Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[C:8]([Si:12](Cl)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:11])([CH3:10])[CH3:9]>O1CCCC1>[Si:12]([O:7][CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)([C:8]([CH3:11])([CH3:10])[CH3:9])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OC1CCNCC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1CCNCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.2 %

Procedure:
Into a 250-mL round-bottom flask was placed a solution of piperidin-4-ol (4 g, 39.55 mmol, 1.00 equiv) in tetrahydrofuran (100 mL), TEA (12 g, 118.59 mmol, 3.00 equiv) and tert-butyl(chloro)diphenylsilane (16 g, 58.21 mmol, 1.47 equiv). The resulting solution was stirred for 16 h at room temperature. The solids were filtered out. The filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). Purification afforded 1.1 g (8%) of 4-[(tert-butyldiphenylsilyl)oxy]piperidine as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@@H:4]([N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:22])[CH2:5][CH2:6][CH2:7][CH3:8].[I-].[CH3:25][N:26]1[C:34]2[C:29](=[C:30]([CH3:35])[CH:31]=[CH:32][CH:33]=2)[C:28]([CH2:36][N+](C)(C)C)=[CH:27]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:23])[C@@H:4]([N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[N:11]([CH2:36][C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])[N:26]([CH3:25])[CH:27]=2)[C:10]1=[O:22])[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: CCCC[C@@H](C(=O)OC)n1c(=O)[nH]c2cc(OC)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC[C@@H](C(=O)OC)n1c(=O)c2ccc(OC)cc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
To a mixture of (S)-2-(7-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-hexanoic acid methyl ester (100 mg, 0.31 mmol) and (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide (160 mg, 0.47 mmol) in DMF (2.5 mL) is added K2CO3 (100 mg, 0.72 mmol). The mixture is stirred at 60° C. for 4 hours. The reaction mixture is allowed to cool to room temperature, diluted with EtOAc (50 mL) and washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate and concentrated. The resulting residue is triturated with EtOAc and hexanes to afford (S)-2-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-7-methoxy-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-hexanoic acid methyl ester (145 mg, 97%).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].CC1[O:8][CH:9]=[CH:10][CH:11]=1.C1[O:14]C1>C1COCC1>[CH3:5][C:4]1[O:8][C:9]([CH2:10][CH2:11][OH:14])=[CH:2][CH:3]=1
Reactant: Cc1ccco1
Reactant: C1CO1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(CCO)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.3 %

Procedure:
A solution of n-BuLi (83.0 mL, 133 mmol, 1.6 M in hexanes) was added to a stirred solution of 2-methylfuran (10.0 mL, 111 mmol) in THF (85 mL) at 0° C. under inert atmosphere. The reaction mixture was stirred for 4 h at room temperature then cooled to 0° C. Ethylene oxide (8.30 mL, 166 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature overnight. After quenching with saturated aqueous NH4Cl, the resulting layers were separated and the aqueous layer was extracted with Et2O (2×250 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Distillation at atmospheric pressure (170-185° C.) gave 10.1 g (80.3 mmol, 72%) of compound 21A as a light yellow oil.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:7]=[C:8]([C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=O)[CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13].C(N(C(C)C)CC)(C)C.[CH2:30]([NH:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:31]([CH3:33])[CH3:32]>ClCCl>[Cl:5][C:6]1[CH:7]=[C:8]([C:15]([CH3:20])([CH3:19])[C:16]([N:34]([CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:18])[CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)CNCC(C)C
Reactant: CC(C)(C(=O)O)c1ccc([N+](=O)[O-])c(Cl)c1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CN(CC(C)C)C(=O)C(C)(C)c1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
Thionyl chloride (0.54 ml, 4 eq) is added to a solution of 2-(3-chloro-4-nitrophenyl)-2-methylpropanoic acid (500 mg) in dichloromethane (1 ml). The mixture is heated under reflux for 16 hours then cooled down to ambient temperature. The solvent is evaporated off under reduced pressure at 40° C. (co-evaporation with toluene). Diisopropylethylamine (0.42 ml, 1.2 eq) and diisobutylamine (0.36 ml, 1 eq) are successively added to a solution of the acid chloride thus obtained in dichloromethane (1 ml), cooled down to 0° C. At the end of the addition, stirring is continued for 3 hours at ambient temperature then the mixture is concentrated under reduced pressure at 40° C. The residue is dissolved in ethyl ether and the organic phase is washed successively with 1N soda, a saturated solution of sodium hydrogen carbonate, salt water then dried over Na2SO4 and concentrated under reduced pressure at 40° C. Purification by flash chromatography on silica gel (eluent: heptane/ethyl acetate 8:2 to 7:3) produces the expected compound in the form of an oil which crystallizes (0.585 g; 82% yield).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:21][P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:48][NH:49][CH:50]([CH:52](F)[CH3:53])[CH3:51].CCN(CC)CC>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([N:49]([CH3:48])[CH:50]([CH2:52][CH2:53][F:21])[CH3:51])=[O:20])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(C)C(C)F
Reactant: O=C(O)c1cc2ccccc2c(-c2cccc(I)c2)n1
Reactant: F[P-](F)(F)(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(CCF)N(C)C(=O)c1cc2ccccc2c(-c2cccc(I)c2)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 63.5 %

Procedure:
To a solution of 1-(3-iodophenyl)-3-isoquinolinecarboxylic acid (52.2 mg, 0.14 mmol), BOP (64.2 mg, 0.15 mmol) in DMF (6 mL) under Ar was added a solution of N-methyl 3-fluoro-2-butylamine (420 mg, crude, excess) and Et3N (20 μL, 0.14 mmol) in DMF (1.0 mL). The resulting mixture was stirred at ambient temperature for 7 h. Then it was quenched by adding H2O (5 mL). The mixture was extracted with CH2Cl2 (3×20 mL). The organic layers were dried (Na2SO4), filtered. The filtrate was concentrated in vacuo. The residue was purified on column chromatography (silica gel, 30% ethyl acetate/hexane, 0.05% Et3N) to give a yellow oil (41.1 mg). This oil was further purified on reverse phase HPLC (75% MeOH/H2O, 0.1% Et3N). After reverse phase HPLC purification, a pale yellow solid (17 mg, 26%) was obtained. mp 50-51.5° C. 1H NMR (CDCl3) d 1.24-1.41 (m, 3 H, CH3), 1.75-2.21 (m, 2 H, CH2), 2.98, 3.01 (two s, total 3 H, N-methyl), 4.29-4.40 (m, 1 H, CH2F), 4.44-4.58 (m, 1 H, CH2F), 4.63-4.74 (m, 0.5 H, CH), 4.96-5.06 (m, 0.5 H, CH), 7.27 (dt, J=9.6, 1.8 Hz, 1 H, aromatic), 7.58-7.64 (m, 2 H, aromatic), 7.74 (t, J=6.9 Hz, 1 H, aromatic), 7.85 (d, J=7.8 Hz, 1 H, aromatic), 7.95 (d, J=8.1 Hz, 1 H, aromatic), 8.01-8.12 (m, 3 H, aromatic). HRMS Cacld for C21H20FIN2O: 462.0604. Found: 462.0607.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:11]([CH3:15])[C:12]([OH:14])=O)=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:12](=[O:14])[C:11](=[N:10][NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:16])=[CH:8][CH:7]=2)[CH3:15])=[CH:21][CH:20]=1
Reactant: CC(=NNc1ccc(C(F)(F)F)cc1)C(=O)O
Reactant: NCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(=NNc1ccc(C(F)(F)F)cc1)C(=O)NCc1ccc(Cl)cc1
Yield: 73.3 %

Procedure:
2-(4-Trifluoromethylphenyl hydrazono) propionic acid (0.74 g, 3.0 mmol) was dissolved in dichloromethane (15 ml), and 4-chlorobenzyl amine (0.42 g, 3.0 mmol) and 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloric acid salt (0.58 g, 3.0 mmol) were added thereto. 20 hours later, the mixture was washed with 1N hydrochloric acid, a saturated sodium bicarbonate water and a saturated brine, and dried on sodium sulfate and then filtrated. The residue obtained by concentrating the resulting filtrate was suspended in a mixed solvent of hexane and chloroform (1:1) and filtered to obtain N-(4-chlorobenzyl)-2-(4-trifluoromethylphenyl hydrazono) propionic acid amide (Compound No. 62) (0.83 g, 2.2 mmol, 75%).
Reaction SMILES: [CH3:1][CH:2]1[S:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Li+].CC([N-]C(C)C)C.CCCCCCC.C1COCC1.C1C=CC=CC=1.Br[CH2:36][C:37]([O:39][CH3:40])=[O:38]>C1COCC1>[CH3:1][C:2]1([CH2:36][C:37]([O:39][CH3:40])=[O:38])[S:6][C:5](=[O:7])[NH:4][C:3]1=[O:8]
Reactant: COC(=O)CBr
Reactant: CC1SC(=O)NC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: c1ccccc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COC(=O)CC1(C)SC(=O)NC1=O
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 38.5 %

Procedure:
To a stirred solution of Compound 1d (300 mg, 2.3 mmol) in THF (20 mL) at −40° C. was added 2 M LDA in heptane/THF/benzene (2.4 mL, 4.8 mmol) dropwise. After 15 minutes, methyl 2-bromoacetate (0.30 mL, 3.2 mmol) was added and the reaction mixture stirred at −40° C. for 2 h then quenched by dropwise addition of AcOH (0.8 mL). The reaction mixture was diluted with EtOAc, and the organic portion washed with water (2×), brine (2×), dried (Na2SO4), filtered and concentrated under reduced pressure. The product was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to afford Compound 1e (180 mg, 39%) as a clear oil. LCMS=1.06 min using analytical method (B), 225.9 (M+Na). 1H NMR (400 MHz, CDCl3) δ 3.75 (s, 3H), 3.24-2.84 (m, 2H), 1.81 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:8][O:9][C:5]=2[CH:4]=1.B(Br)(Br)Br.Cl[CH2:21]Cl>>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([CH2:10][C:11]([O:13][CH3:21])=[O:12])=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(CC(=O)O)coc2c1
Reactant: ClCCl
Agent: BrB(Br)Br
Product: COC(=O)Cc1coc2cc(OC)ccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 2-(6-methoxybenzofuran-3-yl)acetic acid (0.6 g, 2.9 mmol) in anhydrous dichloromethane (20 mL) at −78° C. was added boron tribromide (1.5 eq.) The reaction was stirred at −78° C. for 30 minutes, 0° C. for 2 hours, and at room temperature overnight. The reaction mixture was cooled to 0° C. and quenched slowly with methanol. After stirring for 15 minutes a saturated sodium bicarbonate solution was added slowly to the mixture and allowed to stir at 0° C. for 30 minutes. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give methyl 2-(6-methoxybenzofuran-3-yl)acetate (745) (67%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][CH:6]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][CH2:18][NH2:19])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.[CH:29]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31][CH2:30]1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][CH:6]1[C:15]2[CH:14]=[C:13]([O:16][CH2:17][CH2:18][NH:19][S:33]([CH:29]3[CH2:32][CH2:31][CH2:30]3)(=[O:35])=[O:34])[CH:12]=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCCOc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N1CCCC1)CC2
Reactant: O=S(=O)(Cl)C1CCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=S(=O)(NCCOc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N1CCCC1)CC2)C1CCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-(8-(3,4-Dichlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yloxy)ethanamine (120 mg, 0.286 mmol), para-(N,N-dimethylamino) pyridine (1.40 g, 19.7 mmol), and cyclobutanesulfonyl chloride (46.5 mg, 0.30 mmol) were dissolved in CH2Cl2 (20 ml) and stirred for 14 h at room temperature. 0.5N HCl was added, the organic phase separated and the aqueous phase extracted with CH2Cl2. The combined organic layers were washed with water, NaHCO3 solution, and saturated NaCl solution, dried over Na2SO4, and concentrated to afford a residue that was purified by flash chromatography (silica gel, MeOH/CH2Cl23:97→5:95). The white solid product (164 mg, 32%) was transferred to an HCl salt and precipitated from diisopropyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14](SC)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.O1CCOCC1.O.[C:26]12([CH2:36][NH2:37])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2.O>Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([NH:37][CH2:36][C:26]34[CH2:35][CH:30]5[CH2:29][CH:28]([CH2:34][CH:32]([CH2:31]5)[CH2:33]3)[CH2:27]4)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CSc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(F)cc1)c1cnc(NCC23CC4CC(CC(C4)C2)C3)nc1
Temperature: 110 °C
Yield: 23.1 %

Procedure:
To a solution of 2-methylsulfanylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (50 mg, 0.19 mmol) in 4/1 dioxane/water (0.6 mL) in a sealed tube was added 1-adamantanemethyl amine (250 μL, 1.4 mmol). The solution was heated at 110° C. for 18 h, cooled, diluted with 3% HCl and then poured into water to form a precipitate. The solids were collected by filtration, washed with water and dried. Trituration of the solids with ethyl acetate at about 70° C., followed by a hot filtration and washing with hexane, afforded 16.7 mg (24% yield) of the titled product as a white solid. API-MS m/z 381 (MH)+, 379 (M−H)−.
Reaction SMILES: [C:1]([O-:4])(O)=[O:2].[Na+].[F:6][C@H:7]1[C@H:11]([OH:12])[C@@H:10]([CH2:13][OH:14])[O:9][C@H:8]1[C:15]1[N:23]=[C:22]2[C:18](=[N:19][CH:20]=[N:21]2)[C:17]([O:25][CH3:26])([NH2:24])[N:16]=1>O.[Pt]>[F:6][C@H:7]1[C@H:11]([OH:12])[C@@H:10]([CH:13]([C:1]([OH:4])=[O:2])[OH:14])[O:9][C@H:8]1[C:15]1[N:23]=[C:22]2[C:18](=[N:19][CH:20]=[N:21]2)[C:17]([O:25][CH3:26])([NH2:24])[N:16]=1
Reactant: COC1(N)N=C([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)N=C2N=CN=C21
Reactant: O=C([O-])O
Agent: [Pt]
Agent: [Na+]
Solvent: O
Product: COC1(N)N=C([C@@H]2O[C@H](C(O)C(=O)O)[C@@H](O)[C@@H]2F)N=C2N=CN=C21
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
A mixture of Pt/C (10%, 15 g (20-30% mol equiv.) as a water slurry) and NaHCO3 (1.5 g, 17.94 mmol) in H2O (500 mL) was stirred at 65° C. under H2 for 0.5 h. The reaction mixture was then allowed to cool, placed under a vacuum and flushed with N2 several times to completely remove all H2. Compound 4 (5.1 g, 17.94 mmol) was then added at room temperature. The reaction mixture was stirred at 65° C. under O2 (balloon) until the reaction was complete by LC-MS (typically 24-72 h). The mixture was cooled to room temperature and filtered. The Pt/C was washed with H2O extensively. The combined filtrates were concentrated to ˜30 mL, and acidified (pH 4) by the addition of HCl (4N) at 0° C. A black solid precipitated out which was collected by filtration. The crude product was dissolved in a minimum amount of Methanol and filtered through a pad of silica gel (eluting with Methanol). The filtrate was concentrated and crystallized from water to give compound 5 (2.5 g) as an off-white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][C:5]2[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:9][C:10]=2[N:11]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][CH2:2][C:3]1[S:4][C:5]2[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:9][C:10]=2[N:11]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2nc(CO)sc2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2nc(COS(C)(=O)=O)sc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a dichloromethane solution (15 ml) of tert-butyl 2-(hydroxymethyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (1 eq.) was added triethylamine (2.5 eq.) and methane sulfonylchloride (1.2 eq.) at 0° C. and the resulting reaction mixture was stirred at ambient temperature for 2 h. The reaction was quenched with ice and diluted with dichloromethane. The organic layer was successively washed with water and brine and finally dried over sodium sulfate. Evaporation of the organic layer under reduced pressure gave the crude product which was used directly in the next step without further purification. Yield: 80%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH2:20][NH:21][CH2:22][CH3:23])[CH:8]=[C:9]([Cl:11])[CH:10]=1.[Cl:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](Cl)=[O:33])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH2:20][N:21]([C:32](=[O:33])[CH2:31][O:30][C:29]2[CH:35]=[CH:36][C:26]([Cl:25])=[CH:27][CH:28]=2)[CH2:22][CH3:23])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: CCNCc1ccc(OC)cc1-c1cc(Cl)cc(CC(=O)OC)c1
Product: CCN(Cc1ccc(OC)cc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)COc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (5-chloro-2′-ethylaminomethyl-5′-methoxy-biphenyl-3-yl)-acetic acid methyl ester and 4-chlorophenoxyacetyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:33](Br)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[O:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([CH:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:17][CH2:18]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(OCCCN2CCNCC2)c2ccc(F)cc2)cc1
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Product: Fc1ccc(C(OCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccc(F)cc2)cc1

Procedure:
A solution containing 10.4 g of 1-[3-[bis(4-fluorophenyl)methoxy]propyl]piperazine, 4.6 ml of triethylamine and 8.1 g of benzhydryl bromide in 100 ml of anhydrous xylene is refluxed for 8 hours and then cooled down. The mixture is washedwith water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resiude is recrystallized from n-hexane to give the aimed product, m.p.: 78°-79° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12](Cl)[CH:11]=[C:10]([Cl:15])[N:9]=2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([Cl:15])[CH:11]=[C:12]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:13]=2)=[CH:6][CH:7]=1
Reactant: NCCCN1CCOCC1
Reactant: Clc1cc(Cl)nc(-c2ccc(Br)cc2)n1
Product: Clc1cc(NCCCN2CCOCC2)nc(-c2ccc(Br)cc2)n1

Procedure:
Similarly, 2-(4-bromophenyl)-4,6-dichloropyrimidine is reacted with N-(3-aminopropyl)-morpholine to afford 2-(4-bromophenyl)-4-chloro-6-[3-(morpholino)propylamino]pyrimidine which is then reacted with p-chlorothiophenol to produce 2-(4-bromophenyl)-4-(4-chlorophenylthio)-6-[3-(morpholinopropyl)amino]-pyrimidine.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH3:15])=[CH:11][CH:12]=2)[C:7]1=[O:16].[Br:17]Br.Cl>ClCCl>[Br:17][C:12]1[CH:11]=[C:10]([CH3:15])[CH:9]=[C:8]2[C:13]=1[CH2:14][CH:6]([CH3:5])[C:7]2=[O:16]
Reactant: Cc1ccc2c(c1)C(=O)C(C)C2
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(Br)c2c(c1)C(=O)C(C)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 334 g (2.50 mol) of anhydrous AlCl3 (powder) in 400 ml of dry dichloromethane, a solution of 160 g (1.00 mol) of 2,6-dimethylindan-1-one in 200 ml of dichloromethane was added dropwise while vigorously stirring for 30 min at 0° C. This mixture was stirred for 1 h at ambient temperature, and then a solution of 51.6 ml (161 g, 1.01 mol) of bromine in 800 ml of dichloromethane was added while vigorously stirring for 2 h. The resulting mixture was stirred for 12 h and then poured on 700 cm3 of ice. The mixture was acidified by saturated HCl to pH 1, the organic layer was separated, and the aqueous layer was extracted with 3×350 ml of dichloromethane. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. From the residue, 71.0 g of the starting indanone was distilled off in vacuum (bp 89-91 mm Hg), and the solid material left in the rectification flask was recrystallized from 600 ml of hot hexanes. Crystals that precipitated at room temperature were collected. The pure title product was then isolated by flash chromatography on Silica Gel 60 (40-63 um, d 50 mm, l 1200 mm, eluent: hexanes-dichloromethane, 10:1, vol.). Yield 44.0 g (18%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]#[CH:14].CC1C=CC=C(C)N=1>C1(C)C=CC=CC=1.CC(N(C)C)=O>[CH2:14]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1)[C:13]#[CH:12]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: C#CCBr
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Solvent: CC(=O)N(C)C
Product: C#CCNc1ccc(C(N)=O)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A suspension of 13.62 g (0.1 mol) of 4-aminobenzamide, 17.85 g (0.12 mol) of an 80% solution of 3-bromo-1-propyne in toluene, and 13.98 ml (0.12 mol) of 2,6-dimethylpyridine in 140 ml of dimethylacetamide (DMA) is stirred at 60° C. for two hours and then at 90° C. for one hour. The solution is cooled and the precipitated solid is collected and discarded. The filtrate is poured into a water-ice mixture and stirred. The suspension is extracted with ethyl acetate. The ethyl acetate solution is separated, dried (magnesium sulfate), and concentrated to give 20.7 g of a brown liquid. This is applied to a column of 1 kg of flash silica gel packed in dichloromethane-methanol (50:1). Elution with the same solvent gives 6.73 g (38.7%) of the product as a yellow solid, mp 139°-141° C.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:15]1[CH2:20][CH2:19][S:18][CH2:17][CH:16]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]>ClCCl>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]([N:15]2[CH2:20][CH2:19][S:18][CH2:17][CH:16]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:3][CH:4]=1)=[O:7]
Reactant: CCOC(=O)C1CSCCN1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: CCOC(=O)C1CSCCN1c1ncc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 94.4 %

Procedure:
Methyl 6-chloro-5-nitronicotinate (1.1 g, 5.10 mmol) was added to ethyl thiomorpholine-3-carboxylate (2.0 g, 11.41 mmol) neat while stirring at room temperature. The viscous yellow reaction was heated to 90° C. for one hour and then allowed to cool back to room temperature. The reaction was diluted with dichloromethane (20 mL) and purified via column chromatography (220 g SiO2, 20-30% gradient, ethyl acetate in hexanes) to yield the title compound (1.71 g, 95%) as a yellow oil. [M+H] calc'd for C15H18N2O6S, 356; found, 356.