.37 (d, 1H), 7.79 (d, 1H), 7.85 (d, 1H), 7.94 (m, 2H), 8.07 (d, 1H), 8.45 (m, 2H), 8.55 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[K+]>C1(C)C=CC=CC=1>[CH2:9]([O:16][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Brc1ccc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,5-dibromopyridine (1.0 eq.), benzyl alcohol (1.3 eq.), KOH (2.4 eq.) and DB-18—C-6 (0.0 Seq.) in toluene (0.3M) was refluxed for 3 h, then stirred overnight at rt. The mixture was concentrated, poured in water and extracted with Tol (2×). The combined organic extracts were dried over MgSO4, filtered and concentrated. Recrystallization in Hex:Et2O afforded the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[Cl:14][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][C:25]=1[OH:26])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:14][C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][C:25]=1[O:26][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1ccc(O)c(Cl)c1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCc2nc(-c3ccco3)oc2C)c(Cl)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (8.0 g), ethyl 3-chloro-4-hydroxybenzoate (7.38 g), potassium carbonate (5.09 g) and N,N-dimethylformamide (200 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration and dried to give ethyl 3-chloro-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzoate as brown crystals (9.90 g, yield 74%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 145-146° C.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[Br:14][CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:14][CH2:15][CH2:16][CH2:17][O:7][C:4]1[CH:3]=[CH:2][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: BrCCCOc1ccc(-c2ccccc2)cc1
Reaction time: 24 h
Yield: 63.9 %

Procedure:
To a solution of 4-biphenylol (0.0514 g, 0.302 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (0.310 mL, 3.05 mmol) followed by Cs2CO3 (0.154 g, 0.472 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.0562 g, 64.0%). EI-MS Rt (2.62 min).
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][C:6]1[CH:7]=[C:8]([CH:10]=[C:11]([CH3:25])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH:22]([CH3:24])[CH3:23])[CH:15]=1)[NH2:9].Cl.[Sn](Cl)Cl>O.C(O)C>[CH3:25][C:11]1[CH:10]=[C:8]([NH:9][NH2:1])[CH:7]=[C:6]([CH3:5])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH:22]([CH3:23])[CH3:24])[CH:15]=1
Reactant: O=N[O-]
Reactant: COc1ccc(Oc2c(C)cc(N)cc2C)cc1C(C)C
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Oc2c(C)cc(NN)cc2C)cc1C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
A solution of sodium nitrite (155 mg, 2.24 mmol) in water (1 mL) was added to a suspension of 3,5-dimethyl-4-(4′-methoxy-3′-iso-propylphenoxy)-aniline (J. Med. Chem. 1995, 38, 695, 640 mg, 2.24 mmol) in ethanol (3 mL) and concentrated hydrochloric acid (12 M, 1.12 mL, 13.44 mmol) at 0° C. The yellow heterogeneous solution slowly turns to an orange clear solution. After stirring at 0° C. for 30 minutes, a solution of tin dichloride (1.53 g, 8.06 mmol) in hydrochloric acid (12 M, 1.3 mL, 15.68 mmol) was added. The orange solution turned green and a white precipitate formed. Ethanol (3 mL) was added to dissolve most of the precipitate and the heterogeneous reaction mixture was stirred at 0° C. After 2 hours, water was added and the precipitate collected by filtration. The sticky solid was dissolved in ethyl acetate and washed with water, 1 N sodium hydroxide then brine. The organics were dried over sodium sulfate, concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, dichloromethane/methanol 95/5 to 90/10) to give 3,5-dimethyl-4-(4′-methoxy-3′-iso-propylphenoxy)-phenyl hydrazine (305 mg, 45%): 1H NMR (300 MHz, CDCl3) δ 6.77 (d, J=3.0 Hz, 1H), 6.67 (d, J=9.0 Hz, 1H) 6.58 (s, 2H), 6.37 (dd, J=9.0, 3.0 Hz, 1H), 3.77 (s, 3H), 3.27 (heptuplet, J=6.9 Hz, 1H), 2.09 (s, 3H), 1.18 (d, J=6.9 Hz, 6H); TLC conditions: Merck silica gel, 250 microns; Mobile phase=dichloromethane-methanol (9:1), Rf=0.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[I-].[K+].[CH3:27][CH:28]=[CH:29][CH2:30][NH2:31]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:31][CH2:30][CH2:29][CH:28]=[CH2:27])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: CC=CCN
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCCNCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 32, 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide, and methylallylamine in tetrahydrofuran are reacted to give 8-chloro-1-[(allylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:15]1([C:20]2[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[N:16]1>>[C:1]([O:5][C:6](=[O:14])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:26]([C:23]2[CH:22]=[CH:21][C:20]([N:15]3[CH:19]=[CH:18][CH:17]=[N:16]3)=[CH:25][CH:24]=2)(=[O:27])=[O:28])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(-n2cccn2)cc1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-n3cccn3)cc2)c1

Procedure:
Starting from (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1) and art-known 4-pyrazol-1-yl-benzenesulfonylchloride the title compound can be obtained analogously or similarly as described for compound C1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.O.C(=O)(O)[O-].[Na+].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>C(COC)OC>[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 47 %

Procedure:
2-Chloropyridine-4-carbonitrile 19 (2.96 g, 21.35 mmol) was dissolved in 100 ml of dimethoxyethane. The solution was added with 70 ml of water, sodium bicarbonate (3 equiv., 5.38 g), [4-(trifluoromethyl)phenyl]boronic acid (1.2 equiv., 4.87 g) and the mixture was then stirred at rt for 5′. The mixture was degassed and placed under argon. A catalytic amount of tetrakispalladium was added and the mixture heated at 100° C. overnight. The solvents were evaporated off and the resulting residue dissolved with ethyl acetate and then washed with water and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude was crystallized from ethyl acetate and petroleum ether to give a beige solid. (2.5 g, 47% yield).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH:26]=O)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[NH2:36][CH2:37][CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:26][NH:36][CH2:37][CH2:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3]
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Reactant: NCCc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc(-c2cc3cc(CNCCc4cccnc4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 66.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (100 mg, 0.200 mmol) was dissolved in acetonitrile (5.8 mL), and the solution was treated with 3-(2-aminoethyl)pyridine (0.235 mL, 2.00 mmol), acetic acid (0.229 mL, 4.00 mmol) and sodium triacetoxyborohydride (127 mg, 0.599 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=4/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-{1-(tert-butoxycarbonyl)-5-[(2-(pyridin-3-yl)ethyl)aminomethyl]indol-2-yl}isoindolinone (80.5 mg, yield 66%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:29])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]2[O:15][CH:16]([CH2:18][NH:19][C:20](=[O:26])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])[O:17][C:13]=2[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:31]1[C:35](=[O:36])[CH2:34][CH2:33][C:32]1=[O:37].C(N=C=NCCCN(C)C)C>ClCCl>[O:37]=[C:32]1[CH2:33][CH2:34][C:35](=[O:36])[N:31]1[O:24][C:23](=[O:25])[CH2:22][CH2:21][C:20]([NH:19][CH2:18][CH:16]1[O:15][C:14]2[CH:27]=[CH:28][C:11]([CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:29])=[CH:12][C:13]=2[O:17]1)=[O:26]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(Cc1ccc2c(c1)OC(CNC(=O)CCC(=O)O)O2)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(Cc1ccc2c(c1)OC(CNC(=O)CCC(=O)ON1C(=O)CCC1=O)O2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 32 mg (0.078 mmol) of 3G was added 4 mL of dichloromethane (distilled over CaH2) followed by 14 mg (0.12 mmol) of N-hydroxysuccinimide and 30 mg (0.152 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide. The reaction mixture was allowed to stir at room temperature under argon atmosphere 18 hours. The reaction mixture was diluted with additional 25 mL of dichloromethane and washed with 2×20 mL of water, 2×20 mL of saturated sodium bicarbonate and 1×20 mL of water. The organic layer was dried (Na2SO4) and concentrated to give 36 mg (0.071 mmol) of 3H as a colorless gum.