Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[OH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:23]2.[CH2:35]([O:42][C:43]([NH:45][CH2:46][CH2:47][CH2:48]O)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH2:35]([O:42][C:43]([NH:45][CH2:46][CH2:47][CH2:48][O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:23]2)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)CCc1cc2cc(O)ccc2[nH]1
Reactant: O=C(NCCCO)OCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)CCc1cc2cc(OCCCNC(=O)OCc3ccccc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (370 mg, 1.5 mmol) was added to the solution of methyl 3-(5-hydroxyindolyl)propanoate (220 mg, 1.0 mmol), as prepared in step g of Example 5, 3-(benzyloxycarbonylamino)propanol (230 mg, 1.1 mmol) and tri-n-butylphosphine (305 mg, 1.5 mmol) in tetrahydrofuran (20 mL). After stirring at ambient temperature overnight, the reaction mixture was concentrated and the residue was purified by flash column chromatography on silica gel (0–2% ethyl acetate in methylene chloride) to give the title compound as an off white solid (310 mg, 76%). 1H-NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 7.22 (d, J=8.9 Hz, 1H), 7.09 (d, J=3.1 Hz, 1H), 7.07 (d, J=2.1 Hz, 1H), 6.86 (dd, J=8.8, 2.4 Hz, 1H), 6.38 (d, J=2.9 Hz, 1H), 5.11 (br s, 3H), 4.41 (t, J=6.8 Hz, 2H), 4.07 (t, J=5.9 Hz, 2H), 3.66 (s, 3H), 3.44 (q, J=6.3 Hz, 2H), 2.81 (t, J=6.8 Hz, 2H), 2.02 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:31]=[C:32]([NH:45][S:46]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)(=[O:48])=[O:47])[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:34]2[CH:33]=[C:32]([NH:45][S:46]([C:49]3[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=3)(=[O:48])=[O:47])[CH:31]=[C:30]([F:29])[CH:35]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2cc(F)cc(NS(=O)(=O)c3ccc(O)cc3)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(F)cc(NS(=O)(=O)c4ccc(O)cc4)c3)n(-c3ccccc3)c(=O)c12
Yield: 50.2 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (30 mg, 0.07 mmol) was treated with N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-hydroxybenzenesulfonamide (42 mg, 0.11 mmol), cesium carbonate (2M, 120 μl, 0.24 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8 mg, 0.01 mmol) according to the method described in Example 3 to give 22 mg (52% yield) of the title compound. Purity 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Cl[CH2:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1)=[O:28].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:32][CH:31]=4)=[O:28])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)Nc1ccc(C(F)(F)F)cc1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Yield: 81 %

Procedure:
A solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (30 mg, 0.084 mmol), prepared as described in Example 1, 2-chloro-N-(4-(trifluoromethyl)phenyl)acetamide (22 mg, 0.092 mmol), K2CO3 (35 mg, 0.25 mmol) in DMF (1 ml), was heated at 80° C. for 1 hour. After this time, the solution was cooled to RT and diluted with ethyl acetate. The resultant solution was then washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative HPLC to give the title compound, 2-(7,8-bis(4-chlorophenyl)-3-oxo-[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide (38 mg, 81%) as a yellow solid. MS M+H=558; 1H NMR (CDCl3) δ 8.26 (1H), 7.60 (2H), 7.38-7.20 (8H), 7.11 (2H), 5.07 (2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>>[C:12]([O:11][C:9](=[O:10])[CH2:8][N:4]1[CH:3]=[C:2]([Br:1])[CH:6]=[N:5]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: Brc1cn[nH]c1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)Cn1cc(Br)cn1

Procedure:
The title compound was prepared according to the method described for Preparation 79 using 4-bromo-1H-pyrazole and tert butyl bromoacetate to afford the title compound as a yellow solid in 34% yield, 48.0 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[NH:13][C:12]2[C:7]1=[N:8][C:9]([C:16]1[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=1)=[N:10][CH:11]=2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:46][CH:47]1[CH2:49][CH2:48]1.O>CN(C=O)C>[CH:47]1([CH2:46][N:13]2[C:12]3[C:7](=[N:8][C:9]([C:16]4[C:24]5[C:19](=[N:20][CH:21]=[CH:22][CH:23]=5)[N:18]([CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[F:32])[N:17]=4)=[N:10][CH:11]=3)[N:6]([CH2:5][C:4]3[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:3]=3[O:2][CH3:1])[C:14]2=[O:15])[CH2:49][CH2:48]1
Reactant: COc1ccc(Cn2c(=O)[nH]c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2c(=O)n(CC3CC3)c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
500 mg (0.980 mmol) of the compound from example 82A were dissolved in 10 ml of DMF, 414 mg (1.270 mmol) of cesium carbonate and 150 mg (1.08 mmol) of 2-bromomethylcyclopropane were added and the mixture was stirred at RT for 18 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried under high vacuum. 482 mg (72% of theory, purity 82%) of the title compound were obtained.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1>>[C:1]([O:8][C:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][CH:16]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)O
Reactant: c1ccc2c(c1)CCCC2
Product: CCCCCC(=O)Oc1cccc2ccccc12

Procedure:
The procedure of Example 2 was followed except that hexanoic acid (33 g.; 284 m mols) was used in place of octanoic acid and the reaction time was 31/2 hours. Analysis showed that about 55% of the tetralin was converted producing naphthyl hexanoate in 62% selectivity.
Reaction SMILES: C([C:6]([CH:21](OCC)OCC)([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=1[CH3:20])[C:7]#[N:8])(OCC)=O.[OH-].[K+].[NH2:30][C:31]([NH2:33])=[NH:32]>C(O)C>[NH2:33][C:31]1[N:32]=[C:7]([NH2:8])[C:6]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=2[CH3:20])=[CH:21][N:30]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(C#N)(Cc1cc(OC)c(OC)cc1C)C(OCC)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C)c(Cc2cnc(N)nc2N)cc1OC

Procedure:
A solution of α-carbethoxy-α-diethoxymethyl-β-(4,5-dimethoxy-2-methylphenyl)propionitrile (3.9 g, 0.01 mol) and an equivalent amount of potassium hydroxide in ethanol (70 ml) was heated at reflux for one hour. A solution of guanidine (0.035 mol) in ethanol (50 ml) was added, and reflux was resumed. Ethanol was boiled off until the reaction temperature reached 85° C. After 20 hours at reflux the mixture was allowed to cool, and the product was filtered and washed with ethanol giving 2.57 g (94%) of nearly white solid. After purification as described in Example 5, the product was dried under reduced pressure giving a white solid, m.p. 231°-233° C.
Reaction SMILES: [CH2:1]([C:7]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:15][C:8]=1[O:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:33](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([C:7]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:15][C:8]=1[O:9][CH2:10][CH:11]([OH:14])[CH2:12][O:13][C:33]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCc1ccc(CCCCCC)c(OCC(O)CO)c1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCc1ccc(CCCCCC)c(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 24 h
Yield: 71.2 %

Procedure:
A mixture of 12.77 g of 3-(2-hexyl-5-tetradecylphenoxy)-1,2-propanediol, 13.5 g of trityl chloride and 40 ml of pyridine was stirred for 24 hours, then diluted with chloroform, washed with aqueous sodium bicarbonate, water and dried. This crude material was chromatographed on silica gel, eluting with 17% ethyl acetate in hexane, giving 14 g of the desired compound.
Reaction SMILES: [H-].[Na+].[C@@H:3]1([CH2:13][CH:14]=[CH2:15])[O:11][C@@H:10]([CH3:12])[C@@H:8]([OH:9])[C@@H:6]([OH:7])[C@@H:4]1[OH:5].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:16]([O:5][C@H:4]1[C@H:6]([O:7][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:8]([O:9][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:10]([CH3:12])[O:11][C@H:3]1[CH2:13][CH:14]=[CH2:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=CC[C@@H]1O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]1O
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: C=CC[C@@H]1O[C@@H](C)[C@@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of NaH (3.91 g, 60% dispersion in oil, 98 mmol) in DMF (120 mL) at rt was added portionwise 3-(α-L-fucopyranosyl)-1-propene (4.6 g, 24.44 mmol). After 2 hr, to the resulting mixture was added tetrabutyl ammonium iodide (451 mg, 1.22 mmol) and followed by the slow addition of benzyl bromide (13.1 mL, 110 mml) After stirring at rt for 16 hr, the reaction mixture was concentrated and the residue was partitioned between water (300 mL) and Et2O (150 mL). The aqueous layer was extracted with Et2O (3×150 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (220 g), eluting with 0-40% EtOAc in hexanes to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 1.34 (d, J=6.6, 3H), 2.33 (m, 1H), 2.42 (m, 1H), 3.82 (m, 3H), 3.99 (m, 1H), 4.12 (m, 1H), 4.58 (d, J=11.8, 1H), 4.64 (d, J=11.8, 2H), 4.69 (d, J=12.0, 1H), 4.76 (dd, J=12.0, 8.9, 2H), 5.05, 5.07 and 5.11 (m, 2H), 5.80 (m, 1H), 7.30-7.40 (m, 15H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[NH:10][CH2:11][CH2:12][C:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:10][CH2:11][CH2:12][C:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=2)[C:19]2[CH:20]=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NCCC2=CCCCC2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(NCCC2=CCCCC2)c2cccc(N)c2)cc1

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-[2-(cyclohexen-1-yl)ethyl]amine (2.80 g) [prepared as described in step (a) above] in methanol (60 m), nickel chloride hexahydrate (3.61 g) and sodium borohydride (1.15 g) were reacted, to afford a mixture (2.15 g) of the title compound and the reduction product of the title compound, that is 3-[(4-methoxyphenyl)-(2-cyclohexylethylamino)methyl]phenylamine, as a yellow oil.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:14][C:15]([O:18][C:19]([N:21]1[C@H:25]([C:26]([O:28][CH3:29])=[O:27])[CH2:24][C@@H:23]([OH:30])[CH2:22]1)=[O:20])([CH3:17])[CH3:16]>CC(C)=O>[CH3:29][O:28][C:26]([C@@H:25]1[CH2:24][C:23](=[O:30])[CH2:22][N:21]1[C:19]([O:18][C:15]([CH3:17])([CH3:16])[CH3:14])=[O:20])=[O:27]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Jones' reagent (11 mL, 88.5 mmol) is added dropwise over a period of 5 minutes to a solution of Boc-HYP-OMe (3 g, 12.2 mmol) in acetone (150 mL). The stirring is continued for an additional 30 minutes. The reaction is quenched with methanol (3 mL) and stirred at room temperature overnight. The reaction mixture is filtered through Celite® and the filtrate is concentrated under reduced pressure. It was diluted with water and extracted with dichloromethane 3 times. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound. ESI m/z 144 [M+H+−100].
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:10]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>O>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH3:10])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: O=c1[nH]cc(Br)cc1Br
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: Cn1cc(Br)cc(Br)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
A 1-L round-bottomed flask equipped with a magnetic stirrer was charged with 3,5-dibromo-1H-pyridin-2-one (7.0 g, 27.7 mmol), anhydrous DMF (280 mL) and powdered potassium carbonate (−350 mesh, 8.4 g, 61.1 mmol), and the suspension stirred for 15 min at ambient temperature. After this time, methyl iodide (4.3 g, 30.5 mmol) was added, and the mixture was stirred at room temperature under nitrogen for the further 18 h. The reaction mixture was then diluted with water (200 mL), extracted with ethyl acetate (3×250 mL), dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica to give an 84% yield (6.2 g) of 3,5-dibromo-1-methyl-1H-pyridin-2-one as an off-white solid; mp 87-88° C.; MS (ESI+) m/z 266 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[N:16][N:15]3[CH:24]=2)=[CH:8][CH:7]=1.[I:25]N1C(=O)CCC1=O>C(#N)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH3:23])=[N:16][N:15]3[C:24]=2[I:25])=[CH:8][CH:7]=1
Reactant: CCCOc1ccc2nc(-c3ccc(OCCOC)cc3)cn2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CCCOc1ccc2nc(-c3ccc(OCCOC)cc3)c(I)n2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.9 %

Procedure:
A mixture of 2-[4-(2-methoxyethoxy)phenyl]-6-propoxyimidazo[1,2-b]pyridazine (327 mg, 1.00 mmol), N-iodosuccinimide (225 mg, 1.00 mmol) and acetonitrile (4 mL) was stirred at room temperature for 1.5 hours. The mixture was filtered and the collected solid washed with cold, fresh acetonitrile to afforded Compound 96 (344 mg, 76%) as an off-white solid. 1H n.m.r. (CDCl3) δ 1.08, t, J=7.3 Hz, 3H; 1.8-2.0, m, 2H; 3.47, s, 3H; 3.75-3.83, m, 2H; 4.15-4.23, m, 2H; 4.41, t, J=6.6 Hz, 2H; 6.76, d, J=9.5 Hz, 1H; 7.04, d, J=9.3 Hz, 2H; 7.80, d, J=9.9 Hz, 1H; 8.04, d, J=8.7 Hz, 2H. Mass spectrum (APCI+) m/z 454 (M+H, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>[Pd].CCO>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])c(-n3cccn3)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCN(c2ccc(N)c(-n3cccn3)c2)CC1

Procedure:
1-(4-Nitro-3-pyrazol-1-yl-phenyl)-piperidine-4-carboxylic acid ethyl ester was treated under standard hydrogenation conditions (H2, EtOH, 10% Pd/C) to yield desired 1-(4-Amino-3-pyrazol-1-yl-phenyl)-piperidine-4-carboxylic acid ethyl ester as a glass, which was used for the subsequent reaction without further purification; TLC: 1:1 EtOAc/Hexane Rf 0.5, homogeneous; LC/MS (m/e) 315.28 (M+H).
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[I:12]Cl>ClCCl>[Cl:11][C:2]([Cl:1])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[C:8]([I:12])[CH:9]=1)=[O:4]
Reactant: ClI
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(c1cc(I)c[nH]1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a stirred solution of 50 g (235 mmol, 1.0 equiv.) of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)-ethanone in dry dichloromethane (400 mL) under nitrogen, a solution of iodine monochloride (39 g, 240 mmol, 1.02 equivalents) in of dichloromethane (200 mL) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours. The solution was washed with 10% potassium carbonate, water, 1.0 M sodium thiosulfate, saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The solid was recrystallized from hexanes/methyl acetate to afford the title compound (68.5 g, 86%) as a colorless solid (86%). MS FIA: 335.8, 337.8 ES−.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][CH:3]=1.[O:16]1[C:20]2([CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1>>[C:10]([Si:7]([CH3:9])([CH3:8])[O:6][C:5]1[CH:14]=[CH:15][C:2]([C:23]2([OH:26])[CH2:24][CH2:25][C:20]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:21][CH2:22]2)=[CH:3][CH:4]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2(O)CCC3(CC2)OCCO3)cc1

Procedure:
The title compound was prepared as a white solid from (4-bromo-phenoxy)-tert-butyl-dimethyl-silane (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:25][C:14]3=[N:15][CH:16]=[CH:17][C:18]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[C:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]([C:28]1[C:29](=[O:35])[NH:30][C:31](=[O:34])[NH:32][CH:33]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:25][C:14]3=[N:15][CH:16]=[CH:17][C:18]([N:19]4[CH2:20][CH2:21][N:22]([CH2:26][C:28]5[C:29](=[O:35])[NH:30][C:31](=[O:34])[NH:32][CH:33]=5)[CH2:23][CH2:24]4)=[C:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1c[nH]c(=O)[nH]c1=O
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCNCC4)ccnc3[nH]2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1ccc(-c2nc3c(N4CCN(Cc5c[nH]c(=O)[nH]c5=O)CC4)ccnc3[nH]2)cc1
Reaction time: 18 h
Yield: 36 %

Procedure:
2-(4-tert-Butyl-phenyl)-7-piperazin-1-yl-3H-imidazo[4,5-b]pyridine (7) (50 mg, 0.15 mmol) and 5-formyluracil (21 mg, 0.15 mmol) were dissolved in NMP (4 ml) and sodium triacetoxyborohydride (64 mg, 0.30 mmol) was added. The reaction mixture was allowed to stir for 18 h under nitrogen. It was judged complete by MS, and purified by HPLC Method E to yield the title product 9 (25 mg (36%), 0.054 mmol). 1H NMR (DMSO-d6): δ 11.45 (s, 1H), 11.30 (d, J=3 Hz, 1H), 9.85(bs, 1H), 8.11 (d, J=8.3 Hz, 3H), 7.74 (d, J=6.1 Hz, 1H), 7.54 (d, J=8.3 Hz, 2H), 6.78 (s, 1H), 4.05 (s, 2H), 3.20-3.65 (m, 8H), 1.33 (s, 9H). (ESI-POS): [M+H]+=460; MS(ESI-NEG):[M−H]−=458.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:38]>C(O)C>[ClH:38].[F:1][C:2]1[C:3]([CH2:22][NH:23][CH3:24])=[CH:4][N:5]([S:14]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)N2CCCC2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cn(S(=O)(=O)N2CCCC2)c(-c2cccnc2F)c1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
tert-Butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(pyrrolidin-1-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (260 mg) was dissolved in ethanol (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was stirred at 40° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 148 mg, 66%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([NH2:22])[C:18]=1[C:19]([OH:21])=[O:20]>[Cl-].C[N+](C)(C)CC1C=CC=CC=1.ClCCCl>[Cl:12][C:13]1[C:18]2[C:19](=[O:21])[O:20][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:22][C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Product: O=c1oc(-c2ccccc2)nc2cccc(Cl)c12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 112.6 %

Procedure:
92.3 g of benzoyl chloride and 52.6 g of 50% strength aqueous sodium hydroxide solution are introduced simultaneously via 2 feed apparatuses in the course of 40 minutes at from 22° to 38° C. to a stirred suspension of 128.6 g of 6-chloroanthranilic acid and 1.35 g of trimethylbenzylammonium chloride in 1,870 g of 1,2-dichloroethane. Stirring is continued for 30 minutes at 32° C., after which a further 16.3 g of benzoyl chloride and 9.3 g of 50% strength sodium hydroxide solution, as described above, are added in the course of 5 minutes, and the mixture is stirred for a further 55 minutes at from 25° to 30° C. The mixture is then refluxed for 11/4 hours to separate off water, this procedure being continued until the organic phase in the water separator no longer appears cloudy. 0.2 g of dimethylformamide are added, after which 96 g of gaseous phosgene are passed into the stirred refluxed mixture in the course of 13/4 hours, and excess phosgene is then expelled in the course of 5 minutes by blowing in nitrogen. After cooling to 40° C., the reaction mixture is extracted 3 times with water and once with a little concentrated sodium chloride solution. The organic phase is evaporated down under reduced pressure, in the final stage at 140° C. and under 20 mbar, 190.5 g (98.6%) of 5-chloro-2-phenyl-4H-3,1-benzoxazin-4-one of melting point 153°-156° C. being obtained. The purity according to HPLC is 97.4%.