Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(O)(C(F)(F)F)=O>C(Cl)Cl.O>[CH3:14][C:11]1([CH3:13])[O:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]([S:35]([CH3:34])(=[O:37])=[O:36])[S:35]([CH3:34])(=[O:37])=[O:36])=[CH:3][CH:4]=2)=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)[C:10]1=[O:15]
Reactant: CC1(C)OC(c2ccc(N)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)OC(c2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
To a stirred solution of 5-(4-aminophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (60 mg, 0.13 mmol) in DCM (5 mL) were added methane sulfonyl chloride (0.012 g, 0.15 mmol) and TFA (0.04 mL, 0.27 mmol) at 0° C. under N2 atmosphere. The reaction mixture was stirred at RT for 10 min. The reaction mixture diluted with water and extracted with DCM (2×10 mL). The combined organic layers were washed with water (2×5 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)phenyl)-N-(methylsulfonyl)methane sulfonamide (25 mg, 30%), as a white color solid. 1H NMR (500 MHz, CDCl3): δ 8.22 (d, J=8.5 Hz, 1 H), 8.10 (d, J=7.9 Hz, 1H), 7.76 (d, J=8.4 Hz, 1 H), 7.80 (d, J=8.2 Hz, 2 H), 7.74 (t, J=8.2 Hz, 1 H), 7.70 (d, J=8.5 Hz, 1 H), 7.56 (d, J=7.5 Hz, 1 H), 7.28 (d, J=7.4 Hz, 2 H), 7.12 (d, J=7.5 Hz, 2 H), 7.08 (d, J=7.6 Hz, 2H), 5.42 (s, 2 H), 3.42 (s, 6 H), 1.58 (s, 6H). MS: [M+Na]: m/z=615.1, [M+H]: m/z=593.1. HPLC: 98.9% (RT-2.52 min), Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].O.[NH2:13][NH2:14]>C(O)C>[NH:13]([C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9])[NH2:14]
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1nnc(Cl)cc1C(=O)O
Temperature: 5 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A mixture of 3,6-dichloro-4-carboxy-pyridazine (20 g; 0.103 mole) and 22 ml of 98% hydrazine hydrate in 200 ml of 50% ethanol was refluxed, under stirring, for one hour. After cooling at 5° C., the solid precipitate was collected, washed with 20 ml of anhydrous ethanol. The solid was suspended in 100 ml of water, the mixture was brought to pH 1-2 with 23% HCl, after cooling at 5° C. the solid was filtered, dried under vacuum at 80° C. to give 18.29 g (93.4%) of the title compound, m.p. 198°-201° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].[Cl-].[NH4+].C(OCC)(=O)C.CCCCCC>O1CCCC1>[Cl:10][CH2:11][C:12]1[CH:20]=[C:19]([CH:18]=[CH:17][C:13]=1[C:14](=[O:15])[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:21]#[N:22]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: N#Cc1ccc(C(=O)Cl)c(CCl)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1ccc(C(=O)c2ccc(F)cc2)c(CCl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-fluoro phenylmagnesium bromide (3.76 g) in tetrahydrofuran (15 ml) was added to a cooled solution of 2-chloromethyl-4-cyano-benzoyl chloride (3.95 g) in tetrahydrofuran (10 ml) so that the temperature did not raise above 0° C. The mixture was warmed slowly to room temperature and stirred over night. Saturated ammonium chloride solution (60 ml) was added and stirring continued for 0.5 hours. The phases were separated and the aqueous phase was extracted with diethylether (30 ml). The combined organic phases were dried over sodium sulfate, filtered and dried in vacuo to give a brown solid. Flash chromatography (ethyl acetate/n-hexane=1/10) provided the product as colourless solid. Yield 2.95 g, 58%. 1H NMR (CDCl3, 400 MHz): 4.71 (2H, s), 7.16-7.21 (2H, m), 7.46 (1H, d, J=7.9 Hz), 7.71 (1H, dd, J=1.5, 7.9 Hz), 7.81-7.86 (2H, m), 7.89 (1H, d, J=1.5 Hz). 13C NMR (CDCl3, 100 MHz): 42.3, 115.0, 116.4, 116.6, 117.9, 129.6, 132.95, 132.98, 133.4, 133.5, 134.3, 138.7, 142.4, 165.5, 168.1, 194.5.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[CH:8]=[CH:7]2.C([Li])CCC.[C:18](=[O:20])=[O:19].O>C1(C)C=CC=CC=1>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([C:18]([OH:20])=[O:19])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=C=O
Reactant: Clc1ccc2cccc(Br)c2n1
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1cccc2ccc(Cl)nc12
Reaction time: 0.33 h

Procedure:
To a solution of 8-bromo-2-chloroquinoline (14.3 g, 60 mmol) in toluene (90 mL) at −75° C. was added butyllithium in hexanes (2 mol/L, 30 mL) and the reaction mixture was kept for 20 min at −75° C. The reaction mixture was poured onto an excess of freshly crushed dry ice. Water was added (200 mL), and the aqueous layer was washed with ethyl acetate (3×100 mL), acidified to pH 1 with HCl (aq), and extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried, and concentrated to afford 2-chloroquinoline-8-carboxylic acid as a white solid. Yield 6.56 g (53.6%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH:11]1[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15]I.[H-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9](=[O:14])[N:10]([CH:11]1[CH2:12][CH2:13]1)[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CC1)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of cyclopropyl-carbamic acid benzyl ester (11.8 g) and methyl iodide (excess) in THF (80 mL) and DM (20 mL) at 0° C. was added NaH (2.20 g, 91.6 mmol) and the resulting mixture was warmed to room temperature and stirred overnight. The reaction was then quenched at 0° C. by sat NaHCO3. The separated aqueous phase was extracted several times with EtOAc. The combined extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (5% to 20% EtOAc/hexanes) to give cyclopropyl-methyl-carbamic acid benzyl ester (11.32 g, 91%).
Reaction SMILES: C([N:6]1[CH2:11][CH:10]([CH3:12])[CH:9]([NH:13][CH:14]2[CH2:16][CH2:15]2)[CH:8]([CH3:17])[CH2:7]1)(OCC)=O>[OH-].[Na+]>[CH:14]1([NH:13][CH:9]2[CH:8]([CH3:17])[CH2:7][NH:6][CH2:11][CH:10]2[CH3:12])[CH2:16][CH2:15]1
Reactant: CCOC(=O)N1CC(C)C(NC2CC2)C(C)C1
Agent: [Na+]
Agent: [OH-]
Product: CC1CNCC(C)C1NC1CC1

Procedure:
Mixture A of isomers of 1-carbethoxy-4-cyclopropylamino-3,5-dimethylpiperidine (3.5 g, 1.45 mmol) was stirred in 5 N NaOH solution (25 ml) at 100° C. for hr, cooled, extracted with ethyl acetate, dried (Na2SO4) and concentrated to afford Mixture A of isomers of 4-cyclopropylamino-3,5-dimethyl piperidine as oil.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:9]=[N+:10]=[N-:11].[Na+].Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>O>[C:2]1([C:1]2[NH:11][N:10]=[N:9][N:8]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2nnn[nH]2)cc1
Yield: 84 %

Procedure:
Into the same device as used in Example 1 were placed 5.16 g (0.050 mole) of benzonitrile, 4.23 g (0.065 mole) of sodium azide, 8.95 g (0.065 mole) of triethylamine hydrochloride, 52 ml of toluene and 2.6 g of water. The mixture was reacted at a temperature of 85° to 95° C. for 8 hours, giving 6.12 g (0.042 mole) of 5-phenyl-1H-tetrazole (yield 83.7% based on benzonitrile).
Reaction SMILES: [CH:1](=O)[C:2]([CH3:4])=[O:3].[NH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1.C1(C)C=CC(S([CH:27]([N+:35]#[C-:36])[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[CH2:16]([O:15][C:13]([N:10]1[CH2:9][CH2:8][CH:7]([N:6]2[C:1]([C:2](=[O:3])[CH3:4])=[C:27]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[N:35]=[CH:36]2)[CH2:12][CH2:11]1)=[O:14])[CH3:17]
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: CC(=O)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2C(C)=O)CC1
Reaction time: 15 h
Yield: 74.8 %

Procedure:
In an alternative procedure to that listed above, the title compound was prepared in the following manner: To a solution of pyruvaldehyde (40% w/w solution in water, 3.97 mL, 4.68 g, 25.94 mmol) in 34 mL of DMSO at room temperature was added dropwise ethyl 4-amino-piperidinecarboxylate (4.45 mL, 4.47 g, 25.94 mmol). After 10 min α-(p-toluenesulfonyl)-4-fluoro-benzylisonitrile (5.0 g, 17.3 mmol) and K2CO3 (2.39 g, 17.3 mmol) were added. After 15 h, the solution was diluted with 100 mL of EtOAc and washed with 2×100 mL of 3 N HCl. The aqueous layers were combined and basified with excess solid K2CO3 until the bubbling ceased. The aqueous layer was transferred to a separatory funnel and extracted 2×150 mL of EtOAc. The combined organics were washed with 3×75 mL of water and concentrated in vacuo to yield the imidazole product (4.65 g, 75%) which was used as is in subsequent steps.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:13]2[C@H:22]3[C:23]([O:25][CH2:26][C@@H:21]3[C@@H:20]([OH:27])[C:19]3[CH:18]=[C:17]4[O:28][CH2:29][O:30][C:16]4=[CH:15][C:14]2=3)=[O:24])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9]C.Cl>C(Cl)Cl.C(OCC)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C@H:13]2[C@H:22]3[C:23]([O:25][CH2:26][C@@H:21]3[C@H:20]([OH:27])[C:19]3[CH:18]=[C:17]4[O:28][CH2:29][O:30][C:16]4=[CH:15][C:14]2=3)=[O:24])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[OH:9]
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1OC
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc([C@@H]2c3cc4c(cc3[C@@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O

Procedure:
1 g of podophyllotoxin I is dissolved in a mixture of 15 ml of CH2Cl2 and 5 ml of ethyl ether. A slight stream of gaseous hydrochloric acid is introduced into the solution for 15 min at -10° C. and then stirring is maintained at this temperature for 1 h. After evaporating the reaction mixture without heating, 0.54 g of D,L-methionine and then 5 ml of methanesulfonic acid are added. After dissolving and stirring for 1 h with return to ordinary temperature, the reaction mixture is plunged into a water-acetone mixture and then BaCO3 is added to neutrality. After extracting with ethyl acetate, separating by settling, drying over Na2SO4, filtering and evaporating under reduced pressure, a residue is obtained which is crystallized from ethyl ether to provide 0.5 g (Yd 52%) of white crystals of 4'-demethylepipodophyllotoxin exhibiting a homogeneous spot by TLC.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH2:15]([N:17](CC)CC)[CH3:16].C(N)C>C1COCC1.O>[CH2:15]([NH:17][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)[CH3:16]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: CCN
Solvent: O
Solvent: C1CCOC1
Product: CCNc1nc(SC)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of 15.0 g (64.0 mmol) of ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate and 195 mL (1.39 mol) of triethylamine in 226 mL of THF are added 14.6 mL of aqueous 70% ethylamine solution. The mixture is stirred at room temperature for 2 hours. After diluting in water, the resulting mixture is extracted with ethyl acetate and the organic phase is dried over MgSO4. The product is purified by chromatography on silica gel, eluting with a cyclohexane/EtOAc mixture (8/15). 13.7 g of expected product are obtained in the form of a colourless oil. Yield=89%.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[C:14](=[O:22])[NH:15][C:16]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:18]=1>O1CCOCC1.[OH-].[Na+].O.C(=O)(O)[O-].[Na+]>[CH2:5]([O:4][C:2]([NH:12][C:13]1[C:14](=[O:22])[NH:15][C:16]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:18]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCc1ccc(N)c(=O)[nH]1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCc1ccc(NC(=O)OCc2ccccc2)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
Benzyl chloroformate (1.8 ml, 12.6 mmol) was added to a solution of 3-amino-6-propyl-2-(1H)-pyridinone (1.63 g, 10.8 mmol) in a mixture of dioxane (25 ml) and IN NaOH at 0° C. Within minutes a white precipitate formed. The reaction mixture was stirred at the same temperature for 1 hr then at room temperature for an additional hour. The reaction mixture was diluted with water and extracted with ethyl acetate then methylene chloride. Each extract was washed with brine then combined and dried over magnesium sulfate. Removal of the solvents in vacuo gave a yellow semi-solid which was a mixture of starting material and product. This was redissolved in a mixture of dioxane (24 ml) and 10% aqueous sodium bicarbonate (12 ml) and cooled to 0° C. Benzyl chloroformate(1.5 ml, 10.5 mmol) was once again added and after stirring for 30 min, thereaction mixture was allowed to stir at room temperature for 3 h. After dilution with water, the precipitate was filtered off and washed thoroughly, first with water and then with ether. Drying gave 2.64 g of the title compound as a white powder: 1H NMR (CDCl3) δ0.96 (t, J=7.3 Hz, 3 H), 1.68 (m, 2 H), 2.52 (t, J=7.5 Hz, 2 H), 5.22 (s, 2 H), 6.07 (d, J=7.5 Hz, 1 H), 7.34-7.43 (m, 4 H), 7.68 (s, 1 H),8.05 (brd,J=5.3Hz, 1H).
Reaction SMILES: S(=O)(O)[O-].[Na+].[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][CH2:21][NH2:22].[C-:23]#[N:24].[Na+]>O.C(O)C>[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][CH2:21][NH:22][CH:9]([C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[Cl:6])[C:23]#[N:24]
Reactant: NCCc1cccs1
Reactant: O=Cc1ccccc1Cl
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CC(NCCc1cccs1)c1ccccc1Cl
Temperature: 40 °C
Reaction time: 2 h

Procedure:
104 g (1 mol) of sodium bisulfite is dissolved in the mixture of 900 ml of water and 250 ml of ethanol and to the solution 140.6 g (1 mol) o-chlorobenzaldehyde is added. After a few minutes the aldehyde bisulfite adduct precipitates in the form of white crystals, while the temperature raises to 40° C. After 1 hour of stirring 127.2 g (1 mol) of 2-(2-thienyl)ethylamine is added to the reaction mixture, then it was stirred at 50° C. for 2 hours. During this time the crystalline aldehyde bisulfite transforms into an oily material. The mixture is cooled to room temperature and the solution of 49 g (1 mol) of sodium cyanide in 100 ml of water is added to it. During the addition the temperature of the reaction mixture raises to 40° C. The mixture is then stirred at 60° C. till the reaction is completed (1 hour). The oily organic phase is then extracted with 400 ml of 1,2-dichloroethane, washed to cyanide-free with 2×200 ml of water, traces of 2-(2-thienyl)ethylamine are removed by treatment with 100 ml of 3% hydrochloric acid solution. The dichloroethane phase was dried over anhydrous sodium sulfate and evaporated in vacuo. The residual fast crystallizing oil is the product. Weight: 260 g (94%) mp.: 40-41° C. The product was identified by elementary analysis, IR spectrum and 1H-NMR investigation.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6](Cl)[N:5]=[C:4]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.[F:24][C:25]([F:30])([F:29])[C@@H:26]([NH2:28])[CH3:27]>CN1CCCC1=O.CC(O)C.O>[Cl:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:5]=[C:6]([NH:28][C@@H:26]([CH3:27])[C:25]([F:30])([F:29])[F:24])[C:7]=1[C:8]1[C:9]([F:16])=[CH:10][C:11]([F:15])=[CH:12][C:13]=1[F:14]
Reactant: C[C@H](N)C(F)(F)F
Reactant: Fc1cc(F)c(-c2c(Cl)nc(-c3cnccn3)nc2Cl)c(F)c1
Solvent: CC(C)O
Solvent: O
Solvent: CN1CCCC1=O
Product: C[C@H](Nc1nc(-c2cnccn2)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Temperature: 110 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
To 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluoro-phenyl)-pyrimidine (40 g, 0.112 mol) in 1-methyl-2-pyrrolidinone (40 mL) there is added (S)-2,2,2-trifluoro-1-methyl-ethylamine (31.6 g, 0.28 mol). The mixture is sealed and heated to 110° C. and stirred for 24 h. The reaction mixture is cooled to room temperature and diluted with IPA (120 mL) and water (120 mL) added slowly over 30 minutes to form a solid. The solid is filtered and washed with water (2×60 mL) to give 6-chloro-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine in 84% yield and having a 98% HPLC purity and an enantiomeric excess of >99%. 1H NMR (DMSO-D6): 9.58 (d, 1H, J=1.1 Hz), 8.85 (m, 2H), 7.72 (d, 1H, J=8.8 Hz), 7.49 (m, 2H), 5.52 (m, 1H), 1.35 (d, 3H, J =7.0 Hz).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:26]1([N:23]2[CH2:24][CH2:25][N:20]([C:16]3[N:15]=[C:14]([C:12]4[S:4][C:3]5[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=5[C:1](=[O:10])[N:13]=4)[CH:19]=[CH:18][CH:17]=3)[CH2:21][CH2:22]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N#Cc1cccc(N2CCN(c3ccccc3)CC2)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(N3CCN(c4ccccc4)CC3)n2)sc2ccccc12
Yield: 33.3 %

Procedure:
A mixture of methyl thiosalicylate (0.25 g, 1.5 mmol), 2-cyano-6-(4-phenyl-1-piperazinyl)pyridine (0.40 g, 1.5 mmol), triethylamine (0.32 ml, 2.3 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixture was concentrated under reduced pressure and the crude crystals were recrystallized from ethanol to give the titled compound (0.20 g, 33%) as crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:18]=[C:17]2[N:8]([C:9](=[O:19])[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.CO>O1CCCC1.CCCCCC>[OH:3][CH2:4][C:6]1[CH:18]=[C:17]2[N:8]([C:9](=[O:19])[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[N:7]=1
Reactant: CCOC(=O)c1cc2c3ccccc3[nH]c(=O)n2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCCCCC
Product: O=c1[nH]c2ccccc2c2cc(CO)nn12
Yield: 99.1 %

Procedure:
A suspension of 3.84 g (0.015 mole) of 5,6-dihydro-5-oxopyrazolo[1,5-c]quinazoline-2-carboxylic acid ethyl ester prepared as described in part A above is stirred in 150 ml of tetrahydrofuran under nitrogen at room temperature. There is added 24 ml (0.034 mole) of a 20% solution of diisobutyl aluminum hydride in hexane. The resultant solution is stirred for 1 hour at room temperature whereupon 50 ml of methanol is added and the reaction mixture refluxed for 1 hour. The precipitate of aluminum alkoxide is filtered, air dried and Soxhlet extracted for 48 hours with boiling methanol. The extract is combined with the above filtrate and stripped to give 3.2 g of a white solid (quantitative yield). Recrystallization from methanol gives 2.7 g of pure title compound, m.p. 285°-287° .
Reaction SMILES: [CH2:1]([CH2:8][C:9](=O)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.C1(CS(O)(=O)=O)C=CC=CC=1.C1(CS(N[C@H](C(O)=O)CC(C)C)(=O)=O)C=CC=CC=1.C(N[C@H](C(O)=O)CC(C)C)(=O)C>C1C=CC=CC=1.C(O)C>[CH2:12]([NH:19][C@H:9]([CH3:10])[CH2:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: NCc1ccccc1
Agent: CC(=O)N[C@@H](CC(C)C)C(=O)O
Agent: CC(C)C[C@H](NS(=O)(=O)Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)Cc1ccccc1
Solvent: O
Solvent: CCO
Solvent: c1ccccc1
Product: C[C@H](CCc1ccccc1)NCc1ccccc1
Temperature: 25 °C

Procedure:
In an apparatus fitted with a Dean Stark trap, reflux a solution of 1.0 kg (6.75 mol) of benzylacetone, 725 g (6.75 mol) of benzylamine and 5.0 g of α-toluenesulfonic acid hydrate in 7 liters of benzene for 14 hours. Remove the solvent in vacuo, and dissolve the residue in 6.5 liters of methanol. With cooling and stirring, carefully add 125 g of NaBH4 and stir the mixture for 16 hours at room temperature. Remove the methanol in vacuo, and add 2 liters water and 4 liters benzene, and extract the product into the benzene. After drying (MgSO4), filter and distill (b.p. 145°-150° C./0.5 mm). Dissolve 1,028 g (4.288 mol) of the distillate and 1.23 kg (4.328 mol) of N-α-toluenesulfonyl-(L)-leucine in 7.2 liters of boiling ethanol and allow to cool to room temperature without agitation. Wash the precipitate with a small amount of ice-cold ethanol, recrystallize from 4.8 liters of ethanol, wash with ice-cold ethanol and filter off the solid product that is highly enriched with the salt of the undesired S enantiomer. Combine the mother liquor from the original precipitation and that from the recrystallization, remove the solvent and recover the free base by basifying with 500 ml of 20% aqueous NaOH and extracting with benzene. After drying (MgSO4), filtering and removing the benzene, dissolve the residue [487 g (2.04 mol)] and 346 g (2.06 mol) of N-acetyl-(L)-leucine in 2.0 liters of boiling ethanol and allow the solution to cool to room temperature. Filter and recrystallize once from 1.8 liter of ethanol followed by recrystallization from 4.0 liters of acetonitrile to obtain the desired R salt, m.p. 151°-152° C. Basify with 400 ml of aqueous 2.5N NaOH, extract with ether, dry (MgSO4), filter and remove the solvent in vacuo to obtain the product (2), [α]D26 =+4.5° (c=5.0, ethanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN(C)C=O.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([Cl:20])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Br)ccc1Cl
Temperature: 20 °C

Procedure:
5-bromo-2-chlorobenzoic acid (270 g, 1.15 mol) was suspended in methylene chloride (2700 mL). To the resulting mixture was added N,N-dimethylformamide (1 mL), and then added dropwise oxalyl chloride (288 mL, 3.46 mol) at 0° C. After the completion of dropwise addition, the mixture was warmed up to 20° C. and reacted for 3 h. The reaction mixture became clear, and TLC (Thin layer chromatography) indicated the completion of reaction. The reaction mixture was evaporated by rotation at 30-35° C. to produce a product, which was directly used in the next reaction.
Reaction SMILES: CI.[C:3]1([C:9]2([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[C:3]1([C:9]2([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1(c2ccccc2)CC1
Agent: [K+]
Solvent: CCOCC
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccccc2)CC1
Reaction time: 1 h

Procedure:
Methyl iodide (2.8 mL, 45.0 mmol) was added to a mixture of 1-phenylcyclopropanecarboxylic acid (4.9 g, 30.0 mmol) and potassium carbonate (8.3 g, 60.0 mmol) in DMF (50 mL) at room temperature and the reaction mixture was stirred for 1 h. Then the reaction mixture was diluted with diethyl ether. The resulting mixture was washed with water (×2)and brine successively, then dried and concentrated to afford the desired product.