Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[CH2:10][O:9][CH:8]([CH2:11]Br)[O:7][C:6]=2[CH:13]=1.[CH2:15]([NH2:18])[CH2:16][CH3:17]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[CH2:10][O:9][CH:8]([CH2:11][NH:18][CH2:15][CH2:16][CH3:17])[O:7][C:6]=2[CH:13]=1
Reactant: Fc1cc(Br)cc2c1COC(CBr)O2
Reactant: CCCN
Solvent: CCO
Product: CCCNCC1OCc2c(F)cc(Br)cc2O1
Yield: 82.2 %

Procedure:
Preparation according to Example 3. 7-bromo-2-(bromomethyl)-5-fluoro-4H-1,3-benzodioxine (0.20 g, 0.60 mmol), propan-1-amine (1.0 ml, 12.2 mmol) and EtOH (3.0 ml)was heated at 130° C. for 20 min. Purification by flash column chromatography (EtOAc/MeOH 10:1) gave the title compound (0.15 g, 82%). The amine was converted into the oxalic acid salt and was crystallised with MeOH/DEE (0.17 g). M.p. 215° C. MS m/z (rel. intensity, 70 eV) 304 (M+, 3), 302 (M+, 3), 205 (10), 203 (10), 72 (bp).
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH:40]=1)[O:9][CH:10](OS(C1C=CC=CC=1S(N(C)C1CCN(C)CC1)(=O)=O)(=O)=O)[CH2:11][CH2:12][O:13][NH:14][C:15](=[NH:17])[NH2:16].CC1C=CC([O:64][S:65]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=2[S:74]([N:77]([CH3:85])[CH:78]2[CH2:83][CH2:82][N:81]([CH3:84])[CH2:80][CH2:79]2)(=[O:76])=[O:75])(=[O:67])=[O:66])=C(C=1)OCCCOC1C=CC=C2C(NC(=O)C=12)=O.C(C(=CC1C=CC(O)=CC=1)C(O)=O)#N>>[ClH:1].[ClH:1].[CH3:3][C:4]1[CH:5]=[C:6]([O:64][S:65]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=2[S:74]([N:77]([CH3:85])[CH:78]2[CH2:83][CH2:82][N:81]([CH3:84])[CH2:80][CH2:79]2)(=[O:75])=[O:76])(=[O:67])=[O:66])[CH:7]=[C:8]([CH:40]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15]([NH2:17])=[NH:16]
Reactant: Cc1ccc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C2CCN(C)CC2)c(OCCCOc2cccc3c2C(=O)NC3=O)c1
Reactant: Cc1cccc(OC(CCONC(=N)N)OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C2CCN(C)CC2)c1
Agent: Cl
Agent: N#CC(=Cc1ccc(O)cc1)C(=O)O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)C2CCN(C)CC2)c1
Yield: 76 %

Procedure:
N-{3-[5-Methyl-3-[(2-(N-methyl-N-(1-methyl-4-piperidinyl)aminosulfonyl) phenylsulfonyloxy]phenoxy propoxy}guanidine dihydrochloride: The title compound was prepared in 76% yield from N-{3-[5-methyl-3-[(2-(N-methyl-N-(1-methyl-4-piperidinyl) aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide, as prepared in the preceding step, in a manner analogous to step f of Example 1. 1H-NMR (300 MHz, DMSO-d6) δ 8.25 (d, J=7.9 Hz, 1H), 8.15 (d, J=7.9 Hz, 1H), 8.02 (t, J=7.6 Hz, 1H), 7.89 (t, J=7.7 Hz, 1H), 7.37 (br s, 4H), 6.75 (s, 1H), 6.53 (s, 1H), 6.47 (s, 1H), 4.07 (m, 1H), 3.97 (t, J=6.3 Hz, 2H), 3.87 (t, J=6.3 Hz, 2H), 3.22 (m, 2H), 3.17 (s, 3H), 2.79 (s, 3H), 2.72 (t, J=12.0 Hz, 2H), 2.22 (s, 3H), 1.99 (pentet, J=6.3 Hz, 4H), 1.60 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C24H35N5O7S2: 570.2 (M+H), 592.2 (M+Na). Found: 570.1, 592.1.
Reaction SMILES: [OH-].[K+].[N:3]#[C:4][NH2:5].[F:6][C:7]([F:28])([F:27])[C:8]1[CH:26]=[CH:25][C:11]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.Cl>O.CC(C)=O>[C:4]([NH:5][C:19](=[O:20])[CH:18]([O:17][C:16]1[CH:15]=[CH:14][C:13]([O:12][C:11]2[CH:25]=[CH:26][C:8]([C:7]([F:28])([F:6])[F:27])=[CH:9][CH:10]=2)=[CH:24][CH:23]=1)[CH3:22])#[N:3]
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Cl
Reactant: N#CN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)NC#N
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
10.4 g (0.1575 mole) of 85% potassium hydroxide are dissolved in 75 ml of water. 3.5 g (0.0825 mole) of cyanamide are added at 20° C. and the clear, colourless solution is cooled to 10° C. Then a solution of 25.8 g (0.075 mole) of 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionyl chloride in 15 ml of acetone is added dropwise such that the temperature does not exceed 15° C. After the reaction mixture has been stirred for 45 minutes at this temperature, 9 g (0,09 mole) of 37% aqueous hydrochloric acid are added dropwise at 5° C. The product precipitates as an oil which crystallises on standing over 30 minutes. The colourless crystals are isolated by filtration, washed with water, dried over phosphorous pentoxide, affording 24.9 g (95.0% of theory) of 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid N-cyanamide with a melting point of 125°-127° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH:22]([CH3:24])[CH3:23])[C:4]([N:6]1[CH2:11][CH2:10][C@@:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)([OH:12])[C:8]([CH3:21])([CH3:20])[CH2:7]1)=[O:5].ClC1N=[C:30]([O:32]C)N=C(OC)N=1.C(O)=O.CN1CCOCC1>CN(C1C=CN=CC=1)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C@@:9]2([OH:12])[CH2:10][CH2:11][N:6]([C:4](=[O:5])[C@H:3]([NH:2][CH:30]=[O:32])[CH:22]([CH3:24])[CH3:23])[CH2:7][C:8]2([CH3:20])[CH3:21])=[CH:18][CH:17]=1
Reactant: CC(C)[C@@H](N)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: COc1nc(Cl)nc(OC)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=CO
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](NC=O)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
To a solution of (R)-2-amino-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one hydrochloride (111 mg, 0.296 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (57.1 mg, 0.325 mmol), formic acid (0.012 mL, 0.325 mmol) and NMM (0.068 mL, 0.62 mmol) CH2Cl2 (10 mL), was added DMAP (3.61 mg, 0.03 mmol). The mixture was stirred at rt for 3 h. The reaction was filtered and the filtrate was washed with Na2CO3, 0.5N HCl, and brine. The organic layer was dried over Na2SO4 and Concentrated to give N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)formamide (76 mg, 0.207 mmol, 70.0% yield).
Reaction SMILES: O[CH:2]([C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:3]=[CH2:4].S(Cl)([Cl:13])=O>CCCCCC.CN(C)C=O>[Cl:13][CH2:4][CH:3]=[CH:2][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: C=CC(O)C#CC(C)(C)C
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)C#CC=CCCl
Yield: 88.7 %

Procedure:
Ten grams (0.072 mole) of 3-hydroxy-6,6-dimethyl-hept-1-ene-4-yne was dissolved in 100 ml of hexane, and to the resulting solution were added 50 mg (6.8×10-4 mole) of N,N-dimethylformamide and 12.80 g (0.108 mole) of thionyl chloride. The mixture was reacted overnight at room temperature with stirring with a hydrogen chloride gas trap mounted on the reactor. The reaction mixture was concentrated under reduced pressure to obtain 10 g of a crude 1-chloro-6,6-dimethylhept-2-ene-4-yne.
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH3:15][N:16]([CH3:34])[C:17]([C:19]1[CH:24]=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][N:20]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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:10]([C:4]1[C:3]([O:13][CH3:14])=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([C:17]([N:16]([CH3:34])[CH3:15])=[O:18])=[N:20][CH:21]=2)[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)(=[O:12])[CH3:11]
Reactant: CN(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (0.38 g, 1.4 mmol) and N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (from PepTech, 0.46 g, 1.6 mmol) in 1,4-dioxane (6 mL), potassium carbonate (0.38 g, 2.7 mmol) in water (2 mL) was added. The reaction mixture was bubbled with N2. Tetrakis(triphenylphosphine)palladium(0) (0.095 g, 0.082 mmol) was added and the reaction was stirred overnight at 100° C. The reaction was diluted with water, extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated and purified on silica gel (eluting with 0-100% EtOAc in hexanes) to give the desired product. LCMS calculated for C18H20ClN2O3 (M+H)+: m/z=347.1; Found: 347.1
Reaction SMILES: [CH2:1](I)[CH3:2].[C:4]1([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[K+].O>CN1CCCC1=O.[Cu]>[C:4]1([N:10]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH2:1][CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Reactant: CCI
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCN(c1ccccc1)c1cccc2ccccc12
Yield: 98 %

Procedure:
A mixture of ethyl iodide (0.1M), 1-phenylaminonaphthalene (0.05M), KOH (0.1M) and copper bronze (1 g) was stirred for 31/2 hours in N-methylpyrrolidone (20 cm3) at 120° C. under an atmosphere of nitrogen. The mixture was cooled, poured into water (2 liters) and extracted with CH2Cl2 (3×300 cm3). The combined extracts were washed with water, dried over MgSO4 and the CH2Cl2 solvent removed in vacuo to give 229 g (98% yield) of 1-(N-phenyl-N-ethylamino)naphthalene as a yellow liquid.
Reaction SMILES: [Se].[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH3:13])=[N:10]2)=[CH:5][CH:4]=1.[O:14]1CCOCC1>>[Br:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH:13]=[O:14])=[N:10]2)=[CH:5][CH:4]=1
Reactant: Cc1ccc2ccc(Br)cc2n1
Reactant: C1COCCO1
Agent: [Se]
Product: O=Cc1ccc2ccc(Br)cc2n1
Temperature: 25 °C
Yield: 98 %

Procedure:
Selenium dioxyde (1.6 g, 14 mmol, 1.3 eq) in suspension in dioxane (50 mL) was heated at 60° C. 7-bromoquinaldine (2.5 g, 11.2 mmol) was the introduced and the mixture was left to react at 80° C. for 3 hours. After cooling to room temperature, the mixture was filtered on celite, eluted with dioxane and concentrated under reduced pressure. The product was obtained pure as a white solid (3.3 g, >98%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:16][CH2:15][C:9]2([O:13][N:12]=[C:11]([CH3:14])[CH2:10]2)[CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>CO.O>[CH3:14][C:11]1[CH2:10][C:9]2([CH2:15][CH2:16][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[O:13][N:12]=1
Reactant: CCOC(=O)C1CCC2(CC1)CC(C)=NO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1=NOC2(CCC(C(=O)O)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-methyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid ethyl ester (570 mg, 2.5 mmol) in MeOH (15 ml) and lithium hydroxide monohydrate (284 mg, 3.8 mmol) in H2O (3 ml) was stirred overnight at RT.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[C:12](=[O:33])[N:13]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)[C:14]3[C:19]([C:20]=2O)=[CH:18][CH:17]=[CH:16][N:15]=3)=O)=[CH:4][CH:3]=1.O.[NH2:35][NH2:36].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[C:11]3[C:12](=[O:33])[N:13]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:30])[F:31])[CH:23]=4)[C:14]4[N:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:20]=3[NH:36][N:35]=2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: O=C(Cc1ccc(F)cc1)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccc(F)cc3)n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 115 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-(4-fluorophenylacetyl)-4-hydroxy-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (229 mg, 0.5 mmol) produced in Synthesis Example 28 in DMF (4 mL) was added hydrazine monohydrate (purity of 80%, 80 μL), and the mixture was stirred at 110 to 120° C. for 3 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(4-fluorobenzyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (203 mg, yield 89%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([C:17]([F:20])([F:19])[F:18])([OH:16])[CH2:14][OH:15])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.O.[C:24]1(C)[CH:29]=CC(S(O)(=O)=O)=C[CH:25]=1>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]2([C:17]([F:20])([F:18])[F:19])[CH2:14][O:15][C:24]([CH3:29])([CH3:25])[O:16]2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(CC(O)(CO)C(F)(F)F)c1cc(Br)cc2c1OCC2
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)OCC(CC(C)(C)c2cc(Br)cc3c2OCC3)(C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 144 h
Yield: 372.1 %

Procedure:
A mixture of 7.6 g (20 mmol) of 4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-trifluoromethylpentane-1,2-diol and 0.754 g (4 mmol) of p-toluenesulfonic acid monohydrate in 200 mL of acetone was stirred at room temperature for 6 days and the volatiles removed in vacuo. The residue was dissolved in EtOAc, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated in vacuo. The residue was extracted with diethyl ether and the filtrate concentrated in vacuo to afford 6.3 g (75%) of 5-bromo-7-[2-(2,2-dimethyl-4-trifluoromethyl-[1,3]dioxolan-4-yl)-1,1-dimethylethyl]-2,3-dihydrobenzofuran.
Reaction SMILES: [Na].[C:2]([OH:10])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:11]([O:13][CH:14]([O:18][CH2:19][CH3:20])[CH2:15][CH2:16]Cl)[CH3:12].O>CN(C)C=O>[C:2]([O:10][CH2:16][CH2:15][CH:14]([O:18][CH2:19][CH3:20])[O:13][CH2:11][CH3:12])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCOC(CCCl)OCC
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CCOC(=O)c1ccccc1)OCC
Temperature: 25 °C

Procedure:
A stirred solution of 50.0 grams (0.347 mole) of the sodium salt of benzoic acid and 53.0 grams (0.320 mole) of 3-ethoxy-4-oxahexyl chloride in 500 ml of dimethylformamide was heated at reflux for three hours. The reaction mixture was cooled to ambient temperature, and 500 ml of water was added. The mixture was extracted with two 700 ml portions of diethyl ether. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding 57.5 grams of 3-ethoxy-4-oxahexyl benzoate. The nmr spectrum was consistent with the proposed structure. Further extraction of the aqueous layer with diethyl ether yielded an additional 34.7 grams of the benzoate.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[SH:17]>C(Cl)(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[S:17][Cl:1]
Reactant: Sc1cc(Cl)ccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: ClSc1cc(Cl)ccc1Cl
Yield: 85.6 %

Procedure:
The procedure of Preparation 7 was repeated, reacting a slurry of N-chlorosuccinimide (3.72 g., 27.9 mmoles) in 50 ml. of carbon tetrachloride with 2,5-dichlorothiophenol (5.0 g., 27.9 mmoles) in 25 ml. of carbon tetrachloride. 2,5-Dichlorobenzenesulfenyl chloride (5.1 g.) was isolated as an oil.
Reaction SMILES: [N:1]([C:4]1[C:5]([C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[CH:11][C:10]([CH3:16])=[C:9]([CH3:17])[CH:8]=2)=[O:6])=[N+]=[N-].S(=O)(=O)(O)O.C1(C2C(=CC=CC=2)CO1)=O>>[C:4]([CH:14]=[C:13]1[C:12]2[C:7](=[CH:8][C:9]([CH3:17])=[C:10]([CH3:16])[CH:11]=2)[C:5](=[O:6])[O:15]1)#[N:1]
Reactant: Cc1cc2c(cc1C)C(=O)C(N=[N+]=[N-])=CC2=O
Agent: O=C1OCc2ccccc21
Agent: O=S(=O)(O)O
Product: Cc1cc2c(cc1C)C(=CC#N)OC2=O
Temperature: 3 °C
Reaction time: 0.17 h

Procedure:
2-Azido-6,7-dimethyl naphtho-1,4-quinone (2.0 g) was added in small portions (10 mg) to cold (0°-5° C), vigorously stirred concentrated sulphuric acid (30 ml. over 11/2 hours and the red solution stirred a further 10 minutes at 3° C until nitrogen evolution ceased. Poured onto ice-water (400 g) whereby the phthalide separated as a whitish solid. After recrystallisation from ethanol in the presence of charcoal the white solid had m.p. 165°-181° C (mixture of E and Z isomers). (Found; C, 72.10; H, 4.77; N, 6.91; C12H9NO2 requires; C, 72.35; H, 4.55; N, 7.03%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH2:34][C:35]([F:38])([F:37])[F:36])C(=O)OC(C)(C)C)[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[C:4](=[O:40])[CH2:3]1.[CH2:41]=O.[BH4-].[Na+].CO>C1COCC1>[CH3:39][N:9]1[CH:10]=[C:11]([NH:12][C:13]([C:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:34][C:35]([F:36])([F:37])[F:38])[CH:21]=3)[O:18][CH:19]=2)=[O:14])[C:7]([N:5]2[CH2:6][C@@H:2]([NH:1][CH3:41])[CH2:3][C:4]2=[O:40])=[N:8]1
Reactant: C=O
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2C[C@@H](N)CC2=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN[C@H]1CC(=O)N(c2nn(C)cc2NC(=O)c2coc(-c3ccnc(NCC(F)(F)F)c3)n2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (4-(4-((3-((4S)-4-amino-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-1,3-oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (83 mg) in THF (0.73 mL) was added 37% formalin (32 μl), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was ice-cooled, sodium borohydride (28 mg) and methanol (0.73 mL) were added thereto, and the mixture was stirred under ice-cooling for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in TFA (0.70 mL), and the solution was stirred at room temperature for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and recrystallized from ethyl acetate/hexane to give the title compound (19 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][CH:14]([OH:17])[CH2:15][NH2:16])=[CH:10][CH:9]=1.[CH3:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([CH2:27][C:28](=O)[CH3:29])=[O:26])=[CH:23][N:22]=1.C(O)C>C(O)=O>[CH3:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([CH:27]=[C:28]([NH:16][CH2:15][CH:14]([OH:17])[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:19][CH:18]=2)[CH3:29])=[O:26])=[CH:23][N:22]=1
Reactant: COCCCCOc1ccc(OCC(O)CN)cc1
Reactant: CC(=O)CC(=O)c1ccc(C)nc1
Solvent: CCO
Solvent: O=CO
Product: COCCCCOc1ccc(OCC(O)CNC(C)=CC(=O)c2ccc(C)nc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
54.0 g of 1-(p-[4-methoxybutoxy]-phenoxy)-3-aminopropan-2-ol ##STR66## 37.3 g of 6-methylnicotinoyl-acetone ##STR67## 400 ml of ethanol and 0.1 ml of formic acid are heated to 50° for 1 hour and stirred at room temperature for a further 20 hours. Filtration gives 61.3 g of 1-(2-[6 -methylnicotinoyl]-1-methylvinylamino)-3-(p-[4-methoxy- butoxy]-phenoxy)-propan-2-ol ##STR68## Melting points: 143°-145°. A further 15.0 g of the same substance can be obtained from the filtrate. Yield: 89% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][C:12]([CH2:17][CH2:18]Cl)([CH2:15][CH3:16])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:22][O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([OH:33])[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH3:22][O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][CH2:16][CH2:15][C:12]2([CH2:17][CH3:18])[CH2:11][CH2:10][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:21]=[CH:20][C:5]=4[N:6]=3)[CH2:14][CH2:13]2)[CH:27]=1
Reactant: COC(=O)Cc1ccc(Cl)c(O)c1
Reactant: CCC1(CCCl)CCN(c2nc3ccc(Cl)cc3s2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC1(CCOc2cc(CC(=O)OC)ccc2Cl)CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 75 °C
Reaction time: 24 h
Yield: 78.5 %

Procedure:
A mixture of 6-chloro-2-[4-(2-chloroethyl)-4-ethyl piperidine-1-yl]benzothiazole (150 mg), (4-chloro-3-hydroxyphenyl)acetic acid methyl ester (176 mg), cesium carbonate (285 mg) and dimethylformamide (2 mL) was stirred at 75° C. for 24 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (174 mg). Yield: 79%.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].Cl.[CH2:18](N=C=NCCCN(C)C)[CH3:19].C(O)C>C(OCC)C.CN(C)C1C=CN=CC=1>[CH2:18]([O:15][C:14](=[O:16])[CH2:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)[CH3:19]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CC(=O)O)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 40 h
Yield: 95 %

Procedure:
In an oven-dried 2 L round bottom flask under nitrogen, ((3S)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-pyrrolidinyl)acetic acid (60 g, 262 mmol) dissolved in diethyl ether (600 mL) was treated with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (55.2 g, 288 mmol), 4-(dimethylamino)pyridine (3.20 g, 26.2 mmol), and ethanol (33.6 ml, 576 mmol) at room temperature and the mixture was stirred for 40 h. The reaction mixture began as a white suspension, but then became a pale yellow solution with gummy yellow material at the bottom of the flask after 1 h, which was difficult to stir. Another stir bar was added in order to get the mixture stirring; however, a vortex was not obtained so the reaction was stirred longer than overnight to ensure the reaction went to completion. The reaction mixture was diluted with ether (400 mL) and washed with 1M aqueous sodium hydrogen sulfate solution (800 mL) and saturated aqueous sodium bicarbonate solution (800 mL). The organic phase was isolated, dried over magnesium sulfate, and concentrated to dryness to give the title compound as a clear pale yellow liquid (64.1 g, 249 mmol, 95%). MS(ES)+m/e 258.2 [M+H]+, 280.2 [M+Na]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17]C(C)(C)C)=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][N:4]=[CH:3]1.[C:22](O)(C(F)(F)F)=O.C(OC(=O)C)(=O)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:17])[CH3:22])[CH2:11][CH2:10]2)=[O:8])=[CH:5][N:4]=[CH:3]1
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1cncc1C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCC(C(=O)c2cncn2C)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A homogeneous yellow solution of tert-butyl 4-(1-methyl-1H-imidazole-5-carbonyl)piperidine-1-carboxylate (10.1 g, 34.4 mmol; Intermediate 58: step b) in DCM (172 mL) was treated with TFA (26.4 mL, 344 mmol) and stirred at room temperature for 2.5 hours. The reaction was concentrated from toluene (2×100 mL), and the resulting clear light amber residue was taken up in DCM (344 mL) and TEA (23.9 mL, 172 mmol). Acetic anhydride (3.91 mL, 41.3 mmol) was added dropwise and the reaction stirred at room temperature for 1 hour. The reaction was concentrated under high vacuum and the residue was purified by FCC using 95:5 DCM/MeOH with 2% TEA as eluent. The combined fractions were concentrated, dissolved in DCM (200 mL), and washed with water (2×200 mL) to remove TEA. The organic layer was dried (Na2SO4), filtered, and concentrated, and the residue was triturated with MTBE (75 mL) at reflux for 15 minutes and then allowed to cool to room temperature. The mixture was filtered and the off-white filter cake was washed with MTBE (2×3 mL) to provide the title compound as an off-white fine powder.