Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([C:23](=[O:29])[C:24]([O:26]CC)=[O:25])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[C:10]([C:23](=[O:29])[C:24]([OH:26])=[O:25])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2cc(-c3ccccc3)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2cc(-c3ccccc3)ccc12
Yield: 69.8 %

Procedure:
(1-Benzyl-6-phenyl-1H-indol-3-yl)(oxo)acetic acid was prepared from ethyl (1-benzyl-6-phenyl-1H-indol-3-yl)(oxo)acetate (1.90 g, 4.96 mmol), and potassium hydroxide (0.856 g, 15.3 mmol) in THF (20 mL) and water (20 mL), following the procedure described in Step 4 of Example 5. Crystallization from acetonitrile and drying for 8 hours at 70° C. yielded the title compound as a light yellow solid (1.23 g, 70%), mp: 210-212° C. (dec.). Mass spectrum (+ES, [M+H]+) m/z 356; 1 HNMR (500 MHz, DMSO-d6): δ 13.8-14.2 (br s, 1H), 8.7 (s, 1H), 8.25 (d, 1H, J=8.2 Hz), 7.9 (s, 1H), 7.65 (d, 2H, J=8.1 Hz), 7.6 (d, 1H, J=8.4 Hz), 7.45 (t, 2H, J=7.7 Hz), 7.3-7.35 (m, 5H), 7.25-7.3 (m, 1H), and 5.65 ppm (s, 2H).
Reaction SMILES: CS([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)(=O)=O.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH2:18]>>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH:18][C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: CN(C)CCN
Reactant: CS(=O)(=O)c1nc2ccccc2[nH]1
Product: CN(C)CCNc1nc2ccccc2[nH]1

Procedure:
27.2 G. (0.139 moles) of 2-methanesulfonyl benzimidazole and 26.5 g. (0.3 moles) of N,N-dimethylethylene diamine are combined and heated at 170°-175° C. for 5 hours. The mixture is then cooled and concentrated in vacuo. The residue is dissolved in methylene chloride washed with saturated sodium chloride, dried over sodium sulfate and evaporated to dryness affording 22 g. of N,N-dimethyl-N'-(2-benzimidazolyl)-1,2-ethane diamine compound which is recrystallized from benzene yielding 20.3 g. with a m.p. of 143.5-145.5.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:29]([O:33][C:34]([N:36]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:29]([O:33][C:34]([N:36]1[CH2:40][CH2:39][CH:38]([NH:41][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Agent: CN(C)C(On1nnc2ccccc21)=[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: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)C3)ccc21
Yield: 69.4 %

Procedure:
3-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5 carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (408 mg), 3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (220 mg), HBTU (457 mg), and DIEA (350 uL) in DMF (3 mL).
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)(=O)=O)=CC=1.[I:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.O>[O:16]1[C:15]2([CH2:14][CH2:13][CH:12]([N:25]3[CH:24]=[C:23]([I:22])[CH:27]=[N:26]3)[CH2:21][CH2:20]2)[O:19][CH2:18][CH2:17]1
Reactant: Ic1cn[nH]c1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1cnn(C2CCC3(CC2)OCCO3)c1

Procedure:
A mixture of 1,4-dioxaspiro[4.5]dec-8-yl 4-methylbenzenesulfonate (prepared according to U.S. Pat. No. 4,360,531) (2.0 g, 6.4 mmol), 4-iodopyrazole (1.36 g, 7.0 mmol), K2CO3 (1.06 g, 7.7 mmol), and 18-crown-6 (0.2 g, 0.7 mmol) in DMF (5 mL) was heated under nitrogen at 50° C. for 16 h. Water (50 mL) was added to the reaction mixture, which was then extracted with EtOAc (3×40 mL). The combined EtOAc extracts were washed with water (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using EtOAc/CH2Cl2 (1:9) to give the title compound. 1H NMR (CDCl3, 400 MHz): δ=1.67-1.76 (m, 2 H), 1.84-1.91 (m, 2 H), 1.99-2.17 (m, 4 H), 3.95-3.99 (m, 4 H), 4.18-4.27 (m, 1 H). MS (ES+): m/z=334.96 (100) [MH+]; HPLC: tR=3.26 min (polar—5 min, ZQ3).
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5]([CH3:8])([OH:7])[CH3:6].[CH3:11][C:12]([S:15]([NH2:17])=[O:16])([CH3:14])[CH3:13].S([O-])([O-])(=O)=O.[Mg+2].CC1C=CC(S(O)(=O)=O)=CC=1.O>C(Cl)Cl>[OH:7][C:5]([CH3:8])([CH3:6])[CH2:4]/[CH:3]=[N:17]/[S:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16]
Reactant: CC(C)(C)S(N)=O
Reactant: COC(CC(C)(C)O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)C/C=N/S(=O)C(C)(C)C
Reaction time: 8 h

Procedure:
To a stirred solution of 4,4-dimethoxy-2-methylbutan-2-ol (2.49 g, 16.8 mmol) in DCM (35 mL) were added 2-methyl-2-propanesulfinamide (1.7 g, 14 mmol), magnesium sulfate (8.44 g, 70.1 mmol), and pTsOH.H2O (0.13 g, 0.70 mmol). The reaction mixture was left to stir overnight, filtered through a fritted glass, concentrated, and purified by flash chromatography to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.C(N(CC)CC)C.[C:18](Cl)(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>ClCCl>[C:18]([CH:6]1[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:5])(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Meldrum's acid (7.20 g, 50 mmol) and triethyl amine (5.56 g, 55 mmol) were dissolved in dichloromethane (50 mL), and decanoic acid chloride (10.48 g, 55 mmol) was added to the resulting mixture dropwise while cooling with ice. The reaction mixture was stirred at room temperature for about 12 hours, and then concentrated under reduced pressure. The ethyl acetate layer thus obtained was washed with diluted hydrochloric acid and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified using silica gel chromatography (developing solvent: n-hexane/ethyl acetate=3/7) to obtain 5-decanoyl-2,2-dimethyl-1,3-dioxane-4,6-dione.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:10])[CH2:7][N:6]([CH3:8])[C:5](=[O:9])[NH:4]1.C(O[Cl:16])(C)(C)C>CO>[Cl:16][N:4]1[C:3]([CH2:2][OH:1])([CH3:10])[CH2:7][N:6]([CH3:8])[C:5]1=[O:9]
Reactant: CN1CC(C)(CO)NC1=O
Reactant: CC(C)(C)OCl
Solvent: CO
Product: CN1CC(C)(CO)N(Cl)C1=O
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
A solution of 4-(hydroxymethyl)-1,4-dimethylimidazolidin-2-one (250 mg, 1.72 mmol) in methanol (2.5 ml) was cooled to 0° C. tert-Butylhypochlorite (236 ul, 2.1 mmol) was added. The resulting solution was stirred for 30 minutes, then concentrated under reduced pressure to a crude residue. The crude material was purified by column chromatography (1 to 12% methanol in dichloromethane) to give the desired product as a white solid (168 mg, 0.941 mmol, 54%). 1H NMR (400 MHz, D2O) δ 1.16 (s, 3H), 2.74 (s, 3H), 3.25-3.27 (d, J=9.2 Hz, 1H), 3.38-3.41 (d, J=12.6 Hz, 1H), 3.47-3.49 (d, J=9.2 Hz, 2H), 3.64-3.67 (d, J=12.6 Hz, 1H). 13C NMR (100 MHz, D2O) δ 18.1, 30.8, 53.2, 62.8, 64.5, 161.6. LRMS (ESI/APCI) m/z 179 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:51])=[C:18]([C@:20]2([CH3:50])[CH2:25][O:24][CH2:23][C:22]([NH:26][C:27]([C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:21]2)[CH:19]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>>[CH3:49][O:48][C:45]1[CH:46]=[CH:47][C:42]([C:27]([NH:26][C:22]2[CH2:23][O:24][CH2:25][C@:20]([C:18]3[CH:19]=[C:14]([NH:13][C:10]([C:3]4[C:2]([Cl:1])=[CH:7][C:6]([C:8]#[N:9])=[CH:5][N:4]=4)=[O:12])[CH:15]=[CH:16][C:17]=3[F:51])([CH3:50])[N:21]=2)([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:43][CH:44]=1
Reactant: N#Cc1cnc(C(=O)O)c(Cl)c1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(N)ccc3F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(NC(=O)c4ncc(C#N)cc4Cl)ccc3F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 44 %

Procedure:
In a manner analogous to that described in example E1 (method E), the reaction of 3-chloro-5-cyano-pyridine-2-carboxylic acid with Building block J, [(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine, using the 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM) as the condensating agent, yielded the title compound as a yellow solid (44% of theory). Mass (calculated) C39H33ClFN5O4 [690.160]; (found) [M]+=690.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].O.[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24]>O1CCCC1>[Br:20][C:21]1[CH:22]=[C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(Br)c1
Yield: 64.7 %

Procedure:
The product is prepared according to the procedure described in Example 19, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and using a mixture of 7 ml of water and 1.5 ml of tetrahydrofuran in place of the methanol, and 190 mg of 3-bromo-4-fluoroaniline in place of the 3-(tert-butyl)aniline. 266 mg of N-(3-bromo-4-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:31])[CH2:5][N:6]1[CH2:11][CH2:10][C@H:9]2[CH2:12][C@@H:13]([C:26]([O:28]CC)=[O:27])[N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C@H:8]2[CH2:7]1)[CH3:2].C1COCC1.O.[OH-].[Li+]>O>[CH2:1]([NH:3][C:4](=[O:31])[CH2:5][N:6]1[CH2:11][CH2:10][C@H:9]2[CH2:12][C@@H:13]([C:26]([OH:28])=[O:27])[N:14]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C@H:8]2[CH2:7]1)[CH3:2]
Reactant: CCNC(=O)CN1CC[C@H]2C[C@@H](C(=O)OCC)N(S(=O)(=O)c3ccc(OC)cc3)[C@H]2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)CN1CC[C@H]2C[C@@H](C(=O)O)N(S(=O)(=O)c3ccc(OC)cc3)[C@H]2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of ethyl rel-(2S,3aS,7aR)-6-[2-(ethylamino)-2-oxoethyl]-1-[(4-methoxyphenyl)sulfonyl]octahydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate under step a) (62 mg, 0.13 mmol) was made in 1:1 THF:H2O (20 vols). Lithium hydroxide monohydrate (65.5 mg, 1.56 mmol) was added and the reaction stirred at room temperature for 18 hours. The THF was removed in vacuo, and the aqueous layer extracted with EtOAc (3×10 mL). The organic extracts were collected, dried over magnesium sulfate and filtered. The solvent was then removed in vacuo, before being placed on a high vacuum line for 2 hours. The product was used in the next step with no further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[C:8](=[O:11])[C:7]1[C:12]([OH:20])=[C:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[CH:15][C:6]=1[O:5]2.[CH3:21][N:22]([CH3:27])[S:23](Cl)(=[O:25])=[O:24]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:21][N:22]([CH3:27])[S:23](=[O:25])(=[O:24])[O:16][C:14]1[C:13]([CH2:17][CH2:18][CH3:19])=[C:12]([OH:20])[C:7]2[C:8](=[O:11])[N:9]3[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:5][C:6]=2[CH:15]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCCc1c(O)cc2oc3cc(Cl)cn3c(=O)c2c1O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(OS(=O)(=O)N(C)C)cc2oc3cc(Cl)cn3c(=O)c2c1O
Temperature: 85 °C
Yield: 71.1 %

Procedure:
To 80 mg (0.27 mmol) of 2-chloro-6,8-dihydroxy-7-propyl-9H-pyrrolo [2,1-b][1,3]benzoxazin-9-one in 3 mL of toluene was added 0.3 mL (2.77 mmol) of dimethylsulfamylchloride and 0.066 g (0.54 mmol) of 4-dimethylaminopyridine (DMAP). The mixture was heated to 85° C. for 2 hr. It was cooled, diluted with ethyl acetate and extracted two times with 1N HCl. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by preparative TLC (hexane: CH2Cl2 ; 1:1) to give 77 mg of the title compound mp 159-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1>>[Cl:16][C:17]1[N:18]=[N:19][C:20]([N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:11]=[C:12]2[CH3:15])=[CH:21][CH:22]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: Clc1ccc(Cl)nn1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccc(Cl)nn1

Procedure:
The title compound, MS: m/e=329.1 (M+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 3,6-dichloropyridazine.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8].[CH2:33]([CH2:35][NH2:36])[OH:34].C(N(CC)C(C)C)(C)C>C(O)CCC>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:36][CH2:35][CH2:33][OH:34])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8]
Reactant: NCCO
Reactant: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(Cl)c([N+](=O)[O-])c4)s3)cc2)CC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc(NCCO)c([N+](=O)[O-])c4)s3)cc2)CC1
Temperature: 100 °C
Yield: 27.7 %

Procedure:
A mixture of [4-amino-2-[[4-(4-methyl-1-piperazinyl)phenyl]amino]-5-thiazolyl](4-chloro-3-nitrophenyl)methanone (of Example 15; 0.25 g, 0.53 mmol), ethanolamine (0.13 mL, 2.12 mmol), N,N-diisopropylethylamine (Aldrich) (0.37 mL, 2.12 mmol) in n-butanol (10 mL) was heated at 100° C. overnight. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel using MeOH/CH2Cl2 (1/9) as the eluent to afford 73 mg (28% yield) of the title compound. Mass spectrum (ES) MH+=498.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH3:12].[CH2:13]([O:20][C:21]1[N:22]=[N:23][C:24]([CH:35]=[CH2:36])=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:13]([O:20][C:21]1[N:22]=[N:23][C:24](/[CH:35]=[CH:36]/[C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[CH3:12])=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(C(F)(F)F)ccc1Br
Reactant: C=Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C(F)(F)F)ccc1/C=C/c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 54.7 %

Procedure:
1-Bromo-2-methyl-4-(trifluoromethyl)benzene (1.144 g, 4.79 mmol), 3,4-bis(benzyloxy)-6-ethenylpyridazine (Intermediate 78; 1.27 g, 3.99 mmol), palladium(II) acetate (0.045 g, 0.199 mmol), triethylamine (10.56 ml, 76 mmol), tri-o-tolylphosphine (0.243 g, 0.798 mmol) and acetonitrile (8 ml) were combined. The reaction mixture was subjected to microwave irradiation at 120° C. for 30 minutes before being quenched with water and extracted into ethyl acetate. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to afford an orange gum. This was purified by column chromatography (silica, eluting with 0-30% ethyl acetate in petrol) to afford 3,4-bis(benzyloxy)-6-[(E)-2-[2-methyl-4-(trifluoromethyl)phenyl]ethenyl]pyridazine as a white solid (1.04 g, 55%).
Reaction SMILES: C1C[O:4]CC1.[CH2:6]([C:9]1([OH:22])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[CH:7]=[CH2:8].[OH-].[Na+].OO>O>[OH:22][C:9]1([CH2:6][CH2:7][CH2:8][OH:4])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: C1CCOC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(CCCO)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 117.2 %

Procedure:
A mixture of BH3 in THF (21 mL, 21.0 mmol) was added slowly to a mixture of tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate (500 mg, 2.07 mmol) and THF (5 L) at 0° C. under nitrogen, and then stirred for 30 min. The resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to 0° C. and 3N sodium hydroxide (1 mL) was added followed by the addition of 30% hydrogen peroxide (1 mL). The resulting mixture was allowed to warm to room temperature and stirred for 2.5 hours. The mixture was then treated with water (10 mL) and extracted with EA (3×20 mL). The combined organic extracts were dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel with (30% EtOAc/PE) to give tert-butyl 4-hydroxy-4-(3-hydroxypropyl) piperidine-1-carboxylate 13B (629 mg) as a colorless oil. 1H NMR (CHLOROFORM-d) δ: 3.65 (t, J=5.7 Hz, 4H), 3.36 (br. s., 2H), 3.16 (br. s., 2H), 1.63-1.71 (m, 2H), 1.53-1.62 (m, 4H), 1.41-1.48 (m, 9H).
Reaction SMILES: [N:1]1([CH2:10][C:11]([OH:13])=O)[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].Cl.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([N:27]1[CH2:32][CH2:31][NH:30][CH:29]([CH3:33])[C:28]1=[O:34])(=[O:26])=[O:25])([O-:17])=[O:16].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:33][CH:29]1[N:30]([C:11](=[O:13])[CH2:10][N:1]2[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]2=[O:3])[CH2:31][CH2:32][N:27]([S:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])(=[O:25])=[O:26])[C:28]1=[O:34]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: CC1NCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])C(=O)C2C)c(=O)[nH]c1=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
To a solution of (thymin-1-yl)-acetic acid (55 mg, 0.30 mmol), 1-(2-nitro-benzenesulfonyl)-3-methyl-piperazin-2-one HCl salt (100 mg, 0.30 mmol), and PyBOP (156 mg, 0.45 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (0.08 mL) at room temperature. After stirring for additional 2 h at 40° C., the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in reduced pressure and the residue was purified by column chromatography to give the titled compound (100 mg, 72%). 1H NMR (500 MHz; DMSO-d6) δ 11.31 (s, 1H), 8.33 (d, 1H), 8.10 (d, 1H), 8.04˜7.93 (m, 2H), 7.35 (s, 1H), 4.85˜4.60 (m, 2.5H), 4.55˜4.40 (m, 0.5H), 4.20˜4.10 (m, 0.5H), 4.05˜3.90 (m, 1.5H), 3.78˜3.60 (m, 1H), 3.30 (m, 1H), 1.74 (s, 3H), 1.42 (d, 1H), 1.27 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:13][CH3:14])[C:8]([NH2:12])=[CH:9]2)=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].N1C=CC=CC=1>O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:13][CH3:14])[C:8]([NH:12][C:15](=[O:17])[CH3:16])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2ccc(Br)cc2cc1N
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2ccc(Br)cc2cc1NC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
A mixture of 7-bromo-3-methoxy-naphthalen-2-ylamine (2.2 g, 8.76 mmol), acetic anhydride (1.4 g, 13.14 mmol) and pyridine (20 mL) was stirred at room temperature for 3 hours. Water (300 mL) was added and the solid precipitate was collected by filtration and copiously washed with water. The solid residue was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 2.569 g of N-(7-bromo-3-methoxy-naphthalen-2-yl)-acetamide as a light pink solid.
Reaction SMILES: [CH:1]#[C:2][C@H:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[OH:9][C@H:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[C:1][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: C#C[C@H](O)CCCCC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCC[C@@H](O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, (R)-(+)-1-octyn-3-ol (61 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield (R)-(Z)-1,3-dihydro-4-(3-hydroxy-1-octynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 91 mg, 62%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][N:16]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCCl>[CH3:15][N:16]1[C:20]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[C:19]([CH3:21])[CH:18]=[C:17]1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)Cc1cc(C)cn1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(F)cc2)n1C
Reaction time: 2 h
Yield: 25 %

Procedure:
A solution of 3.95 g. (0.025 mole) of p-fluorobenzoyl chloride and 3.32 g. (0.025 mole) of aluminum chloride in 20 ml. of 1,2-dichloroethane is added dropwise to a solution of 4.52 g. (0.025 mole) of ethyl 1,4-dimethylpyrrole-2-acetate in 20 ml. of 1,2-dichloroethane at room temperature. The reaction mixture is stirred for 2 hours, and then cooled and poured into ice-dilute HCl. The organic phase is separated and washed successively with N,N-dimethyl-1,3-propanediamine, dilute hydrochloric acid and a saturated solution of sodium chloride; dried over anhydrous magnesium sulfate; and the solvent evaporated. The residuc is triturated with hot hexane and crystals form upon cooling. There is obtained about 1.9 g. (25% yield) of ethyl 1,4-dimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetate as a white solid, m.p. 84-86° C. Upon recrystallization from methanol, the m.p. is 87-89° C.