Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][Si](C)(C)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[C:9]([C:3]1[CH:4]=[CH:5][C:6]([NH2:8])=[N:7][C:2]=1[CH3:1])#[CH:10]
Reactant: Cc1nc(N)ccc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1ccc(N)nc1C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a mixture of 6-methyl-5-trimethylsilanylethynyl-pyridin-2-ylamine (450 mg, 1.9 mmol) described in Manufacturing Example 187-1-1 and methanol (5 mL) was added potassium carbonate (390 mg, 2.8 mmol), which was stirred for 30 minutes at the same temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (220 mg, 88%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=2)=[CH:30][CH:29]=1>CN(C)C=O>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:36][CH:35]=2)=[CH:32][CH:33]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: COc1ccc(C2=CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C2=CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 19.4 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1 -dioxide (6.74 g), triethylamine (3.4 cc) and 4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (4.5 g ) in dimethylformamide (70 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 12 hours at this temperature. After purification by flash-chromatography on silica gel, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (60 cc), 2{3-[4-(4-methoxyphenyl)-1,2,3,6-tetrahydro -1-pyridyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (2 g) is obtained, m.p. 178° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]=[C:11]=[O:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]([NH:19][C:18]3[CH:20]=[CH:21][C:15]([O:14][CH3:13])=[C:16]([N:22]4[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]4)[CH:17]=3)=[O:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C=Nc1ccc2c(c1)CCO2
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc3c(c2)CCO3)cc1N1CCN(C)CC1
Yield: 47.3 %

Procedure:
To a stirred solution of 2,3-dihydrobenzofuran-5-yl isocyanate (D3, 0.248 g, 1.5 mmol) in CH2Cl2 (20 ml) was added to a solution of 4-methoxy-3-(4-methylpiperazin-1-yl)aniline (EP 0533268A1, 0.309 g, 1.4 mmol) in CH2Cl2 (10 ml). After 18 hours a precipitate had formed which was filtered off, washed with CH2Cl2 and dried under vacuum to afford the title compound as a cream coloured solid (0.253 g, 47%).
Reaction SMILES: C(O[C:4](=[O:17])[CH:5]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[NH2:18][C:19]([NH2:21])=[O:20].C[O-].[Mg+2].C[O-].CO>>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:4]([NH:18][C:19]([NH2:21])=[O:20])=[O:17])=[CH:15][CH:14]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)C(CC(C)C)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CC(C)CC(C(=O)NC(N)=O)c1ccc(Cl)cc1
Yield: 5.3 %

Procedure:
A mixture of 2-(4-chloro-phenyl)-4-methyl-pentanoic acid ethyl ester (508 mg, 1.99 mmol) and urea (239 mg, 3.99 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 4.28 mL, 2.99 mmol) was heated to reflux for 24 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded [2-(4-chloro-phenyl)-4-methyl-pentanoyl]-urea (28.1 mg, 5.2%) as a white solid: mp 164-165° C.; EI-HRMS m/e calcd for C13H17ClN2O2 (M+) 268.0979, found 268.0972.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]([C:21]1[S:25][N:24]=[CH:23][N:22]=1)[S:7]([C:10]1[C:19]([F:20])=[CH:18][C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:51][CH:52]1[C:61]2[C:56](=[C:57]([CH2:62]O)[CH:58]=[CH:59][CH:60]=2)[CH2:55][N:54]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:53]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]([C:21]1[S:25][N:24]=[CH:23][N:22]=1)[S:7]([C:10]1[C:19]([F:20])=[CH:18][C:13]2[N:14]([CH2:62][C:57]3[CH:58]=[CH:59][CH:60]=[C:61]4[C:56]=3[CH2:55][N:54]([C:64]([O:66][C:67]([CH3:69])([CH3:68])[CH3:70])=[O:65])[CH2:53][CH:52]4[F:51])[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:8])=[O:9]
Reactant: CC(C)(C)OC(=O)N1Cc2c(CO)cccc2C(F)C1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)[nH]c3cc2F)c(OC)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n(Cc4cccc5c4CN(C(=O)OC(C)(C)C)CC5F)c3cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a flask containing N-(2,4-dimethoxybenzyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (11-3) (87 mg, 0.187 mmol), resin bound (PS) TRIPHENYLPHOSPHINE (159 mg, 0.350 mmol), tert-butyl 4-fluoro-8-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-7) (89 mg, 0.316 mmol) & DI-TERT-BUTYL AZODICARBOXYLATE (97 mg, 0.421 mmol) was added THF (2 mL). The reaction mixture was then capped (not under N2) & agitated at room temperature. Followed by LC/MS. After ˜10 min at room temp r×n mixture (clear tan & resin), filtered (to remove resin), then concentrated. Purification by silica gel chromatography (0-50%; EtOAc/Hex; 24 g ISCO); desired fractions concentrated, then the resulting residue was repurified by reverse phase chromatography (10-100% MeCN/H2O; 0.1% TFA in AQ; 20 min gradient; Waters 30×150 mm Sunfire 5 micron C18 column); desired fractions free based (suspended in EtOAc, washed with saturated NaHCO3, then H2O, then brine; organics dried over Na2SO4, filtered & concentrated) to yield tert-butyl 8-((6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-5-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)methyl)-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-8).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[OH:22].[C:26](Cl)(=[O:28])[CH3:27]>>[C:26]([O:22][C:16]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=1[C:14]([NH:13][C:4]1[CH:5]=[C:6]([C:9]([F:10])([F:11])[F:12])[CH:7]=[CH:8][C:3]=1[C:2]([F:1])([F:24])[F:25])=[O:23])(=[O:28])[CH3:27]
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Cl)ccc1O
Reactant: CC(=O)Cl
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Yield: 6.6 %

Procedure:
Using N-[2,5-bis(trifluoromethyl)phenyl] 5-chloro-2-hydroxybenzamide and acetyl chloride as the raw materials, the same operation as the example 96 gave the title compound.
Reaction SMILES: [S:1]1[CH:9]2[C:4]([CH2:5][NH:6][CH2:7][CH2:8]2)=[CH:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:16][CH:17]=1.[C:22]([Si:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)Cl)([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>C(Cl)Cl>[Si:26]([O:10][C:2]1[S:1][C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=C1C=C2CNCCC2S1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](Oc1cc2c(s1)CCNC2)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A mixture of 2.00 g of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one-p-toluenesulfonate, 1.84 g of tert-butyldiphenylchlorosilane, 0.66 g of triethylamine and 7 ml of methylene chloride was stirred at room temperature (20° C.) for 3 hours. The produced 2-(tert-butyldiphenylsilyloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-p-toluenesulfonate was not isolated, and 0.96 g of 2-chlorobenzyl chloride and 1.21 g of triethylamine were added thereto. The mixture was allowed to react at room temperature (20° C.) for 1.5 hours by further stirring and then left to stand overnight to obtain a reaction mixture.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][CH:10]=[C:9](Cl)[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][NH2:8].[Cl:14]C1C=CC=C(Cl)C=1O.ClC1C=CC(O)=CC=1>>[Cl:14][C:11]1[CH:10]=[CH:9][C:3]([O:4][CH2:5][CH2:6][CH2:7][NH2:8])=[CH:2][CH:12]=1
Reactant: Oc1c(Cl)cccc1Cl
Reactant: NCCCOc1c(Cl)cccc1Cl
Agent: Oc1ccc(Cl)cc1
Product: NCCCOc1ccc(Cl)cc1
Yield: 85 %

Procedure:
Intermediate 11 (150 mg, 0.808 mmol, 85% yield) was prepared as a white powder following the procedure described for Intermediate 9 replacing 2,6-dichlorophenol with 4-chlorophenol as starting material. LC-MS (ESI) 186 (M+H), RT=1.41 min (Method B).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[N:5][N:4]=1)[CH3:2].[CH:16]([Cl:19])([Cl:18])[Cl:17].[OH-].[K+]>CN(C=O)C.CO>[Cl:17][C:16]([Cl:19])([Cl:18])[CH:12]([C:11]1[CH:14]=[CH:15][C:8]([C:6]2[O:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=2)=[CH:9][CH:10]=1)[OH:13]
Reactant: CCc1nnc(-c2ccc(C=O)cc2)o1
Reactant: ClC(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CCc1nnc(-c2ccc(C(O)C(Cl)(Cl)Cl)cc2)o1
Temperature: -10 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 4-(5-ethyl-1,3,4-oxadiazol-2-yl)benzaldehyde (1.6 g, 7.9 mmol) in anhydr DMF (7 mL) was added CHCl3 (2.13 g, 17.8 mmol). After cooling to −10° C., a solution of KOH (0.31 g, 5.5 mmol) in anhydr MeOH (1.5 mL) was added dropwise over 20 min. After stirring at −10° C. for 1 hr, the reaction mixture was quenched with 1 M HCl. The solid formed was collected on a Büchner, washed with H2O and dried under vacuum to give 2,2,2-trichloro-1-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)ethanol as a white solid (2.0 g, 80% yield).
Reaction SMILES: [F:1][C:2]1[C:13]([C:14]([OH:16])=O)=[CH:12][C:5]2[N:6]([CH3:11])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.CN1C2C=CC(C(Cl)=O)=CC=2OC1=O.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[C:34]([Cl:40])[CH:33]=1>[Zn].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>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:14]([C:13]2[C:2]([F:1])=[CH:3][C:4]3[O:9][CH2:8][C:7](=[O:10])[N:6]([CH3:11])[C:5]=3[CH:12]=2)=[O:16])=[C:34]([Cl:40])[CH:33]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: CN1C(=O)COc2cc(F)c(C(=O)O)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cn1c(=O)oc2cc(C(=O)Cl)ccc21
Agent: [Zn]
Product: CN1C(=O)COc2cc(F)c(C(=O)Cc3ccc(Br)cc3Cl)cc21

Procedure:
In analogy to Example 49, step 1, 7-fluoro-4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid was converted to the acid chloride and subsequently reacted with 4-bromo-1-bromomethyl-2-chloro-benzene in the presence of zinc and tetrakis(triphenylphosphine)palladium(0) to give the title compound as an off-white solid. MS (m/e)=412.2 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:56][C:57]1[NH:58][C:59]2[CH:65]=[CH:64][CH:63]=[CH:62][C:60]=2[N:61]=1>C(Cl)Cl>[NH:58]1[C:59]2[CH:65]=[CH:64][CH:63]=[CH:62][C:60]=2[N:61]=[C:57]1[NH:56][C:13](=[O:15])[CH:12]([C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Br:1])[CH:3]=1)[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3[nH]2)cc1Br
Yield: 52.9 %

Procedure:
A solution of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (100 mg, 0.266 mmol), triethylamine (110 μL, 0.80 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (187 mg, 0.42 mmol), and 2-aminobenzimidazole (56 mg, 0.42 mmol) in methylene chloride (10 mL) was stirred at 25° C. for 1.5 h. The reaction mixture was partitioned between water and methylene chloride. The organic layer was washed sequentially with a 1N aqueous hydrochloric acid solution (1×10 mL), water (1×10 mL), and a saturated aqueous sodium bicarbonate solution (1×10 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 19/1 chloroform/methanol) afforded N-(1H-benzimidazol-2-yl)-2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (69 mg, 53%) as a white solid: mp>220° C.; EI-HRMS m/e calcd for C22H24BrN3N3OS(M+) 489.722, found 489.727.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.[H-].[Na+].[Cl:20][C:21]1[C:26](Cl)=[N:25][CH:24]=[CH:23][N:22]=1>CN(C=O)C.O>[Cl:20][C:21]1[C:26]([O:17][CH:14]2[CH2:13][CH2:12][N:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH2:16][CH2:15]2)=[N:25][CH:24]=[CH:23][N:22]=1
Reactant: OC1CCN(c2ccc3ccccc3n2)CC1
Reactant: Clc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nccnc1OC1CCN(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 1-(quinolin-2-yl)piperidin-4-ol (see PREPARATION P1.1; 2.0 g, 8.7 mmol) in DMF (30 mL) at room temperature was added sodium hydride (60% wt in mineral oil) (0.47 g, 17.4 mmol) at 0° C. The mixture was stirred at room temperature for 60 min and then 2,3-dichloro-pyrazine (1.2 g, 8.7 mmol) was added. The reaction mixture was heated to 90° C. overnight and then diluted with water (60 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (40 mL) and brine (40 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (10% to 30% EtOAc in petroleum ether) to give the title product (2.0 g, 5.8 mmol, 70% yield) as white solid. ESI-MS (M+1): 341 calc. for C18H12ClN4O 340.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:9]2[C:10](=[O:13])[C:11]=1I)[CH3:5])=[N+:2]=[N-:3].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:9]2[C:10](=[O:13])[C:11]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1ccccc1
Reactant: Cc1cccc2nc(C(C)N=[N+]=[N-])c(I)c(=O)n12
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc2nc(C(C)N=[N+]=[N-])c(-c3ccccc3)c(=O)n12
Temperature: 110 °C

Procedure:
A solution of 2-(1-azidoethyl)-3-iodo-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (100 mg, 0.28 mmol) and phenylboronic acid (48 mg, 0.39 mmol) in 1,4-dioxane (2 mL) was treated with sodium carbonate (45 mg, 0.42 mmol), water (0.50 mL), and dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (2.0 mg, 28 μmol), degassed with nitrogen for 5 minutes, and heated at 110° C. for 18 hours. The reaction mixture was purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min). LCMS for C17H16N5O (M+H)+: m/z=306.1.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]1=O.O=P(Cl)(Cl)[Cl:14]>O>[Cl:14][C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: O=c1cnc2ccccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: Clc1cnc2ccccc2n1

Procedure:
Quinoxalin-2-one (14.62 g, 100 mmol) was added to POCl3 (100 g, 0.65 mmol) and the mixture heated at reflux for 1.5 hours under N2. Upon cooling, the mixture was poured slowly, portionwise onto 700 ml of H2O. The black solution was extracted with CH2Cl2 (2×250 ml). The combined CH2Cl2 portions were washed with H2O, dried over Na2SO4, filtered, and evaporated to give a brown, solid 2-chloroquinoxaline. A portion of said product (4.00 g, 24.3 mmol) was combined with 5 ml of 1 N HCl, and NaN3 (1.89 g, 29.1 mmol) in 220 ml of abs EtOH and heated at reflux for 7 hours. The mixture was allowed to cool overnight, which led to precipitation of yellow-brown needles of tetrazolo[1,5-a]quinoxaline (19).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][O:7][CH3:8].[CH:10](OCC)=[O:11]>>[CH3:1][O:2][C:3](=[O:9])[CH:4]([CH:10]=[O:11])[CH2:5][CH2:6][O:7][CH3:8]
Reactant: CCOC=O
Reactant: COCCCC(=O)OC
Product: COCCC(C=O)C(=O)OC

Procedure:
The title compound was prepared from 4-methoxy-butyric acid methyl ester and ethyl formate employing the procedure set forth in Step 1 of Example 87.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[O:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1
Reactant: OCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCN2CCOCC2)c(F)c1
Temperature: 75 °C
Reaction time: 12 h
Yield: 76.5 %

Procedure:
A mixture of 1,2-difluoro-4-nitrobenzene (1.0 g, 6.29 mmol), 2-morpholinoethanol (1.0 g, 7.62 mmol) and Cs2CO3 in DMF (10 mL) was stirred at 75° C. for 12 h. 30 mL of water was then added and the resulting mixture was extracted with DCM (30 mL×2). The combined organic phases were washed with brine (30 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as yellow oil (1.30 g, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[S:18]1[C:22]([C:23](O)=[O:24])=[CH:21][N:20]=[CH:19]1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:23]([C:22]3[S:18][CH:19]=[N:20][CH:21]=3)=[O:24])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1cncs1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3cncs3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and thiazole-5-carboxylic acid (CAS 14527-41-4) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=353.2 [M+H]+.
Reaction SMILES: ClC1[N:3]=[N:4]C(C)=CC=1.[C:9]1([CH2:15][C:16]#[N:17])C=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2-].[Na+].C1(C(C2N=NC=CC=2)C#N)C=CC=CC=1>C1C=CC=CC=1>[CH3:13][C:12]1[N:4]=[N:3][C:9]([CH2:15][C:16]#[N:17])=[CH:10][CH:11]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: N#CCc1ccccc1
Agent: N#CC(c1ccccc1)c1cccnn1
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccc(CC#N)nn1

Procedure:
To a solution of 6.5 g (0.05 mole) of 3-chloro-6-methylpyridazine and 7.0 g (0.06 mole) of phenylacetonitrile in 50 ml of dry benzene was gradually added 4.0 g of pulverized sodium amide. The mixture was then slowly heated to 80° to 90° C. and maintained at this temperature for one hour. The reaction mixture was thereafter treated in the same manner as in the preparation of 2-phenyl-2-(3-pyridazinyl)-acetonitrile (see Example 1). The resulting product was recrystallized from a mixture of ethanol and isopropyl ether, giving 6.0 g (58% yield) of 2-phenyl-2-(6-methyl-3-pyridazinyl acetonitrile as pale yellow crystals, m.p. 121°-122° C. (decomp.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9]C)=O.O.[NH2:12][NH2:13]>C(O)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([NH:12][NH2:13])=[O:9]
Reactant: NN
Reactant: COC(=O)c1cnccn1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cnccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Methyl 2-pyrazinecarboxylate (I132) (42 g, 304 mmol) was dissolved in ethanol (750 mL) and treated with hydrazine hydrate (22.17 mL, 456 mmol). The solution was stirred at room temperature for 5 minutes whereupon a precipitate started to form. The mixture was cautiously heated to 80° C. for 5 h and cooled to room temperature. Approximately 50% of the solvent was then removed in vacuo, the slurry was heated to reflux and the solution cooled to room temperature overnight. The resulting solid was filtered, washed with a little ethanol, diethyl ether and dried in a vacuum oven to afford product in 39.77 g as beige needles.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[C:12]([NH:21][C:22]2[CH:27]=[C:26]([NH:28][C:29](=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:25]=[CH:24][C:23]=2[Cl:44])=[N:11]1.[C:45](Cl)(=[O:49])[CH2:46][CH2:47][CH3:48].C(OCC)(=O)C>C(#N)C>[C:45]([O:15][C:14]1[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=2[Cl:9])[N:11]=[C:12]([NH:21][C:22]2[CH:27]=[C:26]([NH:28][C:29](=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:25]=[CH:24][C:23]=2[Cl:44])[C:13]=1[N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)(=[O:49])[CH2:46][CH2:47][CH3:48]
Reactant: CCCC(=O)Cl
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2n2cncn2)c1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(Nc2nn(-c3c(Cl)cc(Cl)cc3Cl)c(OC(=O)CCC)c2-n2cncn2)c1
Temperature: 25 °C

Procedure:
20 g of 1-(2,4,6-trichlorophenyl)-3-(2-chloro-5-tetradecanamidoanilino)-4-(1,2,4-triazol-1-yl)-5-oxo-2-pyrazoline (prepared by the method described in U.S. Pat. No. 4,076,533) was suspended in 100 ml of acetonitrile and 3.7 g of butanoyl chloride was added to the mixture, followed by refluxing for 3 hours. After cooling to room temperature, 500 ml of ethyl acetate was added to the reaction mixture and washed several times with water. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated. Upon crystallization of the residue from a solvent mixture of acetonitrile and benzene, 16 g of Coupler (1) was obtained. The melting point of the coupler was 89° to 95° C.