Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.N1CCOCC1>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1COCCN1
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 176.2 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Triethylamine (7.9 ml) is added to the bottle, and morpholine (7.9 ml) is added thereto at the temperature. The above mixture is reacted at the temperature for 1 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50° C. for 5 h to obtain solid purin (11.2 g). The yield is about 65.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:12]([NH2:15])[CH2:13][NH2:14]>Cl>[ClH:1].[NH2:14][CH2:13][CH2:12][NH:15][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Reactant: NCCN
Agent: Cl
Product: NCCNc1cc(O)ccc1[N+](=O)[O-]
Temperature: -10 °C

Procedure:
0.432 mol (75 g) of 3-chloro-4-nitrophenol is introduced into 282 ml of ethylenediamine and the reaction mixture is heated on a boiling waterbath for 13 hours. The cooled solution is then poured into 2.6 liters of ice-water to which 1.09 liters of hydrochloric acid (d=1.18) have been added. After the mixture has been cooled to -10° C. for a few hours, 3-β-aminoethylamino-4-nitrophenol hydrochloride crystallises. It is filtered off with suction and washed with an ice-cold 2N hydrochloric acid solution and then with ethanol. After recrystallisation from water, the dried product melts, with decomposition, at a temperature above 260° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[N:20][CH:21]=1.Cl.O>C(#N)C.O1CCOCC1.C(O)C>[Br:1][C:2]1[C:3]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[N:4][C:5]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[N:20][CH:21]=2)=[N:6][CH:7]=1
Reactant: OCCCCSc1nc(Cl)ncc1Br
Reactant: Nc1ccc(S(N)(=O)=O)nc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(Nc2ncc(Br)c(SCCCCO)n2)cn1

Procedure:
298 mg (1.0 mmol) of 4-(5-bromo-2-chloro-pyrimidin-4-ylsulfanyl)-butan-1-ol is dissolved in 2 ml of acetonitrile and added to a suspension of 172 mg (1.0 mmol) of 5-amino-pyridine-2-sulfonic acid amide (representation according to W. T. Caldwell, E. C. Kornfeld J Am. Chem. Soc. 1942, 64, 1695-1698) in 1 ml of acetonitrile, 0.25 ml of a 4 molar solution of hydrochloric acid in 1,4-dioxane as well as 0.25 ml of water. The reaction mixture is stirred under reflux for 24 hours. It is mixed with 1 ml of ethanol and stirred for another 24 hours under reflux. After cooling, the precipitate that is formed is filtered off, and the filtrate is concentrated by evaporation. The residue is purified by chromatography (Flashmaster II, DCM/MeOH 9:1). The crude product that is obtained is then purified by preoperative thin-layer chromatography. 43 mg (0.10 mmol, 10% of theory) of the product 5-[5-bromo-4-(4-hydroxy-butylsulfanyl)-pyrimidin-2-ylamino]-pyridine-2-sulfonic acid amide is obtained
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[CH:26])[CH2:20][C:19]1=[O:27])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([N:21]1[CH2:22][CH2:23][N:18]([CH2:17][C:9]2[NH:8][C:16]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[CH:10]=2)[C:19](=[O:27])[CH2:20]1)[C:25]#[CH:26]
Reactant: C#CCN1CCN(Cc2cc3cnccc3n2C(=O)OC(C)(C)C)C(=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CCN1CCN(Cc2cc3cnccc3[nH]2)C(=O)C1
Reaction time: 6 h
Yield: 65 %

Procedure:
To a solution containing 2-(2-oxo-4-prop-2-ynyl-piperazin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (1.3 g, 3.53 mmol) in CH2Cl2 (100 mL) is added TFA (20 mL) at 0° C. After 6 h, the reaction mixture is concentrated to dryness and then partitioned between aqueous NaHCO3 (500 mL) and CH2Cl2 (200 mL) and the layers are separated. The aqueous phase is extracted four times with CH2Cl2 (100 mL) and the combined organic phase is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude residue is purified by flash silica gel chromatography (CH2Cl2 to 10% MeOH/CH2Cl2) to provide 616 mg (65%) of the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([OH:12])[CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[C:23]([CH3:25])[CH3:24]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:12][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH:5]=1)[CH3:14]
Reactant: CC(C)=CCBr
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(C=O)c(OCC=C(C)C)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.1 %

Procedure:
To a suspension of 4-diethylamino-2-hydroxybenzaldehyde (300 mg, 1.55 mmol), potassium carbonate (428 mg, 3.10 mmol), and tetrabutylammonium iodide (57 mg, 0.15 mmol) in 1.6 mL of dry N,N-dimethylformamide was added prenyl bromide (0.27 mL, 2.3 mmol) at 0° C. After being stirred at room temperature for 7 h, the reaction mixture was filtered to remove inorganic salts. The filtrate was diluted with diethyl ether, and the solution was washed with water, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 75/25) to obtain the title compound as a pale yellow gum (377 mg, 93%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34].Cl>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH2:32][C:33]([O:35][CH:36]([CH3:38])[CH3:37])=[O:34])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)CBr
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)OC(C)C)(NC(=O)OCc1ccccc1)C(=O)OCC
Temperature: 50 °C
Reaction time: 1 h
Yield: 102.7 %

Procedure:
A suspension of diethyl 2-benzyloxycarbonylaminomalonate (5.0 g), potassium carbonate (2.7 g), potassium iodide (0.32 g), and isopropyl 2-bromoacetate (3.5 g) in DMF (50 mL) was stirred at 50° C. for 1 hour. The reaction mixture was cooled, and then poured into diluted hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, and then purification was performed with n-hexane/ethyl acetate (5:1), to obtain the title compound (6.8 g, yield: 99%) as colorless oil.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([O:11]C)=[C:5]([CH3:13])[C:4]=1[CH2:14][CH2:15][CH2:16][C:17]([NH:19][CH2:20][CH2:21][OH:22])=[O:18].CC#N.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C([O-])(=O)C>O>[OH:22][CH2:21][CH2:20][NH:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:4]1[C:3](=[O:2])[C:8]([CH3:9])=[C:7]([CH3:10])[C:6](=[O:11])[C:5]=1[CH3:13]
Reactant: COc1c(C)c(C)c(OC)c(CCCC(=O)NCCO)c1C
Agent: CC(=O)[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: O
Solvent: CC#N
Product: CC1=C(C)C(=O)C(CCCC(=O)NCCO)=C(C)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
Crude 4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-N-(2-hydroxyethyl)butanamide (1.105 g, 3.57 mmol) was taken up into 40 mL MeCN and 2 mL H2O and cooled to 0° C. To this was added CAN (4.35 g, 7.86 mmol, 2.2 equiv) in 5 mL H2O dropwise over 5 minutes. The reaction was stirred for 0.25 h until judged complete by HPLC and 50 mL ipropyl acetate was added. The organic layer was washed 4×5 mL saturated aqueous NaCl, dried over aqueous Na2SO4 and concentrated to a yellow powder. Flash chromatography (gradient elution 80-100% EtOAc/heptane) yielded 619 mg of N-(2-hydroxyethyl)-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow powder. M++H=280 m/z; 1H NMR (400 MHz, CDCl3) δ=6.38 (s, 1 H), 3.77 (t, 2 H), 3.47 (m, 2 H), 2.54 (t, 2 H), 2.29 (t, 2 H), 2.05 (s, 3 H), 2.01 (s, 6 H), 1.76 (m, 2 H+H2O) ppm.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([NH2:16])[CH3:15]>CO>[CH2:14]([NH:16][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])[CH3:15]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCN
Solvent: CO
Product: CCNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 5 h

Procedure:
To a suspension of 1.85 g of 4-fluoro-3-nitrobenzoic acid (10 mmol) in 25 mL of MeOH is added 20 mL of ethylamine (2.0M in THF). The resulting yellow solution is stirred at 75° C. for 5 h then at RT for 48 h. The solvent is removed under reduced pressure, then water is added to the residue. The resulting orange suspension is acidified with 2N aqueous HCl and the yellow precipitate is collected by filtration, washed with water and dried in vacuo to give 4-ethylamino-3-nitro-benzoic acid: mp=233-236° C.; 1H-NMR (DMSO-d6) δ 12.83 (s, 1H), 8.61 (d, J=1.84, 1H), 8.49 (m, 1H), 7.97 (dd, 1H), 7.12 (d, J=9.2, 1H), 3.46 (m, 2H), 1.23 (t, 3H); [M−1]−=209.
Reaction SMILES: [H][H].[Si:3]([O:10][CH2:11][C@@H:12]([CH3:44])[C@H:13]([NH:24]C1(C2C=CC=CC=2)C2C=CC=CC=2C2C1=CC=CC=2)[C:14]([O:16]CC1C=CC=CC=1)=[O:15])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].CCOC(C)=O.CC(O)C.O>CCOC(C)=O.C(Cl)Cl.[Pd]>[NH2:24][C@@H:13]([C@H:12]([CH3:44])[CH2:11][O:10][Si:3]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4])[C:14]([OH:16])=[O:15]
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A balloon of hydrogen was attached to a mixture of (2S,3S)-benzyl 4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate (836 mg, 1.447 mmol) and 10% Pd/C (213 mg) in EtOAc (16 mL) and the mixture was stirred at room temperature for ˜21 hr, where the balloon was recharged with H2 as necessary. The reaction mixture was diluted with CH2Cl2 and filtered through a pad of diatomaceous earth (CELITE®-545), and the pad was washed with EtOAc (200 mL), EtOAc/MeOH (1:1 mixture, 200 mL) and MeOH (750 mL). The combined organic phase was concentrated, and a silica gel mesh was prepared from the resulting crude material and submitted to a flash chromatography (8:2:1 mixture of EtOAc/i-PrOH/H2O) to afford (2S,3S)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid as a white fluffy solid (325 mg). (2S,3R)-benzyl 4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate was similarly elaborated to (2S,3R)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid. (2S,3S)-amino acid isomer: 1H NMR (methanol-d4, δ=3.29 ppm, 400 MHz), 3.76 (dd, J=10.5, 5.2, 1H), 3.73 (d, J=3.0, 1H), 3.67 (dd, J=10.5, 7.0, 1H), 2.37 (m, 1H), 0.97 (d, J=7.0, 3H), 0.92 (s, 9H), 0.10 (s, 6H). LC-MS: Anal. Calcd. for [M+H]+ C11H26NO3Si: 248.17. found 248.44. (2S,3R)-amino acid isomer: 1H NMR (methanol-d4, δ=3.29 ppm, 400 MHz), 3.76-3.75 (m, 2H), 3.60 (d, J=4.1, 1H), 2.16 (m, 1H), 1.06 (d, J=7.3, 3H), 0.91 (s, 9H), 0.09 (s, 6H). Anal. Calcd. for [M+H]+ C11H26NO3Si: 248.17. found 248.44.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](O)=[O:29].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:28]([C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)=[O:29])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4cccs4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 62 h
Yield: 53.9 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) and commercially available 2-thiophenecarboxylic acid (46 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (99 mg) was added, and the admixture was stirred at room temperature for 62 hours. The reaction mixture was then purified in the same manner as described in Example 51 to obtain 37 mg of the title compound (yield: 54%).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([C:23]2[CH:24]=[N:25][C:26]3[N:27]([C:29]([C:32]4([C:35]5[CH:36]=[C:37]6[C:42](=[CH:43][CH:44]=5)[N:41]=[CH:40][CH:39]=[CH:38]6)[CH2:34][CH2:33]4)=[CH:30][N:31]=3)[CH:28]=2)[CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C@@H:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([O:10]C(C)(C)C)=[O:9])=[O:5].[ClH:45]>O1CCOCC1>[F:1][C:2]1[CH:22]=[C:21]([C:23]2[CH:24]=[N:25][C:26]3[N:27]([C:29]([C:32]4([C:35]5[CH:36]=[C:37]6[C:42](=[CH:43][CH:44]=5)[N:41]=[CH:40][CH:39]=[CH:38]6)[CH2:34][CH2:33]4)=[CH:30][N:31]=3)[CH:28]=2)[CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C@@H:7]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([OH:10])=[O:9])=[O:5].[ClH:45]
Reactant: CC(C)(C)OC(=O)[C@@H](NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)[C@H](NC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1F)C(=O)O
Reaction time: 1 h

Procedure:
A mixture of tert-butyl (2S)-2-(2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoylamino)-3,3-dimethylbutanoate (60 mg, 0.1 mmol) in 2.0 ml of 4N HCl in 1,4-dioxane was stirred for 1 h. The mixture was concentrated to give the desired product as an HCl salt. LCMS: (M+H)=538.1.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([Cl:11])[S:9][CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C.O.O>[Cl:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1
Reactant: CCOC(=O)c1csc(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1csc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
14.0 g (73.1 mmol) of 2-chlorothiazole-4-carboxylic acid ethyl ester were slowly added to a solution of 11.0 g (0.17 mol, 85% purity) of potassium hydroxide in ethanol/water (1:3, 200 ml) at 0° C. The reaction mixture was stirred at room temperature for 16 h, diluted with water and washed twice with diethyl ether. The aqueous layer was acidified (pH=5.5) with conc. HCl and stirred at room temperature for three days. The formed precipitate was collected by filtration and dried at 40° C. under vacuum to yield 7.0 g (56%, 95% purity) of the title compound as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1.C(N(CC)CC)C.Cl[CH2:34][CH2:35][CH2:36][S:37](Cl)(=[O:39])=[O:38].O>ClCCl>[O:38]=[S:37]1(=[O:39])[CH2:36][CH2:35][CH2:34][N:1]1[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCc1cnc(N2CCN(C(=O)c3cnc(N)cc3C)CC2)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCc1cnc(N2CCN(C(=O)c3cnc(N4CCCS4(=O)=O)cc3C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (320 mg) described in Preparation Example 176 was added 4-methoxybenzylamine (1 mL), and the mixture was stirred at 160° C. for 6 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl][6-(4-methoxybenzylamino)-4-methylpyridin-3-yl)methanone (330 mg). The obtained [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl][6-(4-methoxybenzylamino)-4-methylpyridin-3-yl)methanone (330 mg) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated from the reaction mixture, 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography to give (6-amino-4-methylpyridin-3-yl) [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone. The obtained (6-amino-4-methylpyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone and triethylamine (0.30 mL) were dissolved in dichloromethane (10 mL), 3-chloropropane-1-sulfonyl chloride (0.18 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 3.5 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (10 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography to give the title compound (220 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([CH:31]=2)[C:27]([O:29]C)=[O:28])[CH2:21][O:20]1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:21][C:19]([C:22]3[CH:31]=[C:26]([C:27]([OH:29])=[O:28])[CH:25]=[N:24][CH:23]=3)([OH:20])[CH3:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: COC(=O)c1cncc(C2(C)CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cncc(C(=O)O)c2)CCN(C)C1
Reaction time: 0.17 h
Yield: 5.7 %

Procedure:
To a solution of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (90 mg, 0.466 mmol) in DMF (2 mL), sodium hydride (60%, 33 mg, 1.44 mmol) was added. After stirring for 10 min., methyl 5-(2-methyloxiran-2-yl)nicotinate (1.09 g, 12.4 mmol) was added to the reaction mixture, which was stirred at RT for 16 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice-water and extracted with EtOAc (2×100 mL). The aqueous layer was lyophilized and purified by reverse phase HPLC purification to obtain the 10 mg of 5-(1-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-2-hydroxypropan-2-yl)pyridine-3-carboxylic acid. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.9 (d, 1H), 8.7 (d, 1H), 8.57 (d, 1H), 7.11 (s, 1H), 6.74 (d, 2H), 4.67 (dd, 1H),4.33 (m, 2H), 4.29 (dd, 1H), 3.9 (t, 1H), 3.6 (m, 2H), 3.2 (m, 1H), 3.11 (s, 3H), 2.3 (s, 3H), 1.79 (d, 3H). Separation by chiral HPLC provides enantiomers II-141a-b.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:9]#[N:10])=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:9](=[S:21])[NH2:10])=[CH:6][CH:7]=1
Reactant: N#CC(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CCO
Product: NC(=S)C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A solution of 2-(4-chlorophenyl)-2-(4-nitrophenyl)acetonitrile (1.000 g, 3.667 mmol, 1 equip) and phosphorus pentasulfide (1.63 g, 7.334 mmol, 2 equip) in EtOH (20 mL) was heated at reflux temperature for 20 h. The reaction mixture was cooled to room temperature and concentrated. The residue was triturated with hot ethyl ether to yield 2-(4-chlorophenyl)-2-(4-nitrophenyl)ethanethioamide as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:10][C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=1)=[O:11]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Product: CN(C)C=CC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.9 %

Procedure:
A solution of 1-[4-(trifluoromethyl)phenyl]ethanone (2 g, 10.63 mmol, Sigma-Aldrich) in dimethylformamide-dimethylacetal (5 ml, 37.3 mmol) was heated to 110° C. and stirred for 18 hours. The reaction mixture was cooled to room temperature then diluted with iso-hexanes (20 ml). The resulting precipitate was filtered then washed with a minimum of iso-hexane to yield the title compound as a yellow solid (1.29 g)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[N:10][C:9]=2[O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1.Cl.[F:25][C:26]([F:35])([F:34])[C:27]1[N:31]=[C:30]([CH2:32][NH2:33])[O:29][N:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([NH:33][CH2:32][C:30]3[O:29][N:28]=[C:27]([C:26]([F:35])([F:34])[F:25])[N:31]=3)=[O:15])[CH:11]=[N:10][C:9]=2[O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1
Reactant: C[C@H](Oc1ncc(C(=O)O)nc1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: NCc1nc(C(F)(F)F)no1
Agent: Cl
Product: C[C@H](Oc1ncc(C(=O)NCc2nc(C(F)(F)F)no2)nc1-c1ccc(Cl)cc1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1, using (S)-6-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)pyrazine-2-carboxylic acid (example AG) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride (CAN 944905-93-5; example AK) as starting materials. MS: 494.0 (M−H)−.