Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=O)=[CH:4][CH:3]=1.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O.C(O)(=O)C.ClCCl>[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][N:38]([CH2:13][CH2:12][N:9]4[C:10]5[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=5)[CH:6]=[CH:7][C:8]4=[O:15])[CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: Cc1ccc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccc2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
To 8.0 mL of dichloromethane solution containing 0.16 g of (7-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde, 0.28 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 80 μL of acetic acid were added, stirred at room temperature for 15 min, then, 0.25 g of sodium triacetoxyborohydride was added, and stirred at room temperature for 1 hour. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution, water and chloroform were added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:3], to give 0.26 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a brown oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:43])[CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:18]=2)[N:14]=[C:13]1[CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[N:39]=[CH:38][N:37]=[C:36]([NH2:40])[C:35]=2[CH:41]=[CH2:42])[CH2:30][CH2:29]1.CO>[Pd]>[CH3:8][N:9]([CH3:43])[CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]([F:27])([F:25])[F:26])[CH:18]=2)[N:14]=[C:13]1[CH:28]1[CH2:29][CH2:30][N:31]([C:34]2[N:39]=[CH:38][N:37]=[C:36]([NH2:40])[C:35]=2[CH2:41][CH3:42])[CH2:32][CH2:33]1
Reactant: C=Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN(C)C)CC1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN(C)C)CC1
Temperature: 25 °C

Procedure:
In a 10 mL round-bottom flask containing 6-{4-[1-(2-dimethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-vinyl-pyrimidin-4-ylamine; compound with trifluoro-acetic acid (25.00 mg; 0.04 mmol; 1.00 eq.) in methanol (2.00 ml; 49.37 mmol; 1231.95 eq.) under argon was slowly poured 10% Pd/C (80.00 mg; 0.75 mmol; 18.76 eq.). The round-bottom flask was vacuumed and then filled with H2. The procedure was repeated for 4 more times before the mixture was stirred at rt for O/N under H2 (balloon). The obtained mixture was filtered and then purified with Waters pre-HPLC. LC-MS: (M+1=506, obsd.=506).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:25][C@H:26]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:27][C:28](O)=[O:29])(=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(Cl)CCl.CI>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH:11][C:28](=[O:29])[CH2:27][C@H:26]([O:25][C:15](=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OC(=O)CCCCCCCC
Solvent: CI
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)N[C@@H](CO)C(=O)OCc1ccccc1)OC(=O)CCCCCCCC
Yield: 89 %

Procedure:
In the same manner as described in Example 2-(5), L-serine benzyl ester (390 mg, 2.0 mmol) was acylated with (R)-3-nonanoyloxytetradecanoic acid (780 mg, 2.2 mmol) in the presence of EDC·MeI (845 mg, 2.5 mmol) in CH2Cl2 to afford 1.0 g (89%) of N-[(R)-3-nonanoyloxytetradecanoyl]-L-serine benzyl ester: mp 52-53° C.; 1H NMR (CDCl3) δ 0.88 (t, 6H, J=6.6 Hz), 1.1-1.7 (m, 32H), 2.30 (t, 2 H, J=7.7 Hz), 2.51 (d, 2H, J=5.8 Hz), 2.62 (t, 1H, J=6.0 Hz), 3.98 (m, 2H), 4.65 (m, 1H), 5.19 (m, 3H), 6.58 (d, 1H, J=6.8 Hz), 7.35 (br s, 5H).
Reaction SMILES: [O:1]=[C:2]1[N:14]2[C:5](=[N:6][C:7]3[C:12]([CH2:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:4][C:3]1=[CH:15][C:16]([OH:18])=[O:17].O=C1N(N(N2CCOC2=O)P(Cl)(N)=O)CCO1.[C:36]1(O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl.O>[C:36]1([O:17][C:16](=[O:18])[CH:15]=[C:3]2[S:4][C:5]3=[N:6][C:7]4[C:12]([CH2:13][N:14]3[C:2]2=[O:1])=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)C=c1sc2n(c1=O)Cc1ccccc1N=2
Agent: NP(=O)(Cl)N(N1CCOC1=O)N1CCOC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C=c1sc2n(c1=O)Cc1ccccc1N=2)Oc1ccccc1

Procedure:
A solution of 1.30 g (5 mmols) (3-oxo-5H-thiazolo[2,3-b]quinazolin-2(3H)-ylidene)acetic acid, 1.27 g (5 mmols) N,N-bis(2-oxo-3-oxazolidinyl)phosphorodiamidic chloride, 0.49 g (5.2 mmols) phenol, and 1.10 g (10 mmols) triethylamine, in 10 ml dichloromethane was stirred at room temperature, under nitrogen atmosphere for 18 hours. Then, 10 ml of water (made slightly basic with sodium bicarbonate) were added. The precipitate was filtered of and the filtrate was dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. The residual orange-yellow solid was recrystallized from anhydrous ethanol. Yield--0.62 g. Mp 194°-195° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@H:4]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][C:15]([NH:16][S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])=[C:10]3[C:9]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:27]=3)=[CH:8]2)[CH2:3]1.CN1CC[C@H](N2C3=NC=CC(NS(C4C=CC=CC=4)(=O)=O)=C3C(C3C=CC=C(N4CCCC4)C=3)=C2)C1>>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][C:15]([NH:16][S:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)(=[O:18])=[O:19])=[C:10]3[C:9]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:27]=3)=[CH:8]2)[CH2:3]1
Reactant: CN1CC[C@@H](n2cc(-c3cccc(N4CCCC4)c3)c3c(NS(=O)(=O)c4ccccc4)ccnc32)C1
Agent: CN1CC[C@H](n2cc(-c3cccc(N4CCCC4)c3)c3c(NS(=O)(=O)c4ccccc4)ccnc32)C1
Product: CN1CCC(n2cc(-c3cccc(N4CCCC4)c3)c3c(NS(=O)(=O)c4ccccc4)ccnc32)C1

Procedure:
Example 135 was separated by chiral chromatography to give two enantiomers: (R)N-(1-(1-methylpyrrolidin-3-yl)-3-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)benzenesulfonamide and (S)N-(1-(1-methylpyrrolidin-3-yl)-3-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)benzenesulfonamide. The absolute stereochemistry was not determined LCMS (A): m/z (M+H)+ 502, C28H31N5O2S requires 501 (acidic).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:30]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[C:29]([CH3:40])[N:28]=[C:27]([CH3:41])[N:26]=1)(=O)C.C[O-].[Na+]>CO>[C@@H:6]1([O:24][C:25]2[C:30]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)=[C:29]([CH3:40])[N:28]=[C:27]([CH3:41])[N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: COc1ccc(Cc2c(C)nc(C)nc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cc2c(C)nc(C)nc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 64.8 %

Procedure:
To a solution of 4-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-5-(4-methoxybenzyl)-2,6-dimethylpyrimidine (0.24 g) in methanol (4 mL) was added sodium methoxide (28% solution in methanol, 0.040 mL), and the mixture was stirred for 50 minutes at room temperature. After the reaction mixture was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (eluent: dichloro-methane/methanol=7/1) to give 4-(β-D-glucopyranosyloxy)-5-(4-methoxybenzyl)-2,6-dimethylpyrimidine (0.11 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)COC4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1.BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C(OC)=CC(CP(=O)(O)OCC)=C([Cl:97])C=3)N=2)=CC=1.CC1(C)C(C)(C)OB(C2C=NN(CCCO)C=2)O1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[C:25]([O:57][CH3:58])=[CH:26][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][CH2:35][CH2:39][N:40]4[CH:44]=[C:43]([B:45]5[O:49][C:48]([CH3:50])([CH3:51])[C:47]([CH3:53])([CH3:52])[O:46]5)[CH:42]=[N:41]4)[O:30][CH2:31][CH3:32])=[C:55]([Cl:97])[CH:56]=3)[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCOP(=O)(O)Cc1cc(OC)c(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)cc1Cl
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1
Agent: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Product: CCOP(=O)(Cc1cc(OC)c(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)cc1Cl)OCCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
Prepared analogously to Compound 44A using ethyl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-chloro-5-methoxybenzyl)phosphonate (Compound 56B, 200 mg, 0.306 mmol) and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 3E, 81 mg, 0.321 mmol) to afford 181 mg of the title compound as a racemic mixture (67%). MS (ESI): m/z=887.59/889.59 [M+H]+. UPLC: tR=1.74 min (UPLC-TOF: polar—2 min).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:17].C(Cl)Cl.O.NN>C(O)C>[NH2:3][O:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:17]
Reactant: CC(C)(C)OC(=O)NC(=O)NCCON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(=O)NCCON
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a mixture of tert-butyl ({2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]ethyl}carbamoyl)carbamate 83 (0.56 g, 1.59 mmol) in a solution of DCM (10 mL) and ethanol (2 mL) was added hydrazine hydrate (0.091 mL, 1.59 mmol) at room temperature. The mixture was stirred at room temperature overnight, filtered and concentrated to provide a residue which was subjected to chromatography to give 84 (0.25 g, 72%) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:17]=2[O:29][CH3:30])[C@@H:9]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(C)(C)C.FC(C1C=CC(OC(F)(F)F)=C(C=1)CN[C@H]1CCCN[C@H]1C1C=CC=CC=1)(F)C>>[CH3:30][O:29][C:17]1[CH:18]=[CH:19][C:20]([C:22]([F:28])([F:27])[C:23]([F:24])([F:25])[F:26])=[CH:21][C:16]=1[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc(C(F)(F)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: CC(F)(F)c1ccc(OC(F)(F)F)c(CN[C@H]2CCCN[C@H]2c2ccccc2)c1
Product: COc1ccc(C(F)(F)C(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 41 in the same manner of Compound 27.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:42])=[C:28]([CH:41]=1)[C:29]([NH:31][C:32]1[N:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[CH:34][CH:33]=1)=[O:30]>ClCCl>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:38]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:29](=[O:30])[C:28]4[CH:41]=[C:24]([F:23])[CH:25]=[CH:26][C:27]=4[CH3:42])=[N:37][CH:36]=3)=[O:39])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cn1

Procedure:
As described for Example 1, 6,11-dihydro-5H-dibenz[b,e]azepine is reacted in dichloromethane in the presence of triethylamine, with 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride to give the product as a solid.
Reaction SMILES: [NH:1]([C:3]1[N:8]=[N:7][C:6]([N:9]([CH3:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1)[NH2:2].[Cl:17][C:18]1[N:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[CH:20][CH:19]=1.Cl>C(Cl)Cl>[Cl:17][C:18]1[N:23]=[C:22]([C:24]([NH:2][NH:1][C:3]2[N:8]=[N:7][C:6]([N:9]([CH3:16])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:5][CH:4]=2)=[O:25])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: CN(c1ccccc1)c1ccc(NN)nn1
Agent: Cl
Solvent: ClCCl
Product: CN(c1ccccc1)c1ccc(NNC(=O)c2cccc(Cl)n2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
To a solution of 6-hydrazino-N-methyl-N-phenylpyridazine-3-amine (1.14 g) in methylene chloride (10 ml), 6-chloropicolic acid (0.83 g) and WSCD hydrochloride (1.22 g) were added, and the mixture was stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography (eluent: chloroform) to obtain 6-chloro-N′-{6-[methyl(phenyl)amino]pyridazin-3-yl}pyridine-2-carbohydrazide (0.57 g). This compound (0.56 g) was stirred at 150° C. overnight in xylene (20 ml), and the reaction solution was concentrated to obtain 3-(chloropyridin-2-yl)-N-methyl-N-phenyl-1,2,4-triazolo[4,3-b]pyridazine-6-amine (0.54 g) as colorless solids.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(C(C)(C)C)cc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (72 mg, 81%), MS (ISP) m/z=358.5 [(M+H)+], mp 292° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-tert-butyl-phenylboronic acid (57.9 mg, 0.325 mmol).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[S:15][CH:16]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[CH2:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]([CH3:37])[CH3:36]>C(Cl)Cl>[CH3:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]2[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][N:20]([S:38]([CH2:34][CH:35]([CH3:37])[CH3:36])(=[O:40])=[O:39])[CH2:19][CH2:18]3)[S:15][CH:16]=2)=[CH:23][CH:24]=1)(=[O:5])=[O:4]
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1ccc(OCc2csc(N3CCNCC3)n2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CS(=O)(=O)N1CCN(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1
Reaction time: 1 h

Procedure:
A solution of 1-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperazine hydrochloride (100 mg, 0.26 mmol) and DIPEA (134 mL, 3 eq.) in CH2Cl2 (5 mL) was added isobutanesulfonyl chloride (41 mL, 1.2 eq.). The mixture was stirred for 1 hour, then the reaction solution was directly purified on silica gel (EtOAc:hexanes=1:1) to afford the desired product as a pale yellow solid. 1H NMR (CDCl3): δ 7.87 (2H, d, J=8.8 Hz), 7.12 (2H, d, J=8.8 Hz), 6.62 (1H, s), 5.05 (2H, s), 3.61 (4H, m), 3.39 (4H, m), 3.04 (3H, s), 2.78 (2H, d, J=6.8 Hz), 2.32 (1H, m), 1.12 (6H, d, J=6.8 Hz).
Reaction SMILES: C([O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][N:14]2[C:18]([CH2:19][C:20]#[N:21])=[C:17]([Cl:22])[N:16]=[CH:15]2)=[CH:11][C:10]=1[CH3:25])C1C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:22][C:17]1[N:16]=[C:15]([C:9]2[CH:24]=[CH:23][CH:12]=[CH:11][CH:10]=2)[N:14]([CH2:13][C:12]2[CH:23]=[CH:24][C:9]([OH:8])=[C:10]([CH3:25])[CH:11]=2)[C:18]=1[CH2:19][C:20]#[N:21]
Reactant: Cc1cc(Cn2cnc(Cl)c2CC#N)ccc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Cn2c(-c3ccccc3)nc(Cl)c2CC#N)ccc1O
Yield: 77.1 %

Procedure:
1-(4-Benzyloxy-3-methylbenzyl)-4-chloro-5-cyanomethylimidazole (10 g) was boiled in 100 ml of trifluoroacetic acid for 15 minutes. The reaction mixture was then evaporated to dryness and the residue was chromatographed on a column of silica gel (100 g) using chloroform as an eluent. The desired fractions were combined and concentrated to about 20 ml to give 3.7 g of 4-chloro-5-cyanomethyl-1-(4-hydroxy-3-methylbenzyl)-2-phenylimidazole as colorless prisms, m.p. 194°-196° C.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[CH2:5]1.S(Cl)([Cl:17])=O.C(Cl)(Cl)Cl>N1C=CC=CC=1.O>[Cl:17][CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[CH2:5]1
Reactant: O=S(Cl)Cl
Reactant: O=C1CC(CCO)c2ccccc2N1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C1CC(CCCl)c2ccccc2N1
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
A mixture of 5.2 g (0.027 mol) of (±)-4-(2-hydroxyethyl)-3,4-dihydro-2(1H)-quinolinone, 15 g (0.126 mol) of thionyl chloride, 200 ml of dry chloroform and 10 drops of pyridine is heated to reflux for 4 h. After the mixture is cooled, 50 ml of water are added dropwise and the mixture is stirred for 30 minutes. The organic phase is separated after settling has taken place, dried over magnesium sulphate and concentrated under vacuum. The residue is chromatographed on a silica column. Elution with a dichloromethane/acetone (90:10) mixture yields an oil which is crystallized in cyclohexane. 5 g (88%) of (±)-4-(2-chloroethyl)-3,4-dihydro-2(1H)-quinolinone, melting point 112°-113° C., are obtained.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11](Br)[CH:12](Br)[C:13]([O:15]C)=O)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].Cl.[NH2:20][OH:21].[OH-].[K+].S(=O)(=O)(O)O>CO.O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:21][N:20]=[C:13]([OH:15])[CH:12]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: COC(=O)C(Br)C(Br)c1ccc(CC(C)=O)cc1
Reactant: NO
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)Cc1ccc(-c2cc(O)no2)cc1

Procedure:
A solution of methyl 3-(4-acetonylphenyl)-2,3-dibromopropionate, ethylene ketal (4.2 g) in methanol (25 ml) was added dropwise to a stirred mixture of hydroxylamine hydrochloride (0.86 g) and potassium hydroxide (3.9 g) in methanol: water (150 ml) at ambient temperature and stirred for 1 h. The reaction mixture was then heated under reflux for 7 h, cooled, acidified with sulphuric acid (50%), filtered, and the solvent removed under reduced pressure. The residue was partitioned between ethylacetate and water, dried (magnesium sulphate), filtered and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica using chloroform as eluent, and crystallised from diethylether-(60°-80°)petroleum ether to give 5-(4-acetonylphenyl)-3-hydroxyisoxazole (0.5 g).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[N+:20]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27])([O-:22])=[O:21]>>[N+:20]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH:27][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)([O-:22])=[O:21]
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: O=[N+]([O-])c1cccc(CNc2nccc(-n3cnc4ccccc43)n2)c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 3-nitrobenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 347.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.58 (br s, 1H); 8.46 (d, J=5.5 Hz, 1H); 8.31 (s, 1H); 8.17 (d, J=8.5 Hz, 1H); 8.00 (br s, 1H); 7.85 (d, J=8.0 Hz, 1H); 7.77 (d, J=7.6 Hz, 1H); 7.56 (t, J=7.9 Hz, 1H); 7.38 (m, 2H); 6.90 (d, J=5.5 Hz, 1H); 5.94 (br s, 1H); 4.87 (d, J=6.2 Hz, 2H).
Reaction SMILES: [I:1][C:2]1[N:3]=[N:4][C:5](I)=[CH:6][CH:7]=1.[CH3:9][O-:10].[Na+].O>CO>[CH3:9][O:10][C:5]1[N:4]=[N:3][C:2]([I:1])=[CH:7][CH:6]=1
Reactant: Ic1ccc(I)nn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(I)nn1
Temperature: 25 °C
Reaction time: 13 h
Yield: 86 %

Procedure:
To 2.73 g (8.23 mmol) of 3,6-diiodopyridazine were added 80 ml of methanol and 3.17 g (16.46 mmol) of 28 wt % of sodium methylate in methanol, and the mixture was stirred at room temperature for 13 hours. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained crude product was purified by silica-gel column chromatography (200 ml of silica gel, hexane:ethyl acetate=8:1) to give 1.661 g (7.04 mmol) of 3-methoxy-6-iodopyridazine (yield: 86%).
Reaction SMILES: [CH:1]([C@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([OH:13])[O:5]1)([CH3:3])[CH3:2].[CH:14]([Mg]Cl)([CH3:16])[CH3:15]>C1COCC1.CCOCC>[OH:5][C@H:4]([C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@@H:6]([OH:13])[CH:14]([CH3:16])[CH3:15])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H]1OC(O)c2ccccc21
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)[C@H](O)c1ccccc1[C@@H](O)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (3S)-3-isopropyl-1,3-dihydro-isobenzofuran-1-ol (2.0 g, 11.2 mmol) in THF (20 mL) was heated under an atmosphere of nitrogen at reflux. To this solution was added slowly a solution of isopropyl magnesium chloride (39.3 mmol) in THF (ca. 20 ml). This solution had been prepared from the commercial solution (19.6 ml 2N solution in ether), from which the solvent had been removed in vacuum, and where the residue was made up with THF to a volume of 20 ml). After the addition of the Grignard reagent was completed, the mixture was stirred for another 30 minutes, and then allowed to cool to ambient temperature. To the mixture was then added a 10% solution of ammonium chloride (ca. 30 ml). The aqueous layer was removed, and re-extracted with TBME (ca. 20 ml). From the combined organic layers the solvent was removed, and the residue was redissolved in TBME (ca. 50 ml). After washing with water and brine, the organic layer was dried (Na2SO4). Removal of the solvent left the product as an oil, 2.2 g (88%). There was only one isomer present by 13C-NMR, which turned out to be the (S,S)-diol. 1H/13C-NMR (CDCl3, HSQC/HMBC) δ/δ 0.783 (d, J=6.7 Hz)/20.02 (CH3); 1.065 (d, J=6.5 Hz)/18.99 (CH3); 2.02 (m)/35.29 (CHMe2); 4.60 (d, J=7.6 Hz)/76.51 (CH(OH)); 2.38 br s (OH); 7.20-7.26 (m)/126.75 (Ar ortho-CH); 7.33-7.39 (m)/127.55 (Ar meta-CH); 141.41 (Ar ipso-C).