Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7](=O)[CH2:8][O:9][N:10]=[C:11]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:5])[CH3:2].Cl.[O:30]([NH2:32])[CH3:31].C(OCC)(=O)C>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([CH2:6][C:7](=[N:32][O:30][CH3:31])[CH2:8][O:9][N:10]=[C:11]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)=[O:5])[CH3:2]
Reactant: CON
Reactant: CCOC(=O)CC(=O)CON=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(CON=C(c1ccc(OC)cc1)c1ccc(OC)cc1)=NOC
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
3.85 g of the 4,4'-dimethoxybenzophenone O-(3-ethoxycarbonyl-2- oxopropyl)oxime as obtained in Example 1 was dissolved in 5 ml of pyridine and 1 g of methoxylamine hydrochloride was added thereto. Then the obtained mixture was stirred at room temperature. After two hours, the reaction mixture was poured into ethyl acetate, washed with diluted hydrochloric acid and then with a saturated saline solution and purified by silica gel chromatography. Thus 4 g of the title compound was obtained in the form of a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][CH:24]2[CH2:25][CH2:26][N:22]([CH3:21])[CH2:23]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CN1CCC(N)C1
Product: CN1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)C1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 1-methylpyrrolidin-3-amine (10.0 mg, 0.1 mmol). The title compound was obtained as a solid (4.3 mg, 10% yield). MS m/z: 432.84, 434.84 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[CH:31]1([N:37]=[C:38]=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:37]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:38]2=[O:39])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Reactant: O=C=NC1CCCCC1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3C3CCCCC3)CC2)c1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and cyclohexyl isocyanate to give the title compound as a colorless solid. MS: 525.4 ([M+H]+)
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.O>CS(C)=O>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)#[N:2]
Reactant: ClCCCCCCc1ccncc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCCCCc1ccncc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
NaCN (509 mg) in DMSO (4.25 ml) is added to 4-(6-chlorohexyl)pyridine (1.71 g) dissolved in DMSO (4.25 ml). The mixture is stirred at 60° C. for 3 hours, poured into water (100 ml) and extracted with chloroform (3×15 ml). The combined extracts are washed with water (2×20 ml), dried (Na2SO4) and the solvent evaporated to give 4-(6-cyanohexyl)-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([N:21]=[C:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17]1=[O:34])(=[O:14])=[O:13])[CH:6]=[CH:5]2.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([NH:21][CH:22]3[CH2:23][CH2:24][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:26][CH2:27]3)[C:17]1=[O:34])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C1[C@@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1N=C1CCN(c2ccncc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1[C@@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1NC1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
(3S)-3-(6-Chloronaphthalene-2-sulfonylamino)-1-[1-(4-pyridyl)-4-piperidinylideneamino}-2-pyrrolidone (600 mg) was dissolved in methanol (40 ml), combined with acetic acid (761 mg) while cooling on ice, followed by sodium cyanoborohydride (300 mg) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue was combined with an aqueous solution of sodium carbonate, extracted with dichloromethane, dried, concentrated and purified by a column chromatography (dichloromethane: 10% aqueous ammonia-containing methanol=20:1) and crystallized from ethyl acetate to obtain the title compound (576 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:17])[C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:18]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.C([O-])([O-])=O.[K+].[K+]>CO>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[OH:17])=[CH:10][CH:11]=1)#[CH:18]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: O=Cc1ccc(C(O)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
A mixture of the product of Step B (0.21 g, 0.91 mmol), dimethyl(1-diazo-2-oxopropyl)phosphonate (0.21 g, 1.1 mmol) and K2CO3 (0.152 g, 1.1 mmol) in anhydrous MeOH (5 ml) was stirred for overnight at room temperature. The solvent was distilled off and the residue was taken in EtOAc (50 ml), washed with H2O and dried over MgSO4 and filtered. The filtrate was evaporated under reduced pressure to give the crude product (0.195 g; 95%), which was used in the next step without purification. 1H-NMR (CDCl3) 3.05 (s, 1H); 5.76 (s, 1H); 7.0 (tr, 2H, J=8.58 Hz); 7.25-7.33 (m, 4H); 7.44 (d, 2H, J=8.29 Hz).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH2:38][CH:39]=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)#[N:25].O>COC(C)(C)C>[CH3:2][O:3][CH:4]=[CH:39][CH2:38][C@H:35]1[CH2:34][CH2:33][C@H:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)[CH2:37][CH2:36]1
Reactant: N#Cc1ccc([C@H]2CC[C@H](CC=O)CC2)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: O
Product: COC=CC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Reaction time: 1 h

Procedure:
A suspension of 4.5 g of methoxymethyl-triphenylphosphonium chloride in 40 ml of t-butyl methyl ether was treated within 3 minutes with 1.5 g of potassium t-butylate while gassing with argon at -10° C. and the solution was stirred for a further 1 hour at 0°-5° C. The suspension was then treated dropwise within 5 minutes at 0° C. with a solution of 2.0 g of [trans-4-(p-cyanophenyl)cyclohexyl]-acetaldehyde in 20 ml of t-butyl methyl ether and the mixture was stirred for a further 2 hours at room temperature. The reaction mixture was subsequently poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated. The resulting, viscous oil was dissolved in 15 ml of ethyl acetate and the clear solution was treated with 250 ml of petroleum ether. After leaving to stand for 10 minutes at -20° C. the precipitated triphenylphosphine oxide was filtered off and the filtrate was concentrated to dryness. Low-pressure chromatography (0.5 bar) of the residue (3.3 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 2.04 g (91%) of p-[trans-4-(3-methoxy-2-propenyl)cyclohexyl]benzonitrile as a colourless oil; Rf-value (ethyl acetate/petroleum ether vol. 10:90) 0.33.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[Cl:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:36])([F:35])[F:34])[O:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:36])([F:34])[F:35])[O:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:2][C:3]([NH:5][C@@H:6]2[CH2:11][O:10][C:9]3=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]3[CH2:7]2)=[O:4])[CH2:25][CH2:24]1
Reactant: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1Cl
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Product: O=C(CN1CCC(Oc2ccc(OC(F)(F)F)c(Cl)c2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 37.7 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(3-chloro-4-(trifluoromethoxy)phenoxy)piperidine (295 mg, 1.0 mmol) as crude materials, generated 98 mg title compound, yield was 38%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:59]=[CH:58][C:38]([C:39]([NH:41][CH2:42][C:43]3([N:52]4[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]4)[C:48](=[O:49])[NH:47][C:46](=[O:50])[NH:45][C:44]3=[O:51])=[O:40])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>CC(C)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH:2]([N:55]1[CH2:54][CH2:53][N:52]([C:43]2([CH2:42][NH:41][C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([O:34][CH2:33][C:31]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=[C:23]([CH3:22])[CH:32]=4)=[CH:59][CH:58]=3)[C:44](=[O:51])[NH:45][C:46](=[O:50])[NH:47][C:48]2=[O:49])[CH2:57][CH2:56]1)([CH3:3])[CH3:9]
Reactant: Cc1cc(COc2ccc(C(=O)NCC3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: Cc1cc(COc2ccc(C(=O)NCC3(N4CCN(C(C)C)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 52.7 %

Procedure:
Following a procedure analogous to that used in reaction (9), the material from example 8 was reacted with acetone for 7 days to provide the title compound (13.7 mg, 52.7%). MS found: (M+H)+=559.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[NH:22][C:23](CC(C(F)(F)F)CC(O)=O)=[O:24].S(Cl)(Cl)=O.[O:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[C:3]([N:22]2[C:43](=[O:39])[CH2:42][CH:41]([C:16]([F:19])([F:18])[F:17])[CH2:40][C:23]2=[O:24])=[CH:4][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:6]([F:8])[CH:7]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(NC(=O)CC(CC(=O)O)C(F)(F)F)c(Cl)cc2F)c1=O
Reactant: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N3C(=O)CC(C(F)(F)F)CC3=O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.50 g of 4-(N-(2-chloro-4-fluoro-5(1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl)phenyl)carbamoyl)-3-trifluoromethylbutyric acid and 7 ml of dry tetrahydrofuran was added dropwise 0.23 g of thionyl chloride at room temperature. After stirring for 2 hours under reflux, the temperature was cooled to room temperature, and the solvent was removed by distillation under reduced pressure. The resulting crude product was extracted with ethyl acetate, washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and dried over anhydrous sodium sulfate followed by removing ethyl acetate by distillation to obtain 0.50 g of the desired compound as crystal.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.[C:13]([O:21][CH:22]([C@@H:25]1[CH2:29][C@@H:28]([O:30][C:31](=[O:33])[CH3:32])[CH:27](OC(=O)C)[O:26]1)[CH2:23][CH3:24])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C>[C:13]([O:21][CH:22]([C@@H:25]1[CH2:29][C@@H:28]([O:30][C:31](=[O:33])[CH3:32])[C@H:27]([N:8]2[C:6]3[N:7]=[C:2]([NH2:1])[NH:3][C:4](=[O:12])[C:5]=3[S:10][C:9]2=[O:11])[O:26]1)[CH2:23][CH3:24])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1nc2[nH]c(=O)sc2c(=O)[nH]1
Reactant: CCC(OC(=O)c1ccccc1)[C@@H]1C[C@@H](OC(C)=O)C(OC(C)=O)O1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CCC(OC(=O)c1ccccc1)[C@@H]1C[C@@H](OC(C)=O)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a suspension of 5-amino-3,6-dihydrothiazolo[4,5-d]pyrimidine-2,7-dione (2.82 g, 16.8 mmol) in ACN (100 mL) was added BSA (10.4 mL, 42 mmol). The resulting reaction mixture was then stirred at 70° C. under argon for 0.5 hour to form a clear solution. After the solution was cooled to room temperature, 1-[(2S,4R)-4,5-diacetoxytetrahydrofuran-2-yl]propyl benzoate (compound 26b, 4.9 g, 14.0 mmol) and TMSOTf (4.7 mL, 2.3 21 mmol) were added in sequence. After being heated with stirring at 70° C. for 14 hours, the solvent was removed in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3 solution (30 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (30 mL) twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:200 methanol in DCM) to afford 5.27 g crude product of 1-[(2S,4R,5R)-4-acetoxy-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl]propyl benzoate (compound 26c) as a light yellow solid. MS obsd. (ESI+) [(M+H)+]: 475.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]([C:12]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:14])[C:9]([OH:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1cc(Br)c2cccnc2c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cc(Br)c2cccnc2c1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
To a solution of 5-bromo-8-hydroxyquinoline-7-carboxylic acid (0.402 g) of Preparation 2 and 4-chlorobenzylamine (0.219 g) in 20 mL DMF is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g) and 1-hydroxybenzotriazole monohydrate (0.217 g). The mixture is stirred overnight. The solution is then poured into 30 mL ice-water. The resulting solid is collected and dried to yield 0.157 g of the title product as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:16][CH:12]([C:13]2([CH3:15])[CH3:14])[CH2:11][CH2:10][CH:9]3[CH3:17])=[CH:4][C:3]=1[SiH:18]([CH3:20])[CH3:19].C([Li])CCC.CN(C)[CH:28]=[O:29]>C(OCC)C>[C:8]12([C:5]3[CH:6]=[CH:7][C:2]([CH:28]=[O:29])=[C:3]([SiH:18]([CH3:20])[CH3:19])[CH:4]=3)[CH2:16][CH:12]([C:13]1([CH3:15])[CH3:14])[CH2:11][CH2:10][CH:9]2[CH3:17]
Reactant: CC1CCC2CC1(c1ccc(Br)c([SiH](C)C)c1)C2(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC1CCC2CC1(c1ccc(C=O)c([SiH](C)C)c1)C2(C)C
Yield: 96.6 %

Procedure:
28.4 g of p-dibromobenzene was dissolved in diethyl ether, and 51.3 g n-butyl lithium was added to react with p-dibromobenzene at 0° C. Then, 31.2 g of (−)-pinanyldimethylsilyl chloride was added and reacted. A mixture obtained after a routine process was purified by distillation under reduced pressure to obtain 1-bromo-4-(−)-pinanyldimethylsilylbenzene. After dissolving 34.85 g of the obtained 1-bromo-4-(−)-pinanyldimethylsilylbenzene in diethyl ether, 42.4 g of n-butyl lithium and 6.9 g of dimethylformamide were successively added and the mixture was reacted. After processing by a routine method, the reaction mixture was purified by silica gel column chromatography to obtain 27.4 g of 4-(−)-pinanyldimethylsilylbenzaldehyde. After dissolving the obtained aldehyde in 200 ml of tetrahydrofuran, the solution was added to a solution of 36.9 g of methyltriphenyl iodide and 40.0 g of n-butyl lithium to obtain (−)-PSSt. The (−)-PSSt was purified by column chromatography using hexane as a developing solvent to obtain 15.0 g of purified (−)-PSSt. The structure was confirmed using NMR and IR.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])=[O:8])=[O:5].CN1CC[CH2:28][C:27]1=[O:31].C(OC(=O)C)(=O)C>O>[Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:3]=1[C:4]([NH:6][C:7](=[O:8])[NH:9][C:10]1[CH:15]=[C:14]([NH:16][C:27](=[O:31])[CH3:28])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])=[O:5]
Reactant: COc1ccc(N)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Reactant: CN1CCCC1=O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(NC(C)=O)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.10 g (0.3 mmol) of 1-(2-chloro-4,5-difluorobenzoyl)-3-(5-amino-2-methoxyphenyl)urea was admixed with 1 ml of N-methylpyrrolidone, 0.11 g (0.3 mmol) of acetic anhydride and stirred at room temperature for 2 hours. The mixture was diluted with 20 ml of H2O and extracted three times with 20 ml of ethyl acetate each time. The combined organic phase was washed with H2O, concentrated and dried. The crude product was purified by preparative HPLC (column: Waters Xterra™ MS C18, 5 μm, 30×100 mm, eluent: A: H2O+0.2% trifluoroacetic acid, B: acetonitrile, gradient: 2.5 minutes 90% A/10% B to 17.5 minutes 10% A/90% B). 0.03 g of the desired product was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:4]2[N:3]=1.C([O-])(=[O:25])C.[Na+]>C(O)(=O)C>[OH:25][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:4]2[N:3]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc(-c2nnc3c4ccccc4c(Cl)nn23)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(-c2nnc3c4ccccc4c(O)nn23)cc1
Yield: 85 %

Procedure:
6-Chloro-3-(4-methoxyphenyl)-1,2,4-triazolo[3,4-a]phthalazine (0.5 mole) and fused anhydrous sodium acetate in acetic acid are heated to the reflux temperature for about 1 hour. The solvent is evaporated under reduced pressure, the residue is then taken up with water, collected by filtration, and crystallized from ethanol/chloroform. The product of the title is thus obtained in a 85% yield. M.p. 307°-309° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:19]([CH2:21][NH2:22])[OH:20].Cl>O1CCCC1>[OH:20][CH2:19][CH2:21][NH:22][S:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: NCCO
Reactant: O=C(O)c1c[nH]c(=O)c2cc(S(=O)(=O)Cl)ccc12
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)c1c[nH]c(=O)c2cc(S(=O)(=O)NCCO)ccc12
Reaction time: 18 h

Procedure:
7-(Chlorosulfonyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid (1 g) was added to ethanolamine (3 ml) in tetrahydrofuran (3 ml) and the mixture was stirred for 18 h. Hydrochloric acid was added to acidify the mixture, which was filtered to yield 1,2-dihydro-7-[[(2-hydroxyethyl)amino]sulfonyl]-1-oxo-4 isoquinolinecarboxylic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10])=[CH:5][CH:4]=1.[F-].[K+].C(=O)([O-])[O-].[K+].[K+].Br[C:20]1[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][N:21]=1>C(OCC)(=O)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:20]2[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CS)cc1
Reactant: Oc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CSc2ncccc2O)cc1
Temperature: 150 °C
Reaction time: 72 h
Yield: 43 %

Procedure:
4-Methoxy-α-toluenethiol (9.4 mL), potassium fluoride (3.34 g) and potassium carbonate (10.3 g) were added to a DMF (100 mL) solution of 2-bromo-3-hydroxypyridine (10 g, 57.5 mmol), and stirred at 150° C. for 3 days. The reaction liquid was diluted with ethyl acetate, and washed three times with distilled water. The organic layer was dried with magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate and hexane to obtain the intended compound (6.2 g, 43%) as a white solid.
Reaction SMILES: [N:1]1[C:5]2[C@H:6]3[C@H:11]([CH2:12][CH2:13][C:4]=2[O:3][C:2]=1[NH2:14])[NH:10][CH2:9][CH2:8][CH2:7]3.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH2:23][CH3:24]>C(#N)C>[CH2:22]([N:10]1[C@@H:11]2[C@H:6]([C:5]3[N:1]=[C:2]([NH2:14])[O:3][C:4]=3[CH2:13][CH2:12]2)[CH2:7][CH2:8][CH2:9]1)[CH2:23][CH3:24]
Reactant: Nc1nc2c(o1)CC[C@@H]1NCCC[C@@H]21
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC[C@H]2c3nc(N)oc3CC[C@@H]21

Procedure:
A mixture of (±) trans-4,5,5a,6,7,8,9,9a-octahydrooxazolo[4,5-f]quinolin-2-amine, 1.46 g (5.0 mmol), 3.6 g (26 mmol) of finely ground potassium carbonate and 2.5 ml (25.6 mmol) of 1-iodopropane in 250 ml of acetonitrile is refluxed, under nitrogen, for 24 hours. The mixture is cooled, filtered through a pad of Celite, concentrated and partitioned between brine and chloroform. The organic extract is dried and concentrated. Chromatography of the mixture on silica gel gives (±) trans-4,5,5a,6,7,8,9,9a-octahydro-6-propyloxazolo[4,5-f]quinolin-2-amine. The procedure just described can be applied to (±) trans-4,5,5a,6,7,8,9,9a-octahydrooxazolo[5,4-f]quinolin-2-amine to give (±) trans-4,5,5a,6,7,8,9,9a-octahydro-6-propyloxazolo [5,4-f]quinolin-2-amine.
Reaction SMILES: [CH2:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][NH:8][C:9]2[CH:17]=[CH:16][C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)#[N:21].C([O-])([O-])=O.[K+].[K+]>>[C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:8]([CH2:7][C:6]2[CH:18]=[CH:19][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:9]2[CH:17]=[CH:16][C:12]3[NH:13][CH:14]=[N:15][C:11]=3[CH:10]=2)=[CH:24][CH:23]=1)#[N:21]
Reactant: CCc1ccc(CNc2ccc3nc[nH]c3c2)cc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(CN(Cc2ccc(C#N)cc2)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-(4-ethylbenzyl)benzimidazol-5-amine (251 mg; 1 mmol; 1 eq.), 4-cyanobenzylbromide (216 mg; 1.1 mmol; 1.1 eq.) and K2CO3 (152 mg; 1.1 mmol; 1.1 eq.) according to method 6; Yield: 0.127 g (34.7%); MS m/z: 367.2 [M+H]+; 1H-NMR (500 MHz, DMSO d6): (Rotamers) δ 1.14 (t, 3H, 3J=7.6 Hz); 2.55 (q, 2H, 3J=7.6 Hz); 4.63 (s, 0.7H); 4.66 (s, 1.3H); 4.72 (s, 0.7H); 4.76 (s, 1.3H); 6.61 (br s, 0.7H); 6.67-6.68 (m, 0.7H); 6.75-6.77 (m, 0.3H); 6.81 (br s, 0.3H); 7.14 (d, 2H, 3J=7.9 Hz); 7.19 (d, 2H, 3J=7.9 Hz); 7.25-7.27 (m, 0.3H); 7.36 (d, 0.7H, 3J=8.9 Hz); 7.46 (d, 2H, 3J=8.2 Hz); 7.77 (d, 2H, 3J=8.2 Hz); 7.87 (s, 0.7H); 7.97 (s, 0.3H); 11.85 (s, 0.7H); 12.04 (s, 0.3H); HPLC (METHOD [A]): rt 17.49 min (98.4%)