Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([CH:13]([CH3:15])[CH3:14])[C:6]=2[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.[NH2:23][C:24]1[C:29]([C:30]#[N:31])=[C:28](Cl)[N:27]=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:23][C:24]1[C:29]([C:30]#[N:31])=[C:28]([NH:12][C@H:10]([C:8]2[N:7]([CH:13]([CH3:14])[CH3:15])[C:6]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH3:11])[N:27]=[CH:26][N:25]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC(C)n1c([C@H](C)N)nc2ccc(F)c(-c3ccccn3)c21
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1c([C@H](C)Nc2ncnc(N)c2C#N)nc2ccc(F)c(-c3ccccn3)c21
Temperature: 90 °C
Yield: 60 %

Procedure:
(S)-1-(6-Fluoro-1-isopropyl-7-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine (0.166 g, 0.56 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (86 mg, 0.56 mmol) and DIPEA (497 μL, 2.78 mmol) in IPA (5 mL) were added and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue purified by flash chromatography (SiO2, eluting with 0-10% methanol in DCM) to give 408 as a white solid (140 mg, 61%). LCMS (Method K): RT 3.28 min [M+H]+ 417. 1H NMR (DMSO-d6, 400 MHz): δ 8.70 (1H, ddd, J=4.8, 1.7, 0.8 Hz), 7.99 (1H, s), 7.93 (1H, td, J=7.8, 1.8 Hz), 7.67 (1H, dd, J=8.8, 4.9 Hz), 7.61 (1H, d, J=7.6 Hz), 7.48 (1H, ddd, J=7.6, 4.8, 1.2 Hz), 7.29 (3H, br s), 7.12 (1H, dd, J=10.3, 8.8 Hz), 5.64 (1H, sept, J=7.1 Hz), 4.01-3.89 (1H, m), 1.55 (3H, d, J=6.6 Hz), 1.27-1.11 (6H, m)
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:21](OC)=[O:22]>CCCCCC.O1CCCC1>[OH:22][CH:21]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[N:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)c1ccccn1
Reactant: COC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1c2ncccc2C(O)N1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-phenyl-2-pyridinecarboxamide (1.00 g) in dry tetrhydrofuran (20 mL) under N2 atmosphere at -78° C., was added n-butyllithium in hexane (4.0 mL, 2.5M). This mixture was allowed to stir for one hour. Methyl formate (0.62 mL) in dry tetrahydrofuran (5 mL) was added rapidly dropwise. After addition, the cold bath was removed and the mixture warmed to room temperature over two hours. The reaction was quenched with water and the tetrahydrofuran was evaporated in vacuo. The residue was extracted with ethyl acetate and dried (K2CO3). Purification was effected by flash chromatography on silica gel using ethyl acetate/hexane (6/4) as eluant (Rf =0.1). The yield was 310 mg (27.4%).
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([CH3:30])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]([CH2:18][CH3:19])([OH:17])[CH2:15][CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.[CH3:32][O:33][C:34](=[O:39])[C:35]([NH2:38])([CH3:37])[CH3:36].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>>[CH3:32][O:33][C:34](=[O:39])[C:35]([NH:38][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([C:3]([CH2:1][CH3:2])([C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]([CH2:18][CH3:19])([OH:17])[CH2:15][CH3:16])=[C:8]([CH3:20])[CH:7]=2)[CH2:4][CH3:5])=[CH:22][C:23]=1[CH3:30])([CH3:37])[CH3:36]
Reactant: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(C(=O)O)c(C)c2)cc1C)CC
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(C(=O)NC(C)(C)C(=O)OC)c(C)c2)cc1C)CC
Yield: 77.4 %

Procedure:
4-{1-Ethyl-1-[4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (437 mg, 1.07 mmol), α-aminoisobutyric acid methyl ester hydrochloride (247 mg, 1.61 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (309 mg, 1.61 mmol), 1-hydroxybenzotriazole hydrate (218 mg, 1.61 mmol) and triethylamine (597 μL, 4.28 mmol) are reacted and purified analogous to Example 1J to give the title compound (419 mg, 77%).
Reaction SMILES: [CH:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[O:6][CH2:7][CH2:8][C:9]([OH:11])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl.CN(C=O)C>[CH:1]([C:4]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:5]=1[O:6][CH2:7][CH2:8][C:9]2=[O:11])([CH3:2])[CH3:3]
Reactant: CC(C)c1ccccc1OCCC(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1cccc2c1OCCC2=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
3-(2-Isopropylphenoxy)propionic acid (11) was dissolved in dichloromethane (30 mL), and to the mixture were added oxalyl chloride (2.1 g) and DMF (5 mL) under ice-cooling. The reaction mixture was stirred for 30 minutes and cooled at −20° C. To the reaction mixture was added aluminium chloride (4 g), and the reaction mixture was stirred at −20° C. for 2 h. To the reaction mixture was added 2N hydrochloric acid, and the reaction mixture was extracted with dicloromethane. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate=4:1) to obtain the compound (12) 2.3 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[C:29]([C:31]1[CH:32]=[CH:33][C:34]([F:40])=[C:35](B(O)O)[CH:36]=1)#[N:30]>>[Cl:28][C:4]1[CH:3]=[C:2]([C:33]2[C:34]([F:40])=[CH:35][CH:36]=[C:31]([C:29]#[N:30])[CH:32]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:27])[C:9]([OH:14])([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: N#Cc1ccc(F)c(B(O)O)c1
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Product: CC(c1ccc(-c2cc(C#N)ccc2F)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 5-cyano-2-fluorophenylboronic acid to give the title compound as a colorless solid. MS (m/e)=519.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([OH:26])=O)=[N:22][CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[N:3]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][NH2:41].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([NH:41][CH2:40][C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=5)=[O:26])=[N:22][CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)[N:3]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(-c5ccc(C(=O)O)nc5)cc4C3)nc(N)n2)CC1
Reactant: NCc1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CN1CCN(c2cc(N3CCc4ccc(-c5ccc(C(=O)NCc6ccccn6)nc5)cc4C3)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (15 mg, 0.034 mmol) and 2-pyridinemethanamine (7.3 mg, 0.067 mmol, Aldrich, Cat. No. A65204) in N,N-dimethylformamide (1 mL) were added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (21 mg, 0.040 mmol, NovaBiochem, Cat. 01-62-0016) and N,N-diisopropylethylamine (18 μL, 0.10 mmol). The resulting mixture was stirred at r.t. for two hours. Then the reaction solution was diluted in MeOH and purified by RP-HPLC (pH=10 system) to afford the desired compound. LCMS(M+H)+: m/z=536.4.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[N:7]=3)[CH2:13][CH2:12]2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1nccc(N2CCC(C=O)CC2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nccc(N2CCC(CN3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Yield: 36.7 %

Procedure:
To a solution of 1-(2-methylpyrimidin-4-yl)-4-(formyl)piperidine (4.25 g) and N-t-butoxycarbonyl piperazine (5.34 g) in methanol/acetic acid (99:1) (100 ml) was added sodium cyanoborohydride (5.41 g) portionwise over 30 minutes and the resultant suspension stirred at ambient temperature for 3 hours. The suspension was quenched by addition of saturated aqueous sodium bicarbonate solution and the resulting mixture extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 10% methanol in ethylacetate to give 1-(tert-butoxycarbonyl)-4-[1-(2-methylpyrimidin-4-yl)-4-piperidylmethyl]piperazine (2.85 g) as a solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[F:21])[O:7][C:8]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:9]=1[C:10]#[N:11].Cl[C:23]1[CH:24]=[C:25]2[N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[Cl:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:20]=1[F:21])[O:7][C:8]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:23]2[CH:24]=[C:25]3[N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:30][N:26]3[C:27](=[O:29])[N:28]=2)=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(F)c(Cl)c3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, 2-(3-chloro-4-fluorophenoxy)-5-(hydroxymethy)benzonitrile and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1 (5H)-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH3:22])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1
Reactant: Cc1nnc2c(NC(=O)OC(C)(C)C)cc(Cl)nn12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc2c(N(C)C(=O)OC(C)(C)C)cc(Cl)nn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To a stirred solution of tert-butyl (6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl)carbamate (Step 112.4) (202 mg, 0.712 mmol) in DMF (4 mL) under Ar was added NaH (34.2 mg, 0.854 mmol) and the resulting mixture was stirred at RT for 30 min. MeI (0.053 mL, 0.854 mmol) was added to the mixture and stirred for further 30 min. The reaction was quenched with a saturated aq. NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with a saturated aq. NaHCO3 solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/EtOAc 25-40%) to afford the title product (208 mg, 0.699 mmol, 98% yield) as white solid. tR: 4.45 min (HPLC 1); tR: 1.00 min (LC-MS 2); ESI-MS: 298 [M+H]+ (LC-MS 2); Rf=0.45 (hexane/EtOAc 1:1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[NH:28][C:29]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:30]
Reactant: COc1cccc(N=C=O)c1
Reactant: COC(=O)C(Cc1cccc(CCO)c1)C(=O)OC
Product: COC(=O)C(Cc1cccc(CCOC(=O)Nc2cccc(OC)c2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)benzyl]malonate and 3-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([S:14][CH2:15][CH2:16][CH2:17]Cl)[C:7]([OH:13])=[C:8]([CH:12]=1)[C:9]([NH2:11])=[O:10])(=[O:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.Cl>[C:1]([C:4]1[CH:12]=[C:8]([C:9]([NH2:11])=[O:10])[C:7]2[O:13][CH2:17][CH2:16][CH2:15][S:14][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(SCCCCl)c(O)c(C(N)=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc2c(c(C(N)=O)c1)OCCCS2
Temperature: 70 °C
Reaction time: 72 h
Yield: 39.8 %

Procedure:
The 5-acetyl-3-(3-chloro-propylsulfanyl)-2-hydroxy-benzamide (2.87 g, 10 mmol) was dissolved in 8 mL dry DMF. Solid Cs2CO3 (4.93 g, 15.1 mmol) was added, followed by catalytic amounts of KI (0.1 g). The suspension was warmed to 70° C. under nitrogen and was stirred for 72 h. After cooling, it was diluted with ethyl acetate and enough 4 N HCl to make the pH about 2. The aqueous layer was extracted with more ethyl acetate. The combined organic layers were washed with water and brine. Drying over Na2SO4 and concentration yielded the product as a solid (1 g, 40%).
Reaction SMILES: [CH:1]([N:4]([CH:26]([CH3:28])[CH3:27])[C:5](=[O:25])[CH:6]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][C:9]([O:11]C)=[O:10])([CH3:3])[CH3:2].O.[OH-].[Na+].Cl>CCO>[CH:26]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:25])[CH:6]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][C:9]([OH:11])=[O:10])([CH3:27])[CH3:28]
Reactant: COC(=O)CC(c1ccccc1)C(C(=O)N(C(C)C)C(C)C)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)N(C(=O)C(c1cccnc1)C(CC(=O)O)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 5-(diisopropylamino)-5-oxo-3-phenyl-4-pyridin-3-ylpentanoate (Diastereomer 2, 1.095 g, 2.863 mmol) in EtOH (13 mL) was added water (15 mL) followed by 1 N aqueous NaOH (5.725 mL). The reaction mixture was stirred at room temperature. After 24 h, 1N HCl (5.725 mL) was added. The mixture was then extracted with CH2Cl2 (4×). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][C:21]([F:24])=[C:22]([F:23])[C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:23][C:22]1[C:16]2[C:17](=[N:18][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:15]=2)[CH:19]=[CH:20][C:21]=1[F:24]
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1nc2ccc(F)c(F)c2n1
Product: FCc1cccc(C#CCCn2nc3ccc(F)c(F)c3n2)n1
Yield: 58.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (50 mg, 0.27 mmol) and 2-(but-3-ynyl)-4,5-difluoro-2H-benzo[d][1,2,3]triazole (50 mg, 0.24 mmol). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 45 mg (0.14 mmol, 59%) of 4,5-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.I[CH3:14]>O1CCCC1>[CH3:14][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: CI
Reactant: c1ccc2c(c1)CCCN2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCCc2ccccc21
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
NaH (12 g, 60%, 300.00 mmol) was added in several batches, to a solution of 1,2,3,4-tetrahydroquinoline (26.6 g, 199.70 mmol) in tetrahydrofuran (150 mL) at 0-5° C. The resulting solution was maintained at 0-5° C. for 30 minutes, then iodomethane (50 g, 352.11 mmol) was added dropwise (at 0-5° C.). The resulting solution was stirred at room temperature overnight. The mixture was filtered, and the filtrate was purified by column chromatography using a 1:100 ethyl acetate/petroleum ether solvent system to give 19 g (61%) of 1-methyl-1,2,3,4-tetrahydroquinoline as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23]([OH:25])=O)[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[CH3:33][O:34][CH2:35][CH2:36][NH2:37].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:25])[NH:37][CH2:36][CH2:35][O:34][CH3:33])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH3:32])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: COCCN
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)nc1C(=O)NCCOC
Yield: 88 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained by the method described in Example (50a) (120 mg, 0.25 mmol), methoxyethylamine (45 μL, 0.52 mmol), WSC hydrochloride (120 mg, 0.63 mmol) and HOBT (35 mg, 0.26 mmol), to obtain 117.9 mg of the title compound as a white solid (88%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([NH:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])(=[O:15])[CH3:14]
Reactant: COc1ccc(C=O)c(N)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C=O)c(NC(C)=O)c1O
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
2-Amino-3-hydroxy-4-methoxybenzaldehyde (20.0 g, 0.12 mol) [M. Grossa, F. Wessely Monatsh. Chem. 1966, 97, 1384-1390] is dissolved at RT in a mixture of pyridine (250 ml) and acetic anhydride (250 ml). The solution is warmed to 60° C. and stirred for 1.5 h. The reaction solution is then poured onto a mixture of ice and half-concentrated aqueous NaCI solution (1:1), extracted with ethyl acetate (5 times), dried over MgSO4, filtered off and concentrated in vacuo. The title compound is obtained as a slightly yellow solid (12.5 g) after silica gel chromatography [petroleum ether/ethyl acetate (7:3)]. TLC, silica gel (glass plates), petroleum ether/ethyl acetate (7:3), Rf=0.23.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([O:16]C)=[O:15])[CH2:8][C:7]=2[CH:19]=1.Cl>C1COCC1.CO.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([OH:16])=[O:15])[CH2:8][C:7]=2[CH:19]=1
Reactant: COC(=O)C(=O)N1CCSc2ccc(OC)cc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CN(C(=O)C(=O)O)CCS2
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.3 %

Procedure:
Compound 5 (740 mg) was dissolved in 30 mL of a mixture of THF, methanol and 1 M NaOH (1:1:1). The solution was stirred at r.t. for 6 hr and acidified with 1 N HCl. The organic solvent was removed and the resulting solid was collected and washed with water. The solid was dried under vacuum to give 600 mg solid with the yield of 85%.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[CH:17]1([CH2:22][C:23](O)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[C:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:16])[N:2]([NH:1][C:23](=[O:24])[CH2:22][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1nn(N)c(=O)c2ccccc12
Reactant: O=C(O)CC1CCCC1
Product: CC(C)(C)c1nn(NC(=O)CC2CCCC2)c(=O)c2ccccc12

Procedure:
The product from Example 62A and 2-cyclopentylacetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.18 (s, 1H), 8.39 (d, J=2.0 Hz, 2H), 7.93-8.00 (m, 1H), 7.87 (t, J=7.5 Hz, 1H), 2.20-2.31 (m, 3H), 1.74-1.90 (m, 2H), 1.47-1.70 (m, 4H), 1.47 (s, 9H), 1.17-1.33 (m, 2H); MS (ESI+) M/Z 328 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH3:8])[N:6]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[C:19]([C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH3:8])[N:6]=1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCc1csc(N)n1
Product: CCOC(=O)C(=CNc1nc(CC)cs1)C(=O)OCC

Procedure:
2-Amino-4-ethylthiazole (20.5 g., 0.16 mole) and diethyl ethoxymethylenemalonate (35 g., 0.17 mole) were combined and heated on a steam bath for 2 hours. 2-(2,2-dicarbethoxyethenylamino)-4-ethylthiazole was obtained as an oil on cooling, and was used directly in the next step. (Rf 0.75 on silica gel thin layer chromatography with chloroform/1% ethanol as eluant.)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=O)[NH:6][N:7]=1)[CH3:2].[CH2:10]1[CH2:19][O:18][C:17]2[CH:16]=[CH:15][C:14]([NH2:20])=[C:13]([NH2:21])[C:12]=2[O:11]1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([C:8]2[NH:20][C:14]3[CH:15]=[CH:16][C:17]4[O:18][CH2:19][CH2:10][O:11][C:12]=4[C:13]=3[N:21]=2)[NH:6][N:7]=1)[CH3:2]
Reactant: Nc1ccc2c(c1N)OCCO2
Reactant: CCc1cc(C=O)[nH]n1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1cc(-c2nc3c4c(ccc3[nH]2)OCCO4)[nH]n1

Procedure:
Starting with 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 134 mg of 3,4-ethylenedioxy-1,2-phenylenediamine, and 153 mg of sodium metabisulphite, in 1 ml of ethanol and 3 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by a reverse-phase HPLC (5 mm, C18 phase, dimensions 100×25 mm, flow rate 20 ml/min, elution gradient acetonitrile/0.07% TFA-water/0.07% TFA from 5-95 to 95-5 (v/v)), and desalification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol), 60 mg of 2-(5-ethyl-2H-pyrazol-3-yl)-4,5-ethylenedioxy-1H-benzimidazole are obtained in the form of a brown lacquer, the characteristics of which are as follows:
Reaction SMILES: [NH2:1]/[C:2](/[C:7]#[N:8])=[C:3](\[NH2:6])/[C:4]#[N:5].[N:9]#[C:10]Cl>O1CCCC1>[NH2:9][C:10]1[NH:1][C:2]([C:7]#[N:8])=[C:3]([C:4]#[N:5])[N:6]=1
Reactant: N#C/C(N)=C(/N)C#N
Reactant: N#CCl
Solvent: C1CCOC1
Product: N#Cc1nc(N)[nH]c1C#N
Temperature: 25 °C

Procedure:
Diaminomaleonitrile (26.2 g) was added in portions to a solution containing cyanogen chloride (14.9 g) in tetrahydrofuran (200 ml). The mixture was then warmed to room temperature and finally heated under reflux for 1 hour. The resulting brown solid was collected by filtration and washed with a solution of sodium acetate. The remaining solid was dissolved in a sodium bicarbonate solution and treated with charcoal, filtered and acidified to give 2-amino-4,5-dicyanoimidazole, m.p. 276°-278°.