Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2([CH3:11])[CH2:10][NH:9]2)[C:5]([F:12])=[CH:4][N:3]=1.P(C1C=CC=CC=1)(C1C=CC=CC=1)(C1C=CC=CC=1)=O.[N+:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42](Cl)(=[O:44])=[O:43])([O-:35])=[O:34].CN1CCOCC1>C1COCC1.O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2([CH3:11])[CH2:10][N:9]2[S:42]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N+:33]([O-:35])=[O:34])(=[O:43])=[O:44])[C:5]([F:12])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC1(c2cc(Br)ncc2F)CN1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC1(c2cc(Br)ncc2F)CN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of crude 2-bromo-5-fluoro-4-(2-methyl-aziridin-2-yl)-pyridine (3.17 g as a 45% mixture with Ph3PO, 6.17 mmol) and 2-nitrobenzene-1-sulfonyl chloride (1.368 g, 6.17 mmol) in THF (23.15 mL) and H2O (7.72 mL) was added N-methylmorpholine and the reaction mixture was stirred at rt for 1.5 h. Alox neutral (2-3 spatula) was added and the reaction mixture was filtered through celite, washed with DCM and the filtrates were diluted with DCM and 1M aq. NaHCO3 soln. The phases were separated and the aq. phase was reextracted twice with DCM. The combined org. phases were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (heptane:EtOAc 4:1 to 3:1) followed by recrystallization from EtOAc/hexane yielded the title compound as a colourless solid. HPLC RtH4=1.11 min; ESIMS: 416, 418 [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 8.31-8.30 (m, 1H), 8.23 (d, 1H), 7.86-7.77 (m, 3H), 7.68 (d, 1H), 3.28 (s, 1H), 2.78 (s, 1H), 2.09 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C:8]([CH3:14])([CH3:13])[CH2:9][C:10](O)=[O:11].[N+:15]([C:18]1[CH:22]=[CH:21][NH:20][N:19]=1)([O-:17])=[O:16].[H-].[Na+]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[OH:7][C:8]([CH3:14])([CH3:13])[CH2:9][C:10]([N:20]1[CH:21]=[CH:22][C:18]([N+:15]([O-:17])=[O:16])=[N:19]1)=[O:11]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: CC(C)(O)CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(O)CC(=O)n1ccc([N+](=O)[O-])n1
Temperature: 0 °C
Yield: 26.8 %

Procedure:
A solution containing N,N-dimethylformamide (0.22 mL, 2.85 mmol) and tetrahydrofuran (10 mL) was chilled to 0° C. under nitrogen. While stirring, oxalyl chloride (156 μL, 1.80 mmol) was added, gas evolution was observed followed by a white precipitate. The mixture was stirred at 0° C. for 5 min and at 25° C. for 15 min. The mixture was chilled to −5° C. and the 3-hydroxy-3-methyl-butyric acid (224 mg, 1.90 mmol) was added as a solution in tetrahydrofuran (3 mL) and the mixture was allowed to stir for 10 min. 3-Nitro-1H-pyrazole (prepared in example 3, 200 mg, 1.77 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (78 mg, 1.95 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for an additional 10 min, the mixture was added to the 3-hydroxy-3-methyl-butyric acid solution at −5° C. and continued to stir at 0° C. for 2 h. The mixture was diluted with ethyl acetate (100 mL), washed with water (2×25 mL), saturated aqueous brine solution (25 mL), dried over magnesium sulfate and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 15% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 3-hydroxy-3-methyl-1-(3-nitro-pyrazol-1-yl)-butan-1-one (101 mg, 27%) as a clear oil: H1-NMR (400 MHz, CDCl3) δ 1.42 (6H, s), 3.41 (2H, s), 7.05 (1H, d, J=2.8 Hz), 8.34 (1H, d, J=2.8 Hz).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]1[C@@H:24]2[CH2:25][NH:26][CH2:27][CH2:28][N:23]2[C:22](=[O:29])[CH2:21][O:20]1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([N:26]3[CH2:27][CH2:28][N:23]4[C@H:24]([CH2:19][O:20][CH2:21][C:22]4=[O:29])[CH2:25]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1COC[C@@H]2CNCCN12
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: O=C1COC[C@@H]2CN(C3CN(C(c4ccccc4)c4ccccc4)C3)CCN12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.3 %

Procedure:
To a solution of 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, ˜0.65 mmol) and (9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (0.65 mmol), in methanol (10 mL) was added a solution of sodium cyano borohydride (125 mg, 2.0 mmol) and zinc chloride (135 mg, 1.0 mmol) in methanol (20 mL). The reaction mixture was stirred at RT for 15 min and then the solvent was removed by evaporation. The residue was partitioned between ethyl acetate (50 mL) and water (20 mL). The organic solution was washed with brine and then dried over Na2SO4. The solvent was removed by evaporation and the residue was dissolved in a mixture of acetonitrile (10 mL), acetic acid (100 mg) and water (10 mL). The product was purified by means of reversed phase chromatography using a mixture of acetonitrile and aqueous 0.1 M ammonium acetate. The proper fractions were combined and concentrated on a rotavapor. The aqueous residue was extracted with ethyl acetate and the organic solution was dried over Na2SO4. The solvent was removed by evaporation and there was obtained 170 mg (69%) of (9aS)-8-[1-(diphenylmethyl)azetidin-3-yl]hexahydropyrazino-[2,1-c][1,4]oxazin-4(3H)-one. 1H NMR (400 MHz, CDCl3): 1.6-1.7 (m, 1H), 1.8-1.9 (m, 1H), 2.6 (d, 1H), 2.7-2.8 (m, 21-1), 2.8-2.9 (m, 2H), 3.0 (qn, 1H), 3.3-3.7 (m, 4H), 3.9 (dd, 1H), 4.0-4.2 (qt, 2H), 4.4 (s, 1H), 4.5 (dd, 1H), 7.2 (t, 2H), 7.3 (m, 4H), 7.4 (m, 4H); LCMS: m/z 378 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:20]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: Cc1ccccc1C
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(Cl)c(Cl)cc2N1

Procedure:
Compound 1 was prepared from 4,5-dichlorophenylenediamine (Compound J18) (172 mg, 0.97 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (K1) (289 mg, 0.97 mmol) by refluxing in xylene according to the general procedure M. Obtained as an off-white solid (310 mg). MS (ISP) 382.2 [(M+H)+], 384 [(M+2+H)+] and 386 [(M+4+H)+]; mp 241° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1)(=[O:19])=[O:18].C(N(CC)CC)C.O>C(#N)C>[Br:1][C:2]1[C:3]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)(=[O:18])=[O:19])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: NCCCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(S(=O)(=O)NCCCCCNc2nc(Cl)ncc2Br)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 1.2 g (5.3 mmol) of 5-bromo-2,4-dichloro-pyrimidine in 30 ml of acetonitrile is added to a solution of 1.5 g (5.2 mmol) of N-(5-amino-pentyl)-3-nitro-benzenesulfonamide in 50 ml of acetonitrile. The reaction mixture is mixed with 1.0 ml (7.2 mmol) of triethylamine and stirred for 17 hours at room temperature. After water (50 ml) is added, it is extracted (2×) with ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate 2:1, Flashmaster II). 1.5 g (3.1 mmol, corresponding to 60% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[Br:71][C:72]1[CH:77]=[C:76]([Cl:78])[CH:75]=[CH:74][C:73]=1I.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:71][C:72]1[CH:77]=[C:76]([Cl:78])[CH:75]=[CH:74][C:73]=1[N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:21]=[C:12]([S:9]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]1=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Reactant: Clc1ccc(I)c(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(Cl)cc2Br)cc1
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 79.2 %

Procedure:
A microwave vial was charged with INTERMEDIATE M (0.500 g, 1.198 mmol), xantphos (0.139 g, 0.240 mmol), 2-bromo-4-chloro-1-iodobenzene (0.570 g, 1.796 mmol), Pd2(dba)3 (0.110 g, 0.120 mmol) and sodium tert-butoxide (0.230 g, 2.395 mmol). The mixture was diluted with toluene (11.98 mL), and purged with nitrogen, and stirred at 130° C. in the microwave for 15 minutes. After completion, the reaction was diluted with water, and washed with DCM. The organics were dried using a phase separator and concentrated under a vacuum. The material was then purified via silica gel MPLC, eluting with 0 to 50% ethyl acetate in heptanes to yield 4-(2-bromo-4-chlorophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.576 g, 0.949 mmol) as a light yellow solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH:10]1[CH:14]=[CH:13][CH2:12][C:11]1=[O:15])([OH:3])=[O:2].[OH-].[Na+]>>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2]
Reactant: O=C(O)CCCC/C=C\C1C=CCC1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCC/C=C\C1=CCCC1=O

Procedure:
A solution of 3 g. of crude 2-(6-carboxy-2-cis-hexenyl)cyclopent-3-en-1-one (Example 17) in 100 ml. of 2% sodium hydroxide is stirred at 80° C. under nitrogen for 1.5 hours. The cooled solution is acidified to Congo Red and extracted with ether. The ethereal extracts are dried over sodium sulfate and evaporated at reduced pressure to afford the product.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N12CCCN=C1CCCCC2.[I-].[K+].Cl[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1>O.C(#N)C>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1)=[O:5]
Reactant: N#Cc1ccc(OCCCCCCCCCl)cc1
Reactant: O=C(O)c1cc(O)ccc1O
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1ccc(OCCCCCCCCOC(=O)c2cc(O)ccc2O)cc1
Yield: 83.5 %

Procedure:
A mixture of 2,5-dihydroxybenzoic acid (4.2 g; 27.5 mmol), 1.8-diazabicyclo[5.4.0]undec-7-ene (4.2 g; 27.5 mmol), potassium iodide (41.0 g; 247 mmol), p-[(8-chlorooctyl)oxy]benzonitrile (6.6 g; 25 mmol) and acetonitrile (100 ml) was heated under reflux for 72 h. The reaction mixture was cooled, poured into water (500 ml) and extracted with ethyl acetate (3×150 ml). The combined organic layers were washed with 1N-hydrochloric acid (150 ml) and water (2×150 ml), dried over magnesium sulphate and filtered. The solvent was removed in vacuo. The residue was purified by column flash chromatography on silica gel using a toluene/ethyl acetate 80:20 as eluent to give 8.0 g (84%) of 8-(p-cyanophenoxy)octyl 2,5-dihydroxybenzoate.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=O)[CH:10]=[CH:9][C:7](=O)[C:5]=2[CH:6]=1.C1(=O)OC(=O)C2=CC=CC=C12>>[CH:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:7]=2)[CH:3]=[CH:2][CH:1]=1
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: O=C1OC(=O)c2ccccc21
Product: c1ccc2ccccc2c1

Procedure:
Naphthoquinone having a purity of higher than 95% is separated from an aqueous slurry of naphthoquinone and phthalic acid prepared by contacting, with an aqueous medium, a reaction mixture gas containing naphthoquinone and phthalic anhydride formed by a catalytic vapor phase oxidation of naphthalene. An extraction of naphthoquinone is carried out with a chain or cyclic saturated hydrocarbon at 60° to 110° C. under the condition adjusting pH to 1.2 to 5 and substantially dissolving phthalic acid in the aqueous phase and leaving resinous materials as a bottom.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)([CH3:16])[C:12]([O:14]C)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)([CH3:16])[C:12]([OH:14])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(C)(CCNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(C)(C(=O)O)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 98.9 %

Procedure:
Methyl 4-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)-2-methylbutanoate (720 mg, 2.11 mmol) was dissolved in THF (4.2 mL) and water (1.8 mL). The mixture was treated with LiOH—H2O (265 mg, 6.32 mmol) and allowed to stir overnight to completion by LCMS analysis. The mixture was diluted with water and washed twice with diethyl ether (discarded). The aqueous was treated with 3M HCl solution until a pH of about 2 to about 3 (white ppt) and extracted with ethyl acetate several times. The combined organic portions were washed with water, then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford 4-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)-2-methylbutanoic acid as a colorless oil (684 mg, 99%). LCMS (APCI+) [M+H]+ 326.0; Rt: 2.26 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:23])([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH2:9][NH:10][C:11](=[O:14])[CH2:12]Cl)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[CH2:9][NH:10][C:11](=[O:14])[CH2:12][O:23]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C(O)(CNC(=O)CCl)c2ccc(Br)cc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: COc1cccc(C2(c3ccc(Br)cc3)CNC(=O)CO2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a solution of N-[2-(4-bromo-phenyl)-2-hydroxy-2-(3-methoxy-phenyl)-ethyl]-2-chloro-acetamide (3.67 g, 9.2 mmol), in benzene (205 mL) at room temperature was added t-BuOK (4.54 g, 40.5 mmol). The reaction mixture was stirred at room temperature for 2 h. To the mixture was added water (40 mL) and the aqueous layer was washed with CH2Cl2 (2x50 mL). The combined organic extracts were dried over MgSO4 and concentrated. Purification by flash chromatography with hexanes/EtOAc (3:1) afforded 3.34 g of 6-(4-bromo-phenyl)-6-(3-methoxy-phenyl)-morpholin-3-one. 1HNMR (400 MHz, CDCl3) δ 7.46-7.41 (comp, 2H), 7.27-7.17 (comp, 2H), 6.894.70 (comp, 3H), 6.69 (br, 1H), 4.10 (s, 2H), 3.93-3.80 (comp, 2H), 3.76 (s, 3H); MS (M+1) 362.1, 364.1.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([S:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=12.[F:17][C:18]1[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[C:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:24]=[CH:23]2.[F-].[K+].COCCOC.O.CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]([S:12][C:4]1[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]2=[C:2]([C:19]2[C:18]([F:17])=[C:27]3[C:22]([CH:23]=[CH:24][C:25]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:26]3)=[CH:21][CH:20]=2)[N:3]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2F)OC1(C)C
Reactant: CC(C)(C)Sc1nc(Br)c2c(N)nccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)Sc1nc(-c2ccc3ccc(-c4ccccc4)nc3c2F)c2c(N)nccn12

Procedure:
Into a 10 mL microwave vessel was added 1-bromo-3-tert-butylsulfanyl-imidazo[1,5-a]pyrazin-8-ylamine (23 mg, 0.000076 mol), 8-fluoro-2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (0.032 g, 0.000092 mol), potassium fluoride (0.0089 g, 0.00015 mol), DME (2 mL, 0.02 mol), H2O (0.3 mL, 0.02 mol), DMF (0.34 mL, 0.0044 mol) and the reaction mixture was degassed 3×. Pd(PPh3)4 (0.02 g, 0.00002 mol) was then added to the reaction mixture and the vessel was sealed. The reaction mixture was microwaved on 300 watts, 100° C. for 30 min. Reaction mixture was concentrated in vacuo. Purification by Gilson HPLC eluting with 10→75% acetonitrile: H2O afforded the compound with pinacole impurity. The compound was then passed through a 2 g silica gel cartridge eluting with 6% EtOAc in hexanes followed by 4% MeOH in DCM to afford the pure compound as a yellow solid. 1H NMR (400 MHz, CD3OD-d4): δ=1.43 (s, 9H), 7.22 (d, J=5.05 Hz, 1H), 7.50-7.59 (m, 3H), 7.68-7.74 (m, 1H), 7.90-7.96 (m, 2H), 8.20 (d, J=8.59 Hz, 1H), 8.26 (d, J=7.83 Hz, 2H), 8.51 (dd, J=8.84, 1.26 Hz, 1H). MS(ES+):m/z 444.17 (100)[MH+]. HPLC: tR=3.24 min (Open Lynx polar—5 min).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:4]=2[CH:3]=1.[CH3:14][NH:15][NH2:16]>>[CH3:14][N:15]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:4]=2[CH:3]=1)[NH2:16]
Reactant: CNN
Reactant: Clc1cc2c(nn1)CCCCCC2
Product: CN(N)c1cc2c(nn1)CCCCCC2
Reaction time: 24 h

Procedure:
A suspension of 9.8 g of 3-chloro-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine in 50 cc of methylhydrazine is stirred in an oil bath of 45° for 24 hours. The material dissolves completely during heating. After the reaction is complete, the mixture is evaporated to dryness, and the crude crystalline title compound is recrystallized twice from ether. The title compound has a
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21]OS(C)(=O)=O)[CH2:10]1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O>[C:1]([CH2:21][C@@H:11]1[CH2:10][C@@H:9]([CH2:8][C:7]2[CH:27]=[CH:28][C:29]([Cl:30])=[C:5]([Cl:4])[CH:6]=2)[CH2:13][N:12]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[N:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](Cc2ccc(Cl)c(Cl)c2)C[C@H]1COS(C)(=O)=O
Reactant: [C-]#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](Cc2ccc(Cl)c(Cl)c2)C[C@H]1CC#N
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 98.3 %

Procedure:
Sodium cyanide (4.3 g, 87.4 mmol) was added to a solution of crude (2S,4R)-4-(3,4-dichlorobenzyl)-1-tert-butoxycarbonyl-2-(methanesulfonyloxymethyl)pyrrolidine (7.7 g, 17.5 mmol) in dry DMSO (120 mL) and the mixture was heated at 80° C. with stirring for 3.5 hrs. The reaction mixture was cooled and worked up between EtOAc and aqueous Na2CO3. Vacuum drying of the product afforded 6.34 g (17.2 mmol) of (2S,4R)-2-(cyanomethyl)-4-(3,4-dichloro-benzyl)-1-tert-butoxycarbonylpyrrolidine as an amber oil.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>CN(C)C=O>[CH3:15][N:16]([CH3:18])[CH:17]=[CH:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11]
Reactant: CCC(=O)c1ccc(=O)[nH]c1C
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CCC(=O)c1ccc(=O)[nH]c1C=CN(C)C

Procedure:
A mixture containing 25 g of 6-methyl-5-(n-propanoyl)-2-(1H)-pyridinone, 200 ml of dimethylformamide and 25 ml of dimethylformamide dimethyl acetal was heated on a steam bath for 5 and 1/2 hours and the dimethylformamide was removed by heating the reaction mixture on a rotary evaporator. The residue was refluxed with 100 ml of ethanol, the mixture cooled, and the yellow solid was collected, washed with ethanol and dried in an oven at 90°-95° C. to yield 12.8 g of 6-(2-dimethylaminoethenyl)-5-(n-propanoyl)-2(1H)-pyridinone, m.p. 204°-206° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[I-:15].[Na+].CNCCNC>O1CCOCC1.CCOC(C)=O.[Cu]I>[CH3:1][O:2][C:3](=[O:14])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([I:15])=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc(Br)cc1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)c1ccc(I)cc1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To 0.45 g (1.7 mmol) 2-(4-bromo-phenyl)-2-methyl-propionic acid methyl ester (WO2008/002671) in 1.5 mL 1,4-dioxane are added 34 mg (0.18 mmol) copper(I) iodide, 0.53 g (3.5 mmol) sodium iodide and 0.04 mL (0.35 mmol) N,N′-dimethylethylendiamine under inert gas atmosphere. The mixture is stirred at 110° C. for 12 h. After cooling, the mixture is diluted with EtOAc and washed with 5% ammonia and water. The organic layer is dried over sodium sulphate. The solvent is evaporated to yield the desired product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[I:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[I:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][O:10][C:7]1[CH:8]=[CH:9][C:4]2[CH:3]=[CH:2][O:1][C:5]=2[CH:6]=1
Reactant: Oc1ccc2ccoc2c1
Reactant: BrCc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Ic1cccc(COc2ccc3ccoc3c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 1-benzofuran-6-ol (1.0 g, 7.5 mmol) and 3-iodobenzylbromide (2.7 g, 9.0 mmol) in DMF (10 mL) was added potassium carbonate (1.5 g, 11.0 mmol). The reaction mixture was stirred under nitrogen at room temperature for 3 days. The reaction was diluted with ethyl acetate, washed with water (2×) and brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified on a silica gel column, eluting with ethyl acetate (10-50%) in hexane. The final product was collected as a slightly yellow viscous oil.