Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CCOCC>[CH2:16]([C:2]([CH3:1])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: CCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCCCCCCCCCCCC(C)(C(=O)OCC)C(=O)OCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A solution of 48.72 g (0.277 mol) of diethyl methylmalonate (available from Aldrich Chem. Co., Catalog No. 12,613-6) in 60 ml of N1N-dimethyl formamide (DMF) is added dropwise to a stirred solution of 6.86 g (0.277 mol) of sodium hydride (NaH) in DMF. The reaction mixture is heated during the dropwise addition of a solution of 72.17 g (0.284 mol) of 1-bromododecane (Aldrich Chem. Co., catalog no. B6,555-1) in 60 ml DMF. The reaction is heated to 80° C. and stirred overnight, after which the NaBr that precipitated is filtered and the DMF removed in vacuo. The oily residue obtained is dissolved in ether and filtered again to remove all NaBr. The ether solution is washed with water followed by saturated NaCl. The solution is dried over anhydrous sodium sulfate and the ether is removed under reduced pressure to yield a clear, yellow oil. Fractional distillation (130°-138° C., 0.007 mm Hg) gives 82.28 g (88% overall yield) of diethyl dodecyl-methylmalonate as a clear oil. The oil is dissolved in 175 ml of anhydrous ether, and the solution is added dropwise to a suspension of 19.21 g (0.480 mol) of lithium aluminum hydride. The reaction is stirred overnight, carefully quenched, and filtered. The solvent is removed in vacuo and the solid obtained is recrystallized and dried to give 51.00 g (81% overall yield) of 2-dodecyl-2-methylpropane-1,3-diol as a white solid (mp 67°-68° C.).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[C:27]4[C:22](=[CH:23][C:24]([O:28][C:29]5[CH:34]=[C:33](Cl)[N:32]=[CH:31][N:30]=5)=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2].[CH3:36][NH2:37]>C1COCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[C:27]4[C:22](=[CH:23][C:24]([O:28][C:29]5[CH:34]=[C:33]([NH:37][CH3:36])[N:32]=[CH:31][N:30]=5)=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CN
Reactant: CCN1CCN(Cc2ccc(NC(=O)N3CCc4cc(Oc5cc(Cl)ncn5)ccc43)cc2)CC1
Solvent: C1CCOC1
Product: CCN1CCN(Cc2ccc(NC(=O)N3CCc4cc(Oc5cc(NC)ncn5)ccc43)cc2)CC1

Procedure:
A solution of 134 mg (0.27 mMol) 5-(6-chloro-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid [4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-amide in 5 ml THF and 1.2 ml methylamin solution (2 M in THF) is stirred for 3 d in a sealed tube at rt. The reaction mixture is concentrated and the residue chromatographed by reversed phase MPLC (Gilson system), yielding the title compound: MS: [M+1]+=488; HPLC: BtRet=11.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[N:19]1([NH2:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:25][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:14]
Reactant: NN1CCOCC1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NN1CCOCC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-morpholin-4-ylisonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.5 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.81 mmol of morpholin-4-ylamine LC/MS [8.25 min; 443 (M+1)]
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([C:19]1[CH:44]=[CH:43][C:22]([O:23][CH2:24][C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:42])[C:33]3[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=3)[C:36](O)=[O:37])[CH:28]=[CH:29][CH:30]=2)=[C:21]([CH2:45][CH2:46][CH3:47])[C:20]=1[OH:48])(=[O:18])[CH3:17].[CH3:49][C:50]1([CH3:58])[O:55][C:54](=[O:56])[CH2:53][C:52](=[O:57])[O:51]1>ClCCl>[C:16]([C:19]1[CH:44]=[CH:43][C:22]([O:23][CH2:24][C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:42])[C:33]3[CH:41]=[CH:40][CH:39]=[C:35]([C:36](=[C:53]4[C:54](=[O:56])[O:55][C:50]([CH3:58])([CH3:49])[O:51][C:52]4=[O:57])[OH:37])[CH:34]=3)[CH:28]=[CH:29][CH:30]=2)=[C:21]([CH2:45][CH2:46][CH3:47])[C:20]=1[OH:48])(=[O:18])[CH3:17]
Reactant: CCCc1c(OCc2cccc(NC(=O)c3cccc(C(=O)O)c3)c2)ccc(C(C)=O)c1O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCc1c(OCc2cccc(NC(=O)c3cccc(C(O)=C4C(=O)OC(C)(C)OC4=O)c3)c2)ccc(C(C)=O)c1O
Yield: 100 %

Procedure:
Add dicyclohexylcarbodiimide (0.231 g, 1.12 mmol, Aldrich Chemical Co.) to a solution of N-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-isophthalamic acid (0.500 g, 1.12 mmol), 2,2-dimethyl-[1,3]dioxane-4,6-dione (0.161 g, 1.12 mmol), and 4-N,N-dimethylaminopyridine (0.273 g, 2.23 mmol, Chem-Impex) in dichloromethane (50 mL, 0.2 M). Filter precipitate, wash filter cake with dichloromethane, and concentrate filtrate. Dilute residue with dichloromethane and wash with 1N hydrochloric acid. Dry the organic layer with sodium sulfate and concentrate to afford the title compound (0.641 g, 1.12 mmol): MS (m/z): 572 (M−1).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16].O>CN(C)C=O>[O:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1ccccc1
Reactant: ClCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCCCOc1ccccc1
Yield: 93.4 %

Procedure:
60% Sodium hydride (1.4 g) was suspended in dimethylformamide (40 ml), and phenol (3 g) was added under ice-cooilng with stirring. The mixture was stirred at room temperature for 1 hr. The mixture was again ice-cooled, and 1-bromo-5-chloropentane (5.9 g) was added, which was followed by stirring at room temperature for 1.5 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 5.9 g of 5-phenoxypentyl chloride.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:19])C(=O)C1>CN(C=O)C>[Br:19][C:10]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1ccccc1N
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Br)ccc1N
Reaction time: 2 h

Procedure:
To a solution of 2-tert-butylaniline (7.5 g, 50 mmol) in DMF (80 mL) was added NBS (8.9 g, 50 mmol) at 0° C. The reaction mixture was stirred for 2 h, quenched with ice water, extracted with EA (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC to give compound P13a (9.1 g, 80%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]O)([O-:3])=[O:2].C(N(CC)CC)C.[Cl-].[NH4+].[Br-:31].[Li+]>C(OCC)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][Br:31])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Nc1ccccc1CO
Reactant: [Br-]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Nc1ccccc1CBr
Yield: 22.9 %

Procedure:
1.8 g (6.2 mmol) of 2-[(2,6-dinitrophenyl)amino]-benzyl alcohol was dissolved in a mixture of 50 ml of dictloromethane with 50 ml of ethyl ether. Under ice-cooling and stirring, 2.2 ml (15.5 mmol) of triethylamine and 0.58 ml (7.4 mmol) of methane-sulfonuyl chloride were successively added thereto. After stirring for 30 minutes, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. After concentrating, the residue was dissolved in 150 ml of acetone. Then 2.7 g (31 mmol) of lithium bromide was added and the resulting mixture was heated under reflux for 1 hour. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography to thereby give 0.5 g of 2((2,6-dinitrophenyl)amino)-benzyl bromide. This product was dissolved in 10 ml of dimethylformamide. After adding 216 mg (2.8 mmol) of thiourea, the mixture was stirred at room temperature for 5 hours. Then 10 ml of dimethylformamide, 157 mg (2.8 mmol) of potassium hydroxide and 2 ml of water were successively added thereto and the reaction mixture was heated at 100° C. for 3 hours. After cooling, the reaction mixture was poured into a saturated aqueous solution of sodium chloride and extracted with ethyl acetate. After concentrating, the residue was purified by silica gel column chromatography. Thus 0.22 g of the title compound was obtained.
Reaction SMILES: [O:1]([S:8]([C:11]1[CH:12]=[CH:13][C:14]([NH:18][C:19]([NH2:21])=[O:20])=[C:15]([CH:17]=1)[NH2:16])(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([NH:26][C:27](=[N:30][C:31]([O:33][CH3:34])=[O:32])SC)=[O:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[CH3:34][O:33][C:31]([NH:30][C:27]([NH:26][C:24]([O:23][CH3:22])=[O:25])=[N:16][C:15]1[CH:17]=[C:11]([S:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:9])=[O:10])[CH:12]=[CH:13][C:14]=1[NH:18][C:19]([NH2:21])=[O:20])=[O:32]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: NC(=O)Nc1ccc(S(=O)(=O)Oc2ccccc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)NC(=Nc1cc(S(=O)(=O)Oc2ccccc2)ccc1NC(N)=O)NC(=O)OC

Procedure:
15.3 g of 5-phenoxysulfonyl-2-ureidoaniline, 12 g of N,N'-bismethoxycarbonyl-S-methylisothiourea and 100 mg of p-toluenesulfonic acid in 80 ml of methanol and 80 ml of ethyl acetate are stirred under reflux for four hours. After cooling down, the solid is filtered off with suction and washed with ethyl acetate and diisopropyl ether. For recrystallization, the solid is dissolved in dimethylformamide at about 50° C., treated with active charcoal, filtered, ethyl acetate and diisopropyl ether are added and crystallization is allowed to occur, melting point 193° C., decomposition.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[N:14]3[C:21](=[O:31])[N:22]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)[N:23]=[C:13]3[C:12]=2[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CCN(CC)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([N:22]2[C:21](=[O:31])[N:14]3[C:15](=[O:20])[NH:16][C:17]4[CH:18]=[CH:19][C:10]([C:8]#[C:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[CH:11][C:12]=4[C:13]3=[N:23]2)=[CH:25][CH:26]=1
Reactant: Cc1ccc(-n2nc3c4cc(Br)ccc4[nH]c(=O)n3c2=O)cc1
Reactant: C#Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc3c4cc(C#Cc5ccccc5)ccc4[nH]c(=O)n3c2=O)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 52.3 %

Procedure:
To a stirred solution of phenylacetylene (15.0 μg, 0.137 mmol) and 8a (25.3 mg, 0.0682 mmol) in a mixture of 2 mL of DMF and 1 mL of NEt3, was added Pd(OAc)2 (1.53 mg, 6.82 μmol) and triphenylphosphine (3.57 mg, 13.6 μmol) in a seal tube. The tube was sealed under argon and the mixture was stirred at 100° C. for 18 h. The mixture was cooled and concentrated to dryness in vacuo and the crude product was purified by chromatography on a silica gel column. Elution with n-heptane/EtOAc (2:1) as eluent yielded 13a as a white solid (14 mg, 70%). mp: >300° C. (decomp.),
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][NH2:49])=[CH:44][CH:43]=1>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]([C:8]([NH:49][CH2:48][C:45]2[CH:46]=[CH:47][C:42]([F:41])=[CH:43][CH:44]=2)=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(N)sc1C(=O)O
Reactant: NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of 2-amino-4-methylthiazole-5-carboxylic acid (4.20 g, 26.0 mmol) in anhydrous N,N-dimethylformamide (100 mL) was added 1-hydroxybenzotriazole (9.30 g, 69.0 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (6.60 g, 34.0 mmol), diisopropylethylamine (4.40 g, 34.0 mmol), and (4-fluorophenyl)methanamine (3.97 g, 32.0 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and N,N-dimethylformamide was removed in vacuo. The residue was dissolved in ethyl acetate (400 mL) and washed with saturated aqueous sodium bicarbonate (2×100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to afford the title compound as a yellowish solid in 80% yield (5.60 g): 1H NMR (300 MHz, CDCl3) δ 7.39-7.17 (m, 2H), 7.01 (t, J=8.3 Hz, 2H), 5.78 (br s, 1H), 5.34 (br s, 2H), 4.50 (d, J=5.6 Hz, 2H), 2.47 (s, 3H); MS (ES+) m/z 266.2 (M+1).
Reaction SMILES: [NH2-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3.N.[CH2:19](Br)[C:20]#[CH:21]>C1(C)C=CC=CC=1>[CH2:21]([N:8]1[C:7]2[CH:6]=[CH:5][C:4]([Br:3])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([Br:17])[CH:13]=2)[C:20]#[CH:19]
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: C#CCBr
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C#CCn1c2ccc(Br)cc2c2cc(Br)ccc21
Reaction time: 1.67 h
Yield: 63.9 %

Procedure:
Sodium amide (7.73 g, 0.198 mole) was carefully added to a suspension of 3,6-dibromocarbazole (54.7 g, 0.168 mole) in liquid ammonia (ca. 600 ml.) under argon atmosphere. After solution occurred, propargyl bromide (20.2 g, 0.170 mole) in toluene was added dropwise to the solution over 25 minute period. The reaction mixture was stirred for an additional 100 minutes, and the ammonia was allowed to evaporate. The resultant solid was washed with water and recrystallized from ethanol to give 39 g (63% yield) tan needles, mp 193°-194°. This solid gave an infrared spectrum with significant features at 3290, 2120, 870, 830, 800, and 790 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]OCF)=[CH:14][CH:13]=3)[CH:10]([CH2:24][CH2:25][CH:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3F)[OH:27])[C:9]2=[O:36])=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:44]1[S:49](=[O:51])(=[O:50])[O:48]CC[CH2:45]1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:36])[CH:10]([CH2:24][CH2:25][CH:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[OH:27])[CH:11]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:45][CH2:44][S:49]([OH:51])(=[O:50])=[O:48])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCCO1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2F)C(c2ccc(OCCOCF)cc2)N1c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCS(=O)(=O)O)cc2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
250 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one (7) were dissolved in 6 ml of absolute dimethylformamide. 337 mg of powdered potassium carbonate and 69 μl of 1,4,-butanesultone were added. The mixture was stirred at room temperature overnight. The reaction solution was filtered and concentrated under oil pump vacuum. The residue was chromatographed on a 10 g SiO2 cartridge (dichloromethane/methanol=5/1) and crystallized from diethyl ether. The product (131 mg) was obtained as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH2:17][CH3:18])[C:3]=1[C:19]([NH2:21])=[O:20].[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31](OC)=O)[CH:26]=[CH:27][C:28]=1[Cl:29].[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:30][C:31]1[NH:21][C:19](=[O:20])[C:3]2[C:4]([CH2:17][CH3:18])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=2[N:1]=1
Reactant: CCCCCCC(CCC)n1nc(CC)c(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(CC)c2c(=O)[nH]c(Cc3ccc(Cl)c(Cl)c3)nc21
Yield: 43.2 %

Procedure:
10 mg (0.02 mmol) of 5-amino-3-ethyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.091 mmol) of methyl 3,4-dichlorophenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 4 mg (45%) of a solid, Rf=0.67 (dichloromethane/methanol=15:1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][CH:15]=3)[CH2:9][NH:8][C:6]=2[N:7]=1.CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[C:41]([CH:45]1[CH2:49][CH2:48][NH:47][CH2:46]1)([O:43][CH3:44])=[O:42]>CN(C)C=O>[NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]([N:47]4[CH2:48][CH2:49][CH:45]([C:41]([O:43][CH3:44])=[O:42])[CH2:46]4)=[O:21])=[CH:16][CH:15]=3)[CH2:9][NH:8][C:6]=2[N:7]=1
Reactant: COC(=O)C1CCNC1
Reactant: Nc1nc(O)c2c(n1)NCC(CCc1ccc(C(=O)O)s1)C2
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(C(=O)c2ccc(CCC3CNc4nc(N)nc(O)c4C3)s2)C1
Yield: 38.5 %

Procedure:
To a sample of 150 mg (0.47 mmol) of 5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]thien-2-ylcarboxylic acid in a three-necked round bottomed flask under an atmosphere of nitrogen were added 3.6 mL anhydrous dimethylformamide and 0.11 mL (0.99 mmol) of N-methylmorpholine. The reaction mixture was stirred and 90 mg (0.51 mmol) of 2-chloro-4,6-dimethoxy-1,3,5-triazine were added at once. The reaction mixture was stirred at room temperature for 0.5 hours and 162 mg (1.25 mmol) of 3-carbomethoxypyrrolidine were added in 1.0 mL of dimethylformamide. After stirring at room temperature for another 3.5 hours, the reaction was concentrated in vacuo and the residue was chromatographed on silica gel with 2-8% CH3OH/CHCl3 to give 78 mg (40%) of methyl 1-{5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]thien-2-ylcarbonyl}pyrrolidine-3-carboxylate as a white solid. Mass Spectrum (FAB+): M+1=432; IR (KBr, cm-1): 643, 734, 768, 809, 1219, 1336, 1417, 1464, 1601, 1684, 1736, 2854, 2924, 3390; UV (C2H5 OH): λmax =222 (ε=21034), 279 (ε=19777).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[CH:10][C:11]=2[CH3:13])[S:6][CH2:5][CH2:4]1.[CH3:15]O.S(=O)(=O)(O)O>CCCCCC.C(OCC)(=O)C>[CH3:15][O:1][CH2:2][CH:3]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[CH:10][C:11]=2[CH3:13])[S:6][CH2:5][CH2:4]1
Reactant: Cc1ccc(C)c2c1SCCC2CO
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COCC1CCSc2c(C)ccc(C)c21
Temperature: 25 °C
Yield: 60 %

Procedure:
To a mixture of 1.32 g (6.33 mmol) of 4-hydroxymethyl-5,8-dimethylthiochroman with 13 ml of methanol was added 0.1 ml of concentrated sulfuric acid, and the mixture was reacted at reflux under heat for 10 hours. The reaction mixture was cooled to room temperature, poured into ice water and extracted with ethyl acetate. The extract was washed with water and with a saturated sodium chloride aqueous solution. An organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off. The residue was purified by column chromatography (silica gel; hexane/ethyl acetate=2/1)to give 0.84 g (yield 60%) of the titled compound.
Reaction SMILES: [CH:1]([C:3]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH3:12])=[C:5]([C:13]#[N:14])[CH:4]=1)=O.[CH3:15][NH:16][CH3:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:15][N:16]([CH2:1][C:3]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH3:12])=[C:5]([C:13]#[N:14])[CH:4]=1)[CH3:17]
Reactant: CNC
Reactant: Cc1cccc2c(C#N)cc(C=O)n12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc2c(C#N)cc(CN(C)C)n12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-Formyl-5-methyl-indolizine-1-carbonitrile (200 mg, 1.09 mmol) in CH2Cl2 (10 mL) and dimethylamine (2M MeOH solution) (1.09 mL, 2.17 mmol) was added NaBH(OAc)3 (460 mg, 2.17 mmol) at 0° C. Upon complete addition the cooling bath was removed and the reaction mixture was stirred at room temperature for 12 h. When the reaction was complete, the mixture was diluted with CH2Cl2 and washed with saturated NaHCO3. The layers were separated and the organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product 3-Dimethylaminomethyl-5-methyl-indolizine-1-carbonitrile, CAS: 3-Dimethylaminomethyl-5-methyl-indolizine-1-carbonitrile (150 mg, 65%) as a white solid.
Reaction SMILES: CS[C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N1C=CC=CC=1>C(O)(C)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(C)O
Solvent: c1ccncc1
Product: CSC(=C(C#N)C#N)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
With the exclusion of air, 7.22 g (42.4 mmol) of 3,3-bis(methylsulfanyl)-2-cyano-acrylonitrile (Maybridge), 7.90 g (42.4 mmol) of piperazine-N-carboxylic acid tert-butyl ester (Aldrich; Milwaukee/USA) and 0.24 g (3 mmol) of pyridine are heated to boiling in 75 ml of isopropanol for 4 hours. Cooling, concentration by evaporation and drying under a high vacuum yield 3-(4-tert-butoxycarbonyl-piperazin-1-yl)-3-methylsulfanyl-2-cyano-acrylonitrile; C14H20N4SO2: calc. C54.52%, H 6.54%, N 18.17%, S 10.40%; found C54.37%, H 6.50%, N 17.85%, S 10.25%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11](=[O:15])[N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:8]=[C:7]1[C:22]([O:24]CC)=O.O.[NH2:31][NH2:32]>C(OCCO)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11](=[O:15])[N:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:9]=2[CH:8]=[C:7]1[C:22]([NH:31][NH2:32])=[O:24]
Reactant: CCOC(=O)c1cc2c(ccc(=O)n2-c2ccccc2)n1Cc1cccc(Cl)c1
Reactant: NN
Solvent: O
Solvent: CCOCCO
Product: NNC(=O)c1cc2c(ccc(=O)n2-c2ccccc2)n1Cc1cccc(Cl)c1
Temperature: 115 °C
Yield: 31.2 %

Procedure:
A solution of Example 26 (200 mg, 0.49 mmol) in 2-ethoxyethanol (3 ml) was treated with hydrazine hydrate (0.10 ml, 2.04 mmol) and heated at 115° C. overnight. The reaction mixture was concentrated in vacuo. Purification by chromatography (10%-50% EtOAc in DCM, silica) gave the title compound (60 mg, 31%). δH (d3-MeOD) 7.81 (1H, d, J 9.6 Hz), 7.55-7.41 (3H, m), 7.34-7.31 (2H, m), 7.21-7.13 (2H, m), 7.06 (1H, s), 6.99-6.95 (1H, m), 6.42 (1H, d, J 9.6 Hz), 6.17 (1H, s), 5.76 (2H, s). LCMS (ES+) RT 2.78 minutes, 393 [35Cl]:395 [37Cl] 3:1 (M+H+).