Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@H:28]4[C@H:32]([OH:33])[CH2:31][N:30]([C:38](=[O:37])[CH2:39][OH:40])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c1
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CN(C(=O)CO)C[C@H]4O)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f51) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]2[CH:32]=[CH:31]C(Cl)=CC=2Cl)[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:36])[C:18](=[O:35])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[NH:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]2[CH2:32][CH2:31]2)[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:36])[C:18](=[O:35])[NH:19][N:20]=2)[CH2:9]1
Reactant: C[C@H]1C(=O)NN=C2COc3cc(-c4ccc(Cl)cc4Cl)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1C(=O)NN=C2COc3cc(C4CC4)c(NC4CNC4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 3-[7-(2,4-dichloro-phenyl)-4(S)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 2, SFC (Table 1, Method 12) Rt=8.89 min., 0.280 g, 0.655 mmol) in DCM (9 mL) was added TFA (1.5 mL) and the reaction mixture was stirred for 2 h at ambient temperature. The solution was concentrated in vacuo to give 6-(azetidin-3-ylamino)-7-cyclopropyl-4(S)-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (Example #64-2, Enantiomer 2, SFC (Table 1, Method 1) Rt=5.859 min., 0.275 g, 0.624 mmol, 95%). LC/MS (Table 1, Method 4) Rt=1.331 min.; MS m/z: 328 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].[H-].[Na+].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=1>CN(C)C=O>[Cl:16][C:17]1[N:18]=[C:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[C:20]([C:24]([F:27])([F:25])[F:26])=[CH:21][N:22]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 1.6 %

Procedure:
To a solution of 1-Amino-2-(isopropylsulphonyl)benzene (350 mg, 1.6 mmol) in 4 mL of N,N-Dimethyl formamide at 0 degree, was added Sodium hydride (100 mg) and the reaction mixture was allowed to stirred at 0 degree for 20 minutes. 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (350 mg, 1.6 mmol) was added in one portion and the reaction mixture was warmed to room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with Ethyl acetate. The combined Ethyl acetate layers were dried over Sodium Sulfate and solvent was removed under reduced pressure. The residue was purified by Prep-HPLC to yield the desired product as a white solid (10 mg, 2% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:38][CH2:37][CH3:41])[C:23]([O:25][CH3:26])=[O:24]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(F)cc1)CCCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(F)cc1)CCCC3
Yield: 85.9 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(4-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.300 g; 0.82 mmol), LHMDS 1N in THF (0.9 mL; 0.9 mmol), 1-iodopropane (0.12 mL; 1.23 mmol) in DMF (3.3 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.290 g (85%) of the title compound as a yellow oil.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+].IC1C=CC=C2C=1NC(=O)C2=O>O.ClCCl.C(OCC)(=O)C.COCCOC>[C:12]1([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[NH:1][C:2](=[O:3])[C:4]3=[O:5])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1Nc2ccccc2C1=O
Agent: O=C([O-])O
Agent: O=C1Nc2c(I)cccc2C1=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1Nc2c(cccc2-c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
This compound was prepared according to the procedure described by Lisowski et al. J. Org. Chem., 2000, 65, 4193. To a 1 L 3-necked round-bottomed flask fitted with a reflux condenser were added intermediate 6 (2.0 g, 7.33 mmol) and tetrakis[triphenylphosphine]palladium (0.424 g, 0.367 mmol), followed by 225 mL 1,2-dimethoxyethane. The atmosphere in the reaction vessel was made inert by opening to vacuum, then to a positive pressure of nitrogen (3×). Phenylboronic acid (Aldrich, 0.983 g, 8.06 mmol) and a solution of sodium bicarbonate (1.23 g, 14.7 mmol) in 225 mL water were added, and the evacuation/nitrogen procedure repeated one more time. The reaction mixture was then refluxed until t.l.c. (10% ethyl acetate in dichloromethane) showed complete disappearance of 7-iodoisatin (1-2 hours). After cooling to room temperature, the 1,2-dimethoxyethane was removed under reduced pressure. The residue was diluted with 1M aqueous hydrochloric acid and extracted into ethyl acetate (3×). The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to give crude 7-phenylisatin 7.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:8][C:9]1[CH:21]=[CH:20][C:12]2[O:13][C:14]([C:17](O)=[O:18])=[CH:15][O:16][C:11]=2[CH:10]=1>>[OH:8][C:9]1[CH:21]=[CH:20][C:12]2[O:13][C:14]([C:17]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:18])=[CH:15][O:16][C:11]=2[CH:10]=1
Reactant: O=C(O)C1=COc2cc(O)ccc2O1
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)C1=COc2cc(O)ccc2O1
Yield: 72 %

Procedure:
That compound is obtained in a yield of 72% starting from aniline and 6-hydroxy-l.4-benzodioxin-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1.Cl.C(O)C>[Fe].O>[F:18][C:2]([F:1])([F:17])[O:3][C:4]1[CH:5]=[C:6]2[S:10][C:9]([NH2:11])=[N:8][C:7]2=[C:12]([NH2:14])[CH:13]=1
Reactant: Nc1nc2c([N+](=O)[O-])cc(OC(F)(F)F)cc2s1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1nc2c(N)cc(OC(F)(F)F)cc2s1

Procedure:
The procedure is as Example 7, starting with 6-trifluoromethoxy-4-nitro-2-benzothiazolamine, iron powder, concentrated hydrochloric acid and ethanol having a water content of 50% (vol./vol.). After purification on a column of silica with a mixture of cyclohexane and ethyl acetate (10:90 by volume) as eluant, a white solid (1.5 g) is recovered, which solid is recrystallized in toluene (130 cc) to obtain 6-tri-fluoromethoxy-2,4-benzothiazolediamine (1 g), m.p. 206° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11]([Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[CH:10]=2)=[C:6]([F:34])[CH:5]=[CH:4][C:3]=1[OH:35].[H-].[Na+].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41].O>O1CCCC1>[CH3:43][O:42][C:40](=[O:41])[CH2:39][O:35][C:3]1[CH:4]=[CH:5][C:6]([F:34])=[C:7]([CH2:8][C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11]([Si:24]([CH:28]([CH3:29])[CH3:30])([CH:31]([CH3:33])[CH3:32])[CH:25]([CH3:26])[CH3:27])[CH:10]=2)[C:2]=1[F:1]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2c(F)ccc(O)c2F)c2cc(-c3cccnc3)cnc21
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)COc1ccc(F)c(Cc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncc(-c4cccnc4)cc23)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 2,4-Difluoro-3-(5-pyridin-3-yl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenol (549, 427.0 mg, 0.87 mmol) in tetrahydrofuran (20.0 mL) was added sodium hydride (60% in mineral oil, 42.0 mg, 1.1 mmol). 30 minutes later, methyl bromoacetate (146 mg, 0.95 mmol) was added to the reaction. The reaction was stirred at room temperature for 4 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude compound that was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16]2([C:27]#[N:28])[CH2:25][CH2:24][C:23]3[N:22]=[CH:21][NH:20][C:19](=[O:26])[C:18]=3[CH2:17]2)=[CH:5][CH:4]=1.[C:29](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([C:16]2([C:27]#[N:28])[CH2:25][CH2:24][C:23]3[N:22]=[CH:21][N:20]([CH3:29])[C:19](=[O:26])[C:18]=3[CH2:17]2)=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C2(C#N)CCc3nc[nH]c(=O)c3C2)c2c1oc1ccccc12
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(C2(C#N)CCc3ncn(C)c(=O)c3C2)c2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
To a well stirred slurry of compound obtained in example 13 (75 mg, 0.2 mmol) and cesium carbonate (73 mg, 0.22 mmol) in dry DMF (5 ml) was added iodomethane (36.92 mg, 0.26 mol) and the mixture was allowed to stir for 1 hr at room temperature under nitrogen atmosphere. The reaction mixture was quenched with ice water (50 ml), and then extracted with ethyl acetate (50 ml). The organic layer was washed with water followed by brine and dried over sodium sulfate. The organic layer was concentrated under vacuum and the crude product was purified by column chromatography to get 40 mg of the pure product (Yields-52%) MP-235.4-240.8° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][NH:32][C:33](=[O:43])[CH2:34][NH:35]C(=O)OC(C)(C)C)([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:44])[CH3:16])=[CH:11][CH:10]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:35][CH2:34][C:33]([NH:32][CH2:31][CH2:30][C@@:20]1([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[O:19][C:18](=[O:44])[N:17]([C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][CH:13]=2)[CH3:16])[CH2:22][CH2:21]1)=[O:43]
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCNC(=O)CNC(=O)OC(C)(C)C)(c2ccc(F)cc2)OC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCNC(=O)CN)(c2ccc(F)cc2)OC1=O
Yield: 61.1 %

Procedure:
A solution of tert-butyl 2-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethylamino)-2-oxoethylcarbamate (98 mg, 0.16 mmol) in TFA/CH2Cl2 (20%, 5 mL) was stirred at 0° C. for 2 h. The solvent was evaporated to give the crude product, which was purified by preparative HPLC to afford 2-amino-N-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)acetamide (50 mg, 60%). 1H NMR (CDCl3): 1.41-1.49 (d, 3H), 2.15-2.29 (m, 5H), 2.80-2.94 (m, 2H), 3.25-3.36 (m, 1H), 3.70-3.85 (m, 2H), 5.50 (m, 1H), 6.75-6.97 (m, 7H), 7.00-7.14 (m, 3H), 7.26-7.29 (m, 1H).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[O:10][C:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:18]=[C:17]4[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[N:34]=3)=[N:12][N:13]=2)=CC=1>C(Cl)(Cl)Cl.C(O)(C(F)(F)F)=O>[O:42]1[CH2:41][CH2:40][N:39]([C:35]2[N:34]=[C:33]([C:17]3[C:16]4[C:20](=[CH:21][CH:22]=[C:14]([C:11]5[O:10][C:9]([NH2:8])=[N:13][N:12]=5)[CH:15]=4)[N:19]([S:23]([C:26]4[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=4)(=[O:25])=[O:24])[CH:18]=3)[CH:38]=[CH:37][CH:36]=2)[CH2:44][CH2:43]1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cccc(N5CCOCC5)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(N4CCOCC4)n3)c3cc(-c4nnc(N)o4)ccc32)cc1
Yield: 44 %

Procedure:
The solution of N-(4-methoxybenzyl)-5-(3-(6-morpholinopyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (0.21 g, 0.33 mmol) in CHCl3 (2 mL) and TFA (2 mL) was heated at 80° C. for 12 h. Then the reaction mass was evaporated to dryness and ice cold H2O (10 mL) was added and basified with saturated NaHCO3 solution to pH 8. A white colored solid precipitated out which was collected by filtration and dried under vacuum to give 5-(3-(6-morpholinopyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (0.075 g, 44.1%). MS (ESI, pos. ion) m/z: 517 (M+1); 1H NMR (DMSO-d6, 400 MHz): δ ppm 8.94 (s, 1H), 8.51 (s, 1H), 8.14 (d, J=8.8 Hz, 1H), 7.99 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.8 Hz, 1H), 7.68-7.64 (m, 1H), 7.42-7.36 (m, 3H), 7.18 (s, 1H), 6.82 (d, J=8.8 Hz, 1H), 3.77-3.75 (m, 4H), 3.57-3.56 (m, 4H), 2.3 (s, 3H).
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([CH3:30])[NH:23][C:22]([CH2:31][O:32][CH2:33][C:34](O)=[O:35])=[C:21]1[C:37]([O:39][CH2:40][CH3:41])=[O:38].N>O1CCCC1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([CH3:30])[NH:23][C:22]([CH2:31][O:32][CH2:33][C:34]([NH2:3])=[O:35])=[C:21]1[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)C1=C(COCC(=O)O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: N
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(COCC(N)=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
Carbonyldiimidazole (9.80 g) was added to a suspension of 2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}acetic acid (25.4 g) in tetrahydrofuran (400 ml) and the mixture stirred at room temperature for 2 hours. A stream of gaseous ammonia was passed through the resulting solution with stirring until the reaction was complete (as determined by t.l.c.) The reaction mixture was evaporated and the residue partitioned between ethyl acetate and water. The organic layer was washed with water, dried over sodium sulphate and evaported. The residue was triturated with diethyl ether and the resulting solid collected, recrystallised from diethyl ether/n-hexane and dried to give the title compound (17.0 g), m.p. 127°-128° C.
Reaction SMILES: [CH2:1]([N:4]([CH3:20])[CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH3:19])[CH:2]=[CH2:3].[Br:21][C:22]1[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=1>>[CH2:1]([N:4]([CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:25]1[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=1)[CH:14]=[C:13]2[CH3:19])[CH3:20])[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCC#Cc1ccc2[nH]cc(C)c2c1
Reactant: Fc1ccc(Br)cc1
Product: C=CCN(C)CCCC#Cc1ccc2c(c1)c(C)cn2-c1ccc(Br)cc1

Procedure:
In analogy to example 9.1, Allyl-methyl-[5-(3-methyl-1H-indol-5-yl)-pent-4-ynyl]-amine and 1-bromo-4-fluorbenzene were converted to yield Allyl-{5-[1-(4-bromo-phenyl)-3-methyl-1H-indol-5-yl]-pent-4-ynyl}-methyl-amine as light yellow viscous oil, MS: 421 (MH+, 1Br).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][C:12](=O)[C:13](F)(F)F)[CH:3]=1.ICC.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+]>O.CCOC(C)=O.CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11][CH2:12][CH3:13])[CH:3]=1
Reactant: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CCI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNc1cc(Br)sc1C(=O)OC
Temperature: 70 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
A mixture of methyl 5-bromo-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (3.18 g, 9.58 mmol), iodoethane (3.8 mL, 47.9 mmol), cesium carbonate (7.80 g, 24.0 mmol) and DMF (10 mL) was stirred at 70° C. for 3 h. Then, water and EtOAc were added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was dissolved in MeOH (15 mL). To the solution were added potassium carbonate (3.97 g, 28.7 mmol) and water (10 mL). The mixture was stirred at room temperature for 2 h. After removal of the solvent at reduced pressure, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, hexane to 90:10 hexane/EtOAc) to give the title compound (2.46 g, 97%) as a light green oil:
Reaction SMILES: [C:1]([C:4]1[C:5]([N+:20]([O-])=O)=[C:6]([O:18][CH3:19])[C:7]([C:15](=[O:17])[NH2:16])=[C:8]([N+:12]([O-])=O)[C:9]=1[O:10][CH3:11])(=[O:3])[NH2:2].CO.Cl>[Pd].C(O)CCC.C(O)(=O)C.O>[C:15]([C:7]1[C:8]([NH2:12])=[C:9]([O:10][CH3:11])[C:4]([C:1](=[O:3])[NH2:2])=[C:5]([NH2:20])[C:6]=1[O:18][CH3:19])(=[O:17])[NH2:16]
Reactant: COc1c(C(N)=O)c([N+](=O)[O-])c(OC)c(C(N)=O)c1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCCCO
Product: COc1c(N)c(C(N)=O)c(OC)c(N)c1C(N)=O
Reaction time: 4 h

Procedure:
A mixture consisting of 561 mg (1.79 mmol) of 6, 50 mg of 5% Pd/C, and 100 mL of methanol was shaken under 50 psi of H2 for 4 hours. Upon completing the reduction, 10 mL of concentrated hydrochloric acid was added immediately to the reaction mixture with stirring. After filtering the acidified mixture through CELITE and washing with methanol, the solvents were evaporated in vacuo and the solid residue thoroughly dried. The 8·2HCl was purified by dissolution in a minimum amount of hot methanol followed by addition of ethyl acetate: 568 mg (97%) yield; TLC (n-butanol/acetic acid/water [5:2:3]), Rf =0.37; 1H NMR (dimethyl-d6 sulfoxide) δ7.93 and 7.92 (4H, 2 brs, 3- and 6-carbamyls, no assignments made), 3.69 (6H, s, methoxys); mass spectrum (EI mode), m/z 254 (P+).
Reaction SMILES: C(OC([NH:8][CH:9]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:10]1[N:14]2[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][C:13]2=[N:12][N:11]=1)=O)(C)(C)C.CO.[ClH:35]>>[ClH:32].[ClH:35].[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH:9]([C:10]2[N:14]3[CH2:15][CH2:16][NH:17][CH2:18][C:13]3=[N:12][N:11]=2)[NH2:8])=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)NC(c1ccc(Cl)cc1)c1nnc2n1CCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CO
Product: NC(c1ccc(Cl)cc1)c1nnc2n1CCNC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of tert-butyl 3-((tert-butoxycarbonylamino)(4-chlorophenyl)methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (0.652 g, 1.41 mmol) in MeOH (7.03 mL, 1.41 mmol) was saturated with HCl (g). The reaction mixture was stirred at room temperature for 30 minutes and then concentrated in vacuo to afford (4-chlorophenyl)(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)methanamine bishydrochloride as a foam (0.47 g, 99%). LCMS (APCI+) M+H+: 264 (50%), 266 (10%), 267 (3%); rt=1.76 minutes. 1H NMR (400 MHz, d6-DMSO) δ 10.62 (s, 1H), 10.18 (s, 1H), 9.43 (s, 3H), 7.57 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.6 Hz, 2H), 6.13 (m, 1H), 4.51 (m, 2H), 4.44 (m, 1H), 3.56 (m, 3H).
Reaction SMILES: OS(O)(=O)=O.[CH3:6][O:7][C:8]([C:10]1[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23])=[O:9].[CH3:29]O>>[CH3:6][O:7][C:8]([C:10]1[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:19][CH3:29])=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23])=[O:9]
Reactant: CO
Reactant: COC(=O)c1ccccc1Oc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Oc2ccccc2C(=O)OC)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
Concentrated H2SO4 (3 mL) was added to a solution of compound 545 (7.5 g, 23.64 mmol) in MeOH (80 mL) and stirred at 60° C. for 16 h. MeOH was removed under vacuum and the crude product was dissolved in AcOEt and washed with water. The organic layer was separated, dried with Na2SO4, filtered and concentrated via rotary evaporation to afford the title compound 546 (6.2 g, 79%) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]=O)=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[NH2:12][C@H:13]([CH3:16])[CH2:14][OH:15]>>[Cl:11][C:6]1[C:7]2[CH:8]=[CH:9][N:12]([C@H:13]([CH3:16])[CH2:14][OH:15])[C:2]=2[N:3]=[CH:4][N:5]=1
Reactant: C[C@@H](N)CO
Reactant: O=CCc1c(Cl)ncnc1Cl
Product: C[C@H](CO)n1ccc2c(Cl)ncnc21

Procedure:
The title compound was prepared according to the method described for Preparation 1 using (4,6-dichloropyrimidin-5-yl)acetaldehyde and (R)-2-amino-1-propanol to afford the title compound as a yellow solid in 100% yield, 11.12 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][N:13]=3)[NH:9][N:8]=2)=[N:3][CH:2]=1.[H-].[CH3:19]I>O1CCCC1>[CH3:19][N:8]1[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][N:3]=2)=[N:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)=[N:9]1
Reactant: c1cc(-c2n[nH]c(-c3ccncn3)n2)ncn1
Reactant: CI
Agent: [H-]
Solvent: C1CCOC1
Product: Cn1nc(-c2ccncn2)nc1-c1ccncn1

Procedure:
To 3,5-bis(4-pyrimidinyl)-1,2,4-triazole (2.3 g.) in dry tetrahydrofuran (125 ml.) is added 57% sodimm hydride in mineral oil (0.46 g.). After refluxing 0.5 hour, methyl iodide (1.4 g.) is added and the mixture is heated at reflux an additional three hours. The reaction mixture is cooled, filtered and concentrated to a solid which after recrystallization yields substantially pure 1-methyl-3,5-bis(4-pyrimidinyl)-1,2,4-triazole.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)CCC(=O)O)cc1
Yield: 84.6 %

Procedure:
The title compound was prepared from anisole (11 g, 102 mmol) and succinic anhydride (i2 g, 120 m mol) in presence of anhydrous aluminum chloride (30 g) by the same method as described for 2 above to furnish 4-(4-methoxyphenyl)-4-oxo-butanoic acid in 84.6% yield, which on purification and crystallization from methanol/ethyl acetate (1:9) produced white crystals of 3, mp142–43° C., analyzed for C11,H12, O4 (found C64.21, H5.86; requires C63.45, H5.80%).