Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.F[C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38]>>[CH2:2]1[C:35]2[C:41](=[CH:40][CH:39]=[C:37]([NH:38][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:36]=2)[CH2:5][CH2:4][NH:3]1
Reactant: Nc1cccc(F)c1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 3-fluoroaniline in a manner analogous to Example 27, Step D. 1H NMR (400 MHz, DMSO-d6) δ 6.58 (d, 1H, J=5.3 Hz), 6.71 (m, 1H), 7.12 (m, 1H), 7.23 (m, 3H), 7.31 (d, 1H, J=7.7 Hz), 7.44 (m, 3H), 7.53 (m, 1H), 7.76 (m, 2H), 8.00 (s, 1H), 8.29 (d, 1H, J=5.3 Hz), 8.45 (d, 1H, J=9.0 Hz), 8.84 (d, 1H, J=7.0 Hz), 9.83 (s, 1H), 10.92 (s, 1H); ESIMS (M+H)+=537.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:11](=[S:12](=[O:14])=[O:13])[C:10]([O:15][CH3:16])=[C:9]([CH3:17])[CH:8]=[C:4]1[C:5](O)=[O:6].S(Cl)([Cl:20])=O>CN(C)C=O>[CH3:1][O:2][CH:3]1[C:11](=[S:12](=[O:14])=[O:13])[C:10]([O:15][CH3:16])=[C:9]([CH3:17])[CH:8]=[C:4]1[C:5]([Cl:20])=[O:6]
Reactant: COC1=C(C)C=C(C(=O)O)C(OC)C1=S(=O)=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC1=C(C)C=C(C(=O)Cl)C(OC)C1=S(=O)=O
Reaction time: 0.33 h

Procedure:
161 g of 2,4-dimethoxy-5-methyl sulphonyl-benzoic acid is reacted. 590 g of thionyl chloride, 5 drops of dimethylformamide and about half of the organic acid are placed in a 2 liter flask filtered with a reflux condenser. The resultant suspension is heated in a water bath at 55° for about 5 minutes. The second half of the organic acid is added and heating is continued for 20 minutes at 60°-65° then for 45 minutes at 70°-75°. The medium becomes fluid and turns yellow. The acid dissolves gradually, while the acid chloride begins to crystallise. When the reaction is over the excess thionyl chloride is distilled to constant weight, finishing up under vacuum.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:31])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:30])[C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3]1.Cl.[NH2:33][OH:34]>N1C=CC=CC=1>[OH:34][N:33]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13](=[O:31])[C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:30])[C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)=[CH:18][CH:19]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1)c1cc(Cl)cc(Cl)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(C(=O)N2CCCC(=NO)c3ccccc32)cc1)c1cc(Cl)cc(Cl)c1
Yield: 48.4 %

Procedure:
To a mixture of 5-oxo-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (4 g) and pyridine (50 ml) is added hydroxylamine hydrochloride (1.84 g) and the mixture is refluxed for 2.5 hours. The reaction solution is concentrated and water is added to the resulting residue. The precipitated crystal is collected by filtration, and recrystallized from dioxane/water to give 5-hydroxyimino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (2 g) as white powder, m.p. 272-273° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)[CH:4]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[N:27]=[C:28]=[O:29]>O1CCOCC1>[C:16]([C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:5]2[N:6]=[CH:7][N:8]=[C:3]([N:2]([CH3:1])[C:28]([NH:27][C:21]3[C:20]([Cl:19])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:26])=[O:29])[CH:4]=2)=[CH:15][CH:14]=1)(=[O:18])[CH3:17]
Reactant: CNc1cc(Nc2ccc(C(C)=O)cc2)ncn1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: C1COCCO1
Product: CC(=O)c1ccc(Nc2cc(N(C)C(=O)Nc3c(Cl)cccc3Cl)ncn2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 1-[4-(6-methylamino-pyrimidin-4-ylamino)-phenyl]-ethanone (3.77 g, 15.56 mmol), 2,6-dichlorophenyl isocyanate (3.22 g, 17.12 mmol) in dry dioxane (30 mL) is shaken for 16 h at 80° C. After evaporation of the solvent in vacuo, the residue is distributed between ethyl acetate and half-saturated K2CO3 solution. The precipitate is filtered off and washed with H2O and ethyl acetate. The solid residue is suspended in methanol, heated to reflux for several h and the hot yellow suspension filtered. This procedure is repeated once. The residue obtained after the second filtration is washed with CH3OH and dried in vacuo to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13].[OH-].[NH4+]>Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:6]([CH:10]=[CH:11][C:12]([CH3:13])=[N:5]2)=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: C/C=C/C=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1ccc2cc(F)c(Br)cc2n1
Temperature: 106 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
To a solution of 3-bromo-4-fluoroaniline (10.00 g, 52.63 mmol) in 6N HCl (150 mL) was added (E)-but-2-enal (7.524 mL, 92.10 mmol) dropwise over 10 minutes at 106° C. The reaction was stirred at 106° C. for 2 hours. After cooling to ambient temperature, the reaction mixture was basified with ammonium hydroxide to about pH 12, extracted with DCM (2×100 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane/ethyl acetate 5:1) to give 7-bromo-6-fluoro-2-methylquinoline (3.26 g, 25.8%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([O:21][CH3:22])=[CH:14][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:5].Cl.[H][H]>CCO.[Pd]>[NH2:18][C:16]1[C:15]([O:21][CH3:22])=[CH:14][C:3]([C:4]([NH:6][CH:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)=[O:5])=[C:2]([F:1])[CH:17]=1
Reactant: [H][H]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1N
Yield: 100.4 %

Procedure:
To a solution of 2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)-4-nitrobenzamide (55 g, 177 mmol) in EtOH (450 mL) was added 10% Pd/C (11 g), followed by 4.4 mL of concentrated HCl. The reaction mixture was hydrogenated using a hydrogen balloon for 22 h. The solution was filtered through celite and concentrated to a minimum volume, after which solid was filtered, washed with ether. The filtrate concentrated again and trituated with EtOH and repeated several times to get out more products. The solid was combined and further dried to give total 50 g of product as light yellow powder (>98%). 1H NMR (400 MHz, DMSO-d6) δ 1.64-2.02 (m, 4 H) 2.61 (s, 3 H) 2.90 (t, J=11.0 Hz, 2 H) 3.24 (m, 2 H) 3.72-3.81 (m, 3 H) 3.84-4.03 (m, 1 H) 5.60 (s, 2 H) 6.29-6.50 (m, 1 H) 7.01 (d, J=6.8 Hz, 1 H) 7.69 (dd, J=7.3, 4.8 Hz, 1 H). [M+H] calc'd for C14H20FN3O2, 282; found 282.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]2[C:20]([CH3:22])([CH3:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=3)[NH:12]2)[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1>C(O)C.O.Cl.[Fe]>[NH2:8][C:6]1[CH:5]=[C:4]([CH:11]2[C:20]([CH3:21])([CH3:22])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=3)[NH:12]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(Cl)cc([N+](=O)[O-])c1)N2
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(N)cc(Cl)c1)N2
Yield: 83.5 %

Procedure:
To a solution of methyl 2-(3-chloro-5-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (124 mg, 0.33 mmol) in ethanol/water (2 mL/0.5 mL) was added 2 drops of conc. hydrochloric acid and iron (370 mg, 6.62 mmol). The mixture was stirred and heated to reflux for 4 h. LC-MS showed most of SM was consumed. The mixture was dried over silica gel and washed through a short column with petroleum ether:ethyl acetate=3:1 to afford 95 mg of methyl 2-(3-amino-5-chlorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a brown solid. (Yield=83%). MS (ESI+APCI) M+1=345.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16]CC3C=CC=CC=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)[CH3:6])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)[CH3:6])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(C)n1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)n1ccc2cc(O)ccc21

Procedure:
A mixture of 2-(5-Benzyloxy-indol-1-yl)-propionic acid ethyl ester (16 g) and Pd/C (5%, 1.93 g) in ethanol (190 mL) is stirred under 60 PSI of hydrogen overnight. Filtration and concentration yields the title compound.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].C[Si](C)(C)[O:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH2:16]>CCCCCC>[OH:6][CH2:14][C:15](=[O:16])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: C=C(CCCCCCCCCCC)O[Si](C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCCCCC
Product: CCCCCCCCCCCC(=O)CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
3-Chloroperoxybenzoic acid is added in one portion to a cooled (0° C.) solution of 2-trimethylsilyloxy-1-tridecene in hexane (200 mL). The ice bath is removed and the resulting slurry is stirred (4 hours, 25° C.). Ether (200 mL) and 1.5 N HCl (130 mL) are added and the resulting two-phase mixture is stirred vigorously (4.5 hours, 25° C.). The layers are separated and the organic layer is washed with saturated sodium bicarbonate (2×130 mL), washed with brine (1×130 mL), dried (MgSO4), and concentrated in vacuo. The residue is chromatographed on silica (90:10 hexane:ethyl acetate), and concentrated in vacuo. The resulting solid is washed with cold hexane and collected by filtration to yield 1.5 g (29%) of the title compound as white platelets, m.p. 52°-54° C.
Reaction SMILES: [CH2:1]([C:5]1[C:10]([CH2:11]Cl)=[CH:9][N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:23]([O:25][C:26](=[O:38])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)([CH3:29])[CH3:28])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:23]([O:25][C:26](=[O:38])[C:27]([O:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:11][C:10]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)=[N:8][CH:9]=2)=[CH:35][CH:36]=1)([CH3:29])[CH3:28])[CH3:24]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1COc1ccc(OC(C)(C)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
A solution of 367 mg (1.11 mmol) 4-butyl-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 115C]) and 250 mg (1.11 mmol) 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester [Newman, Melvin S.; Cella, James A. Monoalkylation of hydroquinone. Journal of Organic Chemistry (1974), 39(2), p 214–15] in 4 ml DMF was treated with 436 mg (1.34 mmol) cesium carbonate. The reaction mixture was stirred for 24 h at RT and then it was taken up in ether and washed with 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:4 to provide 344 mg pure 2-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12]N1C(=O)CCC1=O>CO>[C:1]1([C:7]2[S:8][C:9]([Br:12])=[CH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-c2cccs2)cc1
Solvent: CO
Product: Brc1ccc(-c2ccccc2)s1

Procedure:
Next, 3.21 g (20 mmol) of the thus synthesized 2-phenylthiophene was dissolved into 20 mL of methanol, and then to this solution was added a solution wherein 3.92 g (22 mmol) of N-bromosuccinimide (Wako Pure Chemicals Industries, Ltd.) was dissolved into 40 mL of methanol, to produce a white precipitation of 2-phenyl-5-bromothiophene immediately. This reaction solution was put into a refrigerator to ensure the production of the precipitation. This precipitation was filtered and then was sufficiently washed with a great deal of a mixture solution of equivalent amounts of water and methanol. The resultant was dried one day and night to obtain a white crystal (2.4 g) of 2-phenyl-5-bromothiophene.
Reaction SMILES: [Br-:1].[C:2]([CH2:5][CH2:6][N+:7]1[C:11]2[CH:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)[CH3:3].C(#N)C>CCOCC>[Br-:1].[CH3:3][C:2]1[CH2:5][CH2:6][N+:7]2[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:14]=[CH:15][C:10]=3[O:9][C:8]=2[C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)CC[n+]1c(Cc2ccccc2)oc2ccc(-c3ccccc3)cc21
Agent: [Br-]
Solvent: CC#N
Solvent: CCOCC
Product: CC1=C(c2ccccc2)c2oc3ccc(-c4ccccc4)cc3[n+]2CC1
Temperature: 30 °C
Reaction time: 124 h
Yield: 93 %

Procedure:
1,3-Dihydro-3-methyl-4-phenylpyrido[2,1-b]-5-phenylbenzoxazolium bromide is prepared by reacting 3-(2-acetylethyl)-2-benzyl-5-phenylbenzoxazolium bromide (5.0 g.) dissolved in 75 ml. of acetonitrile. The reaction mixture is stirred at about 30° C for about 124 hours, after which ether is added to the solution and the resultant precipitate is filtered, washed and dried to give 4.27 g. (93% yield) of 1,2-dihydro-3-methyl-4,8-diphenylpyrido[2,1-b]benzoxazolium bromide having a melting point of 269° C. This product is dissolved in 20 ml. of dimethyl sulfoxide and heated for a few minutes on a hot plate. Sodium perchlorate (0.6 g.) in 20 ml. of ethanol is added with stirring. Excess diethyl ether is added, precipitating an oil. Crystallization of the oily substance is induced from a chloroform-ether solution. Recrystallization from ethanol affords a 70% yield of product having a melting point of 252°-254° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[C:15]1=[O:33].C([O-])([O-])=O.[Na+].[Na+].CS(C)=O>O>[Cl:8][C:7]1[C:2]([NH:13][C@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:24][CH2:25]3)[C:15]2=[O:33])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](N)C2=O)CC1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](Nc3ncc(C(F)(F)F)cc3Cl)C2=O)CC1
Temperature: 130 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
A flask was charged with 2,3-dichloro-5-(trifluoromethyl)pyridine (0.2919 mL, 2.093 mmol), (S)-tert-butyl 3-amino-2-oxo-1,4′-bipiperidine-1′-carboxylate (0.415 g, 1.395 mmol), Na2CO3 (0.2958 g, 2.791 mmol), and DMSO (5 mL). The reaction mixture was stirred at 130° C. overnight. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layers were combined, dried, filtered, concentrated. The residue was purified using silica gel column chromatography with 30% ethyl acetate in hexanes to provide (S)-tert-butyl 3-(3-chloro-5-(trifluoromethyl)pyridin-2-ylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (0.51 g, 76.63% yield). Mass spectrum (apci) m/z=377.2 (M+H-Boc).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[N:15][C:14]([NH2:17])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH:2]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](I)[CH:20]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:17][C:14]2[N:15]=[CH:16][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)[CH:22]=[CH:23][CH:24]=1
Reactant: Clc1cccc(I)c1
Reactant: Nc1ncc(-c2cccnc2)c2cccnc12
Product: Clc1cccc(Nc2ncc(-c3cccnc3)c3cccnc23)c1

Procedure:
The title compound, MS: m/e=333.1 (M+H+), was prepared in accordance with the general method of example 6 step 3 from 5-pyridin-3-yl-[1,7]naphthyridin-8-ylamine and 1-chloro-3-iodobenzene.
Reaction SMILES: C([N:8]1[C:12]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[N:11][N:10]=[N:9]1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:19][C:18]1[C:13]([C:12]2[NH:8][N:9]=[N:10][N:11]=2)=[C:14]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:15]=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: Cc1cccc(NS(=O)(=O)c2ccccc2)c1-c1nnnn1Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cccc(NS(=O)(=O)c2ccccc2)c1-c1nnn[nH]1
Reaction time: 168 h
Yield: 205.7 %

Procedure:
N-[2-(1-Benzyl-1H-tetrazol-5-yl)-3-methylphenyl]-benzenesulfonamide (Intermediate 15, 0.05 g) was dissolved in ethyl acetate (10 mL) under a nitrogen atmosphere. Palladium on carbon (10%, 0.02 g) was added and the nitrogen atmosphere was replaced by hydrogen. The mixture was stirred for 7 days and then filtered through celite and the solvent was removed by evaporation under vacuum. The residue was purified by preparative HPLC (C18). The fractions containing the desired product were combined, and the solvent was removed by evaporation to give the title compound as a white solid (0.08 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][N:18]([CH:20]([CH:24]4[CH2:26][CH2:25]4)[CH2:21][C:22]#[N:23])[CH:19]=3)[C:12]([O:27][CH3:28])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.C(N(CC)CC)C.[Cl:42][CH2:43][CH2:44][CH2:45][S:46](Cl)(=[O:48])=[O:47]>>[Cl:42][CH2:43][CH2:44][CH2:45][S:46]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][N:18]([CH:20]([CH:24]4[CH2:26][CH2:25]4)[CH2:21][C:22]#[N:23])[CH:19]=3)[C:12]([O:27][CH3:28])=[CH:11][N:10]=2)[CH:3]=1)(=[O:48])=[O:47]
Reactant: COc1cnc(Nc2cccc(N)c2)nc1-c1cnn(C(CC#N)C2CC2)c1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1cnc(Nc2cccc(NS(=O)(=O)CCCCl)c2)nc1-c1cnn(C(CC#N)C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-(4-{2-[(3-aminophenyl)amino]-5-methoxypyrimidin-4-yl}-1H-pyrazol-1-yl)-3-cyclopropylpropanenitrile (prepared according to Example 345, 8.0 mg, 0.000021 mol) in 1,4-dioxane (0.1 mL, 0.002 mol) was added triethylamine (0.02 mL, 0.0001 mol), followed by 3-chloropropane-1-sulfonyl chloride (0.0039 mL, 0.000032 mol). The reaction was stirred at room temperature for 1 h, quenched with 1 N HCl. The mixture was extracted with EtOAc and the organic layer was separated. The combined organic layers were washed with brine, dried over MgSO4, and evaporated to dryness to provide the desired sulfonylated intermediate.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[C:17]([CH3:19])[C:5]([CH2:6][NH:7][C:8]2[C:9](=O)[C:10](=[O:15])[C:11]=2[O:12]CC)=[C:4]([CH3:20])[CH:3]=1.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]([CH2:6][NH:7][C:8]2[C:11](=[O:12])[C:10](=[O:15])[C:9]=2[NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:17]([CH3:19])[CH:18]=1
Reactant: CCOc1c(NCc2c(C)cc(Br)cc2C)c(=O)c1=O
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: Cc1cc(Br)cc(C)c1CNc1c(NC(C)(C)C)c(=O)c1=O
Reaction time: 18 h

Procedure:
A solution of 3-(4-bromo-2,6-dimethyl-benzylamino)-4-ethoxy-cyclobut-3-ene-1,2-dione (0.49 g, 1.45 mmol), t-butylamine (26 mL) and dichloromethane (8 mL) was allowed to stand at room temperature for 18 hours, then refluxed for 8 hours. The resulting solid was filtered, rinsed with acetonitrile, and dried (0.4 mm, 40° C.). This gave 0.33 g (62%) of the title compound as an off-white solid: mp 267°-271° C. (dec); 1H NMR (DMSO-d6) δ7.40 (br s, 1H), 7.32 (s, 2H), 7.30 (br t, 1H), 4.76 (d, 2H), 2.34 (s, 6H), 1.34 (s, 9H) ppm. IR (KBr): 3200, 2980, 1790, 1650 cm-1 ; MS (m/z) 364/366 (M+).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.Cl[CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17]1>CN(C)C=O>[C:22]1([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH2:13][O:3][C:4]3[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=3)[CH2:21][CH2:20]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCN2CCN(c3ccccc3)CC2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
Sodium hydride (3.59 g of 60% in oil) is added to 4-hydroxybenzaldehyde (9.95 g) in dimethylformamide (250 mL) and the mixture stirred at 60° C. for 30 minutes. 1-(3-Chloropropyl)-4-phenylpiperazine (Step A) (19.5 g) is added and the mixture stirred for 14 hours at 60° C. The solvent is evaporated and the residue treated with water (300 mL) and extracted with dichloromethane (3×150 mL). The extracts are dried over magnesium sulfate, filtered and evaporated to leave a beige solid. This solid is recrystallized from ethyl acetate/diethyl ether to give 18.4 g of the title compound as a light beige solid.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]([NH2:19])=[O:18])=[CH:10][CH:9]=1.CCN(C(C)C)C(C)C.I.[NH2:32][C:33]1[C:34]([C:41]([NH:43][C:44](=[NH:47])SC)=[O:42])=[N:35][C:36]([Cl:40])=[C:37]([NH2:39])[N:38]=1>C(O)C>[NH2:32][C:33]1[C:34]([C:41]([N:43]=[C:44]([NH2:47])[NH:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]([NH2:19])=[O:18])=[CH:10][CH:9]=2)=[O:42])=[N:35][C:36]([Cl:40])=[C:37]([NH2:39])[N:38]=1
Reactant: NCCCCc1ccc(OCCNCC(N)=O)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: Cl
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: NC(=O)CNCCOc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A solution composed of compound 4 (0.065 g, 0.194 mmol), Hunig's base (0.17 mL, 0.97 mmol) and ethanol (6 mL) was heated at 65° C. for 30 min, then 1-(3,5-diamino-6-chloropyrazine-2-carbony)-2-methylisothiourea hydriodide (5, 0.072 g, 0.213 mmol) was added. The resulting solution was continuously stirred at 65° C. temperature for an additional three hours, then cooled to room temperature. The solvent was then removed by evaporation, and the resulting residue was column chromatographed on silica gel eluting with a mixture of methanol (0-22%), ammonium hydroxide (0-2.2%) and dichloromethane (100-75.8%). This afforded compound 6 (0.078 g, 84%) as a yellow solid. m.p. 92-94° C. (decomposed). 1H NMR (500 MHz, DMSO-d6) δ 1.54 (m, 4H), 2.51 (m, 2H), 2.89 (m, 2H), 3.20 (s, 2H), 3.31 (m, 2H), 4.00 (m, 2H), 6.89 (d, 2H), 7.08 (br, 2H), 7.12 (d, 2H), 7.57 (br, 2H), 9.08 (br, 1H). m/z (ESI) 478.