Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)C>O1CCCC1>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]=[O:12])=[CH:6][CH:7]=1
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(Br)cc1
Yield: 96.2 %

Procedure:
To a solution of N,N-diethyl-4-bromo-benzamide (128 mg, 0.5 mmol) (see structural formula at entry 3 of Table 1) and Cp2ZrCl2(207 mg, 0.7 mmol, 1.4 eq.) in THF (3 mL) at RT was rapidly added a 1 M tetrahydrofuran (THF) solution of LiAlH(Ot-Bu)3 (0.7 mL, 0.7 mmol, 1.4 eq.). After addition, thin layer chromatography (TLC) using EtOAc/Hexanes showed the substrate had been consumed completely. The reaction was quenched by distilled H2O immediately. Dilute acid (0.5 N HCl in distilled water) was added until the pH was less than 5. Then EtOAc was added (3×10 mL) and the mixture was extracted. Combined organic layers were washed with brine, dried over MgSO4 and concentrated via evaporation under reduced pressure. Initial purification of the crude product was performed by passing the solution through a filter of silica gel (silica gel 60, 230-400 mesh). Purity was then checked by TLC. If further purification was needed, it was performed by flash column chromatography (silica gel 60, 230-400 mesh) using EtOAc/hexanes as eluent. 4-Bromobenzaldehyde (89 mg, 96% yield) was obtained as a colorless solid. Its melting point was determined to be 55-56° C. (hexanes).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][C@H:16]([CH2:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[N:26][N:27]2[CH2:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:23][CH:22]=1)[CH:17]([CH3:19])[CH3:18])[C:10](OCC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CCO>[OH:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:15][C@H:16]([CH2:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[N:26][N:27]2[CH2:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:23][CH:22]=1)[CH:17]([CH3:18])[CH3:19]
Reactant: CCOC(=O)[C@H](C[C@H](Cc1ccc2cnn(CCCOC)c2c1)C(C)C)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COCCCn1ncc2ccc(C[C@@H](C[C@@H](CO)NC(=O)OC(C)(C)C)C(C)C)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
To a mixture of (2S,4S)-ethyl 2-(tert-butoxycarbonylamino)-4-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-5-methylhexanoate (7.2 g, 15.2 mmol) in EtOH (100 mL) was added NaBH4 (5.0 g, 131 mmol) in portions such that the temperature remained lower than 40° C. The mixture was stirred at rt for 12 h. TLC showed the starting material had been consumed. The solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, and evaporated to produce tert-butyl (2S,4S)-1-hydroxy-4-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-5-methylhexan-2-ylcarbamate (5.8 g, 88%). MS: 434 (M++1)
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.CC([O-])(C)C.[K+].[SiH:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18]>O1CCCC1>[S:9]1[CH:8]=[C:7]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: CC[SiH](CC)CC
Reactant: c1ccc2sccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1csc2ccccc12
Yield: 82.9 %

Procedure:
The reaction was conducted according to the General Procedure by heating thianaphthene (66 mg, 0.5 mmol, 1 equiv.), KOt-Bu (8.4 mg, 0.08 mmol, 0.15 equiv.) and Et3SiH (239 microliters, 1.5 mmol, 3 equiv.) in 1 mL of tetrahydrofuran for 50 hours at 23° C. After aqueous work up, the crude reaction mixture was purified by chromatography on silica eluting with 80:2 hexanes:triethylamine to obtain 103 mg (83%) of the title compound as a colourless oil. 1H NMR (500 MHz, THF-d8) δ 7.90-7.85 (m, 1H), 7.84-7.76 (m, 1H), 7.53 (d, J=0.8 Hz, 1H), 7.34-7.20 (m, 2H), 1.08-0.99 (m, 9H), 0.95-0.80 (m, 6H). 13C NMR (126 MHz, THF-d8) δ 144.78, 142.34, 139.12, 132.97, 125.10, 124.84, 124.34, 122.91, 7.84, 5.10. HRMS: [C14H20SSi] calculated 248.1051. measured 248.1055. The HSQC spectrum of this reaction product as provided in FIG. 14.
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:61]([C:63]1[CH:71]=[CH:70][C:66]([C:67](O)=[O:68])=[CH:65][CH:64]=1)#[N:62]>CN(C=O)C.O>[C:61]([C:63]1[CH:71]=[CH:70][C:66]([C:67]([NH:17][CH2:18][C:19](=[O:20])[N:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]2)=[O:68])=[CH:65][CH:64]=1)#[N:62]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 48.2 %

Procedure:
DIPEA (53 mg, 0.41 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt (69 mg, 0.16 mmol) in DMF (1 mL). HOBT (22 mg, 0.16 mmol) and EDCI.HCl (31 mg, 0.16 mmol) were then added at room temperature. After 2 minutes, 4-cyanobenzoic acid (20 mg, 0.14 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water (20 mL) was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 30 mg (50% yield) of 4-cyano-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 96.9%, 1H NMR (CDCl3): δ 7.9 (d, 2H), 7.8-7.7 (d, 3H), 7.6 (m, 2H), 7.4-7.3 (d, 2H), 4.2 (m, 2H), 4.4-4.2 (m, 2H), 4.0 (m, 2H), 3.8-3.4 (m, 5H), 3.4 (t, 1H), 3.2 (m, 2H).
Reaction SMILES: N([O-])=O.[Na+].[C:5]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][C:13]([N+:19]([O-:21])=O)=[C:14]([NH2:18])[CH:15]=2)[CH2:10]1)(=[O:7])[CH3:6].S(=O)(=O)(O)O.[N-]=[N+]=[N-].[Na+]>C(O)(=O)C.O>[C:5]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:15][C:14]3[C:13](=[CH:12]2)[NH:19][O:21][N:18]=3)[CH:17]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)NC1Cc2cc(N)c([N+](=O)[O-])cc2C1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [N-]=[N+]=[N-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2cc3no[nH]c3cc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
At 0° C., 0.46 g (6.6 mmol) of NaNO2, and then 1.4 g (6 mmol) of the product of Step 1 dissolved in 10 ml of acetic acid, are added to 3 ml of sulphuric acid. After 15 minutes at 0° C., the mixture is poured onto 20 g of ice. The solution so obtained is poured dropwise into a vigorously stirred solution of 600 mg (9.2 mmol) of sodium azide in 12 ml of water. The whole is stirred for 10 minutes at room temperature and extracted 3 times with 40 ml of CH2Cl2 each time. The organic phases are washed with an aqueous 10% sodium carbonate solution, dried over MgSO4 and filtered and 100 ml of dry toluene are added. The methylene chloride is evaporated off and the toluene solution so obtained is heated at reflux for 3 hours.
Reaction SMILES: Br[C:2]1[C:15]([CH3:16])=[C:14]([C:17]#[N:18])[C:5]2[N:6]=[C:7]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[O:8][C:4]=2[C:3]=1[F:19].[C:20](C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)[CH3:21].C(C([Sn])=C(CCCC)CCCC)CCC.[F-].[K+]>O1CCOCC1.O.[Cl-].[Na+].O.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.C(OCC)(=O)C>[C:17]([C:14]1[C:5]2[N:6]=[C:7]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[O:8][C:4]=2[C:3]([F:19])=[C:2]([CH:20]=[CH2:21])[C:15]=1[CH3:16])#[N:18]
Reactant: Cc1c(Br)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC([Sn])=C(CCCC)CCCC
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=Cc1c(C)c(C#N)c2nc(C(=O)N(C)C)oc2c1F
Temperature: 100 °C
Reaction time: 17 h
Yield: 62 %

Procedure:
6-Bromo-4-cyano-7-fluoro-N,N,5-trimethyl-1,3-benzoxazole-2-carboxamide (I-127) (500 mg, 1.53 mmol), 2,6-di-tert-butylcresol (3 grains) and tetrakis(triphenylphosphine)palladium(0) (177 mg, 0.15 mmol) were dissolved in 1,4-dioxane (10 ml), then at room temperature, tributylvinyltin (601 μl, 1.99 mmol) was added, followed by stirring under nitrogen atmosphere at 100° C. for 17 hours. After cooling to room temperature, the insoluble matter was separated by filtration with washing with ethyl acetate. The filtrate was washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the organic layer was washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated away, the resulting residue was dissolved in tetrahydrofuran (10 ml) and water (5 ml), and at room temperature, potassium fluoride (1.782 g, 30.66 mmol) was added. After vigorously stirring at the same temperature for 23 hours, the reaction liquid was fractionated with ethyl acetate and saturated brine. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, hexane:ethyl acetate=3:1) to obtain the entitled compound (261 mg, 62%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:17][CH:18]=2)[CH:3]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: CC(C)(C)c1ccc(N)cc1
Product: COC(=O)c1cccc(Nc2ccc(C(C)(C)C)cc2)c1

Procedure:
Reaction of methyl 3-bromobenzoate with 4-tert-butylaniline according to general procedure A provided methyl ester of Compound 10 as a yellow oil (81% yield). 1H NMR (CDCl3, 500 MHz): δ=7.73 (s, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.21-7.42 (m, 4H), 7.06-7.13 (m, 2H), 5.85 (s, 1H), 3.92 (s, 3H), 1.36 (s, 9H). 13C NMR (CDCl3, 125 MHz): δ=167.4, 145.1, 144.3, 139.8, 131.4, 129.4, 126.4, 121.3, 120.9, 118.9, 117.7, 52.3, 34.4, 31.6.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH2:12][CH:11]=[CH2:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1cc(C)cc(C)c1
Reaction time: 18 h
Yield: 100 %

Procedure:
3,5-Dimethylphenol, 12.2 g (100 mmole), 10.8 ml (125 mmole) of allyl bromide, and 16.56 g (120 mmole) of potassium carbonate was dissolved and then refluxed in 50 mlacetone, with stirring, under nitrogen for 18 hours. The reaction was cooled, the insoluble inorganics were filtered off and stripped to give 16.2 g (100%) of subtitled product, which was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:21]N1C(=O)CCC1=O.C(N(CC)CC)C.C1(=O)NC(=O)CC1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].O>[C:1]([OH:19])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.5 g of stearoyl chloride was dissolved in 2 ml of 1,4-dioxane, and 0.29 g of N-hydroxysuccinimide and 0.1 ml of triethylamine were added, and the mixture was stirred at room temperature for 3 h. 1 ml of water was added to the mixture, and the pH was adjusted to 5 by addition of alkali. 60 μl of a succinimide-activated stearic acid solution were mixed with 2.5 ml of hirudin solution (21 mg/ml in 0.1 M sodium carbonate pH 9) and 2.5 ml of dioxane, and the mixture was incubated at room temperature with stirring for 12 h. The mixture was then purified by preparative RP-HPLC (see Example 2). The derivatives elute at 48% B, 54% B, 62% B and 74% B. The specific acitivities were 9,600 U/mg, 12,400 U/mg, 12,800 U/mg and 840 U/mg.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH:9]2[CH2:11][CH:10]2[CH2:12][CH:13]=O)[C:3]=1[CH3:15].N1CCCCC1.C(O)(=O)C.[C:26]([O:34]CC)(=O)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(O)C.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[CH2:31]([O:30][C:28]([C:27]1[C:26](=[O:34])[N:5]2[C:4]([C:3]([CH3:15])=[C:2]([Cl:1])[C:7]([F:8])=[CH:6]2)=[C:9]([CH:10]2[CH2:12][CH2:13]2)[CH:11]=1)=[O:29])[CH3:32]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1c(C2CC2CC=O)ncc(F)c1Cl
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Temperature: 235 °C
Reaction time: 0.75 h
Yield: 51.6 %

Procedure:
A sample of 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)cyclopropane acetaldehyde (6.37 mmol) was dissolved in 50 mL of ethanol, and to this were added 1.5 mL of piperidine, 1.5 mL of acetic acid, and 5 mL of diethyl malonate (32.9 mmol). The reaction was heated at reflux under nitrogen for 4 hours. The solvents were then removed, and the residue was dissolved in ether. The ether was washed with water and brine, then dried over MgSO4 and concentrated Purification in a kugelrohr apparatus gave 2.4 g of the crude condensation product. This intermediate product was dissolved in 20 ML of of Dowtherm A™, and this solution was added to 100 mL of Dowtherm A™ heated to 235° C. The reaction was then stirred at 220° C. for 45 min. After cooling, the product was separated from the solvent by flash chromatography, eluting with hexane to remove the solvent and then with 1:4 ethyl acetate hexane to remove the product. In this manner 1.065 g of 8-chloro-1- cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester was obtained after removal of the solvent. MS 324, 326 (M+H)+ ; 1H NMR (CDCl3)∂: 0.75 (m, 2H), 1.07 (m, 2H), 1.42 (t, 3H, J=7 Hz), 2.31 (m, 1H), 3.08 (s, 3H), 4.42 (q, 2H, J=7 Hz), 8.40 (s, 1H), 9.44 (d, 1H, J=6 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][CH:4]=1.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])=[CH:26][CH:25]=1.[H-].[Na+]>O1CCCC1>[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][CH:4]=2)[C:32](=[O:34])[CH3:33])=[CH:26][CH:25]=1
Reactant: CC(=O)NCc1ccncc1
Reactant: CCCCCCCCCCCCCCOc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CN(Cc2ccncc2)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.6 %

Procedure:
The title compound is prepared by the procedure of Example 27 using 2.55 g of product from Example 20, 0.999 g of product from Example 15, 0.319 g of washed 50% sodium hydride and 30 ml of tetrahydrofuran. The reaction is stirred at room temperature for 18 hours, heated at reflux temperature for 24 hours; followed by stirring at room temperature for an additional 48 hours. The residue is purified by column chromatography (silica gel: 5% methyl alcohol/ethyl acetate) to give 0.862 g of the desired product. The spectral data indicates the presence of 2 rotomers.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([OH:13])=O)=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.[CH3:14][CH:15]([NH2:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:17][CH:15]([CH3:16])[CH3:14])=[O:13])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)N
Reactant: O=C(O)c1c[nH]c2ncc(Br)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Reaction time: 4 h
Yield: 61.7 %

Procedure:
A mixture of 2-bromo-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (250 mg, 1.03 mmol), propan-2-amine (0.15 mL, 1.5 mmol) and HATU (456 mg, 1.2 mmol) in 20 mL of dry THF was stirred for 4 hours. The reaction mixture was evaporated to dryness, the residue was suspended in 20 mL of 0.5 N HCl, product extracted with ethyl acetate (3×50 mL), organics combined were dried with sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel. 200-300 mesh, eluting with ethyl acetate/petroleum ether=2:1) to give 2-bromo-N-isopropyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (180 mg, 62%). 1H NMR (300 MHz, DMSO): δ 12.95 (s, 1H), 8.49 (s, 1H), 8.43 (s, 1H), 7.59-7.56 (m, 1H), 4.13-4.06 (m, 1H), 1.24-1.20 (m, 6H). LCMS: (M+H)+=283/285.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][O:5][C:4]2[CH:9]=[C:10](Br)[CH:11]=[N:12][C:3]1=2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O:39][C:40]([CH3:42])=[CH2:41])(=O)C.C[O-].C([Sn+](CCCC)CCCC)CCC>C1C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][N:2]1[C:7](=[O:8])[CH2:6][O:5][C:4]2[CH:9]=[C:10]([CH2:41][C:40](=[O:39])[CH3:42])[CH:11]=[N:12][C:3]1=2
Reactant: C=C(C)OC(C)=O
Reactant: CN1C(=O)COc2cc(Br)cnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[Sn+](CCCC)CCCC
Solvent: c1ccccc1
Product: CC(=O)Cc1cnc2c(c1)OCC(=O)N2C
Temperature: 70 °C

Procedure:
4-Methyl-7-bromo-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (3 g) (0.012 mole) in 80 ml of benzene is treated with 365 mg tri-o-tolylphosphine, 138 mg palladium acetate, 1.87 g (0.018 mole) of isopropenyl acetate and 5.9 g (0.18 mole) of tributyltin methoxide. The mixture is heated to 70° C. for 25 hours. The reaction mixture is then quenched with 20 ml sat. ammonium chloride and diluted with 50 ml ethyl acetate. The organic phase separates, dried over sodium sulfate and concentrated to dryness. The residue is dissolved in methylene chloride, washed with sat. KF solution, filtered through a cotton plug, dried over sodium sulfate and concentrated to dryness to obtain crude product. This is chromatographed using 200×60 mm SiO2, EtOAc (100%) as eluent. The desired product is identified by NMR and used directly in the next step.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[CH2:20][N:19]([CH:24]2[CH2:26][CH2:25]2)[CH2:18][C:17]3([CH3:28])[CH3:27])=[CH:8][C:7]=1[F:29])C.CO.O1CCCC1.O.[OH-].[Li+]>O>[CH:24]1([N:19]2[CH2:18][C:17]([CH3:28])([CH3:27])[C:16]3[C:21](=[CH:22][CH:23]=[C:14]([C:13]#[C:12][C:9]4[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:30])=[O:3])=[C:7]([F:29])[CH:8]=4)[CH:15]=3)[CH2:20]2)[CH2:26][CH2:25]1
Reactant: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CN(C2CC2)C3)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CN(C2CC2)Cc2ccc(C#Cc3ccc(CC(=O)O)c(F)c3)cc21

Procedure:
Following general procedure J and using [4-(2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-ylethynyl)-2-fluoro-phenyl]-acetic acid ethyl ester (Compound 21, 0.055 g, 0.135 mmol), methanol (2 mL), tetrahydrofuran (4 mL), water (1 mL) and lithium hydroxide monohydrate (0.117 g, 2.97 mmol) the title compound was obtained as a pale yellow solid foam (0.040 g, 78%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][O:5][CH2:4][C@H:3]1[O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[N:9]=1.CC(C)=[O:26]>>[C:6]([OH:26])(=[O:5])[CH3:2].[OH:1][C@@H:2]1[CH2:6][O:5][CH2:4][C@H:3]1[O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([N:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[N:9]=1
Reactant: CC(C)=O
Agent: O[C@@H]1COC[C@H]1Oc1nc(N2CCNCC2)nc2ccccc12
Product: CC(=O)O

Procedure:
4-[trans-(4-Hydroxytetrahydrofuran-3-yl)oxy]-2-(1-piperazinyl)quinazoline (cf. Example 11) (200 mg) is dissolved in acetone (20 ml) with heating, and the solution is filtered, and the filtrate is concentrated and thereto is added acetic acid (50 mg), and the mixture is allowed to stand at room temperature. The precipitated crystals are separated by filtration to give 4-[trans-(4-hydroxytetrahydrofuran-3-yl)oxy]-2-(1-piperazinyl)quinazoline monoacetate (171 mg).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:14])=[C:4]([CH2:12][CH3:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[CH2:15]([OH:17])[CH3:16].[O-]CC.[Na+]>O>[CH2:15]([O:17][C:2]1[C:3]([CH3:14])=[C:4]([CH2:12][CH3:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:16]
Reactant: CCO
Reactant: CCc1c(C)c(Cl)nn2c(N)nnc12
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1nn2c(N)nnc2c(CC)c1C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
6-Chloro-8-ethyl-7-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.008, 273 mg) was dissolved in abs. ethanol (20 ml) while stirring. Thereafter, the reaction mixture was admixed with sodium ethoxide (176 mg) and stirred at RT for 3.5 h. After standing over the weekend, the solvent was drawn off, and the residue was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 230 mg of the title compound were obtained. LC-MS rt: 0.75 min [M+H]+: 222.2 (met. b)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:48])([CH3:47])[C:44](O)=[O:45])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:49][NH:50][CH3:51]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:48])([CH3:47])[C:44]([N:50]([CH3:51])[CH3:49])=[O:45])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CNC
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)N(C)C)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 150 mg of 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid (from example 65b) and dimethylamine are used to afford the title compound as a brown oil. Rf=0.45 (EtOAc-heptane 1:1); Rt=5.27.