Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[NH:4][N:3]=1.[CH3:13]C([O-])(C)C.[K+].CI>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[N:4]([CH3:13])[N:3]=1
Reactant: COc1ccc2[nH]nc(I)c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc2c(c1)c(I)nn2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a solution of 3-iodo-5-methoxy-1H-indazole (442 mg, 1.61 mmol) in THF (10.0 mL) at 0° C. was added KOtBu 1M in THF (2.26 mL, 2.26 mmol) and the mixture stirred at 0° C. for 30 min where it became a pale brown reddish solution then added MeI (320 mg, 141 μL, 2.26 mmol). The reaction mixture was stirred at 0° C. for 30 min then warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride in water and extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to a clear oil. Then dissolved in toluene and purified by chromatography (80 g column, 50 μm from Analogix, 0-20% EtOAc in hexanes over 20 min to afford 3-iodo-5-methoxy-1-methyl-1H-indazole (355 mg, 1.23 mmol, 76.4%) as an off-white solid. MS (M+H)+=288.9 (>90% purity); 1H NMR (CDCl3) δ: 7.24 (d, J=9.1 Hz, 1H), 7.10 (dd, J=9.1, 2.6 Hz, 1H), 6.75 (d, J=2.6 Hz, 1H), 4.06 (s, 3H), 3.88 (s, 3H). The regioisomer 3-iodo-5-methoxy-2-methyl-2H-indazole (89 mg, 309 μmol, 19.2%) was also obtained as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29]([OH:31])=O)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][CH:58]([CH2:63][S:64](=[O:67])(=[O:66])[NH2:65])[C:59]([O:61][CH3:62])=[O:60]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([NH:8][C:9]1[C:14]2=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:16]=[CH:17][N:13]2[N:12]=[C:11]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:32]=2)[C:29]([NH:57][CH:58]([CH2:63][S:64](=[O:67])(=[O:66])[NH2:65])[C:59]([O:61][CH3:62])=[O:60])=[O:31])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(N)CS(N)(=O)=O
Reactant: O=C(O)c1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)C(CS(N)(=O)=O)NC(=O)c1cncc(-c2nc(NCc3ccccc3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.9 %

Procedure:
To a solution of 5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinic acid (50.0 mg, 0.119 mmol) in DMF (1 mL) was added DMAP (22.0 mg, 0.178 mmol) followed by HATU (68.0 mg, 0.178 mmol) and the reaction mixture stirred for 10 minutes at room temperature. Methyl 2-amino-3-sulfamoylpropanoate (10.8 mg, 0.0590 mmol) was added and the reaction mixture stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure and water (10 mL) was added to the resulting residue and the solution extracted with DCM (2×25 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-102 as described in general methods) to obtain (methyl 2-(5-(4-(benzylamino)-5-phenylpyrrolo[2,1-f][1,2,4]triazin-2-yl)nicotinamido)-3-sulfamoylpropanoate (10.0 mg, 27.6%). LCMS Condition B-19: retention time 2.11 min, [M+1]=586.1. HPLC Condition B-30: retention time 11.20 min, Purity 98.0%. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.65 (d, J=6.3 Hz, 2H), 3.71 (s, 3H), 4.84 (d, J=5.8 Hz, 2H), 4.93 (d, J=7.1 Hz, 1H), 6.72 (t, J=5.6 Hz, 1H), 6.83 (d, J=2.8 Hz, 1H), 7.08 (br s, 2H), 7.21-7.29 (m, 1H), 7.31-7.42 (m, 5H), 7.44-7.52 (m, 2H), 7.53-7.57 (m, 2H), 7.93 (d, J=2.8 Hz, 1H), 8.95 (t, J=2.1 Hz, 1H), 9.09 (d, J=2.1 Hz, 1H), 9.44 (d, J=7.8 Hz, 1H), 9.50 (d, J=2.1 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CC[N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])C.C[C@H]1CCCN1>CS(C)=O>[CH3:25][C@H:23]1[CH2:24][CH2:22][CH2:20][N:19]1[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Agent: C[C@H]1CCCN1
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCC[C@@H]3C)nc2c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 35.9 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (500.0 mg, crude) in DMSO (6 mL) was added DIEA (543.0 mg, 4.20 mmol), and (S)-2-methylpyrrolidine (268.0 mg, 3.15 mmol). The solution was stirred for 10 h at 100° C. and then quenched by the addition of water (25 mL), extracted with ethyl acetate (3×80 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 1%-5% ethyl acetate in petroleum ether to afford (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a yellow solid (216.0 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[C:20]1([CH2:30][NH2:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:31][CH2:30][C:20]1[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: NCc1cccc2ccccc12
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1cccc2ccccc12
Yield: 80 %

Procedure:
The compound prepared in Example 3 was reacted with 1-naphthalenmethyl-amine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 80%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[N:20]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[N:19]1([CH2:18][CH2:17][CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: c1ccc(COc2ccc(CCCCn3ccnn3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Oc1ccc(CCCCn2ccnn2)cc1
Yield: 99.8 %

Procedure:
1-[4-(4-benzyloxyphenyl)butyl]-1H-1,2,3-triazole (0.38 g) was dissolved in methanol (7.6 ml); 10% palladium carbon (0.1 g) was added, followed by vigorous stirring in a hydrogen atmosphere for 14 hours. The catalyst was filtered off; the filtrate was concentrated to dryness under reduced pressure to yield the titled compound (0.268 g) as a crystalline powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][N:9]=1.[Cl:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22]Cl>C(#N)C>[Cl:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([I:7])=[N:9]1
Reactant: ClCCOCCCl
Reactant: Ic1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: ClCCOCCn1nc(I)c2ccccc21
Yield: 55.7 %

Procedure:
Potassium carbonate (1.1 g, 8.2 mmol) was added to a solution of 3-iodoindazole (1.0 g, 4.1 mmol) and bis(2-chloroethyl)ether (1.5 g, 10.3 mmol) in ACN (20 mL) at rt. The reaction was heated to reflux overnight, and the filtered and concentrated. The residue was purified by silica gel chromatography to give 800 mg (56%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 3.47 (2H, t, J=5.6 Hz), 3.60 (2H, t, J=5.6 Hz), 3.94 (2H, t, J=5.2 Hz), 4.58 (2H, t, J=5.6 Hz), 7.20 (1H, t, J=7.6 Hz), 7.41-7.49 (3H, m). The minor isomer was not isolated or characterized.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([F:10])([F:9])[F:8])=[N:3]1.C([Li])CCC.[B:16](OC)([O:19]C)[O:17]C>O1CCCC1>[CH3:1][N:2]1[C:6]([B:16]([OH:19])[OH:17])=[CH:5][C:4]([C:7]([F:10])([F:9])[F:8])=[N:3]1
Reactant: COB(OC)OC
Reactant: Cn1ccc(C(F)(F)F)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nc(C(F)(F)F)cc1B(O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a stirred solution of 1-methyl-3-(trifluoromethyl)-1H-pyrazole (1.89 g, 12.6 mmol) in anhydrous tetrahydrofuran (20 mL) under nitrogen cooled to −78° C. was added n-butyllithium (8.3 mL, 1.6 M solution in hexanes, 13.2 mmol) slowly over 5 minutes. The resulting yellow solution was stirred at −78° C. for 1 hour and trimethyl borate (1.56 mL, 13.9 mmol) was then added slowly. The reaction flask was covered in foil and allowed to warm to room temperature for 16 hours. The white solution was quenched with aqueous 1 M hydrogen chloride solution (10 mL) and stirred at room temperature for 1.5 hours. The mixture was extracted with ethyl acetate (2×30 mL), dried with anhydrous magnesium sulphate and evaporated in vacuo to give an off-white foam (2.11 g). The foam was triturated with dichloromethane, filtered and dried in vacuo to afford the title compound as a white solid (1.57 g, 64%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=2)[CH:19]=[C:18]1B(O)O)(OC(C)(C)C)=O>>[Cl:26][C:23]1[CH:24]=[C:25]2[C:20]([CH:19]=[C:18]([C:2]3[CH:3]=[N:4][CH:5]=[C:6]([CH:7]=3)[C:8]#[N:9])[NH:17]2)=[CH:21][CH:22]=1
Reactant: N#Cc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(Cl)cc21
Product: N#Cc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1

Procedure:
3-Bromo-5-cyano-pyridine and N-Boc-6-chloro-indoleboronic acid are processed according to the procedure described in Example 103 to give 5-(6-chloro-1H-indol-2-yl)-nicotinonitrile, which is processed according to the procedure described in Example 114 to give 5-(6-Chloro-1-methyl-1H-indol-2-yl)-nicotinonitrile. 1H NMR (400 MHz, MeOD) δ ppm 3.81 (s, 3H), 6.81 (s, 1H), 7.14 (dd, J=8.6, 1.8 Hz, 1H), 7.56 (s, 1H), 7.61 (d, J=8.3 Hz, 1H), 8.46 (t, J=2.1 Hz, 1H), 8.98 (d, J=2.0 Hz, 1H), 9.06 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 268.0636 [(M+H)+ Calcd for C15H10ClN3 268.0636].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[Br:11][CH2:12][C:13](Br)=[O:14]>CN(C=O)C.O1CCOCC1.O>[Br:11][CH2:12][C:13]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1)=[O:14]
Reactant: N#CCc1ccc(N)cc1
Reactant: O=C(Br)CBr
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(NC(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 4-aminobenzyl cyanide (4 g, 0.03 mol) in anhydrous DMF (20 mL) and anhydrous dioxane (20 mL) in a 3-necked flask, fitted with magnetic stirrer and a constant additional funnel, was added, dropwise, bromoacetyl bromide (6.12 g, 2.7 mL, 100 mol %) while keeping the internal temperature between 0° C. and 2° C. After the addition was completed (~25 min), the reaction mixture was stirred overnight at rt. The reaction mixture was diluted with water (100 mL) and then the yellow crystalline compound which precipitated was filtered, washed sequentially with 5% HBr (100 mL) and water (200 mL), and then dried in a vacuum oven at 40°-45° C., affording 5.0 g (66%) of the title compound: mp 129°-131° C.; 1H NMR (DMSO-d6) δ10.46 (s, 1H , NH), 7.60 (d, 2H, J=8.4), 7.31 (d, 2H, J=8.8), 4.04 (s, 2H), 3.98 (s, 2H): 13C NMR (DMSO-d6) δ164.82; 137.99; 128.60; 126.42; 119.61; 30.30; 21.82; MS (EI, m/z) 252 (M+). HRMS (EI) calcd for C10H9N2OBr 251.9898, found 251.9882.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[O:12].[H-].[Na+].[CH3:15]I>CN(C=O)C.Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:15])[CH:6]=[C:5]2[CH:11]=[O:12]
Reactant: O=Cc1c[nH]c2ccc(F)cc12
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C=O)c2cc(F)ccc21
Temperature: 0 °C
Yield: 38.9 %

Procedure:
In DMF (100 ml) was dissolved 5-fluoroindol-3-carbaldehyde (5.17 g, 36.7 mmol). To the resulting solution was added sodium hydride (60% in oil, 1.39 g, 34.9 mmol) in portions under stirring at 0° C. After the reaction mixture was stirred at the same temperature for 1 hour, methyl iodide (4.57 ml, 73.4 mmol) was added thereto at 0° C. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was poured in 1N HCl, followed by extraction with ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was crystallized by adding thereto chloroform/hexane. The crystals thus precipitated were collected by filtration under reduced pressure and dried under reduced pressure to give 5-fluoro-1-methylindole-3-carbaldehyde (2.53 g, 39%) as a white crystalline powder.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32]([CH2:39][C:40]([OH:42])=O)[N:31]=1.Cl.Cl.[Cl:45][C:46]1[C:51]([O:52][CH2:53][CH3:54])=[CH:50][C:49]([N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)=[C:48]([F:61])[CH:47]=1.CCN(C(C)C)C(C)C>>[Cl:45][C:46]1[C:51]([O:52][CH2:53][CH3:54])=[CH:50][C:49]([N:55]2[CH2:60][CH2:59][N:58]([C:40](=[O:42])[CH2:39][N:32]3[C:33]4=[N:34][CH:35]=[CH:36][CH:37]=[C:38]4[C:30]([C:26]4[NH:25][CH:29]=[CH:28][N:27]=4)=[N:31]3)[CH2:57][CH2:56]2)=[C:48]([F:61])[CH:47]=1
Reactant: CCOc1cc(N2CCNCC2)c(F)cc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)CC2)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(Protocol A—the HBTU coupling procedure) A solution of [3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]acetic acid (0.30 M, 0.40 mL, 0.12 Mmol) was transferred to a vial. 1-(4-Chloro-5-ethoxy-2-fluorophenyl)piperazine dihydrochloride (48 mg, 0.14 Mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (55 Mg, 0.14 Mmol) and i-Pr2NEt (0.30 mL) were added to the vial and the mixture was stirred at ambient temperature. After 30 minutes, LC/MS analysis indicated formation of desired product and complete consumption of the carboxylic acid starting material. The mixture was diluted with EtOAc, washed with water (1×) and brine (1×), dried over Na2SO4 and evaporated. The residue was purified by silica gel chromatography (1% to 8% MeOH in CH2Cl2) to provide 1-[4-(4-chloro-5-ethoxy-2-fluorophenyl)piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid: 1H NMR (CDCl3, 400 MHz) δ 8.79 (dd, 0.6 H, J=8.4, 1.6 Hz), 8.66 (dd, 0.4 H, J=8.0, 1.6 Hz), 8.57-8.55 (m, 1H), 7.29-7.26 (m, 1H), 7.22-7.16 (m, 1H), 7.09-7.05 (m, 2H), 6.50-6.45 (m, 2H), 5.45 (s, 0.6H), 5.43 (s, 1.4H), 4.07-4.01 (m, 2H), 3.81-3.69 (m, 4H), 3.17-3.13 (m, 1.6H), 3.08-3.02 (m, 2.4H), 1.50-1.42 (m, 3H); LC/MS m/z (M+H)+ 484.4.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:19]=[CH:18][C:17]([CH3:21])([CH3:20])[C:16]2[C:9]=1[CH:10]=[C:11]1[C:15]=2[CH:14]=[N:13][N:12]1[CH2:22][CH:23](O)[CH3:24].C(N(CC)CC)C.[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:33]([CH:23]([CH3:24])[CH2:22][N:12]1[C:11]2=[CH:10][C:9]3[C:16]([C:17]([CH3:21])([CH3:20])[CH:18]=[CH:19][C:8]=3[O:7][CH3:6])=[C:15]2[CH:14]=[N:13]1)=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: COC1=C2C=c3c(cnn3CC(C)O)=C2C(C)(C)C=C1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C2C=c3c(cnn3CC(C)N=[N+]=[N-])=C2C(C)(C)C=C1
Yield: 67.9 %

Procedure:
0.8 ml (10.2 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.4 g (5.1 mmol) of (RS)-1-(7-methoxy-4,4-dimethyl-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol and 2.9 ml (20.4 mmol) of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 150 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.66 g (10.2 mmol) of sodium azide and the reaction mixture was heated to 70° for 15 hours while stirring. After cooling, the solution was poured into 100 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of diethyl ether each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.03 g (68%) of (RS)-1-(2-azido-propyl)-7-methoxy-4,4-dimethyl-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a yellow oil.
Reaction SMILES: [N:1](=[C:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4](=O)[CH3:5])O.[CH3:11][C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[N:19](Cl)=O.N=C=O>[Zn].C(O)(=O)C>[CH3:11][C:12]1[C:13]([CH2:14][CH2:15][CH2:16][CH3:17])=[N:19][C:4]([CH3:5])=[C:3]([CH2:7][CH2:8][CH2:9][CH3:10])[N:1]=1
Reactant: CCCCCC(C)=O
Reactant: O=NCl
Reactant: CCCCC(=NO)C(C)=O
Agent: N=C=O
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCCc1nc(C)c(CCCC)nc1C

Procedure:
e. 2,5-Dimethyl-3,6-dibutyl-pyrazine was prepared by first forming 3-oximino-2-heptanone by reacting 2-heptanone with nitrosyl chloride according to the method of BOUVEAULT, Bull. [3] 31, 1163 (1904). The autocondensation of two moles of the imino-ketone in the presence of zinc and acetic acid [according to the method described in Chimia 11, 310 (1957)] yielded 2,5-dimethyl-3,6-dibutyl-pyrazine which had a b.p. of 18° C./0.002 mm. Hg.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([O:12][CH2:13][CH3:14])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH3:29])=[N:25][CH:26]=1>CCOCC>[ClH:1].[CH2:13]([O:12][C:8]1[N:7]=[C:6]2[C:11]([C:2]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH3:29])=[N:25][CH:26]=3)=[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:4]=[N:5]2)=[CH:10][CH:9]=1)[CH3:14]
Reactant: CCOc1ccc(N)cn1
Reactant: CCOC(=O)c1cnc2nc(OCC)ccc2c1Cl
Solvent: CCOCC
Product: CCOC(=O)c1cnc2nc(OCC)ccc2c1Nc1ccc(OCC)nc1
Product: Cl

Procedure:
A mixture of ethyl 4-chloro-7-ethoxy-1,8-naphthyridine-3-carboxylate (1.6 g) and 5-amino-2-ethoxypyridine (0.8 g) and IMS (50 ml) was boiled under reflux for 2 hours. The mixture was cooled and ether (200 ml) was added. The mixture was filtered to give ethyl 7-ethoxy-4-(2-ethoxy-5-pyridylamino)-1,8-naphthyridine-3-carboxylate hydrochloride, m.p. 180°-185° C. Active (1/1) at 30 mg/kg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9](I)=[CH:10][C:3]=12.CC1(C)C(C)(C)OB([C:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=2)O1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:9]([C:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=3)=[CH:10][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Br)ccnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(Br)ccnc32)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To as solution of Example 369B (20 g, 41.9 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (16.85 g, 54.5 mmol), and tetrakis(triphenylphosphine)palladium (4.84 g, 4.19 mmol) in N,N-dimethylformamide (500 mL) was added a solution of sodium bicarbonate (7.04 g, 84 mmol) in water (40 mL) and the mixture was stirred at 80° C. for 12 hours. The reaction was quenched by the addition of saturated aqueous sodium thiosulfate, water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered and concentrated to provide the title compound. MS (CI) m/z 532 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH:18]=2)[N:13]=[N:12][C:11]=1[C:29]#[N:30].[OH-].[K+].C([OH:37])(C)(C)C>O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH:18]=2)[N:13]=[N:12][C:11]=1[C:29]([NH2:30])=[O:37]
Reactant: CC(C)(C)O
Reactant: COc1cc2nnc(C#N)c(Nc3ccc(C)cc3F)c2cc1N1CCN(C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cc2nnc(C(N)=O)c(Nc3ccc(C)cc3F)c2cc1N1CCN(C)CC1
Temperature: 25 °C

Procedure:
A 100 mL round bottom flask was charged with 4-(2-fluoro-4-methylphenylamino)-7-methoxy-6-(4-methylpiperazin-1-yl)cinnoline-3-carbonitrile (Method 60) (360 mg, 0.89 mmol) and potassium hydroxide (4.9 g, 88.6 mmol). Anhydrous tert-butyl alcohol (30 ml) was added and the reaction was heated at vigorous reflux 1 h before being allowed to cool to rt. The reaction mixture was then poured into a separatory funnel containing water (˜100 mL) and extracted with EtOAc (2×200 mL). The combined organic layer was washed with sat'd aqueous NaCl (˜100 mL), dried with MgSO4, filtered, and conc. in vacuo to give the crude product which was purified via silica gel chromatography (40 g) using EtOAc/MeOH (1:1) as eluent to give the title compound as a yellow solid. The solid was then recrystallized from 5 mL of MeOH which provided pure title compound (184 mg, 48.9%) as a pale yellow solid. 1HNMR: 11.60 (s, 1H), 8.55 (s, 1H), 7.85 (s, 1H), 7.16 (s, 1H), 7.37 (m, 2H), 7.10 (m, 1H), 6.21 (s, 1H), 4.05 (s, 3H), 2.46 (s, br, 4H), 2.70-2.60 (m, 7H), 2.35 (s, 3H); m/z 425.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[NH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[N:20][C:21]([Cl:27])=[CH:22][CH:23]=2)[N:18]=1.C(O)C>O>[Cl:27][C:21]1[N:20]=[C:19]2[C:24]([CH:25]=[CH:26][C:17]([NH:16][C:6](=[O:8])[C:5]3[CH:9]=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:18]2)=[CH:23][CH:22]=1
Reactant: COc1cc(C(=O)O)cc(OC)c1OC
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)Nc2ccc3ccc(Cl)nc3n2)cc(OC)c1OC
Temperature: 4 °C
Yield: 44.3 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 3,4,5-trimethoxybenzoic acid (17 g), N,N'-carbonyldiimidazole (13 g) and 2-amino-7-chloro-1,8-naphthyridine (8.9 g). The product obtained by precipitation in water (10.3 g; m.p. 90° C.) is dissolved in boiling ethanol (500 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with ethanol (20 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-3,4,5-trimethoxybenzamide (8.2 g), m.p. 210° C., is obtained.