Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].Br[CH2:18][CH2:19][Cl:20]>CS(C)=O>[Cl:20][CH2:19][CH2:18][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: ClCCBr
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: ClCCN1CCN(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.2 %

Procedure:
A mixture of (3,4-dichlorophenyl)piperazine (500 mg) and powdered sodium hydroxide (87 mg) in DMSO (5 mL) was treated with 2-bromo-1-chloroethane (387 mg) and stirred at ambient temperature for 16 hours. The reaction was poured into ice cold water (15 mL) and stirred for 0.5 hours. A solid mass formed and was separated by decanting the water. The aqueous layer was extracted with dichloromethane (5 mL). The solid mass was dissolved with dichloromethane (5 mL) and the combined organics were dried with sodium sulfate, filtered and the solvent removed under vacuum. Flash chromatography (dichloromethane:methanol 1:0 to 10:1) yielded an oil (230 mg) as the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:21][OH:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](N1C=CN=C1)([N:25]1C=CN=C1)=[O:24].N.O>C1COCC1>[C:23]([O:22][CH2:21][C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])(=[O:24])[NH2:25]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(N[C@H](CO)Cc1cccc(F)c1)OCc1ccccc1
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)OC[C@H](Cc1cccc(F)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
In a 100 mL flask equipped with magnetic stirrer, N-benzyloxycarbonyl-m-fluorophenylalaninol (0.007 mole, 2.12 g) was dissolved in 50 ml of THF and was added with 1,1'-carbonyl diimidazole (0.007 mol, 1.14 g) at 0° C. The reaction mixture was stirred at room temperature for 2 hours, followed by the injection of ammonia at 0° C. for 30 min. Following elevating to room temperature, water was added to terminate the reaction. The organic layer was extracted 3 times with dichloromethane, dried over magnesium sulfate and distilled in vacuo, to give a solid. This was recrystallized in a solution mixture of n-hexane and diethyl ether, to produce 2.18 g of O-carbamoyl-N-benzyloxycarbonyl-m-fluorophenylalaninol: Yield 91%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].O.[C:8]([NH:15][C@H:16]([C:21]([OH:23])=O)[CH2:17][CH:18]([CH3:20])[CH3:19])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[C:8]([NH:15][C@H:16]([C:21]([CH2:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6])=[O:23])[CH2:17][CH:18]([CH3:19])[CH3:20])([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COCCCN
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)COCCCN

Procedure:
In substantially the same manner as Working Example 2, 3-methoxypropylamine (6.1 ml, Wako Pure Chemical Industries, Ltd.) was condensed with Boc-L-leucine monohydrate (5.00 g, manufactured by Peptide Institute, Inc.) to afford N-(Boc-L-leucyl)methoxypropylamine (17.5 g) as a colorless waxy product (yield 89%). The Boc group was deprotected by using TFA, and 1.21 g of the resultant compound was condensed, in substantially the same manner as Working Example 2, with (2S,3S)-ethyl hydrogen N-Z-aziridine-2,3-dicarboxylate (Compound 1, 1.93 g) to afford the above-titled compound (Compound 20; 2.55 g) as a white crystalline product (yield 89%).
Reaction SMILES: [OH-].[Al+3:2].[OH-].[OH-].[CH3:5][P:6](=[O:9])([OH:8])[OH:7]>O>[CH3:5][P:6](=[O:7])([O-:9])[O-:8].[Al+3:2].[CH3:5][P:6](=[O:7])([O-:9])[O-:8].[CH3:5][P:6](=[O:7])([O-:9])[O-:8].[Al+3:2]
Reactant: CP(=O)(O)O
Agent: [Al+3]
Agent: [OH-]
Solvent: O
Product: CP(=O)([O-])[O-]
Temperature: 160 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
0.780 g of aluminum hydroxide, 1.47 g of methylphosphonic acid, and 6.64 g of water were mixed and stirred for 1 hour. Then the mixture was placed in an internal cylinder of Teflon in a stainless steel pressure-resistant vessel, which was placed in turn in a constant-temperature bath, and the mixture in the vessel was heated under autogenous pressure at 160° C. for 48 hours. After cooling to room temperature, suspended needle crystals were scooped out, washed with water, and dried in air, to obtain 0.97 g of aluminum methylphosphonate. The product gave essentially the same powder X-ray diffraction pattern as that in Example 4, and the product also contained a phase that gave essentially the same powder X-ray diffraction pattern as that in Example 1.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:28]1[CH:33]=[C:32]([OH:34])[CH:31]=[C:30]([CH:35]([OH:38])[CH2:36][NH2:37])[CH:29]=1>>[OH:38][CH:35]([C:30]1[CH:29]=[CH:28][CH:33]=[C:32]([OH:34])[CH:31]=1)[CH2:36][NH:37][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=3)(=[O:16])=[O:17])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NCC(O)c1cccc(O)c1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4cccc(O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and DL-norphenylephrine according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.35-1.50 (m, 2H), 1.80-2.00 (m, 2H), 2.06 (s, 3H), 2.50-2.90 (m, 5H), 3.45-3.60 (m, 2H), 4.55-4.65 (m, 1H), 5.55 (brs, 1H), 6.60-6.70 (m, 1H), 6.70-6.85 (m, 4H), 6.86 (d, J=9.3 Hz, 2H), 7.11 (t, J=7.8 Hz, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.68 (d, J=8.7 Hz, 2H), 9.35 (s, 1H), 10.33 (s, 1H); MS (ES) m/z: 525.4 (MH+); HRMS Calcd. for C27H33N4O5S(MH+): 525.2172. Found: 525.2177.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[CH3:15][NH2:16]>O1CCCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:16][CH3:15])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: CN
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 4-fluoro-3-nitrobenzoic acid methyl ester (507.3 mg, 2.55 mmol) in tetrahydrofuran (1 ml), methylamine (2.0 M tetrahydrofuran solution, 2.55 ml, 5.09 mmol) was added in an ice bath, and the mixture was stirred at room temperature overnight; The reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate (20 ml), and after washing in saturated aqueous sodium bicarbonate and brine, it was dried over anhydrous magnesium sulfate. It was then concentrated under reduced pressure, the obtained residue was dissolved in a methylamine-tetrahydrofuran solution (2.0 M, 3 ml), and upon sealing, the solution was stirred at 50° C. for 5 hours. The reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate (30 ml), and the solution was washed with saturated aqueous sodium bicarbonate and brine and then dried over anhydrous magnesium sulfate. The dried product was concentrated under reduced pressure to obtain 4-methylamino-3-nitro-benzoic acid methyl ester. The compound was identified by LC-MS.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](C)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([NH:30][CH2:31]C2C=CC(F)=CC=2)[C:25]([O:27][CH2:28]C)=[O:26])=[CH:19][CH:18]=1.[F:39][C:40]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:41]=1C=O>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@H:24]([NH:30][CH2:31][C:41]2[C:40]([F:39])=[CH:47][CH:46]=[CH:45][C:44]=2[F:48])[C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccc(C)cc3)oc2C)cc1)NCc1ccc(F)cc1
Reactant: O=Cc1c(F)cccc1F
Product: COC(=O)[C@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)NCc1c(F)cccc1F

Procedure:
In the same manner as in Example 7, 570.3 mg of the title compound was obtained as colorless powder from 600.8 mg of Referential Compound 3 and 220 μL of 2,6-difluorobenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[C:15]([CH3:16])=[CH:14][C:12]([NH2:13])=[C:11]([CH3:17])[CH:10]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1.C(#N)C.CO[CH:24](OC)[N:25]([CH3:28])[CH2:26][CH3:27]>>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[C:15]([CH3:16])=[CH:14][C:12]([N:13]=[CH:24][N:25]([CH2:26][CH3:27])[CH3:28])=[C:11]([CH3:17])[CH:10]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1
Reactant: CCN(C)C(OC)OC
Reactant: Cc1cc(Oc2cc(C)c(N)cc2C)nc(Cl)n1
Solvent: CC#N
Product: CCN(C)C=Nc1cc(C)c(Oc2cc(C)nc(Cl)n2)cc1C

Procedure:
To a mixture of 310 mg (0.8 mmol) of 4-[(2-chloro-6-methylpyrimidin-4-yl)oxy]-2,5-dimethyl-aniline in 20 ml acetonitrile 208 mg (1.5 mmol) of N-(dimethoxymethyl)-N-methylethanamine (77% pure) was added. The reaction mixture was refluxed for 20 hrs. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and concentrated in vacuo yielded 220 mg (59%) with a purity of 72% log P (pH=2.3)=1.45.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[NH:16][CH:17]2[CH2:22][CH2:21][N:20](C(OCC)=O)[CH2:19][CH2:18]2)=[CH:2]1.[OH-].[K+].O>C(O)(C)C.O>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[NH:16][CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[CH:2]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccoc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: c1ccc2c(c1)nc(NC1CCNCC1)n2Cc1ccoc1
Reaction time: 18 h

Procedure:
Combine (1-(fur-3-ylmethyl)-1H-benzimidazol-2-yl)(1-(ethoxycarbonyl)piperidin-4-yl)amine (0.98 g, 2.67 mmol), potassium hydroxide (1.8 g, 32 mmol) in isopropanol (18 mL) containing 1 drop of water. Heat to reflux. After 18 hours, cool, add water, and extract four times with dichloromethane (200 mL). Combine the organic layers, dry over MgSO4, filter, and concentrate in vacuo to give the title compound: Rf=0.40 (silica gel, ethyl acetate).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16](=[O:18])[CH3:17])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:29][C:30]([F:37])([F:36])[C:31](OCC)=[O:32]>C1COCC1>[F:29][C:30]([F:37])([F:36])[C:31](=[O:32])[CH2:17][C:16]([C:14]1[S:15][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)=[CH:12][CH:13]=1)=[O:18]
Reactant: CC(=O)c1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cccc(-c2ccc(C(=O)CC(=O)C(F)(F)F)s2)c1
Temperature: 1.5 °C

Procedure:
Into a 250 mL flask was weighed 5.42 g (19.3 mmol) of 1-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)ethanone and 42 mL of THF. The resulting suspension was stirred and cooled to 0-3° C. in an ice bath and 23 mL of a lithium bis(trimethylsilyl)amide solution (1.0 M in THF) was added. The resulting thick yellow suspension was stirred and allowed to warm to room temperature then ethyl trifluoroacetate (3.46 mL, 29 mmol) was added. After stirring at room temperature overnight the reaction was concentrated in vacuo to remove THF. The residue was washed into a separatory funnel with ethyl acetate and 1 M HCl. The ethyl acetate was separated, washed with brine, dried (MgSO4), and concentrated in vacuo. The resulting amorphous yellow powder was pure enough for further synthetic transformations, yield: 72 g (99%). 1H NMR (400 MHz, DMSO-d6): δ 8.20 (d, J=7 Hz, 1H), 8.08 (t, J=7 Hz, 1H), 7.95 (d, J=4.0 Hz, 1H), 7.89 (d, J=7 Hz, 1H), 7.78 (d, J=4 Hz, 1H), 7.69 (t, J=7 Hz, 1H), 6.22 (broad s, 1H), 3.26 (s, 3H).
Reaction SMILES: ClC(Cl)C.[OH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[CH:16]=[O:17].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:22]([N:24]([CH2:29][CH3:30])[S:25](Cl)(=[O:27])=[O:26])[CH3:23]>C(Cl)Cl>[OH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([S:25](=[O:27])(=[O:26])[N:24]([CH2:29][CH3:30])[CH2:22][CH3:23])[CH:12]=2)[C:7]=1[CH:16]=[O:17]
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: CCN(CC)S(=O)(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1ccc2c(C=O)c(O)ccc2c1
Temperature: 50 °C
Yield: 85.1 %

Procedure:
600 ml of a dichloroethane solution containing 150 g (0.87 mole) of 2-hydroxy-1-naphthaldehyde and 250 g (1.87 moles) of anhydrous aluminum chloride was stirred with heating at 50° C. To the solution was added dropwise 172.2 g (1 mole) of N,N-diethylsulfamoyl chloride. After the completion of the dropwise addition, the mixture was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was poured into 1 liter of ice water. Methylene chloride was added to the mixture and it was extracted and separated. The organic layer was concentrated to about 500 ml. To the concentrate was added methanol to precipitate crystals. The precipitated crystals were collected by filtration, and washed with methanol to obtain 228 g (0.74 mole) of 2-hydroxy-6-(N,N-diethylsulfamoyl)-1-naphthaldehyde.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4](C(OCC)=O)[NH:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37].CO>CN(C=O)C>[CH3:39][N:38]([CH3:40])[C:36](=[O:37])[CH2:35][O:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[NH:4][N:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: CCOC(=O)n1[nH]c(=O)c2cnc(NC(=O)N[C@H](C)c3ccccc3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(OCC(=O)N(C)C)c2cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-Ethyl 3-oxo-6-(3-(1-phenylethyl)ureido)-2,3-dihydro-1H-pyrazolo[4,3-c]pyridine-1-carboxylate (29 mg, 0.079 mmol), potassium carbonate (32.6 mg, 0.236 mmol), and 2-chloro-N,N-dimethylacetamide (8.8 μL, 0.087 mmol) were stirred in DMF (1 mL) at room temperature for 24 h. MeOH (0.5 mL) was added and the reaction mixture was stirred at room temperature for 1 h. The insoluble inorganics were removed by filtration and the reaction mixture was purified via mass triggered, reverse phase prep-HPLC. Fractions containing pure product were concentrated in vacuo and the residue dissolved in MeOH. The MeOH solution was passed through a PS—HCO3 cartridge and the filtrate concentrated in vacuo to give (R)—N,N-dimethyl-2-(6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yloxy)acetamide. MS ESI calc'd. For C19H22N6O3 [M+1]+ 383. found 383. 1H NMR (500 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.94 (s, 1H), 8.58 (s, 1H), 7.77 (br s, 1H), 7.49 (s, 1H), 7.34-7.31 (m, 4H), 7.25-7.20 (m, 1H), 5.04 (s, 2H), 4.89-4.83 (m, 1H), 2.98 (s, 3H), 2.82 (s, 3H), 1.39 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[S:12]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].[CH:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)([CH3:23])[CH3:22]>>[CH:21]([C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([S:12]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)(=[O:14])=[O:13])[CH:5]=2)=[CH:26][CH:25]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1ccc(N)cc1
Reactant: COc1ccc(C(=O)O)cc1S(=O)(=O)N1CCCCC1
Product: COc1ccc(C(=O)Nc2ccc(C(C)C)cc2)cc1S(=O)(=O)N1CCCCC1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 4-methoxy-3-(piperidin-1-ylsulfonyl)benzoic acid and 4-isopropylaniline as the starting materials.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@:5]1([CH3:31])[C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1.[CH2:32](OC[C@H]1[C@H](C=O)[C@]1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1)C>>[CH2:1]([O:2][CH2:3][C@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C@@:5]1([CH3:31])[C:17]1[CH:26]=[CH:25][C:24]2[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=2[CH:18]=1)[CH3:32]
Reactant: CCOC[C@H]1[C@H](C=O)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@@H](COC)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCOC[C@H]1[C@H](/C=C/C(C)=C/C(=O)OCC)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 74 %

Procedure:
Following a procedure similar to that for the preparation of Compound 16a but using Intermediate 14b as the starting material afforded the title compound (38 mg, 74% yield) as a white solid:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:16]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([NH:15][C:20]([CH:16]3[CH2:19][CH2:18][CH2:17]3)=[O:21])[S:13][CH:14]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)C1CCC1
Reactant: CC(C)c1ccc(-c2csc(N)n2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1ccc(-c2csc(NC(=O)C3CCC3)n2)cc1
Yield: 77.1 %

Procedure:
4-(4-Isopropyl-phenyl)-thiazol-2-yl amine (90 mg, 0.41 mmol) was acylated in CH2Cl2 using cyclobutane carbonyl chloride (60 μL, 0.52 mmol, 1.25 eq.) in the presence of excess pyridine. The reaction was quenched with sat. NH4Cl, extracted with EtOAc and dried over MgSO4. Purification by silica gel chromatography (10% EtOAc in hexanes) afforded 95 mg (80%) of cyclobutanecarboxylic acid [4-(4-isopropyl-phenyl)-thiazol-2-yl]-amide.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[CH2:11](O)[CH3:12]>>[CH3:2][N:3]1[CH2:8][CH2:7][C:6]2[NH:3][C:4]3[C:11]([CH3:12])=[CH:8][CH:7]=[CH:6][C:5]=3[C:5]=2[CH2:4]1
Reactant: CN1CCC(=O)CC1
Reactant: CCO
Agent: Cl
Product: Cc1cccc2c3c([nH]c12)CCN(C)C3
Temperature: 80 °C
Reaction time: 5 h

Procedure:
O-Tolyl hydrazine hydrochloride (3.0 g, 18.9 mmol) was dissolved in of ethanol (10 mL), 1-methylpiperidin-4-one hydrochloride (2.8 g, 18.9 mmol) and ethanolic HCl (10 mL) was added (pH acidic) and stirred at 80° C. for 5 h. Reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated under vacuum. Residue was dissolved in aq NaHCO3 solution, extracted with EtOAc. Organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford 2.5 g of 2,6-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, free base) δ (ppm) 7.65 (s, 1H), 7.01 (t, 1H), 6.9 (d, 1H), 3.61 (s, 2H), 2.89-2.80 (m, 4H), 2.58 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18]C)[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Temperature: 10 °C
Yield: 11.8 %

Procedure:
2-(4-Methoxyphenyl)-3-(4-methoxybenzoyl)-6-methoxybenzo[b]thiophene (53 g, 131 mmol) was dissolved in chloroform and cooled to 10° C. To this stirring mixture was added boron tribromide (75 g, 296 mmol) and the reaction was allowed to proceed for twenty-four hours at ambient temperature. The reaction was terminated by pouring into water. The organic layer was separated, filtered, and evaporated to dryness. The residue was dissolved in benzene, filtered, and evaporated to dryness. The crude product was further purified by chromatography on a silica gel column eluting with diethylether-benzene (9:1) and then rechromatographed on alumina eluting with diethylether followed by a methanol-ether (1:9) wash and evaporation of the solvents to yield 5.8 g of the title compound. mp 138° C.-140° C. EA calculated for C22H16O4S: C, 70.20; H, 4.28; O, 17.00. Found: C, 70.46; H, 4.50; O, 16.87.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]([C:13]2[NH:14][C:15]([CH:20]([CH3:22])[CH3:21])([CH3:19])[C:16](=[O:18])[N:17]=2)=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([CH3:3])=[CH2:2].[N+](=[CH2:25])=[N-]>C(Cl)Cl>[CH3:25][O:10][C:9](=[O:11])[C:8]1[CH:12]=[C:4]([C:1]([CH3:3])=[CH2:2])[CH:5]=[N:6][C:7]=1[C:13]1[NH:17][C:16](=[O:18])[C:15]([CH:20]([CH3:22])[CH3:21])([CH3:19])[N:14]=1
Reactant: C=C(C)c1cnc(C2=NC(=O)C(C)(C(C)C)N2)c(C(=O)O)c1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: C=C(C)c1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)OC)c1
Reaction time: 0.25 h

Procedure:
To a solution of 4.9 g of 5-isopropenyl-2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)nicotinic acid in 50 mL of methylene chloride, stirred at 0°, is added 60 mL of 0.25M ethereal diazomethane. After stirring for 15 minutes, the reaction is concentrated on a steam bath. The residue is chromatographed on silica gel using 2:1 ether-hexanes as eluant to afford the desired product. Recrystallization from ether-hexanes affords a solid, mp 90.5°-92.5°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:39]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[OH:51])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([N:42]2[CH2:41][CH2:40][N:39]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[OH:51])[CH2:44][CH2:43]2)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=1
Reactant: Cc1onc(-c2ccccc2F)c1C(=O)O
Reactant: Oc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Cc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2ccccc2O)CC1
Yield: 61.4 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 3-(2-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 2-(piperazine-1-yl)phenol (424 mg, 1.84 mmol), a white solid required compound (433 mg, 1.13 mmol, 62%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=3)[C:10]([C:18]([OH:20])=O)=[N:9]2)[CH:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.C[N:26](C=O)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=3)[C:10]([C:18]([NH2:26])=[O:20])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2nc(C(=O)O)c3ccc(Br)cc32)n1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: NC(=O)c1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-bromoindazole-3-carboxylic acid (500 mg, 1.32 mmol) in DCM (5 mL), was added thionyl chloride (0.6 mL, 7.9 mmol) followed by DMF (0.02 mL). The mixture was stirred at RT for 1 hr. The mixture was concentrated in vacuo, DCM (2 mL) added and concentration in vacuo was repeated. To this residue was added THF (5 mL) and conc. aq NH3 (0.5 mL). The mixture stirred for 30 min, then diluted with water and the resultant solid was collected by suction filtration. The solid was thoroughly dried under high vacuum, to give the title compound (360 mg): 1H NMR (250 MHz, DMSO) delta 7.15 (1H, br. s.), 7.32 (1H, d, J=5.48 Hz), 7.60 (1H, dd, J=8.60, 1.60 Hz), 7.74 (1H, br. s.), 8.20 (1H, d, J=8.38 Hz), 8.38 (1H, d, J=5.48 Hz), 9.18 (1H, d, J=1.22 Hz); LC-MS: m/z=+332.90/334.70 (M+H)+.