Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[H-].[Na+].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20]>O1CCCC1.C(OCC)(=O)C>[CH3:17][N:18]([CH3:22])[C:19](=[O:20])[O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][N:4]2[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=1
Reactant: C#CCN1CCCc2ccc(O)cc21
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CCN1CCCc2ccc(OC(=O)N(C)C)cc21
Reaction time: 0.5 h

Procedure:
A solution of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (400 mg, 2.14 mM) in dry tetrahydrofuran (THF; 5 mL) was added to the stirred solution of sodium hydride in dry THF at −10° C. during 5 minutes under nitrogen environment at room temperature (25° C.). The reaction mixture was stirred for 30 minutes. Then, N,N-dimethyl carbamoyl chloride (0.25 mL) was added to the stirring reaction mixture. The mixture was stirred further for 7 hours during which the temperature was allowed to reach the room temperature (35° C.). The reaction mixture was diluted with ethyl acetate, washed with water, and dried over sodium sulphate. The combined fractions of ethyl acetate were concentrated under vacuum and chromatographed using ethyl acetate:hexane (1:49) to afford 10g as solid. Yield: 414 mg, 75.6%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>C(OCC)(=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Clc1ccc(NC2CCNCC2)cc1
Yield: 87 %

Procedure:
The tert-butyl-4-(4-chlorophenylamino)piperidine-1-carboxylate (973.2 mg, 3.1 mmol) obtained in step 1 was dissolved in ethyl acetate and mixed at 0 C for 3 hr with 6N HCl (5 mL), with stirring, after which distilled water was added to terminate the reaction. The resulting reaction mixture was washed with ethyl acetate. The pH of the aqueous layer thus formed was adjusted to 10 to 12 with 2N sodium hydroxide, followed by washing with ethyl acetate and saline to separate an organic solvent layer. This organic solvent layer was dried over anhydrous magnesium sulfate and evaporated at reduced pressure to afford N-(4-chlorophenyl)piperidine-4-amine (yield 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[Al].[Pb](Br)Br.[C:15](Cl)([Cl:18])([Cl:17])[Cl:16]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[C:15]([Cl:18])([Cl:17])[Cl:16])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: ClC(Cl)(Cl)Cl
Agent: Br[Pb]Br
Agent: [Al]
Solvent: CN(C)C=O
Product: Oc1ccc(C(O)C(Cl)(Cl)Cl)cc1Cl
Yield: 89 %

Procedure:
3-Chloro-4-hydroxy benzaldehyde (15.6 g, 0.1 mol) was added to 200 ml of dimethylformamide, a mixture was stirred, aluminium (8.09 g, 0.3 mol) and leadbromide (3.67 g, 0.01 mmol) were added thereto. CCl4 (61.53 g, 0.4 mol) was slowly added to the reaction mixture. The mixture was stirred at room temperature for 10 hours, and unreacted solid was filtered to remove therefrom. After sequentially adding 5% HCl, ethylacetate and water thereto, the mixture was extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and distilled. The resulting residue was subjected to column chromatography (ethyl acetate: n-hexane=1:4) to obtain the title compound (24.55 g, 89%).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:23]=1[O:24]C)[C:8]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12](=[O:20])(=[O:19])[CH2:11]1)=[O:9])=[O:4].[Cl-].[Li+].Cl>CN(C)C=O>[CH3:1][N:2]([CH3:30])[C:3]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:26]([F:29])([F:27])[F:28])[C:23]=1[OH:24])[C:8]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12](=[O:20])(=[O:19])[CH2:11]1)=[O:9])=[O:4]
Reactant: COc1c(C(=O)N(C)C)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C(F)(F)F)c1O
Temperature: 120 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
3-(3-dimethylcarbamoyl-4-methoxy-5-trifluoromethylbenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (291 mg) was dissolved in N,N-dimethylformamide (3 mL), and lithium chloride (279 mg) was added to the solution, and then the mixture was stirred at 120° C. for 2 hours. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (257 mg) as a colorless crystal.
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9]3[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>O1CCCC1.[Ni]>[N:1]1([C:7]2[S:8][C:9]3[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cccc2nc(N3CCOCC3)sc12
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cccc2nc(N3CCOCC3)sc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.4 %

Procedure:
To 0.075 g (0.28 mmol) of 2-morpholin-4-yl-7-nitro-1,3-benzothiazole in 6 mL of tetrahydrofuran (THF) was added a pipet tip of Raney nickel. The reaction was kept under a hydrogen atmosphere via a balloon and stirred at room temperature for 5 h. The catalyst was removed via filtration and the filtrate was concentrated in vacuo. Purification by flash chromatography failed to provide clean B so the 0.022 g (33%) of material thus isolated was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[CH3:16][N:17]([CH3:26])[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:22]2[C:21]1[CH:24]=[CH:25][C:18]([N:17]([CH3:26])[CH3:16])=[CH:19][CH:20]=1)([O-:15])=[O:14]
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Product: CN(C)c1ccc(C2Nc3ccccc3-c3c([N+](=O)[O-])cnn32)cc1
Yield: 72 %

Procedure:
5-(o-Aminophenyl)-4-nitropyrazole is reacted with p-dimethylaminobenzaldehyde as described in Example 11 to give 1-nitro-5-(p-dimethylaminophenyl)-5,6-dihydropyrazolo[1,5-c]quinazoline with a yield of 72%. M.p.: 190°-192° C.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:18]=[C:17]2[C:8]([N:9]3[C:14]([CH2:15][O:16]2)=[N:13][NH:12][C:11](=[O:19])[C@H:10]3[CH3:20])=[CH:7][C:6]=1[C@H:21]([C:23]1([CH3:27])[CH2:26][NH:25][CH2:24]1)[CH3:22])([CH3:4])[CH3:3].C=O.[BH3-][C:31]#N.[Na+]>CO.C(O)(=O)C>[CH3:31][N:25]1[CH2:24][C:23]([C@@H:21]([C:6]2[CH:7]=[C:8]3[C:17](=[CH:18][C:5]=2[CH:2]([CH3:3])[CH3:4])[O:16][CH2:15][C:14]2[N:9]3[C@H:10]([CH3:20])[C:11](=[O:19])[NH:12][N:13]=2)[CH3:22])([CH3:27])[CH2:26]1
Reactant: CC(C)c1cc2c(cc1[C@@H](C)C1(C)CNC1)N1C(=NNC(=O)[C@H]1C)CO2
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)c1cc2c(cc1[C@@H](C)C1(C)CN(C)C1)N1C(=NNC(=O)[C@H]1C)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
To a solution of (R)-7-isopropyl-4-methyl-6-[(R)-1-(3-methyl-azetidin-3-yl)-ethyl]-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloric acid (Example #133, Step G, 0.0227 g, 0.064 mmol) in MeOH (2 mL) and acetic acid (0.2 mL) was added paraformaldehyde (0.765 mL, 0.255 mmol) and the reaction mixture was stirred at ambient temperature for 0.5 h. NaBH3CN (0.008 g, 0.127 mmol) was added and the reaction mixture was stirred at ambient temperature for 0.5 h. The reaction mixture was concentrated in vacuo and the residue was purified by prep-TLC (eluting with 10% MeOH in dichloromethane) to give (R)-6-[(R)-1-(1,3-dimethyl-azetidin-3-yl)-ethyl]-7-isopropyl-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.0199 g, 84%) as a solid. 1H NMR (CD3OD-d4, 400 MHz): δ 7.00 (s, 1H), 6.79 (s, 1H), 4.83 (br. s., 1H), 4.60 (s, 2H), 3.96 (m, 1H), 3.91 (m, 1H), 3.76 (d, J=9.8 Hz, 1H), 3.67 (d, J=9.8 Hz, 1H), 3.38 (m, 1H), 3.18 (m, 1H), 2.71 (s, 3H), 1.48-1.43 (m, 6H), 1.38 (d, J=6.8 Hz, 3H), 1.30 (d, J=6.8 Hz, 3H), 1.15 (d, J=6.8 Hz, 3H). LC/MS (Table 1, Method 4) Rt=1.601 min.; MS m/z: 371 [M+H]+. SFC (Table 1, Method 24) Rt=7.354 min.
Reaction SMILES: C[O:2][C:3]1[C:8]2[O:9][C:10]3[C:15]([C@@:16]4([CH2:20][O:19][C:18]([NH2:21])=[N:17]4)[C:7]=2[CH:6]=[C:5]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[N:4]=1)=[CH:14][C:13]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[CH:12][CH:11]=3.B(Br)(Br)Br>C(Cl)Cl>[NH2:21][C:18]1[O:19][CH2:20][C@:16]2([C:7]3[CH:6]=[C:5]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[NH:4][C:3](=[O:2])[C:8]=3[O:9][C:10]3[C:15]2=[CH:14][C:13]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:12][CH:11]=3)[N:17]=1
Reactant: COc1nc(-c2cccnc2)cc2c1Oc1ccc(-c3cccnc3)cc1[C@@]21COC(N)=N1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1c2cc(-c2cccnc2)[nH]c1=O

Procedure:
To a solution of (S)-1-methoxy-3,7-di(pyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (15 mg, 0.034 mmol) in 5 mL of dry CH2Cl2 at rt was added boron tribromide (1 M in CH2Cl2, 1.0 m in DCM (0.34 mL, 0.343 mmol) and the resulting suspension was stirred at rt for 2 h. The reaction was quenched with half saturated NaHCO3 (50 mL) and extracted with EtOAc (3×25 mL). The combined organics were dried over sodium sulfate, filtered and evaporated to dryness. Purification by silica gel chromatography (CH2Cl2/MeOH=100:10 to 100:12 to 100:15 to 4:1) gave (S)-2′-amino-3,7-di(pyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-1(2H)-one.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][NH:11][C:10]2=[O:14])=[CH:5][CH:4]=1>C(O)(=O)C.[C].[Pd]>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[CH:7][CH:8]=1
Reactant: O=c1[nH]ccn1-c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C1NCCN1c1ccc(C(F)(F)F)cc1
Reaction time: 6 h
Yield: 81.9 %

Procedure:
1-(4-Trifluoromethylphenyl)-2(1H,3H)-imidazolone (1.15 g) was dissolved in 20 ml of acetic acid. 10% Palladium-carbon (0.3 g) was added thereto and the mixture was stirred under a hydrogen stream for six hours. The catalyst was filtered off, the solvent was distilled off and the residue was recrystallized from ethyl acetate-diisopropyl ether to give 0.95 g of 1-(4-trifluoromethylphenyl)-2-imidazolidinone as colorless prisms.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH3:13][O:14][CH2:15]Cl.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][O:14][CH3:15])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: COCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCOc1ccc(Br)c(C=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-5-hydroxybenzaldehyde (4.4 g) in tetrahydrofuran (100 ml) were added sodium hydride (1.2 g) and chloromethyl methyl ether (2.1 ml), and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.84 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([Cl:17])=[CH:12][CH:11]=2)=[O:7])[CH3:4].[CH3:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br.O>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:18][C:19]2[CH:26]=[CH:25][CH:24]=[C:21]([CH3:22])[CH:20]=2)[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([Cl:17])=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1Cc1cccc(C)c1
Reaction time: 17.5 h
Yield: 103.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.44 g, 7.45 mmol) was added to a suspension of 5-chloro-1H-indole-2-carboxylic acid ethyl ester (2.00 g, 8.94 mmol) in N,N′-dimethylformamide (DMF) (20 ml) under nitrogen. The mixture was stirred for 1 h before addition of the 3-methylbenzyl bromide (2.07 g, 2.48 ml) and the reaction stirred for 17.5 h. Water was added to reaction mixture which precipitated product as a gummy solid. Supernatant liquid was decanted and the solid washed with water. The product was dissolved in dichloromethane (DCM), washed with water, dried over magnesium sulfate and concentrated. Purification by silica chromatography using DCM as eluent, yielded 5-chloro-1-(3-methylbenzyl)-1H-indole-2-carboxylic acid ethyl ester (3.03 g, 95%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Cl[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[CH3:8][C:7]1[O:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:1]#[C:2][C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Clc1ncccn1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1onc(-c2ccccc2)c1C#Cc1ncccn1
Yield: 32 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-chloropyrimidine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 42 mg, 32%) which was obtained as a brown solid. MS: m/e=262.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[C:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:24].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:23]([CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])#[N:24]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: CCOC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C#N)c1cc(C(C)(C(=O)OCC)C(=O)OCC)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
Diethyl 2-(3-chloro-4-nitrophenyl)-2-methylmalonate (119 mg, 0.36 mmol.), ethyl cyanoacetate (81 mg, 0.72 mmol.), powdery potassium carbonate (119 mg, 0.86 mmol.), and dimethyl sulfoxide (1 mL) were mixed and stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, and washed with diethyl ether after addition of water. The aqueous portion was made acidic by addition of 6N hydrochloric acid, and extracted with diethyl ether. The ether portion was washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off to give 133 mg (yield: 92%) of the desired compound as a yellow oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[N:15]3[C:16]4[C:21]([N:22]=[C:23]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])[C:14]3=[N:13][CH:12]=2)=[CH:20][C:19]([C:29]([F:32])([F:31])[F:30])=[CH:18][CH:17]=4)[NH:8][N:7]=1)=O)C.[CH3:33][NH2:34]>C1COCC1>[OH:28][CH2:27][CH2:26][CH2:25][NH:24][C:23]1[C:14]2[N:15]([C:11]([C:9]3[NH:8][N:7]=[C:6]([C:4]([NH:34][CH3:33])=[O:3])[CH:10]=3)=[CH:12][N:13]=2)[C:16]2[C:21]([N:22]=1)=[CH:20][C:19]([C:29]([F:32])([F:31])[F:30])=[CH:18][CH:17]=2
Reactant: CN
Reactant: CCOC(=O)c1cc(-c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)[nH]n1
Solvent: C1CCOC1
Product: CNC(=O)c1cc(-c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)[nH]n1
Yield: 35 %

Procedure:
A solution of 5-[4-(3-Hydroxy-propylamino)-7-trifluoromethyl-imidazo[1,2-a]quinoxalin-1-yl]-1H-pyrazole-3-carboxylic acid ethyl ester (0.02 mmol; 7 mg), Methylamine (0.40 mmol; 40% wt in H2O; 0.1 mL), in THF (0.2 mL), under argon was stirred at 35° C. for 48 hr. Concentration, then purification by preparative TLC (dichloromethane/methanol) afforded the title compound as a white solid (3 mg; 0.007 mmol; 44%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH2:5]2.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH3:22][S:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:5]2)(=[O:25])=[O:24]
Reactant: Nc1ccc2c(c1)CCN(C(=O)CCc1ccccc1)C2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)CCN(C(=O)CCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of Example 19 in pyridine (10 mL) at 0° C. is added dropwise methanesulfonyl chloride (0.86 mL). After 45 minutes at 0° C., the reaction is allowed to warm to room temperature and stirred an additional 30 minutes. The pyridine is removed and the residue taken up into CH2Cl2 and washed with 10% HCl. The organic phase is washed with brine, dried over MgSO4, filtered and concentrated. Chromatography on silica gel will provide the desired material.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f61) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]5)=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>Cl>[CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]5)=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(CCc6ccccc6)c5)c4c3)cc2)CC1
Agent: Cl
Product: c1ccc(CCn2cc(-c3c[nH]c4ncc(-c5ccc(N6CCNCC6)cc5)cc34)cn2)cc1
Yield: 73.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-phenethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (130 mg, 0.238 mmol) was deprotected in methanolic HCl (5 ml). This afforded 78 mg (58.6% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.49 (s, 1H), 8.327-8.322 (d, 1H), 7.878-7.876 (d, 1H), 7.788-7.7.87 (d, 1H), 7.672-7.644 (m, 3H), 7.23-7.12 (m, 7H), 4.47-4.43 (t, 2H), 3.52-3.49 (m, 4H), 3.43-3.40 (m, 4H), 3.20-3.17 (t, 2H). MS: m/z=449.4 (M+1), HPLC: 95.50% in method A.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][N:8]([C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.C(N(CC)CC)C.[CH3:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>C(Cl)Cl>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][N:8]([C:17]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:36](=[O:37])[C:35]4[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=4[CH3:33])=[CH:22][CH:23]=3)=[O:25])[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Cc1ncc2c(n1)-c1ccccc1N(C(=O)c1ccc(N)cc1)CC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncc2c(n1)-c1ccccc1N(C(=O)c1ccc(NC(=O)c3ccccc3C)cc1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.216 mg of 6,7-dihydro-2-methyl-7-(4-aminobenzoyl)-5H-pyrimido[5,4-d][1]benzazepine in 6 ml of methylene chloride under argon is added 100 μl of triethylamine followed by a solution of 2-methylbenzoyl chloride in 1.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours, washed with water, saturated NaHCO3 and the separated organic layer treated with activated carbon and filtered through MgSO4. The filtrate is evaporated to a residue which is dissolved in ethyl acetate and evaporated in vacuo to give 300 mg of the desired product as a pale yellow foam. HR FABMS: Exact Mass (M+H):449.1974.
Reaction SMILES: Br[C:2]1[C:3]([F:28])=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[CH:19][CH:18]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CC([O-])(C)C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C([O-])(O)=O.[Na+].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]>[F:28][C:3]1[C:2]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:9]1
Reactant: COc1cn(-c2cccc(Br)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cn(-c2cccc(N3CCOCC3)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Yield: 62.1 %

Procedure:
A mixture of 1-(3-bromo-2-fluorophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (221 mg, 0.5 mmol), morpholine (0.0525 mL, 0.6 mmol), NaOt-Bu (67.3 mg, 0.7 mmol), Xantphos (46.3 mg, 0.08 mmol) and Pd2(dba)3 (18.3 mg, 0.02 mmol) in 1,4-dioxane (2.5 mL) was heated to 90° C. for 18 h under Ar. The mixture was diluted with NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and recrystallized with AcOEt/hexane and EtOH/hexane to yield the title compound (139 mg, 59% yield) as a pale yellow solid: mp 187-189° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 2.97-3.08 (4H, m), 3.70-3.80 (7H, m), 6.61-6.72 (1H, m), 6.96 (1H, d, J=1.5 Hz), 7.06-7.17 (2H, m), 7.26-7.47 (5H, m), 7.78 (1H, d, J=1.9 Hz), 8.50 (1H, d, J=1.9 Hz). Anal. Calcd for C24H22FN5O3: C, 64.42; H, 4.96; N, 15.65. Found: C, 64.47; H, 4.99; N, 15.55.
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[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH: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[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from cis-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A141) and acetyl chloride the title compound is obtained as colorless solid.