Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N([CH2:9][CH:10]=[CH:11][C:12]1[CH:16]=[CH:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:24])[CH:13]=1)OC(=O)C)(=O)C.CC1C=CC=C(C)C=1N1C=CC(C=[O:39])=C1.C(OC(OCC)C(CC)(CC)P(O)(O)=O)C>>[CH3:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:17]=1[N:14]1[CH:15]=[CH:16][C:12]([CH:11]=[CH:10][CH:9]=[O:39])=[CH:13]1
Reactant: Cc1cccc(C)c1-n1ccc(C=O)c1
Reactant: CC(=O)ON(CC=Cc1ccn(-c2c(C)cccc2C)c1)C(C)=O
Agent: CCOC(OCC)C(CC)(CC)P(=O)(O)O
Product: Cc1cccc(C)c1-n1ccc(C=CC=O)c1

Procedure:
Similarly prepared is N-acetyl-N-acetyloxy-3-[1-(2,6-dimethylphenyl)-1H-pyrrol-3-yl]-allylamine. The starting material is prepared by condensing 1-(2,6-dimethylphenyl)-1H-pyrrole-3-carboxaldehyde with diethyl phosphonoacetaldehyde diethylacetal to obtain 3-[1-(2,6-dimethylphenyl)-1H-pyrrol-3-yl]-acrolein. The aldehyde is then converted to the oxime and reduced to the hydroxylamine according to previously described procedures.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[N:12]=[N:13][C:14]([O:17]C)=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][N:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)c2cccc(Cl)c2)nn1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc(S(=O)(=O)c2cccc(Cl)c2)n[nH]1
Yield: 43.4 %

Procedure:
A mixture of 3-(3-chloro-benzenesulfonyl)-6-methoxy-pyridazine (148 mg), dioxane (2 mL) and concentrated hydrochloric acid (0.5 mL) was prepared and refluxed for 30 minutes. The reaction mixture was then evaporated to dryness and the residue was extracted with ethyl acetate (2×10 mL). The ethyl acetate mixture was collected, dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated to dryness to afford 6-(3-chloro-benzenesulfonyl)-2H-pyridazin-3-one as white solid (38%, 61 mg); mp, 222-223° C.: NMR, 7.11 (d, 1H), 7.74 (t, 1H), 7.86-8.04 (m, 4H), 13.86 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:9]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:18]([CH2:21][C:22](=[O:24])[CH3:23])(=[O:20])[CH3:19]>C(O)(=O)C.Cl.O.C(O)C>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][N:9]=[C:21]([C:22](=[O:24])[CH3:23])[C:18](=[O:20])[CH3:19]
Reactant: O=N[O-]
Reactant: Nc1ccccc1F
Reactant: CC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=O)C(=NNc1ccccc1F)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 2-fluoroaniline (1000 mg, 9.00 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrochloride solution, sodium nitrite (746 mg, 10.80 mmol) in 4 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (2220 mg, 27.00 mmol) and acetylacetone (990 mg, 9.90 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-[(2-fluorophenyl)hydrazono]pentane-2,4-dione (1280 mg, 64%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=2)[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: ClCc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(Cc3ccc(Cl)cc3)n2)ccc1F
Yield: 46.5 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-chlorobenzyl chloride were reacted to yield a crude product. Without purification, the crude product was reacted further in accordance with the procedure of Example 1(7) to yield the title compound as a pale yellow crystalline powder (46.5%).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=2)[CH2:2][CH3:3].ClS([N:21]=[C:22]=O)(=O)=O.CN(C)C=O.O>C(#N)C>[C:22]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH2:1][CH2:2][CH3:3])#[N:21]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCCc1cc2ccc(C(=O)OC)cc2[nH]1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCc1[nH]c2cc(C(=O)OC)ccc2c1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
To a stirred solution of methyl 2-propylindole-6-carboxylate (911 mg) in acetonitrile (15 ml) was added chlorosulfonylisocyanate (0.6 g) in acetonitrile (1.5 ml) at 0° C. The mixture was stirred at 0° C. for 30 minutes, then N,N-dimethylformamide (0.35 g) in acetonitrile (15 ml) was added at 0° C. The resultant mixture was stirred at 20° C. for 40 minutes, and then poured into water. The mixture was extracted with methylene chloride three times, and the combined organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:3) to give the crystals which were recrystallized from a mixture or ethyl acetate and hexane to give methyl 3-cyano-2-propylindole-6-carboxylate (535 mg) as colorless crystals.
Reaction SMILES: [C:1]1([CH:13]2[CH2:17][CH2:16][C@H:15]([NH2:18])[CH2:14]2)[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3][N:2]=1.Cl[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CCO>[C:1]1([C@H:13]2[CH2:17][CH2:16][C@H:15]([NH:18][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=3)[CH2:14]2)[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3][N:2]=1
Reactant: N[C@H]1CCC(c2n[nH]c3cnc4[nH]ccc4c23)C1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N[C@H]2CC[C@H](c3n[nH]c4cnc5[nH]ccc5c34)C2)nc1
Temperature: 120 °C
Yield: 4.9 %

Procedure:
A mixture of (1S)-3-(3,6-Dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentanamine (0.20 g, 0.83 mmol, Preparation #30), 6-chloronicotinonitrile (0.12 g, 0.83 mmol), DIEA (0.22 mL, 1.2 mmol), and EtOH (3 mL) were heated for about 1 h at about 120° C. in a microwave (250 psi maximum pressure, 1 min ramp, 300 max watts). The reaction mixture was concentrated in vacuo and purified by RP-HPLC (Table 2, Method s) to give 6-((1S,3S)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentylamino)nicotinonitrile (0.014 g, 5%): LC/MS (Table 2, Method a) Rt=1.75 min; m/z: 344 (M+H)+ and 6-((1S,3R)-3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)cyclopentylamino)nicotinonitrile (0.020 g, 7%): LC/MS (Table 2, Method a) Rt=1.81 min; m/z: 344 (M+H)+.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:30])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:17]([CH2:26][NH:27][CH2:28][CH3:29])=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]=1)[CH3:4].[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>>[CH2:3]([O:5][C:6](=[O:30])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:17]([CH2:26][N:27]([CH2:28][CH3:29])[C:34](=[O:35])[CH2:33][O:32][CH3:31])=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]=1)[CH3:4]
Reactant: CCNCc1nc2ccccc2cc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: COCC(=O)Cl
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc3ccccc3nc2CN(CC)C(=O)COC)c1

Procedure:
Prepared according to the procedure described in Example 5, Step 5, using the following starting materials: [3-(2-ethylaminomethyl-quinolin-3-yl)-4-methoxy-phenyl]-acetic acid ethyl ester, dihydrochloride and methoxyacetyl chloride.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30])=O.CC(=O)OCC>CO.[OH-].[Na+]>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccc(F)cc3F)n2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1ccc(F)cc1F
Temperature: 25 °C

Procedure:
The 2-trifluoroacetamido-3-(2,4-difluorophenyl)-6-benzoyl-imidazo[1,2-a]pyridine (9.24 g, 20.8 mmol) was dissolved in 250 ml of MeOH and 170 ml of 1N NaOH. The solution was stirred at RT under N2 for 2 weeks. The precipitant was filtered and the filter cake was dissolved in 900 ml of EtOAc. The solution was washed with brine (3×50 ml), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was recrystalized from EtOAc/hexane to give 2 crops yielding 5.57 g. (76.8%). EA, MS(FD).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.C(O[C@@H:23]1[O:40][C@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[C@@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]1[O:25][C:26](=[O:28])[CH3:27])(=O)C>ClCCl.C1(C)C=CC=CC=1>[C:26]([O:25][C@@H:24]1[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:34]([O:35][C:36](=[O:38])[CH3:37])[C@@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[O:40][C@H:23]1[O:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COC(=O)c1ccc(Cc2ccccc2O)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To a suspension of methyl 4-(2-hydroxybenzyl)benzoate (0.053 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (0.26 g) in dichloromethane (1 mL) and toluene (3 mL) was added boron trifluoride-diethyl ether complex (0.083 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=4/1) to give 2-(4-methoxycarbonyl-benzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.067 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][CH3:14])=[CH:10][C:9]([CH3:15])=[CH:8][CH:7]=2.[F:16][C:17]([F:22])([F:21])[C:18](O)=O.[OH-].[NH4+]>Cl>[CH3:14][N:13]1[C:12]2[C:11]3[CH:10]=[C:9]([CH3:15])[CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:2]=[C:18]1[C:17]([F:22])([F:21])[F:16]
Reactant: O=C(O)C(F)(F)F
Reactant: CNc1c(N)cnc2ccc(C)cc12
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1ccc2ncc3nc(C(F)(F)F)n(C)c3c2c1

Procedure:
A mixture of 4.5 g (0.0201 mole) of 3-amino-6-methyl-4-(methylamino)quinoline hydrochloride (from Example 32), 9.1 g (0.080 mole) of trifluoroacetic acid and 100 ml of 4 N hydrochloric acid was heated at its reflux temperature for three hours. The solution was cooled and basified with ammonium hydroxide. The precipitate was separated by filtration and washed with water. Recrystallization from isopropanol provided 1,8-dimethyl-2-trifluoromethyl-1H-imidazo[4,5-c]quinoline, m.p. 220°-223° C. Analysis: Calculated for C13H10F3N3 : %C, 58.9; %H, 3.8; %N, 15.8; Found: %C, 58.6; %H, 3.7; %N, 16.2.
Reaction SMILES: C([O:3][C:4]1[C:5](=[O:39])[C:6](=O)[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]3[CH3:37])[C:18]3[CH2:24][CH2:23][N:22]([C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:21][C:19]=3[N:20]=2)=[CH:11][CH:10]=1)C.Cl.[CH2:41]([NH2:43])[CH3:42].C(O)C.C(N(CC)CC)C>>[CH2:41]([NH:43][CH:6]1[CH:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]4[CH3:37])[C:18]4[CH2:24][CH2:23][N:22]([C:25]5[N:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH2:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)[C:4](=[O:3])[C:5]1=[O:39])[CH3:42]
Reactant: CCN
Reactant: CCOc1c(Nc2ccc(-c3nc4c(c(N5CCOC[C@@H]5C)n3)CCN(c3ncccn3)C4)cc2)c(=O)c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCNC1C(=O)C(=O)C1Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2ncccn2)C3)cc1

Procedure:
Step 2—Synthesis of compound un: (S)-3-ethoxy-4-(4-(4-(3-methylmorpholino)-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenylamino)cyclobut-3-ene-1,2-dione (0.087 g, 0.00016 mol), Ethylamine Hydrochloride (0.0780 g, 0.000956 mol), and Ethanol (8.00 mL, 0.137 mol) were combined then added Triethylamine (0.230 mL, 0.00165 mol) and stirred overnight. The reaction mixture was concentrated, and chromatographed through silica gel (12 g, 0-5% MeOH in dichloromethane). 1H NMR (400 MHz, DMSO) δ 9.83 (s, 1H), 8.44 (d, J=4.7, 2H), 8.31 (d, J=8.7, 2H), 7.72 (s, 1H), 7.53 (d, J=8.5, 2H), 6.69 (t, J=4.7, 1H), 4.90 (d, J=18.7, 1H), 4.75 (d, J=18.6, 1H), 4.14 (t, J=9.3, 2H), 3.85 (dd, J=20.6, 7.2, 2H), 3.74-3.55 (m, 6H), 3.44 (t, J=11.9, 1H), 2.75 (s, 2H), 1.31-1.15 (m, 6H). LC/MS-m/z+527.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[CH:11][CH:10]=[C:9]([C@@H:13]([OH:24])[C@H:14]3[N:19]4[CH2:20][C@H:21]([CH:22]=[CH2:23])[C@@H:16]([CH2:17][CH2:18]4)[CH2:15]3)[C:7]=2[CH:8]=1.[C:25]([OH:42])(=[O:41])[C:26]1[C:27](=[CH:31][C:32](=[C:36]([CH:40]=1)[C:37]([OH:39])=[O:38])[C:33]([OH:35])=[O:34])[C:28]([OH:30])=[O:29].O.C(O)C>C(O)CC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[CH:11][CH:10]=[C:9]([C@@H:13]([OH:24])[C@H:14]3[N:19]4[CH2:20][C@H:21]([CH:22]=[CH2:23])[C@@H:16]([CH2:17][CH2:18]4)[CH2:15]3)[C:7]=2[CH:8]=1.[C:33]([O-:35])(=[O:34])[C:32]1[C:36](=[CH:40][C:26](=[C:27]([CH:31]=1)[C:28]([O-:30])=[O:29])[C:25]([O-:42])=[O:41])[C:37]([O-:39])=[O:38]
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)O)cc1C(=O)O
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: CCO
Solvent: O
Solvent: CCCO
Product: O=C([O-])c1cc(C(=O)[O-])c(C(=O)[O-])cc1C(=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Four grams of quinine, 2.6 g. pyromellitic acid and 50.0 g. H2O were combined with stirring and heated to 80° C. 310.0 cc ethanol and 5.0 cc n-propanol were added and the mixture held at 70°-80° C. for about 30 minutes. The reaction product was filtered hot and 3.62 g. of dry cake, M.P. 220° C. (not sharp) was obtained.
Reaction SMILES: C(C(C)=[O:4])=C.C1(C=CC(O)=CC=1)O.[CH3:14][O-:15].[Na+].CC(O[CH2:21][C:22]1[C:35]2[C:30](=[CH:31]C=C[CH:34]=2)[C:29](COC(C)=O)=[C:28]2[C:23]=1[CH:24]=[CH:25]C=C2)=O>C(C(CC)=O)C.O>[CH3:21][C:22]1[C:35](=[O:4])[CH:30]([CH3:31])[CH2:29][CH2:28][C:23]=1[CH3:24].[CH3:28][CH:23]1[CH2:24][CH2:25][C:14](=[O:15])[CH:21]=[C:22]1[CH2:35][CH3:34]
Reactant: C[O-]
Reactant: C=CC(C)=O
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: CCC(=O)CC
Solvent: O
Product: CC1=C(C)C(=O)C(C)CC1
Product: CCC1=CC(=O)CCC1C

Procedure:
A mixture of 70 g of methyl vinyl ketone, 10 g of water and 0.1 g of hydroquinone is dripped in the course of one hour into a mixture of 400 g of diethyl ketone and 10 g of a 30% by weight methanolic solution of sodium methylate which is boiling under reflux. The whole is then heated for another two hours under reflux. The mixture obtained is neutralized with glacial acetic and then filtered. Excess diethyl ketone and the water present are distilled off and the residue is fractionated in vacuo. 81 g of 2,3,6-trimethyl-2-cyclohexen-1-one having a boiling point of 89° C. at 12 mm Hg and 9 g of 4-methyl-3-ethyl-2-cyclohexen-1-one having a boiling point of 102° C. at 12 mm Hg are obtained. The total yield of cyclohexenone is 65% with reference to methyl vinyl ketone.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:24])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH2:25]=O.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CCO>[N:4]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH2:25][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:16]3=[O:24])=[CH:9][CH:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: C=O
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(N2CCOCC2)cc1
Reactant: C1CCNCC1
Solvent: CCO
Product: O=C1C(=CNc2ccc(N3CCOCC3)cc2)c2ccccc2N1CN1CCCCC1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
A solution of 3-[(4-morpholinophenylamino)-methylene]-1,3-dihydro-indol-2-one (17.3 g, 53.8 mmol) and paraformaldehyde (2.43 g, 80.9 mmol.) in 125 mL of EtOH was treated with piperidine (5.87 mL, 59.3 mmol). The reaction mixture was then heated at a reflux temperature for 5 hours during which time a yellow precipitate formed. The reaction mixture was allowed to cool to room temperature and the solid was collected by filtration and washed with EtOH and dried under vacuum to give the title compound (21.5 g, 95%) as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[C:12]([O:16][C:17]([N:19]1[CH2:23][CH:22]([CH2:24][O:25][CH3:26])[CH2:21][C@H:20]1[C:27]([OH:29])=[O:28])=[O:18])([CH3:15])([CH3:14])[CH3:13].CCN(CC)CC>CC#N.CCOC(C)=O>[CH3:26][O:25][CH2:24][CH:22]1[CH2:23][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:18])[C@H:20]([C:27]([O:29][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=2)=[O:4])=[O:28])[CH2:21]1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: COCC1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCC1C[C@@H](C(=O)OCC(=O)c2ccc(Br)cc2)N(C(=O)OC(C)(C)C)C1
Yield: 86.7 %

Procedure:
To a solution of 2-bromo-1-(4-bromophenyl)ethanone (2.3 g, 8.39 mmol) and (S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid (2.61 g, 10.06 mmol) in MeCN (100 mL) was added Et3N (1.26 mL, 9.24 mmol). After stirring over night, the solution was diluted with EtOAc, washed with sat. NaHCO3, brine, dried with MgSO4, and concentrated. The residue was purified by silica gel chromatography to yield product (3.32 g).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1)=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:45][CH2:46][CH2:47][NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52]>C(Cl)Cl.CCOC(C)=O>[C:51]([O:50][C:49](=[O:55])[NH:48][CH2:47][CH2:46][NH:45][C:9](=[O:11])[CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:13][CH:12]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCNC(=O)COc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
4-Formylphenoxyacetic acid (0.306 g, 1.70 mmol) was dissolved in DCM (5 mL). DIEA (0.524 g, 4 mmol) and TBTU (0.550 g, 1.70 mmol) were added followed by tert-butyl N-(2-aminoethyl)carbamate (0.250 g, 1.56 mmol). The mixture was stirred 2 h at room temperature, dissolved in EtOAc and washed sequentially with 5% aqueous K2CO3, KHSO4, water and brine. The extract was dried (MgSO4) and concentrated under reduced pressure to give a yellow solid (0.350 g).
Reaction SMILES: C([N:8]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:9]1[C:10](O)=O)(OC(C)(C)C)=O.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([NH2:28])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]2[NH:27][C:10]([C@@H:9]3[CH2:13][C@H:14]([F:16])[CH2:15][NH:8]3)=[N:28][C:23]=2[CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(=O)O
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Product: CC(C)(C)c1ccc2[nH]c([C@@H]3C[C@H](F)CN3)nc2c1

Procedure:
The title compound was prepared according to Method 4 using N-Boc-cis-4-fluoro-L-proline and 4-tert-butyl-1,2-diaminobenzene. The final residue was washed with ethyl acetate and diluted with water, basified with saturated lithium hydroxide solution (pH=8), extracted with ethyl acetate and dried over anhydrous Na2SO4 and concentrated under reduced pressure.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:21][NH:22][C:23]1[CH:24]=[N:25][C:26]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35].C(N(C(C)C)C(C)C)C.O>ClCCl>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14]([N:22]([CH3:21])[C:23]2[CH:24]=[N:25][C:26]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:27][C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc(N2CCOCC2)cc1-c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(N2CCOCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 64.2 %

Procedure:
A solution of 1.2 g (3.8 mMol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride and 0.5 ml dichloromethane were added dropwise over 15 minutes at 0° C. to a solution of 1.0 g (3.5 mMol) methyl-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-amine and 0.85 ml (4.9 mMol) N-ethyl-di-isopropylamine in 7.0 ml dichloromethane. The reaction mixture was stirred 2.5 hours at 0° C., poured onto 8 ml deionized water and stirred further 30 minutes at room temperature. The phases were separated and the aqueous phase extracted with dichloromethane. The organic extracts were washed with deionized water, aqueous sodium hydroxide 2% and aqueous sodium bicarbonate 5%, dried (Na2SO4) and concentrated under reduced pressure. The residue was crystallized from ethanol at −20° C. to yield 1.27 g (64%) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide as a white powder. Concentration of the mother-liquors gave 0.77 g of a slowly crystallizing brown oil which can be further purified.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1.[Na].Cl.O.[CH2:25]([OH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:14][OH:15])[CH2:18][OH:17])=[C:4]([O:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1
Reactant: OCc1ccccc1
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Agent: Cl
Agent: [Na]
Solvent: O
Product: Nc1nc(OCc2ccccc2)c2ncn(CCC(CO)CO)c2n1
Reaction time: 1 h
Yield: 50 %

Procedure:
A suspension of 2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.31 g, 1.0 mmol) in a solution of sodium benzoxide (1M in benzyl alcohol, 2 ml) was stirred at 70° for 1 hour. The resulting solution was allowed to cool, hydrochloric acid (5M, 0.4 ml) and water (0.6 ml) were added and the solution was stirred for 1 hour at room temperature. The solution was then partitioned between chloroform and water. The aqueous layer was neutralised with aqueous sodium bicarbonate and extracted with chloroform. The combined organic layers were washed with aqueous sodium bicarbonate, dried (magnesium sulphate) and the solvent was removed. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol mixtures (10:1, 5:1) to afford 2-amino-6-benzyloxy-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine as a white crystalline solid (0.17 g, 50%), m.p. 146-147.5° C.; λmax (EtOH) 212 (32,300), 250 (8,380), and 283 (10,100) nm; νmax (fBr) 3340, 3220, 1655, 1605, and 1580 cm−1; δH [(CD3)2SO] 1.3-1.6 (1H, m, 3′-H), 1.72 (2H, q, J 7 Hz, 2′-H), 3.38 (4H, AB part of ABX, 2×4′-H), 4.03 (2H, t, J 7 Hz, 1′-H), 4.36 (2H, t, J 5.5 Hz, D2O exchangeable, 2×OH), 5.47 (2H, s, PhCH2), 6.37 (2H, s, D2O exchangeable, 2-NH2), 7.3-7.6 (5H, m, C6H5), and 7.84 (1H, s, 8-H); (Found: C, 58.89; H, 6.12; N, 19.87%; C17H21N5O3 requires C, 59.46; H, 6.16; N, 20.40%).