Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([Cl:16])[C:8]=1[N:17]=[C:18]=S.Cl>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([Cl:16])[C:8]=1[N:17]=[C:18]1[NH:5][CH2:4][CH2:3][CH2:2][NH:1]1
Reactant: NCCCN
Reactant: O=[N+]([O-])c1cc(Cl)c(N=C=S)c(Cl)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Cl)c(N=C2NCCCN2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.8 %

Procedure:
A solution of 1.65 mL (0.02 mol) of 1,3-diaminopropane in toluene (10 mL) was cooled to -10° C. using an ice/methanol bath. To this solution was added 2,6-dichloro-4-nitrophenylisothiocyanate (2.45 g, 0.01 mol) in toluene (10 mL) dropwise over 30 minutes, which reacted to form a red oil. The reaction was stirred for an additional 2 hours, then heated at reflux for 4 hours. The mixture was cooled to room temperature then treated with 30 mL of 1 M HCl. After filtration of some insoluble material, the biphasic mixture was separated and the aqueous phase was basified to pH 9 using 1M NaOH. The resulting yellow precipitate was collected by filtration, washed with water, then hexane and air dried to give 0.6 g (21%) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=O.CO.[NH2:24][C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1.[OH-].[Na+]>[Pd].C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH2:20][NH:24][C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: O=Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Reactant: Nc1ncccn1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CO
Product: O=c1c2cc(F)ccc2nc(CNc2ncccn2)n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.200 g, 0.66 mmol), methanol (20 mL), and 2-aminopyrimidine (0.059 g, 0.62 mmol) was refluxed 29 hours. The mixture was cooled to room temperature and 10% palladium on carbon (0.236 g) and formic acid (1.1 mL) were added. The mixture was allowed to stir at ambient temperature overnight. The reaction was treated with 6 N sodium hydroxide to adjust the pH to 10. The mixture was filtered through celite and the pad was washed with ethyl acetate. The filtrate was dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (20 g) with elution proceeding as follows: 10% ethyl acetate/hexane (500 mL), nil; 20% ethyl acetate/hexane (250 mL), unweighed impurity, 20% ethyl acetate/hexane (100 mL), mixed fraction, unweighed; 20% ethyl acetate/hexane (150 mL) and 30% ethyl acetate/hexane (150 mL), unweighed 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-methanol (a side product). Elution was continued: 30% ethyl acetate/hexane 410 mL), nil; 40% ethyl acetate/hexane (450 mL), nil; 40% ethyl acetate/hexane (50 mL) and 50% ethyl acetate/hexane (450 mL), 0.028 g (8%) of 3-(2-Chloro-phenyl)-6-fluoro-2-(pyrimidin-2-ylaminomethyl)-3H-quinazolin-4-one as a white solid which had: mp 182-185° C.; 1H NMR δ 8.29 (d, J=5 Hz, 2 H), 7.92 (dd, J=3, 8 Hz, 1 H), 7.82 (dd, J=5, 9 Hz, 1 H), 7.66-7.64 (m, 1 H), 7.55-7.49 (m, 3 H), 7.40-7.38 (m, 1 H), 6.63 (t, J=5 Hz, 1 H), 4.28 (dd, J=4.5, 18 Hz, 1 H), 4.11 (dd, J=4, 18 Hz, 1 H). Analysis calculated for C19H11ClFN5O.0.75 H2O: C, 58.05; H, 3.20; N, 17.81. Found: C, 58.06; H, 3.25; N, 17.33. APCI MS m/z=382 (P+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[CH:8][NH:7][N:6]=1)=[O:4].[C:10]1([C:16](Cl)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:6]=1)=[O:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 28.8 %

Procedure:
A solution of 1H-[1,2,4]triazole-3-carboxylic acid methyl ester (3.0 g, 0.023 mol) in N,N-dimethylformamide at 25° C. was treated with triphenylmethylchloride (7.2 g, 0.025 mol) and triethylamine (6.41 mL, 0.046 mol). The reaction was stirred at 25° C. for 4 days. At this time, the reaction was concentrated in vacuo. The residue was diluted with ethyl acetate and then washed with a dilute 1N aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solids were diluted with ether, collected by filtration, washed with ether, and dried in vacuo to afford 1-trityl-1H-[1,2,4]triazole-3-carboxylic acid methyl ester (2.45 g, 84%) as a white solid: LR-FAB for C23H19N3O2 (M+H)+ at m/z=370.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][C:42]1[C:47]([S:48](Cl)(=[O:50])=[O:49])=[CH:46][CH:45]=[CH:44][N:43]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:47]2[C:42]([CH3:41])=[N:43][CH:44]=[CH:45][CH:46]=2)(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ncccc1S(=O)(=O)Cl
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncccc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Yield: 86.1 %

Procedure:
To a suspension of sodium hydride (60% in oil, 34 mg) in tetrahydrofuran (2 mL) were added tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (226 mg), 15-crown-5 (185 mg) and a solution of 2-methylpyridine-3-sulfonyl chloride (174 mg) in tetrahydrofuran (1 mL) at room temperature, and the mixture was stirred for 18 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=17:3→1:1) to give the title compound as a yellow oil (yield 288 mg, 86%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:15][CH3:16])=[C:8]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:9]=1)(=[O:3])[CH3:2].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[OH-].[Na+]>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:15][CH3:16])=[C:8]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:9]=1)(=[O:3])[CH:2]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc(C(C)=O)cc1C=CC(=O)O
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=O)C=Cc2ccccc2)cc1C=CC(=O)O

Procedure:
Using 10 g (0.045 mole) of the acid obtained in step (c), 80 ml of 20% sodium hydroxide and 5 g (0.045 mole) of benzaldehyde and according to a modus operandi similar to the one described in step (c) of preparation I, 11.5 g of the desired pure product are obtained, m.p.=204° C.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([N:13]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN([CH:36]=[O:37])C>>[CH2:26]([N:13]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[C:17]([CH:36]=[O:37])=[CH:16][CH:15]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CN(C)C=O
Reactant: COc1ccc2cccc(N(Cc3ccccc3)Cc3ccccc3)c2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(C=O)ccc(N(Cc3ccccc3)Cc3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of DMF (30 mL) was added POCl3 (10.65 mL, 116 mmol) over 30 minutes at 0° C. The mixture was then stirred at 0° C. for 30 minutes and added 4 (11.75 g, 33.2 mmol) in DMF (120 mL). The mixture was stirred at room temperature for six days and the poured into ice-water. The product mixture was extracted with dichloromethane and the organic layer washed with water, aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated to afford 13.58 g of 4-(dibenzylamino)-6-methoxy-1-naphthaldehyde (5) which was used in next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:11]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])=[CH:10][C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:28](=O)[CH3:29]>>[CH2:28]([N:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[C:9]1[CH:10]=[C:11]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[C:2]([F:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5])[CH3:29]
Reactant: COC(=O)c1cc(NCc2ccc(OC)cc2)cc(N2CCCC2=O)c1F
Reactant: CC=O
Product: CCN(Cc1ccc(OC)cc1)c1cc(C(=O)OC)c(F)c(N2CCCC2=O)c1

Procedure:
Methyl 5-(ethyl{[4-(methyloxy)phenyl]methyl}amino)-2-fluoro-3-(2-oxo-1-pyrrolidinyl)benzoate (D155) was prepared from methyl 2-fluoro-5-({[4-(methyloxy)phenyl]methyl}amino)-3-(2-oxo-1-pyrrolidinyl)benzoate (D154) in an analogous manner to the process described for Ester 35 (B35) using acetaldehyde instead of propionaldehyde. [M+H]+=401.4, RT=3.11 min.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[C:12]4[O:17][CH2:16][O:15][C:13]4=[CH:14][C:8]=3[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][N:5]2[C:24]=1[CH3:25].C([Li])CCC.CN(C)[CH:33]=[O:34].O>O1CCCC1>[CH:33]([C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[C:12]4[O:17][CH2:16][O:15][C:13]4=[CH:14][C:8]=3[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][N:5]2[C:24]=1[CH3:25])=[O:34]
Reactant: CN(C)C=O
Reactant: Cc1c(Br)nc2n1N=C(c1ccccc1)c1cc3c(cc1C2)OCO3
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C=O)nc2n1N=C(c1ccccc1)c1cc3c(cc1C2)OCO3
Reaction time: 0.25 h

Procedure:
120 mg of 9-bromo-8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine is mixed in 15 ml of tetrahydrofuran at −78° C. with 0.36 ml of butyllithium (hexane, 1 mol) and stirred for 15 minutes. It is then mixed at this temperature with 0.6 ml of dimethylformamide and stirred for 15 minutes. After stirring to room temperature, it is mixed with water, the tetrahydrofuran is distilled off and extracted with ethyl acetate. After the solvent is distilled off, it is chromatographed on silica gel with dichloromethane:ethanol=95:5 as an eluant. 46 mg of 9-formyl-8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:36][NH:37][O:38][CH3:39]>C1COCC1>[CH3:39][O:38][N:37]([CH3:36])[C:17]([CH:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12]1)=[O:19]
Reactant: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a cooled (−15° C. to −20° C.) and stirred solution of 1-[(benzyloxy)carbonyl]-3-piperidinecarboxylic acid (4.0 g, 15.2 mmol) in dry THF (50 mL) including methylmorpholine (2 mL) was added dropwise a solution of isobutyl chloroformate (2.28 g, 16.7 mmol) in THF (10 mL). After the mixture was stirred at the same temperature for 20 min, a solution of N,O-dimethylhydroxylamine hydrochloride (1.63 g, 16.7 mmol) in THF (20 mL) including methylmorpholine (2 mL) was added. The reaction mixture was allowed to warm to room temperature, and then stirred for 16 hrs. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The separated organic phase was washed with 1N HCl, saturated NaHCO3, and brine, successively. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give benzyl 3-{[methoxy(methyl)amino]carbonyl}-1-piperidinecarboxylate as a colorless oil (4.7 g, yield; quant.).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH:10]([OH:22])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.C>[Pd].O1CCOCC1>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH:10]([OH:22])[CH2:9][O:8][C:7]2[CH:23]=[CH:24][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(OCC(O)COc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1ccc(OCC(O)COc2ccc(N)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A 33.4 g (0.1 mole)-viscous liquid of 1,3-bis(4-nitrophenoxy)-2-propyl alcohol obtained in Example 6, 3 g of activated charcoal powder containing 5% Pd, and 250 ml of 1,4-dioxane were placed in a reaction vessel (hydrogenating apparatus). And the reaction mixtures were heated at 60° C. under a hydrogen atmosphere. In approximately 8 hours, 14.4 L of hydrogen was absorbed and the reaction was completed when the absorption of hydrogen stopped. Then the reacted solution was separated by filtration and the filtrate was concentrated for removing the catalyst. 27.4 g of 1,3-bis(4- aminophenoxy)-2-propyl alcohol was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11](=O)[CH3:12])=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:14][Mg]Br>CCOCC>[C:11]([C:10]1[C:2]([CH3:1])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12)([CH3:12])=[CH2:14]
Reactant: C[Mg]Br
Reactant: CC(=O)c1c(C)nn2ccccc12
Solvent: CCOCC
Product: C=C(C)c1c(C)nn2ccccc12
Temperature: 25 °C
Reaction time: 7 h
Yield: 54.4 %

Procedure:
A 0° C. solution of 1-(2-methylpyrazolo[1,5-a]pyridin-3-yl)ethanone (1.05 g, 6.0 mmol) in ether (20 mL) was treated with 3.0 M ether solution of methyl magnesium bromide (4 mL, 12.0 mmol). The reaction was allowed to warm to room temperature and stirred for 7 hours. The reaction was quenched with 2N HCl then extracted with ethyl acetate, washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (50% ethyl acetate/heptane) to give 0.562 g (55%) of brown oil as the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J=7.0 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.19–7.15 (m, 1H), 6.82–6.78 (m, 1H), 5.20–5.19 (m, 1H), 5.04–5.03 (m, 1H), 2.42 (s, 3H), 2.16 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 148.1, 137.5, 136.1, 128.2, 123.7, 117.0, 113.7, 111.2, 110.7, 23.6, 13.6; HRMS (FAB) calcd for C11H12N2+H 173.1079. found 173.1076.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[Cl:5][C:6]1[C:11]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[N:16][C:17]([CH3:23])=[CH:18][CH:19]=3)[C:13]2=[O:14])=[C:10]([C:24]#[N:25])[C:9]([CH3:26])=[CH:8][CH:7]=1>O1CCCC1>[CH2:1]([NH:4][C:13]([C:15]1[C:20]([C:21]([NH:12][C:11]2[C:6]([Cl:5])=[CH:7][CH:8]=[C:9]([CH3:26])[C:10]=2[C:24]#[N:25])=[O:22])=[CH:19][CH:18]=[C:17]([CH3:23])[N:16]=1)=[O:14])[CH2:2][CH3:3]
Reactant: Cc1ccc2c(n1)C(=O)N(c1c(Cl)ccc(C)c1C#N)C2=O
Reactant: CCCN
Solvent: C1CCOC1
Product: CCCNC(=O)c1nc(C)ccc1C(=O)Nc1c(Cl)ccc(C)c1C#N
Reaction time: 12 h

Procedure:
0.46 g (7.699 mmol) of n-propylamine was added with stirring at 22° C. to a mixture of 0.6 g (1.92 mmol) of the compound from example 11 in 30 ml of tetrahydrofuran and stirred for 12 h. The reaction mixture was concentrated in vacuo and the residue was stirred with diisopropyl ether/diethyl ether 20:1. After filtering off with suction and drying, 0.6 g (82.4% of theory) of the title compound were obtained as colorless crystals of m.p. 129-131° C.
Reaction SMILES: [H][H].C([O:10][C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]2[C:18]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:24][C:23]=3[CH3:33])=[N:19][N:20]([CH3:21])[C:12]=12)C1C=CC=CC=1>[Pd]>[CH3:21][N:20]1[C:12]2[C:13](=[N:14][C:15]([CH3:17])=[CH:16][C:11]=2[OH:10])[C:18]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[CH:31][CH:30]=[N:29]3)=[CH:24][C:23]=2[CH3:33])=[N:19]1
Reactant: [H][H]
Reactant: Cc1cc(OCc2ccccc2)c2c(n1)c(-c1ccc(-n3cccn3)cc1C)nn2C
Agent: [Pd]
Product: Cc1cc(O)c2c(n1)c(-c1ccc(-n3cccn3)cc1C)nn2C
Yield: 76.9 %

Procedure:
To a solution of compound 3a (2.0 g in 30 mL ethanol) was added 10% palladium on carbon (0.3 g). The reaction was shaken for 2 hours under 40 psi hydrogen. The reaction mixture was filtered through a pad of Celite®, and the filter cake was washed with ethanol. The filtrate was concentrated to afford 1,5-dimethyl-3-(2-methyl-4-pyrazol-1-yl-phenyl)-1H-pyrazolo[4,3-b]pyridin-7-ol (compound 3e, 1.2 g, 77%) as an off white solid; LC/MS: [M+H]=319.0.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][N:16]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][N:16]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(CCCO)CC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Product: CN1CCN(CCCOc2ccc(C#N)cn2)CC1
Yield: 47.2 %

Procedure:
This compound was prepared by the method described in General Procedure 5 in Example 27 using 3-(4-methyl-piperazin-1-yl)-propan-1-ol (1.0 g, 6.32 mmol), 60% sodium hydride (379 mg, 9.48 mmol), and 6-chloronicotinonitrile (876 mg, 6.32 mmol). The reaction mixture was partitioned between satd. aq. NaHCO3 (30 mL) and CHCl3 (60 mL). The organic layer was dried (Na2SO4), filtered, and concentrated. Purification by Method 1 afforded 776 mg (47%) of a beige solid. MS (ESI): mass calcd for C14H20N4O, 260.16; m/z found, 261.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.47 (dd, J=2.3, 0.8, 1H), 7.77 (dd, J=8.6, 2.3, 1H), 6.80 (dd, J=8.6, 0.8, 1H), 4.41 (t, J=6.6, 2H), 2.76-2.35 (m, 10H), 2.29 (s, 3H), 2.01-1.95 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH2:8]=[O:9]>>[CH2:8]([N:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3])[OH:9]
Reactant: O=C1CNC(=O)N1
Reactant: C=O
Product: O=C1CN(CO)C(=O)N1

Procedure:
reacting (i) the at least one hydantoin reactant and (ii) the at least one dehydrated formaldehyde source reactant or substantially anhydrous formaldehyde source reactant in the molten system, while removing reaction water, to yield anhydrous molten methylolhydantoin; and
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: OCc1ccccn1
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2Cc1ccccn1

Procedure:
Compound IIp was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and pyridin-2-ylmethanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:42]1[CH2:52][CH2:51][CH2:50][CH2:49][CH:43]1[C:44]([O:46]CC)=[O:45]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34]([N:42]2[CH2:52][CH2:51][CH2:50][CH2:49][CH:43]2[C:44]([OH:46])=[O:45])=[O:35])=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCCCN1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)O)c2)cc1
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)N3CCCCC3C(=O)O)c2)cc1

Procedure:
The product from Example 116B (57 mg, 0.10 mmole) and ethyl pipecolinate (31 mg, 0.20 mmole) were processed as in Example 279A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.29-13.30 (br.s, 1 H), 8.95 (s, 1 H), 7.24 (m, 8 H), 7.04 (m, 1 H), 6.95 (m, 4 H), 6.69 (m, 1 H), 6.49 (m, 2 H), 5.07 (d, 1 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.94 (m, 2 H), 3.77 (d, 1 H), 3.09 (m, 1 H), 2.91 (s, 3 H), 2.49 (m, 2 H), 2.40 (s, 3 H), 2.12 (m, 1 H), 1.90 (m, 2 H), 1.62 (m, 2 H), 1.49 (m, 1 H), 1.35 (m, 1 H), 1.21 (m, 1 H); MS (APCI+) m/z 685.9 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]([C:11]2[CH:16]=[C:15]([OH:17])[C:14]([Cl:18])=[CH:13][C:12]=2[F:19])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].[CH2:26](I)[CH3:27].O>CN(C)C=O>[Cl:18][C:14]1[C:15]([O:17][CH2:26][CH3:27])=[CH:16][C:11]([N:3]2[CH:2]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]3)=[N:4]2)=[C:12]([F:19])[CH:13]=1
Reactant: Oc1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(-n2cc3c(n2)CCCC3)c(F)cc1Cl
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Into a solution of 3-chloro-2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-indazole (0.9 g) in dimethylformamide (10 ml), there was added potassium carbonate (0.25 g) and ethyl iodide (1 g), and the mixture was stirred for 60° C. for 3 hours. After cooling, water was added to the reaction mixture, followed by extraction with ether. The ether layer was washed with water twice, dried and concentrated. The residue was crystallized from hexane to give 0.2 g of 3-chloro-2-(4-chloro-2-fluoro-5-ethoxyphenyl-4,5,6,7-tetrahydro-2H-indazole (Compound No. 1). m.p., 85.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=O)[C:9]=2[CH2:24][CH3:25])=[CH:4][CH:3]=1.Cl.[NH2:27][CH2:28][C:29]([NH2:31])=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[NH:31][C:29](=[O:30])[CH2:28][N:27]=3)[C:9]=2[CH2:24][CH3:25])=[CH:6][CH:7]=1
Reactant: CCc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: NCC(N)=O
Agent: Cl
Product: CCc1c(C2=NCC(=O)N2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Compound 26 was synthesized from 4c (1.0 g, 2.53 mmol) and 2-amino-acetamide hydrochloride (5k) (0.56 g, 4.56 mmol) as a white solid (0.81 g, 73%) in a manner similar to that described in Example 53. 1H NMR (400 MHz, CDCl3) δ 7.43 (d, 1H), 7.31 (d, 2H), 7.30˜7.27 (m, 2H), 7.07 (d, 2H), 4.35 (d, 2H), 2.77 (q, 2H), 1.20 (t, 3H); ESMS m/z: 433.1 (M+1).