Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5]C(=O)NC1(CCCO)CCC(OC2C=C3C(=CC=2Cl)C(OCC2C=CC=CC=2)=NC=C3)CC1)(C)(C)C.[C:39]([O:43][C:44](=[O:77])[NH:45][C:46]1([CH2:74][CH:75]=[CH2:76])[CH2:53][CH2:52][CH2:51][CH:50]([O:54][C:55]2[CH:56]=[C:57]3[C:62](=[CH:63][C:64]=2[Cl:65])[C:61]([O:66][CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)=[N:60][CH:59]=[CH:58]3)[CH2:49][CH2:48][CH2:47]1)([CH3:42])([CH3:41])[CH3:40].B1C2CCCC1CCC2>>[C:39]([O:43][C:44](=[O:77])[NH:45][C:46]1([CH2:74][CH2:75][CH2:76][OH:5])[CH2:53][CH2:52][CH2:51][CH:50]([O:54][C:55]2[CH:56]=[C:57]3[C:62](=[CH:63][C:64]=2[Cl:65])[C:61]([O:66][CH2:67][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)=[N:60][CH:59]=[CH:58]3)[CH2:49][CH2:48][CH2:47]1)([CH3:42])([CH3:41])[CH3:40]
Reactant: C=CCC1(NC(=O)OC(C)(C)C)CCCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CCC1
Reactant: CC(C)(C)OC(=O)NC1(CCCO)CCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CC1
Agent: B1C2CCCC1CCC2
Product: CC(C)(C)OC(=O)NC1(CCCO)CCCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CCC1

Procedure:
1.14 g of [5-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-1-(3-hydroxy-propyl)-cyclooctyl]-carbamic acid tert-butyl ester (59) were synthesized using the procedure described for the synthesis of [4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-1-(3-hydroxy-propyl)-cyclohexyl]-carbamic acid tert-butyl ester (53) starting from 1.17 g (2.12 mmol) of [1-allyl-5-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-cyclooctyl]-carbamic acid tert-butyl ester (58) and 12.7 mL (6.37 mmol) of 9-BBN (0.5M solution in THF). Rt=1.71 min (Method I). Detected mass: 569.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH3:14][CH:15]([N:19]=[C:20]=S)[CH2:16][CH2:17][CH3:18]>C(OCC)(=O)C>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]2[S:10](=[O:12])(=[O:11])[N:13]=[C:20]([NH:19][CH:15]([CH3:14])[CH2:16][CH2:17][CH3:18])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)c(Cl)cc1S(N)(=O)=O
Reactant: CCCC(C)N=C=S
Solvent: CCOC(C)=O
Product: CCCC(C)NC1=NS(=O)(=O)c2cc(Cl)c(Cl)cc2N1

Procedure:
The title compound was prepared from 2-amino-4,5-dichlorobenzenesulfonamide and 2-pentyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 217-220° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 0.90 (t, 3H, CH3), 1.14 (d, 3H, CH3), 1.20-1.55 (m, 4H, CH2CH2), 3.83 (m, 1H, NHCH), 7.33 (br., 1H, NH), 7.49 (br.s, 1H, ArH), 7.89 (s, 1H, ArH), 10.48 (br.s, 1H, NH); MS: m/e 335/337/339 (M+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].[CH:19]1(Br)[CH2:23][CH2:22][CH2:21][CH2:20]1.O>CS(C)=O>[CH:19]1([O:7][N:8]2[C:9](=[O:18])[C:10]3[C:11](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:13])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: BrC1CCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.6 %

Procedure:
Solid potassium carbonate (8.64 g, 62.5 mmol) was added to a solution of N-hydroxyphthalimide (4.08 g, 25.0 mmol) in dimethyl sulfoxide (38 mL), and the mixture was stirred at 25° C. for 5 min. To the mixture cyclopentyl bromide (37.5 mmol, 4.02 mL) was added, and the mixture stirred at 80° C. for 3 h. After cooling in ice, the mixture was poured into cold water and the resulting precipitate was collected by filtration in vacuo, washed with water (25 mL) and hexanes (15 mL) and dried in vacuo to afford 2-cyclopentyloxy-isoindole-1,3-dione (4.89 g, 85%) as an off-white solid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][NH2:23])[CH:17]=[CH:18][C:19]=1[Cl:20].[BH4-].[Na+].O>CO>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][NH:23][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([Si:2]([CH3:12])([CH3:11])[CH3:1])=[CH:4][CH:5]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: C[Si](C)(C)c1ccc(C=O)cc1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[Si](C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 103.4 %

Procedure:
4-Trimethylsilanyl-benzaldehyde (800 mg, 4.5 mmol) and 2-(3,4-dichloro-phenyl)-ethylamine (1023 mg, 5.4 mmol) were dissolved in methanol (5 ml) and the solution was stirred at rt for 5 min. Sodium borohydride (166 mg, 4.5 mmol) was added under nitrogen and the reaction mixture was stirred at rt for 1 h. Water was added and methanol was evaporated in vacuo. The reaction was extracted twice with diethyl ether and the combined organic layers were washed once with water and once with sat. aq. NaCl solution, dried with sodium sulfate, filtered and concentrated in vacuo to yield [2-(3,4-dichloro-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amine (1640 mg, 100%) as a colorless oil. MS (ISP): 352.2/354.2 (100/74) (M+H)+. 1HNMR (CDCl3, 300 MHz): δ 7.48 (d, 2H), 7.25-7.35 (m, 4H), 7.02 (dd, 2H), 3.79 (s, 2H), 2.75-3.00 (m, 4H), 0.26 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4]Br.[CH3:14][C@@H:15]1[C@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:18][C:17](=[O:26])[NH:16]1>>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][N:16]1[C@H:15]([CH3:14])[C@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:18][C:17]1=[O:26]
Reactant: FC(F)(F)c1ccc(Br)c(CBr)c1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Br

Procedure:
Prepared according to the procedure described in Example 6, Step 3, using the following starting materials: 2-bromo-5-(trifluoromethyl)benzyl bromide and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C:14]([C@@H:16]2[CH2:20][C@@H:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][NH:17]2)=[O:15])=[CH:5][CH:4]=1)#[N:2].[CH:29](=O)[C:30]([CH3:33])([CH3:32])[CH3:31].C1C=CC=CC=1>CCCCC>[CH2:22]([O:21][C@H:19]1[CH2:18][N:17]2[C@@H:29]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:13]([C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[C:14](=[O:15])[C@@H:16]2[CH2:20]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)C=O
Reactant: N#Cc1ccc(NC(=O)[C@@H]2C[C@@H](OCc3ccccc3)CN2)c2ccccc12
Solvent: CCCCC
Solvent: c1ccccc1
Product: CC(C)(C)[C@H]1N(c2ccc(C#N)c3ccccc23)C(=O)[C@@H]2C[C@@H](OCc3ccccc3)CN21
Yield: 86.3 %

Procedure:
A suspension of 33B (151 mg, 0.38 mmol) and pivalaldehyde (100 μl, 0.90 mmol) in a mixture of dry benzene (0.5 ml) and dry pentane (5.0 ml) was refluxed for 25 hr with a Dean-Starke receiver (Ref: Org. Lett., 2 (18) 2781-2783, (2000)). The reaction mixture was evaporated to dryness and dried in vacuo. Purification using automated flash chromatography (35 g silica gel column, EtOAc/hexane gradient) gave the title compound as a light pink-colored solid (144.1 mg, 86.3%). m.p. 155-157° C. MS (ES): m/z 440 [M+1]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].[NH:10]1[C:18]2[C:13](=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[CH3:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[N:10]1[C:18]2[C:13](=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: Cc1cccc(I)c1C
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Product: Cc1cccc(-n2ccc3c(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)cccc32)c1C

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-2,3-dimethylbenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 480.1 (M+H)+.
Reaction SMILES: [H-].[K+].[CH:3]([O:6][P:7]([CH2:13][P:14]([O:20][CH:21]([CH3:23])C)(=[O:19])[O:15][CH:16]([CH3:18])C)(=[O:12])[O:8][CH:9]([CH3:11])C)([CH3:5])C.Cl[CH2:25][C:26]1[C:31]([CH2:32]Cl)=[CH:30][CH:29]=[CH:28][N:27]=1>CS(C)=O>[CH2:21]([O:20][P:14]([C:13]1([P:7]([O:6][CH2:3][CH3:5])(=[O:12])[O:8][CH2:9][CH3:11])[CH:25]=[C:26]2[C:31]([CH:30]=[CH:29][CH2:28][NH:27]2)=[CH:32]1)(=[O:19])[O:15][CH2:16][CH3:18])[CH3:23]
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Reactant: ClCc1cccnc1CCl
Agent: [H-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)C=C2C=CCNC2=C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice bath chilled solution of 35% potassium hydride in mineral oil (5.2 g; 0.045 moles) stirring under argon in 70 ml of DMSO (dry) is added a solution of tetraisopropylmethanediphosphonate (7.82 g; 0.023 moles) in 30 ml of DMSO. On completion of a dropwise addition, the resulting solution is stirred at room temperature for one hour. A solution of 2,3-bis(chloromethyl)pyridine (4.0 g; 0.023 mole) (crude product as isolated by K. Tsuda et.al., Chem Pharm Bull., 1, (1953), 142) in 15 ml of DMSO is slowly added and the reaction mixture is then heated at 90° C. for 1 hour. After cooling, the DMSO is removed under vacuum. 2.1 g (21%) of the desired product is purified via flash chromatography using a 5-15% ethanol in methylene chloride gradient on silica gel.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19]([CH:21]=[CH2:22])[CH:18]=[C:17]([CH:23]=O)[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.[Na].Cl>CO.C(O)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19]([CH:21]=[CH2:22])[CH:18]=[C:17]([CH2:23][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: C=Cc1cc(C=O)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Reactant: C1CCNC1
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: C=Cc1cc(CN2CCCC2)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Eine suspension von 200 mg of the aldehyde described in Example 80.1 and 0.062 ml of pyrrolidine in 2 ml of MeOH was adjusted to pH 6 by the dropwise addition of acetic acid. Then, 46 mg of sodium cyanoborhydride were added and the mixture was stirred overnight at room temperature. It was acidified to pH 3 with 1N HCl and subsequently evaporated. The crude product was isolated by extraction and purified by chromatography on silica gel gereinigt. There were obtained 200 mg of methyl (RS)-(4-cyano-phenylamino)-(3-pyrrolidin-1-ylmethyl-5-vinyl-phenyl)-acetate as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C>[CH2:22]([N:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCI
Reactant: C1=CC2(CCNCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN1CCC2(C=Cc3ccccc32)CC1
Yield: 31.3 %

Procedure:
In the same way as that described in Example 1, step 5, the title compound was prepared, using spiro[1H-indene-1,4'-piperidine] (333 mg, 1.8 mmol), DMF (15 ml), potassium carbonate (0.26 g, 1.9 mmol) and iodobutane (267 μl, 2.4 mmol). The crude residue was chromatographed in dichloromethane:methanol 95:5, to give 1'-butylspiro [1H-indene-1,4'-piperidine] (136 mg, 31%) as a clear oil.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][CH:5]([CH2:24][O:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][CH:8]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:11](=[O:22])[CH2:10][S:9]1=[O:23]>CCOCC>[OH:4][CH:5]([CH2:24][O:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][CH:8]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:3])=[O:20])[C:11](=[O:22])[CH2:10][S:9]1=[O:23]
Reactant: C=[N+]=[N-]
Reactant: CCCOCC(O)CCC1N(CCCCCCC(=O)O)C(=O)CS1=O
Solvent: CCOCC
Product: CCCOCC(O)CCC1N(CCCCCCC(=O)OC)C(=O)CS1=O
Reaction time: 4 h

Procedure:
A solution of diazomethane (approximately 2.5 g., 0.06 mole) in ether (100 ml.) is slowly added to a solution of 7-[2-(3-hydroxy-4-propoxybutyl)-1,4-dioxo-3-thiazolidinyl]heptanoic acid (11.3 g., 0.03 mole) in ether (50 ml.) with stirring and cooling (0° to 5° C.). The resulting solution is allowed to warm to and stand at room temperature for 4 hours. After destroying excess diazomethane with acetic acid, the reaction solution is washed with 5% sodium bicarbonate solution and water, dried over sodium sulfate, and filtered. In vacuo evaporation of the filtrate leaves the title compound as an essentially colorless, viscous oil.
Reaction SMILES: [C:1]([O:5][P:6]([O-:13])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:31][CH2:32][CH2:33]Br>C(COC)OC>[P:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:13][CH2:33][CH2:32][Br:31])=[O:7]
Reactant: BrCCBr
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: COCCOC
Product: CC(C)(C)OP(=O)(OCCBr)OC(C)(C)C
Temperature: 25 °C
Yield: 46.2 %

Procedure:
Tetra-n-butylammonium di-tert-butyl phosphate (4.0 g, 8.87 mmol) and 1,2-dibromoethane (5.0 g, 26.7 mmol) in dimethoxyethane (20 ml) were stirred and refluxed for 4 hr. then cooled to room temperature and filtered. The filtrate was concentrated, diluted with diethyl ether, washed with 20% aqueous potassium carbonate solution, dried over magnesium sulphate and evaporated to leave a colourless oil. The crude product was purified by silica gel chromatography eluting with a 20-50% mixture of ethyl acetate in iso-hexane to give 2-bromoethyl di-tert-butyl phosphate (1.3 g, 46% yield) as a colourless oil:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16])=O)(C)(C)C.[ClH:20]>O1CCOCC1>[ClH:20].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(C#N)c1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cccc(OCCN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.41 g of 3-[2-(t-butoxycarbonylamino)ethoxy]benzonitrile was dissolved in 20 ml of 4 N solution of hydrogen chloride in dioxane, and the solution was stirred at room temperature for 2 hours. The solvent was evaporated. The residue was suspended in dichloromethane, and the obtained suspension was filtered to obtain hydrochloride of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:8][C:7]([CH3:14])=[N:6][N:5]2[C:15]=1[C:16]1[S:17][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=2)=[CH:19][C:20]=1[CH3:21].[CH3:29][CH2:30]OCC.C([Mg]Br)C>CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]([OH:13])([CH2:29][CH3:30])[CH2:11][CH3:12])=[CH:8][C:7]([CH3:14])=[N:6][N:5]2[C:15]=1[C:16]1[S:17][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=2)=[CH:19][C:20]=1[CH3:21]
Reactant: CCOCC
Reactant: CCC(=O)c1cc(C)nn2c(-c3sc(-c4cccc(C)n4)cc3C)c(C)nc12
Agent: CC[Mg]Br
Solvent: CCOC(C)=O
Product: CCC(O)(CC)c1cc(C)nn2c(-c3sc(-c4cccc(C)n4)cc3C)c(C)nc12
Temperature: 25 °C
Yield: 37 %

Procedure:
To a −0° C. solution of 1-{2,6-dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazin-8-yl}-propan-1-one (0.040 g, 0.10 mmol) and Et2O (5 mL) is added 3.0 M ethyl magnesium bromide (0.68 mL, 2.05 mmol). The solution is warmed to ambient temperature, diluted with EtOAc (30 mL) washed with sat. NH4Cl (20 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (20%-30% EtOAc/hexane gradient) furnish the title compound (0.016 g, 0.038 mmol, 37%). 1H NMR (CDCl3), δ 0.89 (t, J=7.4 Hz, 6H), 1.92-2.01 (m, 4H), 2.14 (s, 3H), 2.46 (s, 3H), 2.53 (s, 3H), 3.57 (s, 3H), 6.39 (s, 1H), 6.66 (s, 1H), 7.01 (d, J=7.5 Hz, 1H), 7.46 (d, J=7.9 Hz, 1H), 7.52 (s, 1H), 7.57 (dd, J=7.9, 7.5 Hz, 1H). LC/MS (m/z): calcd. for C24H28N4OS (M+H)+: 421.3; found: 421.3.
Reaction SMILES: [NH:1]1C2(CCCCC2)[NH:4][CH2:3][C:2]1=[O:11].[O:12]1[CH2:22][CH:13]1[CH2:14][C:15]([O:17]CC(C)C)=O>>[CH2:14]1[C:15](=[O:17])[N:4]([CH2:3][C:2]([NH2:1])=[O:11])[CH2:22][CH:13]1[OH:12]
Reactant: O=C1CNC2(CCCCC2)N1
Reactant: CC(C)COC(=O)CC1CO1
Product: NC(=O)CN1CC(O)CC1=O

Procedure:
1.3 g of 1,4-diazaspiro[4,5]decan-2-one ((5); R4 +R5 =--(CH2)5 --) (8.4 mmoles) are heated and stirred with magnetic stirring, with 1.5 g 2-methylpropyl 3,4-epoxybutanoate ((4), X=isobutyl) (9.5 mmoles) up to 110° (external temperature) for 24 h. The mixture is cooled, and the dark mass obtained is washed with 10 ml boiling ethyl acetate. This is decanted, and the solid obtained is crystallised from methanol to give oxiracetam as a crystalline white powder, m.p. 167°-70° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[C:22]([Cl:23])=[C:21]([CH3:24])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:17]2[C:22]([Cl:23])=[C:21]([CH3:24])[S:20][C:18]=2[N:19]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1Cl
Product: COc1ccc(CNc2nc(Cl)nc3sc(C)c(Cl)c23)cc1OC

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dimethoxybenzylamine with 2,4,5-trichloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2,5-dichloro-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]1([C:7]2[N:16]=[C:15]([NH2:17])[C:14]3[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:22]1(=[O:27])[O:26][CH2:25][CH2:24][CH2:23]1>>[NH2:17][C:15]1[C:14]2[C:9](=[CH:10][C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[CH:13]=2)[N:8]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:25](=[O:26])[CH2:24][CH2:23][CH2:22][OH:27])[CH2:3][CH2:2]2)[N:16]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: O=C1CCCO1
Product: COc1cc2nc(N3CCN(C(=O)CCCO)CC3)nc(N)c2cc1OC

Procedure:
5 g of 2-piperazinyl-4-amino-6,7-dimethoxy quinazoline were heated in 15 g of γ-butyrolactone to 100° C. until a sample on thin layer chromatography (as described in Examples 1 and 3) indicated the reaction was complete. The precipitate formed overnight with cooling was removed and recrystallized from ethanol. The 1-(4-amino-6,7-dimethoxy quinazolin-2-yl)-4-(4-hydroxy-butyryl)-piperazine obtained showed a crystal transformation at 135°-140° C. and melted at 241°-243° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:23]1[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][N:26]=[C:25]2[N:34]([CH3:38])[N:35]=[C:36]([CH3:37])[C:24]=12.O>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C:23]2[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][N:26]=[C:25]3[N:34]([CH3:38])[N:35]=[C:36]([CH3:37])[C:24]=23)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)NCc2cccnc2)cc1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2C)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1cnc2c(c(C)nn2C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
To a solution of 1.39 g (5 mmol) of (4-methoxybenzenesulfonyl)(3-pyridinylmethyl) amine in 4 ml of anhydrous 1-methyl-2-pyrrolidinone was added 0.2 g (5 mmol) of sodium hydride (60% in oil) and the mixture stirred at room temperature until gas evolution ceased. To this mixture was added 1.15 g (4.54 mmol) of ethyl 4-chloro-1,3-dimethylpyrazolo[3,4-b]pyridine-5-carboxylate and 2 ml of anhydrous 1-methyl-2-pyrrolidinone. The mixture was stirred in a sealed tube under nitrogen in an oil bath at 90° C. for 3 days. The mixture was cooled, poured into water and extracted with ethyl acetate. The extract was washed with H2O, brine and dried (Na2SO4). The solution was filtered through a thin pad of hydrous magnesuim silicate and the filter pad washed with ethyl acetate. The filtrate was concentrated to dryness under vacuum to give 1.3 g of solid. Chromatography on silica gel with ethyl acetate as solvent gave 0.35 g of product as a solid, mp 152-154° C.
Reaction SMILES: [Cl:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]2[N:6]=[C:7]([C:9]3[CH:28]=[CH:27][C:12]([C:13]([NH:15][CH:16]4[CH2:21][C:20]([CH3:23])([CH3:22])[N:19]([CH3:24])[C:18]([CH3:26])([CH3:25])[CH2:17]4)=[O:14])=[CH:11][C:10]=3[O:29][CH3:30])[NH:8][C:4]=2[CH:3]=1.[OH-].[K+].I[CH3:37]>CC(C)=O>[Cl:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]2[N:6]([CH3:37])[C:7]([C:9]3[CH:28]=[CH:27][C:12]([C:13]([NH:15][CH:16]4[CH2:21][C:20]([CH3:23])([CH3:22])[N:19]([CH3:24])[C:18]([CH3:25])([CH3:26])[CH2:17]4)=[O:14])=[CH:11][C:10]=3[O:29][CH3:30])=[N:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(=O)NC2CC(C)(C)N(C)C(C)(C)C2)ccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1cc(C(=O)NC2CC(C)(C)N(C)C(C)(C)C2)ccc1-c1nc2cc(Cl)c(Cl)cc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 132.4 %

Procedure:
A mixture of 4-(5,6-dichlorobenzimidazol-2-yl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-3-methoxybenzamid (0.16 g, 0.33 mmol), prepared as described in Example 4, and KOH (0.0185 g, 0.33 mmol) in acetone (8 ml) was stirred for 1 h at room temperature. Iodomethane (0.047 g, 0.033 mmol) was added and stirring was continued for 24 h. Solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. the organic layer was washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by column chromatography eluting with CH2Cl2/MeOH/NH4OH 95:5:0.2. Fraction containing the desired product were collected, evaporated to dryness under reduced pressure and the solid was triturated with diisopropyl ether to give 0.022 g of the title compound (yield 13%), mp=178–180° C.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([O:27][C:28](=[O:42])[NH:29][CH2:30][C:31](=O)[NH:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=1[F:40])([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([O:27][C:28](=[O:42])[NH:29][CH2:30][C:31](=[S:10])[NH:32][C:33]1[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=1[F:40])([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1c(F)cccc1F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=S)Nc1c(F)cccc1F
Yield: 63.4 %

Procedure:
A Lawesson's reagent (50 mg, 0.12 mmol) was added to a THF (2 mL) solution of [(2,6-difluorophenylcarbamoyl)methyl]carbamic acid tert-butyl ester (52 mg, 0.18 mmol) in an argon atmosphere, and the mixture was refluxed with heating overnight. After evaporating the solvent, the residue was purified by silica gel column chromatography (13 g, hexane:acetone=10:1 to 8:1) to obtain [(2,6-difluorophenylthiocarbamoyl)methyl]carbamic acid tert-butyl ester (23 mg) as a colorless crystalline substance.