Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[CH:13]1[CH:18]=[C:17]2[C:19]([C:21](O)([OH:24])[C:22](=[O:23])[C:16]2=[CH:15][CH:14]=1)=[O:20]>S(=O)(=O)(O)O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:21]2([OH:24])[C:19](=[O:20])[C:17]3[C:16](=[CH:15][CH:14]=[CH:13][CH:18]=3)[C:22]2=[O:23])=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:4]=1)[CH3:2]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: CCc1cccc(NC(C)=O)c1
Agent: O=S(=O)(O)O
Product: CCc1ccc(C2(O)C(=O)c3ccccc3C2=O)c(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.1 %

Procedure:
N-(3-ethylphenyl)acetamide (500 mg, 3.06 mmol) and ninhydrin (546 mg, 3.06 mmol) were dissolved in conc. sulfuric acid (10 mL) and stirred at room temperature for 3 hrs. The reaction was stopped by slowing pouring the solution to 150 g of ice and stirring. The reaction mixture was extracted with ethylacetate and water, washed with brine. The washed organic layer was dried over sodium sulfate, concentrated in a vacuum, and purified through silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (90 mg, 9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]3[CH:20]=[C:19](I)[N:18]=[CH:17]3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]3[CH:20]=[C:19]([C:26]4[CH:27]=[CH:28][C:23]([NH2:22])=[N:24][CH:25]=4)[N:18]=[CH:17]3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-n2cnc(I)c2)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-n2cnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 4-(3,4-dichloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-methyl-pyridine (example E.84) (0.20 g, 0.47 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.113 g, 0.51 mmol) according to the general procedure VI. Obtained as an off-white solid (0.035 g, 17%). MS (ISP) 396.0 [(M+H)+], 398.1 [(M+2+H)+] and 400 [(M+4+H)+]; mp 245° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([CH2:22][O:23][C:24](=[O:27])[CH2:25]Cl)[C:3]=1[F:28].Cl.[CH3:30][NH:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([CH2:22][O:23][C:24](=[O:27])[CH2:25][N:31]([CH3:32])[CH3:30])[C:3]=1[F:28]
Reactant: Nc1ccc(-c2cc(=O)c3c(N)c(F)c(COC(=O)CCl)c(F)c3o2)cc1F
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
1.50 g (3.63 mmol) of Compound 159 obtained in EXAMPLE 159 was dissolved in 30 mL of dimethylformamide, 1.48 g (18.2 mmol) of dimethylamine hydrochloride and 2.50 g (18.2 mmol) of potassium carbonate were added, and the mixture was stirred at 50° C. for 30 minutes. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane, to give 1.18 g of Compound 161 (yield: 77%). This compound was dissolved in ethyl acetate, 3 mL of a 1N hydrochloric acid/2-propanol solution was added, and the precipitated crystals were collected by filtration, to give a hydrochloride of Compound 161.
Reaction SMILES: [Br:1][C:2]1[S:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Br:1][C:2]1[S:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([Cl:14])[C:4]=2[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2sc(Br)cc12
Product: Clc1ncnc2sc(Br)cc12

Procedure:
6-Bromo-3H-thieno[2,3-d]pyrimidin-4-one (11.64 g, 0.05 mol) was added portion-wise to phosphoryl chloride (220 ml) and the resulting mixture was heated under reflux for 6 hours. The excess phosphoryl chloride was then removed in vacuo. The resulting residue was dissolved in dichloromethane (250 ml) and washed with water (2×100 ml), followed by saturated sodium hydrogen carbonate solution (100 ml). The organic layer was then dried (MgSO4) and the solvent was removed in vacuo to give 6-bromo-4-chlorothieno[2,3-d]pyrimidine (9.06 g) as a yellow solid, which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[NH2:17][CH2:18][C:19]([N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[O:20].C(N(CC)CC)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:17][CH2:18][C:19]([N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[O:20])=[N:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc(-c2ccccc2)nc1Cl
Reactant: CCCN(CCC)C(=O)CN
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)CNc1nc(-c2ccccc2)ncc1[N+](=O)[O-]
Yield: 96.7 %

Procedure:
A mixture of 4-chloro-5-nitro-2-phenylpyrimidine (6.0 g), 2-amino-N,N-dipropylacetamide (6.0 g), triethylamine (5.2 g) and isopropanol (70 ml) is refluxed for six hours. The reaction mixture is concentrated under reduced pressure, and to the residue are added chloroform and water. The chloroform layer is collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from ethanol to give the desired compound (8.8 g), m.p. 142-143° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].[F:19][C:20]([F:27])([F:26])[C:21](=O)[CH2:22][S:23][CH3:24].O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[C:21]([CH2:22][S:23][CH3:24])[C:20]([F:27])([F:26])[F:19])=[O:14])[CH3:2]
Reactant: CSCC(=O)C(F)(F)F
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(CSC)C(F)(F)F
Temperature: 25 °C
Yield: 44.8 %

Procedure:
To a 100 ml volume three-necked flask, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39) (3.04 g) was placed at room temperature, and added dropwise a solution of 1,1,1-trifluoro-3-methylsulfanyl-2-propanone (7-0-2) (2.29 g) in toluene (27 g). After para-toluenesulfonic acid monohydrate (0.028 g) was added, the resulting mixture was stirred under reflux for 45 minutes, and cooled to room temperature. The reaction mixture was poured into water (30 ml), and extracted with ethyl acetate (50 ml) 2 times. The resulting organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (chloroform) to give 2.13 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-2-(1,1,1-trifluoro-3-methylsulfanyl-2-propylidene)-1-methylhydrazine ((4-46)-(1)-39).
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:32].[CH3:41][CH:42]([C:44]1[N:45]=[CH:46][S:47][C:48]=1[CH:49]=O)[CH3:43]>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:32])=[CH:49]/[C:48]1[S:47][CH:46]=[N:45][C:44]=1[CH:42]([CH3:43])[CH3:41]
Reactant: CC(C)c1ncsc1C=O
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1scnc1C(C)C)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.6 %

Procedure:
1,1,3,3-Tetramethylguanidine (41 μL, 0.33 mmol) was added to a solution of rac.-N-[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 141; 75 mg, 0.15 mmol) in tetrahydrofuran (2 mL) at about −25° C. After 5 min, a solution of 4-(1-methylethyl)thiazole-5-carboxaldehyde (Example 56; 26 mg, 0.168 mmol) in tetrahydrofuran (1 mL) was added. The cooling bath was removed and the solution was stirred at room temperature for 17 h. The solvent was evaporated and the residue was partitioned between ethyl acetate (10 mL) and 10% aqueous acetic acid (5 mL). The ethyl acetate layer was washed with brine and each of the aqueous layers was extracted with ethyl acetate (10 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated to give a colorless foam which was triturated with diethyl ether (5 mL). The resulting solids were recovered by filtration to furnish (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[4-(1-methylethyl)thiazol-5-yl]propenoic acid methyl ester (76 mg, 99% yield).
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[N:11]([CH2:14][C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)=[N+:12]=[N-:13]>>[ClH:1].[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[CH2:14][N:11]1[CH:4]=[C:3]([CH2:2][C:5]2[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=2)[N:13]=[N:12]1
Reactant: C#CCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCc1ccco1
Agent: Cl
Product: Nc1nc(Cc2cn(Cc3ccco3)nn2)c[nH]1
Yield: 455.5 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.096 g, 0.061 mmol) was reacted with 2-azidomethyl-furan (0.089 g, 0.729 mmol) following the general procedure for click reactions outlined above to produce 4-(1-Furan-2-ylmethyl-1H-[1,2,3]triazol-4-ylmethyl)-1H-imidazol-2-ylamine hydrochloride (0.078 g, 46%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.93 (s, 1H), δ 7.41 (s, 1H), 6.49 (s, 2H), δ 6.32 (s, 1H), δ 5.56 (s, 2H), δ 3.89 (s, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 146.2, 146.1, 142.4, 141.5, 122.3, 122.2, 108.9, 109.2, 108.8, 51.6, 18.9 ppm; HRMS (ESI) calcd for C11H12N6O (M+) 245.1145. found 245.1147.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH3:13])[C:4]=2[S:5][CH:6]=1.C([Li])CCC.[CH3:19][S:20]SC.Cl>CCCCCC.CCOCC>[CH3:19][S:20][C:6]1[S:5][C:4]2[C:7]([CH2:11][NH:12][CH3:13])=[CH:8][CH:9]=[CH:10][C:3]=2[C:2]=1[Br:1]
Reactant: CSSC
Reactant: CNCc1cccc2c(Br)csc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CNCc1cccc2c(Br)c(SC)sc12
Temperature: 25 °C

Procedure:
To a solution of 2.55 g of N-(3-bromo-7-benzo[b]thienylmethyl)methylamine in abs. ether are added dropwise under inert gas at -70° 13.8 ml (2 equivalents) of a 15% solution of n-butyllithium in n-hexane. 1.9 ml of dimethyldisulfide are then added slowly at -70° and the reaction mixture gradually warmed to room temperature. It is then poured into ice-cooled 2N HCl, shaken and the acid phase separated, made alkaline with NaOH and extracted with ether. The ether phase is dried, concentrated under vacuum and the oil thus obtained directly further reacted.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.Cl[CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:12][CH2:11][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]3[CH2:26][CH2:27][CH2:28][S:29]3(=[O:31])=[O:30])=[CH:3][C:4]=2[CH3:24])=[O:9])[CH2:15][CH2:14]1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3C)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C)CC2)c(C)c1

Procedure:
Using (4-amino-2-methylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (833 mg) described in Preparation Example 148 and 3-chloropropane-1-sulfonyl chloride (0.42 mL) and by the reaction and treatment in the same manner as in Example 78, the title compound (624 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[CH:8](=O)[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:11]>>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[OH:11])=[N:5][N:6]=1
Reactant: O=Cc1ccccc1O
Reactant: Cc1nnc(C)s1
Product: Cc1nnc(C=Cc2ccccc2O)s1
Temperature: 150 °C
Reaction time: 30 h

Procedure:
570 g (5 moles) of 2,5-dimethyl-1,3,4-thiadiazole and 275 g (2.5 moles) of salicylaldehyde are mixed and the mixture is slowly heated to 150° C. whilst passing nitrogen through it. The mixture is kept at 150° C. for 30 hours and is then cooled, the excess 2,5-dimethyl-1,3,4-thiadiazole is distilled off and the residue is recrystallized from methylglycol. 304 g (56% of theory) of yellow crystals of melting point 253°-254° are obtained.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].[Cl:13][C:14]1[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=1>C(O)C>[Cl:13][C:14]1[C:19]([O:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=2)=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: Clc1nccnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1cccc(Oc2nccnc2Cl)c1
Yield: 46 %

Procedure:
In a 250-ml single-necked, round-bottomed flask containing a solution of 3.0 g (75 mmol) of sodium hydroxide in 100 ml of absolute ethanol was added 9.28 g (67 mmol) of 3-nitrophenol at which point the solution turned dark red. To the dark red solution, 10.0 g (66 mmol) of 2,3-dichloropyrazine was added and the resulting solution refluxed for 162 hours. The reaction mixture was cooled and concentrated. Upon pouring the concentrate into approximately 300 ml of water, an off-white solid precipitated which was collected by filtration. Recrystallization from absolute ethanol gave the product, 2-chloro-3-(3-nitrophenoxy)pyrazine, (46% yield) as white needles, mp 119°-121° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[NH:9])=[N:6][CH:7]=1.C([O:13][C:14](=O)[CH2:15][C:16]([CH3:18])=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:10]=[C:14]([OH:13])[CH:15]=[C:16]([CH3:18])[N:9]=2)=[N:6][CH:7]=1
Reactant: N=C(N)c1ccc(N)cn1
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(O)nc(-c2ccc(N)cn2)n1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a solution of compound of example 12 (0.4 g, 2.9 mmol) in water (10 mL) and ethanol (5 mL) was added ethylacetoacetate (0.611 g, 4.7 mmol) and sodium carbonate (0.561 g, 5.29 mmol) and mixture was stirred at room temperature for about 25 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate (3×30 mL). Ethyl acetate layer was dried over anhydrous sodium sulfate and was concentrated to obtain a crude product, which was purified by column chromatography (silica gel, 6% methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]2[CH2:29][N:30]([CH2:33][C:34]3([CH3:38])[CH2:37][O:36][CH2:35]3)[C:31](=[O:32])[C:26]2=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[N:28]=[C:27]3[CH2:29][N:30]([CH2:33][C:34]4([CH3:38])[CH2:35][O:36][CH2:37]4)[C:31](=[O:32])[C:26]3=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC1(CN2Cc3nc(Cl)ccc3C2=O)COC1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC1(CN2Cc3nc(Nc4sc(-c5c(F)cc(C(C)(C)O)cc5F)cc4C(N)=O)ccc3C2=O)COC1

Procedure:
The title compound was prepared according to the general procedure in Example 1 Step 5 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (130 mg, 0.42 mmol) and 2-chloro-6-[(3-methyloxetan-3-yl)methyl]-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (100 mg, 0.40 mmol) as the starting materials.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.CO[CH:14](OC)[CH2:15][C:16](=O)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:15][C:16]([CH3:17])=[N:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(NN)cc1
Reactant: COC(CC(C)=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(-n2ccc(C)n2)cc1

Procedure:
A mixture of 17 parts of (4-methoxyphenyl)hydrazine hydrochloride, 14 parts of 4,4-dimethoxy-2-butanone, 14 parts of potassium carbonate and 240 parts of ethanol is stirred and refluxed for 2 hours. The reaction mixture is evaporated and the residue is stirred and refluxed for 1 hour with 200 parts of a hydrochloric acid solution 10%. The solvent is evaporated and the residue is neutralized with ammonium hydroxide. The product is extracted three times with 2,2'-oxybispropane. The combined extracts are washed with water, dried, filtered and evaporated. The residue is purified by columnchromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from hexane. The product is filtered off and dried, yielding 2.4 parts of 1-(4-methoxyphenyl)-3-methyl-1H-pyrazole.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I:12]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>FC(F)(F)S(O)(=O)=O>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(O)c1cccc(F)c1F
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1cc(I)cc(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
2,3-Difluorobenzoic acid (5.0 g, 31.6 mmol) was dissolved in trifluoromethanesulfonic acid (25 ml), and N-iodosuccinimide (8.55 g, 38.0 mmol) was added by portions at 0° C. under an argon stream. The mixture was stirred at room temperature for 3 hrs., and the reaction solution was poured into sodium sulfite in ice water. The mixture was stirred and the precipitate was collected by filtration, washed with water and vacuum-dried to give an object product (7.5 g, yield 84%) as a pale-pink solid.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=2[F:23])[CH2:10][CH2:9]1)=O)(C)(C)C.F[C:25]1C=C(C=CC=1OC1CCNCC1)C#N>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=2[F:23])[CH2:10][CH2:9]1)(=[O:5])[CH3:25]
Reactant: N#Cc1ccc(OC2CCNCC2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2F)CC1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N1CCC(Oc2ccc(C#N)cc2F)CC1

Procedure:
Synthesized from 4-(4-cyano-2-fluorophenoxy)piperidine-1-carboxylic acid tert-butyl ester (2.8 g) according to an analogous synthetic method to Example 215 described below, the total amount of 3-fluoro-4-(piperidin-4-yloxy)benzonitrile crude product was dissolved in acetic anhydride (30 ml) and pyridine (30 ml), and the solution was stirred overnight at room temperature. The solvent was evaporated in vacuo, the solution was extracted with ethyl acetate, then sequentially washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (2.2 g).
Reaction SMILES: [OH:1][C:2]1[C:9]([Br:10])=[CH:8][C:7]([F:11])=[C:6]([Cl:12])[C:3]=1[CH:4]=O.[Br-].Br[CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+]>O1CCCC1.CCCCCC>[Cl:12][C:6]1[C:3]2[CH:4]=[CH:15][O:1][C:2]=2[C:9]([Br:10])=[CH:8][C:7]=1[F:11]
Reactant: O=Cc1c(O)c(Br)cc(F)c1Cl
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Fc1cc(Br)c2occc2c1Cl
Temperature: 0 °C
Yield: 84.4 %

Procedure:
A suspension of 49.2 gm (0.19 mole) 2-hydroxy-3-bromo-5-fluoro-6-chlorobenzaldehyde and 127 gm (0.29 mole) (bromomethyl)triphenylphosphonium bromide in 230 mL tetrahydrofuran was cooled to 0° C. under a nitrogen atmosphere. To this were added dropwise 330 mL (0.33 mole) potassium tert-butoxide (1M in tetrahydrofuran) over 3 hours. An additional 90 mL (0.09 mole) potassium tert-butoxide (1M in tetrahydrofuran) were then added to react remaining starting material. The reaction mixture was diluted with 700 mL of hexane and the resulting precipitate removed by filtration. The recovered solid was slurried in 300 mL hexane and filtered 4 times. The combined filtrates were washed with 2×500 mL water followed by 500 mL saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure to provide a residual solid. This solid was slurried and filtered with 4×300 mL diethyl ether to remove triphenylphosphine oxide. The filtrates were concentrated and the residue subjected to silica gel chromatography, eluting with hexane. Fractions containing product were combined and concentrated under reduced pressure to provide 40 gm (83%) of the title compound as a white solid.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[C@H:8]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH3:36])[CH:30]=2)[CH2:7]1.C(N(CC)CC)C.[CH3:44][S:45]([Cl:48])(=[O:47])=[O:46]>ClCCl>[ClH:48].[F:22][C:19]([F:21])([F:20])[C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([C:23]([F:24])([F:26])[F:25])[CH:16]=1)[C:12]([N:9]1[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][NH:3][S:45]([CH3:44])(=[O:47])=[O:46])[CH2:7][C@H:8]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([CH3:36])[CH:30]=1)=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C[C@@H]2CN(CCN)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C[C@@H]2CN(CCNS(C)(=O)=O)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of (2R)-4-(2-aminoethyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine dihydrochloride (110 mg), triethylamine (0.2 ml) in dichloromethane (10 ml) was added methanesulfonyl chloride (0.1 ml) at 0° C. After stirring for 1 hour, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed successively with aqueous saturated sodium bicarbonate solution and brine, and dried. After evaporation of the solvent in vacuo, the residue was purified by column chromatography on a silica gel eluting with a mixture of dichloromethane and methanol (40:1) and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[2-(mesylamino)ethyl]piperazine hydrochloride (50 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][NH2:5].[CH3:11][O:12][CH:13]([O:18][CH3:19])[C:14](OC)=[O:15]>CCCCCCC>[Cl:10][C:7]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[CH2:4][NH:5][C:14](=[O:15])[CH:13]([O:18][CH3:19])[O:12][CH3:11]
Reactant: NCc1cc(Cl)ccc1F
Reactant: COC(=O)C(OC)OC
Solvent: CCCCCCC
Product: COC(OC)C(=O)NCc1cc(Cl)ccc1F
Temperature: 25 °C

Procedure:
Equimolar amounts of 2-fluoro-5-chlorobenzylamine (10.0 g, 62.5 mmol) and methyl dimethoxyacetate (8.38 g, 62.5 mmol) were heated in a sealed tube at 100° C. for 16 h. After cooling to RT, to the reaction mixture was added n-heptane (40 mL) and cooled at 4° C. overnight. The solid formed was filtered off and dried in vacuo to give the title compound as off-white solid. 1H NMR (CDCl3, 300 MHz): δ=3.40 (s, 6H), 4.52 (d, J=5.8 Hz, 2H), 4.74 (s, 1H), 6.89 (bs, 1H), 7.01 (t, J=8.4 Hz, 1H), 7.20-7.25 (m, 1H), 7.31-7.36 (m, 1H). MS (ES+): m/z 261.90/263.78 [MH+]. HPLC: tR=2.85 min (ZQ2, polar—5 min).