Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]([C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(OC(=O)c2ccc(N)cc2)cc1
Yield: 100 %

Procedure:
11.0 g of 4-nitrophenyl 4-nitrobenzoate (38.2 mM) were dissolved in 350 ml of ethyl acetate and 1.0 g of palladium on charcoal (10%) was added. The resulting mixture was hydrogenated at atmospheric pressure until the theoretical amount of hydrogen was consumed. The mixture was then filtered, the cake was washed with ethyl acetate and the filtrate was evaporated to dryness to give 8.71 g (38.2 mM, 99%) of 4-aminophenyl 4-aminobenzoate as slightly beige crystals.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20]1(B(O)O)[CH2:24][CH2:23][CH2:22][CH:21]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[C:20]1([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH:21]=1
Reactant: OB(O)C1=CCCC1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2=CCCC2)C1
Yield: 68.1 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (400 mg, 1.21 mmol), a solution of cyclopenten-1-ylboronic acid (204 mg, 1.82 mmol) in ethanol (1.4 ml), 2N aqueous sodium carbonate solution (5 ml), and tetrakis(triphenylphosphine)palladium(0) (168 mg, 0.146 mmol) in toluene (10 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (260 mg, 68.1%) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:8]1[C:13](=[O:14])[CH:12]=[C:11]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:10]=[C:9]1[CH2:21][C:22](=[O:36])[N:23]1[C:31]2[C:26](=[C:27](C(F)(F)F)[CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1.Cl.CN(C)[CH2:40][CH2:41][CH2:42]N=C=NCC.N1(C2N=C(CC([O-])=O)NC(=O)C=2)CCOCC1.[Na+]>CN(C)C=O>[N:15]1([C:11]2[N:10]=[C:9]([CH2:21][C:22](=[O:36])[N:23]3[C:31]4[C:26](=[C:27]([CH:3]5[CH2:4][CH2:5][CH2:6][N:1]([CH2:40][CH2:41][CH3:42])[CH2:2]5)[CH:28]=[CH:29][CH:30]=4)[CH2:25][CH2:24]3)[NH:8][C:13](=[O:14])[CH:12]=2)[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: c1ccncc1
Reactant: Cn1c(CC(=O)N2CCc3c2cccc3C(F)(F)F)nc(N2CCOCC2)cc1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1CCCC(c2cccc3c2CCN3C(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.2 ml of pyridine, 25.7 mg of 4-(1-propylpiperidin-3-yl)-2,3-dihydro-1H-indole (reference example 4d) and 17.8 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are successively added to a solution of 20.5 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (example 1d, step 2d) in 0.8 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 24 hours, and then concentrated under reduced pressure. The residue is taken up in 10 ml of water and then extracted with dichloromethane (4×20 ml). The organic phases are combined and then washed with water and concentrated under reduced pressure. After oven-drying, 16.1 mg of 6-(morpholin-4-yl)-2-{2-oxo-2-[4-(1-propylpiperidin-3-yl)-2,3-dihydro-1H-indol-1-yl]ethyl}pyrimidin-4(3H)-one are obtained in the form of a pink solid, the characteristics of which are the following:
Reaction SMILES: C[Al](C)C.[CH2:5]([NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH2:14])[CH3:6].C(O[C:18](=O)[CH2:19][C:20]1[S:24][CH:23]=[N:22][C:21]=1[C:25]1[S:26][CH:27]=[CH:28][N:29]=1)C>C(Cl)Cl>[S:26]1[CH:27]=[CH:28][N:29]=[C:25]1[C:21]1[N:22]=[CH:23][S:24][C:20]=1[CH2:19][C:18]1[N:7]([CH2:5][CH3:6])[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]=1
Reactant: CCOC(=O)Cc1scnc1-c1nccs1
Reactant: CCNc1ccncc1N
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCn1c(Cc2scnc2-c2nccs2)nc2cnccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylaluminum (2M in toluene)(2.2 mL, 4.4 mmol) is added dropwise under N2 yo a solution of N4-Ethyl-pyridine-3,4-diamine (237 mg, 1.73 mmol) in DCM (5 mL). The mixture is stirred at room temperature for 1 hour. A solution of [2,4′]bithiazolyl-5′-yl-acetic acid ethyl ester (440 mg, 1.73 mmol) in DCM (2 mL) is added. The mixture is reluxed for 3 days. On cooling, the reaction is quenched with water added dropwise and DCM (40 mL) is added. The organic layer is separated and the aqueous layer is extracted with DCM (3×30 mL). The combined organic layers are dried and solvent removed. The residue is purified by PTLC (10% methanol in DCM) to give 2-[2,4′]bithiazolyl-5′-ylmethyl-1-ethyl-1H-imidazo[4,5-c]pyridine as a solid. 1H NMR (CDCl3) δ 9.05 (s, 1H0), 8.76 (s, 1H), 8.41 (d, 1H), 7.88 (d, 1H), 7.41 (d, 1H), 7.25 (d, 1H), 5.35 (s, 2H), 4.26 (q, 2H), 1.25 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[CH:13][C:14](Cl)=[N:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH4+:18].[OH-]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:18])=[N:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=S(=O)(c1ccc(Br)cc1)c1ccc(Cl)nc1
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)c2ccc(Br)cc2)cn1
Temperature: 120 °C

Procedure:
5-((4-Bromophenyl)sulfonyl)-2-chloropyridine (98 mg, 0.29 mmol), concentrated NH4OH (3 mL), and EtOH (3 mL) were added to a high-pressure reaction vessel. The vessel was sealed and heated at 120° C. for 18 h. After cooling to room temperature, the solvent was partially removed under vacuum. The white precipitate obtained was filtered, washed with ether, and dried under vacuum to provide 5-((4-bromophenyl)sulfonyl)-2-pyridinamine (75 mg) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=3[O:31][CH3:32])[CH2:6][CH2:5]2)=[N:8]1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Reactant: c1ccc2c(C3CCNCC3)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2n[nH]c3ccccc23)CC1
Yield: 78.6 %

Procedure:
A mixture of 3-(4-piperidinyl)-1H-indazole (3.2 g, 16 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.0 g, 16 mmol), K2CO3 (2.2 g) and acetonitrile (100 ml) was stirred and refluxed for 6 hours. The reaction was poured into water and the resulting yellow solid that formed was collected to afford 5.3 g of product. The compound was recrystallized from acetonitrile and then from ethyl acetate to yield 3.0 g (45%) of a slightly yellow solid of 1-[4-[4-[4-(1H-indazol-3-yl)-1-piperidinyl]-butoxyl-3-methoxyphenyl]ethanone, m.p.=133°-135° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:15]=[C:16]([F:22])[C:17]([F:21])=[C:18]([F:20])[CH:19]=1)#[CH:13].N>>[F:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]([F:22])[C:17]([F:21])=[C:18]([F:20])[CH:19]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(F)c1
Reactant: C#Cc1cc(F)c(F)c(F)c1
Agent: N
Product: Fc1cncc(-c2cc(-c3cc(F)c(F)c(F)c3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 5-ethynyl-1,2,3-trifluorobenzene (Apollo, 78 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.49 (s, 1H), 7.76 (dd, J=8.3, 6.6 Hz, 2H), 0.16 (ddd, J=9.2, 2.7, 1.7 Hz, 1H), 8.62 (d, J=2.7 Hz, 1H), 8.95 (t, J=1.5 Hz, 1H) ppm; MS (DCI/NH3) m/z 295 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([CH:14]([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=[CH:12][CH:13]=1.[CH2:24]([C:26]([C:45]1[CH:58]=[CH:57][C:48]([O:49][CH2:50][C@@H:51]2[O:55][C:54](=[O:56])[CH2:53][CH2:52]2)=[C:47]([CH3:59])[CH:46]=1)([C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[C:31]([CH3:44])[CH:30]=1)[CH2:27][CH3:28])[CH3:25].C(OCC)(=O)C>CN(C)C=O>[CH3:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:10]1[CH:9]=[C:8]([C:32]2[CH:33]=[CH:34][C:29]([C:26]([C:45]3[CH:58]=[CH:57][C:48]([O:49][CH2:50][C@@H:51]4[O:55][C:54](=[O:56])[CH2:53][CH2:52]4)=[C:47]([CH3:59])[CH:46]=3)([CH2:24][CH3:25])[CH2:27][CH3:28])=[CH:30][C:31]=2[CH3:44])[CH:13]=[CH:12][CH:11]=1)[O:19][Si:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CC(C)(C)C(O[Si](C)(C)C)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(-c2cccc(C(O[Si](C)(C)C)C(C)(C)C)c2)c(C)c1
Temperature: 85 °C
Reaction time: 13.5 h
Yield: 28.6 %

Procedure:
A [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.68 mg, 0.002 mmol), a 2 M sodium carbonate aqueous solution (0.1 mL, 0.2 mmol) and [1-(3-bromo-phenyl)-2,2-dimethyl-propoxy]-trimethyl-silane (Example 18-(1); 43.16 mg, 0.137 mmol) were added to a solution of (R)-5-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (Example 15-(3); 33.7 mg, 0.068 mmol) in N,N-dimethylformamide (0.1 mL) at room temperature, and the mixture was stirred at 85° C. for 13.5 hours. Ethyl acetate was added to the reaction solution. The organic layer was washed with distilled water and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=3/1) to give the title compound (11.7 mg, 28.5%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@@H:12]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:13]([N:15]1[CH:20]=[CH:19][CH2:18][CH:17]=[CH:16]1)=[O:14].FC(F)(F)S(O)(=O)=O.C(OCC)(=O)C.CCCCCC>ClCCl>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C@H:12]1[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH:16]2[CH2:17][CH2:18][CH:19]=[CH:20][N:15]2[C:13]1=[O:14]
Reactant: O=C([C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O)N1C=CCC=C1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1[C@@H](N2C(=O)c3ccccc3C2=O)Cc2ccccc2C2CCC=CN12
Reaction time: 2.5 h

Procedure:
Add a solution of (S)-N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-1,4-dihydro-pyridine (1.1 g, 3.1 mmol) in dichloromethane (2 mL) to trifluoromethanesulfonic acid (1.2 mL). After 2.5 hours, add trifluoromethanesulfonic acid (1.2 mL). After 4 hours, partition the reaction mixture between ethyl acetate and 5% sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and evaporate invacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 10% ethyl acetate/hexane and then 25% ethyl acetate/hexane to give the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:22])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:33])=[CH:29][CH:30]=1
Reactant: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 32 %

Procedure:
In analogy to the procedure described in Example 25, (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 13) and 4-(trifluoromethyl)phenyl isocyanate gave the titled compound in 32% yield as white foam. MS: 497.2 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.CC1(C)C2[C:46](=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:45][C:27]2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C[OH:67]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:22][CH:21]([N:20]1[C:16]([C:10]2[N:11]=[C:12]3[N:8]([CH:9]=2)[CH2:7][CH2:6][O:5][C:4]2[C:13]3=[CH:14][C:15]([C:27]([O:45][CH3:46])=[O:67])=[CH:2][CH:3]=2)=[N:17][CH:18]=[N:19]1)[CH3:23]
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COC(=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Temperature: 80 °C
Yield: 61 %

Procedure:
A mixture of 12-bromo-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (3.00 g, 8.04 mmol), Pd(OAc)2 (0.18 g, 0.81 mmol), Xantphos (930 mg, 1.61 mmol) in MeOH (10.0 mL) and TEA (50.0 mL) was heated at 80° C. under CO (1 atm) overnight. The solid was filtered, the filtrate was concentrated and purified by silica gel chromatography eluting with a 50% gradient of EtOAc in petroleum ether to give methyl 4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-13-carboxylate (1.7 g, 61% yield) as a white solid. LCMS (ESI) m/z: 354.2 [M+H+].
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16]([C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)[CH:15]=[N:14]2)[CH2:9]1.Cl[CH:26]([C:29]1([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[N:38]=[CH:37][CH:36]=[CH:35]3)[CH2:31][CH2:30]1)[CH:27]=O>>[O:8]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[N:22][C:21]4[N:20]([C:26]([C:29]5([C:32]6[CH:33]=[C:34]7[C:39](=[CH:40][CH:41]=6)[N:38]=[CH:37][CH:36]=[CH:35]7)[CH2:31][CH2:30]5)=[CH:27][N:24]=4)[CH:19]=3)[CH:15]=[N:14]2)[CH2:9]1
Reactant: Nc1ncc(-c2cnn(C3CCOC3)c2)cn1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: c1cnc2ccc(C3(c4cnc5ncc(-c6cnn(C7CCOC7)c6)cn45)CC3)cc2c1

Procedure:
The title compound was prepared as a TFA salt from the condensation of 5-[1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde using a procedure analogous to that described for the synthesis of Example 7, Step 8. LCMS: (M+H)=423.1.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N+:9]1[C:17]2[C:12](=[C:13]([F:21])[C:14]([F:20])=[C:15]([F:19])[C:16]=2[F:18])[C:11]([CH3:30])([CH2:22][CH2:23][CH2:24][CH2:25][S:26]([OH:29])(=[O:28])=[O:27])[CH:10]=1)([OH:3])=[O:2].Cl.C1(N=[CH:39][CH2:40][CH:41]=[N:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)C=CC=CC=1.[C:49](OC(=O)C)(=O)C>C(O)(=O)C>[F:21][C:13]1[C:14]([F:20])=[C:15]([F:19])[C:16]([F:18])=[C:17]2[C:12]=1[C:11]([CH3:30])([CH2:22][CH2:23][CH2:24][CH2:25][S:26]([OH:29])(=[O:28])=[O:27])/[C:10](=[CH:49]\[CH:39]=[CH:40]\[CH:41]=[N:42]\[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)/[N:9]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: C(CC=Nc1ccccc1)=Nc1ccccc1
Reactant: CC1(CCCCS(=O)(=O)O)C=[N+](CCCCCC(=O)O)c2c(F)c(F)c(F)c(F)c21
Agent: Cl
Solvent: CC(=O)O
Product: CC1(CCCCS(=O)(=O)O)/C(=C\C=C\C=N\c2ccccc2)N(CCCCCC(=O)O)c2c(F)c(F)c(F)c(F)c21
Temperature: 120 °C

Procedure:
To 1-(5-carboxypentyl)-4,5,6,7-tetrafluoro-3-methyl-3-(4-sulfobutyl)-3H-indolium (12 mg) was added malonaldehyde bis(phenylimine) monohydrochloride (7 mg), acetic anhydride (2 ml) and acetic acid (1 ml). This mixture was heated to 120° C. for 1 hour 50 minutes after which time it was cooled to room temperature. This crude reaction mixture (ca. 5 mg/ml product) was used without purification as further described.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.B(Cl)(Cl)Cl.[Cl:16][CH2:17][C:18]#N.[Cl-].[Ga+3].[Cl-].[Cl-].[OH2:24]>ClCCl>[NH2:11][C:9]1[C:8]([C:18](=[O:24])[CH2:17][Cl:16])=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1
Reactant: O
Reactant: N#CCCl
Reactant: Nc1ccc2c(c1)OCCO2
Agent: ClB(Cl)Cl
Agent: [Cl-]
Agent: [Ga+3]
Solvent: ClCCl
Product: Nc1cc2c(cc1C(=O)CCl)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
1,4-benzodioxan-6-amine, available from the Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, (160 g, 1.06 mol) is dissolved in dichloromethane (2.4 L) and cooled in an ice bath to less than 10° C. Boron trichloride gas (150 g, 1.27 mol, 1.2 eq) is added over 0.75 hour. The resulting brown slurry is then stirred overnight at room temperature. The slurry is then cooled in an ice bath to 10° C. and chloroacetonitrile (94 mL, 1.48 mol, 1.4 eq) is added in one portion. Gallium chloride (205 g, 1.16 mol, 1.1 eq) is dissolved in dichloromethane (310 mL) and added to the reaction over 0.5 h. The resulting brown slurry is then heated at reflux overnight (13-24 h). The brown solution is then cooled to rt and poured into a stirred mixture of dichloromethane (6.4 L)) and water (6.4 L). The mixture is stirred for 1.5 to 2 h to allow the solids to dissolve. The layers are then separated and the aqueous phase is extracted with dichloromethane (2 L). The organic layers are combined and concentrated under vacuum (about 100 mm Hg) to about 320 mL. (Crystallization occurs during the concentration.) Heptane (640 mL) is added over 1 hour and the slurry stirred overnight at room temperature. The slurry is filtered, washing the cake with heptane (200 mL). The cake is then dried overnight at 40° C. under high vacuum (about 1 mm Hg) to give 206 g (86%) of 1-(7-amino-2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-chloro-ethanone as a yellow solid.
Reaction SMILES: N([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1([CH3:9])[CH3:8])=O.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15].C(O)(=O)C>O1CCCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:14]([CH:7]2[CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]2)[OH:15])[CH:16]=[CH:17][CH:18]=1
Reactant: CC1(C)CCCN1N=O
Reactant: O=Cc1cccc(Cl)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(C)CCC(C(O)c2cccc(Cl)c2)N1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
35.4 ml (0.24 mols) of diisopropylamine are dissolved in 350 ml of tetrahydrofuran and cooled to −75° C. under nitrogen with a bath of dry ice and acetone. At this temperature, 180 ml (0.29 mols) of an approximately 1.6 molar solution of butyl lithium in hexane are added dropwise. By removing the cooling bath, the temperature is allowed to rise to −10° C. The solution of lithium-diisopropylamine thus obtained is again cooled to −78° C. This solution is mixed over the course of 20 minutes with 32 g (0.25 mols) of 1-nitroso-2,2-dimethylpyrrolidine and stirred for a further 10 minutes. Then, 35.2 g (0.25 mols) of 3-chlorobenzaldehyde are added dropwise over the course of 15 minutes, and the mixture is stirred for a further 3 hours at −75° C. To the resulting orange-coloured solution is then added dropwise, over the course of 20 minutes, a solution of 40 ml (0.7 mols) of glacial acetic acid in 80 ml of tetrahydrofuran. The reaction mixture which is now light yellow is warmed to room temperature by removing the cooling bath, and is then poured onto a mixture of 1 liter each of saturated sodium chloride solution and methyl chloride. After shaking out, the aqueous phase is separated and washed twice, each time with 200 ml of methylene chloride. The combined organic phases are washed with 200 ml of water, dried over sodium sulphate and the solvent residues are removed in a vacuum. The crystalline residue is dissolved whilst hot in a mixture of 180 ml of toluene and 270 ml of hexane. Upon cooling, the title substance is obtained in the form of white crystals having a m.p. of 143-144° C.
Reaction SMILES: ClCC1C=CC(C#N)=CC=1.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20].[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([N:38]2[CH2:42][CH2:41][NH:40][C:39]2=[O:43])=[N:35][C:34]=1[CH3:44])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([N:38]2[CH2:42][CH2:41][N:40]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[C:39]2=[O:43])=[N:35][C:34]=1[CH3:44])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Agent: N#Cc1ccc(CCl)cc1
Product: Cc1nc(N2CCN(Cc3ccccc3C(F)(F)F)C2=O)sc1C(=O)NCc1ccccc1
Yield: 34 %

Procedure:
Following the procedure as described in Example 23, making variations as required to replace 4-(chloromethyl)benzonitrile with 1-(bromomethyl)-2-(trifluoromethyl)benzene to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 34% yield: mp 138-140° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.67-7.65 (m, 1H), 7.59-7.46 (m, 2H), 7.42-7.27 (m, 6H), 5.89 (t, J=5.5 Hz, 1H), 4.68 (s, 2H), 4.56 (d, J=5.5 Hz, 2H), 4.11-4.05 (m, 2H), 3.49-3.43 (m, 2H), 2.61 (s, 3H); 13C NMR (75 MHz, CDCl3); 162.3, 157.2, 155.7, 153.2, 137.9, 134.7, 132.5, 130.0, 128.8, 127.8, 126.1, 125.9, 122.3, 117.4, 44.0, 43.9, 42.0, 41.9, 17.2; MS (ES+) m/z 475.3 (M+1).
Reaction SMILES: [SH:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:3]=1.[O-]Cl.[Na+].[OH-].[NH4+:18]>[OH-].[Na+].O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[N:3]=[C:2]([S:1][NH2:18])[S:6][N:5]=2)=[CH:8][CH:9]=1
Reactant: Sc1nc(-c2ccc(Cl)cc2)ns1
Reactant: [NH4+]
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: NSc1nc(-c2ccc(Cl)cc2)ns1
Reaction time: 0.17 h

Procedure:
A solution of 11.5 g of 5-mercapto-3-(4-chlorophenyl)-1,2,4-thiadiazole in 200 ml of 5% sodium hydroxide and a solution prepared by diluting 100 ml of 5.25% NaOCl to 200 ml with water were added dropwise simultaneously to 450 ml of ammonium hydroxide solution while maintaining the mixture at 0° with an ice/methanol bath. The resulting mixture was stirred for 10 minutes and the solids were collected, washed with water and dried under high vacuum (with P2O5) to give 7.0 g of solid. Recrystallization of 3 g of this material from 1:1 cyclohexane/benzene (200 ml) gave 1.6 g of crystals, m.p. >150° dec.