Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Br[CH:7]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]>>[CH3:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[CH:7]([N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[N:4]1[CH:3]=[N:2][N:1]=[CH:5]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C(=O)C(Br)N1C(=O)c2ccccc2C1=O
Product: CC(C)(C)C(=O)C(N1C(=O)c2ccccc2C1=O)n1cnnc1
Yield: 23.4 %

Procedure:
21 g (0.3 mol) of 1,2,4-triazole were added to 32.4 g (0.1 mol) of 1-bromo-3,3-dimethyl-1-phthalimido-butan-2-one in 200 ml of acetontrile. The mixture was heated for 24 hours under reflux and was then concentrated in a waterpump vacuum. The residue was taken up in 200 ml of methylene chloride and the solution was washed three times in 100 ml of water at a time, dried over sodium sulphate and concentrated in vacuo by distilling off the solvent. The residue was taken up in 200 ml of acetone, the solution was heated with active charcoal and filtered, and 18 g of 1,5-naphthalenedisulphonic acid were added to the filtrate. The resulting precipitate (25.4 g of the naphthalenedisulphonate salt of melting point 155°-162° C., with decomposition) was neutralized with sodium hydrogen carbonate solution. The oil thereby formed was recrystallized from petroleum ether/ethanol. 7.3 g (23% of theory) of 3,3-dimethyl-1-phthalimido-1-(1,2,4-triazol-4-yl)-butan-2 -one of melting point 189°-196° C. were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:10][CH:6]([C:5]1[CH:11]=[CH:12][C:2]([Br:1])=[CH:3][CH:4]=1)[C:7]([OH:9])=[O:8])(=[O:15])[CH3:14]
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C(=O)O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of 4-bromomandelic acid (20.6 g, 89.0 mmol) dissolved in pyridine (50 mL) was added acetic anhydride (10 g, 98 mmol) dropwise while cooling with an ice bath. After stirring overnight at room temperature, the solvent was removed and the resulting residue dissolved in ethyl acetate (150 mL). This was washed twice with 1N HCl, brine, and then concentrated in vacuo to obtain a white solid (18.2 g, 75%) which was used without further purification.
Reaction SMILES: OC1C=CC(C=O)=CC=1.BrC1CC1.[F:14][C:15]([F:24])([F:23])[C:16]1[N:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.[C:25]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1)#[N:26]>>[F:24][C:15]([F:14])([F:23])[C:16]1[N:21]=[CH:20][C:19]([O:22][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([C:25]#[N:26])=[CH:28][CH:29]=2)=[CH:18][CH:17]=1
Reactant: Oc1ccc(C(F)(F)F)nc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: BrC1CC1
Agent: O=Cc1ccc(O)cc1
Product: N#Cc1ccc(COc2ccc(C(F)(F)F)nc2)cc1
Yield: 96.7 %

Procedure:
Instead of 4-hydroxybenzaldehyde and bromocyclopropane, 6-(trifluoromethyl)pyridin-3-ol (1.21 g) and 4-cyanobenzylbromide (1.45 g) were respectively used and treated by the same technique as in Reference Example 10-1 to give 4-({[6-(trifluoromethyl)pyridin-3-yl]oxy}methyl)benzonitrile as a pale brown solid (1.99 g).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:9]([CH2:10][CH:11]=[O:12])=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1.[NH4+].[Cl-]>C1COCC1.CO>[Cl:3][C:4]1[C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1
Reactant: O=CCc1ccc(Cl)nc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: OCCc1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
NaBH4 (80 mg, 2.11 mmol) was added to a solution of 2-(2,6-dichloropyridin-3-yl)acetaldehyde (200 mg, 1.05 mmol) in THF (1 ml) and MeOH (1 ml) and stirred at RT for 1 hour. The resulting mixture was treated with NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the yellow oil 2-(2,6-dichloropyridin-3-yl)ethanol (200 mg, yield: 99%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([NH2:26])[C:24]#[CH:25]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:26][CH2:23][C:24]#[CH:25])=[O:11])[CH2:7]1
Reactant: C#CCN
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCNC(=O)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Reaction time: 18 h
Yield: 83.2 %

Procedure:
A stirred mixture of 5.6 g (0.02 mole) of 3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride and 3 g (0.02 mole) of potassium carbonate in 20 ml of tetrahydrofuran was treated with 1.1 g (0.02 mole) of 2-propynylamine added dropwise from a needle syringe then stirred for an additional 18 hr. The reaction mixture was diluted with 200 ml of water and the resulting solid collected by filtration to yield 7.1 g of crude product. Recrystallization from isopropyl ether yielded 4.98 g (83.2%) of pale beige crystals, m.p. 119°-121° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:26])CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:26])([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2nccs2)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2nccs2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4-hydroxy-4-thiazol-2-yl-piperidine-1-carboxylic acid tert-butyl ester (4.36 g, 15.3 mmol) in CH2Cl2 (50 mL) at 0° C. was added DAST (2.4 mL, 1.2 eq.). The reaction mixture was stirred for 30 minutes before it was quenched by addition of saturated NaHCO3 solution (20 mL). The organic phase was separated and dried over Na2SO4. After removal of the solvent, the crude product was purified on silica gel (EtOAc:hexanes=1:4) to afford the desired product as a pale yellow oil.
Reaction SMILES: C1(C(C2C=CC=CC=2)([C@H]2CCCN2)O)C=CC=CC=1.B([O-])([O-])[O-].B.C(N(CC)C1C=CC=CC=1)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43](=[O:58])[CH2:44][CH2:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([N+:55]([O-:57])=[O:56])[CH:49]=2)=[O:47])=[CH:39][C:38]=1[N+:59]([O-:61])=[O:60]>C1COCC1>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C@@H:43]([OH:58])[CH2:44][CH2:45][C@@H:46]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([N+:55]([O-:57])=[O:56])[CH:49]=2)[OH:47])=[CH:39][C:38]=1[N+:59]([O-:61])=[O:60]
Reactant: O=C(CCC(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: B
Agent: OC(c1ccccc1)(c1ccccc1)[C@H]1CCCN1
Agent: [O-]B([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)c1ccccc1
Product: O=[N+]([O-])c1cc([C@@H](O)CC[C@H](O)c2ccc(Cl)c([N+](=O)[O-])c2)ccc1Cl
Temperature: 10 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
(R)-(+)-alpha,alpha-diphenyl-2-pyrrolidinemethanol (1.08 g, 4.28 mmol) was dissolved in 70 mL of THF at ambient temperature in a dry flask under nitrogen and the timethyl borate (650 uL, 5.54 mmol) was added dropwise. The resulting solution was stirred for 1 hr. The solution was cooled in a cold bath to ˜10° C. and the N,N-diethylaniline borane (9.18 mL, 51.6 mmol) was added dropwise with some bubbling. After 15 min, this solution was transferred to an addition funnel and added dropwise to 1,4-bis(4-chloro-3-nitrophenyl)butane-1,4-dione (Example 109B) (10.0 g, 25.2 mmol) suspended in 200 mL of THF and cooled to ˜10° C. Bubbling was observed. After the addition, mixture was stirred at ambient temperature for 4 hours. The mixture was cooled in an ice bath and 30 mL MeOH was added dropwise till bubbling stopped, then the mixture was let stir at ambient temperature for 30 min. The mixture was filtered to get rid of a trace of insoluble unreacted SM. The filtrate was concentrated, poured into 1 M HCl and extracted into ethyl acetate, dried over sodium sulfate; concentrated to give the title compound (9.9 g, 99%) as a yellow waxy solid. Chiral HPLC e.e. >99.9% (RR diol was undetectable). 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=1.9 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 7.60 (dd, J=8.4, 1.9 Hz, 2H), 4.65 (m, 2H), 1.62 (m, 4H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16](=[O:17])[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8]2)[CH2:3][CH2:2]1.Cl[C:19]1[C:27]2[NH:26][N:25]=[CH:24][C:23]=2[C:22]2[CH2:28][N:29]([CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C:30](=[O:53])[C@@H:31]([CH2:33][C:34](=[O:52])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:32][C:21]=2[CH:20]=1>>[CH2:54]([N:29]1[C:30](=[O:53])[C@H:31]([CH2:33][C:34](=[O:52])[N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:16](=[O:17])[CH2:15][C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:8]3)[CH2:3][CH2:2]2)[CH2:32][C:21]2[CH:20]=[CH:19][C:27]3[NH:26][N:25]=[CH:24][C:23]=3[C:22]=2[CH2:28]1)[C:55]([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Reactant: O=C1Cc2ccccc2CN1C1CCNCC1
Product: CC(C)(C)CN1Cc2c(ccc3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4CC3=O)CC2)C1=O
Yield: 40 %

Procedure:
2-(Piperidin-4-yl)-1,2-dihydroisoquinolin-3(4H)-one (105 mg, 0.46 mmol) and [9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]acetic acid (110 mg, 0.33 mmol) were combined in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as a white solid in 40% yield. High resolution MS m/e (M+H)+=541.3111.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[N+](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N-].N#N>[Cu].C1CCCCC1>[CH2:21]([O:20][C:18]([CH2:17][O:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])=[O:19])[CH3:22]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C(CCCO)OCc1ccccc1
Agent: [Cu]
Agent: N#N
Solvent: C1CCCCC1
Product: CCOC(=O)COCCCC(=O)OCc1ccccc1
Reaction time: 4 h

Procedure:
65 g (0.33 tool) of benzyl 4-hydroxybutyrate and 260 mg of copper powder are charged to 120 ml of cyclohexane and the mixture is heated to reflux. Then a mixture of 38.7 ml (0.37 mol) of ethyl diazoacetate and 300 ml of cyclohexane are added, whereupon evolution of N2 ensues. The reaction mixture is stirred for 4 hours under reflux and then for 4 hours at room temperature, filtered over a glass fibre filter and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/ethyl acetam 4:1, giving benzyl 4-ethoxycarbonylmethoxybutyrate as a colourless liquid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH3:10].C(=O)([O-])[O-].[K+].[K+].C1C(=O)N([Br:24])C(=O)C1>C1COCC1.CCOC(C)=O.O>[Br:24][C:9]1[N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:6]([CH3:10])=[N:7][CH:8]=1
Reactant: COCCn1ccnc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COCCn1c(Br)cnc1C
Reaction time: 18 h
Yield: 67.3 %

Procedure:
To a solution of 1-(2-methoxyethyl)-2-methyl-1H-imidazole (Preparation 210, 0.5 g, 3.57 mmol) in THF (6.5 ml) was added potassium carbonate (0.1 g, 0.713 mmol) and NBS (0.6 g, 3.39 mmol). The reaction mixture was stirred at r.t for 18 hrs. The reaction mixture was diluted with EtOAc (30 ml) and water (30 ml). The aqueous layer was re-extracted with EtOAc (30 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound (500 mg, 64%).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=2[NH:8]S(C2C=CC(C)=CC=2)(=O)=O)=[O:5])[CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:24].[OH-].[NH4+]>>[NH2:8][C:7]1[CH:19]=[CH:20][CH:21]=[CH:22][C:6]=1[C:4](=[O:5])[CH2:1][CH2:2][CH2:3][OH:24]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccccc2C(=O)C2CC2)cc1
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ccccc1C(=O)CCCO
Temperature: 90 °C
Yield: 80 %

Procedure:
The product of example 2 (1.5 g, 4.7 mmol) is treated with 96% sulfuric acid and heated to 90° C. for 15 minutes. The solution is cooled, adjusted to pH 9 with ammonium hydroxide and extracted with methylene chloride. The combined extracts are concentrated in vacuo to provide 1-(o-aminophenyl)-4-hydroxy-1-butanone (80% yield, mp 58-61° C.). The product is identified by NMR and MS analyses.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][C:8]=1[N+:18]([O-])=O>C(O)C.[C].[Pd]>[NH2:18][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][C:7]=1[NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:21])[CH3:1])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1ccc(NCCCN(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(NCCCN(C)C)c(N)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.9 %

Procedure:
10% of palladium-carbon (0.40 g) was added to a solution containing ethyl 4-{[3-(dimethylamino)propyl]amino}-3-nitrobenzoate (2.02 g) in ethanol (20 ml) and stirred for 5 hours under a hydrogen gas atmosphere at room temperature. After the catalyst was removed out by filtration, the filtrate was concentrated, thereby yielding the entitled compound (1.85 g) as dark red oil.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8])=[N+]=[N-]>C(O)C>[NH2:1][CH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8]
Reactant: CNC(=O)c1ccc(Cl)cc1CN=[N+]=[N-]
Solvent: CCO
Product: CNC(=O)c1ccccc1CN

Procedure:
2-(Azidomethyl)-4-chloro-N-methylbenzamide (0.88 g, 3.94 mmol) was dissolved in ethanol (25 mL), degassed, treated with 10% Pd on carbon (80 mg), and put under one atmosphere of hydrogen. After one hour the reaction was filtered through Celite, and concentrated in vacuo to afford 2-(aminomethyl)-N-methylbenzamide as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:11](/[CH:12]=[CH:13]/[C:14](O)=[O:15])=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:23].S(Cl)([Cl:26])=O>>[CH3:1][N:2]1[C:11](/[CH:12]=[CH:13]/[C:14]([Cl:26])=[O:15])=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:23]
Reactant: O=S(Cl)Cl
Reactant: Cn1c(/C=C/C(=O)O)c(-c2ccccc2)c2ccccc2c1=O
Product: Cn1c(/C=C/C(=O)Cl)c(-c2ccccc2)c2ccccc2c1=O

Procedure:
A solution of (E)-3-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)propenoic acid (0.92 g) in thionyl chloride (15 ml) was heated at reflux for 4 hours. The excess thionyl chloride was then removed by distillation and the residual yellow solid was washed with petroleum ether (b.p. 40°-60° C.), to give (E)-3-(2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)propenoyl chloride (1.0 g) in the form of a yellow solid, m.p.213°-215° C.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([C:16]([CH3:20])([C:18]#[N:19])[CH3:17])[CH:15]=1)[C:9](OC)=[O:10])([CH3:5])[CH3:4])#[N:2].[BH4-].[Li+].Cl>O1CCCC1>[OH:10][CH2:9][C:8]1[CH:7]=[C:6]([C:3]([CH3:5])([CH3:4])[C:1]#[N:2])[CH:15]=[C:14]([C:16]([CH3:20])([CH3:17])[C:18]#[N:19])[CH:13]=1
Reactant: COC(=O)c1cc(C(C)(C)C#N)cc(C(C)(C)C#N)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cc(CO)cc(C(C)(C)C#N)c1

Procedure:
A mixture of methyl 3,5-bis(1-cyano-1-methyl ethyl)benzoate (5.6 g), lithium borohydride (0.44 g) and tetrahydrofuran (30 ml) was heated under reflux for 2 h. The mixture was cooled and stirred while 2N aqueous hydrochloric acid was added dropwise until the solution remained acidic, and then the mixture was extracted twice with ethyl acetate. The combined extracts were washed with 1N aqueous potasium bicarbonate solution and then dried and evaporated to dryness under reduced pressure to give 2,2'-(5-hydroxymethyl-1,3-phenylene)di(2-methylpropiononitrile), mp. 151°-153°, which was used without further purification.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.C([O:26][C:27](=[O:41])[CH:28]=[CH:29][C:30]1[CH:39]=[C:38]2[C:33]([O:34][CH2:35][C:36](=[O:40])[NH:37]2)=[N:32][CH:31]=1)(C)(C)C.[NH4+].[Cl-]>C1COCC1>[CH2:1]([N:8]([C@@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:16])[C@H:29]([C:30]1[CH:39]=[C:38]2[C:33]([O:34][CH2:35][C:36](=[O:40])[NH:37]2)=[N:32][CH:31]=1)[CH2:28][C:27]([OH:41])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](NCc1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C=Cc1cnc2c(c1)NC(=O)CO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N(Cc1ccccc1)[C@@H](CC(=O)O)c1cnc2c(c1)NC(=O)CO2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of N-benzyl-α-(R)-methylbenzylamine (0.82 g, 3.87 mmol) in THF (25 mL) at 0° C. was treated with n-BuLi (1.6 mL of a 2.5 M soln in hexanes). The resulting solution was stirred at 0° C. for 30 min and then cooled to -78° C. A solution of acrylate 20-5 (0.485 g, 1.76 mmol) in THF (5 mL) was added. After stirring for 15 min at -78° C., satd aq NH4Cl soln (5 mL) was added and the cold bath removed. The mixture was warmed to room temperature, and extracted with Et2O (2×40 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (40% ethyl acetate/hexanes) to give the β-aminoester 20-6 as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:11].CCN(C(C)C)C(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:43][C:44]1[S:45][CH:46]=[CH:47][N:48]=1>CN(C=O)C.ClCCCl.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:43][C:44]2[S:45][CH:46]=[CH:47][N:48]=2)=[O:8])=[CH:4][C:3]=1[Cl:11]
Reactant: Nc1nccs1
Reactant: Nc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Nc1ccc(C(=O)Nc2nccs2)cc1Cl
Temperature: 60 °C

Procedure:
4-Amino-3-chloro-benzoic acid (19.8 mmol) was dissolved in DMF (10 mL) and 1,2-dichloroethane (80 mL). DIPEA (19.8 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (19.8 mmol), 1-hydroxybenzotriazole (19.8 mmol) and 2-aminothiazole (19.8 mmol) was added, and the reaction mixture was stirred at 60° C. over night. The volume was reduced in vacuo, and water (60 mL) was added. The mixture was extracted with ethyl acetate, the organic phase was washed with NH4Cl (aq., sat.), dried over MgSO4, filtered and evaporated. The crude product was purified by flash chromatography on silica using gradient elution (heptane/ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH2:11][CH2:12]CO)=[O:9])[NH:5][C:6]=1[Br:7]>CS(O)(=O)=O.CCOCC>[Br:7][C:6]1[NH:5][C:4]([C:8]2[O:9][CH2:12][CH2:11][N:10]=2)=[CH:3][C:2]=1[Br:1]
Reactant: O=C(NCCCO)c1cc(Br)c(Br)[nH]1
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: Brc1cc(C2=NCCO2)[nH]c1Br
Yield: 61.9 %

Procedure:
Method A. A solution of 10 (0.25 g, 0.77 mmol) in 2 mL of methanesulfonic acid was heated at 60° C. for 3 d. The reaction mixture was diluted with ether (100 mL) and washed with sat. NaHCO3 (20 mL×3) and sat. NaCl (20 mL). The organic layer was dried (MgSO4) and evaporated under reduced pressure. The resulting residue was purified by flash chromatography (EtOAc/hexanes 1:1) to give 14 (0.14 g, 59%) as a colorless solid: 1H NMR (CDCl3) d 2.00 (p, 2H, J=5.7), 3.52 (t, 2H, J=5.7), 4.32 (t, 2H, J=5.7), 6.58 (s, 1H), 10.10 (br, 1H); 13C NMR (CD3COCD3) d 22.2 (e), 41.3 (e), 66.6 (e), 99.1 (e), 109.4 (e), 115.0 (o), 127.7 (e), 153.8 (e); UV (CH3OH) lmax 329, 275 nm; MS m/z (relative intensity) 311 (M++5, 50), 309 (M++3, 100), 307 (M++1, 50); Anal. Calcd for C8H8N2OBr2: C, 31.20; H, 2.62; N, 9.10; Found: C, 31.17; H, 2.51; N, 9.29. Method B. To a stirred mixture of 10 (0.25 g, 0.77 mmol) and p-toluenesulfonyl chloride (0.16 g, 0.77 mmol) in 10 mL of THF was added triethylamine (0.6 mL, 4.27 mmol) at room temperature. The mixture was heated at 80° C. overnight. The solvent was evaporated under reduced pressure and the resulting residue was purified by flash chromatography (CH2Cl2/MeOH 19:1) to give 14 (0.15 g, 63%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[C:22](S(C)(=O)=O)[C:23]=2[C:24](=[O:31])[NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[C-:36]#[N:37].[Na+].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[C:22]([C:36]#[N:37])[C:23]=2[C:24](=[O:31])[NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)c1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 6.6 %

Procedure:
To a solution of the compound obtained in Example 33 (300 mg) in dimethylformamide (10 mL) was added sodium cyanide (42.1 mg) and the mixture was stirred at 10° C. for 1.5 hours in a microwave reactor. After cooling to room temperature, to the reaction mixture was added ethyl acetate and an aqueous sodium hydrogencarbonate solution and the mixture was stirred. The organic layer was washed with water and concentrated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=80/20 to 65/35) to give 6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-cyano-3-(N-cyclopentylcarbamoyl)pyrazolo[1,5-a]pyrimidine (17.8 mg; yield: 81%) as a pale yellow solid.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[O:2].C([O:8][C:9](=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)C.[H-].[Na+].Cl>C(OCC)C>[CH2:4]([O:3][C:1](=[O:2])[CH:10]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH:9]=[O:8])[CH3:5]
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Reactant: CCOC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(C=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
Ethyl formate (7.46 g, 0.101 mol) was added dropwise to a stirred ice-cooled suspension of (4-chlorophenyl)acetic acid ethyl ester (20.0 g, 0.101 mol) and NaH (0.131 mol) in diethyl ether (100 mL). The mixture was then allowed to warm to room temperature overnight. The mixture neutralised (1 M HCl); the organic layer was isolated, dried, and the solvent removed to give 2-(4-chlorophenyl)-3-oxo-propanoic acid ethyl ester as a colourless solid (19.8 g, 87%). 1H NMR (CDCl3): δ 12.14 (d, J=12.8, 1H), 7.31-7.18 (m, 4H), 4.29 (q, J=7.2, 2H), 1.57 (br, 1H), 1.29 (t, J=7.2, 3H).