Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:17][CH:18]([CH3:20])[CH3:19])=[C:4]([C:13]([O:15]C)=[O:14])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].O.Cl>CO>[Br:1][C:2]1[C:3]([O:17][CH:18]([CH3:20])[CH3:19])=[C:4]([C:13]([OH:15])=[O:14])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1sc(-c2ccccc2)c(Br)c1OC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)Oc1c(C(=O)O)sc(-c2ccccc2)c1Br
Yield: 98.4 %

Procedure:
Methyl 4-bromo-3-(1-methylethoxy)-5-phenyl-2-thiophenecarboxylate (4.8 g, 14 mmoles) is stirred in methanol (5 mL), 1N NaOH (27 mL) is added, and the mixture is stirred and heated under reflux. After 3 hours the mixture is stirred into water (300 mL) and acidified with concentrated HCl. The precipitate is filtered off, rinsed with water and dried to afford the product (4.7 g); mp 159°-160° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:21][CH2:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:23]([CH:22]=[CH2:21])(=[O:25])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
L-Proline t-butyl ester (6.9 g. 0.04 mol.) and triethylamine (14 ml., 0.1 mol.) are dissolved in 200 ml. of dichloromethane and stirred in an ice bath while 2-chloroethanesulfonyl chloride (8.2 g., 0.05 mol.) in 100 ml. of dichloromethane is added over 20 minutes. After stirring 2 hours, the mixture is washed with 5% potassium bisulfate solution, saturated sodium bicarbonate solution and brine, then evaporated in vacuo. The semi-solid residue is chromatographed on 350 ml. silica gel using 1:1 ethyl acetate/hexane as eluant. The main fraction, comprising N-(vinylsulfonyl)-L-proline t-butyl ester is crystallized from ether/hexane, m.p. 84°-87° (7.1 g., 68%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(O)(C1C=CC(C)=CC=1)(=O)=O>CC(C)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:18])[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(Br)cc2)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(O)(c2ccc(Br)cc2)CC1
Temperature: 75 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
To a mixture of 8-(4-bromophenyl)-1,4-dioxaspiro[4.5]decan-8-ol (0.99 g, 3.2 mmol) in acetone (10 mL) and water (5 mL) was added Ts-OH (12 mg, 0.063 mmol) and the reaction was let stir in at 75° C. oil bath for 1 hr. The resulting reaction mixture was cooled to rt and the acetone was removed by rotary evaporation in vacuo. The resulting aqueous mixture was extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated by rotary evaporation in vacuo to afford 0.9 g of a crude pale yellow solid which was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.84-1.98 (m, 2H), 2.06-2.29 (m, 4H), 2.76 (td, J=13.8, 6.3 Hz, 2H), 5.47 (s, 1H), 7.51 (s, 4H). ESI-MS m/z: not ionized [M+H]+, retention time 1.18 min (condition E).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=3)[N:12]=[C:11]([C:23](OCC)=[O:24])[CH:10]=2)=[CH:5][CH:4]=1.[NH3:30]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=3)[N:12]=[C:11]([C:23]([NH2:30])=[O:24])[CH:10]=2)=[CH:28][CH:29]=1
Reactant: N
Reactant: CCOC(=O)c1cc(OCc2ccc(OC)cc2)c2cc(C(F)(F)F)ccc2n1
Product: COc1ccc(COc2cc(C(N)=O)nc3ccc(C(F)(F)F)cc23)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A methanolic solution of ethyl 4-((4-methoxybenzyl)oxy)-6-(trifluoromethyl)quinoline-2-carboxylate (53 g, 131 mmol) from above step A, was cooled in an ice bath and saturated with ammonia by bubbling in ammonia. The flask was capped and stirred at room temp for 20 h. The white precipitate that formed was collected by filtration and washed with a small amount of MeOH and dried under vacuum to give the title compound.
Reaction SMILES: C([Mg]Br)C.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=1.Br[CH2:21][C:22]#[C:23][C:24]([O:26][CH3:27])=[O:25]>O1CCCC1>[CH3:27][O:26][C:24]([C:23]#[C:22][CH2:21][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[C:7]1[CH:6]=[N:5][CH:10]=[CH:9][CH:8]=1)=[O:25]
Reactant: COC(=O)C#CCBr
Reactant: c1cncc(-c2cc3ccccc3[nH]2)c1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: COC(=O)C#CCc1c(-c2cccnc2)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 30 ml of 2M solution of ethylmagnesium bromide in tetrahydrofuran under nitrogen at 0°-5° is added dropwise over 30 minutes a solution of 10.0 g of 2-(3-pyridyl)indole in 60 ml of tetrahydrofuran. The mixture is stirred fo 0.5 hour at 0°-5° followed by the dropwise addition of 10.6 g of methyl bromotetrolate (J. Chem. Soc. 1950, 3646) in50 ml of tetrahydrofuran. The mixture is stirred for an additional 2 hours, at 0° poured into ice water, and extracted with ether. The aqueous phase is extracted with ether. The ether extract is washed with water, brine, and dried over anhydrous magnesium sulfate. Concentration in vacuo yields 3-(3-methoxycarbonyl-prop-2-ynyl)-2-(3-pyridyl)indole.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=1.CCOC(C)=O>CN(C=O)C.O>[N+:32]([C:29]1[CH:30]=[CH:31][C:26]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[N:27][CH:28]=1)([O-:34])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1 eq) in DMF was added potassium bis-trimethylsilylamide (1.5 eq, 1M solution in tetrahydrofuran). The solution was stirred at room temperature for 10 minutes, and 2-chloro-5-nitropyridine (1.2 eq) was added. The reaction mixture was submitted to microwave irradiation for 600 seconds at 145° C. EtOAc and water were added to the reaction and the layers separated. The organic layer was washed with water, brine, dried over sodium sulfate and evaporated to give brown crude material. Purification by silica gel column chromatography using 10% EtOAc/hexane afforded the product as a light yellow solid. LC/MS (m/z): 324.3 (MH+), Rt 3.33 minutes
Reaction SMILES: C([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][NH:14][C:15](=[O:16])[C:10]=2[CH2:9]1)C1C=CC=CC=1.C(N(CC)CC)C.C(O)=O>CO.[OH-].[Pd+2].[OH-]>[N:12]1[C:11]2[CH2:17][CH2:18][NH:8][CH2:9][C:10]=2[C:15](=[O:16])[NH:14][CH:13]=1
Reactant: O=c1[nH]cnc2c1CN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O=CO
Solvent: CCN(CC)CC
Product: O=c1[nH]cnc2c1CNCC2
Temperature: 60 °C

Procedure:
A mixture of 6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one (Intermediate 1, 18.0 g, 0.0738 mol), triethylamine (48 mL, 0.34 mol), palladium hydroxide (10 g, 0.07 mol) in methanol (242 mL) was heated to 60° C. Formic acid (7.6 mL, 0.20 mol) was added dropwise to the mixture over a 15 minute period. The mixture was heated at 65° C. for three hours, allowed to cool, and filtered over Celite. The filtrate was concentrated under vacuum to yield the title compound as a yellow solid which was used as such for the next step (9.62 g, 77.6%). MS: 152.2 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[N:15]=[CH:14][NH:13][N:12]=1)([O-:3])=[O:2].[CH2:16]([N:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:16]([N:18]([CH2:22][CH3:23])[C:19]([N:13]1[CH:14]=[N:15][C:11]([S:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[N:12]1)=[O:20])[CH3:17]
Reactant: CCN(CC)C(=O)Cl
Reactant: O=[N+]([O-])c1ccccc1Sc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCN(CC)C(=O)n1cnc(Sc2ccccc2[N+](=O)[O-])n1

Procedure:
3-(2-Nitrophenylthio)-1,2,4-triazole (4 g) and diethyl carbamoyl chloride (2.71 g) are dissolved in acetone (50 ml) and potassium carbonate (5.5 g) is added, followed by reaction for 5 h under reflux with stirring. After cooling, water (100 ml) is added to the reaction solution, whereupon the crystal of the end product precipitates. After drying, the crystal is recrystallized from ethyl acetate/n-hexane to produce the titled compound, 1-(diethylcarbamoyl)-3-(2-nitrophenylthio)-1,2,4-triazole, in an amount of 5.08 g; yield, 87.8%; m.p. 101°-103° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([F:14])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[C:7]([F:10])[C:8]=1F)[CH3:2].O.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(O)C.C(N(CC)CC)C>[CH2:1]([C:3]1[C:4]([F:14])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[C:7]([F:10])[C:8]=1[N:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)[CH3:2]
Reactant: CCc1c(F)c(F)cc([N+](=O)[O-])c1F
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CCc1c(F)c([N+](=O)[O-])cc(F)c1N1CCN(C)CC1

Procedure:
To 3-ethyl-2,4,5-trifluoro-nitrobenzene (1.02 g) are added ethanol (4.5 ml) and water (0.5 ml) and the mixture is stirred. To the mixture is added with stirring a mixture of 1-methylpiperazine (0.83 ml), triethylamine (1.0 ml) and ethanol (0.6 ml), and the mixture is refluxed for 5 hours. To the reaction mixture is further added 1-methylpiperazine (1.0 ml), and the mixture is refluxed for 3 hours. The mixture is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (solvent, methylene chloride) to give 3-ethyl-2,5-difluoro-4-(4-methyl-1-piperazinyl)nitrobenzene (1.12 g), as yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[ClH:17]>C(O)C>[ClH:17].[CH3:1][N:2]1[CH2:7][C:6](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5](=[O:8])[C:4](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3]1
Reactant: CN1CCC(=O)CC1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: CN1CC(=Cc2ccccc2)C(=O)C(=Cc2ccccc2)C1
Reaction time: 8 h

Procedure:
A solution of 57.0 g. (0.5 mole) of 1-methyl-4-piperidinone and 106.0 g. (1.0 mole) of benzaldehyde in 400 ml. of ethanol is cooled in an ice bath and treated with HCl gas until 250 g. is absorbed. The red-colored solution is allowed to stand at room temperature overnight. The resulting deep red-brown solution is seeded, allowed to stand overnight at room temperature, and the crystalline solid is filtered on a sintered-glass funnel and washed with cold ethanol, followed by ether. After drying in a desiccator, the solid (146 g.) is digested in 400 ml. of hot ethanol (75°), cooled and filtered to give 120 g. of pale yellow product, m.p. 242-244° (dec.).
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:8][Br:9])([CH2:6][OH:7])[CH2:4][OH:5].Cl.[CH2:11]=O>>[Br:1][CH2:2][C:3]1([CH2:8][Br:9])[CH2:6][O:7][CH2:11][O:5][CH2:4]1
Reactant: OCC(CO)(CBr)CBr
Reactant: C=O
Agent: Cl
Product: BrCC1(CBr)COCOC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A suspension of 26.2 g of 2,2-bis(bromomethyl)-1,3-propanediol, 50 ml of concentrated hydrochloric acid and 50 ml of 38% formaldehyde was stirred in a 50° C. oil bath overnight, then cooled to room temperature and filtered. The filtrate was extracted with three 100 ml portions of ether. The ether extracts were combined, washed with water, dried and evaporated to an oil. A small amount of solid which formed was removed by filtration and washing with ether. The combined filtrate and wash was evaporated under reduced pressure, giving 26.9 g of 5,5-bis(bromomethyl)-1,3-dioxane as a clear oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH3:23])[C:10]([CH3:25])([CH3:24])[CH:9]2O)=[O:5])[CH3:2].FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH3:23])[C:10]([CH3:24])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(F)ccc1C)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)ccc1C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
To a mixture of 2-(5-fluoro-2-methyl-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethylester (3.78 g, 10.6 mmol) and triethylsilane (10 mL) at 25° C. was added trifluoroacetic acid (2 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×50 mL), washed with saturated aqueous sodium bicarbonate solution (2×20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) to afford 2-(5-fluoro-2-methyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.70 g, 19%) as a white solid: LC/MS m/e calcd for C21H24FNO2 (M+H)+: 342.4, observed: 342.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(N(CC)CC)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1COCC1>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][CH2:2][CH2:3][OH:4])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCO)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a solution of 2-aminoethanol (2.3 mL, 39 mmol), and triethylamine (16 mL, 120 mmol) in anhydrous THF (100 mL) was added 4-bromobenzene-1-sulfonyl chloride (10 g, 39 mmol) portion wise and the reaction mixture stirred at room temperature for 16 h. The reaction was filtered, the filtrate was concentrated and the residue was purified by column chromatography (silica, ethyl acetate/hexanes gradient) to afford the desired product (5.5 g, 50%): 1H NMR (500 MHz, CDCl3) δ 7.74 (td, J=9.0, 2.1 Hz, 2H), 7.67 (td, J=9.0, 2.1 Hz, 2H), 5.08 (s, 1H), 3.72 (t, J=5.1 Hz, 2H), 3.12 (t, J=4.8 Hz, 2H), 1.83 (s, 1H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:13][C:14](=[O:32])[CH:15]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[CH:27]1[O:31][CH2:30][CH2:29][O:28]1)[CH2:16][CH2:17][CH3:18])[CH3:12].I[CH2:34][CH2:35][CH3:36]>C1COCC1.C(OCC)(=O)C>[CH2:11]([O:13][C:14](=[O:32])[C:15]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[CH:27]1[O:31][CH2:30][CH2:29][O:28]1)([CH2:34][CH2:35][CH3:36])[CH2:16][CH2:17][CH3:18])[CH3:12]
Reactant: CCCI
Reactant: CCCC(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(CCC)(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
Lithium bis(trimethylsilyl)amide (26 mL, 26 mmol, 1 M in THF) was slowly added to a solution of 2-(4-Chloro-2-[1,3]dioxolan-2-yl-phenoxy)-pentanoic acid ethyl ester (6.6 g, 20 mmol) in anhydrous THF (60 mL) at −78° C. After the mixture was stirred for 30 min at −78° C., 1-iodopropane (4 mL, 40 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 2 h. Then the mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of NH4Cl, and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give the title compound as a yellow oil (5 g).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[F:9][C:10]([F:18])([F:17])[CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1.C(N(CC)CC)C>O1CCCC1>[CH3:8][S:7][C:4]1[N:3]=[C:2]([N:13]2[CH2:14][CH2:15][CH2:16][CH:11]([C:10]([F:18])([F:17])[F:9])[CH2:12]2)[S:6][N:5]=1
Reactant: CSc1nsc(Cl)n1
Reactant: FC(F)(F)C1CCCNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1nsc(N2CCCC(C(F)(F)F)C2)n1
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
In 3 ml of tetrahydrofuran were added 376 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole, 230 mg of 3-trifluoromethylpiperidine and 1.52 g of triethylamine at room temperature. The mixture was stirred for 1.5 hour under reflux condition, and left as it for 14 hours at room temperature. The reaction mixture was extracted with ethyl acetate after the addition of water. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 398 mg of 3-methylthio-5-(3-trifluoromethylpiperidino)-1,2,4-thiadiazole.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](=[O:18])(O)[O-].[Na+]>ClC1C=CC=CC=1Cl>[C:1]([C:9]1[C:10](=[O:11])[O:12][C:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:15]=1[OH:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: O=C(c1ccccc1)c1c(O)cc(-c2ccccc2)oc1=O
Temperature: 0 °C

Procedure:
To a solution of ethyl benzoylacetate (150 g, 0.88 mmol) in 1,2-dichlorobenzene (150 mL) was added a trace amount of sodium bicarbonate. The reaction mixture was heated to reflux. A distillate of ethanol (approximately 20 mL) was collected. The reaction mixture was cooled to 0° C. Ether (100 mL) was added to induce crystallization. The reaction mixture was kept in the refrigerator overnight. The solid formed was collected and washed with ether: m.p. 171°-173° C.; 1H NMR (250 MHz, DMSO-d6) δ 6.91 (s, 1 H), 7.59 (m, 6 H), 7.87 (m, 4 H).
Reaction SMILES: C(C1C=C(N[CH:11]([C:15]2[CH:20]=[CH:19][C:18](OC)=[C:17]([O:23][CH3:24])[CH:16]=2)[C:12]([OH:14])=[O:13])C=CC=1)(=O)N.[NH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[F:35])[C:29]([NH2:31])=[O:30].COC1C=C(B(O)O)C=CC=1[F:44].O.C(O)(=O)C=O>>[C:29]([C:28]1[CH:32]=[CH:33][C:34]([F:35])=[C:26]([NH:25][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([F:44])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:12]([OH:14])=[O:13])[CH:27]=1)(=[O:30])[NH2:31]
Reactant: COc1ccc(C(Nc2cccc(C(N)=O)c2)C(=O)O)cc1OC
Reactant: NC(=O)c1ccc(F)c(N)c1
Reactant: COc1cc(B(O)O)ccc1F
Agent: O=CC(=O)O
Solvent: O
Product: COc1cc(C(Nc2cc(C(N)=O)ccc2F)C(=O)O)ccc1F
Yield: 72 %

Procedure:
27A was prepared in a procedure similar to that of 1A using 19B, 7C and glyoxylic acid monohydrate. Yield: 72%. 1H NMR (400 MHz, Methanol-d4) δ ppm 3.87 (s, 3H) 5.18 (s, 1H) 7.02-7.12 (m, 4H) 7.13-7.18 (m, 1H) 7.27 (d, J=8.79 Hz, 1H), LCMS: 337 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.Cl[CH2:10][C:11](=O)[CH3:12]>C(O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([CH3:12])[N:1]=2)[CH:4]=1
Reactant: CC(=O)CCl
Reactant: Nc1ccc(I)cn1
Solvent: CCO
Product: Cc1cn2cc(I)ccc2n1
Yield: 37.5 %

Procedure:
2-Amino-5-iodopyridine (5 g, 22.73 mmol) was dissolved in ethanol (20 mL). Chloroacetone (2.29 mL, 25 mmol) was added and the mixture was heated at reflux overnight. The reaction mixture was evaporated to dryness. The residue was dissolved in DCM (50 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was dried over MgSO4, filtered and evaporated. The resulting crude residue (4.8 g) was triturated with ethyl acetate to afford pure title compound (2.2 g). The filtrate was concentrated to dryness, yielding an additional quantity of less pure title compound (2.0 g). δH (CDCl3) 7.33 (m, 4H), 2.48 (s, 3H). LCMS: MH+ 259.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:11]([CH3:13])[CH:12]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[NH2:24][C:25]1[C:30]([CH:31]=[O:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C.O>C(#N)C>[NH2:24][C:25]1[C:30]([CH:31]=[O:32])=[C:29]([N:17]2[CH2:18][CH2:19][CH:14]([C:10]3[N:11]([CH3:13])[CH:12]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:20]([F:21])([F:22])[F:23])[CH:4]=4)[N:9]=3)[CH2:15][CH2:16]2)[N:28]=[CH:27][N:26]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Reactant: Nc1ncnc(Cl)c1C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C=O)CC1
Temperature: 40 °C
Yield: 85 %

Procedure:
A mixture of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine (600.00 mg; 1.83 mmol; 1.0 eq.), 4-amino-6-chloropyrimidine-5-carbaldehyde (303.25 mg; 1.92 mmol; 1.05 eq.), DIEA (0.95 ml; 5.5 mmol; 3.0 eq.) in acetonitrile (10.0 ml) was heated at 40° C. for 1 h. The reaction mixture was poured into water. The precipitate was filtered, washed with water and dried under vacuum to afford the title compound in 85% yield. LC-MS: (M+1=449, obsd.=449).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]([C:17]([NH:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:18])=[C:12](Cl)[CH:11]=[CH:10][C:9]=3[N:8]=2)[CH2:3]1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]([C:17]([NH:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:18])=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=2)[CH2:3]1
Reactant: N[C@H]1CCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: N[C@H]1CCN(c2ccc3c(C(=O)NCC4CCCCC4)cccc3n2)C1
Yield: 54.9 %

Procedure:
A suspension of 2-[(5)-3-amino-1-pyrrolidinyl]-6-chloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide (Example 44) (0.10 g) and triethylamine (0.04 mL) in ethanol (20 mL) was treated with 5% palladium on charcoal (0.05 g) and stirred under 2 atmospheres of hydrogen at ambient temperature for 16 hours. The reaction mixture was filtered through Celite and the liquors concentrated to dryness. Recrystallisation from methanol/ethyl acetate afforded to title compound (0.05 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:14]([OH:23])[C:13]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:30]=[C:31]([CH2:44][C:45]([O:47][CH3:48])=[O:46])[CH:32]=[CH:33][C:34]=1B1OC(C)(C)C(C)(C)O1>>[OH:23][C:14]1[C:13]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:11]=[C:10]([CH2:9][O:8][C:5]2[CH:6]=[N:7][C:2]([C:34]3[CH:33]=[CH:32][C:31]([CH2:44][C:45]([O:47][CH3:48])=[O:46])=[CH:30][C:29]=3[CH3:28])=[CH:3][CH:4]=2)[C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CC(C)(C)OC(=O)c1c(COc2ccc(Cl)nc2)ccc(C(F)(F)F)c1O
Product: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cn2)c(C)c1
Yield: 50 %

Procedure:
According to a method similar to Example (76-1), from tert-butyl 6-{[(6-chloro-3-pyridinyl)oxy]methyl}-2-hydroxy-3-(trifluoromethyl)benzoate (240 mg, 0.59 mmol) obtained in Example (84-1) and methyl [3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (224 mg, 0.77 mmol) obtained in Example (84-3), tert-butyl 2-hydroxy-6-{[(6-{4-[(methoxycarbonyl)methyl]-2-methylphenyl}-3-pyridinyl)oxy]methyl}-3-(trifluoromethyl)benzoate was obtained (157 mg, yield: 50%).