Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([C:27]#[C:28][CH2:29][CH2:30][CH3:31])[CH:23]=5)[C:18]4=[O:32])=[CH:13][C:12]=3[F:33])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C2C(=CC=CC=2)C=CC=1>[Pd].N1C=CC=CC=1>[N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22](/[CH:27]=[CH:28]\[CH2:29][CH2:30][CH3:31])[CH:23]=5)[C:18]4=[O:32])=[CH:13][C:12]=3[F:33])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCCC#Cc1ccc2c(=O)n(-c3ccc(N4CC[C@@H](N5CCCC5)C4)c(F)c3)ccc2c1
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: c1ccncc1
Product: CCC/C=C\c1ccc2c(=O)n(-c3ccc(N4CC[C@@H](N5CCCC5)C4)c(F)c3)ccc2c1
Reaction time: 2 h

Procedure:
A mixture of 2-((R)-4-[1,3′]bipyrrolidinyl-1′-yl-3-fluorophenyl)-6-pent-1-ynyl-2H-isoquinolin-1-one (2.7 g), quinoline (0.4 g), pyridine (50 mL) and palladium (5% on barium carbonate; 100 mg) was stirred vigorously for 2 hours under a hydrogen atmosphere (balloon flask). It was sucked off of the catalyst and the filtrate was concentrated. The residue was purified by chromatography on silica gel. In this way the product was obtained with molecular weight 445.59 (C28H32FN3O); MS (ESI): 446 (M+H+).
Reaction SMILES: [CH2:1]([C:8](=[CH2:12])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([O:20][C:21](=[O:24])[CH2:22][NH2:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1.C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:13]([O:20][C:21](=[O:24])[CH2:22][NH:23][C:9](=[O:11])[C:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH2:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=C(Cc1ccccc1)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=C(Cc1ccccc1)C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2.42 g (15 mmoles) of 2-benzyl acrylic acid are dissolved in 30 ml of THF and 10 ml of CHCl3. There is added a solution in 50 ml of THF of 1.87 g of glycine benzyl ester hydrochlorate, 2.2 g of triethylamine, then 2.20 g of HOBT and 3.4 g of DCC. The mixture is stirred for 20 hours at room temperature. The precipitate of DCU formed is collected. After evaporating to dryness and taking up with ethyl acetate the organic phase is washed in succession with 2×20 ml of citric acid, then 3×20 ml of NaHCO3. The material is concentrated under a vacuum and the rest of the DCU formed is suction filtered. A yellow oil which crystallizes slowly is obtained.
Reaction SMILES: [Mg].C(O)C.[C:5]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:6][C:7]([CH3:9])=[O:8].[CH2:16]([S:23][CH2:24][CH2:25][C:26](Cl)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.OS(O)(=O)=O>C(OCC)C.C(Cl)(Cl)Cl>[CH2:16]([S:23][CH2:24][CH2:25][C:26](=[O:27])[CH:6]([C:5]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:7](=[O:8])[CH3:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)CCSCc1ccccc1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CCO
Product: CC(=O)C(C(=O)CCSCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 12 °C

Procedure:
10.7 g (0.44 mol) of magnesium, 2 ml of chloroform and 46 g (1 mol) of absolute ethanol are initially placed, with the exclusion of moisture, in a 1 1 flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser, and are heated under reflux for 1 hour, with stirring. 300 ml of diethyl ether are then added dropwise and the mixture is stirred for 1.5 hours. The mixture is then cooled to approx. 12° C. 63.2 g (0.4 mol) of tert-butyl acetoacetate are added dropwise at this temperature. The reaction mixture is cooled further to approx. -3° C., and 85.8 g (0.4 mol) of benzylthiomethylacetyl chloride in 100 ml of absolute diethyl ether are added dropwise at this temperature in the course of 45 minutes. The mixture is then stirred for a further hour at approx. -3° C. and is then stirred for a further 2 hours without cooling, in the course of which it reaches room temperature. The reaction mixture is stirred into 400 g of ice-water and 48 g of concentrated H2SO4. The organic phase is separated off and is washed with 150 ml of water, 100 ml of bicarbonate and 150 ml of water again and is then dried and concentrated.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[S:6][CH:7]=1.[CH:12]1[C:22]2[CH:21]=[CH:20][C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[CH:17]([C:27]3[C:28](=[O:34])[NH:29][C:30](=[O:33])[NH:31][CH:32]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1>>[CH:12]1[C:22]2[CH:21]=[CH:20][C:19]3[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=3[CH:17]([C:27]3[C:28](=[O:34])[NH:29][C:30](=[O:33])[N:31]([CH2:2][C:3]4[CH:4]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[S:6][CH:7]=4)[CH:32]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cc(CBr)cs1
Reactant: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Product: COC(=O)c1cc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)cs1

Procedure:
The subtitle compound was prepared from the product of step (i) (0.29 g) and the product of example 1 step (iii) (0.373 g) according to the method of example 1 step (iv). Purification was by chromatography eluting with 10% ethyl acetate in toluene. Yield 0.34 g.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[N+:27]([C:30]1[CH:31]=[C:32]([CH:38]=[CH:39][CH:40]=1)[CH:33]=[CH:34][C:35](O)=[O:36])([O-:29])=[O:28]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:35](=[O:36])[CH:34]=[CH:33][C:32]1[CH:38]=[CH:39][CH:40]=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Product: CC(C)CN([C@@H](CCCCNC(=O)C=Cc1cccc([N+](=O)[O-])c1)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 52 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with 3-nitrocinnamic acid under the conditions described in example 86 to yield 52% of the desired product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[CH2:17]([O:19][P:20]([CH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([O:22][CH2:23][CH3:24])=[O:21])[CH3:18]>ClCCl.C(=O)([O-])O.[Na+]>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:30]([C:29]1[CH:33]=[CH:34][C:26]([CH2:25][P:20](=[O:21])([O:19][CH2:17][CH3:18])[O:22][CH2:23][CH3:24])=[CH:27][CH:28]=1)=[O:31]
Reactant: CCOP(=O)(Cc1ccc(C(=O)Cl)cc1)OCC
Reactant: Nc1nc2ccccc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOP(=O)(Cc1ccc(C(=O)Nc2nc3ccccc3s2)cc1)OCC
Reaction time: 10 h
Yield: 84.3 %

Procedure:
In 30 ml of dry dichloromethane were dissolved 3.0 g of 2-aminobenzothiazole and 10 ml of pyridine and while the resulting solution was stirred under ice-cooling, a solution of 5.8 g 4-[(diethoxyphosphoryl)methyl]benzoyl chloride in 10 ml dry dichloromethane was slowly added dropwise. The stirring was continued at room temperature for 10 hours, after which the reaction mixture was diluted with 30 ml of 10% aqueous sodium hydrogen carbonate solution and extracted with chloroform. The chloroform layer was washed serially with 30 ml of 10% hydrochloric acid and 30 ml of water and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: chloroform-ethyl acetate=1:1) and the resulting crude crystals were recrystallized from ethanol to provide 6.8 g of the title compound as colorless crystals. The structure and melting point of the compound thus obtained are shown in Table 1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH:15]=[O:16])[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[C:20]([F:23])([F:22])[F:21].[F-].[Cs+].C(OCC)(=O)C>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH:15]([OH:16])[C:20]([F:23])([F:22])[F:21])[O:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cc(=O)c(OCc2ccccc2)co1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1cc(C(O)C(F)(F)F)occ1OCc1ccccc1
Reaction time: 0.17 h
Yield: 57 %

Procedure:
The entire experiment was performed under an inert atmosphere by bubbling argon gas into the ice-salt cooled reaction mixture. To a cloudy solution of 5-benzyloxy-4-oxo-4H-pyran-2-carbaldehyde (5.00 g, 21.7 mmol) in dry tetrahydrofuran (185 mL) previously purged with argon for 35 min was added trimethyl(trifluoromethyl)silane (10.8 g, 76.0 mmol) dropwise, followed by caesium fluoride (0.34 g, 2.2 mmol). The color of the reaction mixture turned to yellow and almost clear within a min. TLC was used to monitor the reaction (eluant: 50:50, ethyl acetate:hexanes, v:v). The reaction was completed within 10 min. The reaction mixture was quenched with a 6.0N hydrochloric acid solution (20 mL) under cooling, followed by addition of a brine solution (50 mL). The mixture was stirred for 10 min, and then transferred to a separatory funnel. The organic THF fraction was collected, and then concentrated in vacuo to about 10 mL using the rotary evaporator. The residual solution was diluted with dichloromethane (80 mL). The mixture was transferred to a separatory funnel, and the separated dichloromethane layer was collected, dried over Na2SO4 and filtered. Upon concentration under reduced pressure, a first crop of the titled compound was obtained as a solid product (3.72 g, 57% yield, HPLC Method 1 (Example 24), RT=16.8 min, HPLC purity (peak percent area): 96% at λ=280 nm). 1H NMR (DMSO-d6+D2O) 6 ppm: 8.20 (s, 1H), 7.36 (br m, 5H), 6.57 (s, 1H), 5.11 (q, J=7 Hz, 1H), 4.92 (s, 2H).
Reaction SMILES: O.[OH-].[Na+].[CH2:4]([OH:7])[C:5]#[CH:6].[CH2:8](Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>[CH2:4]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]#[CH:6]
Reactant: C#CCO
Reactant: ClCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Product: C#CCOCc1ccccc1
Temperature: 10 °C

Procedure:
In preparing the alkynyl intermediate (used as a second reaction product), water (800 ml) was added to sodium hydroxide pellets (800 g) over 20 minutes using a cooling ice bath. The solution was further cooled to 10° C. Hexane (800 ml) and tetrabutylammonium bromide were added followed by propargyl alcohol (237 ml), dropwise over 20 minutes with ice bath cooling. The reaction was allowed to warm to 30° C. during the addition and benzyl chloride (414 ml) was added over 20 minutes, avoiding exothermic conditions. The reaction was warmed to 40° C. for 6 hours at which time gas chromotagraphy analysis indicated all the benzyl chloride had been consumed. After cooling to 25° C., water (800 ml) was added over 10 minutes with ice bath cooling. During this period, the temperature rose to 30° C. The lower, clear aqueous phase was removed and 25% saturated sodium chloride (800 ml) was added to the turbid upper phase. The two phases became clear and the layers were separated. The isolated organic phase was dried with sodium sulphate (20 g) and the hexane evaporated to afford benzyl propargyl ether as an orange oil (515 g, 98.5% pure). The other 1.5% is benzyl ether produced from benzyl alcohol formed in the reaction.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][OH:20])[O:16][C:15]3=[O:21])=[CH:10][C:9]=2[F:22])[CH2:4][CH2:3]1.C(OP([CH:31]([C:33]#[N:34])[CH3:32])(=O)OCC)C>>[C:33]([C:31](=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][OH:20])[O:16][C:15]3=[O:21])=[CH:10][C:9]=2[F:22])[CH2:4][CH2:3]1)[CH3:32])#[N:34]
Reactant: CCOP(=O)(OCC)C(C)C#N
Reactant: O=C1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1
Product: CC(C#N)=C1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1
Yield: 63 %

Procedure:
The title compound was prepared by following the procedure of Example 1 and by using (R)-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-alcohol and diethyl(1-cyanoethyl)-phosphonate in 63% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11]N3CC4(CCN(C)CC4)C3)=[CH:8][C:6]=2[N:7]=1.[N:28]1([C@H:32]2[CH2:37][CH2:36][NH:35][CH2:34][C@H:33]2[F:38])[CH2:31][CH2:30][CH2:29]1>>[N:28]1([C@H:32]2[CH2:37][CH2:36][N:35]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:34][C@H:33]2[F:38])[CH2:29][CH2:30][CH2:31]1
Reactant: F[C@@H]1CNCC[C@@H]1N1CCC1
Reactant: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Product: F[C@@H]1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC[C@@H]1N1CCC1

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using (cis)-4-azetidin-1-yl-3-fluoro-piperidine in place of 7-methyl-2,7-diaza-spiro[3.5]nonane. The title compound was obtained as a tan solid (284 mg, 57%).
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])=[CH:8][NH:9]2)=[CH:5][C:4]=1[F:19])#[N:2]>CO.[Pd]>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][NH:9]2)=[CH:5][C:4]=1[F:19])#[N:2]
Reactant: CCOC(=O)/C=C/c1c[nH]c2cc(C#N)c(F)cc12
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1c[nH]c2cc(C#N)c(F)cc12
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a solution of ethyl (2E)-3-(6-cyano-5-fluoro-1H-indol-3-yl)-2-propenoate (D153) (200 mg) in methanol (30 mL) was added 10% Pd/C (50 mg). The reaction mixture was then stirred under H2 overnight. The solution was filtered through celite and the filtrate was evaporated to give the designed product ethyl 3-(6-cyano-5-fluoro-1H-indol-3-yl)propanoate (D154) (190 mg). MS (ES): C14H13FN2O2 requires 260.1; found 261.1 (M+H+).
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[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[OH:25][C@@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>>[OH:25][C@@H:26]1[CH2:30][CH2:29][N:28]([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:27]1
Reactant: O[C@@H]1CCNC1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Product: N#Cc1ccc(-c2ccc3oc(CCN4CC[C@@H](O)C4)cc3c2)cc1

Procedure:
The product from Example 1C and 3-(R)-hydroxypyrrolidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.88 (m, 1H), 7.80 (m, 4H), 7.60 (m, 2H), 6.80 (s, 1H), 4.55 (bs, 1H), 3.8-3.9 (m, 4H), 3.25-3.5 (m, 4H), 2.05-2.4 (m, 2H); MS (DCI) m/z 333 (M+H)+;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH2:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[CH3:18]>>[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:9])[CH:5]=[N:6][CH:7]=2)=[CH:21][CH:20]=1)[CH3:18]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: O=C(Nc1ccccc1)c1cncc(Br)c1
Product: CCc1ccc(-c2cncc(C(=O)Nc3ccccc3)c2)cc1

Procedure:
74 g (222 mmol) of 5-bromo-N-phenylpyridine-3-carboxamide and 40 g (266 mmol, 1.2 eq.) of 4-ethylphenylboronic acid were reacted according to General Method 1A. Yield: 68 g (87% of theory)
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]([NH2:16])=[N:14][C:13]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12]2)[CH:8]=[C:7]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:6]=1)(=O)=O.[C-:31]#[N:32].[K+].CCO.C(Cl)Cl.C(OCC)C>CS(C)=O>[NH2:16][C:15]1[N:11]([C:9]2[CH:8]=[C:7]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:6]=[C:5]([C:31]#[N:32])[N:10]=2)[N:12]=[C:13]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)c1nc(Nc2ccccc2)cc(-n2nc(Nc3ccccc3)nc2N)n1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCO
Solvent: CCOCC
Product: N#Cc1nc(Nc2ccccc2)cc(-n2nc(Nc3ccccc3)nc2N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
To a solution of (50 mg; 0.12 mMol) of 1-(2-methanesulfonyl-6-phenylamino-pyrimidin-4-yl)-N3-phenyl-1H-[1,2,4]triazole-3,5-diamine in 2 mL of DMSO was added 8 mg (0.13 mMol) of potassium cyanide and reaction was stirred for 1 hr at ambient temperature. The solvent was removed under reduced pressure. The residue was triturated with water and the solid was isolated via suction filtration. Column chromatography (SiO2, 5% EtOH—CH2Cl2) followed by trituration with diethyl ether affording 5 mg of an off white powder, (11% yield).
Reaction SMILES: [CH2:1]([C@H:8]([NH:33][C:34](=[O:46])[C@@H:35]([N:39]1[CH2:44][CH2:43][CH2:42][NH:41][C:40]1=[O:45])[CH:36]([CH3:38])[CH3:37])[CH2:9][C@H:10]([OH:32])[C@@H:11]([NH:19][C:20](=[O:31])[CH2:21][O:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:30])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:47]([S:49][CH2:50][CH3:51])[CH3:48].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:1]([C@H:8]([NH:33][C:34](=[O:46])[C@@H:35]([N:39]1[CH2:44][CH2:43][CH2:42][NH:41][C:40]1=[O:45])[CH:36]([CH3:38])[CH3:37])[CH2:9][C@H:10]([O:32][CH:47]([S:49][CH2:50][CH3:51])[CH3:48])[C@@H:11]([NH:19][C:20](=[O:31])[CH2:21][O:22][C:23]1[C:24]([CH3:30])=[CH:25][CH:26]=[CH:27][C:28]=1[CH3:29])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)C)N1CCCNC1=O
Reactant: CCSCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCSC(C)O[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)C)N1CCCNC1=O)[C@H](Cc1ccccc1)NC(=O)COc1c(C)cccc1C
Yield: 61 %

Procedure:
To a solution of the compound of Example 3 (0.50 g, 0.80 mmol) and ethyl sulfide (2.1 mL) in acetonitrile (6 mL) at 0° C. was added benzoyl peroxide (1.16 g) in three portions over 3 hours. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient of 50-100% ethyl acetate in chloroform to give the title compound (0.36 g, 61% yield).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[F:28][C:26]([F:27])([F:29])[C:23]1[N:21]2[N:22]=[C:17]([N:4]3[CH2:5][CH2:6][N:1]([C:7]4[CH:8]=[CH:9][C:10]([C:13](=[O:15])[CH3:14])=[CH:11][CH:12]=4)[CH2:2][CH2:3]3)[CH:18]=[CH:19][C:20]2=[N:25][N:24]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Product: CC(=O)c1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
A mixture of 1-(4-piperazin-1-ylphenyl)ethanone and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 1-[4-[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]phenyl]ethanone.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:20](=[O:21])[C:19]3[CH:22]=[N:23][N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]=3[N:17]=[C:16]2[C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[CH:11][CH:10]=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:20](=[O:21])[C:19]3[CH:22]=[N:23][N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]=3[N:17]=[C:16]2[C:31]2[CH:32]=[CH:33][C:34]([C:2]3[N:3]=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:35][CH:36]=2)=[CH:13][CH:14]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Reactant: Clc1cccnn1
Product: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(-c3cccnn3)cc2)n1-c1ccc(Cl)cc1

Procedure:
5-(4-Chloro-phenyl)-1-phenyl-6-(4-pyridazin-3-yl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one is prepared from 3-chloropyridazine and 5-(4-chloro-phenyl)-1-phenyl-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one by using the same method described in example 338. The crude product is purified by flash column chromatography (silica gel, 0˜70% EtOAc/hexane). 1H NMR (CDCl3) δ (ppm) 9.19 (b, 1H), 8.34(s, 1H), 8.15(d, 2H), 8.02(d, 2H), 7.84(d, 1H), 7.51(m, 5H), 7.33 (m, 3H), 7.15(d, 2H). HPLC-MS calculated C27H17ClN6O (M+1+): 477.1. Found: 477.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([N:6]2[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][C:7]2=[O:14])=[CH:2]1.[BH4-].[Na+]>CO>[OH:13][CH2:12][C:9]1[CH:10]=[CH:11][N:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:7](=[O:14])[CH:8]=1
Reactant: O=Cc1ccn(-c2ccsc2)c(=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=c1cc(CO)ccn1-c1ccsc1
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A solution of 1-thiophen-3-yl-2-oxo-1,2-dihydro-pyridine-4-carbaldehyde (0.27 g, 1.3 mmol) in methanol (20 mL) is cooled to 0° C. in an ice-water bath and then treated with sodium borohydride (50 mg, 1.3 mmol). After bring stirred at that temperature for two hours, the reaction mixture is quenched by the addition of 10% aqueous hydrochloric acid. The mixture is extracted with ethyl acetate. The combined organic extracts were washed once with saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure to provide 4-hydroxymethyl-1-thiophen-3-yl-1H-pyridin-2-one (0.18 g, 67%), which is used in the following step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:34])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=O)[CH:24]([NH:26][C:27]([O:29]CC)=O)[CH3:25])=[CH:19][C:18]=2[Cl:33])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.[NH2:36][NH2:37]>C(O)CCC>[Cl:33][C:18]1[CH:19]=[C:20]([C:23]2[CH:24]([CH3:25])[NH:26][C:27](=[O:29])[NH:36][N:37]=2)[CH:21]=[CH:22][C:17]=1[O:16][CH2:15][C:14]([NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:34]
Reactant: CCOC(=O)NC(C)C(=O)c1ccc(OCC(=O)NCCc2ccc(OC)c(OC)c2)c(Cl)c1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: COc1ccc(CCNC(=O)COc2ccc(C3=NNC(=O)NC3C)cc2Cl)cc1OC
Yield: 21.5 %

Procedure:
A mixture of 556 mg of N-[2-(3,4-dimethoxyphenyl)-ethyl]-α-{2-chloro-4-[2-(ethoxycarbonylamino)propionyl]phenoxy}acetamide [prepared as described in step (c) above] and 723 mg of hydrazine hydrate in 7 ml of butanol was heated under reflux for 67 hours. At the end of this time, the mixture was cooled, and the butanol used as the solvent was removed by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel eluted with a 10:1 by volume mixture of chloroform and methanol, to give 112 mg of the title compound as a white powder melting at 167°-169° C. (with decomposition).