Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5]1([CH3:16])[CH:9]=[CH:8][C:7](=[O:10])[CH:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=O)C.S(=O)(=O)(O)[OH:18]>O1CCCC1>[OH:18][CH:9]1[CH2:8][C:7](=[O:10])[C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:5]1[CH3:16]
Reactant: O=S(=O)(O)O
Reactant: CCCCCC1C(=O)C=CC1(C)OC(C)=O
Solvent: C1CCOC1
Product: CCCCCC1=C(C)C(O)CC1=O

Procedure:
In the same flask as in Example 1, there were charged 3-acetoxy-2-n-pentyl-3-methyl-4-cyclopentenone (2.24 g), tetrahydrofuran (10 ml) and 20% sulfuric acid (10 ml), and the resultant mixture was stirred at 30° to 50° C. for 6 hours. After completion of the reaction, the reaction mixture was subjected to post-treatment and purification as in example 1 to give 1.55 g of 4-hydroxy-2-n-pentyl-3-methyl-2-cyclopentenone. Yield, 85%.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)[OH:10].[O:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:24]([NH2:42])=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=3)[CH2:19][CH2:18]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:42][C:24]1[C:23]([N:20]2[CH2:21][CH2:22][O:17][CH2:18][CH2:19]2)=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:2]3[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=3[CH:9]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)[OH:10])[CH:30]=2)[N:25]=1
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Reactant: Cc1cccc(C(O)c2cnccn2)c1Br
Agent: [Pd]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(CCC)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(C(O)c2cnccn2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 140 °C

Procedure:
A mixture of (2-bromo-3-methylphenyl)(pyrazin-2-yl)methanol (0.295 g, 1.056 mmol), 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.25 g, 0.704 mmol, prepared as Example 2, Step 1-2), potassium phosphate tribasic (0.291 mL, 3.52 mmol), Pd2(dba)3 (0.064 g, 0.070 mmol), and 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.067 g, 0.141 mmol) in dioxane/water (3/1.5 mL) was heated in a microwave for 12 min at 140° C. The mixture was concentrated and chromatographed on silica gel using 0-5% 2M NH3 in MeOH/DCM to afford a brown oil which was re-purified by HPLC to afford (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(pyrazin-2-yl)methanol as a yellow solid. MS (ESI, pos. ion) m/z: 428 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[C:5]([NH:7][CH2:8][C@@H:9]([C:31]([OH:33])=[O:32])[NH:10][C:11](=[O:30])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)=[O:19])=[CH:14][C:13]=1[Cl:29])=[O:6].ClC1C=CC=CC=1C(NC[C@@H](C(O)=O)NC(=O)C1C=CC(C(NCC2C=CC=C(O)C=2)=O)=CC=1Cl)=O.ClC1C=C(C=CC=1)C(NC[C@@H](C(O)=O)NC(=O)C1C=CC(C(NCC2C=CC=C(O)C=2)=O)=CC=1Cl)=O.ClC1C=CC(C(NC[C@@H](C(O)=O)NC(=O)C2C=CC(C(NCC3C=CC=C(O)C=3)=O)=CC=2Cl)=O)=CC=1.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)C1C=CC=C(F)C=1)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)C1C=CC=C(I)C=1)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)C1C=C(F)C=C(F)C=1)=O.ClC1C=C(C=C(F)C=1)C(NC[C@@H](C(O)=O)NC(=O)C1C=CC(C(NCC2C=CC=C(O)C=2)=O)=CC=1Cl)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)C1C=C(Cl)C=C(Cl)C=1)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)C1C=C([Br:344])C=C(Br)C=1)=O.ClC1C=C(C(NCC2C=CC=C(O)C=2)=O)C=CC=1C(N[C@H](C(O)=O)CNC(=O)C1C=C(F)C(F)=CC=1F)=O>>[Br:344][C:34]1[CH:35]=[CH:36][CH:2]=[CH:3][C:4]=1[C:5]([NH:7][CH2:8][C@@H:9]([C:31]([OH:33])=[O:32])[NH:10][C:11](=[O:30])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)=[O:19])=[CH:14][C:13]=1[Cl:29])=[O:6]
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cc(Br)cc(Br)c2)C(=O)O)c(Cl)c1
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccc(Br)c2)C(=O)O)c(Cl)c1
Agent: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cc(Cl)cc(Cl)c2)C(=O)O)c(Cl)c1
Agent: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cc(F)c(F)cc2F)C(=O)O)c(Cl)c1
Agent: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cc(F)cc(Cl)c2)C(=O)O)c(Cl)c1
Product: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2ccccc2Br)C(=O)O)c(Cl)c1

Procedure:
3-(3-bromobenzoyl)amino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine; 3-(2-chlorobenzoyl)amino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine; 3-(3-chlorobenzoyl)amino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine; 3-(4-chlorobenzoyl)amino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(3-fluorobenzoyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(3-iodobenzoyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(3,5-difluorobenzoyl)amino-L-alanine; 3-(3-chloro-5-fluorobenzoyl)amino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(3,5-dichlorobenzoyl)amino-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(3,5-dibromobenzoyl)amino-L-alanine); N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(2,4,5-trifluorobenzoyl)amino-L-alanine).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1Br.[C:13]([Cu])#[N:14].O.N>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[C:13]#[N:14]
Reactant: COC(=O)c1cc(N)ccc1Br
Reactant: N#C[Cu]
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(N)ccc1C#N
Temperature: 150 °C

Procedure:
The mixture of 5-amino-2-bromobenzoic acid methyl ester (14.27 g, 62.0 mmol) and CuCN (6.11 g, 68.2 mmol) in DMF (130 ml) was heated at 150° C. for 1 h 10 min under nitrogen atmosphere. The mixture was cooled to 70° C. and poured into the mixture of water (250 ml) and 12.5% NH3 (500 ml). The product was extracted into ethyl acetate (3×250 ml). The organic phase was washed several times with 12.5% NH3 and water, dried over Na2SO4 and concentrated under vacuum.
Reaction SMILES: O.[OH-].[Li+].[N:4]1([CH2:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([C:19]([O:21]CC)=[O:20])[CH:10]=2)[CH2:7][CH2:6][CH2:5]1.[ClH:24].C(#N)C>O1CCCC1.O>[ClH:24].[ClH:24].[N:4]1([CH2:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([C:19]([OH:21])=[O:20])[CH:10]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)c1cc(CN2CCC2)nc(C(F)(F)F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(CN2CCC2)nc(C(F)(F)F)n1
Reaction time: 0.25 h

Procedure:
Lithium hydroxide, monohydrate (108 mg, 2.57 mmol) was added to a mixture of ethyl 6-(azetidin-1-ylmethyl)-2-(trifluoromethyl)pyrimidine-4-carboxylate (0.34 g, 1.2 mmol, from Step A) in tetrahydrofuran (6.0 mL) and water (1.5 mL). After 15 minutes, the THF was removed in vacuo and the mixture was treated with 1.0M hydrogen chloride in water (5.3 mL, 5.3 mmol), and acetonitrile (7.0 mL). The mixture was then filtered and concentrated to afford the product as a yellow solid. LCMS (M+H)+: 262.1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:16])([CH3:15])[O:9][SiH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[C:4]([C:17]([CH3:25])([CH3:24])[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[CH3:26][N:27](C)C=O>C1(C)C=CC=CC=1.[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:20]([SiH2:19][O:18][C:17]([CH3:25])([CH3:24])[C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([C:8]([CH3:16])([CH3:15])[O:9][SiH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1)[C:26]#[N:27])([CH3:23])([CH3:22])[CH3:21]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(Br)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
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]
Solvent: Cc1ccccc1
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(C#N)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
Temperature: 80 °C
Yield: 82 %

Procedure:
To a solution of 1-bromo-3,5-bis-(tert-butyl-dimethyl-silanyloxymethyl)-benzene (2.05 g, 4.601 mmol, example 35) in dimethylformamide (8 mL) at room temperature was added zinc cyanide (324 mg, 2.761 mmol). The reaction mixture was degassed by passing argon through for 1 h before tetrakis(triphenylphosphine)palladium (319 mg, 0.276 mmol) was added. The reaction mixture was heated at 80° C. under argon for 12 h. The reaction mixture was taken up in toluene (40 mL) and washed with 2 N ammonium hydroxide (2×40 mL), brine and dried over anhydrous magnesium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 5% ethyl acetate in hexanes yielded 3,5-bis-(tert-butyl-dimethyl-silanyloxymethyl)-benzonitrile (1.47 g, 82%).
Reaction SMILES: COC[N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[C:16]3[CH:20]=[O:21])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:22]=[CH:23][CH:24]=[N:25][C:5]1=2.C([OH:28])C.[OH-].[Na+]>O1CCCC1.[N+]([O-])([O-])=O.[Ag+]>[N:25]1[C:5]2[NH:4][C:9]3[CH:10]=[C:11]([CH2:14][N:15]4[CH:19]=[CH:18][N:17]=[C:16]4[C:20]([OH:28])=[O:21])[CH:12]=[CH:13][C:8]=3[S:7][C:6]=2[N:22]=[CH:23][CH:24]=1
Reactant: CCO
Reactant: COCN1c2cc(Cn3ccnc3C=O)ccc2Sc2nccnc21
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)c1nccn1Cc1ccc2c(c1)Nc1nccnc1S2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 177 mg of 1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-2-carbaldehyde in a mixture of tetrahydrofuran (10 ml) with ethanol (10 ml) were added 0.5 ml of an aqueous solution of 0.24 g of silver nitrate and 1.5 N sodium hydroxide (4 ml) and the resulting mixture was stirred at room temperature for 15 hours. After filtering off the insoluble matters, the solution was concentrated under reduced pressure and the crystals of 1-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)imidazol-2-carboxylic acid thus precipitated were taken up by filtration. Next, the crystals were treated by the same method as the one of Example 9 to thereby give 55 mg of the title compound as orange crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](I)=[C:5]([O:10][CH3:11])[C:4]=1[O:12][CH3:13].C([Li])CCC.[CH3:19][N:20]([CH3:32])[C:21]1[CH:30]=[C:29]2[C:24]([C:25](=O)[CH2:26][CH2:27][O:28]2)=[CH:23][CH:22]=1.[NH4+].[Cl-].Cl>C1COCC1.CCOC(C)=O.C(O)C>[CH3:19][N:20]([CH3:32])[C:21]1[CH:30]=[C:29]2[C:24]([C:25]([C:7]3[CH:8]=[C:3]([O:2][CH3:1])[C:4]([O:12][CH3:13])=[C:5]([O:10][CH3:11])[CH:6]=3)=[CH:26][CH2:27][O:28]2)=[CH:23][CH:22]=1
Reactant: CN(C)c1ccc2c(c1)OCCC2=O
Reactant: COc1ccc(I)c(OC)c1OC
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C2=CCOc3cc(N(C)C)ccc32)cc(OC)c1OC
Reaction time: 0.17 h

Procedure:
To a solution of trimethoxyiodobenzene (159 mg, 0.54 mmol) in THF (2.5 mL) at −78° C. was added n-butyl lithium solution (1.6 M in hexane, 0.34 mL). The reaction mixture was stirred 10 min, then a solution of 7-dimethylamino-chroman-4-one (103 mg, 0.54 mmol) in THF (2.5 mL) was added and stirring continued at −78° C. for 1 h followed by room temperature overnight. The reaction became orange, NH4Cl saturated solution (1 mL) was added and the mixture was diluted with EtOAc (25 mL). The organic layer was washed with water (25 mL), brine (25 mL), dried over magnesium sulfate and concentrated to yield a yellow oil. The residue was dissolved in ethanol (6 mL) and treated with concentrated hydrochloric acid (2 mL). The mixture was heated to reflux for 90 min, allowed to cool, diluted with EtOAc (25 mL) and washed with water (2×25 mL), 10% sodium thiosulfate (25 mL) and water (25 mL). The organic layer was dried over MgSO4 and concentrated to yield a yellow oil. Purification by Biotage flash chromatography using 50% EtOAc/hexane gave a mixture of compounds. Another purification was done using 20% EtOAc/hexane and yielded 30 mg (16%) as a green oil. 1H NMR (CDCl3): 6.97 (d, J=8.5 Hz, 1H), 6.59 (s, 2H), 6.35-6.25 (2m, 2H), 5.61 (s, 1H), 4.82 (d, J=4.0 Hz, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 2.99 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[S:16][C:15]([C:18]([NH:20][C@@H:21]4[CH:26]5[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]5)[CH2:22]4)=[O:19])=[CH:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]([Cl:36])=[O:35]>>[ClH:36].[N:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([NH:20][C:18]([C:15]1[S:16][C:17]3[C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([NH:2][C:34]([C:30]5[O:29][CH:33]=[CH:32][CH:31]=5)=[O:35])[CH:4]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=1)=[O:19])[CH2:22]2
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Agent: Cl
Product: O=C(Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1)c1ccco1

Procedure:
50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride (Example 21) and 31.5 mg (0.24 mmol) of furan-2-carbonyl chloride are reacted together by general method F. 29.1 mg (51.1% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[CH3:28][C:29]([NH2:32])([CH3:31])[CH3:30]>>[CH3:28][C:29]([NH:32][C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[N:20][CH:21]=1)=[O:24])([CH3:31])[CH3:30]
Reactant: CC(C)(C)N
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC(C)(C)C)cn2)CC1
Yield: 82 %

Procedure:
By the same procedure as described example 24, the synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using 2-methyl-2-propaneamine. And then, the product was recrystallized with isopropanol to give a desired compound.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][NH:20][CH2:19][CH:18]4[CH:22]=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[S:7]1(=[O:25])=[O:24].[F:27][C:28]([F:35])([F:34])[C@@H:29]([OH:33])[C:30](O)=[O:31].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[F:26][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][N:20]([C:30](=[O:31])[C@H:29]([OH:33])[C:28]([F:35])([F:34])[F:27])[CH2:19][CH:18]4[CH:22]=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[S:7]1(=[O:25])=[O:24]
Reactant: O=C(O)[C@H](O)C(F)(F)F
Reactant: CN1c2nc(C3=CC4CNCC4C3)ccc2N(CC2CC2(F)F)S1(=O)=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1c2nc(C3=CC4CN(C(=O)[C@H](O)C(F)(F)F)CC4C3)ccc2N(CC2CC2(F)F)S1(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-[(2,2-Difluorocyclopropyl)methyl]-5-(1,2,3,3a,4,6a-hexahydrocyclo-penta-[c]pyrrol-5-yl)-3-methyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (24-2, 0.79 g, 2.1 mmol, 1.0 equiv), (2S)-3,3,3-trifluoro-2-hydroxypropanoic acid (24-3, 0.30 g, 2.1 mmol, 1.0 equiv), EDC (0.40 g, 2.1 mmol, 1.0 equiv), HOBT (0.32 g, 2.1 mmol, 1.0 equiv) and triethylamine (0.58 mL, 4.2 mmol, 2.0 equiv) were added to anhydrous DMF (13.6 mL) and stirred at RT. After 18 h, the contents were partitioned between ethyl acetate (50 mL) and saturated NaHCO3 (20 mL). The layers were separated and the aqueous layer was back-extracted with ethyl acetate (2×20 mL). The combined organics were washed with H2O (5×20 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a dark red oil. Purification by normal-phase chromatography (0-60% EtOAc:Hex) afforded 24-4 as a white solid. MS m/z (M+H): calculated=509.1276; observed=509.1281.
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])(=[O:13])=[O:12])[C:5]=2[O:4][C:3]1=[O:21].[OH-:22].[K+]>CO>[OH:4][C:5]1[C:10]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])(=[O:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:2]([CH3:1])[C:3]([OH:21])=[O:22]
Reactant: [OH-]
Reactant: CC1C(=O)Oc2c1cccc2S(=O)(=O)c1ccccc1Cl
Agent: [K+]
Solvent: CO
Product: CC(C(=O)O)c1cccc(S(=O)(=O)c2ccccc2Cl)c1O

Procedure:
3-Methyl-7-(2-chlorobenzenesulfonyl)-2,3-dihydrobenzofuran-2-one was treated with potassium hydroxide in methanol in a similar manner to that of Example 21-(10) to give 2-[2-hydroxy-3-(2-chlorobenzenesulfonyl)phenyl]propionic acid, mp. 180°-181° C.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=2[CH:10]=[C:9]1[CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=O)(C)(C)C.C(C(O)=O)(F)(F)F>C(Cl)Cl>[NH:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[CH:10]=[C:9]1[CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCc2c(cc(CC(=O)OCc3ccccc3)n2C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Cc1cc2c([nH]1)CCNC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 5 ml of methylene chloride was dissolved 0.11 g (0.20 mmol) of benzyl 1-t-butoxycarbonyl-5-t-butoxycarbonyl-4,5,6,7-tetrahydropyrrolo [3,2-c]pyridin-2-acetate, and under ice-cooling, 1 ml of CF3CO2H was added to the solution and the resulting mixture was stirred at room temperature for one hour.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:9]=1.Cl>O1CCCC1>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([CH2:12][OH:13])=[C:10]([O:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[CH:9]=1
Reactant: O=C(O)c1ccc(Br)cc1OC1CCCCC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc(Br)cc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 57.4 %

Procedure:
To a suspension of lithium aluminum hydride (2.54 g) in tetrahydrofuran (50 ml) was added dropwise a solution of 4-bromo-2-(cyclohexyloxy)benzoic acid (10 g) in tetrahydrofuran (50 ml) at 5° C. under nitrogen, and the mixture was stirred at room temperature for 2.5 hours. The resulting mixture was poured into 1N hydrochloric acid and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, aqueous-sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=10:1 to 5:1) to give (4-bromo-2-cyclohexyloxyphenyl)methanol (5.47 g).
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][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: C1COCCN1
Reactant: Clc1cc(Cl)n2nc(-c3ccccc3)cc2n1
Solvent: C1COCCO1
Product: Clc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
There was dissolved, in 1,4-dioxane (4 mL), 5,7-dichloro-2-phenyl-pyrazolo-[1,5-a]pyrimidine (168 mg, 0.637 mM), morpholine (111 μL, 1.27 mM) was added to the resulting solution and the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off from the reaction mixture, the resulting residue was diluted with water and then extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting solid was washed with methanol to thus obtain the title compound (200 mg, yield: 100%).
Reaction SMILES: [CH2:1]([CH:8]([NH:22][C:23]([C:25]1[CH:34]=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)=[O:24])[CH:9]([OH:21])[CH2:10][CH:11]([C:18](=[NH:20])[NH2:19])[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[NH2:20][C:18](=[N:19][S:43]([CH3:42])(=[O:45])=[O:44])[CH:11]([CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[CH2:10][CH:9]([OH:21])[CH:8]([NH:22][C:23]([C:25]1[CH:34]=[N:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)=[O:24])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=N)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(N)=NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1.0 equivalents of quinoxaline-2-carboxylic acid (1-benzyl-4-carbamimidoyl-7-fluoro-2-hydroxy-7-methyl-octyl)-amide in methylene chloride is added 1.0 equivalents of triethylamine followed by 1.0 equivalents of methanesulfonyl chloride. The reaction is stirred at ambient temperature for approximately 5 hours. After standard aqueous work-up and extraction, followed by concentration and silica gel chromatography the title compound is obtained.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1)=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccc(F)c(F)c3)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1ccc(F)c(F)c1

Procedure:
The 2-trifluoroacetamido-3-(3,4-difluorophenyl)-6-benzoyl-imidazo[1,2-a]pyridine (7.44 g, 16.7 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 5.09 g. (87.2%). EA, MS(FD).
Reaction SMILES: [C:1]1([C@@H:7]([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH:27]([S:30](Cl)(=[O:32])=[O:31])([CH3:29])[CH3:28]>CCCCCC.C(Cl)Cl>[C:1]1([C@@H:7]([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([C@@H:7]([CH3:10])[CH2:8][NH:9][S:30]([CH:27]([CH3:29])[CH3:28])(=[O:32])=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)S(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Agent: C[C@@H](CN)c1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)NC[C@H](C)c1ccccc1
Reaction time: 0.75 h
Yield: 180.3 %

Procedure:
To a solution of the (2R)-2-phenylpropylamine (1.2 g, 8.87 mmol) in hexane (16.0 mL) was added triethylamine (2.47 mL, 17.74 mmol) and is dimethylaminopyridine (0.30 g, 2.47 mmol). Cooled reaction to 5° C., then added a solution of isopropylsulfonyl chloride (0.97 mL, 8.69 mmol) dissolved in methylene chloride (6.0 mL) over a period of 15.0 minutes. Stirred for 45.0 minutes, then stirred at room temperature for 120.0 minutes. Quenched reaction with 1N HCl (20.0 mL) and extracted organic with methylene chloride (25.0 mL). Dried organic layer with anhydrous magnesium sulfate, filtered and concentrated filtrate to provide the final title compound, ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine, (1.93 g, 90.1%) an oil; 1H nmr (CDCl3, 300 MHz) δ 1.25 (d, 3H, J=6.9 Hz), 1.29(d, 3H, J=6.9 Hz), 1.30 (d, 3H, J=7.2 Hz), 2.98 (m, 1H), 3.05 (m, 1H), 3.22 (m, 1H), 3.36 (m, 1H), 3.89 (b, 1H), 7.23 (m, 2H), 7.34 (m, 2H).