Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.C([O-])([O-])=[O:10].[Na+].[Na+].[O-][Mn](=O)(=O)=O.[K+]>CC(C)=O>[Br:1][C:2]1[S:6][C:5]([C:7]([OH:10])=[O:8])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
5-Bromo-2-thiophenecarboxaldehyde (1.0 g;5.24 mmol) was dissolved in acetone (4 ml) and treated with 20% Na2CO3 (aq) (0.53 ml). KMnO4 (0.827;5.24 mmol) was added portionwise and the solution stirred for 1 hour at RT. The reaction mixture was filtered through kieselguhr and the filtrate treated with H2O2 (0.8 ml of a 27% solution in water). When all effervesence had ceased, the aqueous was acidified with conc.HCl(aq) and a yellow solid precipitated. The suspension was extracted with EtOAc, the extracts combined and dried over Na2SO4, filtered, and the filtrate evaporated in vacuo to a yellow liquid. The liquid was diluted with hexane and cooled to -78° C. The solid that formed was collected by filtration and dried to yield the title compound as a pale yellow solid (0.3 g;28%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:18]([OH:20])=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21](O)[CH:22]=[CH2:23].C(Cl)CCl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:23]([O:19][C:18](=[O:20])[C@@H:9]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:22]=[CH2:21]
Reactant: C=CCO
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: C=CCOC(=O)[C@@H](CCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
N-(t-Butoxycarbonyl)-D-homophenylalanine (2.0 g; 7.16 mmol), allyl alcohol (500 ml; 7.35 mmol) and 4-dimethylaminopyridine (88 mg; 0.72 mmol) were dissolved in dry methylene chloride and stirred at room temperature. EDC (1.4 g; 7.30 mmol) was added to the solution in small batches over 15 minutes and the reaction mixture stirred at room temperature for 6 h. The reaction was quenched by pouring the reaction mixture into water (10 ml) and extracted with methylene chloride (2×25 ml). The combined methylene chloride extracts were washed successively with 5% aqueous citric acid solution (50 ml) and a 10% aqueous sodium carbonate solution. The methylene chloride layer was dried over anhydrous magnesium surf ate powder, filtered and evaporated to leave a thick oily residue which was purified by column chromatography on silica gel using an eluant comprising ethyl acetate and hexanes in the ratio 2:1. The yield of the desired allyl ester product was 1.96 g (85.7%). FAB-MS:- calculated for C18 H25NO4 319.2; found 320. (M+1).
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C1COCC1.CO>[CH2:30]([C:10]1[CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])[CH:13]=[CH:14][C:9]=1[O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:37])=[O:3])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)c(Cc2ccccc2)c1
Temperature: 55 °C

Procedure:
A solution of 2-{2-benzyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid ethyl ester (1.15 g, 2.30 mmol) in THF (15 mL) and MeOH (30 mL) was treated with 2.5N aqueous NaOH (10 mL). The solution was heated at 55° C. for 2 h, cooled to ambient temperature, and concentrated in vacuo. The residue was acidified with 5N aqueous HCl (5 mL) and partitioned between EtOAc (125 mL) and H2O (25 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated to a colorless oil (1.1 g, 100%): 1H NMR (400 MHz, CDCl3) δ 7.97 (dd, 2H, J=7.6, 2.2 Hz), 7.44-7.40 (m, 3H), 7.27-7.15 (m, 5H), 6.77 (d, 1H, J=8.8 Hz), 6.69 (d, 1H, J=2.9 Hz), 6.62 (dd, 1H, J=8.8, 2.9 Hz), 4.12 (t, 2H, J=6.4 Hz), 3.93 (s, 2H), 2.96 (t, 2H, J=6.6 Hz), 2.35 (s, 3H), 1.45 (s, 6H); MS (ES) m/e 472 [M+1].
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:12]=[C:11]([C:20]([O:22]C)=O)[CH:10]=2)=[CH:5][CH:4]=1.[Br:24][CH2:25]Br.C[Li]>C1COCC1>[Br:24][CH2:25][C:20]([C:11]1[CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:12]=1)=[O:22]
Reactant: COC(=O)c1cc(-c2ccc(SC)cc2)n(-c2ccccn2)n1
Reactant: BrCBr
Agent: [Li]C
Solvent: C1CCOC1
Product: CSc1ccc(-c2cc(C(=O)CBr)nn2-c2ccccn2)cc1
Reaction time: 1.5 h
Yield: 68.7 %

Procedure:
To a stirred solution of methyl 5-(4-methylthiophenyl)-1-(2-pyridyl)pyrazole-3-carboxylate (prepared as described in Penning, T. D. et al. J. Med. Chem. 1997, 40, 1347-1365.; 0.39 g, 1.2 mmol) and dibromomethane (0.17 mL, 2.4 mmol) in THF (10 mL) at −78° C. under nitrogen atmosphere was added methyllithium (1.6 M in ether, 1.4 mL, 2.2 mmol). After being stirred at the same temperature for 90 minutes, the solution was quenched with aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Chromatography of the residue on silica gel (2:1 EtOAc:hexane) gave the title compound (0.32 g, 69% yield) as a white foam. 1H NMR (300 MHz, CDCl3) δ 8.42-8.40 (m, 1H), 7.83 (m, 1H), 7.55-7.51 (m, 1H), 7.17-7.09 (m, 4H), 7.02 (s, 1H), 4.70 (s, 2H), 2.46 (s, 3H); LRMS (API-TIS) m/z 388 and 390 (MH+).
Reaction SMILES: C[Si]([N:5]=[N+]=[N-])(C)C.[N:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[C:10]([O:12][C:13]2=[O:18])=[O:11].C(O)C>C(Cl)(Cl)Cl>[NH:5]1[C:9]2[N:8]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13](=[O:18])[O:12][C:10]1=[O:11]
Reactant: O=C1OC(=O)c2ncccc21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=c1[nH]c2ncccc2c(=O)o1
Temperature: 25 °C

Procedure:
Trimethylsilylazide (89.1 ml) was added dropwise, with stirring, to a suspension of quinolinic anhydride (100.0 g) in dry chloroform (450 ml) under nitrogen. The mixture was stirred until nitrogen evolution had subsided (around 30 minutes) and then boiled under reflux with stirring for 45 minutes to give a solution. The mixture was cooled to ambient temperature and ethanol (40.0 ml) was added. The mixture was stirred for 20 minutes and a precipitate was collected by filtration and dried under vacuum overnight. The solid was stirred in cold acetonitrile (850 ml) and filtered. The filtrate was boiled under reflux for 15 minutes with stirring and then cooled in ice and filtered to give 4H-pyrido[2,3-d] [1,3]oxazine-2,4(1H)-dione, m.p. 213°-215° C. (with decomposition).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:28])([CH2:26][OH:27])[CH2:24]O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C1COCC1.CCOCC.O>[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1([CH3:28])[CH2:26][O:27][CH2:24]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(CO)(CO)CCCCCCCCCOCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(CCCCCCCCCOCc2ccccc2)COC1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
n-Butyllithium (2.6 M solution in hexane, 0.295 ml, 0.767 mmol) was added to a solution of 2-(9-benzyloxy-nonyl)-2-methyl-propane-1,3-diol (221 mg, 0.686 mmol) in THF (5.1 ml) at 0° C. over three minutes, and the mixture was then stirred at the same temperature for 30 minutes. A solution of TsCl (138 mg, 0.723 mmol) in THF (0.91 ml) was added to the reaction solution at 0° C. over eight minutes, and the mixture was then stirred at the same temperature for one hour. n-Butyllithium (2.6 M solution in hexane, 0.295 ml, 0.767 mmol) was added dropwise to the reaction mixture at 0° C., and the mixture was then stirred at 60° C. for six hours. The reaction mixture was diluted with ether and water was then added, followed by extraction with ether. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to give 3-(9-benzyloxy-nonyl)-3-methyl-oxetane (188 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[O:26]1[CH:30]=[CH:29][C:28]([CH:31]([OH:35])[CH2:32][NH:33][CH3:34])=[CH:27]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:33]([CH2:32][CH:31]([C:28]4[CH:29]=[CH:30][O:26][CH:27]=4)[OH:35])[CH3:34])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)c1ccoc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CN(C)CC(O)c2ccoc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.6 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 1-(3-furyl)-2-(methylamino)ethanol (Preparation 64) (54 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5.0 mL) was stirred at room temperature for 24 hours. The solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (5 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (102 mg) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[C:34](Cl)[N:33]=[CH:32][N:31]=1.C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[C:34]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([S:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=4)[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:33]=[CH:32][N:31]=1
Reactant: COc1cccc(Sc2ccn3nc([C@H](C)N)n(-c4ccccc4)c(=O)c23)c1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1cccc(Sc2ccn3nc([C@H](C)Nc4ncnc(N)c4C#N)n(-c4ccccc4)c(=O)c23)c1
Yield: 57.1 %

Procedure:
(S)-2-(1-Aminoethyl)-5-((3-methoxyphenyl)thio)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (103 mg, 0.24 mmol) was treated with 4-amino-6-chloropyrimidine-5-carbonitrile (55 mg, 0.36 mmol),), N,N-diisopropylethylamine (126 μl, 0.72 mmol) and tert-butanol as a solvent according to the method described in Example 17. The crude was purified by reverse phase using SP1® Purification to give 70 mg (57% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3([CH3:30])[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH2:13][C@@H:12]1[CH3:31])[CH2:6][CH2:5]2>Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3([CH3:30])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:13][C@@H:12]1[CH3:31])[CH2:6][CH2:5]2
Reactant: C[C@H]1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1C1CCc2cc(Br)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1CN(C2(C)CCNCC2)CCN1C1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The intermediate obtained from step E (0.23 g) was dissolved in a solution of 4 N HCl in dioxane (3 mL). After being stirred at room temperature for 2 h, the solution was concentrated to provide the title compound as a trihydrochloride salt (0.23 g). MS calculated for C20H30BrN3: (M+H)+ 392. found 392.2, 394.2.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH2:9](Br)[C:10]1[CH:18]=[CH:17][C:16]2[O:15][CH2:14][O:13][C:12]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCCCCC.C(OC(=O)C)C>[CH2:14]1[O:15][C:16]2[CH:17]=[CH:18][C:10]([CH2:9][N:7]3[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]3)=[CH:11][C:12]=2[O:13]1
Reactant: BrCc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cn(Cc2ccc3c(c2)OCO3)cn1
Yield: 5.1 %

Procedure:
3.39 g(30 mmol) of 4-nitroimidazole, 6.45 g(30 mmol) of piperonyl bromide and 8.28 g(60 mmol) of potassium carbonate were added to 100 ml of dimethylformamide and the resulting mixture was reacted for 6 hours. The reaction solution was concentrated by removing the solvent. The residue was dissolved in 100 ml of ethylacetate and the combined organic layer was washed twice with 100 ml of water. The organic layer was separated, concentrated and then subjected to column chromatography (eluent: hexane/ethylacetate=2/1, v/v) to give 6.17 g(1.52 mmol, Yield 83%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([NH:40][C:41]([O:43][CH2:44][CH2:45][OH:46])=[O:42])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:47][CH3:48])=[O:5])[CH3:2].CC(C)=[O:51]>S(=O)(=O)(O)O.[O-2].[Cr+6].[O-2].[O-2]>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:37])([F:39])[F:38])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=3)[C:22]([NH:40][C:41]([O:43][CH2:44][C:45]([OH:51])=[O:46])=[O:42])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:47][CH3:48])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(NC(=O)OCCO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: CC(C)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(NC(=O)OCC(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reaction time: 4.5 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(2-hydroxyethoxy-carbonylamino)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (192 mg) is dissolved in acetone (5 ml), and thereto is added 2.67M chromium (VI) oxide in dilute sulfuric acid solution (320 μl) under ice-cooling. The mixture is stirred for 4.5 hours, and partitioned by adding sodium bisulfite, water and ethyl acetate. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=9:1→7:3) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)-benzyl]-(5-carboxymethoxycarbonylaminopyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (78 mg). MS (m/z): 701 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:10]=[N:9][C:8]=2[C:19]([F:22])([F:21])[F:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23](=O)[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCl>O1CCCC1>[CH2:23]([N:16]1[CH2:15][CH2:14][N:13]([C:11]2[N:10]=[N:9][C:8]([C:19]([F:22])([F:21])[F:20])=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:12]=2)[CH2:18][CH2:17]1)[CH3:24]
Reactant: CC=O
Reactant: FC(F)(F)c1nnc(N2CCNCC2)cc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN1CCN(c2cc(-c3ccccc3)c(C(F)(F)F)nn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
To a mixture of 4-phenyl-6-piperazin-1-yl-3-trifluoromethyl-pyridazine (E1) (0.15 g, 0.49 mmol) in tetrahydrofuran (5 ml), was added acetaldehyde (55 ml, 0.97 mmol). The reaction mixture was stirred at room temperature for 30 min., and then sodium triacetoxyborohydride (0.154 g, 0.73 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. Then, more acetaldehyde (55 ml, 0.97 mmol) and sodium triacetoxyborohydride (0.154 g, 0.73 mmol) were added and the mixture was stirred at room temperature for 4 h. Dichloromethane was then added and the mixture was extracted with a saturated solution of ammonium chloride. The organic phase was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography (silica gel; ethyl acetate/10% ammonia in methanol (7M) in dichloromethane 10:0 to 8:2). The desired fractions were collected, the solvent evaporated in vacuo, the residue dissolved in acetonitrile and converted into its hydrochloric acid salt by addition of a saturated solution of hydrochloric acid in diethyl ether. The white solid obtained was filtered and dried affording E2 (0.039 g, 21%). C17H19F3N4.HCl; free base requires 336; Found 337 (MH+).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@@H:20]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH3:21])[C:11]1([CH3:40])[CH3:39])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(N(CC)C(C)C)(C)C>C1CCCCC1.C1(C)C=CC=CC=1>[C:1]([O:9][C@H:10]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@@H:20]([O:22][Si:23]([C:26]([CH3:28])([CH3:29])[CH3:27])([CH3:25])[CH3:24])[CH3:21])[C:11]1([CH3:39])[CH3:40])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCCCC1
Solvent: Cc1ccccc1
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2C3=CC=C4C(C)(C)[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.17 h

Procedure:
xi)—A mixture of (3β,20S)-20-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4-dimethylpregn-5-en-3-ol benzoate (44.6), dry toluene (394 ml), dry cyclohexane (394 ml) and N-bromosuccinimide (17.8 g) was heated at reflux temperature for 10 min. The reaction mixture was cooled, another portion of N-bromosuccinimide (17.8 g) was added, and reflux was continued for another 10 min. The reaction mixture was cooled, a saturated aqueous solution of sodium thiosulfate (802 ml) was added and the resulting mixture was stirred for 30 min. The organic phase and the aqueous phase were separated and the latter extracted two times with toluene. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. A solution of the crude product thus obtained in dry toluene (1381 ml) and N,N-diisopropylethylamine (138 ml) was heated under reflux for 1.5 h. Then it was cooled and washed with a saturated aqueous solution of sodium hydrogen carbonate, a saturated aqueous solution of ammonium chloride and with brine, the aqueous phase each time being extracted with ethyl acetate. The combined toluene and ethyl acetate solutions were dried over sodium sulfate and concentrated under reduced pressure. Column chromatography afforded (3β,20S)-20-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4-dimethylpregna-5,7-dien-3-ol benzoate (compound 12a; 40.0 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:10](F)[CH:9]=1)[C:3]([O:5]C)=[O:4].BrC1C=C(OC)C=C(F)C=1.NC(CC1C=C(O)C=C(F)C=1)C(OC)=O>>[CH:10]1[CH:11]=[C:12]([OH:14])[CH:13]=[C:8]([CH2:7][C@H:2]([NH2:1])[C:3]([OH:5])=[O:4])[CH:9]=1
Reactant: COC(=O)[C@@H](N)Cc1cc(O)cc(F)c1
Agent: COC(=O)C(N)Cc1cc(O)cc(F)c1
Agent: COc1cc(F)cc(Br)c1
Product: N[C@@H](Cc1cccc(O)c1)C(=O)O

Procedure:
(S)-methyl 2-amino-3-(3-fluoro-5-hydroxyphenyl)propanoate was purchased from NetChem (USA). (3-bromo-5-fluoroanisole (9-1) was purchased from Accela ChemBio Co., Ltd., (Shanghai, China) and can also be purchased from Amfinecom Inc (USA) or Apollo Scientific Ltd. (UK)). DL-5-fluoro-meta-tyrosine (9) and methyl 2-amino-3-(3-fluoro-5-hydroxyphenyl)propanoate (10)) were synthesised as follows.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:11][C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=1
Reactant: CO
Reactant: CSc1ccc(CC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(SC)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 4-(methylthio)phenylacetic acid (21.21 g, 116.38 mmol) in methanol (291 mL) was treated slowly with concentrated sulfuric acid (3 mL). The resulting reaction mixture was heated under reflux for 3 d. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The resulting residue was diluted with diethyl ether (600 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (3×300 mL) and a saturated aqueous sodium chloride solution (1×300 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford (4-methylsulfanyl-phenyl)-acetic acid methyl ester (20.95 g, 92%) as a yellow liquid which was used without further purification: EI-HRMS m/e calcd for C10H12O2S (M+) 196.0558, found 196.0559.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[C:11]#[N:12].[Si](I)(C)(C)C.Cl>N1C2C(=CC=CC=2)C=CC=1>[OH:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[C:11]#[N:12]
Reactant: COc1ccc(C#N)cc1C#N
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: N#Cc1ccc(O)c(C#N)c1
Temperature: 120 °C
Reaction time: 14 h
Yield: 6.4 %

Procedure:
4-Methoxyisophthalonitrile (2 g, 0.12 mol; see step (ii) above) was dissolved in quinoline (20 mL) and TMSI (2.7 mL, 0.018 mol) was added. The reaction mixture was stirred at 120° C. for 14 h, before being cooled to RT, acidified with conc. HCl and extracted with ethyl acetate. The organic layer was washed with 10% aqueous NaOH and the aqueous layer was acidified with 1 N HCl. The product was extracted with ethyl acetate, washed with water and brine and dried over Na2SO4. Solvent evaporation under reduced pressure afforded the sub-title compound (1.1 g, 61%) as pale brown solid. This was employed directly in the next step without further purification.