Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Cl:12]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.ClNC1C=CC(C(F)(F)F)=CN=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]([Cl:12])=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: FC(F)(F)c1ccc(NCl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Nc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 208.2 %

Procedure:
Into the same 300 ml four-necked flask as used in Example 1, 16.2 g (0.1 mol) of 2-amino-5-trifluoromethylpyridine prepared in the same manner as in step (1) of Example 1, 10.1 g (0.043 mol) of trichloroisocyanuric acid and 150 g of toluene were added, and the reaction was conducted at 110° C. for 3 hours under heating with stirring. During the reaction, formation of 2-chloroamino-5-trifluoromethylpyridine was confirmed. After completion of the reaction, the reaction mixture was cooled to room temperature, and 100 g of a 25% sodium hydroxide aqueous solution was added thereto and stirred. An aqueous layer and an oil layer were separated. A 20% hydrochloric acid aqueous solution was added to the oil layer, and the mixture was stirred. An aqueous layer and an oil layer were further separated. The aqueous layer was neutralized with a 25% sodium hydroxide aqueous solution. Precipitated slightly yellow crystals were collected by filtration and dried to obtain 17.6 g 2-amino-3-chloro- 5-trifluoromethylpyridine (purity as measured by liquid chromatography: 95%, yield: 85%).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[C:48](Cl)(=[O:50])[CH3:49]>C1COCC1>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH:20]=3)[C:48](=[O:50])[CH3:49])[CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cccc(CNc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cccc(CN(C(C)=O)c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)propanoate (104 mg) in THF (2.0 mL) were added N-ethyldiisopropylamine (52 μL) and acetyl chloride (17 μL) at 0° C., and the mixture was stirred at room temperature for 1.5 hr. Ice water was added at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The is solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (104 mg) as a colorless oil.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[N:9]2[CH:10]=[C:11]([CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=3)[N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1.O1CCCC1.O>CO>[Cl:3][C:4]1[N:9]2[CH:10]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:21][CH:22]=3)[N:12]=[C:8]2[CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OCc2cn3c(Cl)cccc3n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: OCc1ccc(OCc2cn3c(Cl)cccc3n2)cc1
Reaction time: 1 h
Yield: 66 %

Procedure:
Sodium borohydride (232 mg) was added to a solution of 4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzaldehyde (3.52 g) in methanol (10 ml)-tetrahydrofuran (50 ml) at 0° C. After stirring for 1 hour, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate to obtain 4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzylalcohol (2.34 g, yield 66%) as colorless crystals. m.p. 169-171° C.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[Cl:27][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([S:14][CH3:15])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C)nc(SC)nc1O
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1c(C)nc(SC)nc1Cl
Temperature: 100 °C
Yield: 82.8 %

Procedure:
Ethyl 4-hydroxy-6-methyl-2-(methylthio)pyrimidine-5-carboxylate (0.2 g, 0.876 mmol), tetraethylammonium chloride (0.145 g, 0.876 mmol), and N,N-dimethylaniline (0.112 mL, 0.876 mmol) were dispersed in acetonitrile (10 mL). The reaction mixture was stirred briefly followed by the addition of phosphorous oxychloride (0.204 mL, 2.190 mmol). The reaction was heated at 100° C. for 4 h. The solvent was subsequently removed in vacuo. The residue was poured onto ice to give an off-white oil, which was extracted with DCM (2×15 mL), and dried over anhydrous Na2SO4. The solvent was removed in vacuo to give the title compound as a yellowish-green oil (0.179 g, 83%). [M+H] calc'd for C9H11ClN2O2S, 247; found, 247.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13]C(C2C=CC=CC=2)C=C)[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH3:11])[C:6]=2[CH:12]=1.O.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27](S(O)(=O)=O)=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+].O.[C:41]1(C)C=CC=C[CH:42]=1>>[Br:1][C:2]1[C:3]([CH2:41][CH:42]=[CH:34][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:4]([NH2:13])[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH3:11])[C:6]=2[CH:12]=1
Reactant: Cc1ccccc1
Reactant: C=CC(Nc1cc(Br)cc2c1nc(C)n2C)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1nc2c(N)c(CC=Cc3ccccc3)c(Br)cc2n1C
Yield: 64 %

Procedure:
A suspension of 3.8 g (10.7 mmol) (6-bromo-1,2-dimethyl-1H-benzimidazol-4-yl)-(1-phenyl-allyl)-amine and 3.5 g p-toluenesulphonic acid monohydrate in 80 ml toluene was refluxed for 26 h. The suspension was poured into a mixture of 50 ml saturated sodium hydrogencarbonate solution and 150 ml water and extracted with ethyl acetate. The organic phase was separated, dried over anhydrous magnesium sulfphate and evaporated. The residue was purified by column chromatography on silica gel (toluene/dioxane/methanol=6:3.8:0.2). Crystallization from diisopropyl ether gave 2.45 g (64%) of the title compound as a colourless solid. m.p. 186-189° C.
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]4[CH:33]=[CH:32][C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:25]=4)[CH:17]=3)[CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)#[N:2].[N-:34]=[N+:35]=[N-:36].[Na+].Cl.N1C=CC=CC=1.CN(C)C=O>O>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:12]1[CH:11]=[CH:10][C:6]2[C:7](=[O:9])[CH:8]=[C:3]([C:1]3[NH:36][N:35]=[N:34][N:2]=3)[O:4][C:5]=2[CH:13]=1
Reactant: N#Cc1cc(=O)c2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc2o1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(-c2nnn[nH]2)oc2cc(OCc3cccc(OCc4ccc5ccccc5n4)c3)ccc12
Temperature: 100 °C

Procedure:
2-cyano-7-(3-(quinolin-2-ylmethoxy)benzyloxy)-4-oxo-4H-1-benzopyran (2.97 mmoles), sodium azide (965 mg), pyridine hydrochloride (1.72g) and dimethylformamide (7 ml) are combined and heated at 100° C. for 48 hours. The reaction mixture is poured into cold water and the resulting precipitate is collected. The precipitate is dissolved in hot ethanol and reprecipitated by addition of water to give 5-(7-(3-(quinolin-2-ylmethoxy)benzyloxy)-4-oxo-4H-1-benzopyran-2-yl)tetrazole which decomposes at 203° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]([C:11]#[N:12])[CH2:9][CH:8]([CH2:13][CH2:14][CH3:15])[CH2:7][C:5]=2[N:6]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>N1C=CC=CC=1>[CH2:20]([O:19][C:17](=[O:18])[NH:1][C:2]1[S:3][C:4]2[CH:10]([C:11]#[N:12])[CH2:9][CH:8]([CH2:13][CH2:14][CH3:15])[CH2:7][C:5]=2[N:6]=1)[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: CCCC1Cc2nc(N)sc2C(C#N)C1
Solvent: c1ccncc1
Product: CCCC1Cc2nc(NC(=O)OCC)sc2C(C#N)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-5-propyl-7-cyano-4,5,6,7-tetrahydrobenzothiazole (0.10 mol) dissolved in pyridine (125 ml.) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. Ethyl chloroformate (0.12 mol) is then added dropwise to the reaction mixture with stirring and cooling. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 1 hour. After this time the reaction mixture is poured into ice water to form a precipitate. The precipitate is recovered by filtration, is dried and recrystallized to yield the desired product ethyl-N-(5-propyl-7-cyano-4,5,6,7-tetrahydrobenzothiazol-2-yl)carbamate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[CH2:12]Br)[CH3:2].[CH2:15]([O:17][C:18](=[O:32])[CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[O:30][CH3:31])[CH3:16].[Na+].[I-].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[CH2:12][N:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[O:30][CH3:31])[CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:32])[CH3:2]
Reactant: CCOC(=O)c1ccc(Br)cc1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1cc(Br)ccc1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-benzoic acid ethyl ester (34.3 g, prepared according to Zhong, Min and Li, Leping PCT Int. Appl., 2010065674, 10 Jun. 2010), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (32.4 g), NaI (1.6 g), DIPEA (27.8 mL) in DMF was stirred at rt overnight. Then the reaction mixture was diluted with EtOAc, washed with water, diluted NaCl, dried over sodium sulfate, filtered, concentrated and column purified to give the desired product (36.14 g). LC MS ESI+: 495 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[N:3]=1.C(N(CC)CC)C.[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N)CC2)nc1N
Reactant: O=C1CCC(=O)O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NC(=O)CCC(=O)O)CC2)nc1N

Procedure:
To a stirred solution of trans-[4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (100 mg, 0.27 mmol, Example 120) and triethylamine (125 mg, 0.33 mmol) in tetrahydrofuran (5 mL), succinic anhydride (35 mg, 0.35 mmol, Aldrich,) was added and the mixture was refluxed for 2 hours. The mixture was cooled and the solid was filtered and dried to yield a white powder. 130 mg, 100%. MS (ES) MH+=478.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[NH:7][CH2:6][CH2:5]2.[Cl:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:17]1>>[ClH:14].[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[CH2:24][CH2:23][CH2:22][N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([CH2:15][N:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][C:11]([CH3:12])=[C:2]([CH3:1])[CH:3]=3)[C:8]2=[O:13])[CH2:17]1
Reactant: Cc1cc2c(cc1C)C(=O)NCC2
Reactant: ClCC1CCCN(CCCc2ccc3ccccc3c2)C1
Product: Cc1cc2c(cc1C)C(=O)N(CC1CCCN(CCCc3ccc4ccccc4c3)C1)CC2
Product: Cl

Procedure:
Prepared from 6,7-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 3-chloromethyl-N-[3-(naphth-2-yl)-propyl]-piperidine analogously to Example 2.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH2:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20](Cl)(=[O:23])[CH:21]=[CH2:22].C(N(CC)CC)C>ClCCl>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([NH:19][C:20](=[O:23])[CH:21]=[CH2:22])([CH3:17])[CH3:18])=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(N)c1ccc(OCc2ccccc2)cc1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)NC(C)(C)c1ccc(OCc2ccccc2)cc1

Procedure:
1-(4-Benzyloxyphenyl)-1-methylethylamine hydrochloride (25.0 g) was treated with acryloyl chloride (8.43 ml) in dichloromethane (250 ml) containing triethylamine (14.4 ml) to give N-[1-(4-benzyloxyphenyl)-1-methylethyl]acrylamide, m.p. 116-117° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[C:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9]CC>CO>[C:8](=[O:9])([O-:15])[O-:12].[CH3:6][N+:3]([CH2:13][CH3:14])([CH2:4][CH3:5])[CH2:1][CH3:2].[CH3:8][N+:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: CCOC(=O)OCC
Reactant: CCN(CC)CC
Solvent: CO
Product: CC[N+](C)(CC)CC
Product: O=C([O-])[O-]

Procedure:
Triethylamine (1 mol), diethyl carbonate (1.5 mol), and methanol (2 mol) as a solvent were charged into a stirring-type autoclave, and the whole was reacted at the reaction temperature of 110° C. for 12 hours to obtain a methanol solution of methyltriethylammonium carbonate. 2-Ethylhexanoic acid (1 mol) was charged thereto and ethylene glycol was added as a solvent so as to be a predetermined concentration. Thereafter, a solution of 50% of methyltriethylammonium 2-ethylhexanoate and 50% of ethylene glycol was obtained by removing carbon dioxide and methanol produced as by-products by an evaporator.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[C:5](=[C:10]([CH3:18])[C:11]([NH2:17])=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[OH-].[Na+].Cl>C1COCC1.O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[C:4](=[CH:13][C:12]([N+:14]([O-:16])=[O:15])=[C:11]([NH2:17])[C:10]=1[CH3:18])[C:3]([OH:19])=[O:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(C)c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(C(=O)O)cc([N+](=O)[O-])c(N)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.1 %

Procedure:
To a solution of 4-Amino-3-methyl-5-nitro-phthalic acid dimethyl ester (1.8 g, 6.72 mmol) in THF (10 mL) and water (20 mL) was added 5 N NaOH (4.0 mL) and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was acidified with conc. HCl (pH=2.0) and extracted with EtOAc (2×100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford the 4-Amino-3-methyl-5-nitro-phthalic acid 2-methyl ester (1.3 g, 76%) as a yellow solid.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH2:5].[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:12]([O:15]CC)(=[O:14])C>C(OCC)C.CCCCCC>[Cl:2][CH2:3][CH2:4][NH:5][C:12](=[O:14])[O:15][C:8]1[CH:7]=[CH:6][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCCC
Reactant: CCOC(C)=O
Reactant: NCCCl
Agent: Cl
Solvent: CCOCC
Product: O=C(NCCCl)Oc1ccccc1
Yield: 60.99 %

Procedure:
2-Chloroethylamine hydrochloride (5.8 g, 50 mmol) was used for reaction in the same manner as Production Example 310-1, purification was performed by silica gel column chromatography (hexane/ethyl acetate system), the obtained crystals were suspended in diethyl ether/hexane, and the crystals were filtered out, washed with hexane and dried by aspiration to obtain the title compound (6.088 g, 30.49 mmol, 60.99%) as colorless crystals.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.CC(O)=O.CS(O)(=O)=O.CCOC(C)=O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[NH:7][C:1]3[C:6]([C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:14][CH:15]=1
Reactant: NNc1ccccc1
Reactant: CS(=O)(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
A solution of phenylhydrazine (203 uL, 1.73 mmol) and 1-(4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)ethanone (510 mg, 1.73 mmol) (Step 2) in a mixture of toluene/HOAc (2:1; 5 mL) containing 1 drop of methanesulfonic acid was stirred at r.t. overnight. The reaction mixture was diluted with EtOAc and was washed successively with H2O, 1M NaOH, H2O and dried. Evaporation of the solvent gave a residue which was purified by silica gel chromatography using EtOAc/hexane (1:3+10% CH2Cl2) as eluent to afford 339 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH2:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47]O)[CH3:44]>>[CH2:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)[CH3:44]
Reactant: CCN(CC)CCO
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: CCN(CC)CCOC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c(OC)c1

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 2-(diethylamino)ethanol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-diethylamino-ethyl ester. MS (ES+) m/z calcd. for C37H43Cl2F2N4O4: [(M+H)+]: 715. found: 715.
Reaction SMILES: C(O[C:4](=[O:25])[CH2:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])C.[C:26]1([NH:32][C:33]([NH:35][C:36]([NH2:38])=[NH:37])=[NH:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH2:7]([C:6]1[N:37]=[C:36]([NH:35][C:33]([NH:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[NH:34])[NH:38][C:4](=[O:25])[CH:5]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: N=C(N)NC(=N)Nc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)CC(=O)OCC
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCc1cc(=O)[nH]c(NC(=N)Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
In a 50 milliliter round-bottom flask, 3-oxoeicosanoic acid ethyl ester (2.25 grams, 6.60 mmol, prepared as described in Part B of this Example) was added at room temperature to a solution of 1-phenylbiguanide (1.17 grams, 6.60 mmol, prepared as described in Part D of this Example) in anhydrous ethanol (20 milliliters). The mixture was heated at reflux and stirred for 16 hours. Cooling the resulting yellow solution to room temperature gave a colorless precipitate. The precipitate was isolated by filtration and thoroughly washed with water, then with cold ethanol (0° C.), and finally with pentane. The resulting powder was then recrystallized from anhydrous ethanol, recovered by filtration, and dried under reduced pressure to give the targeted N-(4-heptadecyl-6-oxo-1,6-dihydropyrimidin-2-yl)-N′-phenylguanidine as a colorless solid (1.79 grams, 58 percent yield): mp=164° C.; 1H NMR (DMSO-d6, 303 K) δ: 11.16 (s, 1H), 9.04 (s, 1H), 8.5-6.5 (br, 2H), 7.66 (d, 2H, 3J=7.9 Hz), 7.25 (m, 2H), 6.99 (t, 1H, 3J=7.4 Hz), 5.56 (s, 1H), 2.32 (t, 2H, 3J=7.5 Hz), 1.56 (m, 2H), 1.33-1.17 (m, 28H), 0.85 (t, 3H, 3J=6.8 Hz); Exact mass calculated for C28H45N5O=467.3624. Measured Low Resolution Mass Spectrum (MAB/LR/N2)=468.2. Anal. Calcd for C28H45N5O: C, 71.91; H, 9.70; N, 14.97. Found: C, 72.02; H, 9.96; N, 14.92.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]([CH2:16][CH:17]([CH3:19])[CH3:18])[S:8]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:22][C:23]([F:30])([F:29])[S:24]([O:27]C)(=[O:26])=[O:25]>C(Cl)Cl>[O-:27][S:24]([C:23]([F:30])([F:29])[F:22])(=[O:26])=[O:25].[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]([CH2:16][CH:17]([CH3:19])[CH3:18])[S:8]([N:11]2[CH:15]=[CH:14][N+:13]([CH3:23])=[CH:12]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CC(C)CN(Cc1ccc(F)cc1)S(=O)(=O)n1ccnc1
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc(F)cc1)S(=O)(=O)n1cc[n+](C)c1
Product: O=S(=O)([O-])C(F)(F)F
Reaction time: 2 h

Procedure:
A solution of imidazole-1-sulfonic acid (4-fluoro-benzyl)-isobutyl-amide (260 mg, 835 μmol) in DCM (5 mL) at 0° C. was treated dropwise with methyl trifluoromethane sulfonate (101 μL, 918 μmol) and stirred cold for 2 hours. The mixture was concentrated under vacuum and used immediately in the next step. LCMS (m/z, Method A) ES+ 326.0 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[C:28]([O:32][C:33]([N:35]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][C:48](O)=[O:49])=[CH:42][CH:41]=1)[S:36]([CH3:39])(=[O:38])=[O:37])=[O:34])([CH3:31])([CH3:30])[CH3:29].C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[C:28]([O:32][C:33]([N:35]([C:40]1[CH:41]=[CH:42][C:43]([CH2:46][CH2:47][C:48]([O:10][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH:12]=2)[CH2:8][C:7]2[C:6]([Cl:26])=[CH:5][N+:4]([O-:27])=[CH:3][C:2]=2[Cl:1])=[O:49])=[CH:44][CH:45]=1)[S:36]([CH3:39])(=[O:38])=[O:37])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N(c1ccc(CCC(=O)O)cc1)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(c1ccc(CCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (30 mg, 0.07 mmol) and 3-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)phenyl)propanoic acid (48 mg, 0.14 mmol) were dissolved in DMF (2 ml), and DMAP (17 mg, 0.14 mmol) and EDC (40 mg, 0.21 mmol) were added. The mixture was stirred at RT overnight, then was diluted with water. The precipitate was filtered, dissolved in EtOAc and washed with HCl 1N and NaHCO3 sat. sol. The organic phase was dried over Na2SO4 and evaporated under vacuum to give 40 mg of crude product, that was used for the next step without any further purification.