Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C@H:2]1[C:19]2[C@:14]([CH3:22])([CH:15]3[CH2:21][C@@H:16]3[C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:23])[CH2:7][CH2:6]3)[CH2:3]1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O>[N:24]([C@@H:2]1[C:19]2[C@:14]([CH3:22])([CH:15]3[CH2:21][C@@H:16]3[C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:23])[CH2:7][CH2:6]3)[CH2:3]1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@]12CC[C@H]3[C@@H](C[C@@H](Br)C4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]12CC[C@H]3[C@@H](C[C@H](N=[N+]=[N-])C4=CC(=O)[C@H]5CC5[C@@]43C)[C@@H]1CCC2=O
Yield: 70.1 %

Procedure:
A mixture of 6β-bromo-1,2β-methylenandrost-4-ene-3,17-dione (378 mg, 1 mmol), sodium azide (66 mg, 1 mmol) and dimethylformamide (10 ml) is heated from 20° to 100° C. Then the reaction mixture is cooled, poured onto ice water and extracted with ethyl acetate. The organic layer is separated, washed with water, dried and evaporated in vacuo. Purification is achieved by column chromatography over silica gel eluting with benzene/ether to yield pure 6α-azido-1,2β-methylenandrost-4-ene-3,17-dione (238 mg, 70%). Found: C 70.61, H 7.35, N 12.27. C20H25N3O2 requires: C 70.77, H 7.12, N, 12.38.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([C:19](=[O:52])[CH2:20][N:21]2[C:26](=[O:27])[C:25]3[CH:28]=[C:29]([CH2:31][C:32]([F:35])([F:34])[F:33])[S:30][C:24]=3[N:23]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[C:44]([C:49]#[N:50])=[CH:45][CH:46]=[CH:47][CH:48]=4)=[CH:39][CH:38]=3)[C:22]2=[O:51])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O.C(OCC)(=O)C>[CH:13]1([C:19](=[O:52])[CH2:20][N:21]2[C:26](=[O:27])[C:25]3[CH:28]=[C:29]([CH2:31][C:32]([F:34])([F:35])[F:33])[S:30][C:24]=3[N:23]([CH2:36][C:37]3[CH:38]=[CH:39][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49]4[NH:3][C:4](=[O:7])[O:5][N:50]=4)=[CH:41][CH:42]=3)[C:22]2=[O:51])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CC(=O)C3CCCCC3)c(=O)c3cc(CC(F)(F)F)sc32)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: O=C(Cn1c(=O)c2cc(CC(F)(F)F)sc2n(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c1=O)C1CCCCC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
A mixture of hydroxylammonium chloride (0.28 g), sodium hydrogencarbonate (0.43 g) and dimethyl sulfoxide (2.5 mL) was stirred at 50° C. for 30 min, 4′-{[3-(2-cyclohexyl-2-oxoethyl)-2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.29 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.061 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.056 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.095 g, 30%).
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17](O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)CCN.C1(=O)CCCCC1.C([O:44][C:45](=[O:48])CC)C>>[CH:1]1([N:7]([CH2:21][CH2:22][CH:23]([CH3:24])[CH3:28])[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][CH2:17][C:45]([OH:48])=[O:44])=[CH:13][N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Reactant: CCOC(=O)CC
Agent: CC(C)CCN
Solvent: O=C1CCCCC1
Product: CC(C)CCN(C(=O)Nc1ncc(SCCC(=O)O)s1)C1CCCCC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from 3-methylbutylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29].C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:28](=[O:29])[C:27]5[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=5[C:25]([F:24])([F:35])[F:36])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1ccccc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1ccccc1C(F)(F)F
Yield: 75.1 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.484 mmol), 2-(trifluoromethyl)benzoic acid (110 mg, 0.581 mmol), oxalyl chloride (84 mL, 0.969 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (5 mL) and N-methylpyrrolidone (5 mL) as starting materials and in the same manner as in Example 412, the title compound (175 mg, 75%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([CH2:15][CH:16]=[CH2:17])[C:10]([C:18]([O:20]C)=[O:19])=[N:9][C:8]=2[N:7]([CH2:22][CH2:23][CH2:24][CH3:25])[C:6]1=[O:26])[CH2:2][CH2:3][CH3:4].[Li+].[OH-].Cl.CCOC(C)=O>CO.O>[CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([CH2:15][CH:16]=[CH2:17])[C:10]([C:18]([OH:20])=[O:19])=[N:9][C:8]=2[N:7]([CH2:22][CH2:23][CH2:24][CH3:25])[C:6]1=[O:26])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(C(=O)OC)nc2c1c(=O)n(CCCC)c(=O)n2CCCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: C=CCn1c(C(=O)O)nc2c1c(=O)n(CCCC)c(=O)n2CCCC
Yield: 85 %

Procedure:
A stirred solution of methyl 1,3-dibutyl-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purine-8-carboxylate (1.30 g, 3.6 mmol) in MeOH (15 ml) was treated with LiOH (215 mg) and water (1.5 ml). After 3 hours at rt the mixture was diluted with water and the pH adjusted to ca. pH5 with 2M HCl (aq). EtOAc was added and then separated, washed with brine, dried (MgSO4) and concentrated to afford the title compound as a yellow solid 85% pure (1.2 g, 88%). m/z. 349.2[MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].Cl[CH:13]([CH3:17])[C:14]([OH:16])=[O:15].Cl[Si](C)(C)C.[CH2:23](O)[CH:24]([CH3:26])[CH3:25]>>[CH2:23]([O:16][C:14](=[O:15])[C@H:13]([CH3:17])[NH:6][C:5]1[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: COc1cc(N)cc(OC)c1
Reactant: CC(Cl)C(=O)O
Reactant: CC(C)CO
Agent: C[Si](C)(C)Cl
Product: COc1cc(N[C@@H](C)C(=O)OCC(C)C)cc(OC)c1

Procedure:
N-(3,5-dimethoxyphenyl)alamine (crude, 454 mg) (prepared according to the procedure described in U.S. Pat. No. 3,598,859 using 3,5-dimethoxyaniline (Aldrich) and 2-chloropropionic acid (Aldrich)) was treated in dry iso-butanol (10 mL) with 0.1 mL of chlorotrimethylsilane and the reaction mixture refluxed overnight. The excess alcohol was removed at reduced pressure and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated aqueous NaHCO3, dried with Na2SO4 and the solvent removed to provide the title compound. The reaction was monitored by silica gel tlc (Rf=0.3 in 20% EtOAc/hexanes). Purification was by preparative thin layer chromatography using 20% EtOAc/hexanes as the eluant.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[N:11]1[N:12]2[CH2:21][CH2:20][CH2:19][C:13]2=[C:14](B(O)O)[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(O[CH2:32][CH3:33])(=O)C.CO>CS(C)=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>[N:6]1[CH:33]=[CH:32][CH:3]=[CH:4][C:5]=1[C:15]1[C:14]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=2)=[C:13]2[CH2:19][CH2:20][CH2:21][N:12]2[N:11]=1
Reactant: OB(O)c1cnn2c1CCC2
Reactant: CCOC(C)=O
Reactant: Brc1ccc2nccn2c1
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: CS(C)=O
Solvent: CO
Product: c1ccc(-c2nn3c(c2-c2ccc4nccn4c2)CCC3)nc1
Yield: 38 %

Procedure:
Add tetrakis(triphenylphosphine)palladium(0) (0.025 g, 0.022 mmol) to a microwave tube containing a solution of 6-bromo-imidazo[1,2-a]pyridine (0.086 g, 0.44 mmol), 2-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5; 0.1 g, 0.436 mmol), and 2M aqueous potassium carbonate (0.5 mL, 1 mmol) in dimethylsulfoxide (1.5 mL). Irradiate the reaction in a microwave reactor set at 111° C., 50 W., 10 min with internal cooling. Normal phase chromatography using ethyl acetate/methanol mixtures followed by reversed phase preparative chromatography gives the 0.05 g (38%) of the title compound as a white solid. MS (electrospray, m/z) 301.9 (M+1). 1H NMR (400 MHz, DMSO-d) δ 8.57 (s, 1H), 8.4 (d, J=4.8 Hz, 1H), 7.87 (s, 1H), 7.78 (m, 2H), 7.52 (s, 1H), 7.42 (d, J=9.2 Hz, 1H), 7.26 (m, 1H), 7.05 (dd, J=9.2, 2 Hz, 1H), 4.2 (t, J=6.6 Hz, 2H, 2.99 (t, J=6.6 Hz, 2H), 2.59 (m, 1H).
Reaction SMILES: Cl.[CH:2]([C:4]1[S:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=1)=[O:3].C(=O)(O)[O-].[Na+].[CH2:24](O)[CH3:25]>>[CH2:24]([O:3][CH2:2][C:4]1[S:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:5]=1)[CH3:25]
Reactant: O=Cc1ccc(-c2sccc2-c2cccs2)s1
Reactant: CCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOCc1ccc(-c2sccc2-c2cccs2)s1
Reaction time: 2 h

Procedure:
The yield could be increased to 85% or higher by substituting absolute ethanol for alcohol and concentrated hydrochloric acid for diluted hydrochloric acid. More specifically, 5-formyl terthiophene (0.2 g) was first dissolved in absolute ethanol (15 ml) at room temperature. To the solution, 0.03 ml concentrated hydrochloric acid/absolute ethanol mixture (0.3 ml conc. HCl in 10 ml absolute ethanol) was then added. After stirring for 2 hours, 0.8 g sodium bicarbonate (NaHCO3) was added and the stirring was continued for 0.5 hours followed by filtration. The ethanol was removed under reduced pressure. 5-ethoxymethyl terthiophene thus obtained was purified by silica gel chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[CH3:22][NH:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25].C([O-])([O-])=O.[Na+].[Na+].O>CC#N.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:29]3[CH:30]=[CH:31][C:26]([C:24]([NH:23][CH3:22])=[O:25])=[CH:27][CH:28]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1ccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(Br)cc23)cc1
Yield: 121 %

Procedure:
5-Bromo-3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (350 mg, 0.73 mmol), 4-(N-methylaminocarbonyl)phenylboronic acid (160 mg, 0.88 mmol) and dichlorobis(triphenylphosphine)palladium (II) (52 mg, 0.073 mmol) were combined in CH3CN (10 ml) and 1 M Na2CO3 (10 ml) and stirred at 60° C. for 5 hrs. Water was added and the mixture was extracted with DCM, combined organic phases were dried and evaporated to yield 428 mg (121%) of the title compound. 1H NMR (CDCl3, 300 MHz): δ 8.50 (d, J=1.3 Hz, 1H), 8.20 (d, J=1.2 Hz, 1H), 8.09 (d, J=5.1 Hz, 2H), 7.94 (s, 1H), 7.87 (d, J=5.1, 2H), 7.61 (d, J=5.0 Hz, 2H), 7.31 (d, J=5.0 Hz, 2H), 6.21 (bd, J=2.5 Hz, 1H), 3.06, (d, J=2.9 Hz, 3H), 2.39 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:17]([N:19]([CH2:22][CH2:23][Cl:24])[CH2:20][CH3:21])[CH3:18]>>[ClH:24].[CH2:17]([N:19]([CH2:22][CH3:23])[CH:20]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[N:8][NH:9]2)[CH3:21])[CH3:18]
Reactant: c1ccc(-c2n[nH]c3ccccc23)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Product: CCN(CC)C(C)c1cccc2[nH]nc(-c3ccccc3)c12
Yield: 30.4 %

Procedure:
By the procedure similar to that described in Example 1, 3-phenylindazole (3.88 g) and diethylaminoethyl chloride hydrochloride (5.16 g) were treated to obtain 2.0 g of 1-diethylaminoethyl-3-phenylindazole hydrochloride (m.p. 114°-118° C).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([N:24]1[CH2:28][C@H:27]2[C@@H:29]([NH2:32])[CH2:30][CH2:31][C@H:26]2[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:33](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)C1C=CC=CC=1>>[CH2:17]([N:24]1[CH2:28][C@H:27]2[C@@H:29]([NH:32][C:14](=[O:16])[C@@H:9]([N:8]([CH3:33])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:30][CH2:31][C@H:26]2[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: N[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)C[C@@H](C(=O)N[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N(C)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-leucine for N-(tert-butoxycarbonyl)-L-leucine and (3aS,4S,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step C of Example 14 for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (501 MHz, pyridine-d5, temperature 90° C.) δ ppm 7.44-7.49 (m, 2H), 7.36-7.40 (m, 2H), 7.32-7.39 (m, 1H), 7.27 (t, J=7.4 Hz, 1H), 4.82-4.89 (m, 1H), 4.37-4.43 (m, 1H), 3.63 (d, J=13.2 Hz, 1H), 3.50 (d, J=13.0 Hz, 1H), 2.94 (s, 3H), 2.73 (dd, J=9.7, 1.8 Hz, 1H), 2.64-2.70 (m, 1H), 2.44-2.47 (m, 2H), 2.22-2.28 (m, 1H), 2.15-2.19 (m, 1H), 1.88 (ddd, J=14.1, 8.2, 6.0 Hz, 1H), 1.64-1.81 (m, 3H), 1.55-1.65 (m, 2H), 1.50 (s, 9H), 1.28-1.38 (m, 1H), 0.90-0.93 (m, 6H); MS (ESI+) m/z 444 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[NH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[C:21]3[CH:38]=[CH:37][NH:36][C:22]=3[N:23]=[C:24]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=3)[N:25]=2)[CH2:15][CH2:14]1.O>C(Cl)Cl.CN(C=O)C>[C:1]([CH2:3][C:4]([N:13]1[CH2:14][CH2:15][CH:16]([NH:19][C:20]2[C:21]3[CH:38]=[CH:37][NH:36][C:22]=3[N:23]=[C:24]([NH:26][C:27]3[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[O:32])=[CH:29][CH:28]=3)[N:25]=2)[CH2:17][CH2:18]1)=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: NC(=O)c1ccc(Nc2nc(NC3CCNCC3)c3cc[nH]c3n2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CCC(Nc2nc(Nc3ccc(C(N)=O)cc3)nc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 41.9 %

Procedure:
To a suspension of cyanoacetic acid (85 mg, 1.00 mmol) in CH2Cl2 (2 mL) (containing 2 drops of DMF), oxalyl chloride (0.082 mL, 0.94 mmol) was added. The mixture was stirred at room temperature for 50 min. To the above solution cooled in an ice bath, a solution of 4-(4-(piperidin-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)benzamide (20 mg, 0.057 mmol) and TEA (0.450 mL, 3.22 mmol) in DMF (2 mL) was added. The mixture was stirred at room temperature for 20 h. Water was added. CH2Cl2 was removed in vacuo. The residue was purified by HPLC to give the titled compound (10 mg). MS 419.3 (M+H); UV 200.0, 311.9 nm.
Reaction SMILES: [N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O.O.O.C([Si](C)(C)[O:27][C@H:28]1[CH2:37][CH2:36][CH2:35][C@@:34]2([CH3:38])[C@H:29]1[CH2:30][CH2:31][CH:32]=[C:33]2[C@H:39]([CH3:47])[CH2:40][C:41]#[C:42][C:43]([CH3:46])([OH:45])[CH3:44])(C)(C)C>C1COCC1>[OH:45][C:43]([CH3:44])([CH3:46])[C:42]#[C:41][CH2:40][C@H:39]([C:33]1[C@:34]2([CH3:38])[C@@H:29]([CH2:30][CH2:31][CH:32]=1)[C@@H:28]([OH:27])[CH2:37][CH2:36][CH2:35]2)[CH3:47]
Reactant: C[C@H](CC#CC(C)(C)O)C1=CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CC#CC(C)(C)O)C1=CCC[C@H]2[C@@H](O)CCC[C@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
5.43 g (17.2 mmol) of nBu4NF.3H2O in 10 ml of THF was carefully dried by stirring during 2 h at RT over 7.5 g of 3 Å molecular sieve. This solution was then added to 866 mg (2.14 mmol) of (R)-6-[(4aR,5S,8aS)-5-(tert-butyl-dimethyl-silanyloxy)-8a-methyl-3,4,4a,5,6,7,8,8a-octahydro-naphthalen-1-yl]-2-methyl-hept-3-yn-2-ol and the mixture kept for 24 h at 55°. The reaction mixture was then poured onto crushed ice, extracted twice with ether, washed with water and brine, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=7/3) afforded 590 mg of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21]O)=[CH:15][C:14]=3[I:23])=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS(Cl)(=O)=O.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[CH:15][C:14]=3[I:23])=[O:9])=[CH:24][CH:25]=1
Reactant: C1COCCN1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CO)cc2c1O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-8-iodo-3-quinolinecarboxamide (0.36 g), DMAP (0.016 g) and collidine (0.12 mL) in 13 mL DMF at 0° C. is added methanesulfonyl chloride (0.065 mL). The solution is allowed to warm to room temperature and is stirred overnight. Morpholine (0.67 mL) is then added and the solution is stirred at room temperature overnight. The mixture is poured into water. The resulting solid is collected and dried. The crude product is adsorbed onto silica and chromatographed (Biotage flash 40S, eluant 1% MeOH/CH2Cl2, then 2% MeOH/CH2Cl2). Product containing fractions are combined and concentrated to yield 0.322 g (78%) of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide, m.p. 230-233° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[CH2:28][OH:29])[CH2:6][S:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]C)=O)=[CH:16][C:15]=2[CH3:24])[CH:11]=[CH:12][CH:13]=1.[CH2:30]([Mg]Br)[CH3:31].[Cl-].[NH4+].[CH2:36]1COC[CH2:37]1>>[CH2:36]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([S:7][CH2:6][C:5]3[CH:25]=[CH:26][C:27]([CH2:28][OH:29])=[C:3]([CH2:2][OH:1])[CH:4]=3)[CH:9]=2)=[C:15]([CH3:24])[CH:16]=1)([OH:22])[CH2:30][CH3:31])[CH3:37]
Reactant: CC[Mg]Br
Reactant: COC(=O)c1ccc(-c2cccc(SCc3ccc(CO)c(CO)c3)c2)c(C)c1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: CCC(O)(CC)c1ccc(-c2cccc(SCc3ccc(CO)c(CO)c3)c2)c(C)c1
Reaction time: 1 h

Procedure:
130 mg (0.3 mmol) of methyl 3′-(3,4-bis-hydroxymethyl-benzylsulphanyl)-2-methylbiphenyl-4-carboxylate are dissolved in 10 mL of anhydrous THF and 0.7 mL (2 mmol) of an ethylmagnesium bromide solution (3M) are then added. The reaction medium is stirred for 1 h and then treated with ammonium chloride solution. After extraction with ethyl acetate, the organic phases are combined, dried and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica. A colourless oil is obtained (m=105 mg, Y=81%).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([CH3:19])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[N:16][NH:17][CH:18]=3)[CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.Br[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][CH:2]1[C:7]([CH3:19])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[N:16][NH:17][CH:18]=3)[CH:9]=2)[CH2:6][CH2:5][N:4]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=2)[CH2:3]1
Reactant: Cc1cccc(CCBr)c1
Reactant: CC1CNCCC1(C)c1cccc(-c2c[nH]nn2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(CCN2CCC(C)(c3cccc(-c4c[nH]nn4)c3)C(C)C2)c1
Reaction time: 8 h
Yield: 12.9 %

Procedure:
To a solution of 3,4-dimethyl-4-(3-(1H-1,2,3-triazol-4-yl)phenyl)piperidine (Preparation 44, 80 mg, 0.31 mmol) in N,N-dimethyl-formamide (6 mL) was added 1-(2-bromoethyl)-3-methylbenzene (Preparation 46, 67 mg, 0.31 mmol) and sodium hydrogencarbonate (40 mg, 0.47 mmol). The resultant mixture was heated to 80° C. and stirred overnight. The reaction mixture was cooled, poured onto saturated aqueous sodium hydrogencarbonate solution (100 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were dried over MgSO4, filtered and concentrated in vacuo to give an off-white gum. The crude product was partially purified by column chromatography on a 5 g silica Waters Sep-Pak3 eluting with dichloromethane and then 5% methanol in dichloromethane. The pure fractions were collected to give the title compound as a clear oil (15 mg, 12.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH3:13])=[C:7]2O.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([CH3:12])[C:8]=1[CH3:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(Cl)cccc2c(O)c1C
Product: Cc1nc2c(Cl)cccc2c(Cl)c1C

Procedure:
A mixture of 8-chloro-2,3-dimethylquinolin-4-ol (1.83 g, 8.81 mmol) in phosphorous oxychloride (10.00 mL) was heated to reflux for 2 h, after which time LC-MS indicated only product present. The reaction solution was poured into ice and adjusted to pH>10. The aq. mixture was extracted with 2×75 mL DCM. The combined organic extracts were stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a pale yellow solid, which was not further purified. Mass Spectrum (ESI) m/e=226.0 (M+1).