Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:20][CH2:21][O:22][CH3:23])[CH3:19])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.ClC1C=C(NC2C=CC(CN3CCN(C)CC3)=CN=2)C(=O)N(C)N=1.C([O:51][CH2:52][C:53]1[C:58]([N:59]2[N:68]=[CH:67][C:66]3[C:61](=[C:62]([F:73])[CH:63]=[C:64]([C:69]([CH3:72])([CH3:71])[CH3:70])[CH:65]=3)[C:60]2=[O:74])=[CH:57][CH:56]=[CH:55][C:54]=1[B-](F)(F)F)(=O)C.[K+]>>[C:69]([C:64]1[CH:65]=[C:66]2[C:61](=[C:62]([F:73])[CH:63]=1)[C:60](=[O:74])[N:59]([C:58]1[CH:57]=[CH:56][CH:55]=[C:54]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:20][CH2:21][O:22][CH3:23])[CH3:19])=[CH:13][N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[C:53]=1[CH2:52][OH:51])[N:68]=[CH:67]2)([CH3:72])([CH3:70])[CH3:71]
Reactant: CC(=O)OCc1c(-n2ncc3cc(C(C)(C)C)cc(F)c3c2=O)cccc1[B-](F)(F)F
Reactant: COCCN(C)Cc1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Agent: CN1CCN(Cc2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Agent: [K+]
Product: COCCN(C)Cc1ccc(Nc2cc(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)nn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-tert-Butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(5-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one was prepared using the general procedure described in example 41 substituting 6-Chloro-4-(5-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-pyridin-2-ylamino)-2-methyl-2H-pyridazin-3-one for 6-chloro-2-methyl-4-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-ylamino)pyridazin-3(2H)-one in step 3. For the Suzuki reaction, potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate (Eq: 1.2) was used in place of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate. After removal of the acetate protecting group using potassium carbonate in methanol, water was added dropwise and the reaction was stirred at room temperature overnight. The solid that formed was filtered, washed with water then ether and dried in a vacuum oven to give 52 mgs of a crystalline white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (s, 9H) 2.13 (s, 3H) 2.47 (s, 2H) 3.22 (s, 3H) 3.39-3.49 (m, 4H) 3.79 (s, 3H) 4.43 (br. s., 2H) 4.58 (br. s., 1H) 7.41-7.65 (m, 5H) 7.75 (d, J=13.22 Hz, 1H) 7.87 (s, 1H) 8.17 (s, 1H) 8.46-8.59 (m, 2H) 9.40 (s, 1H). MS: (M+H)+=628.
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C@H:38]3[CH2:43][CH2:42][C@H:41]([N:44]4[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]4)[CH2:40][CH2:39]3)[N:19]=[C:20]([C:21]3[C:26]([F:27])=[CH:25][C:24]([NH:28]C(=O)OC(C)(C)C)=[C:23]([O:36][CH3:37])[CH:22]=3)[C:13]=12>ClCCl>[NH2:28][C:24]1[C:23]([O:36][CH3:37])=[CH:22][C:21]([C:20]2[C:13]3[C:14](=[N:15][CH:16]=[N:17][C:12]=3[NH2:11])[N:18]([C@H:38]3[CH2:43][CH2:42][C@H:41]([N:44]4[CH2:45][CH2:46][N:47]([CH3:50])[CH2:48][CH2:49]4)[CH2:40][CH2:39]3)[N:19]=2)=[C:26]([F:27])[CH:25]=1
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of trifluoroacetic acid/dichloromethane (20:80, 7 mL) was added to a solution of trans-tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-fluoro-2-methoxyphenyl)carbamate (250 mg, 0.451 mmol) in dichloromethane (4.0 mL) at 0° C. After 15 minutes, the ice-bath was removed and the reaction mixture was stirred at room temperature for 4 hours. Solvent was then evaporated and the residue was dissolved in dichloromethane. Saturated sodium bicarbonate was added to adjust the pH to 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated give trans-3-(4-amino-2-fluoro-5-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (179 mg, 87%). 1H NMR (CDCl3) δ 1.56 (m, 2H), 2.15 (m, 7H), 2.31 (s, 3H), 2.51 (m, 4H), 2.67 (m, 4H), 3.88 (s, 3H), 4.16 (bs, 2H), 4.74 (m, 1H), 5.64 (bs, 2H), 6.56 (d, J=10.84 Hz, 1H), 6.88 (d, J=6.55 Hz, 1H), 8.33 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=455.2, Rt=0.63 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17](Cl)=[O:18])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Br:20][C:21]1[N:26]=[CH:25][C:24](NC)=[CH:23][CH:22]=1.C[CH2:30][N:31](C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:20][C:21]1[N:26]=[CH:25][C:24]([CH2:30][NH:31][C:17]([C:12]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:18])=[CH:23][CH:22]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)c1cccc2c1cnn2-c1ccc(F)cc1
Reactant: CNc1ccc(Br)nc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NCc1ccc(Br)nc1)c1cccc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid chloride (416 mg, 1.51 mmol), 6-bromo-pyridin-3-yl-methylamine (311 mg, 1.66 mmol) and DMAP (18.5 mg, 0.151 mmol) in DCM (10 mL) was treated with DIEA (1.32 mL, 7.56 mmol). The solution was stirred at room temperature. After 16 hours the mixture was diluted with DCM (30 mL). The organic layer was washed with saturated aqueous NH4Cl (2×10 mL), saturated aqueous NaHCO3 (2×10 mL), water (10 mL), brine (10 mL) and dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-50% ethyl acetate in hexanes to afford the title compound as a white solid.
Reaction SMILES: [OH:1][CH:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([NH:12]C(=O)C)[CH2:5][CH2:4][CH2:3]1.[OH-].[K+]>O.C(O)CO.O>[OH:1][C@H:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C@H:6]([NH2:12])[CH2:5][CH2:4][CH2:3]1
Reactant: CC(=O)NC1CCCC(O)c2sccc21
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: N[C@@H]1CCC[C@@H](O)c2sccc21

Procedure:
A sample of a cis/trans mixture of N-(5,6,7,8-tetrahydro-8-hydroxy-4H-cyclohepta[b]thien-4-yl)acetamide is added to 2 equivalents of KOH in water/ethylene glycol mixture. The mixture is heated at reflux under nitrogen atmosphere until starting material is no longer detectable by thin-layer chromatography. The mixture is cooled, diluted with water and extracted exhaustively with CHCl3. The chloroform extract is added to an equal volume of water and acidified with hydrochloric acid until the mixture is at pH 2. The mixture is then extracted with CHCl3 and then the remaining aqueous solution is made alkaline with NaOH solution. The alkaline solution is then extracted with CHCl3 exhaustively and the extracts are dried over MgSO4 and evaporated to dryness to afford the title compound.
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:10]([NH:17][CH2:18][CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:10]([N:17]1[CH2:18][CH2:19][N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(Br)CBr
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 100 °C

Procedure:
A solution of ethyl 2,3-dibromopropionate (6 mL) in anhydrous toluene (50 mL) was added to a solution of N,N′-dibenzylethylenediamine (5 g) and DIPEA (12 mL) in anhydrous toluene (50 mL) under a Nitrogen atmosphere. The resulting mixture was heated to 100° C. for 21 hours, then allowed to cool to r.t., diluted with AcOEt (100 mL) and washed with brine (3×100 mL). The organic extract was dried and concentrated in vacuo to a residue which was purified by flash chromatography (CH/AcOEt 9:1) to give ethyl 1,4-dibenzyl-piperazine-2-carboxylate (5.65 g) as a yellow oil, which was used without any purification in the next step. Diisobutylaluminium hydride (1M in toluene-29 mL) was dropped into a solution of ethyl 1,4-dibenzyl-piperazine-2-carboxylate (5.47 g) in anhydrous toluene (110 mL) previously cooled to −78° C. under a Nitrogen atmosphere. The solution was stirred at −78° C. for 1 hour, then a 20% sodium hydroxide solution (20 mL) was added and the mixture was allowed to warm to r.t. Further 20% sodium hydroxide solution (50 mL) was added and the solution was extracted with Et2O (2×150 mL). The combined organic extracts were dried and concentrated in vacuo to give the title compound (5.33 g) as a crude, which was used without any further purification in the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>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.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
2,5-Dichloropyridine (30 g, 203 mmol), phenylboronic acid (24.72 g, 203 mmol) and potassium carbonate (84 g, 608 mmol) were added to dimethoxyethane (500 mL) and water (100 mL). The reaction mixture was degassed with nitrogen for 20 min, and Pd(PPh3)4 (2.3 g, 2.0 mmol) was added and reaction mixture was allowed to reflux for 18 h. The reaction was cooled to room temperature, the aqueous layer removed and dimethoxyethane was concentrated to dryness by rotary evaporation under vacuum. The residue was dissolved in DCM and passed through a silica gel plug, eluting with DCM. The solvent was removed and the crude product was chromatographed on silica with 40/60 (v/v) DCM/hexane to 50/50 (v/v) DCM/hexane to yield 28 g (73%) of the product as a white solid (HPLC purity: 99.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C)C=O.O>[CH:12]1([NH:15][C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc(F)cc1)NC1CC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 74.3 %

Procedure:
To a solution of 4-fluorophenylacetic acid (4.5 g) and cyclopropylamine (1.7 g) in N,N-dimethylformamide (60 mL) was added 1-Hydroxybenzotriazole (4.4 g), followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSC) hydrochloride (6.2 g) on an ice bath. This solution was stirred for 4.5 hours while gradually warming to room temperature. The reaction solution was poured into water (120 mL) on an ice bath, and the resulting solid was collected by filtration, washed with water, then dried, and the title compound (4.19 g) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.[NH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.CN1CCOCC1>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:20][CH2:21][CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[O:10])=[CH:11][CH:12]=1
Reactant: NCCc1cccnc1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NCCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
To a stirring solution of terephthalic acid monomethyl ester (500 mg, 2.5 mmol) and oxalyl chloride (0.44 mL, 5.03 mmol) in dichloromethane (20 mL), is added 3 drops of dimethylformamide and the reaction is stirred for 2 h at room temperature. The reaction is concentrated in vacuo and then redissolved in dichloromethane. The solution is slowly added to a stirring solution of 3-(2-aminoethyl)pyridine (308 mg, 2.52 mmol) and n-methylmorpholine (0.28 mL, 2.52 mmol) in dichloromethane (20 mL). After 20 min, the reaction is washed with saturated aqueous sodium bicarbonate while extracting with 10% isopropanol/dichloromethane. The organic portion is dried with sodium sulfate, filtered, and concentrated in vacuo. The resulting residue is purified using radial chromatography, eluting with methanol and dichloromethane to obtain 613 mg (86%) of the title compound. MS (ES+) m/e 285.1 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([CH:28]=[CH:29][N:30]=2)[CH:5]=[C:6]([C:8]2[C:9]([CH3:27])=[C:10]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[CH:11]=[CH:12][CH:13]=2)[CH:7]=1.[CH:31]([N:34]([CH:37](C)C)CC)(C)[CH3:32].C(Cl)(Cl)=[O:41].C1(C)C=CC=CC=1>ClCCl>[C:22]([C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]3[CH:7]=[C:2]([NH:1][C:37]([NH:34][CH2:31][CH3:32])=[O:41])[C:3]4[N:4]([CH:28]=[CH:29][N:30]=4)[CH:5]=3)[C:9]=2[CH3:27])=[O:26])=[CH:17][CH:18]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(Cl)Cl
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(N)c2nccn2c1
Reactant: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCNC(=O)Nc1cc(-c2cccc(NC(=O)c3ccc(C(C)(C)C)cc3)c2C)cn2ccnc12
Reaction time: 0.08 h

Procedure:
To N-[3-(8-Amino-imidazo[1,2-a]pyridin-6-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide (53 mg, 0.133 mmol) in dichloromethane (5 mL) at 0° C. was added diisopropylethylamine (60 μL, 2.5 eq) and the resulting mixture was stirred for 5 minutes. Then at 0° C. with stirring was added a 20% phosgene solution in toluene (84 μL, 1.2 eq) all at once, and the resulting solution was stirred at 0° C. for 5 minutes. Next, ethylamine(g) was bubbled through the solution for about 2 minutes. Additional phosgene solution (0.25 mL) was added at 0° C. and stirred an additional 5 minutes. Finally, ethylamine(g) was bubbled through the solution again for about 2 minutes. The reaction was quenched by adding ethyl acetate (35 mL) and water (25 mL). The layers were partitioned and then separated and the organic layer was further washed with brine (1×25 mL) and finally dried over magnesium sulfate, filtered and concentrated. This crude product was purified by Preparative Thin Layer Chromatography, eluting with 5% methanol in dichloromethane to give the title compound as a foamy solid (17 mg) ((M+H)+=470).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]([CH2:37][CH:38]3[CH2:40][CH2:39]3)[S:33]([CH3:36])(=[O:35])=[O:34])[CH2:22][CH2:21]2)=[O:19])[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]([CH2:37][CH:38]3[CH2:40][CH2:39]3)[S:33]([CH3:36])(=[O:35])=[O:34])[CH2:24][CH2:25]2)=[O:19])[CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2N(CC2CC2)S(C)(=O)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@H](CC(=O)O)Cc2ccc(Cl)cc2)CC1

Procedure:
A solution of tert-butyl (3S)-3-[(4-chlorophenyl)-methyl]-4-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)-amino]phenyl}piperazinyl)-4-oxobutanoate (Step 5) (0.16 g, 0.27 mmol) in 10 mL of 50% TFA in CH2Cl2 mixture was stirred at RT for 2 h. The volatile solvent was removed in vacuo. The residue was dissolved in CH2Cl2 and concentrated in vacuo. (3S)-3-[(4-Chlorophenyl)-methyl]-4-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)-amino]phenyl}piperazinyl)-4-oxobutanoic acid was obtained as a light yellow solid (0.14 g) MS (ESI, pos. ion) m/z: 534.4 (M+1). Calc'd for C26H32ClN3O5S: 533.18. Anal. Calcd for C26H32ClN3O5S 1.5H2O: C, 55.66; H, 6.29; N, 7.49; Cl, 6.32. Found: C, 55.51; H, 5.85; N, 7.35; Cl, 6.12.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:7][CH2:8][C:9]#[N:10])[NH:5][CH:6]=1.[CH3:11][C:12]1[CH:21]=[C:20]([CH3:22])[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:13]=1[C:14]([O:16]C)=O.CC1C=CC(C(OC)=O)=CC=1B1OC(C)(C)C(C)(C)O1.Cl.[F:53][C:54]1([C:58]2[CH:65]=[CH:64][C:61]([C:62]#[N:63])=[CH:60][CH:59]=2)[CH2:57][NH:56][CH2:55]1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[C:9]([CH2:8][CH2:7][C:4]1[NH:5][C:6]([C:19]2[C:20]([CH3:22])=[CH:21][C:12]([CH3:11])=[C:13]([CH:18]=2)[C:14]([N:56]2[CH2:55][C:54]([C:58]3[CH:59]=[CH:60][C:61]([C:62]#[N:63])=[CH:64][CH:65]=3)([F:53])[CH2:57]2)=[O:16])=[C:2]([CH3:1])[N:3]=1)#[N:10]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Reactant: Cc1c[nH]c(CCC#N)n1
Agent: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: Cc1cc(C)c(-c2[nH]c(CCC#N)nc2C)cc1C(=O)N1CC(F)(c2ccc(C#N)cc2)C1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5, except 3-(4-methyl-1H-imidazol-2-yl)propanenitrile (compound 232.4) was used in place of 2,4-dimethyl-1H-imidazole, methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) was used in place of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4), and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 442 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([CH:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28]([CH:31]2[CH2:32][CH2:33][CH:34]([N:1]3[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]4[C:17]5[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=5)[NH:11][N:10]=4)[CH2:4]3)[CH2:35][CH2:36]2)=[CH:27][CH:26]=1
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: COc1ccc(C2CCC(=O)CC2)cn1
Product: COc1ccc(C2CCC(N3CC(NC(=O)CNc4n[nH]c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and 4-(6-methoxy-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]([O:9]CC)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17]C#N.CC[O-].[Na+].[Na]>O.C(O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]([CH2:17][C:16]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([O:13][CH3:12])[CH:15]=2)=[O:9])[CH:3]=1
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CCOC(=O)c1cccnc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: COc1ccc(CC(=O)c2cccnc2)cc1OC

Procedure:
A mixture of 45.4 g of ethyl nicotinate and 35.4 g of 3,4-dimethoxybenzyl cyanide is added dropwise to a boiling solution of sodium ethylate prepared from 6 g of sodium and 100 ml of ethanol. The mixture is kept at reflux for 5 hours and, after cooling, is poured into 1 liter of water. The excess nicotinic ester is removed with toluene, and the aqueous solution is neutralized with glacial acetic acid, 50.7 g of α-cyano-3,4-dimethoxybenzyl 3-pyridyl ketone separating out as crystals (melting point 149°-152° C.). This cyanoketone (31.0 g) is hydrolyzed in 6N hydrochloric acid at 80°-90° C. The hydrochloride of the 3,4-dimethoxybenzyl 3-pyridyl ketone crystallizes from ethanol with melting point 188°-191° C. and the free base has a melting point of 60°-64° C. The compound is converted into the oxime without further purification.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:4]=[C:5]([O:20][CH3:21])[C:6]2[C:15]([CH:16]=1)=[S+:14][C:13]1[C:8](=[C:9]([O:18][CH3:19])[CH:10]=[C:11](Br)[CH:12]=1)[N:7]=2.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[Br-:2].[CH3:21][O:20][C:5]1[C:6]2[C:15](=[S+:14][C:13]3[C:8]([N:7]=2)=[C:9]([O:18][CH3:19])[CH:10]=[C:11]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)[CH:12]=3)[CH:16]=[C:3]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)[CH:4]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(Br)cc2[s+]c3cc(Br)cc(OC)c3nc12
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: COc1cc(N2CCN(C)CC2)cc2[s+]c3cc(N4CCN(C)CC4)cc(OC)c3nc12
Yield: 42.2 %

Procedure:
Performed the reaction as described in the literature starting with 3,7-dibromo-1,9-dimethoxyphenothiazin-5-ium bromide (750 mg, 1.54 mmol), N-methylpiperazine (0.848 mL, 7.7 mmol) and chloroform (35 mL). Purified using flash silica gel chromatography to obtain product as a dark blue residue (35 mg, 0.65 mmol, 4% yield).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:9][N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15](F)=[C:16]([F:21])[CH:17]=2)[N:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]1=[O:30])[CH:7]=[CH2:8].C(N(CC)CC)C>C(#N)C>[CH2:6]([O:9][N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:16]([F:21])[CH:17]=2)[N:12]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:11]1=[O:30])[CH:7]=[CH2:8]
Reactant: C1CCNC1
Reactant: C=CCOn1c(=O)c2cc(F)c(F)cc2n(Cc2ccccc2)c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCOn1c(=O)c2cc(F)c(N3CCCC3)cc2n(Cc2ccccc2)c1=O
Yield: 94.8 %

Procedure:
Pyrrolidine (0.04 mL, 0.52 mmol) was added to a solution of 3-allyloxy-1-benzyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example A-4, 0.15 g, 0.4 mmol) and triethylamine (0.12 mL, 0.9 mmol) in 15 mL of acetonitrile. The solution was warmed to reflux for 17 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with 1N HCl, saturated NaHCO3, brine, and dried over magnesium sulfate. The solution was concentrated to give 0.15 g of the title compound as a solid, mp 148-150° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([SH:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].C(O)CO>[Cu](I)I.CC(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:13]2[CH:12]=[N:11][C:10]([Cl:9])=[CH:15][CH:14]=2)=[N:6][CH:7]=1
Reactant: Clc1ccc(I)cn1
Reactant: Sc1ccc(Br)cn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Clc1ccc(Sc2ccc(Br)cn2)cn1
Temperature: 80 °C
Yield: 31.7 %

Procedure:
5-Bromo-2-pyridinethiol (633 mg, 3.33 mmol, Combi-Blocks, Inc., San Diego, Calif.), 2-chloro-5-iodopyridine (798 mg, 3.33 mmol, Sigma-Aldrich, St. Louis, Mo.), copper iodide (32 mg, 0.17 mmol, Strem Chemical Inc, Newburyport, Mass.), potassium carbonate (921 mg, 6.67 mmol), ethylene glycol (0.37 mL, 6.67 mmol), and 2-propanol (8 mL) were added to a reaction vial. The vial was sealed, purged with nitrogen for several minutes, and heated at 80° C. for 16 h. After cooling to room temperature, the solvents were removed under vacuum. The residue was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 0% to 10% EtOAc in hexanes, to provide 5-bromo-2-((6-chloro-3-pyridinyl)sulfanyl)pyridine (318 mg) as a white solid.