Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](Cl)=[N:25][OH:26])=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[CH:2]=[C:1]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=3)[O:26][N:25]=2)=[CH:19][CH:18]=1
Reactant: C#Cc1cccnc1
Reactant: ON=C(Cl)Cc1ccc(COc2ccccn2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: c1ccc(OCc2ccc(Cc3cc(-c4cccnc4)on3)cc2)nc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 24 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynylpyridine (10 mg, 0.097 mmol) and (4-(pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (42.9 mg, 0.155 mmol) described in Manufacturing Example 2-1-5 was added triethylamine (54.1 μL, 0.388 mmol), which was stirred for 2.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4 to 1:2, then 1:1) to obtain the title compound (8 mg, 24%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]2([CH3:24])[CH3:23].[Br-:25].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[Br:25][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]3([CH3:24])[CH3:23])[C:5]=1[O:9][CH3:10]
Reactant: COc1cccc(OC)c1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(Br)c(OC)c1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of 6-(2,6-dimethoxyphenyl)-1,1,4,4-tetramethy-1,2,3,4-tetrahydronaphthalene (340 mg, 1.05 mmol) in dichloromethane (10 mL) was added pyridinium tribromide (335 mg, 1.05 mmol) and the reaction mixture stirred at room temperature overnight. The solution was diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: ethyl acetate/hexane, 0.5:9.5) to give 0.24 g (57%) of 6-(5-bromo-2,6-dimethoxyphenyl)-1,1,4,4-tetramethy-1,2,3,4-tetrahydronaphthalene. 1H NMR (500 MHz; CDCl3): δ 1.28 (s, 6 H); 1.31 (s, 6 H); 1.70 (s, 4 H); 3.35 (s, 3 H); 3.73 (s, 3 H); 7.14 (dd, J1=1.5 Hz, J2=8.5 Hz, 1 H); 7.15 (dd, J1=2.0 Hz, J2=8.5 Hz, 1H); 7.30 (d, J=8.0 Hz, 1H); 7.36 (d, J=1.5 Hz, 1H); 7.45 (d, J=8.0 Hz, 1 H), 7.95 (br, 1 H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[C:12]1([CH2:18][C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:19](=[O:20])[CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(Cc1ccccc1)Nc1ccccc1C(F)(F)F
Yield: 42.8 %

Procedure:
Using the procedure of Step A of Example 6, 40.28 g of o-trifluoromethyl aniline and 42.5 g of phenylacetyl chloride were reacted in the presence of 27.83 g of triethylamine in 400 ml of benzene to obtain 29.85 g of N-(2-trifluoromethylphenyl)-benzeneacetamide melting at 104° C after crystallization from hexane which was used as is for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:8])=[CH:5][S:6][CH:7]=1.[C:9]([C:14](=[CH:20]OCC)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:13])[CH2:10][CH2:11][CH3:12]>>[C:9]([C:14](=[CH:20][NH:8][C:4]1[C:3]([O:2][CH3:1])=[CH:7][S:6][CH:5]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: COc1cscc1N
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Product: CCCC(=O)C(=CNc1cscc1OC)C(=O)OCC

Procedure:
4-Methoxy-3-thiopheneamine (11 g, 0.085 mol) and ethyl 2-butyryl-3-ethoxyprop-2-enoate (20 g, 0.093 mol) was heated in an inert atmosphere at 120° for 30 minutes. Addition of petroleum ether, b.p. 40°-60°, 200 ml, gave a solid which was collected by filtration and dried, 17.58 g, m.p. 89°-91°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:16][O:17][C:18](=[O:22])[CH2:19][CH2:20]Br.O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:16][O:17][C:18](=[O:22])[CH2:19][CH2:20][N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1
Reactant: COC(=O)CCBr
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.5 %

Procedure:
To a solution of 1-(4-nitro-phenyl)-piperazine (2 g, 9.66 mmol) in DMF (10 mL) was added 3-bromopropionic acid methyl ester (1.6 g, 9.66 mmol) and the mixture was stirred at ambient temperature for 16 h. Water was added to the reaction, followed by adjusting pH to 7 with sat. aqueous NaHCO3. The resulting precipitate was collected by filtration and washed with water to furnish the title compound as a yellow solid (1.8 g, 63.6%): MS (ESI) m/z 294 (M+H); 1H NMR (400 MHz, CDCl3) δ 2.55 (t, J=7.2 Hz, 2H), 2.62 (t, J=4.8 Hz, 4H), 2.77 (t, J=6.8 Hz, 2H), 3.42 (t, J=5.2 Hz, 4H), 3.71 (s, 3H), 6.81-6.83 (m, 2H), 8.11-8.14 (m, 2H).
Reaction SMILES: [CH:1]1[N:6]=[C:5]2[N:7]([C@H:10]3[C@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[CH2:11]3)[CH:8]=[N:9][C:4]2=[C:3]([NH2:19])[N:2]=1.CN(C)C=O.N1C=CN=C1.[CH3:30][Si:31](Cl)([CH3:38])[C:32]([CH:35]([CH3:37])[CH3:36])([CH3:34])[CH3:33]>O>[NH2:19][C:3]1[N:2]=[CH:1][N:6]=[C:5]2[C:4]=1[N:9]=[CH:8][N:7]2[C@@H:10]1[CH2:11][C@H:12]([CH2:17][O:18][Si:31]([C:32]([CH3:34])([CH:35]([CH3:37])[CH3:36])[CH3:33])([CH3:38])[CH3:30])[C@@H:13]([OH:16])[C@H:14]1[OH:15]
Reactant: Nc1ncnc2c1ncn2[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CC(C)C(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
A mixture of aristeromycin (50 g) and dimethylformamide (250 ml) was stirred at room temperature and imidazole (50 g) and then dimethylthexylsilyl chloride (10 ml) were added. Three further 10 ml portions of dimethylthexylsilyl chloride were added after 20 min, 1 h and 1.75 h. After 4 h the resulting mixture was poured into rapidly stirred water (2.5 L). The suspension was filtered and the residue washed with water (2×250 ml). The air dried solid was added to di-isopropyl ether (500 ml) and stirred for 20 min. The suspension was filtered and the residue collected, stirred with diethyl ether (500 ml) and filtered to give the title compound (49 g); 1H nmr (DMSO-d6) δ8.13 (1H), 8.09 (1H), 7.18 (2H), 5.03-4.93 (1H), 4.76-4.60 (2H), 4.41-4.28 (1H), 3.88-3.78 (1H), 3.72-3.57 (2H), 2.28-1.70 (3H), 1.67-1.52 (1H), 0.95-0.75 (12H), 0.1 (6H).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]([NH:14][OH:15])=[NH:13])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[C:16]1([C:22]2[CH:30]=[CH:29][C:25]([C:26](Cl)=O)=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:22]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:23]=[CH:24][C:25]([C:26]2[O:15][N:14]=[C:12]([CH:9]3[CH2:10][CH2:11][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:7][CH2:8]3)[N:13]=2)=[CH:29][CH:30]=1
Reactant: CCC(CC)N1CCC(C(=N)NO)CC1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CCC(CC)N1CCC(c2noc(-c3ccc(-c4ccccc4)cc3)n2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 35a, starting from 1-(1-ethylpropyl)-N-hydroxypiperidine-4-carboxamidine and 4-phenylbenzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[CH3:12][S:13](Cl)(=[O:15])=[O:14].N1C=CC=CC=1>C1COCC1.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][S:13]([CH3:12])(=[O:15])=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])c(Cl)c1
Reaction time: 24 h
Yield: 99.8 %

Procedure:
A mixture of 3-chloro-4-nitroaniline (4.85 g, 28.1 mmol), methanesulfonyl chloride (3.29 mL, 42.2 mmol) and pyridine (6.82 mL, 84 mmol) in THF (100 mL) was stirred for 24 h. Poured in 1M HCl (500 mL). The resulting precipitate was filtered and air-dried to provide the title compound as a solid (7.03 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:17])[C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:18]2C=C[CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[N:19]=2)[CH:3]=1.[Li].C(C1N=C(C([O-])=O)[S:34]C=1)(C)C>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:17])[C:8]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:18]2[S:34][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[N:19]=2)[CH:3]=1
Reactant: COCCOc1ccc2c(Cl)cc(-c3cccc(C(C)C)n3)nc2c1Cl
Reactant: CC(C)c1csc(C(=O)[O-])n1
Agent: [Li]
Product: COCCOc1ccc2c(Cl)cc(-c3nc(C(C)C)cs3)nc2c1Cl

Procedure:
4,8-Dichloro-2-(4-isopropyl-thiazol-2-yl)-7-(2-methoxy-ethoxy)-quinoline was prepared in a similar fashion as 4,8-Dichloro-2-(6-isopropyl-pyridin-2-yl)-7-(2-methoxy-ethoxy)-quinoline except that the lithium salt of 4-isopropyl-thiazole-2-carboxylate was used instead of 6-isopropyl-pyridine-2-carboxylic acid.
Reaction SMILES: C([O:4][C:5]([C:7]1[N:8]([N:12]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[C:36]([Cl:41])[CH:35]=2)[C:13](=[O:32])[CH2:14][C:15]2[NH:20][C:19]3[CH:21]=[CH:22][C:23](CS(C)(=O)=O)=[CH:24][C:18]=3[S:17](=[O:31])(=[O:30])[N:16]=2)[CH:9]=[CH:10][CH:11]=1)=O)C=C.[O-]CC.[Na+].Cl>C(O)C.C(OCC)(=O)C>[Cl:41][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][C:37]=1[F:40])[CH2:33][N:12]1[C:13](=[O:32])[C:14]([C:15]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([NH:16][S:17]([CH3:18])(=[O:31])=[O:30])=[CH:24][C:18]=3[S:17](=[O:31])(=[O:30])[N:16]=2)=[C:5]([OH:4])[C:7]2=[CH:11][CH:10]=[CH:9][N:8]12
Reactant: C=CCOC(=O)c1cccn1N(Cc1ccc(F)c(Cl)c1)C(=O)CC1=NS(=O)(=O)c2cc(CS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccn3n(Cc3ccc(F)c(Cl)c3)c1=O)N2
Temperature: 60 °C
Reaction time: 12 h
Yield: 63.9 %

Procedure:
To a solution of 1-{(3-chloro-4-fluoro-benzyl)-[2-(7-methanesulfonylmethyl-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-1H-pyrrole-2-carboxylic acid allyl ester (Example 171, 304.5 mg, 0.488 mmol) in absolute ethanol (5 mL) was added a 21% solution of sodium ethoxide in ethanol (1.1 mL, 2.95 mmol). After stirring at 60° C. for 12 h, the mixture was diluted with ethyl acetate and acidified with 1.0 M aqueous hydrochloric acid solution upon which a precipitate formed. The solid was collected by vacuum filtration to afford the desired product, N-{3-[1-(3-chloro-4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (88.5 mg, 0.156 mmol, 32% yield) as an off-white solid. The filtrate was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by HPLC purification (Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 25%-100% in 12 min 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water) to afford more of the desired product, N-{3-[1-(3-chloro-4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (18.4 mg, 0.033 mmol, 7% yield; total 39% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 3.06 (3H, s), 5.61 (2H, s), 6.57 (1H, s) 6.98 (1H, s), 7.37 (2H, d, J=7.6 Hz), 7.52 (1H, dd, J1=8.5 Hz, J2=2.4 Hz), 7.59-7.68 (4H, m), 10.17 (1H, s). LC-MS (ESI) calcd for C22H17ClFN5O6S2 565.03. found 566.2 [M+H+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[C:16]([O:25][CH3:26])[CH:15]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCOCC1.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][CH:23]=[N:22][CH:21]=3)=[C:16]([O:25][CH3:26])[CH:15]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cc(NC(=O)Nc2cccc([N+](=O)[O-])c2)ccc1-c1cnco1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(NC(=O)Nc2cccc(N)c2)ccc1-c1cnco1
Yield: 46.2 %

Procedure:
A solution of 0.7 g (2 mmol) of 49A in 60 ml of dioxane and 30 ml of methanol was hydrogenated at rt and one atmosphere pressure over 0.14 g of 10% Pd/C catalyst. The catalyst was removed by filtration through Celite. The filtrate was evaporated to dryness to yield 0.3 g of 49B as a tan solid. The filter cake was suspended in dioxane—methanol and stirred at 50° C. for 1 hr. The hot solution was again filtered, and the filtrate evaporated to dryness to yield an additional 0.6 g of material. The combined batches were triturated with methylene chloride and the insolubles filtered to give 645 mg (2 mmoles, 100%) of 49B as a light tan powder.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([NH2:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][C:24]2[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=2)=[CH:14][N:13]=1.N.O>CCOC(C)=O>[CH:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([CH2:22][CH2:23][C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[CH:14][N:13]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(CCc2cnc(Cl)c3ccccc23)cn1
Reactant: CC(C)[C@H]1CC[C@H](N)CC1
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(CCc2cnc(N[C@H]3CC[C@H](C(C)C)CC3)c3ccccc23)cn1

Procedure:
Under a N2 atmosphere, 600 mg (4.25 mmol) of trans-4-isopropyl-cyclo-hexylamine [for preparation see Arzneim. Forsch. 19 (1969), 140] and 120 mg (0.424 mmol) of 1-chloro-4-[2-(6-methyl-pyridin-3-yl)-ethyl]-isoquinoline are heated to 140° C. in an ampulla for 10 h. The reaction mixture is suspended in EtOAc, and mixed with 0.25 ml of NH3 solution (25%) and water. The separated aqueous phase is extracted twice more with EtOAc, the organic phases washed with water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; hexane/EtOAc 1:1) yields trans 1-(4-isopropyl-cyclohexylamino)-4-[2-(6-methyl-pyridin-3-yl)-ethyl]-isoquinoline; 1H NMR (DMSO-d6) δ8.27 (m, 2H), 7.88 (d, 1H), 7.65 (t, 1H), 7.60 (s, 1H), 7.54 (m, 1H), 7.45 (t, 1H), 7.14 (d, 1H), 6.84 (d, 1H), 3.88 (m, 1H), 3.00 (m, 2H), 2.84 (m, 2H), 2.40 (s, 3H), 2.00 (m, 2H), 1.71 (m, 2H), 1.5-1.0 (m, 6H), 0.86 (d, 6H).
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[CH2:14][C:15]#[N:16].C(OCC)(=O)C>C(O)C>[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[CH:14]([C:2](=[O:3])[CH3:1])[C:15]#[N:16]
Reactant: N#CCc1cc(Cl)cc(Cl)c1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)C(C#N)c1cc(Cl)cc(Cl)c1Cl
Reaction time: 8 h

Procedure:
To a solution of NaOEt (from 0.68 g of sodium) in ethanol (20 ml) was added 2,3,5-trichlorophenylacetonitrile (5 g) and ethyl acetate (4.43 ml). The mixture was heated under reflux, under nitrogen for 2.5 hours. The mixture was left standing at room temperature overnight. The mixture was then concentrated and the residue was dissolved in water. The aqueous phase was washed with ether, acidified with concentrated H2SO4 and extracted with ether. The extracts were bulked, dried (MgSO4) and evaporated, 2.59 g, mp. 134°-135° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[O:31]1[CH2:33][C@@H:32]1[CH2:34][O:35][C:36]1[CH:37]=[CH:38][C:39]2[S:43][C:42]([CH3:44])=[N:41][C:40]=2[CH:45]=1>C(O)C>[OH:31][C@@H:32]([CH2:34][O:35][C:36]1[CH:37]=[CH:38][C:39]2[S:43][C:42]([CH3:44])=[N:41][C:40]=2[CH:45]=1)[CH2:33][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][CH:13]=2)=[O:11])[CH2:2][CH2:3]1
Reactant: Cc1nc2cc(OC[C@H]3CO3)ccc2s1
Reactant: O=C(NCCN1CCNCC1)c1ccc(C(F)(F)F)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCNC(=O)c4ccc(C(F)(F)F)cc4)CC3)ccc2s1

Procedure:
To a solution of N-(2-piperazinylethyl)[4-(trifluoromethyl)phenyl]carboxamide (0.2 g, 0.38 mmol) in ethanol was added diisopropyl ethylamine (0.25 ml, 1.5 mmol) and 5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole (0.09 g, 0.42 mmol). The reaction was heated to 85 degrees for four hours. The mixture was then concentrated in vacuo and purified using preparative thin layer chromatography (10:1 DCM:MeOH) to yield N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)[4-(trifluoromethyl)phenyl]carboxamide (M+1=523.0).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[C:9]3[CH:16]=[C:15]([CH2:17][C:18]([F:21])([F:20])[F:19])[S:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:3][CH2:2]1.[OH:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[F:20][C:18]([F:21])([F:19])[CH2:17][C:15]1[S:14][C:10]2[N:11]=[CH:12][N:13]=[C:8]([NH:7][CH:4]3[CH2:5][CH2:6][N:1]([CH2:27][C:26]4[CH:29]=[CH:30][C:23]([OH:22])=[CH:24][CH:25]=4)[CH2:2][CH2:3]3)[C:9]=2[CH:16]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: FC(F)(F)Cc1cc2c(NC3CCNCC3)ncnc2s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Oc1ccc(CN2CCC(Nc3ncnc4sc(CC(F)(F)F)cc34)CC2)cc1

Procedure:
59 mg of N-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine (0.19 mmol) and 21 mg of p-hydroxybenzaldehyde (0.19 mmol) were dissolved in 0.5 mL of MeOH in the presence of 10 uL of acetic acid. 19 mg of NaBH3CN (0.3 mmol) was slowly added to that mixture and solution was stirred for 24 hs. All volatiles were removed under reduced pressure and residue was partitioned between water and ethyl acetate. Organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified on silica gel column with DCM:MeOH:Et3N as eluent resulting in 62 mg of 4-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)phenol (compound 105). 1H NMR (600 MHz, CDCl3): δ 8.46 (s, 1H), 7.09 (d, 2H, J=8.4 Hz), 7.07 (s, 1H), 6.68 (d, 2H, J=8.4 Hz), 5.28 (d, 1H, J=7.7 Hz), 4.21 (m, 1H), 3.59 (q, 2H, 9.9 Hz), 3.46 (s, 2H), 2.96 (m, 2H), 2.21 (m, 2H), 2.09 (m, 2H), 1.62 (m, 2H). 13C NMR (150 MHz, CDCl3): δC 166.45, 156.08, 155.98, 154.14, 131.01, 128.23, 125.57, 118.65, 116.52, 115.62, 62.48, 52.10, 47.96, 35.50 (q, J=31.5 Hz), 31.89. ESI MS [MH+]: 423.1458. Its monohydrochloride salt was obtained by adding 1 equivalent of 1N HCl solution in diethyl ether to a solution of compound in ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.Cl.[O:18]([NH2:20])[CH3:19]>N1C=CC=CC=1>[CH3:19][O:18][N:20]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C(Cc1ccc(F)cc1)c1ccccc1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(Cc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 2-(4-fluorophenyl)-1-phenyl-1-ethanone (5 g, 30 mmol) in 30 ml pyridine under nitrogen was added methoxylamine hydrochloride (3.8 g, 45 mmol) at 25° C. The resulting mixture was stirred at 25° C. for 17 hours. The pyridine was removed in vacuo with heating. The residual solids were a mixture of the oxime geometrical isomers as a white syrup and it was used for the next step without further purification. Rf : 0.48, 0.70 (CH2C12).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][C:19](O)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:28][C:29]1[S:30][CH:31]=[N:32][N:33]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:18][C:19]([NH:28][C:29]4[S:30][CH:31]=[N:32][N:33]=4)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)CC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: Nc1nncs1
Product: O=C(CC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1)Nc1nncs1
Yield: 50 %

Procedure:
Example 136 was prepared from 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-3-phenylpropanoic acid (504 mg, 1.4 mmol) and 2-amino-1,3,4-thiadiazole using General Coupling Method A to give 310 mg (50% yield). MS found: (M+H)+=444. Resolution of this compound into its enantiomers could be accomplished using chiral HPLC as described above.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].Cl[C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([S:30]([CH3:32])=[O:31])[N:29]=1)[C:23]([O:25][CH3:26])=[O:24]>>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:20]2[CH:21]=[C:22]([CH:27]=[C:28]([S:30]([CH3:32])=[O:31])[N:29]=2)[C:23]([O:25][CH3:26])=[O:24])[CH2:15][CH2:14]1)=[O:11]
Reactant: COC(=O)c1cc(Cl)nc(S(C)=O)c1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Agent: Cl
Product: COC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(S(C)=O)c1

Procedure:
The title compound was prepared in a manner analogous to Example 6 starting from 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1) and methyl 2-chloro-6-(methylsulfinyl)isonicotinate (Intermediate 84).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[C:23]([CH3:31])[C:11]=1[C:12]([C:14]1[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Cl)[C:15]=1[Cl:22])=[O:13]>[C].[Pd].CO>[CH3:8][O:9][C:10]1[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[C:23]([CH3:31])[C:11]=1[C:12]([C:14]1[C:19]([Cl:20])=[CH:18][N:17]=[CH:16][C:15]=1[Cl:22])=[O:13]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cnc(Cl)c2Cl)c(OC)c1OC
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(C)c(C(=O)c2c(Cl)cncc2Cl)c(OC)c1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 708 %

Procedure:
4.6 g (6.9 mmol) of triethylamine and 1.8 g of 10% palladium carbon were added to a methanol 280 ml solution of 17.8 g (4.6 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-2,3,5-trichloropyridine (compound No. 186), followed by stirring under hydrogen atmosphere at room temperature for 7 hours. The mixture was subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 11.6 g (yield 72%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3,5-dichloropyridine (compound No. 191; m.p. 109-111° C.).