Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[NH2:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:29][C:28]3[CH:27]=[C:26]([Cl:25])[CH:32]=[C:31]([Cl:33])[CH:30]=3)[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCn1c(Nc2cc(Cl)cc(Cl)c2)nc2c(Cl)ccc(C(CC)CC)c21
Yield: 40.1 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 500 mg, 1.35 mmol), 3,5-dichloroaniline (655 mg, 4.04 mmol) and p-toluenesulfonic acid monohydrate (257 mg, 1.35 mmol) in 1-methyl-2-pyrrolidinone (4 mL) was irradiated by microwave at 180° C. for 15 min. After cooling, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 5-20% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC to give the title compound (270 mg, 0.542 mmol, 40%) as a colorless amorphous.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][C@@:8]2([CH3:29])[N:12]3[C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)[C:9]2=[O:28])=[CH:5][CH:4]=1)#[N:2].CCO[C:35]([CH3:37])=[O:36]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][C@@:8]2([CH3:29])[N:12]3[C:13]([S:16]([NH:12][C@@H:8]([CH3:7])[C:9]([NH:10][CH2:37][CH2:35][OH:36])=[O:28])(=[O:18])=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)[C:9]2=[O:28])=[CH:5][CH:4]=1)#[N:2]
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(S(=O)(=O)Cl)n21
Reactant: CCOC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: C[C@H](NS(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)NCCO
Reaction time: 2 h

Procedure:
To a solution of above amine salt (0.043 g, 0.254 mmol) in anhydrous DMF, was added DMAP (0.037 g, 0.303 mmol). The reaction mixture was stirred at room temperature for 1 h. (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl chloride (0.036 g, 0.073 mmol) was then added to the reaction mixture and stirred for another 2 h. The reaction mixture was diluted with EtOAc and washed with 1 N HCl and saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The residue was purified by silica gel preparative thin layer chromatography to afford 0.035 g of the title compound as a white foam (M+1, 591.1).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][N:7]=1)=[O:5])C.[OH-].[Na+]>CO>[NH:8]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:6]([C:4]([OH:5])=[O:3])=[N:7]1
Reactant: CCOC(=O)c1n[nH]c2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1n[nH]c2c1CCCC2
Yield: 81.8 %

Procedure:
A solution of 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid ethyl ester [0.606 g, Reference Example 18(a)] in methanol (50 ml) was treated with sodium hydroxide (0.500 g). The mixture was refluxed for 16 hours, then cooled and then evaporated. The residual white solid was treated with hydrochloric acid (30 ml, 2N) and the resulting solution was extracted three times with ethyl acetate (50 ml). The combined organic extracts were dried over sodium sulfate and then evaporated to yield 4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (0.424 g) as a white solid. LC-MS (METHOD B): RT=2.44 minutes; 167 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O>>[F:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(F)c1
Reactant: O=S(Cl)Cl
Product: CS(=O)(=O)c1ccc(C(=O)Cl)c(F)c1

Procedure:
A mixture of 2-fluoro-4-methylsulphonylbenzoic acid (6.0 g) and thionyl chloride were stirred and heated at reflux for 2 hours. The mixture was cooled and evaporated to dryness. Toluene was added and the solvent re-evaporated to give 2-fluoro-4-methylsulphonylbenzoyl chloride (6.5 g) as a brown solid which was not further purified.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].[CH2:24](I)[CH3:25]>CS(C)=O>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:24][CH3:25]
Reactant: O=Cc1ccc(F)cc1
Reactant: NCCCCCCO
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCN(CCCCCCO)c1ccc(C=O)cc1
Temperature: 95 °C
Reaction time: 5 h

Procedure:
To a three-neck flask fitted with a mechanical stirrer, a thermometer, and a condenser is added 124.0 g (1 mole) of 4-fluorobenzaldehyde, 117.2 g (1 mole) of 6-amino-1-hexanol, 276.4 g (2 mole) of potassium carbonate, and dimethylsulfoxide. The reaction mixture is heated at 95° C. for about 3 hours until thin-layer chromatography indicates no more 4-fluorobenzaldehyde is present After cooling to room temperature, 156 g (1 mole) of ethyl iodide is added dropwise, and the reaction is stirred at room temperature for 5 hours The solution is poured into a four-fold excess of ice water, and the solid product is collected by filtration and purified by recrystallization from water.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1.[C:12]1([CH:18]([CH3:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCCl.Cl>[CH:18]([C:12]1[CH:17]=[CH:16][C:15]([C:5](=[O:11])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:14][CH:13]=1)([CH3:20])[CH3:19]
Reactant: CC(C)c1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(C)c1ccc(C(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
To a suspension of aluminum (III) chloride (6.7 g, 50.1 mmol) and succinic anhydride (2 g, 20 mmol) in 1,2-dichloroethane was added Cumene (2 g, 16.7 mmol) at 0-5° C. The reaction mixture was stirred at ambient temperature for 16 hours, diluted with 20 mL of aqueous HCl solution (1 M) and extracted with ethyl acetate (3×80 mL). The combined organic phases were washed with saturated sodium chloride (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica-gel (4×20 cm, petroleum ether:ethyl acetate=8:1 elution) to give 3.1 g of compound 76. 1H NMR (CDCl3, 300 MHz) δ 1.27-1.29 (d, 6H), 2.80-2.84 (t, 2H), 2.95-3.00 (m, 1H), 3.29-3.33 (t, 2H), 7.32-7.34 (d, 2H), 7.92-7.94 (d, 2H). MS m/z 221 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:20])=[O:19])=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])(=[O:19])=[O:20])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(-c2ccc(O)cc2)cc1
Yield: 65.3 %

Procedure:
1,1-Dimethylethyl (2-{[(4′-hydroxy-4-biphenylyl)sulfonyl]amino}ethyl)carbamate (246 mg, 65%) was prepared as an off-white solid from (4-hydroxyphenyl)boronic acid (132 mg, 0.96 mmol), 1,1-dimethylethyl (2-{[(4-bromophenyl)sulfonyl]amino}ethyl)carbamate (362 mg, 0.96 mmol), Pd(PPh3)2Cl2 (100 mg, 0.14 mmol), 2M Na2CO3 (2 mL) and DME (4 mL) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.75 (s, 4H), 7.61 (t, 1H, J=5.9 Hz), 7.54 (d, 2H, J=8.6 Hz), 6.84 (d, 2H, J=8.6 Hz), 6.76 (t, 1H, J=5.6 Hz), 2.97-2.89 (m, 2H), 2.76-2.68 (m, 2H), 1.30 (s, 9H); LRMS (ESI), m/z 391 (M−H).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[C:10]([CH:12](OCC)[O:13]CC)[N:9]=[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:7]=1[F:26])([CH3:4])([CH3:3])[CH3:2].OS(O)(=O)=O>CC#N.O>[C:1]([NH:5][C:6]1[C:7]([F:26])=[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:9]=[C:10]([CH:12]=[O:13])[CH:11]=1)([CH3:4])([CH3:2])[CH3:3].[C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(OCC)c1cc(NC(C)(C)C)c(F)c(-c2ccc(Cl)cc2)n1
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: CC(C)(C)N
Product: CC(C)(C)Nc1cc(C=O)nc(-c2ccc(Cl)cc2)c1F
Temperature: 78 °C
Reaction time: 4 h

Procedure:
A mixture of the N-tert-butyl-2-(4-chlorophenyl)-6-(diethoxymethyl)-3-fluoropyridin-4-amine (130 mg, 0.34 mmol) in CH3CN (1 mL) and H2O (1 mL) was treated with 1 M H2SO4 (0.5 mL) resulting in a light yellow solution. The reaction flask was placed in an oil bath and heated to 78° C. After 4 h, an aliquot of the reaction mixture was partitioned between EtOAc and 10% NaHCO3 and analyzed by HPLC. HPLC analysis showed that all of the starting material had been consumed and only a trace of the desired product formed (mainly aldehyde with t-butylamine still intact). After stirring for 20 h at 78° C., HPLC analysis still showed only a trace of the desired product (<2%). The reaction was stopped at this point.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([NH:14]C(C1NC3C(C=1)=CC(C(=O)NCCNC(OC(C)(C)C)=O)=CC=3)=O)[CH:8]=2)=[O:4].[C:39]([O:42][CH2:43][CH2:44][NH:45][C:46]([C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[NH:53][C:52]([C:57]([OH:59])=O)=[CH:51]2)=[O:47])(=[O:41])[CH3:40]>>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([NH:14][C:57]([C:52]1[NH:53][C:54]3[C:50]([CH:51]=1)=[CH:49][C:48]([C:46](=[O:47])[NH:45][CH2:44][CH2:43][O:42][C:39](=[O:41])[CH3:40])=[CH:56][CH:55]=3)=[O:59])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2ccc(NC(=O)c3cc4cc(C(=O)NCCNC(=O)OC(C)(C)C)ccc4[nH]3)cc2[nH]1
Reactant: CC(=O)OCCNC(=O)c1ccc2[nH]c(C(=O)O)cc2c1
Product: COC(=O)c1cc2ccc(NC(=O)c3cc4cc(C(=O)NCCOC(C)=O)ccc4[nH]3)cc2[nH]1

Procedure:
Compound 151 is synthesized as described for compound 39 in Example 33 except instead of compound 3, compound 150 is used.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.N([O-])=O.[Na+].[S:13](=[O:15])=[O:14].[ClH:16]>>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([S:13]([Cl:16])(=[O:15])=[O:14])=[CH:3][CH:4]=1
Reactant: O=S=O
Reactant: Cl
Reactant: Nc1ccc(Cl)nc1
Agent: O=N[O-]
Agent: [Na+]
Product: O=S(=O)(Cl)c1ccc(Cl)nc1
Yield: 58 %

Procedure:
Under ice-cooling, thionyl chloride (12 mL) was added dropwise over 1 hr to water (70 mL) and the mixture was stirred at room temperature for 12 hr to give a sulfur dioxide-containing solution. Separately, under ice-cooling, 5-amino-2-chloropyridine (5.0 g) was added to concentrated hydrochloric acid (40 mL) and the mixture was stirred. An aqueous solution (12.5 mL) of sodium nitrite (2.88 g) was added dropwise while keeping the inside temperature at not higher than 5° C., and the mixture was further stirred for 15 min. The reaction mixture was gradually added at 5° C. to the above-mentioned sulfur dioxide-containing solution added with cuprous chloride (70 mg). Under ice-cooling, the mixture was further stirred for 30 min. The precipitate was collected by filtration, and washed with water and ethanol to give the title compound (yield 4.79 g, 58%).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:11](I)[CH3:12].[CH2:14]([C:18](C)=O)[CH:15]([CH3:17])[CH3:16]>C#CC1C=CC(O)=CC=1.C(OCC)C>[OH:3][C:2]1[CH:4]=[CH:17][C:15]([CH:14]=[CH2:18])=[CH:16][CH:1]=1.[CH2:11]([O:3][C:2]1[CH:4]=[CH:16][C:15]([CH:14]=[CH2:18])=[CH:17][CH:1]=1)[CH3:12]
Reactant: CC(C)=O
Reactant: CCI
Reactant: CC(=O)CC(C)C
Agent: C#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OCC)cc1
Reaction time: 15 h

Procedure:
Into a reaction vessel were charged 21.0 parts of the same poly(p-vinylphenol) as that used in Example 1 and 84 parts of acetone. They were stirred to form a solution Additionally charged were 12.7 parts of anhydrous potassium carbonate and 8.2 parts of ethyl iodide. The temperature was elevated so that the mixture reached to the reflux state. Subsequently, the reflux state was kept for 15 hours After adding methyl isobutyl ketone, the solution was washed with aqueous oxalic acid solution and then with ion-exchanged water. The organic layer after washing was concentrated to 44 parts, combined with 130 parts of propylene glycol monomethyl ether acetate and further concentrated to 63 parts. The solid content of the concentrate measured by weight-loss on heating was 34.19% by weight. By 1H-NMR measurement. it was confirmed that the resin after reaction was a copolymer in which 28.8% of hydroxyl groups in poly(p-vinylphenol) was converted to ethyl ether. The resin was referred to as Resin RB.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH:6]1[CH2:8][CH2:7]1)=[O:4].[P:9]([O:16]CC)([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>>[CH2:11]([O:10][P:9]([CH2:2][C:3](=[O:4])[NH:5][CH:6]1[CH2:8][CH2:7]1)(=[O:16])[O:13][CH2:14][CH3:15])[CH3:12]
Reactant: CCOP(OCC)OCC
Reactant: O=C(CCl)NC1CC1
Product: CCOP(=O)(CC(=O)NC1CC1)OCC
Temperature: 155 °C
Yield: 14.7 %

Procedure:
2-Chloro-N-cyclopropylacetamide (20 g, 0.15 moles) was added in portions with stirring to triethyl phosphite (28 g, 0.17 moles, Aldrich) at 110° C. The solution was then heated to 155° C. for 30 minutes, cooled to 125° C., and the volatiles were removed by distillation under aspirator vacuum (15 mm Hg) at this temperature. The residual oil was stirred with pentane (200 mL) while cooling in an ice bath to induce crystallization. Filtration gave 5.2 g (14%) of diethyl((cyclopropylcarbamoyl)methyl)phosphonate as white crystals; m.p. 51°-56° C. The liquor was concentrated and cooled to give 25.3 g (71%) of a second crop; m.p. 50°-56° C. Recrystallization from dichloromethane/hexanes gave the analytical sample, m.p. 55°-57° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=[O:7])(=[O:3])C.[P:9]([OH:12])([OH:11])[OH:10].P(Cl)(Cl)Cl>>[CH2:1]=[O:3].[P:9]([CH2:1][NH:4][CH2:5][C:6]([OH:8])=[O:7])([OH:12])([OH:11])=[O:10]
Reactant: CC(=O)NCC(=O)O
Reactant: OP(O)O
Solvent: ClP(Cl)Cl
Product: C=O
Product: O=C(O)CNCP(=O)(O)O

Procedure:
In a further embodiment of the present invention, an N-acylglycine is phosphonomethylated to form N-(phosphonomethyl)glycine (I). For example, the reaction of N-acetylglycine (XVIII), phosphorous acid or phosphorous trichloride, and a source of formaldehyde produces N-(phosphonomethyl)glycine (I) (See Reaction Scheme 9).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1)=[O:13].[C:21](Cl)(=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:21](=[O:26])[CH2:22][CH:23]([CH3:25])[CH3:24])=[C:3]([C:12]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=3)=[O:13])[NH:4]2)=[CH:9][CH:8]=1
Reactant: Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12
Reactant: CC(C)CC(=O)Cl
Product: CC(C)CC(=O)Nc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 from 3-amino-6-chloro-2-(4-chloropyridine-2-carbonyl)indole (Example 68) and isovaleryl chloride. m.p.: 183-184° C. (recrystallized from ethyl acetate) 1H-NMR (DMSO-d6) δ: 11.67 (1 H, br s), 10.08 (1 H, br s), 8.69 (1 H, d, J=5.3 Hz), 8.52 (1 H, d, J=9.2 Hz), 8.37 (1 H, d, J=2.1 Hz), 7.57 (1 H, dd, J=2.0, 5.3 Hz), 7.39 (1 H, d, J=2.0 Hz), 7.06 (1 H, dd, J=2.0, 9.6 Hz), 2.46-2.30 (3 H, m), 1.09 (6 H, d, J=6.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].[F:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19](OC)=[O:20].CCCCCC>O1CCCC1>[F:16][C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19](=[O:20])[CH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(F)cc1F
Reactant: Cc1ncccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Cc1ncccn1)c1ccc(F)cc1F
Yield: 16.4 %

Procedure:
Treatment of 2-methylpyrimidine (8.50 g) with lithium diisopropylamide (0.09 mole) in dry tetrahydrofuran followed by methyl 2,4-difluorobenzoate (15.5 g) according to the method of Example 11(i) gave the title compound (3.45 g), m.p. 86°-88° (from hexane).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16].[C@H:27]1([CH2:37][O:38][C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[C@@H:36]2[N:31]([CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:30][CH2:29][CH2:28]1.O>CN(C=O)C>[C@H:27]1([CH2:37][O:38][C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:15]([NH:12][C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:14][CH:13]=3)=[O:16])=[CH:41][CH:40]=2)[C@@H:36]2[N:31]([CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:30][CH2:29][CH2:28]1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(OC[C@@H]2CCCN3CCCC[C@H]23)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OC[C@@H]2CCCN3CCCC[C@H]23)cc1)Nc1ccc(Oc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4-phenoxyaniline (185 mg) in DMF (1 ml) was added dropwise to a solution, cooled to 0° C., of carbonyldiimidazole (162 mg) in DMF (1 ml). After 30 minutes, 4-[(1R,9aR)-1-(octahydroquinolizin-1-yl)-methoxy]-phenylamine (289 mg) in DMF (1 ml) was added dropwise. The reaction solution was kept firstly at room temperature for 2 hours and then at 80° C. for 30 minutes. The mixture was added dropwise to water (20 ml), and the resulting precipitate was filtered off with suction and washed with water. Alternatively, the product can also be extracted with ethyl acetate and purified after concentration by chromatography. The product with the molecular weight of 471.60 (C29H33N3O3); MS (ESI): 472 (M+H+) was obtained in this way.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH:15]C(=O)OC(C)(C)C)[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[CH:28]=[N:27][NH:26][C:25]=3[CH2:24]2)[C:11](=O)[N:10]1[CH3:32].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46].C(Cl)Cl>ClCCl>[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[F:48][C:47]([F:50])([F:49])[C:45]([OH:51])=[O:46].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH2:15])[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[C:25](=[N:26][N:27]([S:41]([CH3:40])(=[O:43])=[O:42])[CH:28]=3)[CH2:24]2)[CH2:11][N:10]1[CH3:32]
Reactant: CS(=O)(=O)Cl
Reactant: CN1C(=O)[C@H](N2Cc3cn[nH]c3C2)C[C@H](NC(=O)OC(C)(C)C)[C@H]1c1cc(F)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C[C@H](N2Cc3cn(S(C)(=O)=O)nc3C2)C[C@H](N)[C@H]1c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl [(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-1-methyl-6-oxopiperidin-3-yl]carbamate (55.5 mg, 0.128 mmol) in dichloromethane (5 mL) at room temperature, triethylamine (0.045 mL, 0.320 mmol) and methanesulfonyl chloride (0.011 mL, 0.147 mmol) were added. The mixture was stirred for 1 h at room temperature. The residue was purified by prep TLC on silica gel, eluting with EtOAc/MeOH/NH4OH (90/9/1) to give first eluting isomer as isomer A and second eluting isomer as isomer B. Isomer A was treated with TFA/CH2Cl2=1:1 for 1 h to give the title compound. (LC-MS: 411.92 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:13]1([C:19]2[CH:32]=[CH:31][C:22]3[C@@H:23]4[C@H:28]([CH2:29][CH2:30][C:21]=3[CH:20]=2)[NH:27][CH2:26][CH2:25][CH2:24]4)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:27]3[C@@H:28]4[C@@H:23]([C:22]5[CH:31]=[CH:32][C:19]([C:13]6[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=6)=[CH:20][C:21]=5[CH2:30][CH2:29]4)[CH2:24][CH2:25][CH2:26]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: c1ccc(-c2ccc3c(c2)CC[C@@H]2NCCC[C@H]32)cc1
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3ccc(-c4ccccc4)cc3CC[C@@H]21
Yield: 29 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-8-phenyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 29% of theory; TLC: rf=0.49 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=408 [M+H]+.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[CH:7]1([N:10]2[C:14]([S:15][CH3:16])=[N:13][N:12]=[C:11]2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:9][CH2:8]1.S([O-])(O)=[O:24].[Na+].[OH2:28]>C(O)(=O)C>[CH:7]1([N:10]2[C:14]([S:15]([CH3:16])(=[O:24])=[O:28])=[N:13][N:12]=[C:11]2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:9][CH2:8]1
Reactant: O
Reactant: O=S([O-])O
Reactant: CSc1nnc(-c2ccncc2)n1C1CC1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Product: CS(=O)(=O)c1nnc(-c2ccncc2)n1C1CC1
Reaction time: 3 h
Yield: 94 %

Procedure:
A solution of potassium permanganate (525 mg, 3.3 mmol) in water (22.0 mL) was added to a solution of 4-(4-cyclopropyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)-pyridine (514 mg, 2.2 mmol) in acetic acid (11 mL) drop-wise at room temperature. After stirring for 3 hours, sodium hydrogen sulfite was added until the purple color was discharged. The reaction mixture was extracted with chloroform and then the organic layer was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated to afford the titled compound (546.7 mg, 94%, white solid). 1H NMR (CDCl3) δ (ppm): 8.86 (d, 2H), 7.77 (d, 2H), 3.64 (m, 1H), 3.63 (s, 3H), 1.25 (m, 2H), 1.01 (m, 2H).