Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[NH:14][C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)[C:9]#[N:10])([O-:5])=[O:4].[CH3:29]N(C=O)C>O>[CH3:29][N:14]([C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)[C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[N+:3]([O-:5])=[O:4]
Reactant: CC1(C)CCC(C)(C)c2cc(Nc3ccc(C#N)cc3[N+](=O)[O-])ccc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN(c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (60%, 6.44 mmol) is added portionwise to a solution of 3-nitro-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylamino)benzonitrile (30, R4=CH3, 4.29 mmol) in DMF (15 mL) at 0° C. The reaction mixture is slowly warmed up to room temperature and stirred for 1 h. To the mixture is added dropwise Mel (6.44 mmol) and the reaction mixture is stirred at room temperature for 5 h. The mixture is diluted with H2O and extracted with Et2O. The organic layer is dried over MgSO4 and evaporated in vacuo. The resulting solid is washed with hexane to give (31) (R4=CH3).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:19]([Mg]Br)#[CH:20]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]([OH:9])[C:19]#[CH:20])[CH:10]=[CH:11][C:12]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=O)ccc1N1CCCCC1
Reactant: C#C[Mg]Br
Product: C#CC(O)c1ccc(N2CCCCC2)c(C(C)(C)C)c1

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 1 g (4 mmol) of 3-tert-butyl-4-piperidin-1-ylbenzaldehyde with 12 ml (6 mmol) of a 0.5M solution of ethynylmagnesium bromide. 890 mg of 1-(3-tert-Butyl-4-piperidin-1-ylphenyl)prop-2-yn-1-ol are obtained in the form of a colourless oil (yield=82%).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]3[CH:21]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1>>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]3[CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: OC(c1cn2cc(C(F)(F)F)ccc2n1)C1CCCCC1
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2cn3cc(C(F)(F)F)ccc3n2)C2CCCCC2)cc1
Yield: 0.2 %

Procedure:
Using cyclohexyl[6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]methanol (1.1 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.94 g) synthesized in Example 2(2) and in the same manner as in Example 4, the title object compound (3.0 mg, 2%) was obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:18]#[N:19])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([O:12]C)=[O:11].[Li+].[OH-]>CO.O>[Cl:1][C:2]1[N:3]=[C:4]([C:18]#[N:19])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1ccc(C)c(-c2[nH]c(C#N)nc2Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(C#N)nc1Cl
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of methyl 3-(4-chloro-2-cyano-1H-imidazol-5-yl)-4-methylbenzoate (compound 234.4, 130 mg, 0.47 mmol) in methanol (4 mL). Then a solution of LiOH (45.4 mg, 1.90 mmol) in water (2 mL) was added to the reaction. The reaction mixture was stirred overnight at 30° C., then was concentrated under reduced pressure. The pH of the solution was adjusted to 3 with hydrogen chloride (1M) and was concentrated under reduced pressure. Methanol (5 mL) was added to the residue. The salt was filtered off, and the filtrate was concentrated under reduced pressure to give 150 mg (crude) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[F:39])[CH2:5][N:6]1[C:15](=[O:16])[C:14]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][C:20]=3[S:19](=[O:33])(=[O:32])[N:18]=2)=[C:13]([OH:34])[C@H:12]2[C@@H:7]1[C@H:8]1[CH2:35][C@@H:11]2[CH2:10][CH2:9]1.[C:40](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[F:39])[CH2:5][N:6]1[C:15](=[O:16])[C:14]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([N:27]([CH3:40])[S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][C:20]=3[S:19](=[O:33])(=[O:32])[N:18]=2)=[C:13]([OH:34])[C@H:12]2[C@@H:7]1[C@H:8]1[CH2:35][C@@H:11]2[CH2:10][CH2:9]1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)c(F)c3)C1=O)N2
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)c(F)c3)C1=O)N2)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
N-{3-[(1R,2S,7R,8S)-3-(3,4-Difluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (prepared as described in Example 16, 114 mg, 0.20 mmol) was dissolved in N,N-dimethylformamide (7 mL). Potassium carbonate (55 mg, 0.40 mmol) and iodomethane (0.014 mL, 0.22 mmol) were added sequentially. The reaction was stirred at 25° C. for 18 h. The reaction was quenched via the addition of 1.0M aqueous hydrochloric acid solution (20 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with saturated aqueous brine solution (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. Purification by flash column chromatography (Teledyne Isco RediSep column; 0 to 20% ethyl acetate in dichloromethane) afforded the desired product, N-{3-[(1R,2S,7R,8S)-3-(3,4-difluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-N-methyl-methanesulfonamide (94 mg, 0.06 mmol, 77%) as a white powder. 1H NMR (400 MHz, CDCl3) δ: 1.42-1.76 (6H, m), 2.51-2.54 (1H, m), 2.84-2.88 (2H, m), 3.07 (3H, s), 3.38 (3H, s), 3.47-3.49 (1H, m), 5.07-5.10 (2H, m), 6.96-7.16 (3H, m), 7.72-8.01 (3H, m). LC-MS (ESI) calcd for C26H26F2N4O6S2 592.63, found 593.4 [M+H+].
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH:35]([C:37]1([C:43]([OH:45])=[O:44])[CH2:42][CH2:41][CH2:40][O:39][CH2:38]1)=[CH2:36].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1.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]>[OH:32][C@@H:28]([CH:29]([CH3:31])[CH3:30])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2](/[CH:36]=[CH:35]/[C:37]4([C:43]([OH:45])=[O:44])[CH2:42][CH2:41][CH2:40][O:39][CH2:38]4)=[CH:3][CH:4]=3)[N:9]=2)[CH3:13])=[O:16])[NH:18]1)=[O:34])=[O:33]
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Reactant: C=CC1(C(=O)O)CCCOC1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/C4(C(=O)O)CCCOC4)cc3n2)N1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (600 mg, 1.122 mmol), 3-vinyl-tetrahydro-pyran-3-carboxylic acid (175.3 mg, 1.122 mmol), tri(o-tolyl)phosphine (68.3 mg, 0.224 mmol) and triethylamine (0.47 mL, 3.366 mmol) in 1,4-dioxane (15 mL) was degassed by bubbling nitrogen through for 5 minutes then warmed to 50° C. and treated with tris(dibenzylideneacetone)dipalladium(0) (102.7 mg, 0.112 mmol). After stirring at 100° C. for 45 minutes the reaction was cooled to room temperature, filtered through a pad of Celite, which was rinsed with ethyl acetate. The volatiles were removed in vacuo to provide crude title compound as an orange foam that was used without further purification. LCMS (m/z) 610.2 [M+H], Tr=1.97 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.C(N(CC)CC)C.Cl[CH2:18][N:19]([C:26](=[O:28])[CH3:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:26]([N:19]([CH2:18][N:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]1=[O:9])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)N(CCl)c1ccccc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(Cn1cc(Cl)cnc1=O)c1ccccc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
5-Chloropyrimidin-2-one hydrochloride (3.8 mmol) and triethylamine (7.6 mmol) was stirred together in CH2Cl2 (30 ml) for 10 minutes before a solution of N-chloromethyl acetanilide (see Preparation 16) (3.8 mmol) in CH2Cl2 (5 ml) was added. The mixture was stirred at 40° C. for 2 hours before the solvent was distilled off and the residue washed with water and ether. Yield 0.3 g, (28%) M.p. 150°-155° C. (decomp) (CH2Cl2 /pet. ether) 1H NMR (CDCl3, δ): 1.90 (CH3), 5.60 (CH2), 6.9-7.4 (Ph), 8.18 and 8.42 (H-4, H-6, J3Hz). IR (KBr) 1670-1680 cm-1 (CO).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.Cl.Cl.[CH2:20]([O:22][C:23]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:27]([O:36][CH2:37][CH3:38])=[CH:26][C:24]=1[NH2:25])[CH3:21]>>[CH2:20]([O:22][C:23]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:27]([O:36][CH2:37][CH3:38])=[CH:26][C:24]=1[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1)[CH3:21]
Reactant: CCOc1cc(N2CCOCC2)c(OCC)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Agent: Cl
Product: CCOc1cc(N2CCOCC2)c(OCC)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2,5-diethoxy-4-morpholinoaniline dihydrochloride (98 mg, 0.290 mmol) similar to Example 117 and isolated as a brown oil (3 mg, 3%). 1H NMR (CDCl3): 9.64-9.63 (m, 1H), 8.74-8.69 (m, 2H), 7.42-7.38 (m, 1H), 7.33 (s, 1H), 6.83 (s, 1H), 6.60 (s, 1H), 4.13 (q, J=7.2 Hz, 4H), 3.92-3.89 (m, 4H), 3.14-3.11 (m, 4H), 1.26 (t, J=7.2 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)=[N:13]2)=[N:6][CH:7]=1.[O:28]1CCC[CH2:30][CH:29]1OCCO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl.C1COCC1>[OH:28][CH2:29][CH2:30][O:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)=[N:13]2)=[N:6][CH:7]=1
Reactant: OCCOC1CCCCO1
Reactant: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(O)cn4)c3)n2)cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(OCCO)cn4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
252 mg of 2-[3-(5-hydroxypyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one (0.7 mmol) are suspended in abs. THF under a protective-gas atmosphere in a 25 ml three-necked flask, 0.19 ml of 2-(tetrahydropyran-2-yloxy)ethanol (1.4 mmol) and 367 mg of triphenylphosphine (1.4 mmol) are added, and the mixture is stirred at RT for 30 min. 275 μl of diisopropyl azodicarboxylate (1.4 mmol) are subsequently added dropwise, and the reaction mixture is stirred at RT for a further 2 h. For work-up, the reaction mixture is diluted with 20 ml of dichloromethane, washed with 10 ml of water, dried over sodium sulfate, evaporated to dryness and purified by chromatography. (silica gel: MTB ether->DCM->DCM: 30% of MeOH). The THP-protected product is stirred at RT for 20 h in 5 ml of 4 N HCl in dioxane. The reaction solution is evaporated to dryness and crystallised from methanol/diethyl ether, giving “A294”; ESI 405; m.p. 182-3° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11](=O)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.C(OC([NH:26][CH2:27][C:28]([NH:30][C@H:31]1[CH2:35][N:34](C(OC(C)(C)C)=O)[C@H:33]([C:43](O)=[O:44])[CH2:32]1)=[O:29])=O)(C)(C)C>>[NH2:26][CH2:27][C:28]([NH:30][C@H:31]1[CH2:35][NH:34][C@H:33]([C:43]([NH:1][C:2]2[NH:3][C:4]3[CH:10]=[C:9]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:44])[CH2:32]1)=[O:29]
Reactant: Nc1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: NCC(=O)N[C@H]1CN[C@H](C(=O)Nc2nc3ccc(Cc4ccccc4)cc3[nH]2)C1

Procedure:
2-Amino-5-benzoylbenzimidazole(J. Med. Chem., 1984, 27, 914-917) was reduced according to Compounds M73(A,B), coupled with trans-4-(N-tert-butoxycarbonylglycyl)amino-N-tert-butoxycarbonyl-L-proline and deprotected according to Compound M1.
Reaction SMILES: C1C2C(COC([CH2:18][C:19]([N:21]3[CH2:25][C:24]([F:27])([F:26])[CH2:23][C@@H:22]3[C:28]([O:30]C)=O)=[O:20])=O)C3C(=CC=CC=3)C=2C=CC=1.[NH:32]1CCCCC1>CO>[F:26][C:24]1([F:27])[CH2:25][N:21]2[C:19](=[O:20])[CH2:18][NH:32][C:28](=[O:30])[C@@H:22]2[CH2:23]1
Reactant: COC(=O)[C@H]1CC(F)(F)CN1C(=O)CC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: C1CCNCC1
Solvent: CO
Product: O=C1NCC(=O)N2CC(F)(F)C[C@@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with (R)-methyl 1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)acetyl)-4,4-difluoropyrrolidine-2-carboxylate (1.10 g, 2475 μmol) and 25 mL MeOH. Piperidine (1225 μl, 12375 μmol) was added, and the mixture was stirred at RT overnight. The mixture was concentrated and purified by silica gel chromatography, DCM in 90/10 DCM/MeOH to provide (S)-7,7-difluoro-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione as a white solid. GC/MS: [M+H]=191.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[N:14]=2)[C:9](=[O:17])[C:8]([C:18]([OH:20])=O)=[CH:7]1)=[O:2].[NH2:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1>CN(C)C=O>[CH:1]([O:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[N:14]=2)[C:9](=[O:17])[C:8]([C:18]([NH:21][C:22]2[NH:26][N:25]=[N:24][N:23]=2)=[O:20])=[CH:7]1)=[O:2]
Reactant: Cc1ccc2c(=O)c(C(=O)O)cn(CCOC=O)c2n1
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Product: Cc1ccc2c(=O)c(C(=O)Nc3nnn[nH]3)cn(CCOC=O)c2n1
Reaction time: 1 h

Procedure:
1(2-formyloxyethyl)-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.3 g) and N,N'-carbonyldiimidazole (0.8 g) in dimethylformamide (25 ml) were heated at 80° for 5 hours. 5-Amino-1H-tetrazole (0.45 g) was added and the mixture was stirred at 80° for 1 hour. The solid was collected and dried, m.p. 268.5°-269° (d), (40%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([C:11](O)=[O:12])=[CH:8][C:7]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[N:6][C:5]=2[N:4]([CH:27]([CH3:29])[CH3:28])[N:3]=1.[NH2:30][CH2:31][C:32]1[C:33](=[O:40])[NH:34][C:35]([CH3:39])=[CH:36][C:37]=1[CH3:38].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O>[Br:1][C:2]1[C:10]2[C:9]([C:11]([NH:30][CH2:31][C:32]3[C:33](=[O:40])[NH:34][C:35]([CH3:39])=[CH:36][C:37]=3[CH3:38])=[O:12])=[CH:8][C:7]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[CH:18][CH:19]=3)=[N:6][C:5]=2[N:4]([CH:27]([CH3:29])[CH3:28])[N:3]=1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)n1nc(Br)c2c(C(=O)O)cc(-c3ccc(CN4CCOCC4)cc3)nc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)nc3c2c(Br)nn3C(C)C)c(=O)[nH]1
Reaction time: 12 h
Yield: 39 %

Procedure:
A solution of 3-bromo-1-isopropyl-6-(4-(morpholinomethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.8 g, 1.74 mmol) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (0.531 g, 3.49 mmol) in DMSO (8 mL) and was stirred at room temperature for 15 min. Then PYBOP (1.36 g, 2.62 mmol) was added to it and stirring was continued for 12 hr. After completion of the reaction, reaction mass was poured into ice to obtain solid, which was filtered and solid was purified by silica gel column chromatography to obtain the desired compound (39% yield). LCMS: 593.20 (M+1)+; HPLC: 97.49% (@ 254 nm) (Rt;5.338); 1H NMR (DMSO-d6, 400 MHz) δ 11.48 (bs, 1H), 8.67 (t, 1H, J=4.8 Hz), 8.18 (d, 2H, J=8.4 Hz), 7.73 (s, 1H), 7.47 (d, 2H, J=8.4 Hz), 5.87 (s, 1H), 5.33-5.30 (m, 1H), 4.40 (d, 2H, J=4.4 Hz), 3.58 (bs, 4H), 3.53 (s, 2H), 2.38 (bs, 4H), 2.26 (s, 3H), 2.11 (s, 3H), 1.52 (d, 6H, J=6.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:15][C:16](=O)[CH2:17][C:18](=O)[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH3:15][C:16]1[CH:17]=[C:18]([CH3:19])[N:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:2]2[N:1]=1
Reactant: COC(=O)c1c(N)[nH]c2ccccc12
Reactant: CC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: COC(=O)c1c2ccccc2n2c(C)cc(C)nc12
Yield: 75.6 %

Procedure:
A stirred solution of methyl 2-aminoindole-3-carboxylate (I. Forbes et al, J. Chem. Soc. Perkin 1, 1992, 275) (0.25 g, 0.0013 mole) in xylene (5 ml) was treated with 2,4-pentanedione (0.13 g, 0.0013 mole) and a few crystals of 4-toluenesulphonic acid and heated under reflux for 2 h. The mixture was concentrated in vacuo and the residue dissolved in chloroform (20 ml), washed with water (2×20 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound as a brown solid (0.25 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14](Cl)=[O:15].[Cl:17][C:18]1[CH:31]=[C:30]([NH2:32])[CH:29]=[CH:28][C:19]=1[O:20][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25].ClCCl.CO.N>>[Cl:17][C:18]1[CH:31]=[C:30]([NH:32][C:14](=[O:15])[C:13]#[C:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[Cl:1])[CH:29]=[CH:28][C:19]=1[O:20][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25]
Reactant: O=C(Cl)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1Cl

Procedure:
Prepared analogously to Example 4.1.d. from (2-chloro-4-trifluoromethylphenyl)propynoic acid chloride and [2-(2-chloro-4-aminophenoxy)ethyl]diethylamine. Yield: 0.26 g (27.5% of theory); C22H21Cl2F3N2O2 (M=473.32); calc.: molecular ion peak (M+H)+: 473/475; found: molecular ion peak (M+H)+: 473/475; Rf value: 0.5 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: C([O:8]C1C=CC(C(=O)C)=CC=1CO)C1C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([C:42](=[O:44])[CH3:43])[CH:31]=[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:35]([O:34][C:32]1[CH:31]=[C:30]([C:42]([CH:43]=[O:8])=[O:44])[CH:29]=[C:28]([O:27][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:33]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(CO)c1
Product: O=CC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1

Procedure:
The title compound was prepared as a hydrate by the process of Description 54, replacing 1-(4-benzyloxy-3-hydroxymethylphenyl)ethanone. by 1-(3,5-dibenzyloxyphenyl)ethanone. γ(CDCl3) 6.40 (2H, s) 5.00 (4H, s), 2.40-3.50 (14H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[C:18]([F:22])[C:19]([F:21])=[CH:20][C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[F:21][C:19]1[C:18]([F:22])=[CH:17][C:15]2=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=[C:14]2[CH:20]=1
Reactant: C#CCCn1nc2cc(F)c(F)cc2n1
Reactant: Brc1ccccn1
Product: Fc1cc2nn(CCC#Cc3ccccn3)nc2cc1F
Yield: 65517.2 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (50 mg, 0.32 mmol) and 2-(but-3-ynyl)-5,6-difluoro-2H-benzo[d][1,2,3]triazole (60 mg, 0.29 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 54 mg (0.19 mol, 66%) of 5,6-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid (M.P.=131-132° C.).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:15])=[C:7]([F:14])[CH:8]=2)[N:3]=1.[CH:16](OCC)(OCC)OCC>>[Cl:1][C:2]1[C:11]2[N:10]([CH:16]=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][C:6]([F:15])=[C:7]([F:14])[CH:8]=2
Reactant: NNc1nc2cc(F)c(F)cc2nc1Cl
Reactant: CCOC(OCC)OCC
Product: Fc1cc2nc(Cl)c3nncn3c2cc1F
Temperature: 25 °C

Procedure:
A mixture consisting of 5.99 g. (0.026 mole) of 2-chloro-6,7-difluoro-3-hydrazinoquinoxaline and 30 ml. (0.18 mole) of triethyl orthoformate was heated at 100° C. for a period of 24 hours to give a red-brown solid. The resulting slurry was then cooled to room temperature and filtered, and the recovered product subsequently washed with diethyl ether to ultimately afford 5.15 g. (82%) of pure 4-chloro-7,8-difluoro-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. >210° C. (decomp.). Mass Spectrum: m/e, 242/240 (P+).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[K].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:21]>CC(C)=O>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:21])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: COc1ccc(C(=O)Cc2cc([N+](=O)[O-])ccc2O)cc1
Agent: [K]
Solvent: CC(C)=O
Product: CCCCC(=O)Oc1ccc([N+](=O)[O-])cc1CC(=O)c1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
4.23 g (35.0 mmol) of valeroyl chloride (compound of the formula VI) were added with cooling at −10° C. to 20° C. to a stirred suspension of 11.3 g (34.7 mmol) of 2-(2-hydroxy-5-nitrophenyl)-1-(4-methoxyphenyl)-ethanone potassium salt (example 1) in 50 ml of dry acetone. After 30 minutes the reaction was complete, as monitored by LC-MS, and the mixture was filtered through a layer of Celite to remove the precipitated potassium chloride. The solution was evaporated to dryness to give 9.23 g (98%) of a yellow oil which slowly crystallized while standing at room temperature.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31][S:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)(=[O:33])=[O:34])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(Nc1ccccc1Br)c1ccccc1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3NS(=O)(=O)c3ccccc3)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and N-(2-bromophenyl)benzenesulfonamide. MS (ESI): mass calcd. for C22H17FN4O2S, 420.11; m/z found, 421.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 7.85-7.75 (m, 1H), 7.59-7.46 (m, 5H), 7.29-7.10 (m, 6H), 6.71 (s, 2H).