Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:13]([OH:15])=O)[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[C:16]([O:20][CH2:21][O:22][C:23]([C:25]1[N:26]2[CH:29]([S:30][CH2:31][C:32]=1[CH2:33][O:34][C:35](=[O:37])[CH3:36])[CH:28]([NH2:38])[C:27]2=[O:39])=[O:24])(=[O:19])[CH2:17][CH3:18]>C(Cl)Cl.C(O)CC>[C:16]([O:20][CH2:21][O:22][C:23]([C:25]1[N:26]2[CH:29]([S:30][CH2:31][C:32]=1[CH2:33][O:34][C:35](=[O:37])[CH3:36])[CH:28]([NH:38][C:13](=[O:15])[CH:9]([C:6]1[CH:5]=[CH:4][C:3]([CH2:2][Cl:1])=[CH:8][CH:7]=1)[C:10]([OH:12])=[O:11])[C:27]2=[O:39])=[O:24])(=[O:19])[CH2:17][CH3:18]
Reactant: O=C(O)C(C(=O)O)c1ccc(CCl)cc1
Reactant: CCC(=O)OCOC(=O)C1=C(COC(C)=O)CSC2C(N)C(=O)N12
Solvent: CCCO
Solvent: ClCCl
Product: CCC(=O)OCOC(=O)C1=C(COC(C)=O)CSC2C(NC(=O)C(C(=O)O)c3ccc(CCl)cc3)C(=O)N12

Procedure:
α-Carboxy-p-chloromethylphenylacetylnitrophenyl polymer prepared as in the procedure of Example 22, carrying four m. mole of p-chloromethylphenylmalonic acid was suspended for about 8 hours in 20 ml of dry methylene chloride solution containing 1 millimole of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid propionyloxymethyl ester. After only traces of the 7-amino-cephalosporanic acid ester derivative remain in solution, which is determined by thin layer chromatography on cellulose in 70% aqueous propanol, the polymer is filtered off and washed with portions of 50 ml each of methylene chloride. The combined filtrates are evaporated and the residue is dissolved in 20 ml of distilled water. The solution is acidified to a pH of 2 by adding 0.2 normal hydrochloric acid and extracted twice with ethylacetate. The organic solution is dried over sodium sulfate and evaporated at room temperature. The remaining solid is dried overnight over phosphorus pentoxide under vacuum to give 3-[(acetyloxy)-methyl]-7-[[2-[4-(chloromethyl)phenyl]-2-carboxyacetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid propionyloxymethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)(=[O:12])=[O:11])=[CH:5][C:4]=1[CH3:22]>[Pd].C(O)C.CCOC(C)=O>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([NH:9][C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[C:4]([CH3:22])[CH:5]=1)(=[O:11])=[O:12]
Reactant: COc1ncc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ncc(NS(=O)(=O)c2ccccc2N)cc1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 106.5 %

Procedure:
A mixture of N-(6-methoxy-5-methylpyridin-3-yl)-2-nitrobenzenesulfonamide (2.69 g, 8.32 mmol) and 10% palladium on charcoal (1.35 g) in ethanol/EtOAc (1:1, 100 mL total reaction volume) was stirred at rt under an atmosphere of H2 for approximately 2.5 h. Filtration and concentration in vacuo yielded the crude title compound (2.60 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[CH:17][N:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[CH2:35]([NH2:37])[CH3:36].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][S:14][C:15]3[C:20]([C:21]#[N:22])=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:25][CH:24]=4)[C:18]([C:33]#[N:34])=[C:17]([NH:37][CH2:35][CH3:36])[N:16]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1cnc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CCN
Solvent: C1CCOC1
Solvent: O
Product: CCNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 100 mg (0.17 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-ylmethyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.17 ml (0.33 mmol) of ethylamine (2M solution in THF) were stirred in 2 ml of THF for 30 min. Another 0.17 ml (0.33 mmol) of ethylamine (2M solution in THF) was then added, and the mixture was stirred at RT for 2 h. About 15 ml of water were added to the reaction mixture, and the precipitate formed was filtered off, washed with water and dried under high vacuum. This gave 81 mg (89% of theory) of the desired target compound.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.[Br:25][C:26]1[CH:37]=[CH:36][C:29]([C:30](N(OC)C)=[O:31])=[CH:28][CH:27]=1>O1CCCC1>[Br:25][C:26]1[CH:37]=[CH:36][C:29]([C:30]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: Brc1ccc(N2CCOCC2)cc1
Reactant: CON(C)C(=O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)c1ccc(N2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 31.4 %

Procedure:
A solution of n-butyllithium in hexane (1.6 M, 0.49 mL, 0.79 mmol) was added dropwise to a solution of 4-(4-bromophenyl)morpholine (191 mg, 0.79 mmol; described in: Jones, D. H. J. Chem. Soc. (C), 1971, 132-137 ) in tetrahydrofuran (5 mL) under nitrogen at −78° C. After 10 minutes, a pre-cooled solution (−78° C.) of 4-bromo-N-methoxy-N-methylbenzamide (212 mg, 0.87 mmol; described in: Turnbull, K. Tet. Lett. 1998 39(12), 1509-12) in tetrahydrofuran (3 mL) was added via a double-tipped needle. The mixture was stirred at −78° C. for 5 min. The cooling bath was removed and the mixture was allowed to reach ambient temperature under 30 min. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and water. The phases were separated and the organic layer was washed with brine, dried (MgSO4) and the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel using heptane/ethyl acetate, 70:30, as the eluent affording 86 mg (32% yield) of the title compound as colorless crystals: mp 177.8-179.2° C.; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=9.0 Hz, 2 H), 7.61 (s, 4 H), 6.89 (d, J=9.0 Hz, 2 H), 3.89-3.85 (m, 4 H), 3.35-3.32 13C NMR(400 MHz, CDCl3) δ 194.5, 154.6, 137.8, 132.8, 131.8, 131.6, 127.7, 126.8, 113.6, 67.0, 47.9; MS (TSP) m/z 346 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][C:21]=2[N+:23]([O-:25])=[O:24])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@H]1CO
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](Nc2ccc(Br)cc2[N+](=O)[O-])C[C@H]1CO
Temperature: 25 °C
Yield: 72.1 %

Procedure:
Heat a mixture of (2S,4S)-4-amino-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.14 mol, 31 g), 5-bromo-2-fluoronitrobenzene (0.29 mol, 64.0 g) and triethylamine (0.58 mol, 59 g) in ethyl acetate (320 mL) to reflux for 16 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (42 g, crude) as a thick, dark, orange oil.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: NS(=O)(=O)c1nc2ccc([N+](=O)[O-])cc2s1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2nc(S(N)(=O)=O)sc2c1
Yield: 87.2 %

Procedure:
A mixture of 6-nitrobenzothiazole-2-sulfonamide (3.0 g, 0.011 mol), 95% ethanol (290 ml), and 10% Pd on carbon (3.0 g) was hydrogenated at an initial pressure of 50 psig for 36 hours during which time the theoretical amount of hydrogen was consumed. The reduction mixture was vacuum filtered through a pad of Celite contained in a Buchner funnel and the volatiles removed under reduced pressure. The resulting product was purified by dissolving in aqueous 10% sodium carbonate (25 ml), filtering and adjusting the pH of the filtrate to 6 with glacial acetic acid. The precipitated product was collected by vacuum filtration in a Buchner funnel and dried under reduced pressure at 78° C. in an Abderhalden to give 2.2 g (82.9% yield) of 6-aminobenzothiazole-2-sulfonamide: m.p. 221°-222° C., Anal. (C7H7N3O2S2) CHN.
Reaction SMILES: [CH2:1]([Si:3]([CH2:17][CH3:18])([CH2:15][CH3:16])[O:4][C@@H:5]1[C@H:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[NH:7][C:6]1=[O:14])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:28]([O:32][C:33](Cl)=[O:34])[CH2:29][CH2:30][CH3:31]>ClCCl>[CH2:17]([Si:3]([CH2:15][CH3:16])([CH2:1][CH3:2])[O:4][C@@H:5]1[C@H:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:7]([C:33]([O:32][CH2:28][CH2:29][CH2:30][CH3:31])=[O:34])[C:6]1=[O:14])[CH3:18]
Reactant: CC[Si](CC)(CC)O[C@H]1C(=O)N[C@H]1c1ccco1
Reactant: CCCCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCOC(=O)N1C(=O)[C@H](O[Si](CC)(CC)CC)[C@@H]1c1ccco1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
(3R,4R)-3-Triethylsilyloxy-4-(2-furyl)azetidin-2-one (0.58 g, 2.17 mmol) in 30 mL of dichloromethane was stirred with diisopropylethyl amine (0.4 mL, 2.30 mmol) and butylchloroformate (0.3 mL, 2.36 mmol) in addition to a catalytic amount of DMAP (N,N-dimethylaminopyridine). The solution was stirred for 1 h and diluted with dichloromethane and washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed over silica gel (eluted with 3:1 hexane/ethyl acetate) to give 523 mg of product (Y: 65%); IR(KBr) 1820, 1734, 1318, 1018, 734 cm-1 ; 1H NMR (CDCl3,300 MHz) δ7.38 (m, 1H), 6.35 (m, 2H), 5.09 (ABq, J=15.5, 5.6 Hz, 2H), 4.14 (m, 2H), 1.56 (m, 2H), 1.28 (s, 2H), 0.87 (t, J=8.7 Hz, 3H), 0.82 (t, J=7.9, 9H), 0.50 (m, 6H); 13C NMR (CDCl3,75.5 Hz) δ165.4, 149.1, 147.6, 142.9, 110.5, 109.9, 77.7, 66.6, 55.9, 30.5, 18.8, 13.6, 6.3, 4.3; DCIMS M+H calcd for C18H29NO5Si: 368, Found: 368.
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][N:3]=[CH:2]1.[NH:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1>C(O)(=O)CC>[S:1]1[C:5]([C:6]2[C:12]3[NH:8][C:9]([C:6]([C:5]4[S:1][CH:2]=[N:3][CH:4]=4)=[C:9]4[N:8]=[C:12]([C:6]([C:5]5[S:1][CH:2]=[N:3][CH:4]=5)=[C:9]5[NH:8][C:12](=[C:6]([C:5]6[S:1][CH:2]=[N:3][CH:4]=6)[C:9]6[CH:10]=[CH:11][C:12]=2[N:8]=6)[CH:11]=[CH:10]5)[CH:11]=[CH:10]4)=[CH:10][CH:11]=3)=[CH:4][N:3]=[CH:2]1
Reactant: c1cc[nH]c1
Reactant: O=Cc1cncs1
Solvent: CCC(=O)O
Product: C1=Cc2nc1c(-c1cncs1)c1ccc([nH]1)c(-c1cncs1)c1nc(c(-c3cncs3)c3ccc([nH]3)c2-c2cncs2)C=C1
Temperature: 25 °C
Yield: 23.2 %

Procedure:
A 250-mL three-necked flask equipped with a condenser and charged with propionic acid (60 mL) was heated to reflux. 5-Thiazolecarboxaldehyde (1, 373 mg, 3.30 mmol), pyrrole (230 μL, 3.32 mmol), and an additional 5 mL of propionic acid were added. After 3.5 h at reflux, the mixture was cooled to room temperature while exposed to a stream of air. The solvent was removed in vacuo, the residue was redissolved in CHCl3/MeOH/concentrated NH4OH (6:3:1; 100 mL), and the solvent was removed in vacuo. The residue was adsorbed onto silica gel (3 g) and purified by column chromatography (gradient elution, 1-2% MeOH/CH2Cl2) to provide porphyrin 6 (123 mg, 14%) as a solid: 1H NMR (300 MHz, CDCl3) δ −2.70 (s, 2 H), 8.67 (s, 4 H), 9.02 (s, 8 H), 9.38 (s, 4 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:15](Cl)(=[O:17])[CH3:16]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:15](=[O:17])[CH3:16])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine (5 g, 25.2 mmol) was added to aluminum chloride (16.8 g, 126.2 mmol) in dichloromethane (200 ml) under nitrogen. The mixture was allowed to stir at room temperature for 1 hour. Acetyl chloride (9 ml, 126.2 mmol) in dichloromethane was added drop wise and the reaction was allowed to proceed at room temperature overnight. Next day the reaction was cooled to 0° C. and quenched with methanol (˜500 ml) until the reaction turned clear. The reaction was concentrated under vacuum and resuspended in water (300 ml). The pH was adjusted to 4 with 7N sodium hydroxide solution and then extracted with ethyl acetate (300 ml×3). The combined organic layers were extracted with saturated sodium potassium tartrate and brine and dried with Na2SO4. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 1-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-yl)-ethanone (5.2 g, 87% yield). 1H NMR (500 MHz, DMSO-d6) δ 2.48 (s, 3H), 8.41 (s, 1H), 8.57 (s, 1H), 8.58 (s, 1H). MS: m/z 241.0 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[N:26]1[CH2:30][C:29](=[O:31])[N:28](CC[Si](C)(C)C)[S:27]1(=[O:39])=[O:38])[CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[NH:19][C:20](=[O:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[N:26]1[CH2:30][C:29](=[O:31])[NH:28][S:27]1(=[O:39])=[O:38])[CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[NH:19][C:20](=[O:22])[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N[C@@H]1CCCC[C@H]1Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H]1CCCC[C@H]1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of N-((1R*,2S*)-2-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-benzyl}-cyclohexyl)-acetamide (76 mg, 0.133 mmol) in DMF (3 mL) is added CsF (81 mg, 0.533 mmol) and the mixture is stirred at 90° C. for 1 h. Ethyl acetate is added and the mixture is washed with 1N HCl and brine. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [OH:1][C:2]([CH3:22])([CH3:21])[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1)[S:4]([NH2:7])(=[O:6])=[O:5].[C:23](OC)(OC)(OC)[O:24][CH3:25]>C(O)(=O)C>[CH3:23][O:24][C:25]1[O:1][C:2]([CH3:22])([CH3:21])[CH:3]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:10][CH:9]=2)[S:4](=[O:5])(=[O:6])[N:7]=1
Reactant: CC(C)(O)C(c1ccc(CN2CCOCC2)cc1)S(N)(=O)=O
Reactant: COC(OC)(OC)OC
Solvent: CC(=O)O
Product: COC1=NS(=O)(=O)C(c2ccc(CN3CCOCC3)cc2)C(C)(C)O1

Procedure:
2-Hydroxy-2-methyl-1-(4-morpholin-4-ylmethylphenyl)propane-1-sulfonamide (350 mg) was stirred with tetramethyl orthocarbonate (5 ml) and glacial acetic acid (1 ml) at 80° C. for 16 hours. The solvents were removed under reduced pressure and the residue was used further without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[N:26]=[CH:25][NH:24][N:23]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:3]=1.[H-].[Na+].I[CH:30]([CH3:32])[CH3:31].O>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[N:26]=[CH:25][N:24]([CH:30]([CH3:32])[CH3:31])[N:23]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:3]=1
Reactant: CC(C)I
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4nc[nH]n4)nn23)no1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ncn(C(C)C)n4)nn23)no1
Temperature: 0 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
To a stirred solution of 3-(5-methylisoxazol-3-yl)-6-(1,2,4-triazol-3-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine (100 mg, 0.29 mmol) in N,N-dimethylformamide (6 ml) at room temperature under nitrogen was added sodium hydride (17 mg, 0.41 mmol). The mixture was cooled to 0° C. and 2-iodopropane (0.04 ml, 0.36 mmol) added after 0.25 h. The mixture was left to stir at room temperature overnight, water was added and the precipitate filtered off. The crude product was flash chromatographed on silica gel, eluting with ethyl acetate→4% methanol/ethyl acetate, to give the title-product (25 mg, 22%), mp 179-181° C.; 1H NMR (360 MHz, CDCl3) δ 1.58 (6H, d, J=6.7 Hz, 2 of CH3), 2.59 (3H, s, CH3), 4.58 (1H, septet, J=6.7 Hz, CH), 5.72 (2H, s, CH2), 7.01 (1H, s, Ar—H), 7.78 (1H, t, J=7.2 Hz, Ar—H), 7.94 (1H, t, J=7.6 Hz, Ar—H), 8.13 (1H, s, Ar—H), 8.28 (1H, d, J=7.9 Hz, Ar—H), 8.80 (1H, d, J=7.4 Hz, Ar—H); MS (ES30) m/e 391 [MH]+; Anal. Found. C, 56.81; H, 4.68; N, 27.89; C19H18N8O2.0.7H2O requires C, 56.62; H, 4.85; N, 27.80%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=O)[CH2:8][C:7]=2[CH:13]=1.[CH2:14]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([N:17]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:15][CH3:16])[CH2:8][C:7]=2[CH:13]=1
Reactant: COc1ccc2c(c1)CC(=O)CO2
Reactant: CCCNCCC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCCN(CCC)C1COc2ccc(OC)cc2C1

Procedure:
A mixture of 11.58 g of 6-methoxy-3,4-dihydro-2H-[1]-benzopyran-3-one, 26 g of dipropylamine, 0.3 ml of trifluoroacetic acid and 160 ml of toluene is refluxed in a Dean-Stark apparatus for 2 hours. The solution concentrated in vacuo and the residue is added to a solution of 8 g of sodium cyanoborohydride in 160 ml of ethanol and 40 ml of acetic acid. After 15 minutes at room temperature most of the solvent is removed in vacuo. The residue is dissolved in 6N hydrochloric acid and washed with ether. The aqueous layer is made basic and the product is extracted with ether. The aqueous layer is made basic and the product is extracted with ether. The ether layer is dried over magnesium sulfate and the solvent is removed in vacuo, to afford 6-methoxy-3,4-dihydro-N,N-di-propyl-2H-[1]-benzopyran-3-amine. The fumaric acid salt melts at 107°-113°.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:14][C:13](=[O:15])[C:12]1(Cl)Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)C>C(O)(=O)C.[Zn]>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:12][C:13](=[O:15])[CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(CCOCc2ccccc2)C1(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C1CC(CCOCc2ccccc2)C1
Temperature: 60 °C

Procedure:
Zinc dust was added to a solution of 3-(benzyloxyethyl)-2,2-dichlorocyclobutanone in glacial acetic acid at room temperature. The reactants were heated at 60° C. for 1 hr, after which time dry diethyl ether was added to the cooled products, which were then filtered. The residue was washed with diethyl ether and the combined filtrate and washings were concentrated under reduced pressure. The residue was dissolved in CH2Cl2, which was washed with saturated NaHCO3 twice and water once. The organic phase was dried over MgSO4 and the solvent was evaporated to give an oily product, which was purified by silica gel flash chromatography (Hexane: EtOAc=6:1). 1H NMR (CDCl3, 400 MHz): δ 1.85-1.90 (q, J=6.0, 2H), 2.45-2.56 (m, 1H), 2.66-2.74 (m, 2H), 3.07-3.15 (m, 2H), 3.48-3.51 (t, J=6.0, 2H), 4.48 (s, 2H), 7.24-7.35 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ 21.29, 36.02, 52.56, 68.85, 72.99, 127.56, 127.62, 128.40, 138.33, 208.25. Rf=0.45 (Hexane: EtOAc=3:1). IR (neat) νmax 3054, 2927, 2856, 1779, 1266, 737, 704.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Mg+2].FC(F)(F)S([O-])(=O)=O.[CH:18]([Si:21]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[O:22][CH2:23][C@@H:24]([OH:26])[CH3:25])([CH3:20])[CH3:19].[O:33]1[CH2:35][C@@H:34]1[C:36]([O:38][CH3:39])=[O:37]>C(OCC)(=O)C>[OH:33][C@H:34]([CH2:35][O:26][C@@H:24]([CH3:25])[CH2:23][O:22][Si:21]([CH:18]([CH3:20])[CH3:19])([CH:27]([CH3:29])[CH3:28])[CH:30]([CH3:32])[CH3:31])[C:36]([O:38][CH3:39])=[O:37]
Reactant: CC(C)[Si](OC[C@H](C)O)(C(C)C)C(C)C
Reactant: COC(=O)[C@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](O)CO[C@@H](C)CO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 80 °C
Reaction time: 48 h
Yield: 41.2 %

Procedure:
Magnesium trifluoromethanesulfonate (1.263 g, 3.92 mmol) was added to a mixture of (S)-1-(triisopropylsilyloxy)propan-2-ol (4.55 g, 19.59 mmol) and (R)-methyl oxirane-2-carboxylate (2 g, 19.59 mmol) in ethyl acetate (40 mL). The resulting suspension was heated to 80° C. for 72 hours. Further (R)-methyl oxirane-2-carboxylate (2 g, 19.59 mmol) was added and the mixture stirred at 80° C. for 48 hrs. Further (R)-methyl oxirane-2-carboxylate (2 g, 19.59 mmol) was added and the mixture stirred for 24hrs. The mixture was allowed to cool, filtered through a bed of silica (˜10 g), washed through with EtOAc and evaporated. The crude product was purified by flash silica chromatography, elution gradient 10 to 50% EtOAc in isohexane, to afford the product (2.7 g, 41%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[NH2:41][CH:42]1[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:41][CH:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]5)=[O:27])=[CH:24][C:23]=4[F:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Reactant: CN1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a mixture of 0.11 g (0.24 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-benzoic acid (I-182), 0.17 mL (0.96 mmole) of ethyldiisopropyl amine, 0.030 g (0.26 mmole) of 4-amino-1-methyl-piperidine and 3.0 mL of dimethylformamide was added 0.11 g (0.26 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-80:20) gave 0.065 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-N-(1-methyl-piperidin-4-yl)-benzamide (I-183) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6](Cl)[N:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=1.[C:22]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[C:22]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:35][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([O:8][CH2:9][CH2:10][OH:15])[N:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=2)(=[O:33])=[O:34])=[CH:28][CH:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccccc1Oc1c(Cl)nc(C(F)(F)F)nc1Cl
Solvent: Cc1ccccc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C(F)(F)F)nc1OCCO

Procedure:
By reacting 4,6-dichloro-5-(2-methoxyphenoxy)-2-trifluoromethylpyrimidine with p-tert-butylbenzenesulfonamide and with ethylene glycol Na there was obtained p-tert-butyl-N-[6-(2-hydroxyethoxy)-5(o-methoxyphenoxy)-2-(trifluoromethyl)-4-pyrimidinyl]benzenesulfonamide, m.p. 190°-192° C. (from toluene). Sodium salt: M.p. 288°-289° C.