Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][CH2:21][CH2:22]O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:57][C:58]1[CH:59]=[C:60]([N:65]2[C:69](=[O:70])[O:68][N:67]=[C:66]2[C:71]2[C:72]([NH:76]C(=O)C(F)(F)F)=[N:73][O:74][N:75]=2)[CH:61]=[CH:62][C:63]=1[F:64]>O1CCCC1.C(OC)(C)(C)C>[Cl:57][C:58]1[CH:59]=[C:60]([N:65]2[C:69](=[O:70])[O:68][N:67]=[C:66]2[C:71]2[C:72]([NH:76][CH2:22][CH2:21][NH:20][C:1]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:73][O:74][N:75]=2)[CH:61]=[CH:62][C:63]=1[F:64]
Reactant: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1)C(F)(F)F
Reactant: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=c1onc(-c2nonc2NCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)n1-c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
A solution of 2-(tritylamino)ethanol (10 g, 33 mmol) [EP599220 and J. Org. Chem. (2001), 66, 7615] and triphenylphosphine (8.7 g, 33 mmol) in tetrahydrofuran (65 mL) at 0° C. was treated with diisopropyl azodicarboxylate (7.0 mL, 35 mmol) dropwise. The reaction mixture was stirred at 0° C. for 15 min, treated with a solution of N-{4-[4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-2,2,2-trifluoroacetamide (9.3 g, 24 mmol) in tetrahydrofuran (28 mL), and stirred at 25° C. for 16 h. The reaction mixture was concentrated, diluted with ethyl acetate (350 mL), cooled to 0° C., treated with 1 N HCl (200 mL), and stirred at 25° C. for 1 h. The reaction mixture was treated with additional 1 N HCl (150 mL) and stirred at 25° C. for 3 h. The organic layer was separated, washed with saturated sodium bicarbonate (200 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to a yellow foam which was reconcentrated from hexanes to give an oily solid. The oily solid was treated with methyl tert-butyl ether (50 mL) and stirred to give a heterogeneous mixture. The solid was filtered, washed with methyl tert-butyl ether (30 mL), and dried to give the desired product (10 g, 74%) as a white solid. LCMS for C31H24ClFN6O3Na (M+Na)+: m/z=605.2. 1H NMR (300 MHz, DMSO-d6): δ 7.97 (dd, J=6.7, 2.6 Hz, 1H), 7.71-7.66 (m, 1H), 7.60 (dd, J=9.1, 8.8 Hz, 1H), 7.40-7.37 (m, 6H), 7.28-7.23 (m, 6H), 7.18-7.12 (m, 3H), 6.59 (dd, J=5.9, 5.6 Hz, 1H), 3.37-3.31 (m, 2H), 2.96 (dd, J=7.6, 7.6 Hz, 1H), 2.27-2.19 (m, 2H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[C:14]2=[CH:15][N:16]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([Cl:31])[CH:29]=4)[CH:24]=[C:17]3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:13]2[CH:12]=[N:11]1.O>CN(C)C=O>[Cl:1][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[C:30]2[C:25]=1[CH:24]=[C:17]1[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:13]3[CH:12]=[N:11][N:10]([CH3:9])[C:14]3=[CH:15][N:16]12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN1N=CN2C1=Cn1c(cc3ccc(Cl)cc31)-c1ccccc12
Solvent: CN(C)C=O
Solvent: O
Product: CN1N=CN2C1=Cn1c(cc3c(Cl)cc(Cl)cc31)-c1ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.7 %

Procedure:
A solution of 1.91 g N-chlorosuccinimide in 45 ml dimethylformamide was added dropwise to a solution of 3.33 g 1-methyl-12-chloro-4H-indolo[1,2-d][1,2,4]triazolo[4,3-a][1,4]benzodiazepine in 100 ml dimethylformamide. The reaction mixture was stirred for three hours at room temperature. Upon addition of water and stirring overnight, a solid precipitated. This was collected, triturated with hexane and dried to yield 1.72 g. Recrystallization from methanol/water yielded 1.17 g solid, m.p. 266°-270° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[N:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([NH2:31])=[N:23]1>C(O)C>[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([NH:31][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:20])[F:19])[N:3]=2)=[N:23]1
Reactant: FC(F)(F)c1ccccc1-c1cc2ccccc2c(Cl)n1
Reactant: Nc1n[nH]c2ccccc12
Solvent: CCO
Product: FC(F)(F)c1ccccc1-c1cc2ccccc2c(Nc2n[nH]c3ccccc23)n1
Reaction time: 18 h
Yield: 26.5 %

Procedure:
A solution of 1-chloro-3-(2-trifluoromethyl-phenyl)-isoquinoline (100 mg, 0.326 mmol) and 1H-indazol-3-ylamine (86 mg, 0.651 mmol) in ethanol (3 mL) was heated at 160 C. and the solvent evaporated with a stream of nitrogen. The remaining oil was then heated at 160 C. for 18 hours under nitrogen. The resulting melt was dissolved in 5% methanol:dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (1×25 mL) then dried over magnesium sulfate. Purification by silica gel chromatography (25% to 50% hexane:ethyl acetate) afforded V-2 as a yellow solid (35 mg, 27%). 1H NMR (500 MHz, d6-DMSO) δ 9.78 (br s, 1H), 8.62 (d, 1H), 7.9-7.85 (m, 1H), 7.78-7.72 (m, 1H), 7.70-7.68 (m, 1H), 7.65-7.62 (m, 1H), 7.60-7.55 (m, 1H), 7.52-7.45 (m, 3H), 7.41-7.38 (m, 1H), 7.28-7.25 (m, 1H), 7.18 (s, 1H), 6.95-6.92 (m, 1H), 5.76 (s, 1H); LC-MS (ES+) m/e=405.18 (M+H); HPLC-Method D Rt 2.74 min.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[C:13]([Cl:27])[C:12]2=[O:28])=[CH:6][CH:5]=1.[NH3:30]>CO>[Cl:27][C:13]1[C:12](=[O:28])[N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH2:30])=[O:2])=[CH:5][CH:6]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26]
Reactant: COC(=O)c1ccc(Cn2ccc(OCc3ccc(F)cc3F)c(Cl)c2=O)cc1
Reactant: N
Solvent: CO
Product: NC(=O)c1ccc(Cn2ccc(OCc3ccc(F)cc3F)c(Cl)c2=O)cc1
Temperature: 75 °C
Yield: 60 %

Procedure:
A sealed tube containing a solution of 4-[3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzoic acid methyl ester (0.25 g, 0.60 mmol) and NH3 (20 mL of a 7 N solution in MeOH, 140 mmol) was heated at 75° C. for 16 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Trituration with Et2O/MeOH afforded 4-[3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-1-ylmethyl]benzamide as a white solid (0.14 g, 60%): mp 235-238° C.; 1H NMR (500 MHz, DMSO-d6) δ 7.93 (d, J=8 Hz, 2H), 7.79 (d, J=8 Hz, 2H), 7.60 (app q, J=8 Hz, 1H), 7.35-7.27 (m, 4H), 7.20-7.10 (m, 1H), 6.61 (d, J=8 Hz, 1H), 5.28 (s, 2H), 5.14 (s, 2H). ESHRMS m/z 405.0788 (M+H C20H16ClF2N2O3 requires 405.0812)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].[H-].[Na+].CS(C)=O.Cl[CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[C:23]([O-])=[O:24]>O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([C:23](=[O:24])[C:22]([CH3:27])([CH3:26])[CH2:21][CH3:20])[C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12]
Reactant: CC(C)(CCCl)C(=O)[O-]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCC(C)(C)C(=O)n1cnc2c1c(=O)[nH]c(=O)n2C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
This example illustrates a synthesis of 1-(8,9-Oxidohexyl)-3-methyl-7-ethylpivaloylxanthine (inventive compound no. 1410). A mixture of 3-methylxanthine (Aldrich, 1.00 g, 6.0 mmol), sodium hydride (145 mg, 6.0 mmol) and dimethyl sulfoxide (20 mL) was stirred until homogeneous (0.5 hours). Chloromethylpivalate (865 mL, 904 mg, 6.0 mmol) was added and the reaction stirred for 18 hours. The reaction mixture was poured into water (70 mL) and then extracted with 25% ethanol/dichloromethane (4×60 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum to a volume of 40 mL. This solution was cooled in icewater, whereupon a thick white precipitate formed. The solid was filtered off under suction and dried under vacuum to yield 1.43 g (90% yield) 3-methyl-7-(methylpivaloyl)xanthine (inventive compound no. 1404).
Reaction SMILES: Cl.CC(C1C=[C:8](C=C(C(C)(C)C)C=1O)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=[NH:20])=[CH:14][CH:13]=1)=O)(C)C.[CH3:34][O:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[NH:41][CH:40]=[C:39]2[CH2:45][C:46]([N:48]1CCN(C2C=CC(N)=CC=2)[CH2:50][CH2:49]1)=[O:47].CC(C1C=C(C=C(C(C)(C)C)C=1O)C(NC1C=CC(N)=CC=1)=O)(C)C>>[CH3:34][O:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[NH:41][CH:40]=[C:39]2[CH2:45][C:46]([N:48]1[CH2:8][CH2:9][N:11]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[NH:20])=[CH:16][CH:17]=2)[CH2:50][CH2:49]1)=[O:47]
Reactant: CC(C)(C)c1cc(C(=O)Nc2ccc(NC(=N)c3cccs3)cc2)cc(C(C)(C)C)c1O
Reactant: COc1ccc2[nH]cc(CC(=O)N3CCN(c4ccc(N)cc4)CC3)c2c1
Agent: CC(C)(C)c1cc(C(=O)Nc2ccc(N)cc2)cc(C(C)(C)C)c1O
Agent: Cl
Product: COc1ccc2[nH]cc(CC(=O)N3CCN(c4ccc(NC(=N)c5cccs5)cc4)CC3)c2c1
Yield: 20 %

Procedure:
The experimental protocol used is the same as that described for the compound 1, with 1-[(5 methoxy-1H-indole-3-yl)methylcarbonyl]-4-(4-aminophenyl)-piperazine replacing the 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. The expected product is isolated in the form of the free base with a yield of 20% (pale yellow powder). Melting point: 221-222° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][C@H:2]12.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=1>>[Cl:16][C:17]1[N:18]=[CH:19][C:20]([N:1]2[CH2:5][CH2:4][C@@H:3]3[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][C@H:2]23)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCN[C@H]2C1
Reactant: Clc1ccc(I)cn1
Product: CC(C)(C)OC(=O)N1C[C@H]2CCN(c3ccc(Cl)nc3)[C@H]2C1
Yield: 89.1 %

Procedure:
tert-Butyl cis-hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (550 mg, 2.60 mmol), prepared as described in (U.S. Pat. No. 5,071,999) and 2-chloro-5-iodopyridine (660 mg, 2.76 mmol), prepared as described in (Tetrahedron Lett. (1993), 34, 7493-7496), were processed as described in Example 1E to provide the title compound as a tan foam (750 mg, 89% yield). MS (DCI/NH3) m/z 324, 326 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:28]([NH2:29])=[N:27][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:15]=[CH:16][C:11]=2[CH:10]=1.[H-].[Na+].[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:28]([NH:29][C:39]([NH:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:40])=[N:27][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCN(CC)CCCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: O=C=Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(NC(=O)Nc3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
To a solution of 6-(2,6-dichlorophenyl)-N2 -(4-diethylamino-butyl)-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 53 in DMF (15 mL) was added one equivalent of 60% sodium hydride suspension (0.93 g). After stirring for approximately 1 hour at room temperature, one equivalent of phenyl isocyanate (0.275 g) was added, and the reaction was monitored by thin layer chromatography. After approximately 24 hours, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, and this solution was washed several times, first with water and then a saturated solution of sodium chloride. The ethyl acetate layer was dried with magnesium sulfate and concentrated in vacuo. Chromatography of the residue over silica gel using ethyl acetate:methanol:triethylamine (90:10:1) followed by ethyl acetate:ethanol:triethylamine (9:2:1) gave 0.8461 g of the title compound 1-[6-(2,6-dichlorophenyl)-2-(4-diethylamino-butylamino)-pyrido[2,3-d]pyrimidin-7-yl]-3-phenyl-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH) M+ +H=552 (Base), 433; mp 81-87.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[C:13]=1[O:14][CH3:15])[C:8](O)=[O:9])=[O:4].C1(C)C=CC=CC=1.S(Cl)([Cl:30])=O>CN(C)C=O>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[C:13]=1[O:14][CH3:15])[C:8]([Cl:30])=[O:9])=[O:4]
Reactant: COc1c(C(=O)N(C)C)cc(C(=O)O)cc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(C(=O)N(C)C)cc(C(=O)Cl)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To 3-dimethylcarbamoyl-4-methoxy-5-trifluoromethylbenzoic acid (333 mg), toluene (3 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.13 mL) was added, and then the mixture was stirred at 60° C. for 6 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (f).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:16]1[C:17]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:18]=2[N:19]=[CH:20][N:21]=1>>[CH2:25]([C:23]1[S:22][C:18]2[N:19]=[CH:20][N:21]=[C:16]([N:11]3[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH:10]3[CH3:14])[C:17]=2[CH:24]=1)[CH3:26]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CCc1cc2c(Cl)ncnc2s1
Product: CCc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3C)ncnc2s1
Yield: 96 %

Procedure:
1-BOC-3-Methylpiperazine was coupled with 4-chloro-6-ethylthiopheno[2,3-d]pyrimidine according to Example 87. Yield=96%, ES-MS: (M+H)+ 363.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:29])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH2:30][OH:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[S:39](Cl)([CH3:42])(=[O:41])=[O:40].Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:29])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:26])([F:27])[F:28])[CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH2:30][O:31][S:39]([CH3:42])(=[O:41])=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1cccc(OC(F)(F)F)c1)[C@@H]1CC[C@H](CO)N1C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2R,5S)-2-hydroxymethyl-5-(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (500 mg, 1.14 mmol) in CH2Cl2 (5 mL) was added at 0° C. under nitrogen atmosphere Et3N (350 μl, 2.5 mmol) and mesylchloride (197 μl, 2.5 mmol) and the mixture was further stirred at RT for 3 h. CH2Cl2 and HCl 0.1N were added, the layers were separated and the aqueous one re-extracted with CH2Cl2. The crude organic extracts were washed with brine dried over Na2SO4, filtered and concentrated. The crude material was used without further purification in the next step. MS (LC-MS): 517 [MH−Boc]+; tR (HPLC conditions b) 5.15 min.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([I:15])[N:12]=[C:11]1[CH2:16][O:17][CH3:18])(C)(C)C.[ClH:20].O1CCOCC1>C(Cl)Cl>[I:15][C:13]1[N:12]=[C:11]([CH2:16][O:17][CH3:18])[N:10]([CH2:9][CH2:8][NH2:7])[CH:14]=1.[ClH:20]
Reactant: COCc1nc(I)cn1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COCc1nc(I)cn1CCN
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of [2-(4-iodo-2-methoxymethyl-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (3.051 g; 8.003 mmol) in DCM (60 ml) was added slowly 4N HCl in dioxane (40 ml; 160 mmol). The resulting suspension was stirred at 0° C. for 15 min., then at rt for 2 h. The volatiles were removed under reduced pressure, then under HV. The product 2-(4-iodo-2-methoxymethyl-imidazol-1-yl)-ethylamine was obtained as a pale beige solid (2.750 g; 100%; presence of 2 eq. of HCl). LC-MS: tR=0.21 min.; [M+H]+=282.24 g/mol.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:15])[NH:11][CH:12]([CH3:14])[CH3:13])[CH2:6][C:5]1=[O:16])[CH:2]=[CH2:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:27](OCC)(=[O:33])[C:28](OCC)=[O:29]>CN(C=O)C.C1COCC1>[OH:33][C:27]1[C:28](=[O:29])[N:11]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:15])[N:7]2[CH2:8][CH2:9][N:4]([CH2:1][CH:2]=[CH2:3])[C:5](=[O:16])[C:6]=12
Reactant: CCOC(=O)C(=O)OCC
Reactant: C=CCN1CCN(C(=O)NC(C)C)CC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CCN1CCn2c(c(O)c(=O)n(C(C)C)c2=O)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(2-propenyl)-4-(N-2-propylcarbamoyl)-2-piperazinone (8.0 g, 35 mmol) in DMF (80 mL) at 0° C. was added lithium bis(trimethylsily)amide (40 mL of a 1.0 M solution in THF, 40 mmol). Diethyl oxalate (5.84 g, 40 mmol) was added and the mixture was stirred for 1 h at 0° C. More lithium bis(trimethylsily)amide was added (35 mL of a 1.0 M solution in THF, 35 mmol) and the mixture was stirred for 1 h at 0° C., and then at ambient temperature for 18 h. The reaction was quenched by the addition of 0.5 N aqueous HCl to pH 3 and the solvents were removed in vacuo. The residue was vigorously stirred in methanol-water, and the precipitate was collected by filtration and dried in vacuo to give the title compound. HPLC RT=2.72 min (Method A); ES MS (M+H)=280; 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 5.80 (ddt, 1H), 5.29 (d, J=17 Hz, 1H), 5.22 (d, J=10 Hz, 1H), 5.05 (septet, J=7 Hz, 1H), 4.10 (d, J=7 Hz, 2H), 3.94 (t, J=7 Hz), 3.58 (t, J=7 Hz, 2H), 1.38 (d, J=7 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:10][CH:9]=1)=[O:6].[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([NH2:39])[N:34]=2)[CH:30]=[CH:31][CH:32]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1COCC1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:24][C:23]1[CH:22]=[CH:21][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[NH:39][C:35]1[N:34]=[C:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:41])([F:25])[F:40])[CH:28]=2)[CH:38]=[CH:37][N:36]=1
Reactant: Nc1nccc(-c2cccc(C(F)(F)F)c2)n1
Reactant: Cc1ccc(C(=O)Nc2ccc(CCN3CCCC3)cc2)cc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2ccc(CCN3CCCC3)cc2)cc1Nc1nccc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 150 °C

Procedure:
A mixture of 3-bromo-4-methyl-N-(4-(2-(pyrrolidin-1-yl)ethyl)phenyl)benzamide (59 mg, 0.13 mmol) and 4-(3-(trifluoromethyl)phenyl)pyrimidin-2-amine (31 mg, 0.13 mmol), KOBut (22 mg, 0.2 mmol), Pd2(dba)3 (4.6 mg, 0.005 mmol) and Xantphos (4.6 mg, 0.008 mmol) in a microwave reaction vessel was suspended in 1 mL of THF. The reaction mixture was heated in a microwave at 150° C. for 90 min. After cooling, the mixture was diluted with DMF, and then filtered with a 0.45 μm microfilter. The obtained filtrate was separated by a semi-preparative HPLC. Collected product fraction was lyophilized to give pure product as a while powder. MS (ESI+) m/z 546.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.C([Li])CCC.[F:23][C:24]([F:37])([F:36])[C:25]([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)=[O:26]>C1COCC1.CCCCCC>[F:37][C:24]([F:23])([F:36])[C:25]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2)([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[OH:26]
Reactant: O=C(c1c[nH]c2ccccc12)C(F)(F)F
Reactant: Fc1ccc(-n2ncc3cc(Br)ccc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)(c1c[nH]c2ccccc12)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a chilled (−78° C.) solution of 2.67 g (9.20 mmol) 5-bromo-1-(4-fluorophenyl)-1H-indazole in 10 mL of anhydrous THF was added 7.36 mL (18.40 mmol) of a 2.5 M solution of n-butyllithium in hexane followed by a solution of 1.00 g (4.69 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-yl)ethanone in 5 mL of THF in one portion. The reaction was then stirred at −78° C. for 30 minutes and quenched with 5 mL of water. The mixture was warmed to room temperature and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (20%-40% ethyl acetate in hexanes). The major fractions were combined and concentrated to afford 978 mg of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-(1H-indol-3-yl)ethanol. MS m/z 426.39 (MIT).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:12].C(=O)(O)[O-].[Na+].[Br:18][CH2:19][C:20](Br)=[O:21]>C(Cl)Cl>[NH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20](=[O:21])[CH2:19][Br:18])=[C:3]([Cl:12])[CH:4]=1)(=[O:9])=[O:10]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(S(N)(=O)=O)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(NC(=O)CBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 750 mg (3.63 mmol) of 4-amino-3-chlorobenzenesulfonamide (A-2) and 610 mg (7.26 mmol) of sodium bicarbonate in 25 mL of CH2Cl2 was stirred at room temperature for 18 hours. Bromoacetyl bromide (A-1) was then added, and the mixture was stirred for an additional 12 hours. The mixture was then concentrated in vacuo to a yellow oil. The oil was washed with three 25 mL portions of diethyl ether, decanted, and concentrated in vacuo to give the desired product A-3 as a tan solid. MS: M+1=329.0.
Reaction SMILES: [K].[S:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[S:15])SC)([OH:5])(=[O:4])=[O:3].[N-:16]=[N+:17]=[N-:18].[Na+]>>[S:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:12]([SH:15])=[N:18][N:17]=[N:16]1)([OH:5])(=[O:4])=[O:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NCCCCCS(=O)(=O)O
Agent: [K]
Agent: [Na+]
Product: O=S(=O)(O)CCCCCn1nnnc1S

Procedure:
Reaction of methyl 5-sulfopentyldithiocarbamate potassium salt with sodium azide as described in Example 7 gave 1-(5-sulfopentyl)tetrazole-5-thiol.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:19]CC(C1C=CC(OCC(N2CCOCC2)=O)=CC=1)=O>>[Br:19][CH2:2][C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C(CBr)c1ccc(OCC(=O)N2CCOCC2)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(C)=O)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=O)CBr)cc1

Procedure:
Ethyl 2-[4-acetylphenoxy]-2-methylpropionate was brominated using an analogous procedure to that described for 4-[4-(bromoacetyl)phenoxyacetyl]morpholine, used as a starting material for Example 6, to give ethyl 2-[4-(bromoacetyl)phenoxy]-2-methylpropionate as an oil, which was pure by thin layer chromatographic (TLC) analysis (on silica plates; eluant : 50% ether/50% petrol).