Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10](O)=[O:11])=[CH:7][CH:6]=[CH:5][N:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][OH:11])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ncccc1CCO
Yield: 54.6 %

Procedure:
2.4 g of (2-methoxy-3-pyridyl)acetic acid, 550 mg of lithium aluminum hydride and 20 ml of THF were stirred at room temperature for 0.5 hour. 0.27 ml of water, 3.9 ml of a 3.8N aqueous sodium hydroxide and 0.78 ml of water were successively added thereto, and the resulting solid was filtered off. The filtrate was evaporated, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1, subsequently 1:1), to give 1.2 g of a yellow oil.
Reaction SMILES: [OH:1][CH:2]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9].S(O[CH2:30][CH2:31][O:32][CH3:33])(=O)(=O)C.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[OH:1][CH:2]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:30][CH2:31][O:32][CH3:33])=[CH:20][CH:19]=1)[CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9]
Reactant: COCCOS(C)(=O)=O
Reactant: O=C(NCCNCC(O)COc1ccc(O)cc1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCOc1ccc(OCC(O)CNCCNC(=O)N2CCOCC2)cc1

Procedure:
17 g of N-(2-((2-hydroxy-3-(4-hydroxyphenoxy)propyl)amino)ethyl)-4-morpholinecarboxamide and 6 g of 2-methoxyethyl mesylate and 6.9 g of K2CO3 was refluxed in acetonitril for 20 h. The resulting mixture was filtered and evaporated. The residue was dissolved in methylene chloride and extracted with water containing 1 g of NaOH, then with water and then dried over Na2SO4, filtered and evaporated. The residue was crystallized from ethyl acetate yielding N-(2-((2-hydroxy-3-(4-(2-methoxyethoxy)phenoxy)propyl)amino)ethyl)-4-morpholinecarboxamide. Melting point 69° C. (base).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)#[N:2].Cl.[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH2:22].O1CCCC1.C([BH3-])#N.[Na+]>CO>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:22][CH2:21][C:20]([O:19][CH3:18])=[O:23])=[CH:13][CH:14]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1ccc(C=O)cc1
Reactant: COC(=O)CN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CNCc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of 2.0 g of 2'-cyano-4-formyl-biphenyl, 1.22 g of 2-aminoethanoic acid methyl ester hydrochloride, 9.6 g of molecular sieve 5 A and 26 ml of tetrahydrofuran is stirred at room temperature for 36 hours and then cooled to 0° to 5°. 680 mg of sodium cyanoborohydride (90%) dissolved in 4.8 ml of methanol are added. The mixture is stirred at room temperature for 24 hours and then concentrated in vacuo. The crude product is purified by means of flash chromatography (180 g of silica gel; ethyl acetate/petroleum ether=1:1). 1H-NMR (DMSO-d6): 3.63 ppm (s, 3 H); 3.79 ppm (s, 2H); 7.4 to 8.0 ppm (m, 10H); 2.6 ppm (1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@@H:12]1[O:16][C:15](=[O:17])[NH:14][C@H:13]1[CH3:18].[CH:19]([C:22]1[CH:23]=[CH:24][C:25]([O:31][CH3:32])=[C:26](B(O)O)[CH:27]=1)([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:19]([C:22]1[CH:23]=[CH:24][C:25]([O:31][CH3:32])=[C:26]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[C@@H:12]2[O:16][C:15](=[O:17])[NH:14][C@H:13]2[CH3:18])[CH:27]=1)([CH3:21])[CH3:20]
Reactant: C[C@@H]1NC(=O)O[C@H]1c1cc(C(F)(F)F)ccc1I
Reactant: COc1ccc(C(C)C)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1[C@@H]1OC(=O)N[C@H]1C
Reaction time: 1.5 h

Procedure:
To a solution of 0.036 g of trans-5-[2-iodo-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one, 0.024 g of (5-isopropyl-2-methoxyphenyl)boronic acid, and 0.04 g of potassium carbonate in 2 mL of acetone and 0.5 mL of water was added ca. 2 mg of palladium acetate. The mixture was heated to reflux and stirred at this temperature for 1.5 h. Acetone was removed by rotary evaporation and the residue was diluted with 10 mL of EtOAc and 10 mL of water. The aqueous phase was extracted with 10 mL of EtOAc. The combined organics were washed with 10 mL of brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 CV of 10% EtOAc in hexanes, followed by a linear gradient of EtOAc in hexanes from 10 to 100% over 10 CV to provide the title compound. Mass spectrum (ESI) 394.2 (M+1). 1H NMR signals are doubled because of atropoisomerism. 1H NMR (500 MHz, CDCl3): δ 7.80, 7.78 (s, 1H), 7.64, 7.63 (d, J˜8 Hz, 1H), 7.35 (d, J=7.5 Hz, 1H), 7.27, 7.26 (d, J˜8 Hz 1H), 7.00, 6.95 (d, J=2.5 Hz, 1H), 6.93, 6.92 (d, J˜8 Hz, 1H), 5.87, 5.81 (s, 1H), 5.16, 5.10 (d, J˜5 Hz, 1H), 3.70-3.78 (m, 3.5H), 3.49 (m, 0.5H), 2.89 (m, 1H), 1.24 (m, 6H), 0.90, 0.70 (d, J=6.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16]Cl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])[C:7]=2[CH:25]=1.[CH2:28]([NH:31][CH2:32][CH2:33][CH3:34])[CH2:29][CH3:30].[I-].[Na+]>>[CH2:28]([N:31]([CH2:16][C:13]1[N:12]2[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:27])([F:26])[F:1])=[CH:25][C:7]=3[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])=[N:9][CH2:10][C:11]2=[N:15][N:14]=1)[CH2:32][CH2:33][CH3:34])[CH2:29][CH3:30]
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1Br)=NCc1nnc(CCl)n1-2
Reactant: CCCNCCC
Agent: [I-]
Agent: [Na+]
Product: CCCN(CCC)Cc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Br)=NC2

Procedure:
In the manner given in Example 1, 8-trifluoromethyl-1-(chloromethyl)-6-(o-bromophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine was reacted with dipropylamine in the presence of sodium iodide to give 1-[(dipropylamino)methyl]-8-trifluoromethyl-6-(o-bromophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[CH:23]=[C:22]([CH3:36])[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:36][C:22]1[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=3)[N:19]=2)[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=2)[CH:23]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)n2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3ccc(S(N)(=O)=O)s3)n2)n1
Temperature: 23 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
To 5-{4-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidin-2-yl}-thiophene-2-sulfonic acid tert-butylamide (example 303) (0.250 g, 0.469 mmol) was added TFA (5 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was evaporated to dryness and partitioned between TBME and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as a white solid (0.200 g, 89%). MS (ISP) 477.1 [(M+H)+]; mp>250° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[S:17][CH3:18].[C:19](=[O:21])=[O:20].Cl>CCOCC>[CH3:18][S:17][C:8]1[CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:12][C:7]=1[C:19]([OH:21])=[O:20]
Reactant: CSc1cc(C(F)(F)F)ccc1Br
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CSc1cc(C(F)(F)F)ccc1C(=O)O

Procedure:
n-Butyllithium (2.5M in hexane, 25 ml) was added under an inert atmosphere to a stirred solution of 4-bromo-3-(methylsulphenyl)benzotrifluoride (16.4 g) in ether maintaining the temperature below -70° C. for 2 hours. The mixture was poured onto solid carbon dioxide pellets, stirred for 10 rains and aqueous hydrochloric acid added. The layers were separated and the aqueous layer was extracted with ether. The combined organic layers were washed with water, dried (MgSO4) and filtered. The filtrate was evaporated and the residue was triturated with cyclohexane and filtered to give 2-(methylsulphenyl)-4-trifluoromethylbenzoic acid (12.4 g) as a white solid NMR (CDCl3 +DMSO-d6): 2.45 (s,3H), 7.2(d,1H), 7.3(s,1H), 8.0(d,1H), 10.7-11(bs,1H).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[N:8][C:7]([NH2:10])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:11][C:12]1[C:16]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[C:15]([CH3:29])[O:14][N:13]=1>N1C=CC=CC=1>[CH:1]1([C:4]2[N:9]=[N:8][C:7]([NH:10][S:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]4[C:12]([CH3:11])=[N:13][O:14][C:15]=4[CH3:29])=[CH:24][CH:23]=3)(=[O:26])=[O:27])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(C2CC2)nn1
Solvent: c1ccncc1
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C3CC3)nn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
To a solution of 6-cyclopropylpyridazin-3-amine (50 mg, 0.370 mmol) in pyridine (1 mL), stirred under nitrogen at room temperature, was added 4-((3,5-dimethylisoxazol-4-yl)methoxy)benzene-1-sulfonyl chloride (346 mg, 1.147 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was evaporated and purified by solid phase extraction (SPE) using an aminopropyl (NH2) cartridge with sequential solvents methanol then 2M ammonia/methanol. The appropriate fractions were combined and evaporated in vacuo to give the crude product. The crude was further purified by mass directed autoprep (formic acid modifier). The relevant fractions were removed under a stream of nitrogen to give the title product (51 mg). LCMS (2 min, formic) Rt 0.86 min, m/z (ES+) 401 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)C.[CH3:14][N:15](C)[C:16](=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:15]([CH3:16])[CH3:14]
Reactant: O=Cc1cccc(I)c1
Reactant: CC(=O)N(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)Cc1cccc(I)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a cold (0° C.) solution of 3-iodo-benzaldehyde (3 g, 12.9 mmol) in anhydrous dichloromethane (130 ml) were added acetic acid (1.9 ml) and N,N-dimethylacetamide. The yellow solution is stirred 10 minutes at 0° C. and sodium triacetoxyborohydride (6.85 g, 32.33 mmoles) is added by portions. The resulting mixture is stirred at room temperature for 90 minutes and evaporated to dryness under reduced pressure. Ethyl acetate and a saturated aqueous hydrogen carbonate solution were added to the residue and the two layers were separated The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to yield (3-iodo-benzyl)-dimethyl-amine (3.05 g, 90%) as a brown oil.
Reaction SMILES: [O:1]=[C:2]([CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)CC1C=CC=CC=1)[C:3]([OH:5])=[O:4].C(Cl)C1C=CC=CC=1>O1CCCC1>[C:14]1([CH2:6][C:2](=[O:1])[C:3]([OH:5])=[O:4])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C(=O)C(Cc1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: ClCc1ccccc1
Product: O=C(O)C(=O)Cc1ccccc1
Yield: 68 %

Procedure:
By the same operation as in Example 61 except that 6 ml of tetrahydrofuran was used as the solvent, 2-oxo-3,4-diphenylbutanoic acid formed in a yield of 68 % by the reaction of 0.49 g (3 mmoles) of phenylpyruvic acid with 0.5 ml of benzyl chloride, as determined by NMR spectral analysis.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[S:23][CH:24]=[CH:25][C:5]=2[C:4](=[O:26])[N:3]1[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:42]=[O:43]>C(Cl)(Cl)Cl>[CH:42]([C:24]1[S:23][C:6]2[N:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)[C:2](=[O:1])[N:3]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:4](=[O:26])[C:5]=2[CH:25]=1)=[O:43]
Reactant: CN(C)C=O
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CCc3ccccc3)c(=O)c3ccsc32)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CCc3ccccc3)c(=O)c3cc(C=O)sc32)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 4′-{[2,4-dioxo-3-(2-phenylethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (2 g), phosphorus oxychloride (30 mL) and N,N-dimethylformamide (10 mL) was stirred at 50° C. for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (1.96 g, 92%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)([O-])=O.[H][H]>C(O)C.[Pd]>[O:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]2[CH:5]=[C:4]([NH2:1])[C:16]([NH2:17])=[CH:15][CH:14]=2)[CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CN2CCOCC2)cc1N
Reaction time: 24 h
Yield: 65 %

Procedure:
4-(3,4-Dinitrobenzyl)morpholine (200 mg, 0.748 mmol) and 10% Pd/C (10 mg) were suspended in ethanol (10 mL) under nitrogen. The reaction mixture's atmosphere was exchanged for hydrogen and hydrogenation continued at ambient temperature and pressure for 24 h. The vessel was purged with nitrogen, and then the mixture was filtered through Celite with an ethanol (10 mL) rinsing. The solvent was removed in vacuo and purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound in a 65% yield. 1H NMR: (400 MHz, DMSO-d6): δ 6.46 (s, 1H), 6.40 (d, 1H, J=7.6 Hz), 6.27 (d, 1H, J=7.2 Hz), 4.37 (s, 2H), 4.32 (s, 2H), 3.52 (m, 4H), 3.18 (m, 4H), 2.26 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[CH:3]=1.[CH2:11]=[O:12].Cl.S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[CH2:11][OH:12]
Reactant: C=O
Reactant: COc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(Cl)c(CO)c(Cl)c1
Temperature: 100 °C
Yield: 39.9 %

Procedure:
To a mixture of 1,3-dichloro-5-methoxybenzene (10.0 g), paraformaldehyde (2.21 g), and concentrated hydrochloric acid (100 mL) was added concentrated sulfuric acid (1.00 mL) at room temperature. After heating and refluxing at 100° C. for 8 hours, and leaving to be cooled to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue were added dioxane (56.0 mL) and a 1 M aqueous sodium hydroxide solution (113 mL), followed by heating and refluxing at 100° C. for 3 hours. The reaction solution was left to be cooled, and then water was added thereto, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain (2,6-dichloro-4-methoxyphenyl)methanol (4.67 g).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH:27]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28]1>ClCCl>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:31]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[O:32])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: O=C(Cl)C1CCC1
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc2ccc(-c3cccc(NC(=O)C4CCC4)c3)nn12
Reaction time: 4 h
Yield: 25.7 %

Procedure:
To a solution of 7.0 g of methyl-6-(3-aminophenyl)-1,2,4-triazolo[4,3-b]pyridazine in 1.5 liters of dichloromethane was added 6 ml of N,N-diisopropylethylamine and 4.0 g of cyclobutane carboxylic acid chloride. This soltution was stirred for 4 hours, washed with 200 ml of saturated aqueous sodium bicarbonhate, dried and evaporated in vacuo. A small amount of dichloromethane was added and the mixture warmed to give 2.45 g of crystals. A second crop (3.5 g) was recovered from the mother liquor. Recrystallization from dichloromethane-hexane gave the desired compound as white crystals, mp 242°-245° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[OH:18])[O:9][C:6]2=[N:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:32](I)([CH3:34])[CH3:33]>O>[CH:32]([O:18][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:12]=1[C:10]1[O:9][C:6]2[C:5]([N:11]=1)=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][N:7]=2)([CH3:34])[CH3:33]
Reactant: CC(C)I
Reactant: Oc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Temperature: 60 °C
Yield: 53.5 %

Procedure:
To a mixture of 0.26 g of 4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2-yl)pyridin-3-ol, 0.14 g of potassium carbonate and 3 ml of DMF, 0.17 g of isopropyl iodide was added at room temperature and stirred while heating at 60° C. for 1.5 hours. To the reaction solution, 38 mg of potassium carbonate and 47 mg of isopropyl iodide were added, and the reaction solution was stirred while heating at 60° C. for two hours. The reaction solution was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.16 g of 2-(3-isopropoxypyridin-4-yl)-6-trifluoromethyl-oxazolo[5,4-b]pyridine (hereinafter, referred to as “active compound 160”).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@H:5]([N:13]([CH2:28][C:29]([OH:31])=O)[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:6]([C@@H:5]1[CH2:4][CH2:3][CH2:2][NH:1][C:29](=[O:31])[CH2:28][N:13]1[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:24]([F:25])([F:26])[F:27])(=[O:15])=[O:16])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NCCC[C@@H](Cc1ccccc1)N(CC(=O)O)S(=O)(=O)c1ccccc1OC(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CN(S(=O)(=O)c2ccccc2OC(F)(F)F)[C@H](Cc2ccccc2)CCCN1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.9 %

Procedure:
To a solution of compound 31l (2.3 g, 5.0 mmol) in DCM (50 mL) was added DIPEA (2.6 g, 20 mmol) and BOP-Cl (1.5 g, 6.0 mmol). The reaction mixture was stirred at rt for 5 h under nitrogen, then 50 mL DCM and 10% citric acid were added to the mixture. The organic layer was separated, washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated and the residue was purified by CC (hexane/EA=3:1) to give compound 31m (1.9 g, 88% yield).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[OH:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:22]3[CH2:31][CH2:30][CH2:29][CH:23]3[C:24](=[O:28])[NH:25][C:26]=2[CH:27]=1>CN(C=O)C.C(OCC)(=O)C>[Si:1]([O:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:22]3[CH2:31][CH2:30][CH2:29][CH:23]3[C:24](=[O:28])[NH:25][C:26]=2[CH:27]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1Nc2cc(CCCO)ccc2C2CCCC12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCc1ccc2c(c1)NC(=O)C1CCCC21
Reaction time: 3 h
Yield: 105.3 %

Procedure:
At 0° C., 3.65 g (24.5 mmol) of tert-butyldimethylsilyl-chloride and 3.29 g (48.9 mol) of imidazole are added to a solution of 3.0 g (12.2 mmol) of 7-(3-hydroxypropyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one in 50 ml of DMF. After 3 hours, the batch is diluted with ethyl acetate, washed with water, 10% citric acid and saturated NaHCO3, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography with hexane-ethyl acetate on silica gel yields 4.62 g of product.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][S:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:7]=1[O:15][CH3:16].CC1C=C(C2C=NC=CN=2)C=CC=1C1C=CC(C(O)=O)=CC=1>>[NH2:12][C:10]1[CH:9]=[CH:8][C:7]([O:15][CH3:16])=[C:6]([S:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:17])[CH:11]=1
Reactant: COc1ccc([N+](=O)[O-])cc1SCCN(C)C
Agent: Cc1cc(-c2cnccn2)ccc1-c1ccc(C(=O)O)cc1
Product: COc1ccc(N)cc1SCCN(C)C

Procedure:
The title compound was prepared from 2-(2-dimethylaminoethylthio)-4-nitroanisole (D47) (788 mg) using a similar procedure to Description 2 (88%).
Reaction SMILES: Br.COC(=O)[NH:5][CH2:6][C@H:7]([CH2:12][C:13](=[O:23])N[C@H](C1C=CC=CC=1)C)[CH2:8][CH:9]([CH3:11])[CH3:10].[OH-:25].[Na+]>O>[CH3:11][CH:9]([CH2:8][C@H:7]([CH2:6][NH2:5])[CH2:12][C:13]([OH:23])=[O:25])[CH3:10]
Reactant: COC(=O)NC[C@H](CC(=O)N[C@@H](C)c1ccccc1)CC(C)C
Reactant: [OH-]
Agent: Br
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 25 °C
Yield: 51 %

Procedure:
A flask was loaded with 47% HBr (30 ml), water (15 ml), and compound 26 (15 g), and then was heated to reflux for 3 hours. The solution was cooled to room temperature and water (30 ml) was added. An aqueous 47% sodium hydroxide solution was added to obtain pH of 3. The solution was then extracted twice with iso-butanol (37.5 ml). The organic layers were combined and Bu3N (9.5 g) was added. The mixture was cooled to 2° C. for 1 hour, then (S)-Pregabalin was filtered, and washed with of iso-butanol (10 ml). After drying at 55° C. under vacuum, (S)-Pregabalin was obtained as white crystals in a 51% yield.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH:35][C:36]([CH2:40][OH:41])([CH3:39])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[C:28]([S:32]([NH:35][C:36]([CH2:40][OH:41])([CH3:39])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(CO)(CO)NS(=O)(=O)c1cccc(Br)c1
Product: CC(CO)(CO)NS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1
Yield: 41.3 %

Procedure:
The tide compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2)(340 mg, 1.0 mmol) and 3-Bromo-N-(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-benzenesulfonamide (example B.9) (294 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (240 mg, 41%). MS (ISP) 581.2[(M+H)+]; mp 172–174° C.