Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][NH2:14].CC(O)=O.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:14][CH2:13][CH:12]([O:15][CH3:16])[O:11][CH3:10])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COC(CN)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(CNCc1ccc(Br)cc1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To an ice-cold solution of 4-bromo-benzaldehyde (10 g, 0.05 mol) and 2,2-dimethoxy-ethylamine (6.8 g, 0.06 mol) in MeOH (200 mL) was added AcOH (2 mL), and the reaction mixture was stirred at RT for 1 h. The reaction mixture was cooled to 0° C. and NaBH4 (6.2 g, 0.15 mol) was added portionwise. The reaction mixture was stirred at RT for 10 h. After completion, The resulting reaction mixture was concentrated under reduced pressure and 10% aqueous NaOH was added. The mixture was extracted with EtOAc, the organic layer separated, dried over Na2SO4, and concentrated under reduced pressure. Purification was done by column chromatography using 100-200 mesh silica gel eluting with 5-15% EtOAc in hexanes to afford N-(4-bromobenzyl)-2,2-dimethoxyethanamine (10 g, 67%) as a pale yellow liquid.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([NH:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]1CCN2C(=NCCC2)CC1.Cl.[N+:34]([CH3:37])([O-:36])=[O:35]>>[N+:34]([CH2:37][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:22])=[O:17])=[CH:20][CH:21]=1)=[O:10])([O-:36])=[O:35]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)c1ccc(NC(=O)C=Cc2ccccc2)cc1
Reactant: C1CCC2=NCCCN2CC1
Agent: Cl
Product: CCOC(=O)c1ccc(NC(=O)CC(C[N+](=O)[O-])c2ccccc2)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
A mixture of 41 (1.340 g, 4.44 mmol) in nitromethane (4 ml) was heated a microwave reactor (Biotage Initiator) at 100° C. for 15 min in presence of DBU (0.811 g, 5.328 mmol, 1.2 eq). After cooling to room temperature, the reaction mixture was poured into HCl 1M (10 ml). The product extracted with ethyl acetate (2×15 ml). The organic extracts were collected, dried over Na2SO4 and the solvent removed under reduced pressure. Chromatography on silica gel (7:3 hexanes/ethyl acetate, Rf 0.20) afforded 47 (0.980 g, 2.75 mmol, 62%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.37 (3H, t, J 7.6 Hz), 2.79 (1H, dd, J 7.2, 15.2 Hz), 2.86 (1H, dd, J 7.2, 15.2 Hz), 4.07 (1H, quint, J 7.2 Hz), 4.34 (2H, q, J 7.2 Hz), 4.72 (1H, dd, J 7.8, 12.6 Hz), 4.83 (1H, dd, J 6.4, 12.4 Hz), 6.63 (1H, d, J 16 Hz), 7.11 (1H, t, J 7.6 Hz), 7.24-7.26 (2H, m), 7.27-7.36 (2H, m), 7.45 (1H, s), 7.47 (2H, d, J 8.8 Hz), 7.96 (2H, d, J 8.8 Hz). 13C NMR (400 MHz, CDCl3) δ 14.55, 40.67, 40.93, 61.20, 79.50, 119.17, 126.54, 127.53, 128.45, 129.48, 130.98, 138.51, 141.60, 166.30, 168.39. MS (API-ES): m/z found 357 [M+H]+ (100%), HRMS (API-ES) m/z found 357.1344 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:29][C:30]3[CH:31]=[C:32]4[C:36](=[CH:37][CH:38]=3)[N:35](C(OC(C)(C)C)=O)[N:34]=[CH:33]4)=[N:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20](=[O:28])[CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[O:46][CH2:47][CH2:48][O:49][CH3:50].[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>C(Cl)Cl>[F:54][C:53]([F:56])([F:55])[C:51]([OH:57])=[O:52].[NH:35]1[C:36]2[C:32](=[CH:31][C:30]([NH:29][C:7]3[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:46][CH2:47][CH2:48][O:49][CH3:50])[CH:5]=4)[N:10]=[C:9]([C:13]4[CH:14]=[C:15]([NH:19][C:20](=[O:28])[CH2:21][N:22]5[CH2:23][CH2:24][O:25][CH2:26][CH2:27]5)[CH:16]=[CH:17][CH:18]=4)[N:8]=3)=[CH:38][CH:37]=2)[CH:33]=[N:34]1
Reactant: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(NC(=O)CN4CCOCC4)c3)nc2cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOc1cc2c(Nc3ccc4[nH]ncc4c3)nc(-c3cccc(NC(=O)CN4CCOCC4)c3)nc2cc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43 %

Procedure:
To a suspension of tert-butyl 5-(7-methoxy-6-(2-methoxyethoxy)-2-(3-(2-morpholinoacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (0.321 g, 0.47 mmol) in CH2Cl2 (3 mL) was added TFA (3 mL). The resulting mixture was stirred at RT for 1.5 h, upon which it was concentrated in vacuo and the residue purified by preparative HPLC (10-35-90 method) to give N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)quinazolin-2-yl)phenyl)-2-morpholinoacetamide trifluoroacetate salt (0.141 g, 0.202 mmol, 43% over two steps). MS 584 (M+1). HPLC retention time 4.40 mins.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH3:10]OC(OC)N(C)C.Cl.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH3:5][C:3]1[N:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:26]=[CH:10][C:2]=1[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(C)=O
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccccc2)c1C
Temperature: 120 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
A mixture of ethyl acetoacetate (1.5 g, 11.5 mmol) and dimethylformamide dimethyl acetal (1.68 mL, 12.7 mmol) was stirred at 120° C. for 2 hours. The reaction solution was cooled to room temperature, and a solution of phenyl hydrazine hydrochloride (1.67 g, 11.5 mmol) in ethanol (30 mL) was then added thereto. The obtained mixture was stirred at 80° C. for 2.5 hours. The reaction solution was cooled to room temperature, and it was then concentrated under reduced pressure. The residue was purified with a fractionation purification apparatus (Biotage, ethyl acetate:hexane=1:19-3:7), so as to obtain the title compound (2.32 g, 87%) in the form of a yellow oily product.
Reaction SMILES: C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].[C:8](Cl)(=[O:10])[CH3:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]3[CH2:26][CH2:27][S:28][C:29]4[S:33][CH:32]=[CH:31][C:30]=4[C:21]3=[N:20]2)=[CH:15][CH:14]=1>O>[C:8]([C:32]1[S:33][C:29]2[S:28][CH2:27][CH2:26][C:22]3[C:21](=[N:20][N:19]([C:16]4[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=4)[C:24](=[O:25])[CH:23]=3)[C:30]=2[CH:31]=1)(=[O:10])[CH3:9]
Reactant: O=c1cc2c(nn1-c1ccc(Cl)cc1)-c1ccsc1SCC2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1cc2c(s1)SCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2

Procedure:
To a mixture of 50 ml of methylene chloride and 1.9 g of aluminum chloride is added 1.0 ml of acetyl chloride with stirring under ice-cooling and then the mixture is stirred at room temperature for 10 minutes. To the mixture is further added 2.0 g of 2-(4-chlorophenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one under ice-cooling and the mixture is stirred for 3 hours at room temperature. To the mixture is added water and the solution is extracted with chloroform. The extract is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting crystals are recrystallized from a mixed solvent of chloroform and ethanol to give 2.0 g of 9-acetyl-2-(4-chlorophenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one, as white crystals, melting at 248°-250° C.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C@@H:21]([OH:28])[CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:31].[N:32]1[CH:37]=C[CH:35]=[CH:34][CH:33]=1.ClC(OC1C=CC=CC=1)=[O:40].C1(N)CC1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:31][C:3]1[CH:4]=[C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C@@H:21]([OH:28])[CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH:29]=[CH:30][C:2]=1[NH:1][C:37]([NH:32][CH:33]1[CH2:35][CH2:34]1)=[O:40]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCN(CC)C[C@H](O)COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1C#N
Reactant: c1ccncc1
Agent: NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)C[C@H](O)COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)c2cc1C#N
Reaction time: 1 h
Yield: 40 %

Procedure:
After dissolving 4-(4-amino-3-chlorophenoxy)-6-cyano-7-(((2S)-3-(diethylamino)-2-hydroxypropyl)oxy)quinoline (78.6 mg, 0.18 mmol) in dimethylformamide (1 ml) under a nitrogen atmosphere, pyridine (0.022 ml, 0.27 mmol) and phenyl chloroformate (0.028 ml, 0.22 mmol) were added dropwise at room temperature, and the mixture was stirred for 1 hour. Cyclopropylamine (0.10 ml) was added dropwise, and the mixture was further stirred overnight. The reaction solution was distributed between ethyl acetate and saturated aqueous sodium bicarbonate, and the organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was subjected to silica gel column chromatography (eluent-ethyl acetate), the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (37.8 mg, 0.072 mmol, 40.5%) as light yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([NH2:13])[S:11][CH:12]=2)[CH:5]=[C:4]([Cl:14])[N:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([NH:13][C:15](=[O:17])[CH3:16])[S:11][CH:12]=2)[CH:5]=[C:4]([Cl:14])[N:3]=1
Reactant: Nc1nc(-c2cc(Cl)nc(Cl)c2)cs1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc(-c2cc(Cl)nc(Cl)c2)cs1
Reaction time: 16 h
Yield: 93.8 %

Procedure:
7.38 g (0.03 mol) of [4-(2,6-dichloropyridin-4-yl)-thiazol-2-yl]-amine and 70 ml of acetic anhydride are heated under reflux for 30 minutes, a solution initially forming but a precipitate then separating out. The reaction mixture is left to stand at room temperature for 16 hours, 200 ml of ice-water are then added and the mixture is filtered with suction. The residue is first washed several times with water and then digested with 200 ml of 5% strength aqueous sodium bicarbonate solution, and is filtered off with suction again. The product is dried at 50° C. under reduced pressure. 8.1 g (93.8% of theory) of N-[4-(2,6-dichloropyridin-4-yl)-thiazol-2-yl]-acetamide are obtained in this manner in the form of a solid substance of melting point 301° C.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][S:10][C:6]2=[N:5][CH:4]=[CH:3]1.C[N:12]([CH3:15])C=O.[CH2:16]([N:18](CC)CC)C.CNN>P(Cl)(Cl)(Cl)=O.C(O)C>[CH3:16][N:18]1[C:4]2[N:5]=[C:6]3[S:10][CH:9]=[CH:8][N:7]3[C:2](=[O:1])[C:3]=2[CH:15]=[N:12]1
Reactant: CN(C)C=O
Reactant: CCN(CC)CC
Reactant: O=c1ccnc2sccn12
Agent: CNN
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: Cn1ncc2c(=O)n3ccsc3nc21
Yield: 71 %

Procedure:
In 8 ml of phosphorus oxychloride was dissolved 2.00 g (11.9 mmol) of 5-oxo-5H-thiazolo[3,2-a]pyrimidine [Zh. Org. Khim., 11, 2200 (1975)], and 1.13 ml of dimethylformamide was added dropwise to the solution with stirring under ice-cooling. Then, the reaction mixture was heated under reflux for 30 minutes. After concentration of the reaction mixture to dryness under reduced pressure, the oily residue was dissolved in 60 ml of ethanol under ice-cooling. To the solution were added 10 ml of triethylamine and 2.52 ml (47.6 mmol) of methylhydrazine, followed by heating under reflux for 3 hours. After evaporation of the solvent, the residue was subjected to partition between chloroform and water, and the chloroform layer was concentrated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform to give 1.74 g (71%) of Compound 51. The compound was recrystallized from dimethylformamide/water for purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]>[Pd].CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)nc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Reaction time: 5 h

Procedure:
To a dimethylformamide solution of 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene}-2,4-thiazolidinedione (1.0 g) was added palladium black (0.2 g) and catalytic reduction was carried out at 50° C. and 50 kg/cm2 for 5 hours. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was dissolved in 6N-hydrochloric acid and the solution was neutralized with sodium hydrogen carbonate to give 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4thiazolidinedione as crystals. Yield: 650 mg (64.8%); m.p.: 173°-174° C.
Reaction SMILES: ClC([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Cl:12])=[CH:7][CH:6]=1)=O.CN(C)C=O.CO>C(#N)C>[Cl:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc(CCl)cc1
Solvent: CC#N
Solvent: CO
Solvent: CN(C)C=O
Product: Oc1ccc(CCl)cc1

Procedure:
Equimolar quantities of p-chloromethylphenyl chloroformate and dimethyl formamide were reacted at room temperature for one hour in acetonitrile (590 parts acetonitrile for every mole of dimethyl formamide or p-chloromethylphenyl chloroformate). Equimolar quantities of methanol were then added to the immonium salt mixture, and the solution was then stirred for about one half hour (with cooling) at 25°-30°C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(Cl)(=O)OCC.N[C@H:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][C@H:22]1[O:32][CH3:33].C([N:36](CC)CC)C>ClC(Cl)Cl>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:36][C@H:23]2[C@@H:22]([O:32][CH3:33])[CH2:21][CH2:26][CH2:25][N:24]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CCOC(=O)N1CC[C@H](N)[C@H](OC)C1
Reactant: CCN(CC)CC
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC[C@H](OC)[C@@H]1NC(=O)c1cc(Cl)c(N)cc1OC
Reaction time: 0.75 h
Yield: 80 %

Procedure:
To a stirred solution of 22.5 parts of 4-amino-5-chloro-2-methoxybenzoic acid in 405 parts of trichloromethane were added dropwise successively 11.8 parts of N,N-diethylethanamine and 13 parts of ethyl carbonochloridate at a temperature below 10° C. Stirring was continued for 45 minutes at a temperature below 10° C. Then there was added dropwise a solution of 19.15 parts of cis-ethyl 4-amino-3-methoxy-1-piperidinecarboxylate in 360 parts of trichloromethane at the same temperature. Upon completion, stirring was continued for 18 hours at room temperature. The reaction mixture was washed successively three times with water, once with a 5% sodium hydroxide solution and again twice with water. The organic phase was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 29.3 parts (80%) of cis-ethyl (4-amino-5-chloro-2-methoxybenzoylamino)-3-methoxy-1 -piperidinecarboxylate as a residue (compound 168).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].Br[C:28]1[N:29]=[C:30]([N:38]2[CH2:43][CH2:42][N:41]([CH2:44][CH3:45])[CH2:40][CH2:39]2)[C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.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>[CH2:44]([N:41]1[CH2:40][CH2:39][N:38]([C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:37]=[C:28]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][CH:2]([C:3]([O:5][CH3:6])=[O:4])[CH3:1])=[CH:13][CH:12]=3)[N:29]=2)[CH2:43][CH2:42]1)[CH3:45]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CC(C)C(=O)OC)cc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc(CC(C)C(=O)OC)cc3)cc3ccccc23)CC1
Yield: 88.6 %

Procedure:
Methyl 2-methyl-3-(4-tributylstannylphenyl)propionate (2.69 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.16 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium (0) (0.17 g) in xylene in nitrogen atmosphere. Af ter cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid. The aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (toluene/acetone system), to give obtain 1-(4-ethylpiperazin-1-yl)-3-[4-(2-methoxycarbonylpropyl)phenyl]isoquinoline (1.34 g) in pale yellow viscous oil.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]([CH3:7])[O:5][S:4](=[O:8])[N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].I([O-])(=O)(=O)=[O:17].[Na+].Cl>C(#N)C.O>[CH3:1][CH:2]1[CH:6]([CH3:7])[O:5][S:4](=[O:17])(=[O:8])[N:3]1[C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC1OS(=O)N(C(=O)OC(C)(C)C)C1C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC1OS(=O)(=O)N(C(=O)OC(C)(C)C)C1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 89.1 %

Procedure:
tert-Butyl 4,5-dimethyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (4.7 g, 20.0 mmol) is dissolved in acetonitrile (50 mL) and H2O (30 mL) is added. The reaction mixture is cooled to 0° C. and sodium periodate (6.4 g, 30.0 mmol) is added. After 5 min, the pH of the mixture is adjusted to 7-8 by addition of saturated Na2HPO4 solution. Then the solution of RuCl3 (42 mg, 0.2 mmol) in H2O (0.5 mL) is added. The pH of the reaction mixture is kept between 6 and 9 by addition of Na2HPO4 solution. After stirring for 2 h, H2O (100 mL) is added and the pH is adjusted to 6 by addition of 2M HCl solution. The mixture is extracted with EtOAc and the organic layer is separated, washed with NaHCO3 and brine. The aqueous layers are back extracted once with EtOAc. Then all organic layers are combined, dried (MgSO4) and concentrated. Purification by flash column chromatography using a gradient elution of 5-80% ethyl acetate/hexanes affords the title compound (4.48 g, 89%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].CC(C)=O.N1[CH:16]=[CH:15][CH:14]=CC=1.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>O>[CH3:1][NH:2][C:3]1[S:6][C:15]([CH3:14])([CH3:16])[N:5]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[N:4]=1
Reactant: c1ccncc1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CNC(=S)NN
Solvent: CC(C)=O
Solvent: O
Product: CNC1=NN(C(=O)C(C)(C)C)C(C)(C)S1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 52.5 g. portion of 4-methylthiosemicarbazide was suspended and partially dissolved in 250 ml. of acetone, and 39.5 g. of pyridine was added. The mixture was stirred for 15 minutes at ambient temperature, and then 60.5 g. of pivaloyl chloride was added slowly while the temperature of the reaction mixture was held at 20°-25°. The mixture was stirred at ambient temperature for 3 hours after the addition, and then 200 ml. of water was added. The reaction mixture was filtered, and the filter cake was washed with 100 ml. of nitromethane and vacuum dried at 50° to obtain 91.4 g. of the desired intermediate product, m.p. 162°-164°.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:26])[CH:4]=[CH:5][C:6](=[O:25])[CH:7]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].B(F)(F)F.[CH3:38][CH2:39][O:40]CC>ClCCl>[C:27]([O:23][C@H:22]1[CH2:21][C@@:20]2([CH3:24])[C@@H:12]([CH2:13][CH:14]=[C:15]2[C:16](=[O:19])[CH2:17][O:18][C:39](=[O:40])[CH3:38])[C@H:11]2[C@@:2]1([F:1])[C@:3]1([CH3:26])[C:8]([CH2:9][CH2:10]2)=[CH:7][C:6](=[O:25])[CH:5]=[CH:4]1)(=[O:29])[CH3:28]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Reactant: CC(=O)OC(C)=O
Reactant: CCOCC
Agent: FB(F)F
Solvent: ClCCl
Product: CC(=O)OCC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](OC(C)=O)C[C@]12C
Reaction time: 1.5 h

Procedure:
A solution of 5 g of 9-fluoro-11β,21-dihydroxypregna-1,4,16-triene-3,20-dione, 21-acetate, 50 ml each of acetic anhydride and dichloromethane and 2.5 ml of boron trifluoride etherate is stirred at room temperature under nitrogen for 2.5 hours. Because the reaction is slow, another 1.5 ml of boron trifluoride etherate is added and the reaction is continued for another 1.5 hours. The resulting solution is diluted with 200 ml of dichloromethane, washed with a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated in vacuo to give 5.2 g of a solid. This is chromatographed on a column of 100 g of silica gel. Elution with 1:4 hexane-chloroform gives 4.8 g of material. Crystallization from chloroform-hexane gives 4.2 g of the title compound, melting point 294-296°C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[CH:4]=[O:5].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=Cc1c(Cl)cccc1Oc1ccccc1
Yield: 83.6 %

Procedure:
A mixture of 15.8 g (100 mmol) of 2-chloro-6-fluorobenzaldehyde, 9.4 g (100 mmol) of phenol and 20.7 g (150 mmol) of potassium carbonate in 150 ml of dimethylacetamide is heated under reflux for 4 hours. The mixture is allowed to cool, water is added and the mixture is extracted 3× with tert-butyl methyl ether. The organic phases are washed with 2N sodium hydroxide solution and brine, dried over sodium sulfate and concentrated. Bulb tube distillation (175° C., 0.04 mbar) yields 19.46 g (83.64 mmol)=83.6% of 2-chloro-6-phenoxy-benzaldehyde in the form of a yellow oil; 1H-NMR (CDCl3, 200 MHz): 6.75-7.45 (m, 8H); 10.58 (s, 1H).