Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[C:9]3[CH:16]=[CH:15][N:14](S(C4C=CC(C)=CC=4)(=O)=O)[C:10]3=[CH:11][CH:12]=2)[CH:7]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH2:6][CH:5]1[CH3:35])(=[O:3])[CH3:2].[OH-].[Na+].[Cl-].[NH4+]>CO>[C:1]([N:4]1[C:13]2[C:8](=[C:9]3[CH:16]=[CH:15][NH:14][C:10]3=[CH:11][CH:12]=2)[C@H:7]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH2:6][C@@H:5]1[CH3:35])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c2C(Nc2ccc(Cl)cc2)CC1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N1c2ccc3[nH]ccc3c2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
[Step 4] 9.5 mg of the 6-acetyl-9-(4-chlorophenylamino)-7-methyl-3-tosyl-6,7,8,9-tetrahydro-3H-pyrrolo[3.2-f]quinoline were dissolved in methanol (1 mL) followed by adding 4 M aqueous sodium hydroxide solution (1 mL) and stirring for 30 minutes at 80° C. After allowing to cool to room temperature, the reaction liquid was neutralized by addition of saturated aqueous ammonium chloride solution followed by extracting with chloroform, washing the organic layer with saturated brine, dehydrating with anhydrous sodium sulfate and concentrating under reduced pressure. The resulting residue was purified by PLC (chloroform:methanol=20:1) to obtain 3.8 mg of the target compound in the form of a yellow oil (59.4%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]([O:20]CC)=[O:19])[N:6]2[CH2:13][C:14]([F:17])([F:16])[F:15].[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]([OH:20])=[O:19])[N:6]2[CH2:13][C:14]([F:17])([F:16])[F:15]
Reactant: CCOC(=O)c1cc2c(Cl)c(C#N)ccc2n1CC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc2c(cc(C(=O)O)n2CC(F)(F)F)c1Cl
Temperature: 70 °C
Yield: 93.6 %

Procedure:
To a solution of ethyl 4-chloro-5-cyano-1-(2,2,2-trifluoroethyl)-1H-indole-2-carboxylate (0.02 g, 0.06 mmol) in 1:1 THF/MeOH (4 mL) was added 1N NaOH (1 mL) and the mixture was heated at 70° C. for 1.25 h. Upon cooling, the mixture was partially concentrated under vacuo. The residue was partitioned between EtOAc and 0.2N HCl. The organic phase was washed with sat'd brine. The combined aqueous phases were reextracted twice with EtOAc. The organic phases were combined and washed with sat'd brine, dried (Na2SO4) and concentrated in vacuo to afford the title compound (0.017 g, 94% yield): MS (ES) m/z 301 (M−1).
Reaction SMILES: Cl.Cl.[CH2:3]([C@@H:10]1[NH:15][CH2:14][CH2:13][N:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[CH:17]=2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[CH2:3]([C@H:10]1[CH2:11][N:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)[CH:17]=2)[CH2:13][CH2:14][N:15]1[C:32](=[O:34])[CH3:33])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCN(C)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(N2CCN(C(C)=O)[C@@H](Cc3ccccc3)C2)cc1OC1CCN(C)CC1

Procedure:
Prepared using the same procedure described in Example 338 from (S)-3-benzyl-1-[4-methoxy-3-(1-methyl-piperidin-4-yloxy)-phenyl]-piperazine dihydrochloride (103 mg, 0.22 mmol) and acetic anhydride (200 μL, 2.11 mmol), and pyridine (2 mL) to afford the title compound as brown waxy solid (47 mg, 49%). LC/MS (Method B) 2.32 min, [M+1]+ 338.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[Cl:33])=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[Cl:33][C:27]1[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=1[O:25][CH2:24][CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][CH:18]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)COc4cc(Cl)ccc4Cl)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(NCCOc4cc(Cl)ccc4Cl)cc3)c2cc1OC
Temperature: 0 °C
Yield: 79.7 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-2-(2,5-dichlorophenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 486 (M++1)
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[NH:7][CH:8]=[CH:9][N:10]=1)([CH3:5])[CH3:4].CN(C)C=O.S(C1C=CC(C)=CC=1)(O[CH2:20][C@@H:21]1[CH2:35][C@H:34]2[C@@H:24]([CH2:25][C:26]3[C:36]4[C:29](=[CH:30][CH:31]=[CH:32][C:33]2=4)[NH:28][CH:27]=3)[N:23]([CH3:37])[CH2:22]1)(=O)=O>CO.C(O)(C)C>[CH:3]([C:6]1[N:7]([CH2:20][C@@H:21]2[CH2:35][C@H:34]3[C@@H:24]([CH2:25][C:26]4[C:36]5[C:29](=[CH:30][CH:31]=[CH:32][C:33]3=5)[NH:28][CH:27]=4)[N:23]([CH3:37])[CH2:22]2)[CH:8]=[CH:9][N:10]=1)([CH3:5])[CH3:4]
Reactant: CC(C)c1ncc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(C)O
Product: CC(C)c1nccn1C[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
0.9 g of 50% sodium hydride in an oil was added to a mixture of 4.0 g of 2-isopropylimidazole and 40 ml of dimethylformamide, and the mixture was stirred for 30 minutes. 2.0 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 2 hours. The solvent was distilled off under reduced pressure, and water was added to the residue. The precipitated crystals were filtered, washed with water and purified by silica gel column chromatography (eluted with acetone). The crystals thus obtained were dissolved in methanol, and isopropyl alcohol was added thereto. The mixture was concentrated and allowed to cool to obtain 0.6 g of the titled compound as colorless needles having a melting point of 283°-288° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=O)[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:4].[CH2:21]([SH:25])[CH2:22][CH2:23][SH:24]>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8]2([S:25][CH2:21][CH2:22][CH2:23][S:24]2)[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:4]
Reactant: SCCCS
Reactant: COC(=O)C1CC(=O)CN1C(=O)OCc1ccccc1
Solvent: ClCCl
Product: COC(=O)C1CC2(CN1C(=O)OCc1ccccc1)SCCCS2
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
Ketone 2 (250 mg) in CH2Cl2 at 15° C. was treated with 1,3-propanedithiol (100 uL) dropwise followed by BF3OEt2 (119 uL). The mixture was warmed to room temperature and stirred overnight. The reaction was quenched by adding 1 mL potassium carbonate aqueous solution (2 g/30 mL) followed by 321 uL of saturated sodium bicarbonate to adjust to pH 7-8. Washed organics with water, brine, then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification on a plug of silica gel eluting with toluene→hexane/ethyl ether (2:3→0:1) yielded 200 mg (60%) of desired 6,10-dithia-2-aza-spiro[4.5]decane-2,3-dicarboxylic acid-2-benzyl ester 3-methyl ester 26 as a clear oil. 1H NMR (CDCl3) δ 7.30 (m, 5H), 5.05-5.25 (m, 2H), 4.6 (t, 0.5H), 4.55 (t, 0.5H), 3.8 (s, 1.5H), 3.75 (m, 1H), 3.6 (s, 1.5H), 2.95 (m, 1H), 2.85 (m, 3H), 2.75 (m, 1H), 2.4 (m, 0.5H), 2.35 (m, 0.5H), 2.0 (m, 2H) ppm.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=1[C:20]([O:22][CH3:23])=[O:21])(=O)=O.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[Cl:33].C([O-])([O-])=O.[Na+].[Na+].[NH4+].[Cl-]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:28]=[C:29]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]=2[C:20]([O:22][CH3:23])=[O:21])[CH:30]=[CH:31][C:32]=1[Cl:33]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(c2ccc(Cl)c(Cl)c2)CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a mixture of 1-(1,1-dimethylethyl) 3-methyl 4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydro-1,3(2H)-pyridinedicarboxylate (200 mg, P2), 3,4-dichlorophenylboronic acid (108 mg) and Pd(PPh3)4 (21 mg) under nitrogen, toluene (2.5 mL), ethanol (2 mL) and Na2CO3 (aqueous 2M solution, 2 mL) were added in sequence. The mixture was stirred at 80° C. for 1 hour then the reaction mixture was allowed to reach room temperature. Saturated aqueous NH4Cl solution (15 mL) was poured into the solution and the mixture was transferred in a separator funnel. The mixture was extracted with ethyl acetate (3×20 mL), the combined organic phases were dried on anhydrous Na2SO4 and the solvent evaporated obtaining a crude product that was purified by flash-chromatography (eluting with ethyl acetate/cycloexane 1:3) to give the title compound (198 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH:13]=[CH:14]/[CH:15]=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23]>>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:21]2[S:17][C:18](=[O:23])[NH:19][C:20]2=[O:22])=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)Oc1ccc(/C=C/C=C/C=O)cc1
Product: CC(C)Oc1ccc(CCCCCC2SC(=O)NC2=O)cc1
Yield: 26 %

Procedure:
According to the same manner as that described in Example 23, (E,E)-5-(4-isopropoxyphenyl)-2,4-pentadienal was condensed with 2,4-thiazolidinedione, and the resulting compound was subjected to catalytic hydrogenation to give 5-[5-(4-isopropoxyphenyl)pentyl]-2,4-thiazolidinedione as an oil (yield: 26%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.NC1C=C([N:37]2[CH2:41][CH2:40][CH2:39][C:38]2=[O:42])C=CC=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:37]3[CH2:41][CH2:40][CH2:39][C:38]3=[O:42])[CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: Nc1cccc(N2CCCC2=O)c1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(N2CCCC2=O)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 1-(3-aminophenyl)pyrrolidin-2-one in step 1. MS: 410.5 (M+H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[C:11](=[CH:12][CH:13]=[C:14]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:40])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:31])[CH2:20][CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C)[C:10]1([CH3:42])[CH3:41])(C(C)(C)C)(C)C>C(O)C.C1C=CC=CC=1.Cl>[CH3:42][C:10]1([CH3:41])[C@@H:9]([OH:8])[CH2:38][CH2:37][C@@:36]2([CH3:39])[C@H:11]1[CH2:12][CH2:13][C:14]1[C:15]3[C@:32]([CH3:40])([CH2:33][CH2:34][C:35]=12)[C@@H:18]([C@H:19]([CH3:31])[CH2:20][CH2:21][CH2:22][OH:23])[CH2:17][CH:16]=3
Reactant: C[C@H](CCCO[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: c1ccccc1
Solvent: CCO
Product: C[C@H](CCCO)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Reaction time: 8 h
Yield: 71.4 %

Procedure:
A mixture of 3β,24-bis(tert-butyldimethylsilyloxy)-4,4-dimethylchola-5,7-diene (18.8 g) in 99.9% ethanol (375 ml), benzene (55 ml) and concentrated hydrochloric acid (55 ml) is heated to reflux for 4 hours. After standing overnight at room temperature, the reaction mixture is concentrated under reduced pressure. Crystallization of the remanens from ethanol/water gives 8.44 g of the title compound. Melting point: 203-208° C. 1H-NMR (CDCl3, 400 MHz): δ=5.36 (1H, s); 3.62 (2H, m); 3.23 (1H, m).
Reaction SMILES: [C:1]([NH:4][C:5](=[N:7]/[N:8]=[CH:9]/[C:10]1[CH:11]=[C:12]2[C:18]([CH3:19])=[N:17][NH:16][C:13]2=[N:14][CH:15]=1)[SH:6])(=[O:3])[CH3:2].C(OO)(=O)C>C(O)(=O)C>[CH3:19][C:18]1[C:12]2[C:13](=[N:14][CH:15]=[C:10]([C:9]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:7][N:8]=3)[CH:11]=2)[NH:16][N:17]=1
Reactant: CC(=O)NC(S)=N/N=C/c1cnc2[nH]nc(C)c2c1
Agent: CC(=O)OO
Solvent: CC(=O)O
Product: CC(=O)Nc1nnc(-c2cnc3[nH]nc(C)c3c2)s1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
The starting material 1-acetyl-3-((E)-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyleneamino)isothiourea (5 g) (80 mg, 0.22 mmol) was taken up in 5 ml acetic acid and 1.2 ml peracetic acid in a round bottom flask. The mixture was heated to 60° C. After 15 min, the product was precipitated out. The solid was filtered off and washed with ether (50 ml). The yield for this reaction was quantitative and the product was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C@@H:15]([CH3:32])[CH2:14]2)[C:9](=[O:12])[CH2:10]C)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:31])[C:24]3[CH:25]=[CH:26][C:27]([O:30][CH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43])=[CH:28][CH:29]=3)[C@@H:15]([CH3:32])[CH2:14]2)[C:9](=[O:12])[CH3:10])=[CH:6][CH:7]=1
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: CC(C)(CO)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCC(C)(C)CO)cc2)c2ccccc21
Temperature: 95 °C

Procedure:
(±)-Cis-N-(4-chloro-phenyl)-N-{1-[4-(3-hydroxy-2,2-dimethyl-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-acetamide was prepared from (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide. (±)-Cis-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-propionamide (210 mg, 0.484 mmol) was dissolved in DMF (10 mL) at room temperature. Potassium carbonate (1 g, 7.1 mmol) was added, followed by 3-bromo-2,2-dimethyl-propan-1-ol (813 mg, 4.84 mmol), the reaction was heated to 95° C. and stirred over night. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (95/5 dichloromethane/ethyl acetate—70/30 dichloromethane/ethyl acetate) to afford the pure ester (110 mg, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.CN(C)C=O.[CH3:22][N:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH2:29]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH3:30])[CH3:22]
Reactant: CN(C)CCCCCN
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)CCCCCN/C=C1\C(=O)NC(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A mixture of 6-bromo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (70.5 mg, 0.25 mmole), dimethylformamide (2 mL) and N1,N1-dimethylpentane-1,5-diamine (32.6 mg, 0.25 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with ether, filtered and washed with fresh ether and dried to give a light salmon solid, 61.1 mg, (64% yield) MS (ES+): 382.2, (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1.C1([O:23][C:24](=O)[NH:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C=CC=CC=1>O1CCOCC1>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([NH:9][C:24]([NH:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:23])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(N)CC1
Reactant: O=C(NCCCc1ccccc1)Oc1ccccc1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(NC(=O)NCCCc2ccccc2)CC1

Procedure:
4-Dimethylamino-4-phenyl-cyclohexylamine (more polar diastereomer) (218 mg, 1.0 mmole) was added to a solution of (3-phenylpropyl)carbamic acid phenyl ester (255 mg, 1.0 mmole) in dioxane and refluxed for 12 h. Working up was performed by removing the dioxane by distillation and combining the residue with water. The batch was adjusted to pH 11 with 5M NaOH and extracted with ethyl acetate. The organic phase was dried with Na2SO4 and evaporated. The more polar product was obtained as a colorless oil in a yield of 379 mg (100%).
Reaction SMILES: [CH:1](=[C:8](/[CH2:13][Cl:14])\[C:9]([O:11]C)=[O:10])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)(=O)C>[CH:1](=[C:8](/[CH2:13][Cl:14])\[C:9]([OH:11])=[O:10])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C(=C/c1ccccc1)CCl
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C(=C/c1ccccc1)CCl
Temperature: 100 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
Into a 500-ml pressure bottle were charged 40 g (0.19 mol) of methyl (Z)-2-benzylidene-3-chloropropionate, 150 ml of a 35% hydrochloric acid and 50 ml of acetic acid. The reaction mixture was then heated to a temperature of 100° C. with stirring overnight. After the completion of the reaction, the reaction solution was then poured into ice water. The reaction solution was then extracted with 200 ml of ethyl acetate. The resulting organic phase was washed with saturated brine, and then dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The resulting crude crystal was then recrystallized from a mixture of acetone and toluene to obtain 27.3 g (yield: 73%) of the desired compound in the form of colorless crystal. For the measurement of purity, the product was silylated with N,O-bis(trimethylsilyl)acetamide for gas chromatography. The result was 100%.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH2:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)=[N:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[CH2:13][C:10]4[O:9][C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[N:12][N:11]=4)=[CH:20][CH:21]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1Cc1nnc(Cc2ccccc2)o1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cc4nnc(Cc5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 2-benzyl-5-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-[1,3,4]oxadiazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]([OH:14])(=[O:13])[CH3:12].C(N(CC)CC)C>CC(O)CC>[C:11]([O:14][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:13])[CH3:12]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CCC(C)O
Product: CCOC(=O)CC(=O)COC(C)=O

Procedure:
71 ml of ethyl 4-chloro-3-oxobutyrate are reacted with 57 ml of acetic acid and 132 ml of triethylamine in 1 l of 2-butanol by the procedure described in Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:12]N(C)C)=[CH:5][NH:6]2.[C-:16]#[N:17].[K+]>CN(C=O)C.O>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:12][C:16]#[N:17])=[CH:5][NH:6]2
Reactant: Cc1cc(C)c2c(CN(C)C)c[nH]c2c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c2c(CC#N)c[nH]c2c1

Procedure:
A solution of [(4,6-dimethyl-1H-indol-3-yl)methyl]dimethylamine from Step A (98.0 mg, 0.484 mmol) and potassium cyanide (315 mg, 4.84 mmol) in DMF (2 mL) and H2O (2 mL) was heated at 100° C. for 2 h. The reaction mixture was partitioned between EtOAc (20 mL) and saturated NaCl (10 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude product by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 98:2, gave the title compound. MS: m/z=185 (M+1).
Reaction SMILES: [CH3:1][C:2]([OH:8])([CH2:4][CH:5]([OH:7])[CH3:6])[CH3:3].[H-].[Na+].F[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]>C1COCC1>[F:18][C:16]1[CH:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]([CH:17]=1)[O:7][CH:5]([CH3:6])[CH2:4][C:2]([CH3:3])([OH:8])[CH3:1]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(O)CC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CC(C)(C)O)Oc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
2-Methylpentane-2,4-diol (2.8 ml) was dissolved in THF (20.0 ml) and NaH (60% in mineral oil; 1 g) was added. At room temperature 2,4-difluoronitrobenzene was added and the reaction mixture was stirred overnight. Then the reaction was quenched with water and concentrated in vacuo. The residue was dissolved in dichloromethane, washed with water and concentrated in vacuo.
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.[CH3:22][CH:23]([CH3:25])[O-:24].[Na+].Cl.C(=O)(O)[O-].[Na+]>C(O)(C)C.O>[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:24][CH:23]([CH3:25])[CH3:22])[N:3]=1
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Reactant: CC(C)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1nc(N)nc2c1ncn2CCC(CO)CO
Reaction time: 0.42 h

Procedure:
A solution of 2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.25 g, 0.8 mmol) in isopropanol (2.5 ml) containing sodium isopropoxide 0.5 M) was stirred at 60° for 25 minutes. After cooling, hydrochloric acid (5 M, 0.3 ml) and water (0.7 ml) were added and the solution was stirred for 15 minutes at room temperature. The solution was neutralised by addition of aqueous sodium bicarbonate and the solvent was removed. The residue was extracted with chloroform-ethanol (2:1) and the solution purified by column chromatography on silica gel eluting with chloroform-methanol (7:1) to afford 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)-6-isopropoxypurine which was crystallised from chloroformcarbon tetrachloride (0.18 g, 76%), m.p. 111.5°-113.5° C.; δH [(CD3)2SO] 1.34 (6 H, d, J 6.3 Hz, C(CH3)2), 1.45 (1H, m, 3' -H), 1.74 (2 H, q, J 7.2 Hz, 2'-H), 3.3-3.5 (4 H, AB part of ABX, 2×4'-H), 4.06 (2 H, t, J 7.3 Hz, 1'-H), 4.40 (2 H, br, 2×OH), 5.49 (1 H, septet, J 6.3 Hz, CH(CH3)2), 6.27 (2 H, s, 2-NH2), and 7.83 (1 H, s, 8 -H).