Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[N+:16]([O-])([O-:18])=[O:17].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:16]([C:15]1[CH:14]=[CH:13][C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])=[CH:3][C:2]=1[OH:1])([O-:18])=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(O)c1
Reaction time: 24 h
Yield: 30 %

Procedure:
3-Hydroxybenzophenone (3.00 g, 15.1 mmol) was dissolved in methylene chloride (40 mL) followed by the addition of sodium nitrate (1.42 g, 16.7 mmol). The addition of sulfuric acid (25 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2CH2) gave the desired product (1.10 g, 30%). 1H NMR (CD3COCD3): d 8.25 (d, 1H), 7.86 (d, 1H), 7.71 (m, 1H), 7.59 (d, 1H), 7.48 (s, 1H), 7.39 (dd, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].C1C(=O)N([Br:18])C(=O)C1>C(#N)C>[NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:7]([Br:18])=[C:4]([CH:3]=1)[C:5]#[N:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(F)c(N)c1
Solvent: CC#N
Product: N#Cc1cc(N)c(F)cc1Br
Yield: 62.1 %

Procedure:
3-amino-4-fluorobenzonitrile (9.82 g, 72.1 mmol) was dissolved in acetonitrile to give a pale yellow solution. NBS (13.5 g, 75.7 mmol) was added in portions; the reaction mixture turned brown-blackish but remained a solution. After the completion of the reaction was confirmed by TLC and HPLC, silica gel was added to the reaction mixture and the solvent was evaporated under reduced pressure. The crude product was leaded on a CombiFlash column (330 g) and the product was eluted with hexanes/ethyl acetate (0→15% gradient). The clean fractions were combined to give 9.63 g (62%) of a yellowish off-white solid. More product was found in mixed fractions which were discarded. 1H NMR (300 MHz, dmso) δ 7.57 (d, J=10.9 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 5.85 (s br, 2H); MS (ES) 213/215 (M−H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][C:11]([F:16])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[F:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:18][C:19]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=1)[C:6]([C:4]([OH:3])=[O:5])=[C:14]2[CH3:15]
Reactant: CCOC(=O)c1[nH]c2ccc(F)cc2c1C
Reactant: BrCc1cccc2ccccc12
Product: Cc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(F)cc12

Procedure:
Using general procedure B, 5-fluoro-3-methyl-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 332.1 ([M−H]−).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[CH:9]=2)[CH2:4][C:3]21[CH2:26][C:25]1[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:19]2.[C:27](=[N:33][Si](C)(C)C)=[N:28][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:14]([C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH2:4][C:3]2([CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]2)/[C:2]/3=[N:28]/[C:27]#[N:33])[CH:18]=[CH:17][CH:16]=1)#[N:15]
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(Cc4ccccc4C2)C3)c1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\c2cc(-c3cccc(C#N)c3)ccc2CC12Cc1ccccc1C2
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 100.2 %

Procedure:
To a solution of 3-(1-oxo-1,1′,3,3′-tetrahydro-2,2′-spirobi[indene]-6-yl)benzonitrile (34 mg, 0.1 mmol) in DCM (5 mL) was added TiCl4 (76 mg, 0.4 mmol) dropwise, the mixture was stirred at 50° C. at Ar2 under microwave for 5 minutes, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (74 mg, 0.4 mmol) was added dropwise. The mixture was stirred at 60° C. at Ar2 under microwave for 10 minutes and poured into ice-water (10 mL). The aqueous layer was extracted with CH2Cl2, which was combined with the organic layer. The organic layer was dried and concentrated to give crude ((Z)—N-(5-(3-cyanophenyl)-1′,3′-dihydro-2,2′-spirobi[indene]-3(1H)-ylidene)cyanamide (36 mg, 99%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.FC1C=CC(C=O)=CC=1.[CH3:16][O:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35](N4C=CN=C4C)=[CH:34][CH:33]=3)[CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[CH3:16][O:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N:5]4[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]4)=[CH:34][CH:33]=3)[CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: COC1(c2cccc(OCc3ccc(-n4ccnc4C)cc3)c2)CCOCC1
Reactant: Cc1c[nH]cn1
Agent: O=Cc1ccc(F)cc1
Product: COC1(c2cccc(OCc3ccc(-n4cnc(C)c4)cc3)c2)CCOCC1

Procedure:
The title compound was prepared using 4-methylimidazole and 4-fluorobenzaldehyde according to the procedure as described for 4-methoxy-4-[3-[4-(2-methylimidazol- 1-yl)benzyloxy]phenyl]-3,4,5,6-tetrahydro-2H-pyran (Example 2).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[C:19]([CH3:22])([CH3:21])[CH3:20].CCCCC.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CCOCC>[CH2:32]([O:31][C:29](=[O:30])[C:2]1[CH:18]=[CH:17][C:5]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:33]
Reactant: CC(C)[Si](Oc1ccc(Br)c(C(C)(C)C)c1)(C(C)C)C(C)C
Reactant: CCOC(=O)Cl
Solvent: CCCCC
Solvent: CCOCC
Product: CCOC(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1C(C)(C)C
Temperature: 25 °C
Yield: 124.9 %

Procedure:
To a solution of (4-bromo-3-tert-butyl-phenoxy)-triisopropyl-silane (Intermediate 105, 1.00 g, 2.60 mmols) in 15 mL Et2O cooled to −78° C. was added 3.6 mL of tert-butyl]ithium, 1.7 M in pentane (395.0 mg, 6.2 mmols). After stirring for 30 minutes ethyl chloroformate (607.6 mg, 5.6 mmols) was added. The resulting solution was warmed to room temperature and quenched by the addition of saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the combined organic layers dried (MgSO4) concentrated under reduced pressure The residue was chromatographed (2-5% EtOAc-hexanes) to give 1.23 g (88%) of the title compound as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:25]=[CH:24][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:26][NH:27][CH3:28]>>[CH3:26][N:27]([CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:25]=[CH:24][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1
Reactant: CNC
Reactant: FC(F)(F)c1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Product: CN(C)CCCCOc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole and Dimethylamine were converted to yield Dimethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amine, MS: 395 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45](=[O:54])[N:46]([CH3:53])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:40][CH:39]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:63]>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:35][CH2:36][CH2:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][C:45](=[O:54])[N:46]([CH3:53])[C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)=[CH:42][CH:43]=3)=[O:14])=[CH:15][CH:16]=2)[CH2:6][CH2:7]1.[ClH:63]
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: ClCCl
Reactant: CN(C(=O)Oc1ccc(CCN)cc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(C(=O)NCCc3ccc(OC(=O)N(C)c4ccccc4)cc3)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(4-methylpiperazino)benzoic acid (0.3 mmol), EDAC (0.36 mmol) and triethylamine (1.0 mmol) in CH2Cl2 (10 mL) was added N-hydroxybenzoetriazole and N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.3 mmol). The mixture was stirred 16 h at rt and purified by preparative HPLC (Gilson) to give the title compound in 54% yield as its crystalline hydrochloride after treatment with HCl in diethyl ether.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:5][CH:4]([C:17]([OH:19])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:33][NH:34][O:35][CH3:36].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:36][O:35][N:34]([CH3:33])[C:17]([CH:4]1[CH2:3][C:2](=[O:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=2)[CH2:5]1)=[O:19]
Reactant: O=C(O)C1CC(=O)N(c2cccc(C(F)(F)F)c2)C1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)C1CC(=O)N(c2cccc(C(F)(F)F)c2)C1
Reaction time: 0.08 h
Yield: 82.1 %

Procedure:
To a stirred solution of [5-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidine-3-carboxylic acid (1 g, 3.66 mmol) in DCM (15 mL) was added 1,1′-carbonyldiimidazole (0.65 g, 4.02 mmol) portion wise over a period of 10 min at 10-15° C. N,O-dimethylhydroxylamine hydrochloride (0.42 g, 4.39 mmol) was added portion wise and stirred for 5 min at that temperature. To the reaction mixture triethylamine (0.66 ml, 4.75 mmol) was added drop wise and it was stirred for 2 hr at 20-25° C. The reaction mixture was diluted with water (10 ml) and aqueous layer was separated. The aqueous layer was extracted with DCM (2×25 ml). The combined organic layer was washed with 5% HCl (25 ml) and saturated brine solution (25 ml). The organic layer was dried over Na2SO4, evaporated under reduced pressure to obtain 5-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidine-3-carboxylic acid methoxy-methyl-amide (0.95 g, 83%) as a colorless sticky mass.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]=1[C:33]1[O:37][N:36]=[C:35]([C:38](O)=[O:39])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[F:64][CH2:65][CH2:66][NH2:67].CCN(C(C)C)C(C)C>C1COCC1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]=1[C:33]1[O:37][N:36]=[C:35]([C:38]([NH:67][CH2:66][CH2:65][F:64])=[O:39])[CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCF
Reactant: O=C(O)c1cc(-c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc([N+](=O)[O-])cc2)on1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCF)c1cc(-c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc([N+](=O)[O-])cc2)on1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
To a stirred solution of 5-[2,4-bis(benzyloxy)-6-(4-nitrophenoxy)phenyl]isoxazole-3-carboxylic acid (0.45 g, 0.84 mmol) in THF (30 mL) was added TBTU (0.300 g, 1.1 mmol). After stirring for 15 minutes at room temperature, 2-fluoroethylamine hydrochloride (0.1 g, 1 mmol) and DIPEA (0.58 mL) were subsequently added. After stirring overnight, the suspension was diluted with DCM and washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was carefully chromatographed on silica gel eluting with hexane/ethyl acetate 3/1, to provide the title compound (0.46 g, 94% yield).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:10][CH:11]=2)[N:6]([CH3:19])[CH:5]=1.[CH3:20][S-:21].[Na+].CO>O>[CH3:19][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[C:13](=[O:14])[C:4]([CH2:3][S:21][CH3:20])=[CH:5]1
Reactant: C[S-]
Reactant: Cn1cc(CCl)c(=O)c2ccc(C(F)(F)F)cc21
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CSCc1cn(C)c2cc(C(F)(F)F)ccc2c1=O
Temperature: 25 °C

Procedure:
3-Chloromethyl-1-methyl-7-trifluoromethyl-4-quinolone hydrochloride (4.7 g.) was added to a stirred solution of sodium methanethiolate in methanol (16 ml. containing 0.039 mole NaSMe) at 0° during 5 minutes. The resulting mixture was allowed to warm to room temperature then poured into water (100 ml.). The resulting precipitate was collected, dried and crystallised from dichloromethane:petroleum ether (b.p. 60°-80°) to give the novel 1-methyl-3-methylthiomethyl-7-trifluoromethyl-4-quinolone, m.p. 182°-184°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:10](=O)[NH:9][C:8]2=[C:12]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[C:13](=[O:15])[NH:14][C:7]=12.[C:21]([O-:24])([O-])=O.[Cs+].[Cs+].CN(C=O)C.[CH2:32]([CH:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37]I)[CH2:33][CH2:34][CH3:35]>CCCCCC>[CH2:32]([CH:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][N:14]1[C:13](=[O:15])[C:12]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[C:8]2[N:9]([CH2:10][CH:6]([CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8][CH2:12][CH2:16][CH2:20][CH3:19])[C:21](=[O:24])[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[C:7]12)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCC(CI)CCCC
Reactant: O=C([O-])[O-]
Reactant: O=C1NC2=C(c3cccs3)C(=O)NC2=C1c1cccs1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCCCCC(CCCC)CN1C(=O)C(c2cccs2)=C2C1=C(c1cccs1)C(=O)N2CC(CCCC)CCCCCC
Temperature: 60 °C
Reaction time: 24 h
Yield: 26.2 %

Procedure:
To a round bottom flask under nitrogen, 3,6-di-thiophen-2-yl-1,4-dihydropyrrolo[3,2-b]pyrrole-2,5-dione (Example 2A, 1.8 g, 6 mmol), Cs2CO3 (4.89 g, mmol) and anhydrous DMF (60 mL) were added and stirred at 60° C. 2-Butyloctyl iodide (3.0 mL, 12 mmol) was added in one portion and the reaction mixture was kept at 60° C. for 24 hours. After removing the solvent, chloroform (30 mL) was added and the mixture was stirred for 10 minutes before it was filtered through coarse Celite® diatomaceous earth particles. After concentration, the crude was purified by a short column with a 3:1 mixture of chloroform:hexane as the eluent to give an orange solid (500 mg, yield 13%). 1H NMR (CDCl3, 500 MHz), δ=7.62 (d, J=5.0 Hz, 2H), 7.30 (d, J=3.5 Hz, 2H), 7.13 (dd, J=5.0, 3.5 Hz, 2H), 3.74 (d, J=7.5 Hz, 4H), 1.40-1.00 (m, 38H), 0.87 (t, J=7.5 Hz, 6H), 0.83 (t, J=7.0 Hz, 6H).
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH:15]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)(C1C=CC(C)=CC=1)(=O)=O.[I-:33].[Na+].O>CC(C)=O>[CH2:26]([O:25][CH:15]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH2:14][CH2:13][CH2:12][I:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCC(COc2ccc(F)cc2)OCc2ccccc2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Fc1ccc(OCC(CCCI)OCc2ccccc2)cc1
Yield: 79.7 %

Procedure:
A solution of 4-benzyloxy-5-(4-fluorophenoxy)-1-pentanol tosylate (3.78 g., 8.24 mmoles) and sodium iodide (3.71 g., 25 mmoles) in acetone (70 ml.) is stirred at room temperature overnight (ca. 17 hours) and then heated on the steam bath for 15 minutes. The mixture is poured into cold water and extracted with ether three times. The combined extracts are washed with aqueous sodium thiosulfate and dried over anhydrous magnesium sulfate. The solvent is removed on a rotary evaporator to leave an oil residue which is further purified by chromatography on a silica gel (70 g.) column. Elution with chloroform gives the pure title compound (2.72 g., 6.57 mmoles, 79%). ir (neat) 3.28, 3.40, 6.20, 6.62, 6.87, 8.00, 8.23, 9.10, 12.07, 13.16, 13.58, 14.37μ; pmr (CCl4)δ1.4-2.2 (4H, m), 3.08 )2H, t, J=6Hz), 3.5-4.1 (3H, m), 4.47 (1H, d, J=12 Hz), 4.69 (1H, d, J=12Hz), 6.6-7.1 (4H, m), 7.20 (5H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([NH:14][C:15](=[O:21])[CH:16]([CH3:20])[CH2:17][S:18][CH3:19])=[C:11]([CH3:13])[N:12]=2)[CH:5]=[N:6][CH:7]=1.[N:22]#[C:23][NH2:24].IC1C=CC=C(CC([O-])=[O:34])C=1CC([O-])=O>ClCCl>[C:23]([N:24]=[S:18]([CH2:17][CH:16]([CH3:20])[C:15]([NH:14][C:10]1[S:9][C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:12][C:11]=1[CH3:13])=[O:21])([CH3:19])=[O:34])#[N:22]
Reactant: CSCC(C)C(=O)Nc1sc(-c2cncc(F)c2)nc1C
Reactant: N#CN
Reactant: O=C([O-])Cc1cccc(I)c1CC(=O)[O-]
Solvent: ClCCl
Product: Cc1nc(-c2cncc(F)c2)sc1NC(=O)C(C)CS(C)(=O)=NC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of N-[2-(5-fluoro-pyridin-3-yl)-4-methyl-thiazol-5-yl]-2-methyl-3-methylsulfanyl-propionamide (0.250 g, 0.76 mmol) in dichloromethane (3.07 ml) at 0° C. was added cyanamide (0.064 g, 1.53 mmol) and iodobenzenediacetate (0.272 g, 0.84 mmol) and subsequently stirred at room temperature for 1 hour. The reaction was concentrated to dryness. The crude material was purified by silica gel column chromatography (10% methanol/ethyl acetate) to give the desired product as a light yellow solid (0.220 g, 60%): mp 75-81° C.; 1H NMR (400 MHz, CDCl3) δ 9.85 (s, 1H), 8.94-8.70 (m, 1H), 8.57-8.34 (m, 1H), 8.07-7.77 (m, 1H), 3.69-3.40 (m, 2H), 3.22-3.00 (m, 1H), 2.92-2.77 (m, 3H), 2.50 (m, 3H), 1.49 (m, 3H); ESIMS m/z 363.9 (M−2).
Reaction SMILES: [N:1]1([C:7]2[CH:29]=[CH:28][C:10]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]([CH3:26])=[N:20][CH:19]=4)[C:15]([F:27])=[CH:14][N:13]=3)=[CH:9][C:8]=2[CH3:30])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:31](O)(=[O:35])[C@H:32]([CH3:34])[OH:33].C1C=CC2N(O)N=NC=2C=1.O.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[OH:33][C@@H:32]([CH3:34])[C:31]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:29]=[CH:28][C:10]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]([CH3:26])=[N:20][CH:19]=4)[C:15]([F:27])=[CH:14][N:13]=3)=[CH:9][C:8]=2[CH3:30])[CH2:2][CH2:3]1)=[O:35]
Reactant: Cc1cc(Nc2ncc(F)c(-c3cnc(C)n3C(C)C)n2)ccc1N1CCNCC1
Reactant: C[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ncc(F)c(-c3cnc(C)n3C(C)C)n2)ccc1N1CCN(C(=O)[C@H](C)O)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 2-[4-(piperazin-1-yl)3-methylanilino]-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)-5-fluoropyrimidine (Example 122; 490.8 mg, 1.20 mmol), L-lactic acid (129.7 mg, 1.44 mmol), HOBt.H2O (220.5 mg, 1.44 mmol) and DIPEA (0.24 ml, 1.44 mmol) in DMF (5 ml) was cooled to 0° C., followed by addition of EDAC (230.05 mg, 1.44 mmol) in portions. The mixture was then stirred at ambient temperature for 3.5 hours. The solution was concentrated in vacuo, then the residue was partitioned between DCM and water+sat. sodium hydrogen carbonate. The organic extract was washed with water (3 times), brine, dried and concentrated. To a solution of crude product in MeOH (5 ml) was added 1 pellet of KOH and the mixture was stirred at ambient temperature for 20 min. The residue obtained on evaporation was purified by chromatography on silica gel with MeOH:DCM (1:99 to 5:95) to yield the title compound, after trituration with ether, as a solid which was dried in vac oven overnight at 50° C. (415 mg, 72%). NMR: (500 MHz at 373K) 1.27 (d, 3H), 1.40 (d, 6H), 2.28 (s, 3H), 2.48 (s, 3H, under DMSO signal), 2.82 (m, 4H), 3.65 (m, 4H), 4.47 (m, 2H), 5.38 (septet, 1H), 7.00 (d, 1H), 7.35 (m, 2H), 7.40 (dd, 1H), 8.40 (d, 1H), 8.80 (s, 1H); 19F NMR (400 MHz) −149.33 (t, 1F); m/z 482.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[CH3:9][N:10]1[CH2:30][CH2:29][C:14]2=[C:15]([N:22]3[CH2:25][CH:24]([C:26](O)=[O:27])[CH2:23]3)[N:16]3[C:20]([N:21]=[C:13]2[CH2:12][CH2:11]1)=[CH:19][CH:18]=[N:17]3.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:15]2([N:22]3[CH2:25][CH:24]([CH:26]=[O:27])[CH2:23]3)[C:14]3[CH2:29][CH2:30][N:10]([CH3:9])[CH2:11][CH2:12][C:13]=3[N:21]=[C:20]3[N:16]2[N:17]=[CH:18][CH2:19]3)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CN1CCc2nc3ccnn3c(N3CC(C(=O)O)C3)c2CC1
Reactant: CCN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CCN(C2(N3CC(C=O)C3)C3=C(CCN(C)CC3)N=C3CC=NN32)CC1
Reaction time: 2 h

Procedure:
To 11.4 mg (0.10 mmol) N-ethylpiperazine was added a solution of 43 mg (0.10 mmol) 1-(7-Methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]inden-10-yl)-azetidine-3-carboxylic acid and 0.026 mL (0.15 mmol) DIPEA in 0.5 mL DMF at room temperature. 35.3 mg (0.11 mmol) TBTU was dissolved in 0.5 mL DMF and the solution was added to the reaction mixture. Stirring was continued for 2 h and the reaction mixture was allowed to stand for overnight. The mixture was filtered over basic alumina followed by two washing cycles with 1.5 mL DMF. The solvent was removed and the residue was purified by column chromatography to yield the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4](=[O:15])[N:3]=1.[Cl:16][CH2:17][C:18]([CH2:20]Cl)=O.ClCC1N=C2C=CN(C3C=CC(F)=CC=3)C(=O)N2C=1>>[CH2:8]([N:5]1[CH:6]=[CH:7][C:2]2=[N:1][C:18]([CH2:17][Cl:16])=[CH:20][N:3]2[C:4]1=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ccn(Cc2ccccc2)c(=O)n1
Reactant: O=C(CCl)CCl
Agent: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Product: O=c1n(Cc2ccccc2)ccc2nc(CCl)cn12

Procedure:
6-Benzyl-2-chloromethyl-6H-imidazo[1,2-c]pyrimidin-5-one was prepared from 4-amino-1-benzyl-1H-pyrimidin-2-one and 1,3-dichloroacetone using the methods described above for the preparation of 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: Nc1ccccc1
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)Nc2ccccc2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with aniline
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17]>C(=S)=S>[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCCc1ccc(C(=O)c2ccccc2)cc1
Reaction time: 18 h
Yield: 96.5 %

Procedure:
A 2.8 g (0.02 mole) of benzoic acid chloride was dissolved in 30 ml of carbon disulfide and then, 4.0 g (0.03 mole) of anhydrous aluminum chloride was added to the solution. A 2.68 g (0.02 mole) of n-butyl benzene was further added to the mixture with stirring, and the reaction was carried out at room temperature for 18 hours. Carbon disulfide was distilled off from the reaction mixture and water was added and the reaction product was extracted with benzene. The benzene phase was separated and washed with 1N-NaOH and with water and was dried with anhydrous sodium sulfate. The solvent was distilled off to obtain a pale yellow oily product. The oily product was distilled under a reduced pressure to obtain 4.6 g of 4-n-butyl benzophenone having a boiling point of 184° to 188° C./6 mmHg. (yield of 96.8%).