Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[C:2]([O:21][CH2:22][C@H:23]([CH2:44][O:45][P:46]([O:49][CH2:50][C@@H:51]([C:53]([O-:55])=[O:54])[NH2:52])([OH:48])=[O:47])[O:24]C(=O)CCCCCCC/C=C\CCCCCCCC)(=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(O)C(N)(CO)CO.Cl.[Cl-].[K+].Cl>O>[C:2]([O:21][CH2:22][C@H:23]([CH2:44][O:45][P:46]([O:49][CH2:50][C@@H:51]([C:53]([OH:55])=[O:54])[NH2:52])([OH:48])=[O:47])[OH:24])(=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC[C@H](COP(=O)(O)OC[C@H](N)C(=O)[O-])OC(=O)CCCCCCC/C=C\CCCCCCCC
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: [Cl-]
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC[C@@H](O)COP(=O)(O)OC[C@H](N)C(=O)O

Procedure:
After 1,2-dioleoyl-sn-glycero-3-phospho-L-serine sodium salt (SIGMA, P1060) (85 mg) was dissolved in distilled water (25 ml), 200 mM Tris-HCl buffer (pH 8.0) (1.5 ml) and 100 mM potassium chloride (1.5 ml) were added to the solution, and phospholipase A2 (0.3 ml) (10 mg/ml, 5 mM sodium acetate buffer (pH 5.0)) was further added thereto. The mixture was reacted at room temperature for 20 hours, and the pH was rendered 2 to 3 with 5M hydrochloric acid to terminate the reaction. After the reaction solution was concentrated to dryness, the residue was dissolved in a chloroform-methanol solvent mixture and the solution was adsorbed on silica gel column chromatography. Elution was performed with a chloroform-methanol solvent mixture to give 1-oleoyl-sn-glycero-3-phospho-L-serine. Subsequently, 1-oleoyl-sn-glycero-3-phospho-L-serine was catalytically hydrogenated with gaseous tritium (3H2) in the presence of palladium, in accordance with publicly known methods (e.g., the methods described in R. F. Glascock, Isotopic Gas Analysis for Biochemists, 227, Academic Press, New York, 1954) to introduce tritium into the double bond. Thus, the objective product, 1-[9,10-3H2]-stearoyl-sn-glycero-3-phospho-L-serine was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13].Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[C:3]2[N:10]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[C:18](=[O:20])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(NCC(=O)N(C)C)c(N)c1
Product: Cc1cc(C)c2c(c1)[nH]c(=O)n2CC(=O)N(C)C
Reaction time: 1 h

Procedure:
To a solution of N2-(2-amino-4,6-dimethylphenyl)-N′,N′-dimethylglycinamide from Step B (930 mg, 4.20 mmol) in CH3 CN (20 mL) at 0° C. was added triphosgene (1.25 g, 4.20 mmol). The reaction mixture was stirred for 1 h, then quenched with H2O (50 mL) and extracted with CH2 Cl2 (3×50 mL). The combined organic layers were dried over Na2 SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2 Cl2:MeOH—100:0 to 95:5, to give the title compound. MS: m/z=248 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:13]([NH:15][C:16]2([S:22][CH3:23])[CH:19]([CH3:20])[NH:18][C:17]2=[O:21])=[O:14])=[O:10])[C:5](=[O:30])[C:4]1=[O:31])[CH3:2].C(OO)(=[O:34])C>O1CCOCC1.C(O)(=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][CH:12]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:13]([NH:15][C:16]2([S:22]([CH3:23])=[O:34])[CH:19]([CH3:20])[NH:18][C:17]2=[O:21])=[O:14])=[O:10])[C:5](=[O:30])[C:4]1=[O:31])[CH3:2]
Reactant: CCN1CCN(C(=O)NC(C(=O)NC2(SC)C(=O)NC2C)c2ccccc2)C(=O)C1=O
Reactant: CC(=O)OO
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCN1CCN(C(=O)NC(C(=O)NC2(S(C)=O)C(=O)NC2C)c2ccccc2)C(=O)C1=O

Procedure:
The azetidinone (60) (250 mg) in dry dioxan (10 ml) was treated with a (5.07% w/v) solution of peracetic acid in acetic acid (0.69 ml) for 1.5 hour. The solvent was then evaporated in vacuo, the complete removal of acidic residues being ensured. Silica gel chromatography of the residue gave the title compound as a pale--white solid (149 mg), νmax. (Nujol) 3300, 1760, 1710, and 1670 cm-1, δ[(CD3)2SO]0.65, 0.93, 1.16 and 1.19 (each d, J 6.4 Hz, together 3H), (1.07 (t, J 7 Hz, 3H), 1.99, 2.14, 2.39, 2.64 and 2.68 (each s, together 3H), 3.37 (q, J 7 Hz, 2H), 3.47-3.52 (m, 2H), 3.179-3.92 (m, 2H), 3.92-4.10 (complex m, together 1H), [5.45-5.60 (complex m) and 5.86 (d, J 7 Hz), together 1H], 7.27-7.55 (m, 5H), 8.63 and 8.74 br (each s, together 1H, exch), 9.14 and 9.35 br (each s, together 1H, exch.) and 9.65-10.00 (complex m, together 1H, exch).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH:6]([C:8]([OH:10])=O)[CH2:5][CH2:4][NH:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:23][NH:24][O:25][CH3:26].Cl.O1CCOCC1>C(Cl)Cl>[CH3:26][O:25][N:24]([CH3:23])[C:8]([CH:6]1[CH2:5][CH2:4][NH:3][C:2](=[O:1])[CH2:7]1)=[O:10]
Reactant: CNOC
Reactant: O=C1CC(C(=O)O)CCN1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCNC(=O)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 2-oxopiperidine-4-carboxylic acid (CAS #24537-50-6) (1.4 g, 9.78 mmol) in DCM (20 ml) was added portion wise CDI (1.665 g, 10.27 mmol). The suspension was stirred at room temperature for 5 hrs and N,O-dimethylhydroxylamine (1.002 g, 10.27 mmol) was added to the suspension and the reaction mixture was stirred overnight at room temperature. HCl (4M) in 1,4-dioxane (2.445 ml, 9.78 mmol) was added to the cloudy brown-orange solution and the reaction was stirred for 30 min (pH 7). The white precipitate was filtered off and the filtrate was washed with aqueous NaHCO3 solution. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to obtain the title compound as brown liquid.
Reaction SMILES: C([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[N:22][N:21]4[CH:27]=3)[O:17][C:13]=2[CH:12]=[C:11]([O:28][CH3:29])[CH:10]=1)C1C=CC=CC=1.[H][H]>ClCCl.CO.[Pd]>[CH3:29][O:28][C:11]1[CH:12]=[C:13]2[O:17][C:16]([C:18]3[N:19]=[C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[N:22][N:21]4[CH:27]=3)=[CH:15][C:14]2=[C:9]([OH:8])[CH:10]=1
Reactant: COc1cc(OCc2ccccc2)c2cc(-c3cn4nc(C)ccc4n3)oc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(O)c2cc(-c3cn4nc(C)ccc4n3)oc2c1
Reaction time: 18 h
Yield: 99.4 %

Procedure:
A solution of 2-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-6-methylimidazo[1,2-b]pyridazine (Example 39A, 1.00 g, 2.59 mmol) in a mixture of dichloromethane (420 mL) and methanol (150 mL) in a 1 L flask was hydrogenated over. 10% Palladium over carbon (0.30 g, i.e., 30 mg Pd) and under 1 atm of hydrogen for 6 h. The reaction mixture was maintained under vacuum for 2 min and then flushed with nitrogen. The catalyst was filtered and washed with warm dichloromethane-methanol (8:2, 100 mL) and the combined filtrate was concentrated under reduced pressure. The yellow residue was boiled with 1,2-dichloroethane (30 mL) and allowed to stand at room temperature for 18 h. The solid was filtered (contains methanol by NMR) and dried in vacuo at 120° C. for 12 h to give the title material (0.760 g, 99% yield) of a yellow solid. LC (Method A): 1.844 min. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 2.54 (s, 3H), 3.77 (s, 3H), 6.28 (d, J=1.96 Hz, 1H), 6.70 (dd, J=1.96, 1.17 Hz, 1H), 7.20 (d, J=9.39 Hz, 1H), 7.24 (d, J=0.78 Hz, 1H), 8.03 (d, J=9.78 Hz, 1H), 8.50 (s, 1H), 10.10 (br s, 1H).
Reaction SMILES: [C:1]([O:7][CH2:8][Cl:9])(=[O:6])[C:2](C)([CH3:4])[CH3:3].C(Cl)(=O)C1C=[CH:15][C:14]([O:17][CH3:18])=[CH:13]C=1.C=O>[Cl-].[Zn+2].[Cl-]>[CH3:18][O:17][C:14]1[CH:15]=[CH:4][C:2]([C:1]([O:7][CH2:8][Cl:9])=[O:6])=[CH:3][CH:13]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: C=O
Agent: [Cl-]
Agent: [Zn+2]
Product: COc1ccc(C(=O)OCCl)cc1
Reaction time: 16 h
Yield: 12 %

Procedure:
A similar procedure (Iyer, R. P. et al. Synth. Commun. 1995, 25, 2739-2749) to that described for the preparation of 41 was followed using p-anisoyl chloride (5.0 g, 29.4 mmol), paraformaldehyde (883 mg, 29.4 mmol) and zinc chloride (31 mg, 0.22 mmol), at 80° C. for 16 h. Purification by flash chromatography (hexane/ethyl acetate 4:1) afforded chloromethyl p-methoxybenzoate (48) as a yellow oil (0.74 g, 3.69 mmol, 12%). 1H NMR (300 MHz, CDCl3) δ 3.87 (3H, s, OMe), 5.94 (2H, s, CH2), 6.92-6.96 (2H, m, Ar), 8.01-8.06 (2H, m, Ar).
Reaction SMILES: [CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14](=[C:15]([N+:25]([O-])=O)[C:16](=[O:24])[CH2:17][CH2:18]2)[CH2:13][CH2:12]4)[CH2:3][CH2:2]1>C(O)(=O)C.[Zn]>[NH2:25][C:15]1[C:16](=[O:24])[CH2:17][CH2:18][C@@:19]2([CH3:20])[C:14]=1[CH2:13][CH2:12][C@@H:11]1[C@@H:21]2[CH2:22][CH2:23][C@@:6]2([CH3:7])[C@H:8]1[CH2:9][CH2:10][CH:5]2[O:4][CH:1]1[CH2:2][CH2:3]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=C([N+](=O)[O-])C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: C[C@]12CCC(=O)C(N)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(OC3CC3)CC[C@@H]12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64.1 %

Procedure:
A solution of 17β-cyclopropyloxy-4-nitroandrost-4-en-3-one (1.0 g, 2.71 mM), either prepared above or by other known techniques, in acetic acid (10 ml) is treated with zinc dust (1.0 g). The combination (mixture) is vigorously stirred for 1.5 hours at room temperature. The zinc salts are removed by filtration and washed with ethyl acetate. The combined filtrate and wash are combined and concentrated to a yellow solid which is then redissolved in ethyl acetate and extracted three times with 1M hydrochloric acid (150 ml), The combined acid extracts are neutralized with sodium hydroxide (pH 14) and extracted with ether. The combined organic layers are then dried over sodium sulfate and concentrated to give 4-amino-17-cyclopropyloxyandrost-4-en-3-one (0.59 g), m.p. 100°-102° C. (aqueous methanol).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[CH2:23]O>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[CH2:23][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(Cl)cc1Cl
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2Cl)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2,4-dichlorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.29 (2H, s), 5.79 (1H, d, J=1.6 Hz), 7.29-7.32 (1H, m), 7.42 (1H, dd, J=1.2, 5.2 Hz), 7.45 (1H, d, J=2.4 Hz), 7.53 (1H, d, J=8.4 Hz), 7.59 (1H, d, J=1.6 Hz), 8.06 (1H, s), 8.71 (1H, d, J=4.8 Hz). [M+H] Calc'd for C16H10C12N4O, 345. Found, 345.
Reaction SMILES: Cl.[OH:2]C1N=CC(NC(C2C=CC=CN=2)=O)=CC=1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21].N12CCN(CC1)CC2.O>CN(C)C=O.ClCCl>[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](=[O:2])[OH:21]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(Nc1ccc(O)nc1)c1ccccn1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C(=O)O)c1ccccc1
Yield: 126.3 %

Procedure:
A solution of pyridine-2-carboxylic acid (6-hydroxy-pyridin-3-yl)-amide hydrochloride (0.50 g, 1.99 mmol), N-methyl-N-phenylcarbamoyl chloride (0.44 g, 2.59 mmol) and 1,4-diazabicyclo[2,2,2]octane (0.54 g, 4.81 mmol) in dimethylformamide (15 mL) was stirred at room temperature for 1 hour. Water was added and the solids were isolated by suction, re-dissolved in dichloromethane. The solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 50:50) yielding the title compound (0.38 g, 55% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CCOCC>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1Cl
Temperature: 80 °C
Reaction time: 18 h
Yield: 97.6 %

Procedure:
To a solution of 2-chlorophenol (2.06 mL, 19.9 mmol) in DMF (40 mL) is added potassium carbonate (3.03 g, 21.9 mmol) and ethyl bromoacetate (2.3 mL, 20.7 mmol), and the mixture is stirred at 80° C. for 18 h. Et2O is added, and the mixture is washed with water, brine, dried (MgSO4), and filtered. The filtrate is evaporated, and the residue is purified by chromatography in silica gel; elution with EtOAc: dichloromethane:hexane (10:5:85) gives 4.17 g of the product 465. 1H NMR (CDCl3) δ 7.38 (d, 1H), 7.21 (t, 1H), 6.92 (t, 1H), 6.84 (d, 1H), 4.70 (s, 2H), 4.27 (q, 2H), 1.29 (t, 3H); MS: m/z 215, 217 (M++1).
Reaction SMILES: [Cl-].[Li+].[CH2:3]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1)[CH2:4][CH2:5][CH3:6].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([CH:22]2[O:24][CH2:23]2)=[CH:20][CH:19]=1.O>CN(C=O)C>[CH2:3]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:23][CH:22]([C:21]3[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:26][CH:25]=3)[O:24][C:14]2=[O:15])=[CH:9][CH:8]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1ccc(N=C=O)cc1
Reactant: COc1ccc(C2CO2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1ccc(N2CC(c3ccc(OC)cc3)OC2=O)cc1
Yield: 14.5 %

Procedure:
In a 20 ml-three necked flask, 0.013 g of lithium chloride and 3.8 ml of DMF were placed. To the mixture, a solution of 1.09 g (6.22 mM) of 4-butylphenyl isocyanate and 6.20 mM of optically active 4-methoxystyrene oxide in 1.3 ml of DMF was added dropwise in 12 minutes under refluxing and stirring in nitrogen atmosphere, followed by refluxing for 50 minutes under stirring. After the reaction, the reaction mixture was left standing for cooling, then poured into water, and subjected to extraction with ethyl acetate. The organic layer was washed with water, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain a residue The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=10/1) and recrystallized from methanol to obtain 0.29 g of optically active 3-(4-butylphenyl)-5-(4-methoxyphenyl)-2-oxazolidinone (Yield: 14.5%).
Reaction SMILES: C(O[CH:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH2:30][C:31]3[CH:40]=[CH:39][C:34]4[O:35][CH2:36][CH2:37][O:38][C:33]=4[CH:32]=3)[CH:24]=2)[O:6]1)(=O)C.[BrH:41]>CC(O)=O.C(Cl)Cl>[C:12]([O:11][C@H:10]1[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][C:20](=[O:22])[CH3:21])[C@H:7]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH2:30][C:31]3[CH:40]=[CH:39][C:34]4[O:35][CH2:36][CH2:37][O:38][C:33]=4[CH:32]=3)[CH:24]=2)[O:6][C@H:5]1[Br:41])(=[O:14])[CH3:13]
Reactant: CC(=O)OC1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](c2ccc(Cl)c(Cc3ccc4c(c3)OCCO4)c2)O[C@@H](Br)[C@H]1OC(C)=O
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Compound 137 (100 mg, 0.17 mmol) was treated with 33% HBr in AcOH (350 μL) for 30 min at room temperature. The reaction mixture was diluted with CH2Cl2 (1 mL), stirred for 30 min, diluted with more CH2Cl2 (50 mL), and washed with cold water (10 mL×2), and saturated NaHCO3 solution (40 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound (100 mg, 99%) as an off-white solid. The obtained product was used for the next step without purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[NH:10][CH:9]=[N:8][C:7]=1[CH3:11].[CH2:12]([C:19]1[C:20](=[O:28])[NH:21][C:22](SC)=[N:23][C:24]=1[CH3:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:11][C:7]1[N:8]=[CH:9][NH:10][C:6]=1[CH2:5][S:4][CH2:3][CH2:2][NH:1][C:22]1[NH:21][C:20](=[O:28])[C:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:24]([CH3:25])[N:23]=1
Reactant: CSc1nc(C)c(Cc2ccccc2)c(=O)[nH]1
Reactant: Cc1nc[nH]c1CSCCN
Product: Cc1nc[nH]c1CSCCNc1nc(C)c(Cc2ccccc2)c(=O)[nH]1
Yield: 65.9 %

Procedure:
An intimate mixture of 5-(2-aminoethyl)thiomethyl-4-methylimidazole (1.28 gms) and 5-benzyl-6-methyl-2-methylthio-4-pyrimidone (1.84 gms) was heated at 150°-160° C. (oil-bath temperature) for 41/2 hours. The mixture was cooled, washed with water and recrystallised from isopropanol to give 2-[-2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5-benzyl-6-methyl-4-pyrimidone (1.82 gms) m.p.=140°-141.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH2:26]([S:33](Cl)(=[O:35])=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N1C=CC=CC=1.C(OCC)(=O)C>O1CCOCC1.O>[CH2:26]([S:33]([NH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1)(=[O:35])=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: O=c1c(Cc2ccccc2)nc2cccnc2n1-c1cccc(NS(=O)(=O)Cc2ccccc2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
To a mixture of 4-(3-aminophenyl)-3-oxo-2-benzyl-3,4-dihydropyrido[2,3-b]pyrazine (150 mg), benzylsulfonyl chloride (96 mg) and pyridine (0.04 ml) in 1,4-dioxane (3 ml) was stirred at 80° C. for 2 hours. The mixture was poured into a mixture of ethyl acetate and water. The organic phase was washed with water and brine, dried over magnesium sulfate, concentrated, and subjected to silica gel column chromatography (hexane-ethyl acetate 1:1) to afford 4-(3-benzylsulfonylaminophenyl)-3-oxo-2-benzyl-3,4-dihydropyrido[2,3-b]pyrazine (49 mg) as a solid.
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@H:2]([C:15](O)=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:50]([SH:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH:1]([C:18]([O:20][CH2:21][CH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[C:34]1=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:19])[C@H:2]([C:15]([S:57][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:6][CH:5]=1
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: SCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)SCc2ccccc2)cc1

Procedure:
4.6 g (10.0 mmol) Fmoc-Tyr(But)-OH, 2.1 g (10.1 mmol) dicylohexylcarbodiimide (DCC), 1.26 g (10.1 mmol) benzylmercaptan and 0.12 g DMAP were reacted in DCM as described by Ho and Ngu (J. Org. Chem. 58:2315 (1993), which is incorporated herein by reference). After workup, Fmoc-Tyr(But)-S—CH2C6H5 was isolated and, upon reduction of the thioester by stirring with triethylsilane in the presence of 10% Pd on carbon and purification by flash chromatography, gave a 81% yield of Fmoc-Tyr(But)-H. The NMR and mass of the product were in accordance with the expected range.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)=[CH:4][CH:3]=1.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2nn(C3CCCCO3)c3ccc(C#Cc4ccccc4)cc23)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Fc1ccc(-c2n[nH]c3ccc(C#Cc4ccccc4)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 3-(4-fluorophenyl)-5-(2-phenylethynyl)-1-(tetrahydropyran-2-yl)-1H-indazole in tetrahydrofuran (15 mL) was added 6 N hydrochloride solution (10 mL) and the mixture was stirred at ambient temperature overnight. After tetrahydrofuran was evaporated, the aqueous phase was neutralized with 5% sodium carbonate and extracted with ethyl acetate. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 15-30% ethyl acetate/hexane) to provide the title compound (0.071 g, 90% yield). 1H NMR (CDCl3) δ 10.19 (br, 1H), 8.20 (s, 1H), 7.94-7.98 (m, 2H), 7.55-7.61 (m, 3H), 7.48 (dd, 1H), 7.34-7.41 (m, 3H), 7.23 (t, 2H); ES-MS (m/z) 313 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[S:18][C:19]([CH3:22])=[CH:20][N:21]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[S:18][C:19]([CH3:22])=[CH:20][N:21]=2)=[O:12])[C:3]1=[O:15]
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: Cc1cnc(N)s1
Solvent: Brc1ccccc1
Product: Cc1cnc(NC(=O)c2c(O)cc(C)n(C)c2=O)s1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 73.2 %

Procedure:
212 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxyl ate and 105 mg of 2-amino-5-methylthiazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 5.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 188 mg of 1,6-dimethyl-4-hydroxy-N-(5-methylthiazol-2-yl)-2-oxo-1,2-d ihydropyridine-3-carboxamide (hereinafter, referred to as present compound 20) represented by the formula:
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:11]=[C:10]3[CH:12]=[N:13][CH:14]=[CH:15][C:9]3=[N:8][C:7]=2[N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[CH2:18][CH2:17]2)[CH2:4][CH2:3][CH2:2]1.[CH3:31][C:32](OC(C)=O)=[O:33]>CC(C)=O.O1CCOCC1.[Pd]>[CH:1]1([NH:5][C:6]2[N:11]=[C:10]3[CH2:12][N:13]([C:32](=[O:33])[CH3:31])[CH2:14][CH2:15][C:9]3=[N:8][C:7]=2[N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[CH2:18][CH2:17]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(OC2CCN(c3nc4ccncc4nc3NC3CCC3)CC2)c(F)c1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CC(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NC3CCC3)nc2C1
Temperature: 60 °C
Reaction time: 72 h
Yield: 45.7 %

Procedure:
To a solution of N-cyclobutyl-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)pyrido[3,4-b]pyrazin-3-amine (12.0 g, 29.2 mmol) in acetone (200 mL) and dioxane (300 mL) was added Ac2O (30 mL, 318 mmol) and Pd/C (1.80 g, 16.91 mmol). The reaction was then stirred at 60° C. under H2 atmosphere (345 kPa) for 72 h. Then the mixture was filtered through a pad of Celite™, washing with EtOAc. The reaction solution was diluted with EtOAc (50 mL) and poured into saturated aqueous NaHCO3 (50 mL), then washed with brine (2×30 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was recrystallized with PEEtOAc, lyophilized and washed with PEEtOAc (5:1) to give pure title compound (6.1 g). 1H NMR (500 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.57-1.74 (m, 2H), 1.85-1.95 (m, 2H), 1.97-2.08 (m, 4H), 2.08 (s, 1.3H), 2.09 (s, 1.7H), 2.19-2.30 (m, 2H), 2.58 (t, J=5.9 Hz, 0.9H), 2.71 (t, J=5.9 Hz, 1.1H), 2.88 (t, J=10.5 Hz, 2H), 3.23-3.33 (m, 2H), 3.70 (dt, J=11.7, 5.9 Hz, 2H), 4.32-4.47 (m, 3H), 4.52 (tt, J=8.1, 3.8 Hz, 1H), 6.05 (d, J=7.8 Hz, 0.4H), 6.08 (d, J=8.3 Hz, 0.6H 6.96-7.07 (m, 1H), 7.24-7.36 (m, 2H); ESI-MS m/z [M+H]+ 458.00.