Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3.[CH:16]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][N:18]([CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH2:17]2>>[CH:20]12[CH2:23][CH2:24][CH:16]([CH2:22][CH2:21]1)[CH2:17][N:18]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:2]1[N:3]=[N:4][C:5]([CH3:15])=[C:6]3[N:14]4[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]4)=[CH:8][C:7]=13)[CH2:19]2
Reactant: Cc1nnc(Cl)c2cc3n(c12)CCCC3
Reactant: NCCCCN1CC2CCC(CC2)C1
Product: Cc1nnc(NCCCCN2CC3CCC(CC3)C2)c2cc3n(c12)CCCC3

Procedure:
Following the procedure in Example 9, compound XII was allowed to react with 4-(3-azabicyclo[3.2.2]non-3-yl)butylamine to give the title compound which was converted to the dihydrochloride salt: m.p.210° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:37])[C:10]=1[CH2:11][S:12][C:13]1[N:14]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:15]([C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[CH:22]=2)([CH3:20])[CH3:19])=[CH:16][N:17]=1)[C:5]([OH:7])=O.[NH2:38][C@@H:39]([CH2:47][CH2:48][CH2:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:54]([O:53][C:51]([NH:50][CH2:49][CH2:48][CH2:47][C@H:39]([NH:38][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([F:37])[C:10]([CH2:11][S:12][C:13]2[N:14]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:15]([C:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28][CH3:29])[CH:22]=3)([CH3:20])[CH3:19])=[CH:16][N:17]=2)=[C:2]([Cl:1])[CH:3]=1)[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:52])([CH3:56])([CH3:57])[CH3:55]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)O)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a 0° C. solution of 3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluoro-phenyl)-1H-imidazol-2-ylthio)methyl)-5-fluorobenzoic acid (0.94 g, 0.17 mmol), (S)-tert-butyl 2-amino-5-(tert-butoxycarbonylamino)pentanoate (0.050 g, 0.18 mmol) and HATU (0.067 g, 0.18 mmol) in DMF (4 mL) was added DIPEA (0.058 mL, 0.33 mmol). The ice bath was removed and the reaction was stirred for 2 h at room temperature. The reaction was quenched with satd NaHCO3 and diluted with EtOAc. The organic layer was washed with H2O (2×5 mL), brine, and dried with Na2SO4. The solvent was removed in vacuo and the residue was purified by column chromatography to afford 114 mg of (S)-tert-butyl 5-(tert-butoxycarbonylamino)-2-(3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-5-fluorobenzamido)pentanoate. The compound was then dissolved in 4N solution of HCl in dioxane and stirred for 2 h, when the reaction was determined to be complete by LCMS. Ether was added to the reaction mixture. Then the solids were collected by filtration and dried under vacuum to afford the title compound (75 mg). 1H-NMR (DMSO6, 400 MHz) δ 9.00 (d, J=8.3 Hz, 1H), 8.01 (s, 3H), 7.93 (s, 1H), 7.82-7.75 (m, 2H), 7.23 (d, J=8.5 Hz, 1H), 7.06-6.99 (m, 2H), 6.67-6.64 (m, 1H), 6.61-6.57 (m, 1H), 6.53-6.52 (m, 1H), 6.50-6.47 (m, 1H), 4.43-4.38 (m, 1H), 4.19 (s, 2H), 3.70 (s, 3H), 2.84-2.80 (m, 2H), 1.97-1.80 (m, 2H), 1.75-1.66 (m, 2H), 1.51 (m, 6H); MS (ES): 677 [M]+.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][NH:11]2)=O)(C)(C)C.C[Si]([N:19]=C=O)(C)C.[ClH:22]>C(Cl)Cl>[ClH:22].[C@H:9]12[CH2:14][C@H:12]([NH:11][CH2:10]1)[CH2:13][N:8]2[C:6]([NH2:19])=[O:5]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: ClCCl
Product: NC(=O)N1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl-(S,S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (35.6 g, 179 mmol) in CH2Cl2 (600 mL) was added trimethylsilylisocyanate (82.5 g, 716 mmol, 4 equiv.). The reaction was stirred at rt for 2 h. After concentration, the resulting white solid was dissolved in CH2Cl2 (500 mL) and treated with a solution of HCl (4 M in dioxane, 135 mL, 3 equiv.). The solution quickly became heterogeneous. The suspension was then stirred at rt overnight. Upon concentration, the desired product was isolated as a white solid (33 g, 104%), which was used directly in the next step. [Note: the mass balance was found to be 104%, which arises from additional HCl that could not be removed by standard evaporation under vacuum]. 1H NMR (500 MHz, CD3OD): 4.77 (s, 1H), 4.55 (s, 1H), 3.69 and 3.64 (AB, JAB=12.1, 2H), 3.47 and 3.40 (AB, JAB=11.3, 2H), 2.22 and 2.15 (AB, JAB=11.5, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:20]([O:24][C:25]([N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH2:29][N:30]([C:35]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[CH:41][CH:42]=1)=[O:36])[CH2:31]2)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH:28]2[CH2:34][CH2:33][CH:32]1[CH2:31][N:30]([C:35]([C:37]1[CH:38]=[N:39][C:40]([NH:43][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[NH:2][CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:41][CH:42]=1)=[O:36])[CH2:29]2)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)c1ccc(N)nc1)C2
Reactant: CNC(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CNC(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1

Procedure:
Following general N—C coupling procedure 1, 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide, see WO 2010020675, (0.150 g, 0.538 mmol) was combined with 3-(6-amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.188 g, 0.565 mmol, 1.05 eq), which gave 3-[6-(7-cyclopentyl-6-methylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester as a yellow solid and was used directly in step 3. MS m/z 575.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([CH:8]([OH:21])[C:9]([F:20])([F:19])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:7]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C:8](=[O:21])[C:9]([F:19])([F:20])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:13])[CH3:14])[CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(F)(F)C(O)c1cc(Br)ccc1F
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(F)(F)C(=O)c1cc(Br)ccc1F

Procedure:
A mixture of 1-(5-bromo-2-fluorophenyl)-3-(tert-butyldimethylsilyloxy)-2,2-difluoropropan-1-ol (19.0 g, mmol) and Pyridinium dichromate (90.0 g, 239.2 mmol) in Dichloromethane (200 mL) was refluxed for 16 h under constant stirring. The catalyst was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to obtain brown colored thick mass. Crude product was purified by column chromatography on silica gel with 1% ethyl acetate in Hexane to obtain title compound as colorless oil. Yield=17.0 g (90%). TLC (10% ethyl acetate in Hexane): Rf=0.56),
Reaction SMILES: Br[C@H:2]1[C@H:22]([OH:23])[CH2:21][CH2:20][C@@:19]2([CH3:24])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:18]2[C:17](=[O:25])[CH2:16][C@@:15]2([CH3:26])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:11](=[O:14])[CH2:12][Br:13].C([O-])([O-])=O.[Ca+2].[Br-].[Li+]>CC(N(C)C)=O>[Br:13][CH2:12][C:11](=[O:14])[C@@H:10]1[C@:15]2([CH3:26])[C@H:7]([C@H:6]3[C@H:18]([C:17](=[O:25])[CH2:16]2)[C@:19]2([CH3:24])[C:3](=[CH:2][C@H:22]([OH:23])[CH2:21][CH2:20]2)[CH2:4][CH2:5]3)[CH2:8][CH2:9]1
Reactant: C[C@]12CC[C@@H](O)[C@H](Br)[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Ca+2]
Solvent: CC(=O)N(C)C
Product: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=C[C@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CBr
Reaction time: 2 h
Yield: 41.9 %

Procedure:
4β,21-Dibromo-3α-hydroxy-5α-pregnane-11,20-dione (200 mg.) in dry dimethyl acetamide (10 ml.) was treated with calofort U (1.5 g.) and lithium bromide (0.9 g.). The mixture was stirred at 85° for 31/2 hours. The reaction mixture was filtered, and the solid residue was washed with ether and ethyl acetate. The combined filtrate and washings were washed well (5 times) with water, dried over sodium sulphate and evaporated to a brown oil which was purified by preparative T.L.C. in ethyl acetate/petrol 1/1, the main band yielding title compound (70 mg.) as a colourless foam, [α]D + 140°.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:36]([C:40]1[CH:45]=[CH:44][C:43]([C:46]#[CH:47])=[CH:42][CH:41]=1)[CH2:37][CH2:38][CH3:39].Cl>[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2].C1COCC1>[CH2:36]([C:40]1[CH:41]=[CH:42][C:43]([C:46]#[C:47][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=2)=[CH:44][CH:45]=1)[CH2:37][CH2:38][CH3:39]
Reactant: O=Cc1ccc(Br)nc1
Reactant: C#Cc1ccc(CCCC)cc1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCc1ccc(C#Cc2ccc(C=O)cn2)cc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 34.2 %

Procedure:
To a solution of 6-bromo-nicotinaldehyde (9.3 g, 50 mmol), Et3N (15.2 g, 150 mmol), CuI (190 mg, 1.0 mmol) and PPh3 (1.05 g, 4.0 mmol) in anhydrous degassed THF (250 mL) was added Pd(OAc)2 (225 mg, 1 mmol). The mixture was heated at 70° C. for 30 min. Then, a solution of 1-butyl-4-eth-1-ynylbenzene (11.9 g, 75 mmol) in anhydrous degassed THF (1M) was added dropwise. The reaction mixture was stirred at 70° C. for 15 h. Then, an aqueous solution of HCl 1N was added and the resulting mixture was extracted with Et2O (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give an orange oil. Purification by chromatography on silica gel (c-Hex/EtOAc 85/15) gave 4.5 g of the title compound as an orange oil (34%). M+ (ESI): 264.3. HPLC, Rt: 4.87 min (purity: 96.7%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C([O:25][CH2:26][C:27]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=[CH:29][C:28]=1[N:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:51]([CH3:54])([CH3:53])[CH3:52])[CH:48]=2)[C:43]1=[O:55])(=O)C.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.O1CCOCC1>[C:51]([C:47]1[CH:48]=[C:49]2[C:44](=[CH:45][CH:46]=1)[C:43](=[O:55])[N:42]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:20][CH:19]([OH:21])[CH2:18]5)=[CH:13][N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:27]=1[CH2:26][OH:25])[CH2:50]2)([CH3:54])([CH3:52])[CH3:53]
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CC(O)C3)cn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccc(N3CC(O)C3)cn2)c1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was purged with nitrogen and charged with 120c (215 mg, 0.613 mmol), 103f (340 mg, 0.735 mmol), sodium carbonate (195 mg, 1.84 mmol), 1,4-dioxane (8 mL) and water (2 mL). This mixture was degassed with nitrogen for 30 min. Tetrakis(triphenylphosphine)palladium (71 mg, 0.061 mmol) was added. After heating at 100° C. for 3 h, the reaction mixture was cooled to room temperature and partitioned between water (40 mL) and methylene chloride (100 mL). The layers were separated, and the aqueous phase was extracted with methylene chloride (2×50 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was dissolved in methanol (5 mL), and potassium carbonate (500 mg, 3.62 mmol) was added. After stirring at room temperature for 2 h, the reaction mixture was partitioned between water (20 mL) and methylene chloride (20 mL). The layers were separated, and the aqueous phase was extracted with methylene chloride (2×20 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 120 in 21% yield (72 mg) as an off-white solid: >250° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.25 (d, 1H, J=2.0 Hz), 7.73-7.71 (m, 2H), 7.62 (d, 1H, J=8.5 Hz), 7.51-7.42 (m, 3H), 7.36 (d, 1H, J=7.5 Hz), 7.28 (d, 1H, J=2.0 Hz), 7.17 (d, 1H, J=9.0 Hz), 6.87 (dd, 1H, J=9.0, 3.0 Hz), 5.56 (d, 1H, J=6.5 Hz), 4.94 (s, 2H), 4.88 (t, 1H, J=5.0 Hz), 4.54 (m, 1H), 4.33 (d, 2H, J=5.0 Hz), 4.02 (t, 2H, J=7.0 Hz), 3.58 (s, 3H), 3.43 (t, 2H, J=7.0 Hz), 1.36 (s, 9H); MS (ESI+) m/z 566.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[C:16]([Br:32])=[CH:17][C:18]([F:31])=[C:19]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH:20]=3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[C:33]([CH2:35][C:36](OCC)=[O:37])#[N:34]>CN1C(=O)CCC1>[Br:32][C:16]1[CH:17]=[C:18]([F:31])[C:19]([NH:21][C:22]([NH:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:23])=[CH:20][C:15]=1[C:7]1[C:8](=[O:14])[N:9]([CH2:12][CH3:13])[C:10]2[C:5]([CH:6]=1)=[CH:4][N:3]=[C:2]([NH:1][C:36](=[O:37])[CH2:35][C:33]#[N:34])[CH:11]=2
Reactant: CCOC(=O)CC#N
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Br)cc2cnc(N)cc21
Solvent: CN1CCCC1=O
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Br)cc2cnc(NC(=O)CC#N)cc21
Temperature: 125 °C
Reaction time: 48 h
Yield: 8.5 %

Procedure:
A suspension of Example 57 (135 mg, 0.272 mmol) in ethyl cyanoacetate (2.307 g, 20.40 mmol) was heated at 105° C. for 4.5 h, then at 125° C. for 2 days. The mixture was treated with NMP (0.3 mL), heated at 125° C. for 5 h, then cooled to RT and purified via silica gel chromatography (EtOAc/Hex). The material was re-purified via silica gel chromatography (THF/Hex), dissolved in 4:1 MeCN/H2O, frozen and lyophilized. The material was treated with MTBE, the resulting solid collected via filtration and dried to afford N-(3-(2-bromo-4-fluoro-5-(3-phenylureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)-2-cyanoacetamide (13 mg, 8.5% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 9.10 (s, 1H), 8.74 (m, 2H), 8.23 (d, J=8.5 Hz, 1H), 8.17 (s, 1H), 7.98 (s, 1H), 7.70 (d, J=10.7 Hz, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 6.97 (t, J=7.4 Hz, 1H), 4.22 (q, J=7.2 Hz, 2H), 4.05 (s, 2H), 1.26 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 565.1 [M+H]+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([F:41])[C:19]([S:21]([N:24](CC4C=CC(OC)=CC=4OC)[C:25]4[S:29][N:28]=[CH:27][N:26]=4)(=[O:23])=[O:22])=[CH:20][C:15]=3[O:14][C:13]2=[O:42])[CH2:4][CH2:3][C:2]21OCC[O:43]2.C(O)(C(F)(F)F)=O>C(Cl)Cl.CS(C)=O.CO>[F:41][C:18]1[C:19]([S:21]([NH:24][C:25]2[S:29][N:28]=[CH:27][N:26]=2)(=[O:22])=[O:23])=[CH:20][C:15]2[O:14][C:13](=[O:42])[N:12]([CH2:11][C:9]3[C:10]4[CH2:1][C:2](=[O:43])[CH2:3][CH2:4][C:5]=4[CH:6]=[CH:7][CH:8]=3)[C:16]=2[CH:17]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n(Cc4cccc5c4CC4(CC5)OCCO4)c3cc2F)c(OC)c1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCc2cccc(Cn3c(=O)oc4cc(S(=O)(=O)Nc5ncns5)c(F)cc43)c2C1
Temperature: 25 °C

Procedure:
To a flask containing 3-((3′,4′-dihydro-1′H-spiro[[1,3]dioxolane-2,2′-naphthalen]-8′-yl)methyl)-N-(2,4-dimethoxybenzyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (19-4) (1.65 g, 2.467 mmol) in DCM (10 ml) was added TFA (8 ml, 104 mmol). The reaction mixture (clear pink/purple with R2 addition) was then capped (not under N2) & stirred at room temperature. Followed by LC/MS . . . added 3 additional portions of TFA then after several hours at room temperature the reaction mixture was diluted with DMSO/MeOH, then concentrated (to remove DCM), then filtered to yield a portion of 5-fluoro-2-oxo-3-((7-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-N-(1,2,4-thiadiazazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (19-5). The filtrate was then purified by reverse phase chromatography (5-75% MeCN/H2O; 0.1% TFA in AQ; 20 min gradient; Waters 30×150 mm Sunfire 5 micron C18 column); desired fractions concentrated (GENEVAC), then dissolved in MeOH/DCM & concentrated to yield another portion of 5-fluoro-2-oxo-3-((7-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)methyl)-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (19-5). HRMS [M+H] calculated; 475.0541, observed; 475.0528.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][CH:4]=[C:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[O:18][CH2:17]2)[CH:9]=1.[NH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:31]=[C:27]([C:28]([NH2:30])=[O:29])[C:26]([OH:32])=[CH:25][CH:24]=1.CO>C(O)(C)C>[C:28]([C:27]1[CH:31]=[C:23]([CH:24]=[CH:25][C:26]=1[OH:32])[O:22][CH2:21][CH2:20][NH:19][CH2:17][CH:16]([OH:18])[CH2:15][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:3]2[N:2]([CH3:1])[C:6]([CH3:7])=[CH:5][CH:4]=2)[CH:9]=1)(=[O:29])[NH2:30]
Reactant: Cc1ccc(-c2cccc(OCC3CO3)c2)n1C
Reactant: NCCOc1ccc(O)c(C(N)=O)c1
Solvent: CO
Solvent: CC(C)O
Product: Cc1ccc(-c2cccc(OCC(O)CNCCOc3ccc(O)c(C(N)=O)c3)c2)n1C

Procedure:
Solutions of 5.0 g of crude 1,5-dimethyl-2-[3-(2,3-epoxypropoxy)-phenyl]-pyrrole in 15 ml of isopropanol and of 3.0 g of 5-(2-aminoethoxy)-salicylamide in 30 ml of isopropanol are combined and boiled under reflux for 2.5 hours. A portion of the precipitated reaction product is dissolved by the addition of 50 ml of methanol. The filtered solution is evaporated to dryness and the residue is recrystallised twice from ethyl acetate, yielding 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[3-(1,5-dimethylpyrrol-2-yl)-phenoxy]-2-propanol having a melting point of 108°-112°.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[NH:12][C:13](=O)[C:8]=2[C:7]([CH3:22])=[N:6]1)[CH2:2][CH2:3][CH3:4].C(Cl)(Cl)[Cl:24]>P(Cl)(Cl)(Cl)=O>[CH2:1]([N:5]1[C:9]2=[N:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])=[N:12][C:13]([Cl:24])=[C:8]2[C:7]([CH3:22])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: ClC(Cl)Cl
Reactant: CCCCn1nc(C)c2c(=O)[nH]c(-c3ccccc3F)nc21
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCn1nc(C)c2c(Cl)nc(-c3ccccc3F)nc21
Temperature: 0 °C
Yield: 55 %

Procedure:
1-Butyl-6-(2-fluoro-phenyl)-3-methyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (1.23 g, 4.1 mmole) was dissolved in phosphorous oxychloride (15 ml) and heated to reflux overnight. Removed excess phosphorous oxychloride under vacuum, treated residue with ice water, extracted product into ethyl acetate, washed with water, sat'd sodium chloride, dried over sodium sulfate (anh.) and removed solvent to give crude product. Chromatographed product on silica gel eluting with chloroform to give 723 mg purified product (yield: 55%).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1([N+:12]2[C:17](Cl)=[CH:16][C:15]([NH2:19])=[CH:14][N:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(N(CC)CC)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1([N+:12]2[CH:17]=[CH:16][C:15]([NH2:19])=[CH:14][N:13]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: Nc1cn[n+](C2CCCCC2)c(Cl)c1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Product: Nc1cc[n+](C2CCCCC2)nc1

Procedure:
The procedure of Example 4 is adopted but without triethylamine and 15.6 parts of 1-cyclohexyl-4-amino-6-chloropyridazinium perchlorate is used. 8.6 parts (62.1% of theory) of 1-cyclohexyl-4-aminopyridazinium perchlorate is obtained; C10H16O4N3Cl, melting point 114° to 116°C after having been recrystallized from water.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH4+].[Cl-].CCO.C1COCC1>C(Cl)Cl.[Fe].O>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([NH2:16])=[CH:14][N:13]=[C:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cnc(-c2ccccc2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 23 °C
Yield: 77.2 %

Procedure:
A mixture of N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitro-2-phenylpyrimidin-4-amine (500 mg, 1.55 mmol, 1.0 eq), NH4Cl (1.0 g, 19.39 mmol, 12.5 eq), EtOH (12 mL), THF (12 mL) and H2O (5 mL) was heated to reflux. Iron powder (0.59 g, 10.54 mmol, 6.8 eq) was added in three portions over 15 minutes under N2 atmosphere. The resulting mixture was continued to reflux for 1 hour, cooled down to 23° C., diluted with CH2Cl2 and filtered through celite. The organic phase was washed (brine), dried (Na2SO4), filtered and concentrated to give target product N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-phenylpyrimidine-4,5-diamine (Compound 5) (350 mg, 38.6%). LC-MS (m/z)=293.1 [M+H]+. 1H-NMR (300 MHz, DMSO-d6): δ 0.71-0.72 (m, 2H), 0.95-1.00 (m, 2H), 1.92-1.95 (m, 1H), 5.29 (s, 2H), 6.59 (s, 1H), 7.31-7.43 (m, 3H), 7.81 (s, 1H), 8.18 (d, J=6.9 Hz, 2H), 8.81 (s, 1H), 12.02 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[CH2:7]([NH2:10])[CH2:8][NH2:9].[OH-].[Na+]>>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:9][CH2:8][CH2:7][NH2:10]
Reactant: OCC(O)CCl
Reactant: NCCN
Agent: [Na+]
Agent: [OH-]
Product: NCCNCC(O)CO
Yield: 42.9 %

Procedure:
Following the procedure of Surrey et al., J. Am. Chem. Soc. (1952) 74:4102, 3-chloro-1,2-propanediol (8.36 ml, 0.10 mole) was added dropwise over 15 min to stirring ethylenediamine (66.8 ml, 1.0 mole) at room temperature. After the addition was complete, the solution was heated at approx. 60° C. until the 3-chloro-1,2-propanediol was consumed (about 1 hour), as determined by TLC. NaOH (4.4 g, 0.11 mole) was added to the solution and excess ethylenediamine was vacuum distilled off followed by careful fractional distillation to yield 5.76 g (43%) of (36) (b.p. 162° C./2.0 mm).
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]#[N:14])=[CH:4]1.[CH:15]([OH:18])([CH3:17])[CH3:16]>>[ClH:1].[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13](=[NH:14])[O:18][CH:15]([CH3:17])[CH3:16])=[CH:4]1
Reactant: Cn1cc(CC#N)c2ccccc21
Reactant: CC(C)O
Agent: Cl
Product: CC(C)OC(=N)Cc1cn(C)c2ccccc12
Reaction time: 4 h
Yield: 44 %

Procedure:
Hydrogen chloride was bubbled through a stirred solution of 7.5 g (44 mmol) of 1-methylindole-3-acetonitrile in 100ml of dry isopropanol at room temperature. After 4 hours, the solvent was removed under reduced pressure and the residue was triturated with diethyl ether to give 5.17 g (44%) of isopropyl 1-methyl-3-indoleacetimidate hydrochloride as a white solid of melting point 133° C.