Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:21][NH2:22])=[N:14][C:15]=1[O:16][CH2:17][CH:18]([CH3:20])[CH3:19].Cl[C:24]1[N:29]=[CH:28][N:27]=[C:26]([CH:30]([CH:37]2[CH2:39][CH2:38]2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=1.C(N(CC)C(C)C)(C)C.O>C(#N)C>[CH:37]1([CH:30]([C:26]2[CH:25]=[C:24]([NH:22][CH2:21][C:13]3[CH:12]=[CH:11][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:15]([O:16][CH2:17][CH:18]([CH3:19])[CH3:20])[N:14]=3)[N:29]=[CH:28][N:27]=2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:39][CH2:38]1
Reactant: COc1ccc(F)c(-c2ccc(CN)nc2OCC(C)C)c1
Reactant: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CC(c1cc(NCc2ccc(-c3cc(OC)ccc3F)c(OCC(C)C)n2)ncn1)C1CC1
Temperature: 70 °C
Reaction time: 15 h
Yield: 54.1 %

Procedure:
To a solution of 1-(5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methanamine (56 mg) and ethyl 3-(6-chloropyrimidin-4-yl)-3-cyclopropylpropanoate (137 mg) in acetonitrile (3.0 mL) was added N,N-diisopropylethylamine (96 μL), and the mixture was stirred at 70° C. for 15 hr. Water was added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified to by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (52 mg) as a colorless oil.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:15])[N:4]2[CH:10]=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][C:5]=12.[CH3:16]N(C)C=O.[OH-].[Na+].CI>O>[CH3:16][N:2]1[C:3](=[O:15])[N:4]2[C:5]([CH2:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10]2)=[N:1]1
Reactant: O=c1[nH]nc2n1C=Cc1ccccc1C2
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: Cn1nc2n(c1=O)C=Cc1ccccc1C2

Procedure:
To a solution of 8 parts of 2,11-dihydro-3H-s-triazolo-[3,4-b][3]benzazepin-3-one in 80 volume parts of dimethylformamide is added 9 volume parts of 5N aqueous sodium hydroxide solution and then 3 volume parts of methyl iodide is added dropwise under stirring. After stirring for 1 hour, the reaction mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate layer is washed with water and the solvent is distilled off. The precipitate is collected by filtration to give 2,11-dihydro-2-methyl-3H-s-triazolo[3,4-b][3]benzazepin-3-one as crystals. Recrystallization from isopropyl ether gives light-brown needles melting at 123° -124° C.
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.[O:32]1[CH2:36][CH2:35][O:34][CH:33]1[C:37]1[O:41][C:40]([S:42](Cl)(=[O:44])=[O:43])=[CH:39][CH:38]=1.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:42]([C:40]1[O:41][C:37]([CH:33]2[O:34][CH2:35][CH2:36][O:32]2)=[CH:38][CH:39]=1)(=[O:43])=[O:44]
Reactant: O=S(=O)(Cl)c1ccc(C2OCCO2)o1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(C2OCCO2)o1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (50 mg, 0.120 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 5-(1,3-dioxolane-2-yl)furan-2-sulfonyl chloride (24 mg, 0.130 mmol) and pyridine (11 uL, 0.130 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 71 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-5-(1,3-dioxolane-2-yl)furan-2-sulfonamide (percentage yield: 94%), was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:28][CH2:27][N:11]2[C:12](=[O:26])[C:13]3[CH:14]=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:16]=[C:17]([CH2:20][CH3:21])[C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)=O)(C)(C)C.[ClH:29].O1CCOCC1.C(OCC)C>CCO.[Pd]>[ClH:29].[CH2:20]([C:17]1[C:18]2[CH2:19][C@@H:10]3[CH2:9][NH:8][CH2:28][CH2:27][N:11]3[C:12](=[O:26])[C:13]=2[CH:14]=[C:15]([C:22]([F:23])([F:25])[F:24])[CH:16]=1)[CH3:21]
Reactant: CCc1cc(C(F)(F)F)cc2c1C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C2=O
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CCO
Product: CCc1cc(C(F)(F)F)cc2c1C[C@@H]1CNCCN1C2=O
Yield: 40 %

Procedure:
MS (ESI) 340 (M+H). Crude (R)-2-N-(t-butoxycarbonyl)-10-ethyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydropyrazino[1,2-b]isoquinolin-6-one was dissolved in EtOH (2 mL) and hydrogenated [10% Pd/C (50 mg), H2 (30 psi)]. The reaction mixture was filtered through diatomaceous earth, and then purified by flash column chromatography (silica gel, 4:1 hexanes/EtOAc). The resulting material was deprotected using 4 N HCl in 1,4-dioxane (200 μL, 0.8 mmol), followed by trituration with diethyl ether, to provide the desired product (18 mg, 40% over 3 steps) as a white solid. MS (ESI) 299 (M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[CH:11]=[C:10]([CH:12]=[N:13][CH3:14])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.COC1C=C(C=CC=1OC)CN=CC1SC2N=CN=CC=2C=1.CC1C=CC(S([CH:47]([C:50]2[CH:55]=[CH:54][C:53]([Br:56])=[CH:52][CH:51]=2)[N+:48]#[C-:49])(=O)=O)=CC=1>>[Br:56][C:53]1[CH:52]=[CH:51][C:50]([C:47]2[N:48]=[CH:49][N:13]([CH3:14])[C:12]=2[C:10]2[S:9][C:5]3[N:6]=[CH:7][N:8]=[C:3]([S:2][CH3:1])[C:4]=3[CH:11]=2)=[CH:55][CH:54]=1
Reactant: CN=Cc1cc2c(SC)ncnc2s1
Reactant: [C-]#[N+]C(c1ccc(Br)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: COc1ccc(CN=Cc2cc3cncnc3s2)cc1OC
Product: CSc1ncnc2sc(-c3c(-c4ccc(Br)cc4)ncn3C)cc12

Procedure:
The title compound was prepared by a similar process to that described for Example 6 but using N-[4-(methylthio)thieno[2,3-d]pyrimidin-6-ylmethylidene]methanamine (Intermediate 16) in place of N-(3,4-Dimethoxybenzyl)-N-[thieno[2,3-d]pyrimidin-6-ylmethylidene]amine. (intermediate 14) and (4-bromophenyl)(isocyano)methyl 4-methylphenyl sulfone (Intermediate 66) in place of PhTosMIC. Pale yellow solid (1.7 g, 81%);
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][CH2:4][C:5]([N:11]=[C:12]=[O:13])(OC)[C:6]([OH:8])=O.CN([C:19]([O:23]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:40]([O:44][C:45]([N:47]1[CH2:51][CH2:50][CH2:49][CH:48]1[C:52]1[NH:53][C:54]([C:57]2[CH:62]=[CH:61][C:60]([C:63]3[CH:68]=[CH:67][C:66]([C:69]4[NH:70][C:71]([CH:74]5[CH2:78][CH2:77][CH2:76][NH:75]5)=[N:72][CH:73]=4)=[CH:65][CH:64]=3)=[CH:59][CH:58]=2)=[CH:55][N:56]=1)=[O:46])([CH3:43])([CH3:42])[CH3:41].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:40]([O:44][C:45]([N:47]1[CH2:51][CH2:50][CH2:49][CH:48]1[C:52]1[NH:53][C:54]([C:57]2[CH:58]=[CH:59][C:60]([C:63]3[CH:68]=[CH:67][C:66]([C:69]4[NH:70][C:71]([CH:74]5[CH2:78][CH2:77][CH2:76][N:75]5[C:6](=[O:8])[CH:5]([NH:11][C:12]([O:23][CH3:19])=[O:13])[CH2:4][CH2:3][C:2]([F:1])([F:14])[F:15])=[N:72][CH:73]=4)=[CH:65][CH:64]=3)=[CH:61][CH:62]=2)=[CH:55][N:56]=1)=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: COC(CCC(F)(F)F)(N=C=O)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5)[nH]4)cc3)cc2)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)NC(CCC(F)(F)F)C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Reaction time: 0.08 h
Yield: 59 %

Procedure:
(194 mg, 0.80 mmol) in methanol (3 mL) was added an aqueous LiOH solution (1M, 2 mL, 2 mmol). The resulting solution was stirred at room temperature for 45 minutes and then washed with ethyl acetate. The ethyl acetate washing was discarded and the aqueous layer was acidified with concentrated HCl. The acidified aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with brine, dried (MgSO4), and concentrated to give clean 5,5,5-Trifluoro-2-methoxy-carbonylamino-pentanoic acid. To a solution of the pentanoic acid in dimethylformamide (2 mL) was added HATU (300 mg, 0.79 mmol). After stirring for 5 minutes, a solution of 2-{5-[4′-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (412 mg, 0.79 mmol) in dimethylformamide (1.9 mL) was added to the reaction, followed immediately by diisopropylethylamine (275 μL, 1.58 mmol). The reaction was stirred for 1 hour at room temperature then diluted with ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4), concentrated and purified by flash chromatography to yield 2-[5-(4′-{2-[1-(5,5,5-trifluoro-2-methoxycarbonylamino-pentanoyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (340 mg, 59%). LCMS-ESI+: calculated for C38H44F3N7O5: 735.34; observed [M+1]+: 736.05.
Reaction SMILES: [N+]([O-])([O-])=O.[IH2+:5].[CH3:6][N:7]([CH3:19])[C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:11]=[CH:12][CH:13]=1.CCOCC.C(Cl)(Cl)[Cl:26]>>[ClH:26].[CH3:19][N:7]([CH3:6])[C:8]1[CH:13]=[CH:12][C:11]([I:5])=[C:10]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:9]=1
Reactant: [IH2+]
Reactant: ClC(Cl)Cl
Reactant: CC(=O)CCc1cccc(N(C)C)c1
Agent: O=[N+]([O-])[O-]
Solvent: CCOCC
Product: CC(=O)CCc1cc(N(C)C)ccc1I
Product: Cl
Reaction time: 2 h

Procedure:
A solution of 0.16 moles of iodonium nitrate in 280 ml of CHCl3 was added to 30.4 g of 4-(3-dimethylaminophenyl)-2-butanone. The mixture was stirred for 2 hr. Ether was added and the precipitated solid was removed by filtration. The solvent was evaporated in vacuo. The residue was paartitioned between water and ether. The ether solution was washed with sodium thiosulfate solution and brine. The solution was dried (K2CO3) and the solvent evaporated. The residue was taken up in ether and ethereal hydrogen chloride added. The precipitate (47.4 g, 85% yield) of the title compound was collected mp 120°-121° C.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[C-:8]#[N:9].[Na+].[CH2:11]([S:18][CH2:19][CH:20]([CH3:23])[CH:21]=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([S:18][CH2:19][CH:20]([CH3:23])[CH:21]([NH:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)[C:8]#[N:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [C-]#N
Reactant: NN1CCOCC1
Reactant: CC(C=O)CSCc1ccccc1
Agent: [Na+]
Product: CC(CSCc1ccccc1)C(C#N)NN1CCOCC1
Yield: 95.7 %

Procedure:
5.8 g of 4-aminomorpholine, 2.7 g of sodium cyanide and 10.7 g of 3-benzylthio-2-methylpropionaldehyde are reacted analogously to 7a). 16.1 g of 4-benzylthio-2-morpholinoamino-3-methylbutyronitrile are obtained, which are employed in the following step without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[CH3:12][C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH2:22][CH2:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28][CH2:27]1)=O)=[CH:19][C:18]([F:38])=[CH:17][CH:16]=2.O>O1CCCC1>[CH3:12][C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH2:22][CH2:23][CH2:24][N:26]1[CH2:31][CH2:30][N:29]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:28][CH2:27]1)=[CH:19][C:18]([F:38])=[CH:17][CH:16]=2
Reactant: Cc1[nH]c2ccc(F)cc2c1CCC(=O)N1CCN(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cc1[nH]c2ccc(F)cc2c1CCCN1CCN(c2ccccc2)CC1
Reaction time: 4 h

Procedure:
To a stirred mixture of 21 g of lithium aluminum hydride and 100 ml of dry ether was added dropwise a solution of 67.5 g of 1-[β-(2-methyl-5-fluoro-3-indolyl)propionyl]-4-phenylpiperazine in 900 ml of tetrahydrofuran over a period of 90 minutes under gentle refluxing. Stirring and refluxing were continued for additional 4 hours and to the reaction mixture was added dropwise a mixture of water and tetrahydrofuran under cooling with ice. The resulting precipitate was filtered off and the filtrate was evaporated to dryness. Recrystallization of the residue from benzene gave 2-methyl-3-[γ-(4-phenylpiperazino)propyl]-5-fluoroindole having a melting point of 146.0°-147.0°C.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C:11]2([CH3:15])[CH3:14])=[C:7]([C:16](=O)[CH3:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:19](O)(=O)C.[CH:23]([NH2:25])=[NH:24]>C(O)CCC>[C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C:11]2([CH3:15])[CH3:14])=[C:7]([C:16]2[CH:17]=[CH:19][N:25]=[CH:23][N:24]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1cc(C(C)(C)C)cc2c1CCC2(C)C
Reactant: CC(=O)O
Reactant: N=CN
Solvent: CCCCO
Product: CC(C)(C)c1cc(-c2ccncn2)c2c(c1)C(C)(C)CC2
Temperature: 125 °C
Yield: 59.4 %

Procedure:
A 5 L reaction vessel was charged with 1-(6-tert-butyl-1,1-dimethyl-indan-4-yl)-ethanone (300 g, 1.2 mol) (commercially available at IFF), formamidine acetate (639 g, 6.1 mol), and butanol (1.0 L). The reaction mixture was heated to 125° C. for 10 hours and then cooled to 25° C. The reaction mixture was washed twice with brine (1 L) and purified by vacuum distillation to afford 4-(6-tert-butyl-1,1-dimethyl-indan-4-yl)-pyrimidine (200 g) having a boiling point of 180° C. at a pressure of 0.5 mmHg
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[C:7]([OH:9])=[O:8].[CH3:11]O>CCC(CCCCC(NC(C(NC(C(NC(C(NC1C(=O)NC(CCN)C(=O)NC(CC2C=CC=CC=2)C(=O)NC(CC(C)C)C(=O)NC(CCN)C(=O)NC(CCN)C(=O)NC(C(O)C)C(=O)NCC1)=O)CCN)=O)C(O)C)=O)CCN)=O)C.OS(O)(=O)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[C:7]([O:9][CH3:11])=[O:8]
Reactant: CO
Reactant: O=C(O)C(=O)c1cccs1
Agent: CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(Cc2ccccc2)NC(=O)C(CCN)NC1=O)C(C)O
Agent: O=S(=O)(O)O
Product: COC(=O)C(=O)c1cccs1

Procedure:
To a stirred solution of 2-thiopheneglyoxylic acid (1 g) in methanol (10 ml) was added 5 drops of concentrated sufuric acid and the mixture was refluxed for 4 hours. Then the methanol was evaporated off and the residue was partitioned between ethyl acetate and water. The organic extract was washed with water and brine, dried (sodium sulfate) and evaporated to give methyl 2-thiopheneglyoxylate as an oil (1.01 g).
Reaction SMILES: C(O[CH:4]=[N:5][C:6]1[NH:10][N:9]=[N:8][N:7]=1)C.[C:11]([O:20][CH3:21])(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:14]>C(OCC)(=O)C>[NH:7]1[C:6]([NH:5][CH:4]=[N:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11]([O:20][CH3:21])=[O:19])=[N:10][N:9]=[N:8]1
Reactant: COC(=O)c1ccccc1N
Reactant: CCOC=Nc1nnn[nH]1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1N=CNc1nnn[nH]1
Temperature: 25 °C

Procedure:
To a mixture of 5 g of 5-(ethoxymethyleneamino)tetrazole in 50 ml of ethyl acetate, stirred at room temperature under nitrogen, there was added a solution of 10.2 g of methyl anthranilate in 50 ml of ethyl acetate and the mixture was stirred for 24 hours. The white solid which formed was separated by filtration, washed with ethyl acetate and vacuum oven dried to give crude N1 -(1H-tetrazol-5-yl)-N2 -(2-carbomethoxyphenyl)formamidine. This was recrystallized from a mixture of N,N-dimethylformamide and ethyl acetate to give pure product identical with authentic material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[NH:12][C:11](=[O:19])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH2:37])[CH:35]=3)[NH:30][N:29]=2)=[CH:23][CH:22]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([NH:37][C:15]([C:14]4[CH:9]([C:4]5[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=5)[NH:10][C:11](=[O:19])[NH:12][C:13]=4[CH3:18])=[O:17])[CH:35]=3)[NH:30][N:29]=2)=[CH:25][CH:26]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(F)c(F)c2)NC(=O)N1
Reactant: Nc1ccc2[nH]nc(Nc3ccc(F)cc3)c2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Nc4ccc(F)cc4)c3c2)C(c2ccc(F)c(F)c2)NC(=O)N1

Procedure:
The titled compound was prepared following the procedure of Example 175 using 4-(3,4-Difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid, N3-(4-fluoro-phenyl)-1H-indazole-3,5-diamine, PyBroP and diisopropylethylamine in methylene chloride. MS (ESI) m/z=493 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)[CH:7]=[CH:6]2.[ClH:34].B(Br)(Br)Br>ClCCl.C(#N)C.O>[ClH:34].[N:21]1([CH2:20][CH2:19][O:18][C:17]2[CH:16]=[CH:15][C:14]([O:13][C:9]3[C:8]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[CH:7][CH:6]=[C:5]4[C:10]=3[CH:11]=[CH:12][C:3]([OH:2])=[CH:4]4)=[CH:28][CH:27]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cccs3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: Oc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cccs3)ccc2c1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 54.5 %

Procedure:
Dissolve 1-(2-(4-(6-methoxy-2-(thiophen-2-yl)naphthalen-1-yloxy)phenoxy)ethyl)piperidine (100 mg, 0.22 mmol) in dichloromethane and treat with HCl (1M in ether; 220 μL, 0.22 mmol). Concentrate in vacuo to give a yellow solid and add dichloromethane (7.3 mL). Cool the resulting solution to 0° C. and add boron tribromide (1M in dichloromethane; 870 μL, 0.87 mmol). Stir the resulting mixture at 0° C. for 2.5 hours. Quench the mixture with saturated aqueous sodium bicarbonate and allow to warm to room temperature. Separate the layers and extract the aqueous layer with 20% methanol in dichloromethane (10 mL×3). Dry combined organic layers (Na2SO4), filter and concentrate in vacuo to give a yellow residue. Purify the residue by silica gel flash chromatography to give an off-white foam. Suspend the foam in ACN and add HCL (5M in water; 1 mL). Freeze the resulting solution and lyophilize to obtain the title compound (50.5 mg, 0.12 mmol): mass spectrum (m/z): 446 (M+1-HCl).
Reaction SMILES: [N:1]#[C:2]Br.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]3[CH:18]=[N:19][C:20]([CH2:23][NH2:24])=[CH:21][CH:22]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:7][C:6]=1[CH3:25].CCN(C(C)C)C(C)C.C1(C)C=CC=CC=1>C(#N)C>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]4[N:19]([C:2]([NH2:1])=[N:24][CH:23]=4)[CH:18]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:7][C:6]=1[CH3:25]
Reactant: Cc1cc(-c2ncccc2-c2ccc(CN)nc2)ccc1F
Reactant: N#CBr
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2ncccc2-c2ccc3cnc(N)n3c2)ccc1F
Reaction time: 4 h

Procedure:
Cyanogen bromide (62 mg) in dry acetonitrile (1 mL) was added to a screw capped vial containing a stirring solution of (2′-(4-fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methanamine.xHCl (120 mg), i-Pr2NEt (0.2 mL) and anhydrous toluene. After 4 h, the reaction mixture was concentrated and purified by reverse phase preparative HPLC conditions provided 6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridin-3-amine (28 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.Br[CH2:40][CH2:41][O:42][Si](C(C)(C)C)(C)C>C(#N)C.CN1CCCC1=O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([CH2:40][CH2:41][OH:42])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(CCO)C3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a suspension of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (301 mg, 0.759 mmol) in Acetonitrile (1.3 mL), N-Methylpyrrolidinone (0.44 mL) and N,N-Diisopropylethylamine (0.40 mL, 2.3 mmol) was added (2-Bromoethoxy)-tert-butyldimethylsilane (0.82 mL, 3.8 mmol), and the reaction was kept at 50° C. overnight. LC-MS showed the reaction was completed (desired peak m/z=555 (M+H)). The yellow solution was evaporated to dryness as much as possible, followed by dilution in Methylene chloride (6.0 mL) and Methanol (3.0 mL). Then, 4.0 M of Hydrogen chloride in 1,4-Dioxane (5.7 mL) was added, and the yellow solution was stirred at room temperature for 2.5 h. The solvents were removed and the residue was purified to give the final product ry (174.4 mg, 52% yield after two steps) as off-white powder: 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.15 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.7 Hz, 2H), 6.18 (t, J=5.5 Hz, 1H), 4.48 (m, 1H), 4.12 (m, 1H), 3.87 (d, J=10.6 Hz, 1H), 3.75-3.48 (m, 8H), 3.40 (t, J=11.3 Hz, 1H), 3.17-3.04 (m, 2H), 2.80-2.53 (m, 6H), 1.22 (d, J=6.6 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H); LC-MS m/z=441 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:14][CH3:15])[C:11](=[O:13])[CH3:12])=[C:6]([CH3:16])[CH:5]=1.Cl.[N:18]1([C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[S:26][N:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[S:26]1[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:24]([N:18]2[CH2:19][CH2:20][N:21]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([N:10]([CH2:14][CH3:15])[C:11](=[O:13])[CH3:12])=[C:6]([CH3:16])[CH:5]=3)[CH2:22][CH2:23]2)=[N:25]1
Reactant: CCN(C(C)=O)c1ccc(CCCl)cc1C
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Product: CCN(C(C)=O)c1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1C
Yield: 70 %

Procedure:
Starting with N-[4-(2-chloro-ethyl)-2-methyl-phenyl]-N-ethyl-acetamide (0.169 g, 0.706 mmol) and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (0.271 g, 1.059 mmol) and following the procedure as outlined in Example 501, N-{4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenyl}-N-ethyl-acetamide (0.227 g, 0.494 mmol) was isolated in 100% purity @ 254 nm; LCMS (APCI): 423 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 11.37 (bs, 1H), 8.13 (d, J=7.84 Hz, 1H), 8.09 (d, J=7.84 Hz, 1H), 7.57 (t, J=7.12 Hz, 1H), 7.45 (t, J=7.12 Hz, 1H), 7.28 (s, 1H), 7.23–7.11 (m, 2H), 4.07 (bd, J=13.09 Hz, 2H), 3.88 (sextet, J=6.23 Hz, 1H), 3.66 (bd, J=11.22 Hz, 2H), 3.51 (bt, J=11.22 Hz, 2H), 3.45–3.37 (m, 2H), 3.35 (bs, DMSO-H2O), 3.33–3.22 (m, 3H), 2.14 (s, 3H), 1.58 (s, 3H), 0.97 (t, J=7.11 Hz, 3H).