Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:12]1(N=C=NC2CCCCC2)CCCCC1.CO>ClCCl.CN(C)C1C=CN=CC=1>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromophenylacetic acid (1.0 g, 4.65 mmol), 1,3-dicyclohexylcarbodiimide (1.44 g, 6.98 mmol) and MeOH (149 mg, 4.65 mmol) in dichloromethane (40 ml) was added 4-dimethylaminopyridine (57 mg, 0.465 mmol). The reaction mixture was stirred at RT for 1 hr. The white solid was precipitated out which was removed with filtration. The reaction solution was concentrated to give a crude product which was purified on silica gel column with dichloromethane. The product was collected which contain a little amount of DCU (1.36 g). NMR (CDCl3): □ 7.20-7.46 (4H, m), 3.72 (3H, s), 3.621(2H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[Na+].[Na+].Cl>O.CN(C)C=O>[CH2:31]([O:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 79.1 %

Procedure:
A mixture of 2,4-dinitrophenol (85 wt %, 6.72 g, 31 mmol), octadecyl bromide (20.7 g, 62 mmol), sodium carbonate (6.57 g, 62 mmol) and dimethylformamide (31 mL) was heated to 100° C. under a nitrogen atmosphere for 22 h. The cooled mixture was diluted with water (200 mL), acidified with 10N hydrochloric acid (50 mL) and extracted with ether. The extracts were washed with water and brine, and dried over magnesium sulfate. The solvent was removed and the solid recrystallized to give 1-octadecyloxy-2,4-dinitrobenzene (10.7 g, 79%): mp 63.5°-64.0° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.[CH3:33][N:34]([CH3:40])[C@@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:33][N:34]([CH3:40])[C@@H:35]1[CH2:39][CH2:38][N:37]([C:15](=[O:16])[CH2:14][NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([O:28][C:29]([F:32])([F:30])[F:31])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:36]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Reactant: CN(C)[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)[C@@H]1CCN(C(=O)CNC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(OC(F)(F)F)cc4s2)n3C)C1
Yield: 45.8 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-((R)-3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]amide (45 mg) was prepared by following General Procedure F starting from {[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (95 mg), dimethyl-(R)-pyrrolidin-3-yl-amine (20 mg), HBTU (85 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 561.4.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[NH2:7][CH2:8][C@@H:9]([CH3:37])[O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[C:24]([CH3:36])[CH:23]=1)=[N:14][CH:15]=[N:16]2>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][C@H:9]([O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[C:24]([CH3:36])[CH:23]=1)=[N:14][CH:15]=[N:16]2)[CH3:37])=[O:6]
Reactant: O=C=NCCCl
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(O[C@H](C)CN)c34)cc2C)cn1
Solvent: ClCCl
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(O[C@H](C)CNC(=O)NCCCl)c34)cc2C)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
Chloroethylisocyanate (116 μl, 1.36 mmol) was added drop wise to an ice-cooled solution of 5-[(1R)-2-amino-1-methylethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (516 mg, 1.24 mmol, obtained as described in Example 112, preparation of starting materials) in DCM (10 ml). The mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 3% to 5% 7N ammonia-methanol in DCM) to give the title compound (584 mg, 74%); NMR Spectrum: (CDCl3) 1.46 (d, 3H), 2.28 (s, 3H), 2.52 (s, 3H), 3.46 (m, 1H), 3.57 (m, 4H), 4.00 (m, 1H), 4.76 (m, 1H), 6.40 (m, 1H), 6.62 (m, 1H), 6.67 (d, 1H), 6.91 (d, 1H), 7.08 (d, 1H), 7.12 (dd, 1H), 7.18 (d, 1H), 7.34 (t, 1H), 7.53 (dd, 1H), 7.67 (s, 1H), 8.27 (s, 1H), 8.34 (s, 1H), 9.82 (s, 1H); Mass spectrum: MH+ 521.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:15]O>C(=O)(O)[O-].[Na+]>[CH3:15][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[N:4][CH:5]=1
Reactant: O=C(O)c1cncc(Cl)c1
Reactant: CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cncc(Cl)c1
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of 5-chloro-nicotinic acid (20.0 g, 127 mmol, purchased from Matrix Scientific, Columbia, S.C., USA) in methanol (200 mL) at 0° C. was added thionyl chloride (18.6 mL, 255 mmol). The reaction mixture was refluxed for 4 hours. After cooling to room temperature the mixture was diluted with saturated aqueous sodium bicarbonate, extracted with AcOEt (3×300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude 5-chloro-nicotinic acid methyl ester (17.2 g, 79%). 1H NMR (400 MHz, CDCl3) δ ppm 9.10 (d, J=1.4 Hz, 1 H), 8.75 (d, J=2.3 Hz, 1 H), 8.29 (d, J=2.0 Hz, 1H), 3.98 (s, 3 H). MS m/z 171.8
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[CH:48]([C:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[N:52][CH:51]=1)=[CH2:49]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([CH:49]=[CH:48][C:50]4[C:59]5[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=5)[CH:53]=[N:52][CH:51]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: C=Cc1cncc2ccccc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C(=O)CC[C@]2(C)c3ccc(C=Cc4cncc5ccccc45)cc3CC[C@@H]12
Reaction time: 20 h

Procedure:
A 508 mg portion of (4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one, 4 mg of palladium acetate, 20 mg of tri-o-tolylphosphine, 0.34 mL of triethylamine and 5 mL of dimethylformamide were combined in a sealable tube with a stir bar, and the mixture was warmed to 50 under argon. An 0.26 g portion of 4-ethenylisoquinoline was added. Then the vessel was blanketed with argon and sealed and the mixture was heated with stirring at 120° for 20 hours. It was then cooled, and concentrated under vacuum and the residue was purified by chromatography on silica gel, eluting with 5% isopropanol in chloroform. An 0.29 g portion of an oil was obtained, which was recrystallized from ethyl acetate/hexane to obtain the desired product in crystalline form. mp 183°-185°; FDMS 382 M+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:24]=[CH:23][C:6]([CH2:7][O:8][N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19]C(=O)C)=[CH:15][CH:14]=2)[CH2:11][CH3:12])=[CH:5][CH:4]=1.[OH-].[K+]>C(O)C.O>[F:1][C:2]([F:25])([F:26])[C:3]1[CH:24]=[CH:23][C:6]([CH2:7][O:8][N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:11][CH3:12])=[CH:5][CH:4]=1
Reactant: CCC(=NOCc1ccc(C(F)(F)F)cc1)c1ccc(NC(C)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(=NOCc1ccc(C(F)(F)F)cc1)c1ccc(N)cc1
Temperature: 85 °C
Reaction time: 36 h
Yield: 84.6 %

Procedure:
To a solution of the product of step 1 (10 g, 0.0275 moles) in ethanol (70 ml), a solution of potassium hydroxide (6.15 g, 0.1098 moles) in water (30 ml) was added and the reaction mixture was stirred at 80-90° C. for 36 hours. The reaction mixture was poured into ice cold water and extracted by dichloromethane. The combined dichloromethane extract was washed with water and brine, dried over sodium sulphate and evapourated under reduced pressure to yield 7.5 gm (84%) of product as liquid.
Reaction SMILES: [S-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].Br[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=2)[CH:15]=1>CN1CCCC1=O>[N+:19]([C:16]1[N:14]2[CH:15]=[C:10]([S:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:11]=[CH:12][C:13]2=[N:18][CH:17]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cn12
Reactant: [S-]c1ccccc1
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cnc2ccc(Sc3ccccc3)cn12

Procedure:
A solution of 1.61 g. (0.012 mole) of sodium thiophenoxide and 2.42 g. (0.01 mole) of 6-bromo-3-nitroimidazo [1,2-a] pyridine in 10 ml. N-methylpyrolidinone is heated at 150° C for 0.40 minutes under a nitrogen atmosphere. The cooled solution is poured onto 100 ml. of ice-water and the resultant suspension is extracted with ethyl acetate. The combined extracts are washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Evaporation of the solvent to a small volume and dilution with N-hexane yields crystalline material. The solids are purified by chromatography on silica gel. Elution with methylene chloride yields pure 3-nitro 6-phenylthioimidazo [1,2-a] pyridine m.p. 108°-109° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].CCN(CC)CC.[O:19](S(C(F)(F)F)(=O)=O)[S:20]([C:23]([F:26])([F:25])[F:24])(=O)=[O:21]>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[S:20]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11])(=[O:21])=[O:19]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1cc(C=O)ccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of 4-hydroxy-3-(methoxy)benzaldehyde (0.760 g; 5.00 mmol) and Et3N (1.39 mL; 10.0 mmol) in anhyd CH2Cl2 (10 mL) at 0° C. was added Tf2O (0.92 mL; 5.5 mmol), dropwise over 2 min. The mixture was allowed to warm slowly to room temperature (overnight), diluted with CH2Cl2, washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.01 (s, 3H), 7.42 (d, J=8.2 Hz, 1H), 7.52 (dd, J=8.2, 1.8 Hz, 1H), 7.57 (d, J=1.7 Hz, 1H), 9.99 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[NH2:14].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([NH2:11])[C:5]=1[NH2:14]
Reactant: [H][H]
Reactant: COC(=O)c1cc(C)cc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(C)cc(N)c1N
Yield: 96 %

Procedure:
A solution of 2-amino-5-methyl-3-nitro-benzoic acid methyl ester (5.5 g, 26 mmol) in methanol (200 mL) was hydrogenated with hydrogen balloon in presence of 10% Palladium on charcoal (1.5 g) for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to get the required product as a brown coloured solid 4.5 g (95%).
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[N:32]1([C:37]2[N:42]=[CH:41][C:40]([C:43]([OH:45])=O)=[CH:39][N:38]=2)[CH:36]=[CH:35][N:34]=[CH:33]1.[CH:46]1([NH:49][CH:50]2[CH2:55][CH2:54][N:53]([C:56]3[O:60][N:59]=[C:58]([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)[N:57]=3)[CH2:52][CH2:51]2)[CH2:48][CH2:47]1>CN(C)C=O>[CH:46]1([N:49]([CH:50]2[CH2:51][CH2:52][N:53]([C:56]3[O:60][N:59]=[C:58]([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)[N:57]=3)[CH2:54][CH2:55]2)[C:43]([C:40]2[CH:41]=[N:42][C:37]([N:32]3[CH:36]=[CH:35][N:34]=[CH:33]3)=[N:38][CH:39]=2)=[O:45])[CH2:48][CH2:47]1
Reactant: c1ccc(-c2noc(N3CCC(NC4CC4)CC3)n2)cc1
Reactant: O=C(O)c1cnc(-n2ccnc2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnc(-n2ccnc2)nc1)N(C1CC1)C1CCN(c2nc(-c3ccccc3)no2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (75 mg) and ethyldiisopropylamine (74 μL) are added to a solution of 2-imidazol-1-yl-pyrimidine-5-carboxylic acid (40 mg) in N,N-dimethylformamide (5 mL) at room temperature. The solution is stirred for 10 min prior to the addition of cyclopropyl-[1-(3-phenyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]amine (60 mg). The resulting mixture is stirred at 60° C. for 3 h, cooled to room temperature over night, and concentrated in vacuo. The crude product is purified by HPLC(H2O/MeOH/TFA). LC (method 1): tR=1.50 min; Mass spectrum (ESI+): m/z=457 [M+H]+.
Reaction SMILES: [N:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[NH:3][CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[S].[S:19]1(CCCC1)(=O)=O>>[NH:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[N:3]=[C:2]1[SH:19])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: O=S1(=O)CCCC1
Reactant: c1ccc2c(c1)c1ccccc1c1[nH]cnc21
Agent: [S]
Product: Sc1nc2c3ccccc3c3ccccc3c2[nH]1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Ten grams of the imidazole was suspended in 100 ml of sulfolane (tetramethylene sulfone) and 3 gms of powdered sulfur was added; the resulting mixture was heated in an atmosphere of nitrogen at 200°-205° with thorough stirring for eight hours. The reaction mixture was then cooled, and diluted with 500 ml of ice-cold water. The dark brown mass that separated was collected by filtration and thoroughly washed with water and dried in a vacuum oven at 100° for ten hours. The crude product was purified by column chromatography using basic alumina (Woelm grade 1) and dimethylformamide as the eluent. The purified product was triturated with boiling acetonitrile, melting point above 375°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=O)=[CH:15][CH:16]=3)[C:11](=[O:33])[NH:10][N:9]=2)[CH:7]=1.[N:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[N:38][CH:37]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:42][C:39]4[CH:40]=[CH:41][N:36]=[CH:37][N:38]=4)(=[O:21])=[O:20])=[CH:15][CH:16]=3)[C:11](=[O:33])[NH:10][N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1ccncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1-c1n[nH]c(=O)c2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reaction time: 2 h
Yield: 25.8 %

Procedure:
A vial was charged with perfluorophenyl 1-(5-chloro-2-methoxyphenyl)-4-oxo-3,4-dihydrophthalazine-6-sulfonate (From Step 6, Example 501; 126 mg, 0.236 mmol), pyrimidin-4-amine (33.7 mg, 0.355 mmol), and THF (1.18 mL). The resulting solution was cooled in an ice-water bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (591 μl, 0.591 mmol) was added drop wise. LCMS after 2 h showed complete conversion of SM to product. The reaction was quenched with 1 mL of MeOH. Purification was done via RPLC with 0.1% NH4OH in ACN and water as mobile phase to afford 1-(5-chloro-2-methoxyphenyl)-4-oxo-N-(pyrimidin-4-yl)-3,4-dihydrophthalazine-6-sulfonamide (27 mg, 25.7% yield). m/z (ESI) 444.0 (M+H)+.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:11][C@@H:12]1[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:16]([O:22][C:23](=[O:25])[CH3:24])[CH2:15][S:14][C@@H:13]1Br)(=[O:10])[CH3:9]>>[C:8]([O:11][C@@H:12]1[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:16]([O:22][C:23](=[O:25])[CH3:24])[CH2:15][S:14][C@H:13]1[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])[CH3:9]
Reactant: Sc1ccccc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccccc2)SC[C@H]1OC(C)=O
Yield: 52.3 %

Procedure:
If the procedure described in Preparation I is followed starting from 4 g (36.3.10-3 mol) of benzenethiol, 14 g (39.4.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-xylopyranosyl bromide and 10 g (39.10-3 mol) of mercuric cyanide (Hg(CN)2), 7.3 g of the expected product are obtained after crystallization from ether.
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]([O:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[CH3:9])=[O:5]>C(Cl)Cl>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH:8]([CH3:9])[CH2:7][O:6][C:4]([NH:1][NH:2][C:4]([O:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[CH3:9])=[O:5])=[O:5])([O-:18])=[O:17]
Reactant: CC(COC(=O)Cl)c1ccccc1[N+](=O)[O-]
Reactant: NN
Solvent: ClCCl
Product: CC(COC(=O)NNC(=O)OCC(C)c1ccccc1[N+](=O)[O-])c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
A solution of hydrazine (0.32 mL, 10.25 mmol) in DCM (20 mL) was added dropwise to a solution of 2-(2-nitrophenyl)propyl chloroformate (5.0 g, 20 mmol) in methylene chloride (25 mL) over a period of 30 min. The reaction mixture was stirred at room temperature for an additional 15 min. The solvent was evaporated and the residue was purified on a silica gel column. Elution of the column with 20% ethyl acetate in hexanes gave 1.46 g (3.26 mmol 32% yield) of di-(2-(2-nitrophenyl)propoxycarbonyl)hydrazine. 1H-NMR (300 MHz, DMSO-d6): δ 9.06-8.73 (d, 1 H, CONH), 7.84 (d, J=7.8 Hz, 1 H, Ar—H), 7.63 (m, 2 H, Ar—H), 7.48 (m, 1 H, Ar—H), 4.20 (m, 2 H, CH2), 3.39 (m, 1 H, CH), 1.26 (d, J=6.9 Hz, 3 H, CH3). 13C-NMR (75 MHz, DMSO-d4): δ 156.19 (OCOR), 149.85 (C ipso to NO2), 136.53 (C ipso to CH(CH3)CH2OCOR), 132;91 (C para to NO2), 128.52.(C para to CH(CH3)CH2OCOR), 127.76 (C ortho to CH(CH3)CH2OCOR), 123.77 (C ortho to NO2), 67.86 (CH2OCOR), 33.30 (CH), 17.99 (CH3). Mass analysis (MALDI-TOF): calculated for C20H22N4O8 446.42, found 446.24 (C20H22N4O8Na 469.38 is the major peak). TLC: 5% methanol in chloroform, Rf=0.7.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([F:13])[C:9]=1[CH2:10][C:11]#[N:12].Br[CH2:15][CH2:16]Br>C1COCC1>[F:13][C:8]1[CH:7]=[N:6][CH:5]=[C:4]([F:3])[C:9]=1[C:10]1([C:11]#[N:12])[CH2:16][CH2:15]1
Reactant: BrCCBr
Reactant: N#CCc1c(F)cncc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(c2c(F)cncc2F)CC1
Yield: 174.1 %

Procedure:
Sodium hydride 60% in mineral oil (3.35 g, 83.7 mmol) was suspended in 10 ml THF. At −10° C. a solution of 2-(3,5-difluoro-4-pyridyl)acetonitrile (4.30 g, 27.9 mmol) in 45 ml THF was added drop wise. The reaction mixture was stirred until no more gas evolution was visible. The reaction mixture was then a yellow suspension. At 0° C. 1,2-dibromoethane (9.71 mL, 112 mmol) was added drop wise. The reaction mixture was stirred 2 h at 0° C. then over night at rt. It was quenched with aq. NH4Cl, diluted with EtOAc. The organic layer was separated and dried with Na2SO4. Filtrated, the filtrate was evaporated. The residue gave a brown oil (8.75 g). The crude product was purified by flash chromatography (Solvent: Cyclohexane/EtOAc 1/1). The desired product was isolated as a colorless oil which crystallised upon standing (3.816 g).
Reaction SMILES: [CH2:1]([CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1)[CH3:2].C([Li])CCC.[F:14][C:15]([F:22])([F:21])[C:16]([O:18]CC)=O>>[F:22][C:15]([F:14])([F:21])[C:16]([C:3]1([CH2:1][CH3:2])[S:8][CH2:7][CH2:6][CH2:5][S:4]1)=[O:18]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CCC1SCCCS1
Agent: [Li]CCCC
Product: CCC1(C(=O)C(F)(F)F)SCCCS1
Yield: 34.9 %

Procedure:
The same operation as in Example (36a) was performed using 2-ethyl-1,3-dithiane obtained in Example (39a) (3.51 g, 23.7 mmol), n-butyllithium (1.58 M solution in hexane, 18 mL, 28.3 mmol) and ethyl trifluoroacetate (4 mL, 33.6 mmol), to obtain 2.02 g of the title compound as a pale yellow oily substance (35%).
Reaction SMILES: [Cl-:1].[Cl-].[CH-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Ti+2:13]>C1COCC1.[Zn]>[Cl-:1].[CH:3]1([Ti+:13][CH:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)[CH:7]=[CH:6][CH:5]=[CH:4]1
Reactant: c1cc[cH-]c1
Reactant: [Ti+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: C1CCOC1
Product: C1=CC([Ti+]C2C=CC=C2)C=C1
Reaction time: 1 h

Procedure:
To a red solution of titanocene dichloride (0.500 g, 2.00 mmol) in anhydrous THF (4.0 mL) was added zinc dust (0.392 g, 6.00 mmol). The resulting suspension was vigorously stirred for 1 h under an argon atmosphere to give a green suspension. Excess zinc was removed by filtration through a 0.45 μm microfilter to give a green solution of dicyclopentadienyl titanium (III) chloride. To a solution of compound 505A (0.207 g, 0.399 mmol) and 1,4-cyclohexadiene (0.380 mL, 4.02 mmol) in anhydrous THF (1 mL) was added dropwise a 0.5 M solution of the above described dicyclopentadienyl titanium (D) chloride (0.9 mL, 0.45 mmol). After 1 h, an additional aliquot of the 0.5 M solution of dicyclopentadienyl titanium (D) chloride (0.9 mL, 0.45 mmol) was added and stirring was continued for 1 h. The reaction was then quenched with water (2 mL) and diluted with ethyl acetate (10 mL). The layers were separated and the organic layer was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow gum. The crude material was dissolved in a minimum amount of methylene chloride and loaded on a 35 g silica gel ISCO column. Gradient elution with 0-80% ethyl acetate in hexane gave 0.043 g (21%) of compound 505Bi as a white solid and 0.023 g (11%) of compound 505Bii as a white solid. Compound 505Bi: HPLC: 3.92 min (retention time) (YMC CombiSreen ODS-A column, 4.6×50 mm, eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over 4 min, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 521.36 [M+H]+. Compound 505Bii : HPLC: 91% at 3.97 min (retention time) (YMC CombiScreen ODS-A column, 4.6×50 mm, eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over 4 min, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 521.34 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]Br)[CH:7]=1)[CH3:2].[CH3:24][C@H:25]1[C@@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][C:27](=[O:36])[NH:26]1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:26]2[C@@H:25]([CH3:24])[C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:28][C:27]2=[O:36])[CH:7]=1)[CH3:2]
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Reactant: CCOC(=O)Cc1cc(Cl)cc(Oc2ccc(Br)cc2CBr)c1
Product: CCOC(=O)Cc1cc(Cl)cc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-5-chloro-phenyl]-acetic acid ethyl ester and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.