Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.O.[H][H]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([NH2:31])=[CH:29][CH:30]=4)=[CH:20][CH:19]=3)=[CH:13][CH:14]=2)=[CH:40][CH:41]=1
Reactant: CCCCCCC(Cc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1)Cc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCC(Cc1ccc(Cc2ccc(N)cc2)cc1)Cc1ccc(Cc2ccc(N)cc2)cc1
Yield: 96.9 %

Procedure:
In a 1-liter three-necked flask having a fit equipped with a stirring device and a nitrogen substituting device, 40.9 g of 1,3-bis(4-(4-nitrobenzyl)phenyl)-2-n-hexyl propane, 5 g of a Pd-C catalyst (a 5% product, containing 55.9% of water) and 300 milliliters of tetrahydrofuran were introduced, and contacted with hydrogen gas at a normal pressure with stirring. After hydrogen absorption was stopped, the catalyst was filtered off and the solution was concentrated. Residues were dissolved in chloroform, and then subjected to a separating operation by a column chromatography with silica gel. By removing off the solvent again, 35.3 g of 1,3-bis(4-(4-aminobenzyl)phenyl)-2-n-hexyl propane was obtained as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:17]=[CH:16][C:12]3[S:13][CH:14]=[CH:15][C:11]=3[CH:10]=2)[N:5]=[C:4]([C:18]([O:20]C)=[O:19])[C:3]=1[Cl:22].O1CCCC1.O.O.[OH-].[Li+]>CO>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:17]=[CH:16][C:12]3[S:13][CH:14]=[CH:15][C:11]=3[CH:10]=2)[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[Cl:22]
Reactant: COC(=O)c1nc(-c2ccc3sccc3c2)c(Cl)c(N)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(Cl)c(C(=O)O)nc(-c2ccc3sccc3c2)c1Cl
Temperature: 25 °C

Procedure:
In a 100 mL round bottom flask, methyl 4-amino-6-(benzo[b]thiophen-5-yl)-3,5-dichloropicolinate (210 mg, 0.595 mmol) was dissolved in methanol (2.3 mL), tetrahydrofuran (2.3 mL), and H2O (1.2 mL). Lithium hydroxide hydrate (74.8 mg, 1.784 mmol) was added as a solid. The reaction was stirred at room temperature until complete. The reaction mixture was concentrated to dryness. The resulting residue was dissolved in H2O (2.0 mL) and 1 N HCl was used to adjust the pH to 3.0, causing a precipitate to form. This suspension was extracted with ethyl acetate (3×15 mL). The organic extracts were combined, washed with Saturated NaCl solution, dried (MgSO4), filtered and concentrated. Additional purification of the resulting solid was performed, as needed, using a Teledyne ISCO reverse phase system with a gradient eluent system of acetonitrile and H2O to yield the title compound as a white solid (110 mg, 55.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][C:20]([CH3:25])=[CH:19]4)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH:31]=[C:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1>CS(C)=O.C(OCC)(=O)C>[NH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([C:30]2[CH2:31][CH2:32][N:27]([CH2:12][CH:13]3[O:26][C:17]4=[C:18]5[C:22](=[CH:23][CH:24]=[C:16]4[O:15][CH2:14]3)[NH:21][C:20]([CH3:25])=[CH:19]5)[CH2:28][CH:29]=2)=[CH:34]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]c(C)cc4c3O2)cc1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc2c3c(ccc2[nH]1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3

Procedure:
A solution of 0.55 g (1.5 mmole) of [(2R)-8-methyl-2,3-dihydro-7H-[1,4]dioxino[2,3-e]indol-2-yl]methyl 4-methylbenzenesulfonate and 0.50 g (2.5 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 6.0 mL of DMSO was heated at 65-7° C. for 4 hours. The mixture was diluted with 300 mL of ethyl acetate, washed with 200 ml portions of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 1% methanol in chloroform as eluant to give 0.21 g of the (S)-enantiomer of the title compound as a yellow solid, m.p. 212-215° C.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[C:7](=O)([O-])O.[Na+].[C:12]([N:15]1[CH2:21][CH2:20][C:19]2[CH:22]=[CH:23][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:25][C:18]=2[CH2:17][CH2:16]1)(=[O:14])[CH3:13].CI>O.O1CCCC1>[C:12]([N:15]1[CH2:21][CH2:20][C:19]2[CH:22]=[CH:23][C:24]([S:26]([CH3:7])(=[O:28])=[O:27])=[CH:25][C:18]=2[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2CC1
Reactant: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCc2ccc(S(C)(=O)=O)cc2CC1
Temperature: 75 °C
Reaction time: 24 h
Yield: 73.2 %

Procedure:
To a stirred solution of sodium sulphite (1.60 g, 12.6 mmol) and sodium hydrogen carbonate (1.14 g, 13.56 mmol) in water (25 ml) was added 3-acetyl-7-chlorosulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.6 g, 9.04 mmol) in tetrahydrofuran (10 ml). The reaction mixture was then heated at 75° C. for 2 h, cooled to 30° C. and methyl iodide (2.8 ml, 45.20 mmol) added. After stirring at 50° C. for 24 h, the reaction mixture was cooled to room temperature and partitioned between water (50 ml) and ethyl acetate (100 ml). The aqueous layer was then separated and further extracted with ethyl acetate (2×80 ml). The combined organics were then dried (Na2SO4) and the solvent removed in vacuo to give the title compound (1.77 g, 73%) as a pale yellow solid.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][C:14]1[CH:15]=[C:16]([CH:37]=[CH:38][CH:39]=1)[NH:17][C:18]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:19]=1[C:20]([NH:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21]>>[F:13][C:14]1[CH:15]=[C:16]([N:17]2[C:18]3[C:19](=[CH:31][C:32]([F:36])=[C:33]([F:35])[CH:34]=3)[C:20](=[O:21])[N:22]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:1]2=[O:2])[CH:37]=[CH:38][CH:39]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1cccc(F)c1
Product: O=c1c2cc(F)c(F)cc2n(-c2cccc(F)c2)c(=O)n1OCc1ccccc1
Yield: 31.2 %

Procedure:
Using General Method 3, the reaction of carbonyldiimidazole (4.7 g, 29 mmol) and crude 2-(3-fluoro-anilino)-N-benzyloxy-4,5-difluoro-benzamide (Example Z, 5.4 g, 14.5 mmol) provided 1.8 g of the title compound as a solid, mp 179-181° C.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[C@H:15]2[CH2:21][NH2:22])=[O:13])[N:3]=[CH:4][CH:5]=1.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1>>[N:1]1[N:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[C@H:15]2[CH2:21][NH:22][C:24]2[N:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)=[O:13])[N:3]=[CH:4][CH:5]=1
Reactant: C[C@@H]1CCCN(C(=O)c2ccccc2-n2nccn2)[C@@H]1CN
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2ccccc2-n2nccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using (2-(2H-1,2,3-triazol-2-yl)phenyl)((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 446 [M+1]. 1H NMR (300 MHz, DMSO-d6) δ 8.75-6.80 (m, 9H), 4.95-2.80 (m, 5H), 1.80-0.50 (m, 8H); ESI MS (M+H) 446.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][NH:12][CH3:13])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].F[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([NH:24][C:25]2[N:30]=[C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH3:40])[CH:32]=3)[CH:28]=[CH:27][N:26]=2)=[C:17]([O:41][CH3:42])[CH:16]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CCOC(C)=O>[CH3:42][O:41][C:17]1[C:18]([NH:24][C:25]2[N:30]=[C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH3:40])[CH:32]=3)[CH:28]=[CH:27][N:26]=2)=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:15]([N:12]([CH3:13])[CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH:16]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: CNCCN(C)C(=O)OC(C)(C)C
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(N(C)CCN(C)C(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 100 °C
Yield: 57.7 %

Procedure:
tert-Butyl N-methyl-N-(2-methylaminoethyl)carbamate (Intermediate 173, 300 mg, 1.59 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methy-lindol-3-yl)pyrimidin-2-amine (Intermediate 129, 522 mg, 1.33 mmol) and DIPEA (0.462 mL, 2.65 mmol) in DMA (5 mL). The mixture was heated in a microwave at 100° C. for 4 h. The mixture was then diluted with EtOAc and washed with water (5×), brine, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-2% CH3OH in CH2Cl2 gave the title compound (431 mg, 58%) as an orange solid after trituration with iii diethyl ether; 1H NMR: 1.37 (9H, s), 2.79 (3H, s), 2.88 (3H, s), 3.29-3.36 (2H, m), 3.39-3.44 (2H, m), 3.89 (3H, s), 3.99 (3H, s), 6.85 (1H, d), 7.14 (1H, t), 7.21-7.28 (2H, m), 7.53 (1H, br d), 8.04 (1H, s), 8.31-8.38 (3H, m), 8.72 (1H, br s); m/z: ES+ MH+ 562.35.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1.[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:36]2[CH2:37][CH2:38][N:33]([C:30]3[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=3)[CH2:34][CH2:35]2)=[O:48])[C:44]=1[CH3:45]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1ccc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)cc1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Methoxyphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (CDCl3, 400 MHz) 6.88 (m, 4H), 5.00 (s, 2H), 3.78 (m, 3H), 3.76 (m, 2H), 3.70 (m, 2H), 3.08 (m, 4H), 2.30 (s, 3H) ppm; MS (ES) M+Na expected=439.0, found 439.0.
Reaction SMILES: [CH2:1](O)[CH2:2]CC.Cl.Cl.[C:8]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:35])[O:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]([C:27](=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH3:26])[CH2:19][CH2:18]1.Br[C:43]1[S:44][C:45]([C:48]([O:50]CC)=[O:49])=[CH:46][N:47]=1.C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([C:46]1[N:47]=[C:43]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:27]([N:25]([CH2:24][CH2:23][N:20]2[CH2:19][CH2:18][CH:17]([O:16][C:15](=[O:35])[NH:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:22][CH2:21]2)[CH3:26])=[O:34])[S:44][C:45]=1[C:48]([OH:50])=[O:49])[CH3:2]
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN
Reactant: CCCCO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCc1nc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)sc1C(=O)O
Temperature: 160 °C
Reaction time: 23 h
Yield: 79 %

Procedure:
1-Butanol (3.0 mL) was added to the compound (205 mg, 0.380 mmol) obtained in Example 11c, ethyl 2-bromo-1,3-thiazole-5-carboxylate (179 mg, 0.760 mmol) and triethylamine (212 μL, 1.52 mmol), and the mixture was stirred at 160° C. for 23 hours. The mixture was left to stand for cooling, then ethyl acetate was added to dilute the mixture, and the organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried with anhydrous magnesium sulfate, and then solvent was evaporated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate, 50:50→0:100, v/v) to give the title compound (186 mg; 79%) as a colorless oily substance.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([CH:16]=[CH2:17])[C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12]1)=O)C1C=CC=CC=1.[Na].N>O1CCCC1>[C:22]([O:21][C:19]([NH:18][C@H:13]1[C@@H:14]([CH:16]=[CH2:17])[CH2:15][NH:11][CH2:12]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: C=C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Product: C=C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
A solution of (3S,4S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-vinylpyrrolidine (275 mg, 0.794 mmol) in tetrahydrofuran (5 mL) and sodium (300 mg, 13.0 mmol) were sequentially added to liquid ammonia (80 mL) at −78° C., and the mixture was stirred at the same temperature for 0.5 hours. The solvent was removed, followed by dilution with chloroform (80 mL). The resultant mixture was washed sequentially by 1 mol/L sodium hydroxide (30 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, to thereby yield the title compound as a colorless oily substance (168 mg, 100).
Reaction SMILES: [CH:1]1[C:10]([S:11]([OH:14])(=[O:13])=[O:12])=[CH:9][C:8]2[C:3](=[C:4]([S:16]([OH:19])(=[O:18])=[O:17])[CH:5]=[CH:6][C:7]=2[NH2:15])[CH:2]=1.[OH-].[Na+:21].C(O)C>O>[Na+:21].[Na+:21].[NH2:15][C:7]1[C:8]2[C:3](=[CH:2][CH:1]=[C:10]([S:11]([O-:14])(=[O:13])=[O:12])[CH:9]=2)[C:4]([S:16]([O-:19])(=[O:18])=[O:17])=[CH:5][CH:6]=1
Reactant: Nc1ccc(S(=O)(=O)O)c2ccc(S(=O)(=O)O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)[O-])c2ccc(S(=O)(=O)[O-])cc12

Procedure:
A 50.0 g amount of (61.5%) 1-naphthylamine-4,7-disulfonic acid is dissolved in 150 ml of water and 5 N sodium hydroxide is added until basic pH (10-11). The solution is warmed and ethyl alcohol is added until a precipitate forms. The solid is collected by filtration, washed with 85% ethyl alcohol, ethyl alcohol and ether and is dried in vacuo at 110° C. to give 31.0 g of 4-amino-1,6-naphthalenedisulfonic acid disodium salt.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([O:17][C:18](=[O:20])[CH3:19])[CH2:14][CH2:15][CH3:16].[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C:23](=[O:29])[CH2:22]2>O1CCCC1.O>[CH2:13]([O:17][C:18](=[O:20])[CH2:19][C:23]1([OH:29])[CH:24]2[CH2:27][CH2:28][N:21]([CH2:26][CH2:25]2)[CH2:22]1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C1CN2CCC1CC2
Reactant: CCCCOC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: CCCCOC(=O)CC1(O)CN2CCC1CC2
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a 0° C. solution of diisopropylamine (6.7 ml) in tetrahydrofuran (THF) (20 ml) was added 2.3M nBuLi (20 ml). The reaction mixture was stirred for 40 minutes and then cooled to -78° C. To this mixture was added dropwise a solution of 1 butylacetate (6.4 ml) in 10 ml of THF and stirring continued for an additional 15 minutes. Quinuclidin-3-one (free base) (5.0 g) in THF (15 ml) was added to the mixture dropwise and the mixture was allowed to warm to 0° C. over 1 hour. To this solution was added water (100 ml), the solution was extracted twice with chloroform and the combined extracts were washed once with brine. The resulting solution was dried over MgSO4, filtered and dried in vacuo to give 9.53 g of the subtitle compound as an off-white solid.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH3:7][C:8]1[N:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([Cl:26])[C:23](Cl)=[N:22][CH:21]=1>COCCOC.O.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>[CH3:17][O:18][C:19]([C:20]1[CH:25]=[C:24]([Cl:26])[C:23]([C:11]2[CH:12]=[N:13][C:8]([CH3:7])=[CH:9][CH:10]=2)=[N:22][CH:21]=1)=[O:28]
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Reactant: Cc1ccc(B(O)O)cn1
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: COCCOC
Product: COC(=O)c1cnc(-c2ccc(C)nc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 888.2 %

Procedure:
0.29 of Na2CO3 (0.273 mmol), 0.25 g of 6-methylpyridin-3-ylboronic acid (11) (0.18 mmol) and 0.11 g of Pd(PPh3)4 were added to 0.4 g of 5,6-dichloro-nicotinic acid methyl ester (10) (0.2 mmol) prepared in Example 7 dissolved in 14 mL of 1,2-dimethoxyethane and 7 mL of distilled water, and refluxed under heating and stirring for 18 hours. The mixture was cooled to room temperature, and concentrated about 50% under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate, concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=10/1) to obtain 0.42 g of 3-chloro-6′-methyl-[2,3′]bipyridyl-5-carboxylic acid methyl ester (yield 88%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21]C(=O)OC(C)(C)C)[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.Cl.O1CCOCC1.[OH-].[Na+]>C(Cl)Cl.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4([NH2:21])[CH2:18][CH2:19][CH2:20]4)=[CH:15][CH:16]=3)[N:10]=2)[N:7]=1
Reactant: Cc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a mixture of tert-butyl {1-[4-(6-methyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]-cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-1 (200 mg, 0.440 mmol, 1.0 eq) in DCM (2.2 mL) and methanol (1.8 mL) was added a solution of 4 M hydrogen chloride in dioxane (2.2 mL, 8.80 mmol, 20.0 eq) and the mixture was stirred for overnight at rt. The mixture was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted with DCM. The combined organic phases were washed with brine, dried and concentrated in vacuo. Purification was achieved by crystallization from diisopropyl ether. The resulting solid was filtered and dried under high vacuum overnight to give 130 mg (83% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:9][CH2:10][N:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:4][CH:3]=1.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26].[NH:37]([C:41]1[S:42][CH:43]=[C:44]([CH2:46][S:47][CH2:48][CH2:49][NH2:50])[N:45]=1)[C:38]([NH2:40])=[NH:39]>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:25]([NH:50][CH2:49][CH2:48][S:47][CH2:46][C:44]2[N:45]=[C:41]([NH:37][C:38]([NH2:40])=[NH:39])[S:42][CH:43]=2)=[O:26])[CH3:18])=[CH:4][CH:3]=1
Reactant: CN(CCCCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(CCCCCNC(=O)NCCSCc1csc(NC(=N)N)n1)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 1.04 g (3 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,5-pentanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.75 g (3.3 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography (eluant: chloroform/methanol 9+1) analogously to Example 63 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%])=603 ([M+H]+, 1), 155 (18), 230 (100); IR (KBr): 1640 cm-1 (C=O).
Reaction SMILES: Cl[C:2]1([NH2:20])[N:19]=[CH:18][N:17]=[C:16]2[C:3]1=[N:4][CH2:5][N:6]2[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].O.[NH2:22][NH2:23]>CO>[NH:22]([NH:20][C:2]1[C:3]2[N:4]=[CH:5][N:6]([C:16]=2[N:17]=[CH:18][N:19]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9])[NH2:23]
Reactant: NC1(Cl)N=CN=C2C1=NCN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NN
Solvent: O
Solvent: CO
Product: NNNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 6-chloroadenosine (1 g, 3.5 mmol) and hydrazine monohydrate (5 mL) in MeOH (10 mL) was stirred at 50° C. for 1 hr. The reaction mixture was allowed to cool to room temperature and was then concentrated in vacuo to provide a crude residue which was suspended in MeOH and (10 mL) and stirred at room temperature. The solid product that separated out from the suspension was filtered, washed with MeOH and dried in vacuo to provide N6-hydrazinoadenosine (970 mg) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:14])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([Cl:14])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(F)cc(F)c1
Product: O=C(Cl)c1cc(F)cc(F)c1
Reaction time: 2 h

Procedure:
1.63 g (10.00 mmol) 3,5-difluoro-benzoic acid were mixed with 20 mL thionyl chloride and boiled for 2 h. The reaction mixture was evaporated to dryness and coevaporated twice with toluene. The residue was reacted further as the crude product.
Reaction SMILES: Cl.[C:2]12([CH2:12][NH:13][C:14]([C:16]3[C:17]4[N:18]([N:22]=[C:23](CC#N)[CH:24]=4)[CH:19]=[CH:20][CH:21]=3)=[O:15])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[CH3:28][C:29]([OH:31])=[O:30]>>[C:2]12([CH2:12][NH:13][C:14]([C:16]3[C:17]4[N:18]([N:22]=[C:23]([CH2:28][C:29]([OH:31])=[O:30])[CH:24]=4)[CH:19]=[CH:20][CH:21]=3)=[O:15])[CH2:11][CH:6]3[CH2:5][CH:4]([CH2:10][CH:8]([CH2:7]3)[CH2:9]1)[CH2:3]2
Reactant: CC(=O)O
Reactant: N#CCc1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Agent: Cl
Product: O=C(O)Cc1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Temperature: 60 °C

Procedure:
A solution of conc. HCl (2.3 mL) and AcOH (4.6 mL) is added to 2-cyanomethylpyrazolo[1,5-a]pyridine-4-carboxylic acid (adamantan-1-ylmethyl)amide. The solution is warmed to 60° C. for 20 h. The volatiles are removed under reduced pressure, and the residue is dissolved in 1 M aq. NaOH (10 mL). The solution is washed with Et2O (20 mL). The aqueous layer is acidified to ˜pH 3 with 1 M aq. HCl. The mixture is filtered and the filtrate dried to afford the title compound as a light tan solid. 1H NMR (400 MHz, ((CD3)2SO) δ: 8.71 (d, 1H), 8.40 (bt, 1H), 7.60 (d, 1H), 6.90 (t, 1H), 6.79 (s, 1H), 3.75 (s, 2H), 2.99 (d, 2H), 1.88-1.96 (m, 3H), 1.46-1.70 (m, 12H). LC-MS m/z+H+): 368.3; RT=1.27 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:18]([C:17]1[CH:21]=[C:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]=1[O:15][CH:12]([CH3:14])[CH3:13])=[O:19])[CH2:6][CH2:5]2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Clc1ccc2c(c1)CCNC2
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cc(Cl)ccc2C1

Procedure:
Prepared in analogy to example 1.1 from 6-chloro-1,2,3,4-tetrahydro-isoquinoline (CA [33537-99-4]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).