Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([S:15][CH2:16][CH2:17][C:18](OC)=O)[CH:8]=[N:9][C:10]=1[O:11][CH2:12][O:13][CH3:14].[K].[O-]CCCC.BrC[C:30]1C=C[CH:33]=[C:32]([F:36])[CH:31]=1>C1COCC1>[F:36][C:32]1[CH:33]=[C:17]([CH:18]=[CH:30][CH:31]=1)[CH2:16][S:15][C:7]1[CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:10]([O:11][CH2:12][O:13][CH3:14])=[N:9][CH:8]=1
Reactant: COCOc1cc(SCCC(=O)OC)cnc1OCOC
Reactant: Fc1cccc(CBr)c1
Agent: CCCC[O-]
Agent: [K]
Solvent: C1CCOC1
Product: COCOc1cc(SCc2cccc(F)c2)cnc1OCOC
Temperature: -45 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a solution of methyl 3-{[5,6-bis(methoxymethoxy)pyridin-3-yl]sulfanyl}propanoate (Intermediate 42; 1 g, 3.15 mmol) in THF (17 ml) at −45° C. was added potassium ten-butoxide (0.389 g, 3.47 mmol). After stirring at −45° C. temperature for 1 hour, 1-(bromomethyl)-3-fluorobenzene (0.715 g, 3.78 mmol) was added and the reaction mixture stirred for 3 hours. Upon warming to room temperature the reaction mixture was partitioned between dichloromethane and water. The aqueous phase was re-extracted and the combined organic extracts were washed with brine, dried and concentrated in vacuo. The crude product was purified by column chromatography (SiO2; 0-50% ethyl acetate/petrol) to yield 5-[(3-fluorobenzyl)sulfanyl]-2,3-bis(methoxymethoxy)pyridine (690 mg, 64%).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.C[CH:20]1[CH2:24][C:23]2=[C:25]([C:30]([OH:32])=[O:31])[CH:26]=[CH:27][C:28]([NH2:29])=[C:22]2[O:21]1.Cl>C(O)C.O>[CH:16]([N:5]1[C:4]2[N:3]=[C:2]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([C:30]([OH:32])=[O:31])=[C:23]4[C:22]=3[O:21][CH2:20][CH2:24]4)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]1[CH2:14][CH3:15])([CH3:18])[CH3:17]
Reactant: CC1Cc2c(C(=O)O)ccc(N)c2O1
Reactant: CC[C@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC[C@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C(C)C
Yield: 57.9 %

Procedure:
(7S)-2-Chloro-8-isopropyl-7-ethyl-5-methyl-7H-pteridin-6-one 43d (2.50 g, 9.24 mmol) and methyl 7-amino-2,3-dihydrobenzofuran-4-carboxylateic acid 1g (1.50 g, 8.40 mmol) were dissolved in 120 mL of the mixture solvent of ethanol and water (V/V=1:2) followed by the addition of 1.5 mL of concentrated hydrochloric acid. The reaction mixture was heated to reflux for 24 hours with stirring and the precipitate was filtered. The filter cake was washed with dichloromethane (50 mL×3) and dried by heating to obtain the crude compound 7-[[(7S)-8-isopropyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 43e (2 g) as a gray solid, which was used in the next step without further furification.
Reaction SMILES: Br[C:2]1[C:3]([Cl:12])=[N:4][C:5]([O:10][CH3:11])=[N:6][C:7]=1[O:8][CH3:9].C([Li])CCC.[CH3:18][C:19]([CH3:21])=[O:20]>C1COCC1>[Cl:12][C:3]1[C:2]([C:19]([OH:20])([CH3:21])[CH3:18])=[C:7]([O:8][CH3:9])[N:6]=[C:5]([O:10][CH3:11])[N:4]=1
Reactant: CC(C)=O
Reactant: COc1nc(Cl)c(Br)c(OC)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc(Cl)c(C(C)(C)O)c(OC)n1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 54.7 %

Procedure:
To a solution of 5-Bromo-4-chloro-2,6-dimethoxy-pyrimidine (0.546 g, 2.16 mmol) in THF (22 mL) at −78° C. was added n-butyllithium (1.6 M in hexanes, 1.48 mL, 2.37 mmol) over 2 min. Reaction mixture was stirred from 45 min at −78° C., then acetone (0.31 mL, 4.32 mmol) was added. Reaction mixture was stirred for 1 h at −78° C., then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. Organic layer was washed with saturated ammonium chloride solution, dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 10 to 30% ethyl acetate/hexane) to give a colorless oil (0.275 g, 55%). 1H NMR (300 MHz, CDCl3): δ 3.97 (br s, 1H), 3.92 (s, 3H), 3.82 (s, 3H), 1.54 (s, 6H). Mass spectrum: 233.0, 235.0 (M+H)+.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>C(N(CC)CC)C.C(O)C>[Br:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[N:7]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:8]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=c1ncc(Br)c[nH]1
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(Br)cnc1=O)c1ccccc1

Procedure:
A solution of 5-bromopyrimidin-2-one hydrobromide (512 mg) and α-bromoacetophenone (398 mg) in triethylamine (2 ml) and ethanol (10 ml) was stirred at ambient temperature for three and a half hours. After evaporation of solvents, the residue was triturated with water. The product was filtered off and recrystallised from ethanol to give the title pyrimidinone: yield 253 mg: m.p. 161°-163°, λmaxEtOH 241.5 nm (ε 18810), 285 nm (ε 1690), 334.5 nm (ε 3190).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[S:25]1[CH:29]=[CH:28][C:27]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:26]1=2.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[S:25]1[CH:29]=[CH:28][C:27]2[CH:30]=[C:31]([C:2]3[N:7]4[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)[CH:3]=3)[CH:32]=[CH:33][C:26]1=2
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: OB(O)c1ccc2sccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4sccc4c3)n2n1
Temperature: 110 °C
Yield: 36.4 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 60 mg, 0.174 mmol), benzo[b]thiophen-5-ylboronic acid (40 mg, 0.226 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 13.6 mmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.58 mL of 1,4-dioxane and 0.29 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (65-65% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (28 mg, 36%). 1HNMR (DMSO-d6) δ: 11.21 (s, 1H), 8.62 (d, J=1.3 Hz, 1H), 8.26 (d, J=8.6 Hz, 1H), 8.05 (s, 1H), 7.99-8.04 (m, 3H), 7.93 (d, J=5.3 Hz, 1H), 7.67 (d, J=5.6 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H), 6.41 (s, 1H), 5.20 (s, 1H), 2.41 (s, 3H), 1.46 (s, 6H); ESI-MS: m/z 443.2 (M+H)+.
Reaction SMILES: N1C=CC(NC[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=CN=1.O=C1CCC(=O)N1[O:22][C:23](=O)[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([O:24][C:23]([N:12]1[CH2:11][CH2:10][CH2:9][CH2:14][CH2:13]1)=[O:22])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1cc(NCC2CCNCC2)cnn1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-[(pyridazin-4-ylamino)-methyl]-piperidine (0.20 g, 1.04 mmol), in DMF (3 mL) was added carbonic acid benzyl ester 2,5-dioxo-pyrrolidin-1-yl ester (0.26 g, 1.04 mmol). The resulting reaction solution was stirred at rt for 0.5 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (1–7 (10% NH4OH in MeOH)/99–93 CH2Cl2) to give 4-(pyridazin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[CH3:11][C:12]1[CH:13]=[C:14]([NH:19][NH2:20])[CH:15]=[CH:16][C:17]=1[CH3:18].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:2]([C:1]1[CH:7]=[C:8]([NH2:9])[N:19]([C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([CH3:11])[CH:13]=2)[N:20]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: Cc1ccc(NN)cc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1C
Yield: 66.9 %

Procedure:
To a solution of pivaloylacetonitrile (400 mg) in toluene (10 mL) were added 3,4-dimethylphenylhydrazine hydrochloride (520 mg) and triethylamine (0.4 mL) and refluxed with heating for 5 hours. The reaction mixture was added with a saturated sodium hydrogen carbonate aqueous solution. The obtained organic layer was washed with a saturated sodium chloride aqueous solution. The obtained organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified on silica gel column chromatography (hexane:ethyl acetate=4:1) to give the titled compound (490 mg) having the following physical data.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(C)=[O:13].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C.O>CC(C)=O>[N+:1]([C:4]1[S:8][C:7]([C:9]([OH:13])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1ccc([N+](=O)[O-])s1

Procedure:
To a solution of 5-nitro-2-thiophenecarboxaldehyde (1.00 g, 6.24 mmol) in acetone (50 ml) was added Jones reagent (8N in acetone, 8.12 ml, 65 mmol) at −20° C. After stirring for 1H, 30 ml of isopropanol was added to the mixture. H2O was added to the mixture and extracted with CH2Cl2. The extract was washed with water, brine, dried (Na2SO4), and concentrated to give 967 mg (90%) of yellow armorphous. p 1H NMR (270 MHz, CDCl3) δ7.88 (1H, d, J=4.4 Hz), 7.66 (1H, d, J=4.0 Hz), 5.14 (1H, br. s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[NH2:8][C:6]1[C:5]([NH:9][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: Nc1ccc(Cl)nc1N
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccc(Cl)nc1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
A stirred mixture of 6-chloropyridine-2,3-diamine (E-24) (7.2 g, 50 mol, 1.0 eq) and potassium carbonate (6.9 g, 50 mmol, 1 eq) in DMF (100 mL) was stirred for 30 min and then ethyl bromoacetate (9.2 g, 55 mmol, 1.1 eq) was added, the resulting mixture was stirred at 60-70° C. for 3 h. The reaction was complete based on TLC analysis. The reaction mixture was poured into ice-water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the desired product ethyl 2-(2-amino-6-chloropyridin-3-ylamino)acetate (E-25) (5.8 g, 50.5% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ: 6.39 (m, 2H), 5.93 (bs, 2H), 5.32 (m, 1H), 4.08 (m, 2H), 3.88 (d, J=6.0 Hz, 2H), 1.15 (m, 3H); ESI-MS m/z: 230.05 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([O-:3])=[O:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20]Br.C(N(CC)CC)C>ClCCl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][N:13]1[CH2:12][CH2:11][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Reactant: Clc1ccc(CBr)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A mixture of 1-(2-nitro-phenyl)-piperazine (4.53 g) (commercially from Emkachem) and 3,4-dichlorobenzyl bromide (4.6 g) in 100 mL of dichloromethane was treated with triethylamine (3.4 mL). The reaction was stirred at ambient temperature under inert atmosphere overnight. After solvent removal, the crude reaction mixture was subjected directly to flash chromatography using silica. Elution with hexanes, then 20% ethyl acetate in hexanes, and finally 33% ethyl acetate in hexanes furnished the product as an oil (6.4 g), which was carried on as is.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:22][CH3:23])[C:4]1[CH:5]=[C:6]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:8]=1.[CH3:24][C:25](C)(CO)[CH2:26]O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:24][C:25]1([CH3:26])[CH2:23][O:22][CH:3]([C:4]2[CH:5]=[C:6]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[N:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[N:8]=2)[O:2][CH2:1]1
Reactant: COC(OC)c1cc(-c2ccncc2)n(-c2ccc(F)cc2)n1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)COC(c2cc(-c3ccncc3)n(-c3ccc(F)cc3)n2)OC1
Temperature: 25 °C
Yield: 29.6 %

Procedure:
A solution of 4-[5-dimethoxymethyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-pyridine (3 g, Reference Example 1), 2,2-dimethylpropane-1,3-diol (2.2 g) and p-toluene sulfonic acid (2 g) in dry toluene (50 ml) was refluxed for 1 hour with azeotropic removal of water. The reaction mixture was cooled to room temperature then evaporated. The residue was partitioned between ethyl acetate (50 ml) and saturated aqueous sodium carbonate solution (50 ml). The organic phase was washed three times with water (50 ml), then dried over magnesium sulphate and then evaporated. The residual oil was triturated twice with diethyl ether then recrystallised from diethyl ether to give the title compound as white needles (1 g), m.p. 150-151° C. [Elemental analysis: C,67.69; H,5.98; N,12.09%. Calculated for C20H20FN3O2: C,67.97; H,5.70; N,11.89%]. MS: 354 [MH]+. RF=0.42 (ethyl acetate, determined by thin layer chromatography on silica).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([I:10])[CH:9]=1)[CH:5]=O.[C:11]([S@:15]([NH2:17])=[O:16])([CH3:14])([CH3:13])[CH3:12]>ClCCCl.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([I:10])[CH:9]=1)/[CH:5]=[N:17]/[S@@:15]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:16]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cc(F)cc(I)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1cc(F)cc(I)c1
Temperature: 60 °C

Procedure:
To a solution of 3-fluoro-5-iodobenzaldehyde (8.75 g, 35 mmol) and (R)-(+)-t-Butylsulfinamide (4.67 g, 38.5 mmol) in DCE (117 mL) was added copper(II) sulfate (anhydrous) (16.76 g, 105 mmol) and the resulting suspension was heated at 60° C. overnight. LCMS indicated desired product formation. Reaction mixture was filtered through Celite and the filtrate concentrate in vacuo and then taken to the next step as such. LCMS (m/z): 354.1 (MH+), 1.08 min.
Reaction SMILES: [CH2:1]([CH:4]([S:8]([CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13])(=[O:10])=[O:9])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[C:17](NC(=O)CCC(N)=O)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].CN1CCOCC1>C(Cl)Cl>[CH2:20]([O:19][C:17]([NH:13][C@H:12]([C:14]([OH:16])=[O:15])[CH2:11][S:8]([CH:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])(=[O:9])=[O:10])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCCC(CCC)S(=O)(=O)C[C@H](N)C(=O)O
Reactant: NC(=O)CCC(=O)NC(=O)OCc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCC(CCC)S(=O)(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 109.5 %

Procedure:
A 250 ml round bottom flask equipped with magnetic stir bar and N2 inlet was charged with 7.8 g (27 mmole) 3-[(1-propylbutyl)sulfonyl]alanine and 7.4 g (30 mmole) N-Cbz succinamide in 100 ml methylene chloride. The reaction was cooled to 0° C., and 6.9 g NMM was added dropwise. The reaction was allowed to warm to room temperature and stirred for 4 hours at which point HPLC analysis indicated complete reaction. The reaction was concentrated in vacuo and partitioned between ethyl acetate and 1 N HCl. The organic layer was washed with water, brine, dried over sodium sulfate, and concentrated in vacuo to give 11.4 g of N-[(benzyloxy)carbonyl]-3-[(1-propylbutyl)sulfonyl]alanine that was used without further purification. M+H=386.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([O:22][CH2:23][CH2:24]NC(OC(C)(C)C)=O)[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(CC2C(C(OC)=O)=C(O)C(C3C=COC=3)=CC=2)(=O)=O)C=CC=CC=1.[C:64]([O:68][C:69]([NH:71][CH2:72]CCBr)=[O:70])([CH3:67])([CH3:66])[CH3:65]>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:22][CH2:23][CH2:24][CH2:72][NH:71][C:69]([O:68][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:70])[C:14]([C:33]3[CH:37]=[CH:36][O:35][CH:34]=3)=[CH:13][CH:12]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCNC(=O)OC(C)(C)C
Agent: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCCCNC(=O)OC(C)(C)C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 10, starting from methyl 6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 114) and 3-(t-butoxycarbonylamino)propyl bromide.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:8][NH:9]2)=[CH:5][CH:4]=1)#N.C(O)(=[O:21])C>N1C=CC=CC=1.O.[Ni]>[CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](/[CH:12]=[CH:13]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:8][NH:9]2)=[CH:5][CH:4]=1)=[O:21]
Reactant: CC(=O)O
Reactant: CCOC(=O)/C=C/c1n[nH]c2cc(C#N)ccc12
Agent: [Ni]
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)/C=C/c1n[nH]c2cc(C=O)ccc12
Temperature: 55 °C
Yield: 65 %

Procedure:
To a solution of (E)-ethyl 3-(6-cyano-1H-indazol-3-yl)acrylate (723 mg, 3 mmol) in pyridine (10 mL) was added acetic acid (3 mL), followed by a solution of NaH2PO2 (1.056 g, 12 mmol) in H2O (3 mL). The resulting mixture was stirred for 0.5 min at rt before Raney-Nickel 2400 (slurry in H2O, 0.6 mL) was added in one portion. The resulting mixture was heated at 55° C. (oil temp.) for 1 h before cooling to rt. H2O (30 mL) was added and the mixture was extracted with EtOAc (50 mL×2). Combined extracts were washed with H2O (20 mL), 2 M HCl (20 mL), H2O (20 mL×2), brine (15 mL) and dried (Na2SO4). Removal of solvent gave an orange red oil which solidified upon standing O/N under high vacuum. It was then triturated with H2O (30 mL) and suction filtered, rinsed with H2O, dried to give the title compound (476 mg, 65%) as an orange red solid. 1H NMR (400 MHz, DMSO-d6) δ 14.16 (s, 1H, NH), 10.14 (s, 1H, CHO), 8.30 (d, J=8.8 Hz, 1H), 8.22 (s, 1H), 7.92 (d, J=16.4 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 4.22 (q, J=6.8 Hz, 2H), 1.28 (t, J=6.8 Hz, 3H); MS ESI 245.0 [M+H]+, calcd for [C13H12N2O3+H]+ 245.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[N:11]3[N:17]=[CH:18][C:19](I)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=1)#[CH:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[N:11]3[N:17]=[CH:18][C:19]([C:22]#[C:21][C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: CCCc1cc(-c2ccc(Cl)cc2)nc2c(I)cnn12
Product: CCCc1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(N)nc3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-iodo-7-propyl-pyrazolo[1,5-a]pyrimidine (99 mg, 0.25 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (30 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (48 mg, 50%). MS (ISP) 388.4 [(M+H)+]; mp 215-217° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[Br:16]N1C(=O)CCC1=O.O>CN(C=O)C.BrN1C(=O)CCC1=O>[Br:16][C:7]1[CH:6]=[CH:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15])=[CH:9][CH:8]=1
Reactant: CCCOCCN(CC)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CCCOCCN(CC)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 79.2 %

Procedure:
To a solution of N-ethyl-N-(2-propoxyethyl)aniline (10.18 g) in DMF (50 ml) was added at room temperature a solution of N-bromosuccinimide (7.45 g) in DMF (50 ml) for 40 minutes, and the mixture was stirred for 3 hours. To the mixture was added a solution of N-bromosuccinimide (0.2 g) in DMF (10 ml), and the mixture was stirred for 15 hours. The reaction mixture was added to water, and the mixture was extracted with diethylether. The organic layer was washed with water (twice) and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was distilled under reduced pressure (0.7 mmHg, 134° C.) to give pale yellow oil of 4-bromo-N-ethyl-N-(2-propoxyethyl)aniline (9.49 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[I:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.[CH2:20]([O:22][C:23](=[O:32])[C@@:24]([CH3:31])([C:27]([NH:29][CH3:30])=[O:28])[NH:25][CH3:26])[CH3:21]>C(Cl)(Cl)Cl>[CH2:20]([O:22][C:23](=[O:32])[C:24]([N:25]([CH3:26])[C:15]([C:14]1[CH:18]=[CH:19][C:11]([I:10])=[CH:12][CH:13]=1)=[O:16])([CH3:31])[C:27]([NH:29][CH3:30])=[O:28])[CH3:21]
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CCOC(=O)[C@](C)(NC)C(=O)NC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)(C(=O)NC)N(C)C(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 98 %

Procedure:
DIPEA (0.34 mL) and 4-iodobenzoyl chloride (0.13 g) were added to a chloroform (2.3 mL) solution of O-ethyl-N,N2,2-trimethyl-3-oxoserinamide (Intermediate 9-1, 0.25 g) under ice cooling, and the mixture was stirred for 40 minutes at room temperature, whereafter the reaction mixture was concentrated. The resulting residue was purified by NH type silica gel column chromatography (gradient elution with hexane/ethyl acetate=70/30→35/65) to obtain 1-{[1-ethoxy-2-methyl-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}-4-iodobenzene (Intermediate 10-1, yellow oil) (0.20 g, 72%).
Reaction SMILES: [C:1]([NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:21](#[N:25])[CH2:22][C:23]#[N:24]>C1(C)C=CC=CC=1>[C:23]([CH:22]([C:21]#[N:25])[C@@H:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][C:1]([NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])=[O:10])#[N:24]
Reactant: O=C(/C=C/c1ccccc1)NC(=O)c1ccccc1F
Reactant: N#CCC#N
Solvent: Cc1ccccc1
Product: N#CC(C#N)[C@H](CC(=O)NC(=O)c1ccccc1F)c1ccccc1

Procedure:
(E)-N-Cinnamoyl-2-fluorobenzamide (26.9 mg, 0.1 mmol), malononitrile (13.2 mg, 0.2 mmol) and the compound (10 mol %) shown in the following Table 2 as an asymmetric catalyst were stirred in toluene (1.0 mL) at room temperature for 27 hr. The reaction mixture was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:19][CH2:18][C:16]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1-c1ccc(F)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1-c1ccc(F)cc1

Procedure:
A solution of methyl 2-(4-fluorophenyl)-4-methylbenzoate (54.18 g; 0.22 mol), N-bromosuccinimide (39.6 g; 0.22 mol), 2,2′-azobis(2-methylproprionitrile) (0.25 g; 1.5 mmol) and benzoylperoxide (0.25 g; 1 mmol) in tetrachloromethane (550 ml) was heated at reflux for 6 hours. The solid was filtered and the filtrate evaporated to give methyl 4-bromomethyl-2-(4-fluorophenyl)benzoate as an oil (79.7 g; 79%) which was used in the next step without purification.