Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([CH3:23])=[N:19][O:20][C:21]=3[CH3:22])=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1.C1(C)C=CC=CC=1.[OH-].[Na+]>C(#N)C.[Cl-].[Na+].O>[CH3:23][C:18]1[C:17]([C:14]2[CH:15]=[CH:16][C:10]3[O:9][C:8]([CH2:7][CH2:6][N:26]4[CH2:27][CH2:28][CH2:29][C@H:25]4[CH3:24])=[CH:12][C:11]=3[CH:13]=2)=[C:21]([CH3:22])[O:20][N:19]=1
Reactant: Cc1noc(C)c1-c1ccc2oc(CCOS(C)(=O)=O)cc2c1
Reactant: C[C@@H]1CCCN1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: Cc1noc(C)c1-c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Temperature: 25 °C
Yield: 69 %

Procedure:
A 3.3 mL (1 mmol) aliquot of the product from Example 161B in 8.33 mL of acetonitrile was transferred to a separate flask. Mono-(L)-tartaric acid salt of (R)-2-methylpyrrolidine (0.82 g, 3.5 mmol) was converted to the free base by shaking with 1 mL of toluene, 0.5 mL of 50% wt/vol sodium hydroxide, and 2 mL of brine. After separating, the toluene layer was decanted by pipette and added to the 3.3 mL aliquot of the product from Example 16 1B. After stirring for one week at room temperature, the reaction was poured into dichloromethane and washed with aqueous ammonia, dried over sodium sulfate, and purified by flash chromatography, eluting with 97:3 dichloromethane/methanol/0.1% NH3, to give 225 mg (69%) of the title compound as a clear oil. MS (DCI) m/z 325.2 (M+H)+; 1HNMR (300 MHz, CDCl3) δ 1.18 (d, 1H, J=6.3 Hz), 2.24 (s, 3H), 2.40 (s, 3H), 1.5-2.0 (m, 6H), 2.5 (m, 1H), 3.02 (t, 2H, J=7.5 Hz), 3.23 (m, 2H), 6.48 (s, 1H), 7.08 (dd, 1H, J=9.0, 2.1 Hz), 7.34 (d, 1H, J=2.1 Hz), 7.44 (d, 1H, 9.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][CH2:11][CH2:10][NH:9][CH2:8][C:7]=2[CH:13]=1.C(N(CC)CC)C.[Br:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>C1COCC1>[Br:21][CH2:22][CH2:23][C:24]([N:9]1[CH2:8][C:7]2[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[S:12][CH2:11][CH2:10]1)=[O:25]
Reactant: O=C(Cl)CCBr
Reactant: COc1ccc2c(c1)CNCCS2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(C(=O)CCBr)CCS2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.250 g) and triethyl amine (0.53 g) in THF (10 ml) at 0° C. was added dropwise 3-bromopropionic chloride (0.444 g). The resulting mixture was stirred at 0° C. for 1 hour and at room temperature overnight. After dilution with ethyl acetate, the organic phase was washed with saturated NaHCO3/H2O and H2O. After drying over sodium sulfate and filtration, removal of solvent gave to the product.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([NH:14][C:15](=[NH:18])[NH:16][CH3:17])=[O:13])[CH3:2].[CH3:19]N(C(OC)OC)C.[ClH:27].CO>CC#N>[ClH:27].[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[N:11]1[CH:17]=[N:16][C:15]([NH:18][CH3:19])=[N:14][C:12]1=[O:13])[CH3:10]
Reactant: COC(OC)N(C)C
Reactant: CCc1cccc(CC)c1NC(=O)NC(=N)NC
Agent: Cl
Solvent: CC#N
Solvent: CO
Product: CCc1cccc(CC)c1-n1cnc(NC)nc1=O
Yield: 47 %

Procedure:
To a suspension of 22.8 g (80.0 mmol) of 1-(2,6-diethylphenyl)-3-methylamidinourea in CH3CN (100 ml) were added 19.1 g (160.0 mmol) of DMF-DMA and the reaction mixture was heated to reflux for 3 hours. The CH3CN was removed under reduced pressure and the residue partitioned between CHCl3 and H2O. The layers were separated and the aqueous layer extracted with CHCl3 (1×100 ml), dried (MgSO4) and concentrated under reduced pressure to give an off-white solid, which by NMR confirmed the desired free base. The solution was dissolved in H2OH and acidified with HCl/MeOH and the MeOH removed under reduced pressure to give an off-white solid which was crystallized from CH3CN to give after vacuum drying and weekend (105° C., house vacuum) 16.7 g (71%) of crude product. The material was recrystallized from CH3CN (a hot filtration was necessary to remove some undissolved solid) to give 11.0 g (47%) of desired product as a white crystalline solid:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=O)[C:8]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:9][N:10](C)C)=[CH:4][CH:3]=1.O.[NH2:22]N>C(O)C>[Cl:19][C:15]1[CH:14]=[C:13]([C:8]2[C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:22][NH:10][CH:9]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)s1)c1ccnc(Cl)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Clc1cc(-c2c[nH]nc2-c2ccc(Cl)s2)ccn1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 101.3 %

Procedure:
A mixture of 1-(5-chloro-2-thienyl)-3-(dimethylamino)-2-(2-chloropyridin-4-yl)prop-2-en-1-one (10 mmol), hydrazine hydrate (20 mmol) in 90 mL ethanol was stirred at 80° C. for 1.5 h. The solvent was evaporated under reduced pressure to afford 3 g 2-chloro-4-[3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (95% yield).
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:22]=[C:21](F)[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]>O>[Cl:12][C:13]1[CH:22]=[C:21]([NH:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: NCC1CC1
Reactant: COC(=O)c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1ccc(NCC2CC2)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.8 %

Procedure:
Cyclopropylmethylamine (1.51 g) and potassium carbonate (1.46 g) were added to a solution of methyl 2-chloro-4-fluorobenzoate (1.00 g). The reaction mixture was stirred at room temperature for 6 hours and then heated with stirring at 100° C. for 6 hours under a microwave reactor. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (1.23 g).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:23].Br[CH2:25][C:26]#[N:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[S:15][CH:16]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:23][CH2:25][C:26]#[N:27]
Reactant: N#CCBr
Reactant: Oc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#CCOc1ccc2cc(-c3csc(-c4ccccc4)n3)ccc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
A mixture of 1-bromo-6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthol (351 mg, 0.918 mmol), prepared in step 1 of Example 3, bromoacetonitrile (77 μL, 1.11 mmol) and cesium carbonate (1.505 g, 4.62 mmol) in 25 mL of acetone was stirred under nitrogen at room temperature for 19 h (overnight). The reaction was concentrated under reduced pressure to remove the acetone. The residue was partitioned between methylene chloride and water. The aqueous layer was separated and extracted three times with methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give {[1-bromo-6-(2-phenyl-1,3-thiazol-4-yl)-2-naphthyl]oxy}acetonitrile (382 mg, 99%) as a light tan solid, mp 157-160° C. Elemental Analysis for C21H13BrN2OS Calc'd: C, 59.87; H, 3.11; N, 6.65. Found: C, 59.56; H, 3.28; N, 6.56.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[CH:16]=[C:15]([CH2:17][O:18][CH3:19])[O:14][N:13]=2)=[C:10]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[C:11]([C:12]2[CH:16]=[C:15]([CH2:17][O:18][CH3:19])[O:14][N:13]=2)=[C:10]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COCc1cc(-c2c(S(C)(=O)=O)ccc(C(=O)OC)c2Cl)no1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCc1cc(-c2c(S(C)(=O)=O)ccc(C(=O)O)c2Cl)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
1.23 g (3.4 mmol) of methyl 2-chloro-3-(5-methoxymethylisoxazol-3-yl)-4-methylsulfonylbenzoate are dissolved in 30 ml of tetrahydrofuran/20 ml of water and treated with 0.15 g (3.8 mmol) of sodium hydroxide. After stirring at room temperature for 18 hours, the reaction mixture is concentrated, adjusted to pH 2 using 2N hydrochloric acid and extracted with dichloromethane. 1.05 g (94.8% of theory) of 2-chloro-3-(5-methoxymethylisoxazol-3-yl)-4-methylsulfonylbenzoic acid are obtained as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][NH:13][CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[C:19](O)=[O:20].O.ON1C2C=CC=CC=2N=N1.CCN(CC)CC>C(Cl)Cl>[CH3:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[C:19]([N:13]1[CH2:12][CH2:11][NH:10][CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14]1)=[O:20]
Reactant: Clc1ccc(C2CNCCN2)cc1Cl
Reactant: Cc1cc(C)cc(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C)cc(C(=O)N2CCNC(c3ccc(Cl)c(Cl)c3)C2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 57.8 %

Procedure:
To a cooled solution of CH2Cl2 (600 mL) containing 2-(3,4-dichlorophenyl)piperazine (6.934 g, 30 mmol), 3,5-dimethylbenzoic acid (4.55 g, 30 mmol), and N-hydroxybenzotriazole monohydrate (4.05 g, 30 mmol) at -20° C. were added Et3N (4.2 mL, 30 mmol) and N,N-dimethylaminopropylethylcarbodimide (DEC) (5.86 g, 30 mmol) under nitrogen. The reaction was kept at -20° C. for an hour and gradually warmed to RT overnight. After stirring 22 hours, the reaction was complete and CH2Cl2 (200 mL) was added. The organic solution was washed with brine (150 mL, 3×), dried over MgSO4 , filtered and concentrated under vacuum to give 8.2 g of crude product. The product was crystallized from CH2Cl2 /Hexane to give a light yellow solid (6.3 g, 17.34 mmol, 57.8%), m.p.139°-141° C.; FAB MS [M+1]+ 35 Cl 363.1.
Reaction SMILES: [Br:1][CH2:2][CH2:3][NH:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]2[N:21]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:22](=[O:24])[NH:23][C:19]=2[CH:18]=1>CN(C)C=O>[BrH:1].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]2[N:21]([CH:25]3[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][NH:4][C:5](=[O:15])[C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[N+:12]([O-:14])=[O:13])[CH2:29][CH2:30]3)[C:22](=[O:24])[NH:23][C:19]=2[CH:18]=1
Reactant: O=C(NCCBr)c1ccccc1[N+](=O)[O-]
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Solvent: CN(C)C=O
Product: Br
Product: O=C(NCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1)c1ccccc1[N+](=O)[O-]
Yield: 67 %

Procedure:
A mixture of 1.5 parts of N-(2-bromoethyl)-2-nitrobenzamide, 1.55 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one and 27 parts of N,N-dimethylformamide is stirred and refluxed for 5 hours. The reaction mixture is evaporated and the oily residue is crystallized from ethanol. The product is filtered off and dried, yielding 2.2 parts (67%) of N-{2-[4-(5-chloro-2,3-dihydro-2-oxo- 1H-benzimidazol-1-yl)-1-piperidinyl] ethyl}-2-nitrobenzamide hydrobromide. hemihydrate; mp. 273.2° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH2:20])=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+].O>CCO>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:20][CH2:19][CH2:18][C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: COc1nc(Cl)cc(Cl)n1
Reactant: NCCc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2)n1
Yield: 94.3 %

Procedure:
A solution of 4,6-dichloro-2-methoxypyrimidine [0.7 g, Intermediate (4)], 2-(4-chlorophenyl)-ethylamine (0.66 g) and sodium bicarbonate (0.88 g) in EtOH (25 ml) is heated at 80° C. for three hours, poured into water (400 mL) and the solid is filtered and air dried affording (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(4-chlorophenyl)-ethyl]amine [1.1 g, Intermediate (14)]. MS: 299 (M+H). 1H NMR (CD3)2SO]: δ 8 (d, 2H, J=3 Hz); 7.4 (2H, d, J=3 Hz); 6.05 (1H, s); 4 (3H, s): 3.6-3.7 (2H, m); 2.95 (2H, t).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:12])[O:8][CH2:9][CH2:10][F:11])[C@H:3]1[C:13]([OH:15])=[O:14].[C:17]([CH:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[CH:18]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:12])[O:8][CH2:9][CH2:10][F:11])[C@H:3]1[C:13]([O:15][CH:19]([C:17]#[CH:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)=[O:14]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCCF
Reactant: C#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: C#CC(OC(=O)[C@@H]1[C@H](/C=C\C(=O)OCCF)C1(C)C)c1cccc(Oc2ccccc2)c1

Procedure:
Using the procedure of Step F of Example 9, (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2-fluoroethoxy)-1-propenyl]-cyclopropane-carboxylic acid and α-ethynyl-3-phenoxybenzyl alcohol were reacted to obtain α-ethynyl-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2-fluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+47°±1.5° (c=1% in CHCl3).
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[OH-].[K+].[CH3:7][N:8]1[C:12](Cl)=[C:11]([Cl:14])[C:10]([Cl:15])=[N:9]1.O>CS(C)=O>[CH3:7][N:8]1[C:12]([S:4][CH2:1][CH2:2][CH3:3])=[C:11]([Cl:14])[C:10]([Cl:15])=[N:9]1
Reactant: CCCS
Reactant: Cn1nc(Cl)c(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCSc1c(Cl)c(Cl)nn1C
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A stirred mixture of 4.9 g (0.064 moles) propanthiol and 3 g (0.054 moles) potassium hydroxide in 50 ml dimethylsulfoxide was heated (at about 120° C.) for thirty minutes. Then 10 g (0.054 moles) 1-methyl-3,4,5-trichloropyrazole was added in one portion. Heating (at about 120° C.) of the stirred reaction mixture was continued for about 6 hours. The reaction mixture was allowed to cool. The reaction mixture was added to water (about 50 ml); the resulting mixture was extracted with ether. The etheral phase was separated, washed with water twice, and dried over magnesium sulfate. The solvent was then stripped. The product was distilled out at 124° C. under high vacuum and heat.
Reaction SMILES: [CH:1]([N:4]([CH3:46])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:35])[CH2:13][C:14]([NH:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[NH:27]C(=O)OC(C)(C)C)=[O:15])[C@H:7]([CH2:36][S:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=[O:39])=[O:38])[CH2:6]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][C:18]1[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:24])[F:25])=[CH:22][C:17]=1[NH:16][C:14](=[O:15])[CH2:13][C:12]([NH:11][C@H:8]1[CH2:9][CH2:10][C@@H:5]([N:4]([CH:1]([CH3:2])[CH3:3])[CH3:46])[CH2:6][C@H:7]1[CH2:36][S:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:38])=[O:39])=[O:35]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)[C@H](CS(=O)(=O)c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2N)[C@H](CS(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(3-((1S*,2R*,4R*)-4-(isopropyl(methyl)amino)-2-(phenylsulfonylmethyl)cyclohexylamino)-3-oxopropanamido)-4-(trifluoromethyl)phenylcarbamate (10 mg, see procedure 35b) in CH2Cl2 (1.5 mL) was added TFA (0.5 mL) at 0° C. The reaction was warmed to RT and stirred for one hour at which time it was concentrated in vacuo. The title compound (presumed mono-TFA salt) was obtained as a white powder after reverse-phase HPLC and lypholization. MS found: (M+H)+=569.32.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH2:6][C@H:7]([OH:12])[C:8]([O:10][CH3:11])=[O:9])[CH3:4].Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([C:23]3[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][C:26]([Cl:33])=[CH:25][N:24]=3)[N:21]=[CH:22][C:15]=12>O1CCCC1>[Cl:33][C:26]1[CH:27]=[C:28]([C:29]([F:32])([F:30])[F:31])[C:23]([N:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([O:12][C@@H:7]([CH2:6][O:5][CH2:3][CH3:4])[C:8]([O:10][CH3:11])=[O:9])[C:15]=3[CH:22]=[N:21]2)=[N:24][CH:25]=1
Reactant: FC(F)(F)c1cc(Cl)cnc1-n1ncc2c(Cl)ncnc21
Reactant: CCOC[C@H](O)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncc(Cl)cc1C(F)(F)F)C(=O)OC
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
60% Sodium hydride in mineral oil (0.316 g, 7.90 mmol) was added portionwise to (S)-methyl 3-ethoxy-2-hydroxypropanoate (Intermediate G4) (0.976 g, 6.59 mmol) in tetrahydrofuran (50 mL) cooled to 5° C. over a period of 1 minute under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. A solution of 4-chloro-1-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate K3) (1.1 g, 3.29 mmol) was added portionwise over a period of 1 minute. The resulting mixture was allowed to warm to ambient temperature and stirred for 2 hours. The mixture was cooled to 10° C., quenched with 1M citric acid (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (25 mL) and saturated brine (25 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 20 to 50% ethyl acetate in isohexane to give the product (1.1 g, 73%). 1H NMR (400 MHz, CDCl3) δ 1.25 (3H, t), 3.72 (2H, d), 3.81 (3H, s), 3.99-4.13 (2H, m), 5.84 (1H, dd), 8.22-8.24 (1H, m), 8.38 (1H, s), 8.57 (1H, s), 8.81-8.82 (1H, m); m/z (ESI+) (M+H)+=446; HPLC tR=2.52 min.
Reaction SMILES: O[C:2]1[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:2]1[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: CCOC(=O)c1nn(C)c(=O)c(C)c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nn(C)c(=O)c(C)c1Cl
Temperature: 85 °C
Yield: 86 %

Procedure:
A mixture of ethyl 4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (1.85 g, 8.72 mmol) and POCl3 (9 mL) was heated for 16 hours at 85° C. POCl3 was removed under reduced pressure. Then the crude material was quenched with ice-water. The mixture was neutralized with saturated aqueous NaHCO3 (pH ˜6 to 7) and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (100% hexanes to 5 to 10 to 20% EtOAc in hexanes) to afford 1.72 g (86%) of the desired product.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[O:2].[C:6]([CH2:9][CH:10](C)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[NH2:7]>>[CH3:14][O:13][C:11](=[O:12])[CH2:10][CH:9]([CH3:6])[C:1]([O:3][CH2:4][CH3:5])=[O:2].[CH:6]([NH2:7])=[O:8]
Reactant: CCOC=O
Reactant: COC(=O)C(C)CC(N)=O
Product: CCOC(=O)C(C)CC(=O)OC
Product: NC=O

Procedure:
The procedure in Example 3 (3) was repeated except that ethyl formate was used in place of methyl formate. As a result, the conversion of methyl 3-carbamoylisobutyrate was 83.7% and there were obtained methylsuccinic acid ethyl methyl ester at a selectivity of 99.8% and formamide at a selectivity of 98.6%, each based on the reacted methyl 3-carbamoylisobutyrate.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](I)[CH3:22].C(OCC)(=O)C>C(#N)C.O>[CH2:11]([O:10][C:8]([C:7]1[C:3]([C:2]([F:1])([F:13])[F:14])=[N:4][N:5]([CH2:21][CH3:22])[CH:6]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cn(CC)nc1C(F)(F)F

Procedure:
Ethyl 3-trifluoromethylpyrazole-4-carboxylate (5 g), potassium carbonate (3.48 g) and ethyl iodide (2.3 ml) in acetonitrile were heated at reflux overnight. After cooling, ethyl acetate and water were added and the organic phase separated. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were dried (magnesium sulphate) and evaporated under reduced pressure to give a yellow oil which was purified by crystallisation in hexane to produce 4-ethoxycarbonyl-1-ethyl-3-trifluoromethylpyrazole as white crystals (3.65 g), 1H NMR (CDCl3) δ1.25(3H,t), 1.45(3H,t), 4.10(2H,q), 4.20(2H,q) 7.90(1H,s) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][C:13]2[C:22]3[C:17](=[C:18]([C:23]([O:25]C)=O)[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH3:27].CO>>[N+:1]([C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][C:13]2[C:22]3[C:17](=[C:18]([C:23]([NH2:27])=[O:25])[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cccc2c(N[C@H](C)c3cccc([N+](=O)[O-])c3)ncnc12
Reactant: N
Solvent: CO
Product: C[C@@H](Nc1ncnc2c(C(N)=O)cccc12)c1cccc([N+](=O)[O-])c1

Procedure:
A suspension of Methyl 4-{[(1R)-1-(3-nitrophenyl)ethyl]amino}quinazoline-8-carboxylate (7.26 g, 20.60 mmol) in 7 N ammonia/methanol (100 mL)
Reaction SMILES: [Na].[C:2]([O:9]C)(=O)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Si:11]([O:28][CH2:29][CH2:30][CH2:31][CH:32]1[O:34][CH:33]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:41](O)C>>[Si:11]([O:28][CH2:29][CH2:30][CH2:31][C@H:32]1[O:34][C:2](=[O:9])[CH:3]([C:4]([O:6][CH2:7][CH3:41])=[O:5])[C@@H:33]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)CC(=O)OC
Reactant: CC(C)(C)[Si](OCCCC1OC1c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCO
Agent: [Na]
Product: CCOC(=O)C1C(=O)O[C@H](CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium (0.64 g) was added to ethanol (30 ml) at ambient temperature, followed by dimethyl malonate (3.2 ml), and the resulting mixture was stirred at ambient temperature for 15 minutes. A solution of (2R*, 3R*)-3-[3-(t-butyldiphenylsilyloxy)propyl]-2phenyloxirane (2.90 g) in ethanol (30 ml) was added thereto. After being refluxed for 12 hours, the reaction mixture was evaporated in vacuo and the residue was dissolved in ethyl acetate. The organic solution was washed with lN hydrochloric acid, water and brine successively, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (150 g) eluting with a mixture of hexane and ethyl acetate (50:1 to 10:1) to give ethyl (4R*,5R*)5-[3-(t-butyldiphenylsilyloxy)propyl]-2-oxo-4-phenyltetrahydro-3-furancarboxylate (2.64 g).
Reaction SMILES: [CH3:1][Li].[C:3]([C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1)(=[O:5])[CH3:4].O>CCOCC.O1CCCC1>[O:10]1[C:9]2[CH:13]=[CH:14][C:6]([C:3]([OH:5])([CH3:1])[CH3:4])=[CH:7][C:8]=2[O:12][CH2:11]1
Reactant: [Li]C
Reactant: CC(=O)c1ccc2c(c1)OCO2
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(c1)OCO2
Reaction time: 1 h

Procedure:
About 600 ml of a 1.5M solution of methyllithium in ether was added to 500 ml of tetrahydrofuran to obtain a mixture. A suspension of 93.45 g of 5-acetyl-1,3-benzodioxole in 900 ml of tetrahydrofuran was added to the mixture, while keeping it at -20° C. by cooling and the obtained mixture was stirred as such for one hour. Water was added to the reaction mixture and the obtained mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of common salt and dried over anhydrous magnesium sulfate. The resulting mixture was filtered and the filtrate was concentrated to obtain 97 g of the title compound as an oil.