Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CI.N12CCCN=C1CCCC[CH2:4]2.[O:14]=[C:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([C:27]([OH:29])=[O:28])=[CH:16]1>CC(C)=O>[O:14]=[C:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:17]([C:27]([O:29][CH3:4])=[O:28])=[CH:16]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C1C=C(C(=O)O)C(c2ccccc2)CC1
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)C1=CC(=O)CCC1c1ccccc1
Temperature: 10 °C
Yield: 92.8 %

Procedure:
358 g (2.52 mol) of methyl iodide and 361 g (2.38 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene were successively added to a solution of 428 g (1.98 mol) of (RS)-3-oxo-6-phenylcyclohex-1-ene-1-carboxylic acid, which was obtained according to J. Org. Chem., 1971, 36, 3707, in 4.5 cm3 of acetone and then the reaction mixture was brought to reflux for five hours. The acetone was subsequently distilled off and then the residue was stirred with 2.5 dm3 of water. After cooling to 10° C., the precipitate formed was filtered off, washed with ice-cold water and then dried at 30° C. 423 g (93%) of methyl (RS)-3-oxo-6-phenylcyclohex-1-ene-1-carboxylate were thus obtained in the form of a yellow powder, the characteristics of which were as follows:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3[CH:13]=[N+:14]([O-])[CH:15]=[CH:16][CH:17]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)(=[O:21])C>>[O:21]=[C:13]1[C:12]([C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)=[CH:17][CH:16]=[CH:15][NH:14]1
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1cccc(-c2nc(-c3ccccc3)cs2)c1
Product: O=c1[nH]cccc1-c1nc(-c2ccccc2)cs1

Procedure:
In 25 ml of acetic anhydride was dissolved 2.8 g of 3-(4-phenylthiazol-2-yl)pyridine-N-oxide. The solution was refluxed for 6 hours with heating. The solvent was removed by distillation. The residue was treated with ammonia water and extracted with dichloromethane. The extract was water-washed, dried and subjected to solvent removal by distillation. The residue was mixed with a small amount of dichloromethane. The resulting crystals were collected by filtration and recrystallized from methanol to obtain 60 mg of 2-(2-oxopyridin-3-yl)4-phenylthiazole as light brown plate crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].O1CCCC1.[CH3:11][C:12](=O)[CH2:13][C:14](=[O:16])[CH3:15]>O>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:12]([CH3:11])=[CH:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)CC(C)=O
Reactant: COCCN
Solvent: C1CCOC1
Solvent: O
Product: COCCNC(C)=CC(C)=O
Reaction time: 8 h

Procedure:
7.50 g of 2-Methoxyethylamine (0.1 moles) were dissolved into 100 ml of tetrahydrofuran to which 10.0 g of 2,4-pentanedione (0.1 moles) were added dropwise over 5 minutes. The resulting mixture was then stirred overnight after which time the solvent and water of condensation formed during the reaction was removed by vacuum distillation. The final product was then vacuum distilled as a clear liquid. Yield of MeC(O)CH2C(NCH2CH2OMe)Me=11.8 g (75% of theoretical).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:17]3[CH:18]=[C:19]([C:22]([OH:24])=O)[S:20][CH:21]=3)=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=[CH:4][NH:3]1.CC[N:27]=C=NCCCN(C)C.Cl.O>CN(C=O)C>[O:1]=[C:2]1[C:7]2[C:8]([C:17]3[CH:18]=[C:19]([C:22]([NH2:27])=[O:24])[S:20][CH:21]=3)=[N:9][N:10]([CH:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[C:6]=2[CH:5]=[CH:4][NH:3]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(-c2nn(C3CCOCC3)c3cc[nH]c(=O)c23)cs1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(-c2nn(C3CCOCC3)c3cc[nH]c(=O)c23)cs1
Yield: 86.9 %

Procedure:
A solution of 4-(4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylic acid (105 mg) obtained in Example 23, HOBt ammonium salt (139 mg) and EDCI hydrochloride (175 mg) in DMF (15 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol) to give the title compound (91 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCCCCCBr
Reactant: O=c1c2ccc(Br)cc2nc2[nH]c3ccccc3n12
Product: CCCCCCn1c2ccccc2n2c(=O)c3ccc(Br)cc3nc12

Procedure:
3-Bromo-6-(n-hexyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 3-bromobenzimidazo[2,1-b]quinazolin-12(6H)one and n-hexyl bromide.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[C:6]([CH3:19])([CH3:18])[CH2:5]1)(=O)C.Cl.O1CCOCC1>CO>[CH3:18][C:6]1([CH3:19])[C:7]2[C:12](=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([O:16][CH3:17])[CH:8]=2)[NH:4][CH2:5]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)CC2(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])NCC2(C)C
Temperature: 70 °C
Yield: 109.1 %

Procedure:
A solution of 1-acetyl-3,3-dimethyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (2.55 g, 9.65 mmol) in methanol (75 mL) was treated with 4.0N HCl in dioxane (19.30 mL, 77 mmol) and maintained at 70° C. for 16 hours. The solution was concentrated under reduced pressure, solids were triturated with diethyl ether and the slurry was filtered to afford 3,3-dimethyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (2.340 g, 94% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.68 (s, 1 H), 7.36 (s, 1 H), 3.89 (s, 3 H), 3.41 (s, 2 H), 1.33 (s, 6 H).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[N:19]=[C:18]([C:20]([N:22]([CH2:28][CH2:29][CH3:30])[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[O:21])[CH:17]=[CH:16][CH:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:27][N:25]([CH3:26])[C:23]([N:22]([C:20]([C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[N:19]=1)=[O:21])[CH2:28][CH2:29][CH3:30])=[O:24]
Reactant: COC(=O)c1ccccc1S
Reactant: CCCN(C(=O)c1cccc(C#N)n1)C(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCN(C(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1)C(=O)N(C)C
Yield: 73 %

Procedure:
A mixture of methyl thiosalicylate (1.6 g, 9.6 mmol), N-[(6-cyano-2-pyridyl)carbonyl]-N′,N′-dimethyl-N-propylurea (1.2 g, 4.7 mmol), triethylamine (2.0 ml, 14 mmol) and toluene (4 ml) was refluxed for 9 hrs as described in Example 1. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.36 g, 72%) as crystals.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C[Si](C)(C)[O:41][NH2:42].CO>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[N:16]=2)[CH2:11][C:12]([NH:42][OH:41])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)ON
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2cccnc2)no1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CO
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(Cc2cccnc2)no1)NO
Reaction time: 1 h
Yield: 33 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(3-pyridinylmethyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 109) (410 mg, 1.04 mmol) in dichloromethane (10 ml) was treated with 1,1′-carbonyldiimidazole (169 mg, 1.04 mmol) and stirred under a nitrogen atmosphere for 1 hour. O-(Trimethylsilyl)hydroxylamine (418 μl, 3.12 mmol) was added and the reation mixture was stirred for 18 hours. The reaction mixture was then treated with methanol (5 ml) and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water (3×30 ml) and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 (dichloromethane:methanol) gradually changing to 95:5 (dichloromethane:methanol) to afford a white waxy solid. The solid was recrystallised from ethyl acetate to afford the title compound as a white solid (128 mg).
Reaction SMILES: C([C:3]1[N:10]=[C:9](Br)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6])C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][N:10]=1
Reactant: CCc1nc(Br)ccc1C#N
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccc(C#N)cn1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of ethyl 6-bromonicotinonitrile (1.81 g, 10 mmol) described in the Journal of Organic Chemistry 2001, 66, 1500-1502, 2-methoxyphenylboronic acid (1.22 g, 10 mmol), Pd(PPh3)4 (5% mol), K2CO3 (5 g) in DMF/water (3/1) is stirred at 50° C. for 12 hours. The reaction mixture is then pored on water (150 mL). The aqueous phase is extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water (3×200 mL). The organic phase is dried over magnesium sulfate and evaporated under vacuum to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[CH:16])[CH2:10][C@@H:9]1[C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20](OC(N1CCN(C(C)C)C[C@@H]1C(O)=O)=O)(C)(C)C.C(Br)C#C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([CH3:20])=[CH2:16])[CH2:10][C@@H:9]1[C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Reactant: C#CCN1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Agent: C#CCBr
Product: C=C(C)CN1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1

Procedure:
(2R)-1-(tert-Butoxycarbonyl)-4-(prop-2-yn-1-yl)piperazine-2-carboxylic acid used in Route E1 was prepared using the procedure described for (2R)-1-(tert-butoxycarbonyl)-4-isopropylpiperazine-2-carboxylic acid above but using prop-2-ynyl bromide.
Reaction SMILES: C([C@@H]1C[O:7]C(C2C=CC=CC=2NC2C(NC3C=CC=CC=3C3OC[C@@H](C(C)C)N=3)=CC=CC=2)=N1)(C)C.[CH:37]1([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([C:46]3[CH:47]=[N:48][C:49]([N:52]4[C:60]5[C:55](=[CH:56][CH:57]=[C:58]([C:61]([O:63][CH3:64])=[O:62])[CH:59]=5)[C:54]([S:65][CH3:66])=[CH:53]4)=[N:50][CH:51]=3)[CH:41]=2)[CH2:39][CH2:38]1.C(O)(=O)C.OO>ClCCl>[CH:37]1([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([C:46]3[CH:51]=[N:50][C:49]([N:52]4[C:60]5[C:55](=[CH:56][CH:57]=[C:58]([C:61]([O:63][CH3:64])=[O:62])[CH:59]=5)[C:54]([S:65]([CH3:66])=[O:7])=[CH:53]4)=[N:48][CH:47]=3)[CH:41]=2)[CH2:38][CH2:39]1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4cc(C5CC5)ccn4)cn3)c2c1
Reactant: CC(C)[C@@H]1COC(c2ccccc2Nc2ccccc2Nc2ccccc2C2=N[C@H](C(C)C)CO2)=N1
Agent: OO
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4cc(C5CC5)ccn4)cn3)c2c1
Temperature: 6.5 °C
Reaction time: 0.5 h

Procedure:
N1,N2-bis(2-((R)-4-isopropyl-4,5-dihydrooxazol-2-yl)phenyl)benzene-1,2-diamine (6.95 mg, 0.014 mmol) and Mn(OTf)2 (5.09 mg, 0.014 mmol; for synthesis and application of this ligand see: Dai. W. et al. Org. Lett. 2013, 15, 5658; Dai. W. et al. Org. Lett. 2013, 15, 4138) in dichloromethane (10 mL) were stirred at room temperature for 3 h. 333a) (0.3 g, 0.721 mmol), acetic acid (0.263 mL, 4.61 mmol) and 30% aqueous hydrogen peroxide solution (0.147 mL, 1.47 mmol) were added at room temperature and the resulting mixture was immediately cooled with an ice bath to 5-8° C. The reaction mixture was stirred at this temperature for 30 min, quenched with saturated sodium sulfite solution (10 mL) and further stirred for 15 min. The mixture was then diluted with dichloromethane (30 mL) and washed with brine (20 mL). The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography [silica; dichloromethane with 1.5% methanol]. White solid. Yield: 0.14 g (45% of theory). Enantiomeric excess: >99% (chiral HPLC)
Reaction SMILES: Cl[C:2]1[C:3]([F:15])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[NH:7][CH:8]1[CH2:10][CH2:9]1.[C:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:18])[CH3:17].C(N(CC)CC)C>O>[C:16]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:11]=[C:6]([NH:7][CH:8]3[CH2:10][CH2:9]3)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=2[F:15])[CH2:21][CH2:20]1)(=[O:18])[CH3:17]
Reactant: CC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1NC1CC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CCN(c2cc(NC3CC3)c([N+](=O)[O-])cc2F)CC1
Reaction time: 12 h
Yield: 93.3 %

Procedure:
5-Chloro-N-cyclopropyl-4-fluoro-2-nitroaniline (3.5 g, 15.2 mmol) is heated with N-acetylpiperazine (3.89 g, 30.4 mmol) and triethylamine (2.3 g 22.8 mmol) while stirring vigorously and held at 60° for 12 hours. The mass obtained is dissolved in water (200 ml) and extracted with ethyl acetate. The organic phase is washed with 10 percent sodium chloride solution and then dried over magnesium sulfate. After distillation of the solvent the residue is recrystallized from ethanol. There are obtained 4.57 g (93%) of 1-acetyl-4-[5-(cyclopropylamino)-2-fluoro-4-nitrophenyl]piperazine with a m.p. of 142°-143°.
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[C:11]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:11][O:10][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1cc(I)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(I)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
5-Iodo-salicylaldehyde (1.0 g, 4.0 mmol) was dissolved in DMF (10 mL) and to the stirred solution K2CO3 (0.828 g, 6.0 mmol) and CH3I (1.14 g, 8.0 mmol) were added. The mixture was stirred at room temperature overnight. The suspension was concentrated in vacuo, and the residue was partitioned between water (30 mL) and Et2O (30 mL). The aqueous phase was separated and extracted with ether (20 mL×2). The combined organic phases were dried over Na2SO4, filtered and concentrated to give 67 (1.02 g, 98%). 1H NMR (CDCl3, 300 MHz) δ 10.34(s, 1H), 7.82-7.78 (m, 1H), 7.26 (s, 1H), 6.78 (d, J=8.7 Hz, 1H), 3.91 (s, 3H). MS (m/e) (positive FAB) 262.1 (M+H)+, m.p. 140-142° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:10]([CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:31][C:32]1[CH:33]=[C:34]([CH2:38][S:39]([N:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])[CH:35]=[CH:36][CH:37]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1>[CH3:43][N:42]([CH3:44])[S:39]([CH2:38][C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([NH:31][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:16]4[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]5[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=5)=[N:15]4)=[C:10]([CH3:30])[N:9]=3)[CH:3]=2)[CH:33]=1)(=[O:40])=[O:41]
Reactant: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)cc(OC)c1OC
Reactant: CN(C)S(=O)(=O)Cc1cccc(N)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Nc5cccc(CS(=O)(=O)N(C)C)c5)c4)n3n2)cc(OC)c1OC
Temperature: 140 °C
Yield: 24.4 %

Procedure:
In a similar manner as described in Example 66, 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (40 mg, 0.085 mmol), 1-(3-aminophenyl)-N,N-dimethylmethanesulfonamide (21.9 mg, 0.102 mmol), (S)-(−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl ((S)-BINAP) (15.9 mg, 0.026 mmol), Tris(dibenzylidineacetone)dipalladium (0) (7.8 mg, 0.008 mmol) and sodium t-butoxide (11.4 mg, 0.12 mmol) in 1,4-dioxane (1.5 mL) were heated with microwave radiation at 140° C. for 60 minutes in a sealed reaction vessel to give N,N-dimethyl-1-{3-[(3-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}phenyl)amino]phenyl}methanesulfonamide (0.0125 g) as a yellow solid. 1H NMR (CDCl3) δ8.80 (s, 1H), 8.15 (dd, J=1.8, 1.8 Hz, 1H), 8.06-8.04 (m, 1H), 7.36 (dd, J=8.0, 7.9 Hz, 1H), 7.25-7.22 (m, 2H), 7.16 (dd, J=1.9, 1.8, 1H), 7.10 (ddd, J=8.1, 2.4, 0.9 Hz, 1H), 6.93-6.91 (m, 4H), 6.10 (s, 1H), 4.17 (s, 2H), 3.84-3.83 (m, 9H) 2.76 (s, 6H), 2.60 (s, 3H). MS m/z 605 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([F:25])[C:8]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=3[F:24])=[C:9]([C:12]([NH:14][NH2:15])=[O:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.Br[C:27]#[N:28].C([O-])(O)=O.[Na+]>O1CCOCC1.O>[NH2:28][C:27]1[O:13][C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[C:7]([F:25])[C:8]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=2[F:24])[N:5]=[N:4][CH:3]=[C:2]3[NH2:1])=[N:14][N:15]=1
Reactant: N#CBr
Reactant: NNC(=O)c1cc2c(N)cnnc2c(F)c1Nc1ccc(Br)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nnc(-c2cc3c(N)cnnc3c(F)c2Nc2ccc(Br)cc2F)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-amino-7-(4-bromo-2-fluorophenylamino)-8-fluorocinnoline-6-carboxylic acid hydrazide (1.00 equiv.) in 1,4-dioxane at room temperature is added BrCN (2.00 equiv.) followed by a solution of NaHCO3 (1.00 equiv.) in H2O. After stirring for 3 hours at room temperature, the reaction mixture is diluted with water and extracted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that is purified by trituration or flash column chromatography to afford 6-(5-amino-[1,3,4]oxadiazol-2-yl)-N7-(4-bromo-2-fluoro-phenyl)-8-fluorocinnoline-4,7-diamine.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1.[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>C(O)CO.C(OCC)(=O)C>[CH2:18]([NH:22][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1)[CH2:19][CH2:20][CH3:21]
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Reactant: CCCCN
Solvent: CCOC(C)=O
Solvent: OCCO
Product: CCCCNc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 120 °C

Procedure:
To a solution of 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (10 g) in dry ethylene glycol (50 ml) at room temperature and under nitrogen was added n-butylamine (16 ml) in one go. The reaction was heated at 120° C. overnight. The reaction was cooled to room temperature, diluted with ethyl acetate (150 ml) and washed with water (2×50 ml). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. This afforded the title compound as a viscous green oil (10.2 g) that was used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:23](=[CH:24][CH:25]=1)[O:22][C:9]1([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH2:8][C:7]2=[O:26])([OH:3])=O.Cl.[NH2:28][CH2:29][C:30]([NH2:32])=[O:31].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:30]([CH2:29][NH:28][C:1]([C:4]1[CH:5]=[C:6]2[C:23](=[CH:24][CH:25]=1)[O:22][C:9]1([CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:13][CH2:14]1)[CH2:8][C:7]2=[O:26])=[O:3])(=[O:31])[NH2:32]
Reactant: NCC(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(C(=O)O)ccc1O2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(C(=O)NCC(N)=O)ccc1O2
Temperature: 25 °C
Reaction time: 23 h

Procedure:
tert-butyl 6-carboxy-4-oxospiro(chroman-2,4′-piperidine)-1′ carboxylate (7.50 g, 20.8 mmol), glycinamide hydrochloride (2.76 g, 24.9 mmol), EDCI (4.78 g, 24.9 mmol), HOBT (3.78 g, 24.9 mmol), and TEA (5.80 ml, 41.6 mmol) were suspended in DMF (75 ml) and stirred at room temperature for 23 h. After removal of the solvent, the residue was diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with saturated NaHCO3 aq. and brine, dried over MgSO4. The desiccant was removed through filtration and the filtrate was concentrated under reduced pressure. The residue was triturated with MeOH—Et2O and the insoluble solid was collected through filtration to obtain the intended compound as a colorless solid.
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:5]=[CH:6][C:7]([NH:13]N)=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10].O=[C:16]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17]1>C(O)(=O)C.C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:7](=[C:8]([C:9]([OH:11])=[O:10])[CH:12]=1)[NH:13][C:16]1[CH2:17][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][CH2:20][C:21]2=1
Reactant: CCOC(=O)C1CCCC(=O)C1
Reactant: NNc1ccc(Br)cc1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)cc(Br)cc23)C1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
A cream colored suspension of 5-bromo-2-hydrazinylbenzoic acid dihydrochloride (6 g, 19.74 mmol) and ethyl 3-oxocyclohexanecarboxylate (3.70 g, 21.71 mmol) in glacial acetic acid, (˜0.4M) (45 mL) was heated at reflux for 4h. The reaction mixture turned in to dark yellow suspension. The reaction mixture was cooled to room temperature and it was concentrated to afford a dark yellow solid. The solid was then suspended in ethyl acetate (˜50 ml) and the solid was filtered, washed with water and ethyl acetate to give 4.14 g of 6-bromo-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid. MS (ESI) m/z 366.3 (M+H). 1H NMR (DMSO-d6) δ ppm 13.4-12.3 (b, 1H), 10.99 (s, 1H), 7.79 (d, 1H, J=1.9 Hz) 7.69 (d, 1H, J=1.8 Hz), 4.08-4.17 (m, 2H), 3.05 (dd, 1H, J=16.5, 5.0), 2.97-2.84 (m, 2H), 2.76-2.69 (m, 1H), 2.67-2.59 (m, 1H), 2.19-2.12 (m, 1H), 1.88-1.78 (m, 1H), 1.21 (t, 3H, J=7.2).
Reaction SMILES: I.C(O[C:6](=O)[CH3:7])(=O)C.[PH2](O)=O.[CH3:12][C:13]1[NH:14][CH:15]=[C:16]([CH3:21])[C:17]=1[C:18](=[O:20])[CH3:19]>C1(=O)CCCCC1.O>[CH3:12][C:13]1[NH:14][C:15]([CH:7]2[CH2:6][CH2:16][CH2:17][CH2:13][CH2:12]2)=[C:16]([CH3:21])[C:17]=1[C:18](=[O:20])[CH3:19]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: CC(=O)OC(C)=O
Agent: I
Agent: O=[PH2]O
Solvent: O
Solvent: O=C1CCCCC1
Product: CC(=O)c1c(C)[nH]c(C2CCCCC2)c1C
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of 10 ml of aqueous hydriodic acid, 10 ml of acetic anhydride and 2 ml of 50% hypophosphorous acid was stirred magnetically at 40° C. while 548 mg of 2,4-dimethyl-3-acetyl-pyrrole were dissolved in it, 0.5 ml of cyclohexanone was then added, and an additional 0.5 ml of cyclohexanone was added after a few minutes'. The solution was stirred at 40° C. for 11/2 hrs. then poured into water. The crude product which separated, m.p. 186°-188° C. was recrystallized from ethanol as colourless rhombic prisms (82%), m.p. 188.5°-189° C. after changing to flat prisms above 153° C.