Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](N(CC)CC)C.B.Cl.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][NH2:26])[CH2:20][CH2:19]1>O1CCCC1.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:19][CH2:20][N:21]([CH2:24][C@H:25]([NH2:26])[CH3:1])[CH2:22][CH2:23]1
Reactant: CCN(CC)CC
Reactant: COc1ccccc1N1CCN(CCN)CC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccccc1N1CCN(C[C@@H](C)N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The above mentioned (R)-{1-methyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-amino-propan-2-1-one hydrochloride (5.90 g, 19.7 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) at room temperature. Triethylamine (6.3 mL, 45 mmol) was added, followed by dropwise addition of a 1M solution of borane in tetrahydrofuran (77.5 mL, 45 mmol). The resulting mixture was refluxed for 18 hours. After cooling the reaction mixture to room temperature, ethyl acetate (60 mL) and 2N aqueous HCl were added and the resulting mixture was stirred at room temperature for one hour. The layers were separated and the aqueous layer was made basic by careful addition of 50% aqueous NaOH. The resulting basic mixture was extracted with three 50 mL portions of ethyl acetate. The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. Filtration and concentration on a rotary evaporator yielded 4.62 g (94%) of the desired of 2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethylamine as a colorless oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3([O:16][C:7]=2[C:6]([C:17](OC)=[O:18])=[CH:5][CH:4]=1)[CH2:15][CH2:14][S:13][CH2:12][CH2:11]3.[Cl:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:29])[C:27]=1[CH3:28].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH4+].[Cl-]>O1CCCC1>[Cl:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:29])[C:27]=1[CH2:28][C:17]([C:6]1[C:7]2[O:16][C:10]3([CH2:15][CH2:14][S:13][CH2:12][CH2:11]3)[O:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:18]
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COC(=O)c1ccc(OC)c2c1OC1(CCSCC1)O2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OC1(CCSCC1)O2
Reaction time: 8 h
Yield: 63.7 %

Procedure:
A solution of methyl 7-methoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-thiopyran]-4-carboxylate (40 mg, 0.14 mmol) and 3,5-dichloro-4-picoline (33 mg, 0.20 mmol) in tetrahydrofuran (1.1 mL) was cooled to 0° C. A 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.41 mL, 0.41 mmol) was added and the reaction mixture was allowed to reach room temperature overnight. Saturated aqueous NH4Cl (20 mL) was added. The aqueous phase was extracted with dichloromethane (3×15 mL). The combined organic phase was dried over MgSO4 and evaporated to dryness under reduced pressure. Standard HPLC purification afforded 2-(3,5-dichloropyridine-4-yl)-1-(7-methoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-thiopyran]-4-yl)ethanone (38 mg, 67%). 13C NMR (DMSO) δ 189.1, 148.2, 147.7, 147.0, 141.3, 134.5, 132.8, 122.0, 119.1, 113.0, 107.9, 56.3, 43.6, 35.9, 25.5.
Reaction SMILES: C([O:5][C:6](=[O:46])[CH2:7][N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[CH:29][CH:28]=2)[NH:16][S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[N:10]=1)(C)(C)C.O.Cl>O1CCCC1>[N:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH:15]([NH:16][S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[C:11]2[N:10]=[C:9]([NH:8][CH2:7][C:6]([OH:46])=[O:5])[CH:14]=[CH:13][CH:12]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(Cc2ccc(-c3ccccn3)cc2)NS(=O)(=O)c2cccnc2)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNc1cccc(C(Cc2ccc(-c3ccccn3)cc2)NS(=O)(=O)c2cccnc2)n1
Temperature: 65 °C
Reaction time: 4.5 h
Yield: 41.4 %

Procedure:
To a solution of tert-butyl[tert-butoxycarbonyl(6-{[4-(pyridin-2-yl)benzyl]-(pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-yl)amino]acetate (1.76 g) (containing 1.95 mmol of a pure content) obtained in Example 19-(a) in tetrahydrofuran (5.6 ml) were added water (5.6 ml) and concentrated hydrochloric acid (2.3 ml), followed by stirring at 65° C. for 4.5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. After the concentrate was adjusted to pH 10.9 with a 1N aqueous sodium hydroxide solution, the insolubles were filtered off. The filtrate was then adjusted to pH 5.6 with 1N hydrochloric acid, followed by addition of ethyl acetate. A precipitated solid was collected by filtration, and then dried under reduced pressure to afford the title compound (553 mg) as a white solid. (Yield: 58%)
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=4[CH3:25])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:4][CH:3]=1.O[N:32]1[C:36]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN>CN(C)C=O.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[CH:24]=[CH:23][C:19]([C:20]([NH:32][CH3:36])=[O:22])=[CH:18][C:17]=4[CH3:25])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:26]([CH2:27][CH3:28])[CH2:29][CH3:30])=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(C(=O)O)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(C(=O)NC)cc1C
Temperature: 25 °C
Reaction time: 11 h

Procedure:
To a solution of 4-[10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-1-yl]-3-methylbenzoic acid (330 mg, 0.775 mmol) in N,N-dimethylformamide (4.0 mL) were added 1-hydroxy-1H-benzotriazole (155 mg, 1.01 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (163 mg, 0.853 mmol), and methylamine (2.0 M solution in tetrahydrofuran, 0.78 mL, 1.56 mmol). The mixture was stirred at room temperature for 11 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give a mixture contained an intermediate of the title compound as the trifluoroacetic acid salt. The mixture was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was recrystallized from ethanol/diisopropyl ether to give the title compound as a colorless crystal (129 mg, 0.294 mmol, 38%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:11]2[CH:16]=[C:15]([CH3:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:11]3[CH:16]=[C:15]([CH3:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: Cc1cc2c(NCc3ccc(F)cc3)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:20](=[CH:21][CH:22]=2)[O:19][C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:12][C:11]3=[O:23])[CH:5]=[N:4]1.[CH2:24]([O:26][C:27]1[CH:32]=[C:31]([C:33](O)=[O:34])[CH:30]=[C:29]([O:36][CH2:37][CH3:38])[C:28]=1[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[C:41]([C:46]([O:48][CH3:49])=[O:47])[CH:40]=1)[CH3:25]>>[CH2:24]([O:26][C:27]1[CH:32]=[C:31]([C:33]([N:16]2[CH2:15][CH2:14][C:13]3([CH2:12][C:11](=[O:23])[C:10]4[C:20](=[CH:21][CH:22]=[C:8]([C:6]5[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=5)[CH:9]=4)[O:19]3)[CH2:18][CH2:17]2)=[O:34])[CH:30]=[C:29]([O:36][CH2:37][CH3:38])[C:28]=1[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[C:41]([C:46]([O:48][CH3:49])=[O:47])[CH:40]=1)[CH3:25]
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)cn1
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1ccc(F)c(C(=O)OC)c1
Agent: Cl
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cnn(C)c4)ccc2O3)cc(OCC)c1-c1ccc(F)c(C(=O)OC)c1

Procedure:
In the same manner as in Reference Example 3-1, the intended compound was obtained as a colorless solid using 6-(1-methyl-1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride and 2,6-diethoxy-4′-fluoro-3′-(methoxycarbonyl)biphenyl-4-carboxylic acid.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][CH2:13][OH:14])[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH2:13][O:14][C:23](=[O:25])[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCN(CCO)Cc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OCCN(Cc2ccccc2)CCO1
Yield: 227.6 %

Procedure:
The procedure of Example 1 was followed using N-benzyl diethanolamine (16.4 g, 83.9 mmol), triethylamine (24.0 mL, 167.8 mmol), dry THF (600 mL) and triphosgene (8.3 g, 28.8 mmol). The filtrate was concentrated yielding a yellow oil product (14.5 g, 78%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=[C:7]2[CH3:21])(=[O:3])[CH3:2].O.[CH2:23](O)[CH3:24]>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH2:23][CH3:24])=[O:19])[CH:8]=[C:7]2[CH3:21])(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CCCc1c(O)c(C(C)=O)cc2c(C)cc(C(=O)O)nc12
Solvent: O
Product: CCCc1c(O)c(C(C)=O)cc2c(C)cc(C(=O)OCC)nc12

Procedure:
The product of step (b) (6.5 g) was dissolved in dry ethanol (500 mls). Dry hydrogen chloride gas was then bubbled into this solution until a saturated solution resulted. This solution was heated on a steam bath for 1.5 hours. The mixture was poured into water and extracted into ether. The ethereal layer was washed with water, saturated sodium bicarbonate solution, dried using magnesium sulphate and filtered. On partial removal of the solvent a yellow solid crystallised out of solution. This was filtered off affording (1.1 g) of the sub-title compound. M.P. 150°-151° C.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([NH2:18])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](O)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>>[CH:1]1([C:6]2[CH:7]=[C:8]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=3)[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cccnc1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(C2CCCC2)c1)c1cccnc1
Yield: 50.6 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 1c) (100 mg, 0.38 mmol) and nicotinic acid (40.6 mg, 0.33 mmol) as starting materials. The title compound (61 mg, 43.3%) was isolated as off white solid; MS (ESI): 366 [M+H]+.
Reaction SMILES: [C:1]([O:7][C:8]1[C:9]([CH3:18])=[C:10]2[N:15]([CH:16]=1)[N:14]=[CH:13][N:12]=[C:11]2Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[F:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]([NH:30][C:31](=[O:39])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[S:29])[CH:23]=[CH:24][C:25]=1[OH:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:7][C:8]1[C:9]([CH3:18])=[C:10]2[N:15]([CH:16]=1)[N:14]=[CH:13][N:12]=[C:11]2[O:26][C:25]1[CH:24]=[CH:23][C:22]([NH:27][C:28]([NH:30][C:31](=[O:39])[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[S:29])=[CH:21][C:20]=1[F:19])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(O)c(F)c1
Reactant: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Cl)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c12
Temperature: 100 °C
Yield: 23.2 %

Procedure:
A vial was charged with 4-chloro-5-methylpyrrolo[2,-f][1,2,4]triazin-6-yl pivalate (13.3 mg, 0.19 mmol, Compound D of Example 1), 1-(3-fluoro-4-hydroxyphenyl)-3-(2-phenylacetyl)thiourea (16 mg, 0.05 mmol), cesium carbonate (spatula tip) and DMF (2 mL) and warmed to 100° C. for 26 h. The mixture was concentrated in vacuo. The residue was purified by flash chromatography to give the title compound (6.2 mg, 25%) as a white solid. 1H NMR (CDCl3) δ 12.46 (s, 1H), 8.50 (s, 1H), 7.88 (m, 3H), 7.40 (m, 4H), 7.31 (m, 2H), 3.75 (s, 3H), 2.44 (s, 3H), 1.40 (s, 9H); MS(ESI+) m/z 536 (M+H)+.
Reaction SMILES: [Br:1][C:2]([N+:7]([O-:9])=[O:8])([CH2:5][OH:6])[CH2:3][OH:4].[CH3:10][O:11][CH:12]([O:19][CH3:20])[CH2:13][CH:14](OC)OC.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>>[Br:1][C:2]1([N+:7]([O-:9])=[O:8])[CH2:5][O:6][CH:14]([CH2:13][CH:12]([O:19][CH3:20])[O:11][CH3:10])[O:4][CH2:3]1
Reactant: COC(CC(OC)OC)OC
Reactant: O=[N+]([O-])C(Br)(CO)CO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Product: COC(CC1OCC(Br)([N+](=O)[O-])CO1)OC
Temperature: 25 °C

Procedure:
2-Bromo-2-nitro-1,3-propanediol (0.02 m) and malonaldehyde bis (dimethyl acetal) (3.3 ml, 0.02 m) were heated, under nitrogen, in an oil bath at 96° C. Toluene sulfonic acid monohydrate (50 mg) was added after the solid melted. The reaction flask was sealed with a rubber septum and returned to the bath. Every 10 minutes the flask was flushed for one minute with a vigorous nitrogen stream to remove methanol. After 2 hours the brown viscous oil was cooled and subsequently solidified. The dark oily solid was treated with 20 ml of boiling hexane. The hot light yellow hexane solution was decanted from an insoluble black tar. Upon cooling to room temperature a slightly yellow solid crystallized out. The solid was collected and washed with hexane to give 5-bromo-5-nitro-2-(2',2'-dimethoxyethyl)-1,3-dioxane (3.5 g) m.p. 95°-97° C. A sample recrystallized from methanol melted at 96°-98° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6][C:5]2=[O:16].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:22][O:21][C:19]([CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6][C:5]2=[O:16])=[O:20]
Reactant: COC(=O)CBr
Reactant: CCC(=O)N1CCC(=O)c2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)N1CCC(=O)c2cc(OCC(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 119.1 %

Procedure:
A mixture of 6-hydroxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.314 g), methyl bromoacetate (1.01 g), and potassium carbonate (0.828 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 24 hours, poured into water, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (15 g) with chloroform as an eluent to give 6-methoxycarbonylmethoxy-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.08 g).
Reaction SMILES: [C:1]([C:3]([CH3:28])([CH3:27])[C@H:4]([NH:6][C:7]1[C:8]2[N:9]([CH:16]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH:18]=2)[N:10]=[CH:11][C:12]=1[C:13]([NH2:15])=[O:14])[CH3:5])#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:2][CH2:1][C:3]([CH3:27])([CH3:28])[C@H:4]([NH:6][C:7]1[C:8]2[N:9]([CH:16]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH:18]=2)[N:10]=[CH:11][C:12]=1[C:13]([NH2:15])=[O:14])[CH3:5]
Reactant: COc1ccc(-c2cc3c(N[C@H](C)C(C)(C)C#N)c(C(N)=O)cnn3c2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3c(N[C@H](C)C(C)(C)CN)c(C(N)=O)cnn3c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of (R)-4-((3-cyano-3-methylbutan-2-yl)amino)-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (120 mg, 0.317 mmol) taken in THF (20 mL) under nitrogen atmosphere was added LAH (1M solution in THF) (12 mL, 12.00 mmol) at 0° C. slowly. The reaction mixture was stirred at 25° C. for overnight. Reaction was monitored by LCMS. Reaction mixture was quenched with saturated sodium sulfate and filtered through celite. The filtrate was taken and the two layers were separated. The organic layer was dried and concentrated under reduced pressure to get (R)-4-((4-amino-3,3-dimethylbutan-2-yl)amino)-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (100 mg, 0.261 mmol, 82% yield) as yellow colored semi solid. LCMS Purity: Column: Purospher@star RP-18 (4×55) mm, 3 μm. Buffer: 20 mM NH4OAc in water Mobile Phase A: Buffer: CH3CN (90:10). Solvent B: Buffer: CH3CN (10:90). Flow: 2.5 mL/min, Time: 0-0, 2-100, 2.5-100, 3.0-0 min. Retention Time: 1.173 min. Purity: 93.15% (m/z=383.2 M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[N:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]3)[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Cc1ccc2ccnc(Cl)c2n1
Product: Cc1ccc2ccnc(Nc3cccc(Cl)c3)c2n1

Procedure:
The title compound, MS: m/e=270.3/272.2 (M+H+), was prepared in accordance with the general method of example 1 from 8-chloro-2-methyl-[1,7]naphthyridine (Example E) and 3-chloroaniline.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12](OC)=[O:13])[C:3]=1[C:16]([O:18]C)=O.O.[NH2:21][NH2:22]>C(O)C>[NH2:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[C:12](=[O:13])[NH:21][NH:22][C:16](=[O:18])[C:3]=12
Reactant: NN
Reactant: COC(=O)c1nc2ccccc2c(N)c1C(=O)OC
Solvent: CCO
Solvent: O
Product: Nc1c2ccccc2nc2c(=O)[nH][nH]c(=O)c12
Temperature: 25 °C
Yield: 98.8 %

Procedure:
To a stirred solution of dimethyl 4-aminoquinoline-2,3-dicarboxylate (0.15 g, 0.58 mM) in ethanol (4 mL) was added hydrazine hydrate (1.46 g, 29.2 mM) and the resulting solution was refluxed for 3 hr. The reaction mixture was cooled to room temperature and filtered to separate the yellow precipitate (0.12 g). This material was stirred in refluxing acetic acid (4.5 mL) for 1 hr. After cooling to room temperature the react!ion mixture was filtered and the collected solids washed with acetic acid and ethyl acetate. Air drying provided the title compound (0.13 g, 68%) as an orange solid, mp >400° C.; MS(CI): 229 (M+H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[O:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH2:23])[CH2:17][CH2:16]1>>[CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([NH:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1)=[O:13]
Reactant: NCCN1CCOCC1
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Product: Cc1[nH]c2c(c1C(=O)NCCN1CCOCC1)CCCC2=O
Yield: 81.9 %

Procedure:
Similar procedure as Example 2, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 2-morpholinoethanamine 0.27 g (2.1 mmol) was reacted to give 0.25 g (82%) of the titled compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]4[CH2:29][CH2:28][NH:27][CH2:26]4)[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]4[CH2:29][CH2:28][N:27]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:26]4)[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(C3CCNC3)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c2cc(C3CC3)c(N(C3CCN(S(C)(=O)=O)C3)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36 %

Procedure:
To a solution of 2-(4-bromophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)(pyrrolidin-3-yl)amino]-2H-indazole-3-carboxamide in DCM at 0° C. was added DIPEA (4 μL, 0.023 mmol), followed by methanesulfonyl chloride (3 μL, 0.039 mmol) and the mixture was stirred at RT for 20 min. The mixture was concentrated to dryness and purified by preparative LCMS (5-40-100% ACN in 0.1% aqueous formic acid) to afford Compound (52) as a white solid (1.4 mg, 36%). ESI-MS m/z calculated for [M+H]+: 610.1/612.1; found: 610.0/612.0; 1H NMR (400 MHz, CDCl3) δ 7.72 (2×s, 1H), 7.70-7.64 (m, 2H), 7.51-7.44 (m, 2H), 7.36 (2×s, J=2.6 Hz, 1H), 5.75 (2×d, J=5.0 Hz, 1H), 4.92-4.68 (m, 1H), 3.88-3.68 (m, 1H), 3.54-3.37 (m, 1H), 3.38-3.16 (m, 2H), 3.10 (d, J=4.6 Hz, 3H), 3.00 (2×d, 3H), 2.79 (2×s, 3H), 2.43-2.17 (m, 2H), 2.17-1.82 (m, 1H), 1.21-0.95 (m, 3H), 0.80-0.62 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH3:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40].N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:39]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH3:32])(=[O:41])=[O:40]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1S(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 2-methylbenzene-1-sulfonyl chloride (13 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([OH:27])=O)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[O:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[O:27])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: C1CCNCC1
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@@H]4CN5CCC4CC5)oc23)c1
Agent: Cl
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(C(=O)N4CCCCC4)c3)c2o1

Procedure:
50 mg (0.12 mmol) of 3-(2-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzofuran-7-yl)benzoic acid hydrochloride (Example 153) and 20.0 mg (0.23 mmol) of piperidine are reacted together by general method E. 29.7 mg (49.9% of theory) of the title compound are obtained.