Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: Clc1ccc(-c2cc3nc(Cl)cc(Cl)n3n2)cc1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: Clc1ccc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
There was dissolved, in 1,4-dioxane (5 mL), 5,7-dichloro-2-(4-chlorophenyl)-pyrazolo[1,5-a]pyrimidine (200 mg, 0.670 mM), then morpholine (117 μL, 1.34 mM) was added to the solution and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off from the reaction mixture and the resulting residue was diluted with water and extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and then the resulting solid was washed with methanol to give the title compound (222 mg, yield: 94%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([C:19](OCC)=[O:20])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[NH3:25]>CO>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([C:19]([NH2:25])=[O:20])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: N
Solvent: CO
Product: NC(=O)[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 60 °C

Procedure:
A mixture of ethyl (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinecarboxylate (Step 1, 0.22 g, 0.65 mmol) in 2M ammonia in methanol (5–6 mL) is heated in a closed vial at 60° C. for approximately 1 h. The resulting mixture is cooled to ambient temperature and concentrated under reduced pressure, and the crude product is recrystallized from methanol to give the title compound, MS (ESI+) for C14H16N3O4F m/z 310 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][NH2:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([N:13]2[CH2:14][CH2:15][CH:16]([CH2:19][NH:20][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([OH:21])=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)(=[O:11])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccc(F)cc2)CC1
Product: O=C(NCC1CCN(S(=O)(=O)CCc2ccc(F)cc2)CC1)c1ccc(O)cc1

Procedure:
N-{1-[2-(4-Fluoro-phenyl)-ethanesulfonyl]-piperidin-4-ylmethyl}-4-hydroxy-benzamide was prepared from C-{1-[2-(4-fluoro-phenyl)-ethanesulfonyl]-piperidin-4-yl}-methylamine and 4-hydroxybenzoic acid as described above in EXAMPLE 1, Step 2
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][C@H:28]([CH3:34])[CH2:29][NH:30][C:31](=[O:33])[CH3:32])[N:20]=[CH:19][N:18]=2)=[CH:12][C:11]=1[CH3:35]>>[CH3:35][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][C@H:28]([CH3:34])[CH2:29][NH:30][C:31](=[O:33])[CH3:32])[N:20]=[CH:19][N:18]=2)[CH:14]=[CH:15][C:10]=1[O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: ClCc1ccccn1
Reactant: CC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(C)c3)c12
Product: CC(=O)NC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c12
Yield: 43 %

Procedure:
The procedure described in Example 3 was repeated using 2-(chloromethyl)pyridine and N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]acetamide to give the title compound as a white solid in 43% yield; NMR spectrum (DMSO-d6) 1.41 (d, 3H), 1.77 (s, 3H), 2.27 (s, 3H), 3.41 (dt, 1H), 3.58 (dt, 1H), 4.87 (m, 1H), 5.20 (s, 2H), 7.01 (d, 1H), 7.22 (d, 1H), 7.29 (d, 1H), 7.35 (dd, 1H), 7.55 (m, 2H), 7.58 (dd, 1H), 7.69 (t, 1H), 7.85 (td, 1H), 8.23 (t, 1H), 8.45 (s, 1H), 8.58 (d, 1H), 9.97 (s, 1H); Mass spectrum MH+ 458.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([C@H:14]1[C:23]3[C:18](=[C:19]([F:28])[CH:20]=[C:21]([C:24]([O:26]C)=[O:25])[CH:22]=3)[O:17][CH2:16][CH2:15]1)[CH2:9]2>C(O)C.O>[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[C:11](=[O:13])[N:10]([C@H:14]1[C:23]3[C:18](=[C:19]([F:28])[CH:20]=[C:21]([C:24]([OH:26])=[O:25])[CH:22]=3)[O:17][CH2:16][CH2:15]1)[CH2:9]2
Reactant: COC(=O)c1cc(F)c2c(c1)[C@H](N1Cc3cccc(Cl)c3C1=O)CCO2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(F)c2c(c1)[C@H](N1Cc3cccc(Cl)c3C1=O)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
KOH (1 mol/l aq) (2 eq) was added to a suspension of (R)-methyl 4-(7-chloro-1-oxoisoindolin-2-yl)-8-fluorchromane-6-carboxylate (D-05) (0.8 mmol, 1 eq) in a mixture of ethanol (4.6 ml) and water (1.6 ml). The reaction mixture was stirred overnight at RT. Ethanol was removed in vacuo and the residue was taken up in diethyl ether and water. The phases were separated and the aqueous phase was adjusted to pH 3 with 1N HCl. The aqueous phase was extracted with ethyl acetate (3×) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate:cyclohexane 1:1). Yield: 62% B. Amine Structural Units Overview: Amine Structural Units
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]=[C:13]=[S:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][CH:21]=[C:20]2[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=1[CH3:37].C1(C)C=CC=CC=1>C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][CH:21]=[C:20]2[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][C:13]([NH:12][C:10](=[O:11])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[S:14])=[CH:32][C:31]=1[CH3:37]
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc([N+](=O)[O-])cc4)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.7 %

Procedure:
Commercially available 4-nitro-1-benzenecarbonyl isothiocyanate (30 mg) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (79 mg, yield 94%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[F:20])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:12])[NH:27][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[F:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CCCCC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cc(F)ccc1F
Product: CC(C)(C)OC(=O)NC(C(=O)NC1CCCCC1)c1cc(F)ccc1F
Yield: 89.9 %

Procedure:
Using general procedure E, tert-butoxycarbonylamino-(2,5-difluorophenyl)-acetic acid (1.84 g, 6.40 mmol) and cyclohexylamine (730 μL, 634 mg, 6.40 mmol) afforded [cyclohexylcarbamoyl-(2,5-difluorophenyl)-methyl]-carbamic acid tert-butyl ester (2.12 g, 90%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[N:10]=[C:9]([N:11]([CH2:14][C:15]2[S:19][C:18]([Cl:20])=[N:17][CH:16]=2)[CH2:12][CH3:13])[C:8]([N+:21]([O-:23])=[O:22])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][N:2]([CH3:3])[C:5]1[N:10]=[C:9]([N:11]([CH2:14][C:15]2[S:19][C:18]([Cl:20])=[N:17][CH:16]=2)[CH2:12][CH3:13])[C:8]([N+:21]([O-:23])=[O:22])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: CCN(Cc1cnc(Cl)s1)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(Cc1cnc(Cl)s1)c1nc(N(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 32 %

Procedure:
1.15 g of 33% aqueous dimethylamine solution, 10 mL of N,N-dimethylformamide (DMF) and 2.80 g of 6-chloro-N-((2-chloro-thiazole-5-yl)methyl)-N-ethyl-3-nitropyridin-2-amine, prepared according to the example 1, in 5 mL of DMF were added into a 100 mL three-necked flask equipped with a magnetic stirrer, a condenser and a drying tube, under stirring at room temperature, 1.40 g of potassium carbonate was added in batches. Reacted at the room temperature until the reaction was complete. The reaction solution was treated by the method according to example 1 to obtain 0.92 g of 6-dimethylamino-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-nitropyridine-2-amine, the content of 98.0%, as a golden yellow solid in a yield of 31.4%, mp: 74.6-78.4° C., GC-MS (M+) (EI, 70 eV, m/z) calc: 341. found: 341. 1H NMR (CDCl3/TMS, 300 MHz) δ (ppm) 1.193 (t, J=7.2 Hz, 3H, CH3), 3.192 (s, 6H, 2*CH3), 3.216 (q, J=7.2 Hz, 2H, CH2), 4.811 (s, 2H, CH2), 6.022 (d, J=9.0 Hz, 1H, Py H), 7.458 (s, 1H, thiazole-H), 8.165 (d, J=9.0 Hz, 1H, Py H).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)\[C:5]([NH:7][CH3:8])=[O:6].Cl>CO>[CH3:1][O:2]/[N:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)/[C:5]([NH:7][CH3:8])=[O:6]
Reactant: CNC(=O)/C(=N\OC)c1ccccc1Oc1ccccc1
Agent: Cl
Solvent: CO
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccccc1

Procedure:
To Z-2-methoxyimino-N-methyl-2-(2phenoxyphenyl)acetamide VI" (0.28 g, 1.0 mmole) were added dried methanol (3 ml) and 10% hydrochloric acid solution in methanol (0.36 g, 1.0 mmole) and the mixture was heated under reflux for 6 hours to conduct isomerization.
Reaction SMILES: [Na+:1].[NH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([S:17]([OH:20])(=[O:19])=[O:18])[CH:9]=[C:10]2[S:13]([O-:16])(=[O:15])=[O:14])=[CH:5][CH:4]=1.[OH-].[Na+].[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30])([O-:25])=[O:24].Cl>O>[Na+:1].[Na+:1].[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([S:17]([O-:20])(=[O:19])=[O:18])[CH:9]=[C:10]2[S:13]([O-:16])(=[O:15])=[O:14])=[CH:5][CH:4]=1)=[O:30])([O-:25])=[O:24]
Reactant: Nc1ccc2cc(S(=O)(=O)O)cc(S(=O)(=O)[O-])c2c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1ccc2cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c2c1)c1cccc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
A 52.2 g portion of 7-amino-1,3-naphthalenedisulfonic acid monosodium salt (technical) is suspended in 80 ml of water and 160 ml of 1N sodium hydroxide is added, then 60.0 g of m-nitrobenzoyl chloride is added all at once (a large lump of crystalline solid is separated on addition of the acid chloride). The mixture is diluted with an additional 80 ml of water and a second 160 ml portion of 1N sodium hydroxide is added after brief initial shaking. Shaking is continued and the latter addition of sodium hydroxide and shaking is repeated two more times with intermitent attempt at breaking up any crystalline lumps with a spatula. The resulting mixture is shaken at least one hour after the final base treatment. Since complete solution is not attained, eight 150 ml portions of water are added then two 500 ml portions still without complete solution. The material is allowed to stand overnight and a gel is formed which is further diluted with water and is broken up with a spatula. The mixture is then acidified with 17 ml of concentrated hydrochloric acid and is copiously extracted with ether. The ether is removed after each extraction by vacuum siphoning. The gel is filtered over a period of 2 days in two funnels. The residue is combined and dissolved in boiling water then is filtered. The filtrate (about 710 ml) is diluted with an equal amount of 3A alcohol and is allowed to stand at room temperature overnight. The resulting precipitate is filtered and is washed with several 100 ml portions of 50% ethyl alcohol then is slurried twice with 250 ml portions of absolute ethyl alcohol and finally with two 250 ml portions of ether to give 7-(m-nitrobenzamido)-1,3-naphthalenedisulfonic acid disodium salt which is oven dried at 120° C.
Reaction SMILES: [N:1]1[C:2]([CH2:10][N:11]([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[I:18]N1C(=O)CCC1=O.O>C(#N)C>[I:18][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][C:2]=1[CH2:10][N:11]([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)CN(C)Cc1cn2ccccc2n1
Solvent: CC#N
Solvent: O
Product: COC(=O)CN(C)Cc1nc2ccccn2c1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.4 %

Procedure:
0.107 g (0.459 mmol) of methyl 2-((imidazo[1,2-a]pyridin-2-ylmethyl)(methyl)amino)acetate were dissolved in 4 ml of acetonitrile with magnetic stirring, to this solution were added 0.112 g (0.482 mmol) of N-iodosuccinimide. The mixture was stirred at r.t. for 16 h. The reaction mixture was treated with 10 ml of water and then extracted with 3×10 ml of ethyl acetate. The combined organic phases were washed with 20 ml of a saturated NaCl aqueous solution, and then dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: ethyl acetate 100%). 0.093 g (yield=46%) of methyl 2-(((3-iodoimidazo[1,2-a]pyridin-2-yl)methyl)(methyl)amino)acetate were obtained as a yellow oil. LC-MS: m/z=360 (MH+); UV purity at 254 nm=82%. 1H NMR (300 MHz, DMSO) δ 8.30 (d, J=6.8 Hz, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.41-7.23 (m, 1H), 7.03 (t, J=6.7 Hz, 1H), 3.79 (s, 2H), 3.62 (s, 3H), 3.37 (s, 2H), 2.34 (s, 3H).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[CH:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)C1CCCCC1
Temperature: 2 °C
Reaction time: 12 h

Procedure:
A solution of cyclohexanecarbonyl chloride (9.1 ml) in CH2Cl2 (25 ml) was added slowly under nitrogen atmosphere at 0-4° C. to a stirred mixture of AlCl3 (9.1 g), CH2Cl2 (25 ml) and benzene (50 ml). The resulting mixture was stirred for 1 hour at 0-4° C. and 12 hours at the room temperature. The mixture was poured into ice-water (200 ml, contains 1 ml of concentrated HCl) and stirred for 5 minutes. The phases were separated and the aqueous phase was washed with CH2CO2 (2×20 ml). The organic phases were combined and extracted with water (2×20 ml), 2.5% NaOH solution (2×30 ml) and water (2×20 ml). The organic phase was dried over Na2SO4 and evaporated. Yield was 12.0 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[N:15][C:16]=3[O:18][CH2:19][CH3:20])[NH:11][C:10]([CH3:21])=[C:9]2[C:22]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[O:23])=[C:4]([O:29][C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][N:35](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:34]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[N:15][C:16]=3[O:18][CH2:19][CH3:20])[NH:11][C:10]([CH3:21])=[C:9]2[C:22]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[O:23])=[C:4]([O:29][C:30]([F:32])([F:33])[F:31])[CH:3]=1)#[N:35]
Reactant: CCOc1nccc2c1C(c1ccc(Br)cc1OC(F)(F)F)C(C(=O)OCCC#N)=C(C)N2
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOc1nccc2c1C(c1ccc(C#N)cc1OC(F)(F)F)C(C(=O)OCCC#N)=C(C)N2
Temperature: 220 °C

Procedure:
4.59 g (8.72 mmol) of the compound from Example 35A, 758 mg (6.45 mmol) of zinc cyanide and 504 mg (0.436 mmol) of tetrakis(triphenylphosphine)palladium(0) are dissolved in 40 ml of DMF and then, divided into three mixtures, heated in a single mode microwave (Emrys Opzimizer) at 220° C. for 5 min. The individual mixtures are then recombined, and the solvent is removed in a rotary evaporator. The crude product is taken up in ethyl acetate and filtered through kieselguhr. The organic phase is washed with water (2×) and with saturated sodium chloride solution. After removal of the solvent by distillation, the crude product is purified by column chromatography (silica gel; mobile phase: cyclohexane/ethyl acetate 7:3→1:1). 1.40 g (31% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[C:7]([CH:12]=[CH:13][O:14]CC)[CH:6]=2.Cl.[OH-].[Na+]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:12][CH:13]=[O:14])[CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: CCOC=Cc1cnc2cc(Br)cnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=CCc1cnc2cc(Br)cnc2c1
Yield: 95 %

Procedure:
To a mixture of the product from Example 153C (0.25 g, 0.89 mmol) in 15 mL of THF was added 1.5 mL of HCl (6N). The mixture was heated to reflux for 5 hr, cooled and the pH adjusted to 8.0 with NaOH. The mixture was diluted with 75 mL of CH2Cl2 and washed successively with a saturated solution of sodium bicarbonate, brine and water. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give the desired product in 95% yield. 1H NMR (CDCl3, 300 MHz) δ3.75 (m, 2H), 8.25 (m, 1H), 8.60 (m, 1H), 8.85 (m, 1H), 9.00 (m, 1H), 9.90 (s, 1H). MS (ESI) [M+H]+ at 252.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:19])[F:20])=[CH:10][CH:9]=2)[S:28]([CH3:27])(=[O:30])=[O:29])[CH:14]=1
Reactant: FC(F)(F)COc1ccc(NCc2cccnc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccnc1)c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 4.2 g. portion of 3-[4-(2,2,2-trifluoroethoxy)phenylaminomethyl]pyridine was dissolved in 15 ml. of dichloromethane, and to it were added 2.7 g. of potassium carbonate and 1.6 ml. of methanesulfonyl chloride. The mixture was stirred at ambient temperature for 3 days, and it was then diluted with dichloromethane, extracted with 25 ml. of water, dried over magnesium sulfate and evaporated to an oil. The residue was taken up in diethyl ether, and the insoluble portion was separated. The product slowly crystallized upon standing, and the solids were triturated with petroleum ether and washed with diethyl ether and petroleum ether to obtain 3.7 g. of the desired product, m.p. 69°-70°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:34]2[C:35]([CH:40]=O)=[N:36][CH:37]=[CH:38][CH:39]=2)([CH3:33])[CH3:32])=[CH:27][CH:26]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=1)[CH2:40][C:35]1[C:34]([C:31]([C:28]2[CH:27]=[CH:26][C:25]([F:24])=[CH:30][CH:29]=2)([CH3:33])[CH3:32])=[CH:39][CH:38]=[CH:37][N:36]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Cl)cnc1CNCCCCN(C)C(=O)OC(C)(C)C
Reactant: CC(C)(c1ccc(F)cc1)c1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1cc(Cl)cnc1CN(CCCCN(C)C(=O)OC(C)(C)C)Cc1ncccc1C(C)(C)c1ccc(F)cc1

Procedure:
Using General Procedure B: Reaction of {4-[(5-chloro-3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-methyl-carbamic acid tert-butyl ester, 3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridine-2-carbaldehyde and NaBH(OAc)3 gave [4-((5-chloro-3-methyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-amino]-butyl]-methyl-carbamic acid tert-butyl ester as a light brown solid. Deprotection with TFA using General Procedure F gave N-(5-Chloro-3-methyl-pyridin-2-ylmethyl)-N-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-N′-methyl-butane-1,4-diamine (326 mg, excess) which was used immediately in the next reaction.
Reaction SMILES: [NH2:1][C@@:2]1([C:19]2[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=2[F:26])[CH2:7][O:6][C@@H:5]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][C@H:3]1[CH2:17]O.C([N:35]=[C:36]=[S:37])(=O)C1C=CC=CC=1.Cl>ClCCl.CO>[CH2:10]([O:9][CH2:8][C@@H:5]1[O:6][CH2:7][C@@:2]2([C:19]3[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=3[F:26])[C@H:3]([CH2:17][S:37][C:36]([NH2:35])=[N:1]2)[CH2:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N[C@@]1(c2cc(Br)ccc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: NC1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
[(2R,4R,5S)-5-Amino-2-benzyloxymethyl-5-(5-bromo-2-fluorophenyl)tetrahydropyran-4-yl]methanol (2.22 g) was dissolved in dichloromethane (30 ml), and benzoyl isothiocyanate (776 μl) was added. The mixture was stirred at room temperature for five hours, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain an intermediate. The resulting intermediate was dissolved in methanol (50 ml), and concentrated hydrochloric acid (2 ml) was added. The mixture was heated under reflux for six hours and then cooled to room temperature. The solvent was evaporated under reduced pressure. Methanol (30 ml) and DBU (2 ml) were added to the residue, followed by heating under reflux for three hours. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (2.30 g).
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15](O)([CH3:17])[CH3:16])=[CH:14][C:9]=2[O:8][CH2:7]1>C1C=CC=CC=1>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([S:1][CH2:2][C:3]([OH:5])=[O:4])([CH3:17])[CH3:16])=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: O=C(O)CS
Reactant: CC(C)(O)c1ccc2c(c1)OCO2
Solvent: c1ccccc1
Product: CC(C)(SCC(=O)O)c1ccc2c(c1)OCO2
Yield: 45.8 %

Procedure:
600 ml of benzene, 59.5 g of mercaptoacetic acid and a catalytic amount of D-100camphorsulfonic acid were added to 97 g of 2-(1,3-benzodioxol-5-yl)-2-propanol. The obtained mixture was heated under reflux for 4 hours and distilled to remove the solvent. The pH of the residue was adjusted to 10 with a 1N aqueous solution of sodium hydroxide. The resulting mixture was washed with ethyl acetate. 4N hydrochloric acid was added to the mixture under cooling with ice to acidify the aqueous layer. The resulting mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to obtain a crude crystal. This crude crystal was recrystallized from diisopropyl ether to obtain 62.70 g of the title compound as a colorless crystal.