Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([O-:13])=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Na+].Cl[CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[N:17]1[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[N:29][C:30]([Cl:36])=[CH:31][CH:32]=2)[N:27]=1.N12CCCN=C1CCCCC2.O>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([O:13][CH:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]2[C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[N:29][C:30]([Cl:36])=[CH:31][CH:32]=3)[N:27]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(CC(=O)[O-])CC1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(=O)N1CCN(CC(=O)OC2c3ccccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 38.6 %

Procedure:
Sodium (4-acetyl-1-piperazinyl)acetate (4.2 g) is added to a solution, maintained at a temperature in the region of 20° C., of 3-chloro-2-(7-chloro-1,8-naphthyridin-2yl)-1-isoindolinone (6.6 g) in anhydrous dimethylformamide (60 cc), and the reaction mixture is maintained for 15 hours at a temperature in the region of 20° C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (3g) is then added, and the mixture is then stirred again for 24 hours at a temperature in the region of 20° C. The reaction mixture is taken up with water (250 cc) and extracted with methylene chloride (3×150 cc). After the organic phase has been washed with water and concentrated to dryness under reduced pressure (2.7 kPa), the residue obtained is recrystallized in ethanol. 2-(7-Chloro-1,8-naphthyridin-2-yl-)-3-oxo-1-isoindolinyl (4-acetyl-1-piperazinyl)acetate (3.7 g), m.p. 192° C., is thereby obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][C@H:9]1[CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.Cl>ClCCl>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([O:19][CH2:18][C@@H:9]2[CH2:10][C@@H:11]([O:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OC(C)(C)C)cc1
Yield: 92 %

Procedure:
To a solution of (2S,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (12.0 g) in dichloromethane (180 ml) stirring under ice cooling, triethylamine (6.23 ml), p-toluenesulfonyl chloride (8.52 g) and N,N-dimethylaminopyridine (993 mg) are successively added. The mixture is heated to reflux for 3 hours, supplemented with triethylamine (0.57 ml) and p-toluenesulfonyl chloride (775 mg), and heated to reflux for 1 hour. The reaction mixture is acidified with dilute hydrochloric acid. The organic layer is taken, washed with water, dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography and recrystallized from n-hexane to give (2S,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol p-toluenesulfonate (16.8 g). Yield: 92%. mp. 65° to 66° C. NMR δ(CDCl3) ppm: 1.42(s, 9H), 2.15 to 2.55(m, 2H), 2.45(s, 3H), 3.03(s, 3H), 3.3 to 4.5(m, 5H), 5.1 to 5.25(m, 1H), 7.35(d, J=8.0 Hz, 2H), 7.76(d, J=8.0 Hz, 2H). IR ν (CHCl3) cm-1 : 1693.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:11][C:10]=3[C:23](=[O:25])[O:24][C:4]=2[CH:3]=1.[CH2:26](OS(OCC)(=O)=O)[CH3:27].C([O-])([O-])=O.[K+].[K+].[CH3:41][C:42](C)=O>>[CH2:26]([O:1][C:2]1[C:7]([O:8][CH2:41][CH3:42])=[CH:6][C:5]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[CH2:11][C:10]=3[C:23](=[O:25])[O:24][C:4]=2[CH:3]=1)[CH3:27]
Reactant: O=c1oc2cc(O)c(O)cc2c2c1CN(CCN1CCOCC1)CC2
Reactant: CCOS(=O)(=O)OCC
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1cc2oc(=O)c3c(c2cc1OCC)CCN(CCN1CCOCC1)C3

Procedure:
A mixture of 0.01 m of 1,2,3,4-tetrahydro-8,9-dihydroxy-3-(2-morpholinoethyl)-5H-[1]benzopyrano[3,4-c]-pyridin-5-one, 0.022 m of diethylsulfate, and 0.1 m of K2CO3 in 500 ml of acetone was refluxed for 18 hr, filtered hot and evaporated. Residue was dissolved in CHCl3 and washed with 3% NaOH soln. CHCl3 soluble material was crystallized from MeOH containing an excess of HCl gas affording 1 g of product; mp 240°-260° C.
Reaction SMILES: [CH:1](=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[N:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[CH2:17]([O:19][C:20]([C@@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29]Br)[CH2:23]1)=[O:21])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([O:19][C:20]([C@@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][O:15][N:14]=[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:8]2=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:23]1)=[O:21])[CH3:18]
Reactant: ON=C1CCCCC1=Cc1ccccc1
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H]1CCCN(CCON=C2CCCCC2=Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 264 h
Yield: 35.3 %

Procedure:
A mixture of the above oxime (3.7 g, 18.4 mmol), (R)-1-(2-bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (7.0 g, 20.2 mmol, EP 374801), potassium carbonate (10.2 g, 73.5 mmol) and acetone (150 ml) was stirred at ambient temperature for 11 days. The mixture was filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography on silica gel (200 g, heptane/ethyl acetate=3/2) to give 2.5 g of (R)-1-(2-(((2-(benzylidene)cyclohexylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=2)[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:14]=1)C1C=CC=CC=1>C(O)C.[Pd]>[CH2:18]([O:17][C:15]([CH:13]1[CH2:12][N:11]2[C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=[C:10]2[CH:9]([OH:8])[CH2:14]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)c1cc(OCc2ccccc2)c2nc(C)c(C)n2c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CC(O)c2nc(C)c(C)n2C1

Procedure:
A mixture of 4 g of 8-benzyloxy-6-bromo-2,3-dimethylimidazo[1,2-a]pyridine, 0.4 g of palladium(II) acetate, 1.33 g of triphenylphosphine, 10 ml of triethylamine and 50 ml of ethanol is heated for 16 h in a carbon monoxide atmosphere in an autoclave (5 bar), the volatile portions are stripped off in vacuo and the residue is chromatographed on silica gel (eluent: ethyl acetate). 2.4 g of the title compound of melting point 140-1° C. (diethyl ether) are obtained. 4. 6-Ethoxycarbonyl-2,3-dimethyl-5,6,7,8-tetrahydrolmidazo[1,2-a]pyridine-8-one 3 g of 8-benzyloxy-6-ethoxycarbonyl-2,3-dimethylimidazo[1,2-a]pyridine, suspended in 50 ml of ethanol, are treated with 0.5 g of 10% strength palladium/active carbon and hydrogenated under a hydrogen pressure of 50 bar for 20 hours at an oil bath temperature of 75° C. After cooling, the catalyst is filtered off, the filtrate is concentrated to ⅕ of the volume in vacuo and the colorless precipitate formed here is filtered off. The filtrate from the precipitate is concentrated to dryness and chromatographed on silica gel (eluent: methylene chloride/methanol 100/3). 0.32 g of 6-ethoxycarbonyl-8-hydroxy-2,3-dimethyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine is obtained. For conversion into the title compound, it is dissolved in chloroform, treated with 1.6 g of manganese dioxide and stirred at room temperature for 20 h. It is then filtered off, the filtrate is concentrated to dryness in vacuo and the residue obtained is purified on silica gel (eluent: methylene chloride/methanol 13/1). 0.2 g of the title compound of melting point 138-40° C. (diethyl ether) is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([CH3:15])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:17][C:18](C)([O-])C.[K+].Br[CH2:24][C:25]1[C:26]([C:31]([O-:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=1>CN(C)C=O>[CH2:17]([O:33][C:31](=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:16])([CH3:15])[CH3:14])=[CH:12][CH:11]=1)[CH3:18]
Reactant: CCOC(=O)C(C)(C)Cc1ccc(O)cc1
Reactant: O=C([O-])c1ccccc1CBr
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1COc1ccc(CC(C)(C)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(4-hydroxyphenyl)-2,2-dimethylpropanoic acid ethyl ester (12.2 g) was added to a slurry containing 6.46 g of potassium tert-butoxide in 55 ml dry dimethylformamide at 0° C. After 30 minutes, a solution containing 12.6 g of ethyl (α-bromo-ortho-toluate in 15 ml dry dimethylformamide was added and the solution stirred for 2 hours at room temperature, then at 50° C. overnight. Dilution with water, extraction with ether and evaporation left an oil which was purified by HPLC (silica gel, 7:3 dichloromethane-heptane) to give 20.3 g of 2-[4-(2-ethoxycarbonyl-2-methylpropyl)phenoxymethyl]benzoic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:19][CH2:20][C:21]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:3]=1[O:2][CH3:1])=[O:22]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(N)c(OC)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(NC(=O)CCl)c(OC)c1
Temperature: 0 °C
Yield: 99.2 %

Procedure:
A mixture of 2,4-dimethoxy aniline (30.6 g, 0.2 mol), triethylamine (27.9 mL, 0.2 mol) in 600 mL methylene chloride was stirred at 0° C. under nitrogen. Chloroacetyl chloride (16 mL, 0.2 mol) was added dropwise, and the reaction mixture was stirred for 15 minutes at 0° C., and then stirred for an additional two hours during which time the reaction mixture was allowed to warm to room temperature. The reaction was quenched by addition of 1N HCl, followed by saturated aqueous sodium bicarbonate. The aqueous mixture was partitioned with EtOAc, and the organic phase was separated, dried (MgSO4), filtered, and evaporated under reduced pressure to give 45.58 g of crude 2-Chloro-N-(2,4-dimethoxy-phenyl)-acetamide. MS (M+H)=230.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C@@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[CH3:12][C@@H:13]1[CH2:18][N:17]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Product: C[C@@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from 4-nitrobenzaldehyde and 1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate using a method similar to that described for D21 in Description 21. MS (ES): [M-(CH2═CMe2)]H+ 280.2, [M—(CH2═CMe2)—CO2]H+ 236.3, no molecular ion.
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[C:6]2[N:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[N:5]2[N:4]=1)[CH3:2].[Cl:18]N1C2C=CC=CC=2N=N1>ClCCl>[Cl:18][C:17]1[C:3]([CH2:1][CH3:2])=[N:4][N:5]2[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][CH:8]=[N:7][C:6]=12
Reactant: CCc1cc2nccc(-c3cccnc3)n2n1
Reactant: Cln1nnc2ccccc21
Solvent: ClCCl
Product: CCc1nn2c(-c3cccnc3)ccnc2c1Cl

Procedure:
As for Example 34, 1.95 g. of 2-ethyl-7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine is reacted with 1.47 g. of N-chlorobenzotriazole in 50 ml. of dichloromethane to give the product of the example, m.p. 132°-133° C.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[CH2:14]I.C([Zn]CC)C.CCCCCC>ClCCCl.CCOC(C)=O.Cl>[CH2:14]1[C:2]2([CH2:3][CH2:4][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH2:1]1
Reactant: C=C1CCC(C(=O)OCC)CC1
Reactant: ClCI
Agent: CC[Zn]CC
Agent: Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C1CCC2(CC1)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., to a solution of ethyl 4-methylenecyclohexanecarboxylate (0.08 g) in DCE (1 mL) was added chloroiodomethane (0.110 mL, 1.522 mmol), followed by the addition of 1 N diethylzinc in hexane (0.761 mL, 0.761 mmol). The reaction was stirred at 0° C. for 1 hr, then stirred at rt for 18 hrs. The reaction mixture was diluted with EtOAc and 1 N HCl, the organic phase was washed with sat. NaCl, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was charged to a 25 g silica gel cartridge which was eluted with a 20 min gradient of 0-6% EtOAc in hexane to yield ethyl spiro[2.5]octane-6-carboxylate. 1H NMR (400 MHz, CDCl3) δ ppm 4.08-4.18 (2H, m), 2.32 (1H, tq, J=11.01, 3.53 Hz), 1.85-1.93 (2H, m), 1.53-1.74 (4H, m), 1.28-1.35 (2H, m), 1.22-1.28 (3H, m), 0.28 (2H, ddd, J=8.53, 5.52, 1.51 Hz), 0.17-0.25 (2H, m).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[N:16]([CH3:17])[C:15]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:14]=2[N:13]=1)[CH2:9][C:10]#[CH:11]>>[F:22][C:20]1[CH:19]=[CH:18][C:15]2[N:16]([CH3:17])[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:13][C:14]=2[CH:21]=1
Reactant: C#CCCc1nc2cc(F)ccc2n1C
Reactant: Ic1ccccn1
Product: Cn1c(CCC#Cc2ccccn2)nc2cc(F)ccc21
Yield: 27.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 192(A), from 2-iodopyridine (74 mg, 0.36 mmol) and 2-(but-3-ynyl)-5-fluoro-1-methyl-1H-benzo[d]imidazole (73 mg, 0.36 mmol). The crude residue was purified over silicagel chromatography (prepacked 2 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 28 mg of 5-fluoro-1-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole as a orange oily solid (Yield: 27%).
Reaction SMILES: [NH2:1][C@@:2]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH2:6][O:5][CH2:4][C@H:3]1[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:22]O>>[NH2:1][C@@:2]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH2:6][O:5][CH2:4][C@H:3]1[C:7]([O:9][CH3:22])=[O:8]
Reactant: N[C@@]1(c2ccccc2F)COC[C@H]1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H]1COC[C@@]1(N)c1ccccc1F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
(±)-(3S*,4S*)-4-Amino-4-(2-fluorophenyl)tetrahydrofuran-3-carboxylic acid (0.22 g) was transferred into the reaction vessel. Methanol (15 mL) was transferred into the reaction vessel. Sulphuric acid (1 mL) was transferred into the reaction vessel. The reaction was stirred at 70° C. for 8 h. The reaction mixture was concentrated under reduced pressure. Saturated sodium bicarbonate (40 mL) was then added followed by an extraction with DCM (3×40 mL). The combined organic phases were dried over MgSO4, filtered and concentrated. The crude product was purified by preparative HPLC (Method B) to give the title compound (120 mg). 1H NMR (400 MHz, CDCl3) δ ppm 3.73 (s, 3H) 3.78 (t, J=8.21 Hz, 1H) 4.02 (dd, J=8.91, 2.97 Hz, 1H) 4.15 (d, J=8.97 Hz, 1H) 4.22 (t, J=8.72 Hz, 1H) 4.36-4.44 (m, 1H) 7.09 (ddd, J=12.41, 8.12, 1.20 Hz, 1H) 7.18 (td, J=7.64, 1.14 Hz, 1H) 7.29-7.35 (m, 1H) 7.63 (td, J=8.05, 1.45 Hz, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=1>CS(C)=O>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([O:20][C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: Cc1cccnc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cccnc1OC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Potassium tert-butoxide (1.08 g, 8.62 mmol) was added to a solution of 1-benzyl-4-hydroxypiperidine (1.5 g, 7.84 mmol) in dimethylsulfoxide (5 mL) and the mixture was stirred at room temperature for 1 hour. 2-Fluoro-3-methylpyridine (957 mg, 8.62 mmol) was then added and the reaction mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water, and the organic layer was separated and washed with sodium hydrogen carbonate solution and brine. The organic solution was then dried over magnesium sulfate concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol, 100:0 to 70:30, to afford the title compound as a solid in 85% yield, 1.9 g. 1H NMR (CDCl3, 400 MHz): 1.79-1.94 (m, 2H), 1.98-2.09 (m, 2H), 2.17 (s, 3H), 2.37-2.47 (m, 2H), 2.68-2.77 (m, 2H), 3.61-3.51 (bs, 2H), 5.12-5.20 (m, 1H), 6.74 (m, 1H), 7.24-7.37 (m, 6H), 7.95 (m, 1H); LRMS APCI m/z 283 [M+H]+.
Reaction SMILES: Cl[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[Cl:9][C:10]1[CH:11]=[C:12]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[O:13][C:14]1[C:15]([CH3:23])=[N:16][N:17]([CH2:20][CH2:21][OH:22])[C:18]=1[CH3:19].N1C=CN=C1.O>CN(C)C=O>[Si:2]([O:22][CH2:21][CH2:20][N:17]1[C:18]([CH3:19])=[C:14]([O:13][C:12]2[CH:24]=[C:25]([Cl:27])[CH:26]=[C:10]([Cl:9])[CH:11]=2)[C:15]([CH3:23])=[N:16]1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1nn(CCO)c(C)c1Oc1cc(Cl)cc(Cl)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(CCO[Si](C)(C)C(C)(C)C)c(C)c1Oc1cc(Cl)cc(Cl)c1
Reaction time: 48 h
Yield: 100 %

Procedure:
Chloro-t-butyldimethylsilane (1.93 g, 12.8 mmol) was added in one portion to a stirred solution of the pyrazole of Example 1 (3.50 g, 11.6 mmol) and imidazole (1.03 g, 15.1 mmol) in N,N-dimethylformamide (23 ml) at room temperature under nitrogen. The reaction was stirred for 2 days and water (200 ml) was added. The aqueous phase was extracted with diethyl ether (3×200 ml) and the combined organic phases were washed with water (2×50 ml) and brine (2×50 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (80:20, by volume) to provide the title compound (4.82 g) as a colourless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[N:16]=[CH:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12]1)([CH3:3])[CH3:2].[C:19](=[S:21])=[S:20].[H-].[Na+].[CH2:24](Cl)[CH:25]=[CH2:26]>CN(C)C=O.O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[N:16]([C:19]([S:21][CH2:26][CH:25]=[CH2:24])=[S:20])[CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12]1)([CH3:3])[CH3:2]
Reactant: C=CCCl
Reactant: S=C=S
Reactant: CC(C)c1ccccc1N=C1N=CC(C)(C)CS1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCSC(=S)N1CC(C)(C)CSC1=Nc1ccccc1C(C)C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a solution of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.26 g), carbondisulfide (0.10 g) in N,N-dimethylformamide (3 ml) was added 60% sodium hydride (0.05 g) under ice-cooling. The reaction mixture was stirred for 30 minutes. Allylchloride (0.10 g) was added thereto. The reaction mixture was stirred at 0° C. for 1 h. To a reaction mixture was added water (80 ml), extracted with diethylether (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-isopropylphenyl)imino-3-(allylthio)thiocarbonyl-5,5-dimethyl-1,3-thiazine (0.26 g, yield: 69%) as a pale yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH:3](O)[CH3:4].C(=O)([O-])[O-:7].[K+].[K+].[C:12]1([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[OH:7][CH2:4][CH2:3][N:2]([CH3:1])[C:19](=[O:20])[CH:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CNC(C)O
Agent: [K+]
Solvent: CC(C)=O
Product: CN(CCO)C(=O)C(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a mixture of 9 g (0.12 mole) of N-methylaminoethanol and 17 g (0.12 mole) of potassium carbonate in 100 ml of acetone was added 25 g (0.11 mole) 2,2-diphenylacetylchloride. The mixture was stirred for 0.5 hours and then refluxed for 3 hours. The mixture was cooled and filtered. The salt was extracted with 3×125 ml methylene chloride. The collected organic extracts were evaporated.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]([C:26]([OH:28])=O)[N:20]=[N:19]3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C[C:32]2N(O)N=[N:35][C:33]=2[CH:34]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:33]1([NH:35][C:26]([C:21]2[N:20]=[N:19][N:18]([C:15]3[CH:14]=[CH:13][C:12]([C:10]([NH:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:11])=[CH:17][CH:16]=3)[C:22]=2[CH2:23][CH2:24][CH3:25])=[O:28])[CH2:34][CH2:32]1
Reactant: On1nnc2ccccc21
Reactant: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCCN2CCCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 61 h
Yield: 126.6 %

Procedure:
1-(4-{[(2-Piperidin-1-ylethyl)amino]carbonyl}phenyl)-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (650 mg, 1.52 mmol) obtained in Example 62b), HOBt (104 mg, 0.759 mmol, 0.5 eq.) and cyclopropylamine (0.152 ml, 2.12 mmol, 1.4 eq.) were dissolved in acetonitrile-DMF (1:1, 10 ml), WSC (386 mg, 1.97 mmol, 1.3 eq.) was added, and the mixture was stirred at room temperature for 61 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (35 ml) and washed sequentially with 2% aqueous sodium carbonate solution-saturated brine (1:1, 40 ml×2, 1:4, 40 ml×1). The aqueous layers were each extracted with ethyl acetate (30 ml). The organic layers were combined and dried over anhydrous sodium sulfate and concentrated, the residue was dissolved in toluene, and the solution was subjected to column chromatography on NH silica gel (Fuji Silysia Chemical Ltd., 100-200 mesh, DM1020, 6 g). The flow-through solution and the fraction obtained by elution with ethyl acetate-hexane (1:1-2:1) were concentrated, and ethyl acetate and diethyl ether were added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (408 mg, 0.961 mmol, 63.2%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[F:21][C:22]([F:28])([F:27])[C:23]1([NH2:26])[CH2:25][CH2:24]1>>[F:21][C:22]([F:28])([F:27])[C:23]1([NH:26][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:25][CH2:24]1
Reactant: NC1(C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: O=C(NC1(C(F)(F)F)CC1)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 1-(trifluoromethyl)cyclopropanamine (CAN 112738-68-8) as starting materials. MS (EI): m/e=392.4 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:13]([CH3:15])=O)[C:8]([O:10][CH2:11]C)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC(OCC)=[O:18].P(Cl)(Cl)(Cl)=O.[NH3:27]>>[CH3:15][C:13]1[NH:27][C:11](=[O:18])[O:10][C:8](=[O:9])[C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C(C)=O)c1ccccc1
Reactant: N
Reactant: CCOC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1[nH]c(=O)oc(=O)c1-c1ccccc1

Procedure:
Ethyl 2-phenylacetoacetate (1.0 g, 4.85 mmol) and urethane (0.43 g, 4.85 mmol) were heated, neat, with Phosphorous oxychloride (3 mL) at 90° C. for 3 hours. The excess reagents were removed under vacuum and the resulting residue was triturated with benzene and filtered. This solid was triturated with diethyl ether, filtered, and dried to yield 0.818 g (83%). MS (DCI/NH3) m/z 204 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.98 (s, 3 H) 7.28 (m, 2 H) 7.39 (m, 3 H) 11.65 (s, 1 H).