Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[C@H:4]([F:35])[CH2:3]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:31]1([CH2:30][O:29][C:21]2[CH:22]=[CH:23][C:24]([CH:26]([F:28])[F:27])=[CH:25][C:20]=2[C:19]2[C:14]3[NH:13][C:12]([CH3:34])=[C:11]([C:9]([NH:8][C@@H:5]4[CH2:6][CH2:7][C@@H:2]([NH:1][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:3][C@H:4]4[F:35])=[O:10])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:32][CH2:33]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CC[C@@H](N)C[C@H]1F
Reactant: COCC(=O)Cl
Product: COCC(=O)N[C@@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)[C@H](F)C1

Procedure:
Starting from N-[(1R*,2R*,4R*)-4-amino-2-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f67) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1.[CH2:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C.C([O-])(=O)C.[Li+]>CO>[CH2:1]([O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([OH:16])=[C:10]([C:12]([CH3:14])([CH3:13])[CH3:15])[CH:11]=1)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: CC(=O)[O-]
Agent: [Li+]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 100 °C
Yield: 96.5 %

Procedure:
109 g (0.374 mol) of β-(3,5-di-tert-butyl4-hydroxyphenyl)propionic acid methyl ester, 92.5 g (0.34 mol) of stearyl alcohol and 0.1 g of lithium acetate in the dihydrate form (0.001 mol) are introduced into a vessel and melted and stirred at 100° C. under nitrogen. As soon as a melt is obtained, cautiously evacuation is carried out and at the same time the melt is heated to an internal temperature (IT) of from 150 to 160° C. The methanol formed is distilled off and condensed in a cold trap. As soon as an internal pressure of <10 mbar is reached, the internal temperature (IT) is increased to from 170 to 180° C. and further evacuation to <1 mbar is carried out. As soon as IT=180° C. and a pressure of <1 mbar is reached, those conditions are maintained for one hour and then, in the course of from 1 to 2 hours at IT=200-210° C., the excess β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid methyl ester is removed by distillation. The reaction melt then contains <0.2% starting materials and has a content of >98% β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid octadecyl ester. The reaction melt is cooled, and left to stand for crystallisation. Yield 96.5%; m.p. 51° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10](OC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Li+].[BH4-].[Na+].C(O)(=O)C>C1COCC1.C(O)C>[OH:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][NH:15][C:16](=[O:17])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.3 %

Procedure:
To a solution of methyl (2S)-2,3-bis[(tert-butoxycarbonyl)amino]-propanoate (3.57 g, 11.2 mmol) in THF (60 mL) at 0° C. was added lithium chloride (523 mg, 12.3 mmol) and then sodium borohydride (467 mg, 12.3 mmol) portionwise. Ethanol (30 mL) was added slowly. The reaction mixture was allowed to warm to rt and stirred for 18 h. Acetic acid (0.707 mL, 12.3 mmol) was added and the solvents were evaporated. The residue was purified by chromatography (SiO2, EtOAc/hexane) to yield the title compound as a white solid (2.35 g, 72.2%). LCMS: (FA) ES+ 291.2 (M+1).
Reaction SMILES: ClC1N=CC(C(Cl)=O)=CN=1.C(O)C.Cl[C:15]1[N:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][N:16]=1.[NH2:26][NH2:27]>>[NH:26]([C:17]1[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:20]=[CH:15][N:16]=1)[NH2:27]
Reactant: NN
Reactant: CCOC(=O)c1cnc(Cl)nc1
Agent: O=C(Cl)c1cnc(Cl)nc1
Solvent: CCO
Product: CCOC(=O)c1cncnc1NN
Yield: 44 %

Procedure:
The title compound was prepared by (a) treating 2-chloropyrimidine-5-carbonylchloride (Example 13, 110 mg, 0.62 mmol) with ethanol (200 mg, 4.4 mmol in 1 mL of ethyl acetate) to provide 60% of ethyl 2-chloropyrimidine-5-carboxylate, (b) reaction of ethyl 2-chloropyrimidine-5-carboxylate (70 mg, 0.37 mmol) with hydrazine (100 mg, 3 mmol) to afford 44% of ethyl 4-hydrazinopyrimidine-5-carboxylate as in Example 19, (c) reaction of ethyl 4-hydrazinopyrimidine-5-carboxylate (0.36 g, 2.0 mmol) with citraconic anhydride (0.34 g, 3.0 mmol) in analogy to Example 21 to afford 10% (0.05 g) of the title compound; m.p. 95-98° C.
Reaction SMILES: [Na].[OH:2][NH:3][C:4]([NH2:6])=[NH:5].[C:7]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([NH2:18])[CH3:17])=[CH:12][CH:11]=1)(O)=O>C(O)C>[NH2:5][C:4]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([NH2:18])[CH3:17])=[CH:12][CH:11]=2)[O:2][N:3]=1
Reactant: CC(N)c1ccc(C(=O)O)cc1
Reactant: N=C(N)NO
Agent: [Na]
Solvent: CCO
Product: CC(N)c1ccc(-c2nc(N)no2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.8 g of sodium is dissolved in 60 ml of absolute ethanol, and 12 g of molecular sieve (4 Å) and 2.63 g of N-hydroxyguanidine are added. The batch is stirred for 1 hour at room temperature and then 1.14 g of 1-(4-carboxyphenyl)ethylamine are added. The resulting turbid yellowish solution is heated under reflux for 2 hours after which time it can be established by thin layer chromatography that the reaction is complete. The batch is filtered and the solvent is removed under reduced pressure. The residue is digested in water and cooled in an ice bath, and then the precipitate is isolated by filtration, washed with a small amount of water and dried under reduced pressure to give 1-[4-(3-amino-1,2,4-oxadiazol-5-yl)phenyl]ethylamine having a melting point of 150°-151°.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[CH:29]=O>>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[CH2:29][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cc2ccccc2[nH]1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cc5ccccc5[nH]4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1H-indole-2-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1H-indol-2-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: CCOP(OCC)([CH:6]1[NH:12][C:10](=[O:11])[NH:9][C:7]1=[O:8])=O.C(N(CC)CC)C.[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:32]=O)[CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH2:32][CH:6]2[NH:12][C:10](=[O:11])[NH:9][C:7]2=[O:8])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(CC2NC(=O)NC2=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a stirred solution of diethyl 5-hydantoylphosphonate (10 g, 42.3 mmol) and triethylamine (5.70 g, 56 mmol), in dry acetonitrile (100 ml), at room temperature was added a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (8 g, 36.3 mmol) in dry acetonitrile (75 ml), dropwise over 30 minutes. The resulting mixture was stirred at room temperature overnight, after which volatiles were removed in vacuo. The residue was diluted with 0.05N HCl (120 ml) and the precipitate collected by filtration. Recrystallization of this material with methylene chloride/methanol/diethyl ether afforded the title compound as a pale yellow solid (8.54 g). m.p. 220-222° C.
Reaction SMILES: [C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:19])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[F:26][CH:27]([F:30])[CH2:28]I>>[C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:28][CH:27]([F:30])[F:26])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:19])(=[O:6])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)CI
Reactant: CC(C)(C)S(=O)(=O)c1cc2c(Cl)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)S(=O)(=O)c1cc2c(Cl)ccnc2cc1OCC(F)F
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 6-(tert-butylsulfonyl)-4-chloroquinolin-7-ol (100 mg, 0.334 mmol) was added K2CO3 (138 mg, 1.001 mmol) followed by 1,1-difluoro-2-iodoethane (44.1 μl, 0.500 mmol). This was heated to 60° C. overnight. LCMS showed incomplete conversion. Additional 1,1-difluoro-2-iodoethane (44.1 μl, 0.500 mmol) was added and the reaction was stirred at 60° C. for 5 hr. Reaction was still not complete by LCMS, so another aliquot of 1,1-difluoro-2-iodoethane (44.1 μl, 0.500 mmol) was added and the reaction was stirred at 60° C. overnight again. LCMS showed complete and clean conversion to the desired product. The crude sample was purified via Biotage normal phase chromatography (25 g SNAP column, 0% -50%, 50% hex/EtOAc). The pure product containing-fractions were combined and concentrated leading to the product as an off-white solid: 6-(tert-butylsulfonyl)-4-chloro-7-(2,2-difluoroethoxy)quinoline (88.8 mg, 0.244 mmol, 73.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (s, 9H) 4.66 (td, J=14.53, 3.54 Hz, 2H) 6.28-6.63 (m, 1H) 7.80 (d, J=4.80 Hz, 1H) 7.85 (s, 1H) 8.67 (s, 1H) 8.97 (d, J=4.80 Hz, 1H). MS: m/z: 364.1 [M+H]+.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][O:12][C@H:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH3:32][O:31][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][C@H:11]2[O:12][CH2:13][CH2:14][NH:9][CH2:10]2)[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cccc(CCc2ccccc2OC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(CCc2ccccc2OC[C@@H]2CNCCO2)c1
Reaction time: 1 h
Yield: 78 %

Procedure:
5 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution of 420 mg of (S)-4-t-butoxycarbonyl-2-{2-[2-(3-methoxyphenyl)ethyl]phenoxymethyl}morpholine [prepared as described in step (a) above] in 5 ml of dioxane, and the resulting solution was allowed to stand at room temperature for 1 hour. At the end of this time, the solution was concentrated by evaporation under reduced pressure, the resulting oily residue was dissolved in 20 ml of ethyl acetate, and the resulting solution was allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo, to give 279 mg (yield 78%) of the title compound as colorless needles, melting at 105°-106° C.
Reaction SMILES: O[C:2]1([C:12]#[N:13])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].S(Cl)(Cl)=O.Cl>N1C=CC=CC=1>[CH3:8][C:6]1([CH3:9])[CH2:5][CH2:4][C:3]([CH3:10])([CH3:11])[C:2]([C:12]#[N:13])=[CH:7]1
Reactant: CC1(C)CCC(C)(C)C(O)(C#N)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC1(C)C=C(C#N)C(C)(C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.9 %

Procedure:
To a mixture of the product of Example 10e (2.22 g, 12.3 mmol) in pyridine (40 mL) was added thionyl chloride (4.4 mL, 61.3 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction was acidified with 5 N hydrochloric acid to pH=1, then it was poured into ice-water (20 mL). The aqueous mixture was extracted with ethyl acetate (20 ml×3) and the organic phase washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound as a colorless oil (600 mg, Yield: 30%). 1H NMR (400 MHz, CDCl3) δ 6.23 (s, 1H), 1.56 (t, J=2.8 Hz, 2H), 1.56-1.43 (m, 4H), 1.16 (s, 6H), 1.03 (s, 6H) ppm.
Reaction SMILES: C([NH:4][C:5]1([CH2:22][CH2:23][CH3:24])[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)(=O)C.[ClH:25]>C(O)C>[ClH:25].[NH2:4][C:5]1([CH2:22][CH2:23][CH3:24])[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2.[ClH:25].[ClH:25].[NH2:4][C:5]1([CH2:22][CH2:23][CH3:24])[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2
Reactant: CCCC1(NC(C)=O)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: Cl
Solvent: CCO
Product: CCCC1(N)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reaction time: 2 h

Procedure:
1.5 g of 10-acetamido-10-propyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are dissolved in 80 ml of boiling 2N hydrochloric acid and the solution is stirred for 2 hours at boiling, cooled and concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 60° C. The product obtained is suspended in 35 ml of ethanol and the insoluble product is isolated by filtration, washed twice with 20 ml in total of ethanol and dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 0.87 g of 10-amino-10-propyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one sesquihydrochloride is thus obtained, decomposing without melting above 250° C. (Analysis, % calculated C: 57.36, H: 5.27, Cl: 15.87, N: 16.72, O: 4.78, % found C: 56.9, H: 5.3, Cl: 16.4, N: 16.4).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N:7]1([C:12]2[C:13]3[NH:20][CH:19]=C(C(O)=O)[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:11]=[CH:10][CH:9]=[N:8]1>C(Cl)Cl.CN(C=O)C>[N:7]1([C:12]2[C:13]3[NH:20][CH:19]=[C:1]([C:2]([Cl:4])=[O:3])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:11]=[CH:10][CH:9]=[N:8]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1c[nH]c2c(-n3cccn3)ncnc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c[nH]c2c(-n3cccn3)ncnc12
Reaction time: 14 h
Yield: 1042.6 %

Procedure:
Oxalyl chloride (4.5 mL, 51 mmol) was added to a solution of diazaindole carboxylic acid 50 (1.08 g, 4.7 mmol) in CH2Cl2 (8 mL) and the reaction mixture was stirred 14 h. Catalytic DMF (3 drops) was added to the reaction mixture and after 3 h the reaction was quenched with MeOH. The crude reaction mixture was concentrated to dryness to yield 51 (1.21 g, 49 mmol, 96%) as a tan solid with was used without further purification. 1H NMR: (500 MHz, DMSO-d6) δ 12.45 (br s, 1H), 8.87 (s, 1H), 8.87 (d, J=2.6 Hz, 1H), 8.32 (d, J=3.3 Hz, 1H), 8.14 (d, J=1.5 Hz, 1H), 6.77 (dd, J=2.6, 1.5 Hz, 1H); Methyl ester (obtained by stirring 51 in MeOH): LC/MS: (ES+) m/z (M+H)+=244; HPLC Rt=0.95 min., column 0, conditions B.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([C:11]([O:13][CH3:14])=[O:12])[OH:10].[C:15]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O.N>CC(C)=O.C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]([C:11]([O:13][CH3:14])=[O:12])[O:10][CH3:15]
Reactant: COC(=O)N(O)c1c(C)cccc1C
Reactant: O=C([O-])[O-]
Agent: N
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Solvent: ClCCl
Product: COC(=O)N(OC)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.4 g (7.2 mmol) of N-(2,6-dimethylphenyl)-N-methoxycarbonyl-hydroxylamine (Example 1a), 1.3 g (9 mmol) of K2CO3 and 10 g (8 mmol) of dimethyl sulfate in 10 ml of acetone is stirred overnight at room temperature. The reaction mixture is then diluted with CH2Cl2 and stirred with dilute NH3 solution. The phases are then separated and the organic phase is extracted another twice with water. The organic phase is dried over MgSO4 and evaporated down, and the residue is purified by column chromatography with mixtures of cyclohexane and ethyl acetate. There is obtained 1.2 g (6 mmol=83%) of the title compound as a colorless solid (mp=81° C.).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.Br[C:13]1[C:14](=[O:21])[N:15]([CH3:20])[N:16]=[C:17]([Cl:19])[CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[Cl:19][C:17]1[CH:18]=[C:13]([NH:9][C:6]2[CH:5]=[N:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][N:7]=2)[C:14](=[O:21])[N:15]([CH3:20])[N:16]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: Nc1cnc(C(F)(F)F)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1nc(Cl)cc(Nc2cnc(C(F)(F)F)cn2)c1=O
Temperature: 90 °C
Yield: 71.6 %

Procedure:
To a solution of 5-(trifluoromethyl)pyrazin-2-amine (146 mg, 0.90 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (200 mg, 0.90 mmol), cesium carbonate (1.02 g, 3.13 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine (77.7 mg, 0.13 mmol) in dioxane (10.0 ml) was added tris(dibenzylideneacetone)dipalladium(0) (61.5 mg, 0.07 mmol) and the reaction mixture purged with argon (3×) before being warmed to 90° C. for 18 hr. The mixture was cooled, diluted with dichloromethane and water (50 mL) and the layers separated. The aqueous phase was extracted with methylene chloride (2×25 mL). The organic phases were combined and dried over MgSO4. The mixture was filtered and evaporated and the residue purified via automated flash chromatography (Analogix, SF15-24 g column, 1%-10% methanol/dichloromethane gradient) to give 6-chloro-2-methyl-4-(5-trifluoromethyl-pyrazin-2-ylamino)-2H-pyridazin-3-one (197 mg, 72%) as a yellow solid: LC/MS m/e calculated for C10H7ClF3N5O [M]+ 305.03, observed 305.9
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(O)=O.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[NH:30][C:31]([C:33]2[S:34][C:35]([Cl:38])=[CH:36][CH:37]=2)=[O:32])[C:21]1=[O:39].Cl.[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=1>CN(C)C1C=CN=CC=1.C1COCC1.ClCCl>[Cl:38][C:35]1[S:34][C:33]([C:31]([NH:30][C:26]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:27]=2[C:28](=[O:29])[N:20]([CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=2)[C:21]3=[O:39])=[O:32])=[CH:37][CH:36]=1
Reactant: NCCCCN1C(=O)c2cccc(NC(=O)c3ccc(Cl)s3)c2C1=O
Reactant: O=C(Cl)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCCCN1C(=O)c2cccc(NC(=O)c3ccc(Cl)s3)c2C1=O)c1ccncc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
25 mg (0.24 mmol) of triethylamine and a catalytic amount of 4-dimethylaminopyridine are added to 40 mg (0.08 mmol) of N-[2-(4-aminobutyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-5-chloro-2-thiophenecarboxamide trifluoroacetate in 2 ml of THF. At 0° C., 17.4 mg (0.10 mmol) of isonicotinoyl chloride hydrochloride are then added. The reaction mixture is warmed to RT, stirred at RT for 3 h and then heated at reflux for 20 h. After cooling to RT, the reaction mixture is diluted with dichloromethane and washed with aqu. sat. NaHCO3 solution. The organic phase is dried over MgSO4, filtered and concentrated. The crude product is chromatographed on silica gel (CH2Cl2/EtOH=50/1). This gives 18.5 mg (47% of theory) of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][C:10]([O:12]CC)=[O:11])=[CH:7][N:6]([CH2:15][C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[O:31][CH:32]=[CH:33][CH:34]=4)[O:27][C:28]=3[CH3:29])=[CH:20][CH:21]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][N:6]([CH2:15][C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:30]4[O:31][CH:32]=[CH:33][CH:34]=4)[O:27][C:28]=3[CH3:29])=[CH:20][CH:21]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)nc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)nc2)cc1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
After a mixture of ethyl 3-ethoxy-1-[6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethyl]-1H-pyrazol-4-ylacetate (364 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (2 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-ethoxy-1-[6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-pyridylmethyl]-1H-pyrazol-4-ylacetic acid (308 mg, yield: 90%). This was recrystallized from ethanol-hexane. Melting point: 155–156° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH3:15])=[CH:10][CH:9]=2)[CH2:6][N:5]=[C:4]2[S:16][CH:17]=[CH:18][C:3]=12.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[N:30]=[C:31]=[O:32].[N-]=C=O>>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([N:14]([C:31]([NH:30][C:21]3[CH:22]=[C:23]([C:26]([F:27])([F:29])[F:28])[CH:24]=[CH:25][C:20]=3[F:19])=[O:32])[CH3:15])=[CH:12][CH:13]=2)[CH2:6][N:5]=[C:4]2[S:16][CH:17]=[CH:18][C:3]=12
Reactant: CNc1ccc(N2CN=c3sccc3=C2N)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Agent: [N-]=C=O
Product: CN(C(=O)Nc1cc(C(F)(F)F)ccc1F)c1ccc(N2CN=c3sccc3=C2N)cc1

Procedure:
The compound was prepared following the procedure described in Example 429, substituting 4-amino-3-(4-(methylamino)phenyl)-thieno[2,3-d]pyrimidine as the amine and using 2-fluoro-5-trifluoromethyl-phenyl isocyanate as the isocyanate of choice. MH+=462.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12.C([O-])(=O)C.[Na+].[Br:15]Br>CO.[Br-].[K+]>[Br:15][C:3]1[N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: c1cn2ccnc2cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: Brc1cnc2cnccn12
Yield: 99.7 %

Procedure:
Imidazo[1,2-α]pyrazine (90 mg, 0.76 mmol) and sodium acetate (75 mg, 0.91 mmol) were dissolved in methanol (2 ml) saturated with potassium bromide and cooled to −10° C. before dropwise addition of bromine (121 mg, 0.76 mmol) over 5 min. On complete addition the mixture was quenched by addition of 1N sodium sulfite solution (2 ml) and the solvent removed in vacuo. The residue was dissolved in water (15 ml) and saturated sodium hydrogencarbonate solution (15 ml) and extracted with ethyl acetate (2×40 ml). The organics were combined then washed with brine (40 ml), dried over anhydrous sodium sulfate and evaporated to give 3-bromoimidazo[1,2-α]pyrazine (150 mg, 100%) as a white crystalline solid: δH (400 MHz, CDCl3) 7.80 (1H, s), 6.87 (1H, d, J 7), 7.71 (1H, s), 8.27 (1H, d, J 7).