Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[Cl:38][C:39]1[CH:47]=[CH:46][C:45]2[N:44]([C:48]#[CH:49])[C:43]3[CH2:50][CH2:51][N:52]([CH3:54])[CH2:53][C:42]=3[C:41]=2[CH:40]=1>C(#N)C.O>[Cl:38][C:39]1[CH:47]=[CH:46][C:45]2[N:44]([C:48]#[C:49][C:2]3[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=3)[C:43]3[CH2:50][CH2:51][N:52]([CH3:54])[CH2:53][C:42]=3[C:41]=2[CH:40]=1
Reactant: C#Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reactant: FC(F)(F)c1ccc(Br)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CN1CCc2c(c3cc(Cl)ccc3n2C#Cc2ccc(C(F)(F)F)nc2)C1
Temperature: 80 °C
Yield: 3.8 %

Procedure:
A mixture of 5-bromo-2-(trifluoromethyl)pyridine (4.6 g, 0.02 mol), triphenylphosphine (0.053 g, 0.00020 mol), triethylamine (1.7 mL, 0.01227 mol) and 8-chloro-5-ethynyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 0.00409 mol) was dissolved in acetonitrile (30 mL) and heated by microwave at 80° C. for 30 min. The reaction was monitored by TLC. After completion of reaction, the mixture was cooled to RT and diluted with water (100 mL). The mixture was extracted with EtOAc (3×100 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain product. Product was purified by column chromatography using silica (100-200 mesh) and 3% MeOH:DCM as eluent, diameter of column—5 cm, height of silica—approx. 5 inch) then further purified by preparative TLC to give the desired compound as a yellow colored solid (0.06 g, 4% yield). The product (0.02 g, 0.000051 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.007 g, 0.000055 mol) in THF (2 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as an off-white solid (0.015 g, 60% yield). 1H NMR (CD3OD, oxalate salt) δ (ppm): 8.90 (s, 1H), 8.25 (d, 1H), 7.85 (d, 1H), 7.70 (d, 1H), 7.60 (s, 1H), 7.40 (d, 1H), 4.50 (m, 2H), 3.80 (m, 2H), 3.40 (m, 1H), 3.18 (m, 1H), 3.10 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH2:10]([N:14]1[C:19](=[O:20])[CH:18]=[N:17][C:16]([CH3:21])=[N:15]1)[CH2:11][CH2:12][CH3:13].[NH4+].[Cl-].C(OCC)(=O)C>CCOCC>[CH2:10]([N:14]1[C:19](=[O:20])[CH:18]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[NH:17][C:16]([CH3:21])=[N:15]1)[CH2:11][CH2:12][CH3:13]
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: CCCCn1nc(C)ncc1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCN1N=C(C)NC(c2ccc(C)cc2)C1=O
Yield: 86 %

Procedure:
4-Methylphenylmagnesium bromide (1.64 mL, 1.0 M in ether) was added all at once via syringe to a well-stirred solution of 1-n-butyl-3-methyl-1,2,4-triazin-6-one (178 mg, 1.06 mmol) in ether (9.85 mL) under N2 at room temperature. After stirring the resulting mixture overnight, saturated aqueous NH4Cl (10 mL) and ethyl acetate (10 mL) were added, the organic phase was separated, and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (5 g, 4:1 hexanes:ethyl acetate) to afford Compound 22 as a tan solid (236 mg, 86% yield).
Reaction SMILES: CC(C)([O-])C.[Na+].Cl[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C:22]2[O:26][N:25]=[C:24]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[N:23]=2)[CH2:16][CH2:15]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:30]1[CH:31]=[CH:32][C:27]([C:24]2[N:23]=[C:22]([CH2:21][O:20][CH:17]3[CH2:18][CH2:19][N:14]([C:8]4[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=4)[CH2:15][CH2:16]3)[O:26][N:25]=2)=[CH:28][CH:29]=1
Reactant: Clc1cccnc1
Reactant: c1cc(-c2noc(COC3CCNCC3)n2)ccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1cncc(N2CCC(OCc3nc(-c4ccncc4)no3)CC2)c1
Temperature: 80 °C

Procedure:
Sodium tert-butoxide (86 mg, 900 μmol) was added to a solution of 3-chloropyridine (23 mg, 200 μmol), 4-[5-(piperidin-4-yloxymethyl)[1,2,4]oxadiazol-3-yl]pyridine (Preparation 17, 65 mg, 250 μmol), Pd2 dba3 (4 mg, 4 μmol) and 2,8,9-trisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (6 mg, 16 μmol) in toluene (3 ml) and the resulting mixture heated at 80° C. for 48 h. After cooling and filtering through celite, the solvent was removed and the residue purified by HPLC to afford the title compound: RT=2.64 min; m/z (ES+)=338.0 [M+H]+.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[C:14]([C:16]1[CH:17]=[CH:18][C:19]([OH:44])=[C:20]([CH:43]=1)[CH2:21][N:22]1[CH2:26][CH2:25][CH:24]([NH:27][S:28]([C:31]2[S:32][C:33]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[CH:34][CH:35]=2)(=[O:30])=[O:29])[C:23]1=[O:42])#[N:15]>CN(C=O)C.CCOC(C)=O>[C:6]([Si:10]([CH3:13])([CH3:12])[O:44][C:19]1[CH:18]=[CH:17][C:16]([C:14]#[N:15])=[CH:43][C:20]=1[CH2:21][N:22]1[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([C:31]2[S:32][C:33]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[CH:34][CH:35]=2)(=[O:30])=[O:29])[C:23]1=[O:42])([CH3:9])([CH3:8])[CH3:7]
Reactant: N#Cc1ccc(O)c(CN2CCC(NS(=O)(=O)c3ccc(-c4cccnc4)s3)C2=O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C#N)cc1CN1CC[C@H](NS(=O)(=O)c2ccc(-c3cccnc3)s2)C1=O
Reaction time: 8 h
Yield: 74.5 %

Procedure:
Imidazole (0.094 g, 1.37 mmol) and t-butyldimethylchlorosilane (0.099 g, 0.66 mmol) are added to a solution of 5-pyridin-3-yl-thiophene-2-sulfonic acid {1-[5-cyano-2-hydroxy-benzyl]-2-oxo-pyrrolidin-3-yl}-amide (0.25 g, 0.55 mmol) in 10 mL of DMF. The resulting mixture is stirred overnight, then diluted with EtOAc and washed with saturated NaHCO3 (aq) and brine. The organic layer is dried over MgSO4, filtered and concentrated. The product is purified by column chromatography eluting with 3% MeOH/CH2Cl2 to give a brown oil (0.236 g, 0.41 mmol).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:8])[CH2:5][CH2:6][CH:7]=1)#[N:2].N(C(C)(C)C#N)=NC(C)(C)C#N.C([SnH](CCCC)CCCC)CCC.Br[CH2:35][CH2:36][C:37]1[CH:49]=[CH:48][C:40]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:39][CH:38]=1>C1C=CC=CC=1>[C:1]([CH:3]1[CH:7]([CH2:35][CH2:36][C:37]2[CH:49]=[CH:48][C:40]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])=[CH:39][CH:38]=2)[CH2:6][CH2:5][C:4]1=[O:8])#[N:2]
Reactant: CC(C)(C)OC(=O)c1ccc(CCBr)cc1
Reactant: N#CC1=CCCC1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(CCC2CCC(=O)C2C#N)cc1

Procedure:
A solution of the 2-cyano-2-cyclopenten-1-one (2.41 g, 22.5 mmol) prepared in the Preparative Example 101 in anhydrous benzene and a solution of azobisisobutyronitrile (AIBN) (0.05 g, a catalytic amount) and tri-n-butyltin hydride (3.62 g, 12.4 mmol) in anhydrous benzene were simultaneously gradually dropped into a solution of t-butyl 4-(2-bromoethyl)benzoate (3.21 g, 11.3 mmol) prepared in the Preparative Example 104 in anhydrous benzene under reflux by heating. The obtained mixture was heated under reflux for about 20 minutes and distilled to remove the solvent. The residue was purified by silica gel column chromatography to give the objective compound. yield: 0.43 g
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][S:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[C:13]1([S:12][C:8]2[C:6]3[N:7]=[C:2]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][S:22][CH2:21][CH2:20]4)[C:5]=3[N:11]=[CH:10][N:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1CNCCN1
Reactant: Clc1nc(N2CCSCC2)c2ncnc(Sc3ccccc3)c2n1
Product: c1ccc(Sc2ncnc3c(N4CCSCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-8-phenylthio-4-thiomorpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 236°-238° C.) and piperazine.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19][CH2:18]2)=[O:16])=[C:9]([CH3:29])[CH:8]=1>C1COCC1.O>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:30])=[O:5])=[CH:8][C:9]=2[CH3:29])[CH2:18][CH2:19]1
Reactant: COC(=O)c1ccc(CCC(=O)N2CCN(CCC(C)(C)C)CC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)ccc1CCC(=O)N1CCN(CCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
Lithium hydroxide monohydrate (2.4 g, 56.7 mmol) was added to a solution of 4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-3-oxo-propyl}-3-methyl-benzoic acid methyl ester from Example E44.1 (8.5 g, 22.7 mmol) in THF (200 ml) and water (100 ml). The mixture was stirred for 24 h at room temperature then solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 2% acetic acid:4% methanol:94% dichloromethane) to yield the title compound (8.1 g, 99%).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:22])(=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:7]=1.CO>>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([NH:13][S:12]([C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:23])=[O:2])[CH:11]=[CH:10][CH:9]=2)(=[O:21])=[O:22])=[CH:19][CH:18]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2ccc(C)cc2)c1
Solvent: CO
Product: Cc1ccc(NS(=O)(=O)c2cccc(C=CC(=O)O)c2)cc1
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To a suspension of 3-(3-p-tolylsulfamoyl-phenyl)-acrylic acid methyl ester (4d) (0.89 g, 2.70 mmol) in methanol (12 ml) 1N NaOH solution (8.10 ml, 8.10 mmol) was added and the resultant mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2N HCl solution and stirred for 30 min. The precipitated solid was filtered, washed with water and dried in desiccator over P2O5 to give the title compound as a white solid (0.75 g, 87%).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:8](=[O:11])[CH:9]=[CH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:22]1[CH:26]=[CH:25][N:24]=[C:23]1[CH:27]=[O:28].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:8](=[O:11])[CH2:9][CH2:10][C:27]([C:23]2[S:22][CH:26]=[CH:25][N:24]=2)=[O:28])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1nccs1
Reactant: C=CC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)CCC(=O)c2nccs2)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution (5 mL) of 5-cyclopentyl-4-[4-(methylsulfonyl)phenyl]pent-1-en-3-one (790 mg) in ethanol were added 1,3-thiazole-2-carbaldehyde (275 μL), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (80 mg) and triethylamine (160 μL), and the mixture was stirred with heating under reflux for 8 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (850 mg, yield 79%) was obtained as colorless amorphous crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 420 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH3:11]>CO.[Ni]>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH3:11])[NH2:8]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Agent: [Ni]
Solvent: CO
Product: Cc1ccc(N)cc1Br
Reaction time: 3 h
Yield: 95.8 %

Procedure:
A solution of 50.0 g (0.23 mol) 2-Bromo-4-nitro-toluene in 500 ml methanol was placed in a Parr hydrogenation bottle. To the solution was added 5.0 g Raney nickel. This mixture was hydrogenated at 30 psi H2 on the Parr hydrogenator for three hours with agitation. The Parr bottle was vented, the reaction mixture was filtered through diatomaceous earth (celite), and the filtrate was evaporated to yield 41.0 g (95%) of a yellow oil. IR (neat) 3329, 3144, 2604, 1609, 1288, 1030, 812 cm-1 ; 1H NMR (DMSO-d6) δ 2.13 (s, 3H), 5.60 (bs, 2H), 6.46 (dd, 1H, J=8.1 Hz, 2.3 Hz), 6.79 (d, 1H, J=2.3 Hz), 6.94 (d, 1H, J=8.2 Hz). HRMS calcd. for C7H8BrN: 184.9843. Found: 184.9840.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][C:6]([C:12]#[N:13])=[CH:5]2>N.CO.[Ni]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH:6]([CH2:12][NH2:13])[CH2:5]2
Reactant: N#CC1=Cc2cc(F)ccc2OC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCC1COc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of Example 28A (780 mg, 4.45 mmol) in 7M NH3 in MeOH (5.00 mL) was added to Ra—Ni 2800 water slurry (1.56 g, 26.6 mmol) in a 50 mL pressure bottle. The reaction mixture was and stirred for 10 hours at 30 psi at ambient temperature. After 3 hours, the solution was filtered and concentrated. The resulting residue was purified by silica gel chromatography (gradient elution: 1-15% MeOH/CH2Cl2 with 1% NH4OH) to provide the title compound. MS (DCI+) m/z 182 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][C:4]=1[CH2:5][NH:6][C:7](=[O:20])[C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1C(OC(C)(C)C)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][C:4]=1[CH2:5][NH:6][C:7](=[O:20])[C@@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1
Reactant: COc1cc(C#N)ccc1CNC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: COc1cc(C#N)ccc1CNC(=O)[C@@H]1CCCN1
Reaction time: 2 h

Procedure:
11.4 g (31.7 mmol) of Boc-proline 2-methoxy-4-cyanobenzylamide were dissolved in 130 ml of methylene chloride and, at 0-5° C., saturated with HCI [sic]. After 2 h the Boc group had been completely eliminated. The solvent was removed under reduced pressure, and the product was used without further purification in the next reaction. 1H-NMR (DMSO-d6 ; δ in ppm): 10.25 (s, 1H); 8.60 (s, 1H); 7.50 (d, 1H; 7.42 (dd, 1H); 7.39 (d, 1); 4.40-4.20 (m, 3H); 3.88 (s, 3H); 3.20 (m, 2H); 2.35 (m, 1H); 2.00-1.80 (m, 3H)
Reaction SMILES: [NH2:1][C:2](=[O:37])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]([CH2:21][NH:22]C(=O)OC(C)(C)C)=[C:10]2[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1>FC(F)(F)C(O)=O>[NH2:22][CH2:21][C:11]1[C:12]([CH2:17][CH:18]([CH3:20])[CH3:19])=[N:13][C:14]2[C:9]([C:10]=1[C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1)=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][C:2]([NH2:1])=[O:37])=[CH:16][CH:15]=2
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCCCC(N)=O)cc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2c(CN)c(CC(C)C)nc3ccc(OCCCC(N)=O)cc23)cc1
Yield: 62.3 %

Procedure:
A solution of tert-butyl {[6-(4-amino-4-oxobutoxy)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (0.5 g, 0.99 mmol) in trifluoroacetic acid (10 ml) was stirred at 0° C. for 3 hrs. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The obtained-solution was washed twice with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from diethyl ether to give the title compound (0.25 g, yield 63%) as crystals.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][C:16](=[O:21])[CH2:15][C:14]2([CH3:23])[CH3:22])([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([C:11]1[CH:20]=[CH:19][C:18]([OH:17])=[C:13]([C:14]([CH3:23])([CH3:22])[CH2:15][CH2:16][OH:21])[CH:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccc2c(c1)C(C)(C)CC(=O)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(O)c(C(C)(C)CCO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a chilled suspension of 1.99 g of LAH in 60 mL of THF at 0° C. was added a solution of 6-tert-butyl-4,4-dimethylchroman-2-one (8.1 g, 34.9 mmol) in 10 mL of THF by addition funnel. The reaction mixture was warmed to room temperature and stirred until TLC indicated the reaction was complete. After 1 hour, the reaction mixture was cooled in ice bath and carefully quenched with a minimum amount of water. The reaction mixture was then dried over magnesium sulfate and filtered through diatomaceous earth. The filtrate was concentrated in vacuo, the residue was taken up in hexanes, and the solids isolated by filtration to afford 5 g of 4-tert-butyl-2-(3-hydroxy-1,1-dimethylpropyl)phenol.
Reaction SMILES: [Br:1]P(Br)Br.O[CH:6]([C:8]1[CH:9]=[C:10]([C:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[CH:14][C:13]2=[O:24])[CH3:7]>ClCCCl.C(OCC)C>[Br:1][CH:6]([C:8]1[CH:9]=[C:10]([C:25]([N:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:26])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)=[CH:14][C:13]2=[O:24])[CH3:7]
Reactant: BrP(Br)Br
Reactant: CC(O)c1cc(C(=O)N2CCCC2)cc2c(=O)cc(N3CCOCC3)oc12
Solvent: CCOCC
Solvent: ClCCCl
Product: CC(Br)c1cc(C(=O)N2CCCC2)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 129.4 %

Procedure:
A solution of tribromophosphine (0.491 mL, 5.22 mmol) in 1,2-dichloroethane (4 mL) at 10° C., was added dropwise to 8-(1-hydroxyethyl)-2-morpholino-6-(pyrrolidine-1-carbonyl)-4H-chromen-4-one (1.62 g, 4.35 mmol) suspended in 1,2-dichloroethane (18 mL) under nitrogen. The resulting suspension was stirred at 50° C. for 1 hour. The reaction mixture was allowed to cool to RT under stirring and diluted with diethyl ether (18 mL). The precipitate was collected by filtration, washed with diethyl ether and dried to a constant weight to afford 8-(1-bromoethyl)-2-morpholino-6-(pyrrolidine-1-carbonyl)-4H-chromen-4-one (2.45 g, 100%) hydrobromide as a white solid, which was used without further purification. NMR Spectrum (DMSOd6): 1.79-1.93 (m, 4H), 2.11 (d, 3H), 3.37-3.44 (m, 2H), 3.46-3.53 (m, 2H), 3.57-3.70 (m, 4H), 3.73-3.80 (m, 4H), 5.66 (s, 1H), 5.92 (q, 1H), 7.99-8.03 (m, 2H).
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[N:4][N:3]=1.[CH3:22]I.C[O-].[Na+]>CO>[CH3:22][S:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:5]([CH2:14][N:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)=[N:4][N:3]=1
Reactant: CI
Reactant: CN1CCN(Cc2nnc(S)n2Cc2ccccc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSc1nnc(CN2CCN(C)CC2)n1Cc1ccccc1

Procedure:
The reaction of 3-mercapto-4-benzyl-5-[(4-methyl-piperazinyl)methyl]-1,2,4-triazole prepared as in Example 1 with methyl iodide and sodium methoxide in methanol by standard techniques yields 3-methylthio-4- benzyl-5-[(4-methyl-1-piperazinyl)methyl]-1,2,4-triazole.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[CH:14][CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>CO>[CH:6]1([CH2:5][CH:4]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][CH:13]=[N:12]2)[C:3]([OH:18])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)n1ncccc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(CC1CCCC1)n1ncccc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A solution of 3-cyclopentyl-2-(6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (2.99 g, 11.97 mmol) in methanol (7.9 mL, 1.5M) was treated with a 4N aqueous sodium hydroxide solution (3.29 mL, 13.16 mmol) and stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was partitioned between water (100 mL) which was acidified with a 2N aqueous hydrochloric acid solution and a solution of 90/10 methylene chloride/methanol (3×75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 3-cyclopentyl-2-(6-oxo-6H-pyridazin-1-yl)-propionic acid (2.45 g, 86%) as a light pink solid; ES+-HRMS m/e calcd for C12H16N2O3 [M+H+] 237.1234, found 237.1233.
Reaction SMILES: [Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[C:19]([O:23][C:24]([N:26]1[C@H:30]([C:31]([OH:33])=O)[CH2:29][S:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].[NH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C@H:39]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:40]([OH:42])=[O:41]>CN(C=O)C.O>[C:47]([O:46][C:44]([NH:43][C@@H:39]([CH2:38][CH2:37][CH2:36][CH2:35][NH:34][C:31]([C@@H:30]1[CH2:29][S:28][CH2:27][N:26]1[C:24]([O:23][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:25])=[O:33])[C:40]([OH:42])=[O:41])=[O:45])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (247 mg, 0.892 mmol) was added to a solution of (R)-3-(tert-butoxycarbonyl)thiazolidine-4-carboxylic acid (Compound tk81) (208 mg, 0.892 mmol) in DMF (1 ml), and the mixture was stirred at room temperature for 30 minutes. A solution of (S)-6-amino-2-((tert-butoxycarbonyl)amino)hexanoic acid (220 mg, 0.892 mmol) in water (1 ml) was added dropwise at room temperature over 3 minutes. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes. The reaction solution was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol) to afford (S)-2-((tert-butoxycarbonyl)amino)-6-((R)-3-(tert-butoxycarbonyl)thiazolidine-4-carboxamido)hexanoic acid (Compound tk82) (156 mg, 38%).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:21])[CH2:17][C:18](=[O:20])[CH3:19])=[CH:11][N:10]=3)[N:7]=[C:6]([C:22]([F:25])([F:24])[F:23])[CH:5]=2)[CH2:3][CH2:2]1.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>>[CH:1]1([C:4]2[N:8]([C:9]3[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:21])[C:17](=[CH:28][N:29]([CH3:31])[CH3:30])[C:18](=[O:20])[CH3:19])=[CH:11][N:10]=3)[N:7]=[C:6]([C:22]([F:24])([F:25])[F:23])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)CC(=O)Nc1cnc(-n2nc(C(F)(F)F)cc2C2CC2)nc1
Reactant: COC(OC)N(C)C
Product: CC(=O)C(=CN(C)C)C(=O)Nc1cnc(-n2nc(C(F)(F)F)cc2C2CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
Step-2: N-{2-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidin-5-yl}-3-oxobutanamide (445 mg, 1.3 mmol) and N,N-Dimethylformamide dimethylacetal (859 mg, 7.2 mmol) were mixed and stirred at rt for overnight. Workup (AcOEt/H2O) followed by purification on 60-120 mesh silicagel using AcOEt and Peteher (1:1) as eluent afforded N-{2-[5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]pyrimidin-5-yl}-2-[(dimethylamino)methylene]-3-oxobutanamide (0.3 g).