Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].CCN=C=NCCCN(C)C.[CH:35]1[CH:40]=[C:39]2N=N[N:43](O)[C:38]2=CC=1.O.CCN(C(C)C)C(C)C.C[C@H]1C[C@@H]1N.Cl>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:43][C@H:38]4[CH2:39][C@@H:40]4[CH3:35])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: On1nnc2ccccc21
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: C[C@H]1C[C@@H]1N
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1C[C@@H]1NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
Combine 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (100 mg, 0.327 mmol), EDCI (94 mg, 0.490 mmol), HOBT hydrate (75 mg, 0.490 mmol) in DMF (1 mL) and added Hunig's base (127 mg, 0.980 mmol). Then (1s,2s)-2-methylcyclopropanamine (34.8, 0.490 mmol) was added and the mixture was stirred at 60° C. for 3 h. The reaction mixture was diluted with water (4 mL) and acidified with 1N HCl to pH=5-6 to give a solid. The solid was collected by filtration, washed with water (2 mL), and recrystallized from hot MeOH (3-6 mL) to give the title compound (79.2 mg, 67.5% yield) as a white solid. MS m/z [M+H]+ 360.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH:10]1([NH2:14])[CH2:13][CH2:12][CH2:11]1>CCN(C(C)C)C(C)C>[CH:10]1([NH:14][C:6]2[C:5]([Cl:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: NC1CCC1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncc(Cl)c(NC2CCC2)n1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
2,4,5-trichloro-pyrimidine (0.5 M in DMSO) cyclobutyl amine (0.5 M in DMSO, 160 μL) and DIEA (neat, 30 μL) were added to an 8-ml reaction vial. The vial was capped and the contents shaken at 25° C. for 22 h. The reaction mixture was concentrated in Genevac to provide 4-cyclobutylamino-2,5-dichloro-pyrimidine. The solid was treated with C16 (0.5 M in DMSO, 160 μL), concentrated in Genevac, and the resultant residue treated with EtOAc (160 ul). The vial was capped and the contents shaken at 75° C. for 22.5 hours. The reaction mixture was then concentrated in Genevac. The resultant crude product was dissolved in DMSO and purified by HPLC to provide 418 (11.9 mg, 35%). APCI LCMS: Retention time: 3.00 min (Method A), Observed mass: 419.99 [M+H].
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH3:26])=[C:10]([C:12]2[C:23](=[O:24])[N:22]([CH3:25])[C:15]3[N:16]=[C:17](SC)[N:18]=[CH:19][C:14]=3[CH:13]=2)[CH:11]=1.OOS([O-])=O.[K+].[NH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH3:26])=[C:10]([C:12]2[C:23](=[O:24])[N:22]([CH3:25])[C:15]3[N:16]=[C:17]([NH:33][CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[N:18]=[CH:19][C:14]=3[CH:13]=2)[CH:11]=1
Reactant: NC1CCOCC1
Reactant: CSc1ncc2cc(-c3cc(-c4ncc[nH]4)ccc3C)c(=O)n(C)c2n1
Agent: O=S([O-])OO
Agent: [K+]
Product: Cc1ccc(-c2ncc[nH]2)cc1-c1cc2cnc(NC3CCOCC3)nc2n(C)c1=O

Procedure:
6-[5-(1H-Imidazol-2-yl)-2-methyl-phenyl]-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one was treated with OXONE™ following the procedure of step 3 of Example 1, and the resulting sulfonyl compound was treated with 4-amino-tetrahydropyran using the procedure of step 4 of Example 1, to give 2.5 mg of 6-[5-(1H-imidazol-2-yl)-2-methyl-phenyl]-8-methyl-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one: MS (M+H)=417.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([CH:21]=[O:22])=[CH:19][N:18]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.S(=O)(=O)([OH:33])N.Cl([O-])=O.[Na+].P([O-])(O)(O)=O.[K+]>O1CCOCC1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:33])=[O:22])=[CH:19][N:18]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)O
Reactant: Cn1nc(-c2cnc3c(n2)c(C=O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a stirred suspension of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (500 mg, 1.18 mmol) and sulfamic acid (685 mg, 7.05 mmol) in dioxane (25 mL) and water (0.556 mL) in an ice bath was added a solution of sodium chlorite (146 mg, 1.61 mmol) and potassium dihydrogen phosphate (1.92 g, 14.1 mmol) in water (2.78 mL). The reaction mixture was stirred at room temperature for overnight. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine then dried (sodium sulfate), filtered and concentrated in vacuo. The crude residue was recrystallized from ethyl acetate and hexane to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (467 mg, 89%) as a light yellow solid. This was used directly in the next step without further purification. LCMS, [M+H]=442.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[F:9][C:10]([F:20])([F:19])[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[Cl-]>C(OCC)(=O)C.O.CN(C=O)C>[F:9][C:10]([F:19])([F:20])[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(Oc2ccncc2)cc1
Temperature: 34 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
4-Chloropyridine hydrochloride (17.3 g), 4-Trifluoromethoxyphenol (24.6 g), K2CO3 (35.1 g) and DMF (173 mL) were placed in a vessel and stirred at 28-40° C. for 1.5 hr. and then stirred at 75-84° C. for 6 hr. and then stirred at 139-146° C. for 34.5 hr. The reaction mixture was then cooled to room temperature and water (256 mL), a small amount of NaCl and ethyl acetate (256 mL) were added. The organic material was taken up in ethyl acetate. The organic layer was washed with water (256 mL) and a small amount of NaCl. And then the organic layer was extracted three times with 10 v/v % HCl (256 mL×3). The organic material was taken up in 10 v/v % HCl. And then the aqueous layer was basified to pH 9 by NaOH and was extracted with ethyl acetate (256 mL). The organic material was taken up in ethyl acetate. The organic layer was washed with water (256 mL) and a small amount of NaCl. The organic layer was condensed under reduced pressure to give 15.3 g (52.0% yield) of a brown oily target compound.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.Cl.[NH2:14][OH:15].C(=O)(O)[O-].[Na+]>C(O)C>[OH:15][NH:14][C:11]([C:6]1[C:5]2[CH:4]=[CH:3][N:2]=[CH:1][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[NH:12]
Reactant: N#Cc1cccc2cnccc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1cccc2cnccc12
Temperature: 65 °C
Reaction time: 12 h
Yield: 119.2 %

Procedure:
5-Isoquinolinecarbonitrile (2 g, 13 mmol; available from Fulcrum Scientific Product List), hydroxylamine.hydrochloride (7.21 g, 104 mmol) and sodium bicarbonate (10.9 g, 130 mmol), were added to a 0.5 L round bottomed flask containing ethanol (250 ml). The reaction mixture was heated at 65° C. for 3 hours and stirred for 12 hours. The cooled reaction mixture was evaporated to a smaller volume under reduced pressure and chromatographed over a 4×6 inch silica column eluting with ethanol to provide the title compound as a yellow solid (2.9 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:39]2[CH:40]=[C:41]3[O:45][CH2:44][CH2:43][C:42]3=[C:46]([CH:48]=[O:49])[CH:47]=2)O1>O1CCOCC1.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>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:39]4[CH:47]=[C:46]([CH:48]=[O:49])[C:42]5[CH2:43][CH2:44][O:45][C:41]=5[CH:40]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cc(C=O)c3c(c2)OCC3)OC1(C)C
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: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C=O)c5c(c4)OCC5)cc23)CC1
Temperature: 120 °C
Yield: 90.9 %

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (113 mg, 0.274 mmol) in dioxane (9.0 mL) and H2O (3.0 mL) was added sodium carbonate (174 mg, 1.64 mmol), and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-4-carbaldehyde (150 mg, 0.547 mmol). The reaction mixture was flushed under Argon for 10 min before addition of tetrakis(triphenylphosphine)palladium (0) (16 mg, 0.014 mmol). The reaction was heated in a microwave at 120° C. for 30 min. All solvent was then concentrated and purified by flash chromatography using DCM and MeOH to give 120 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formyl-2,3-dihydro-1-benzofuran-6-yl)-1H-indole-7-carboxamide (91%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[C:15]=2[CH:29]=[O:30])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(#N)C.CCOCC>ClCCl>[N:11]1([C:14]2[N:22]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[C:15]=2[CH:29]=[O:30])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3cccnc3n2-c2cccnc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1c(N2CCNCC2)n(-c2cccnc2)c2ncccc12
Temperature: 25 °C
Reaction time: 96 h
Yield: 117.1 %

Procedure:
A solution of 4-(3-formyl-1-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (60 mg, 0.15 mmol) in dichloromethane (6 mL) is treated with trifluoroacetic acid (0.18 mL, 0.18 mmol). The resulting solution is allowed to stir at room temperature for 4 days to form a creamy suspension before treating the reaction with a further aliquot of trifluoroacetic acid (0.20 mL, 2.0 mmol) to give an orange solution. After stirring for a further 20 hours, the reaction mixture is evaporated to give an orange oil. Trituration of the crude product salt with acetonitrile and ether gives 54 mg of 2-piperazin-1-yl-1-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde; bis-trifluoro-acetic acid salt as a tan solid (68% yield). LC/MS: retention time 1.72 min, m/e 308 (M+H). 1H NMR (300 MHz, DMSO-d6): 10.16 (1H, s), 8.86 (1H, d), 8.78 (2H, br.s), 8.74 (1H, d), 8.41 (1H, d), 8.17-8.13 (2H, m), 7.70 (1H, dd), 7.30 (1H, dd), 3.50-3.46 (4H, m), 3.06-3.00 (4H, m).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([CH2:12][C:13]([OH:15])=O)[CH:3]=1.[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)[S:20][CH:21]=1
Reactant: O=C(O)Cc1cc(F)cc2ncccc12
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(Cc1cc(F)cc2ncccc12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(7-fluoroquinolin-5-yl)acetic acid (0.025 g, 0.122 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl-amine (0.20 g, 0.083 mmol) according to protocol A. The desired product was submitted to prep HPLC for further purification. Retention time (min)=2.33, method [7], MS(ESI) 434.0 (M+H). 1H NMR (CDCl3) δ 11.79 (s, 1H), 8.94 (d, J=4.0 Hz, 1H), 8.54 (d, J=8.1 Hz, 1H) 8.38 (s, 1H broad), 7.80 (d, J=10.1 Hz, 1H), 7.70 (d, J=10.1 Hz, 1H), 7.59-7.55 (m 1H), 7.22 (s, 1H), 4.47 (s, 2H).
Reaction SMILES: [Si]([O:8][CH:9]1[C:17]2[C:12](=[C:13]([C:18]3[O:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([CH:30]=4)[C:28]#[N:29])=[N:20][CH:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH:9]1[C:17]2[C:12](=[C:13]([C:18]3[O:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([CH:30]=4)[C:28]#[N:29])=[N:20][CH:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CCC4O[Si](C)(C)C(C)(C)C)o2)cc1C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CCC4O)o2)cc1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
To a solution of 5-(5-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)oxazol-2-yl)-2-isopropoxybenzonitrile INT-33 (350 mg, 0.737 mmol) in anhydrous THF (2 mL) was added a 1M solution of tetrabutylammonium fluoride in THF (3.6 mL, 3.6 mmol) at 0° C. The reaction mixture was allowed to stir at room temperature for 16 h before quenching with brine (5 mL). The THF was removed under vacuum, the residue was diluted with water (5 mL), and the aqueous layer was extracted with EA. The combined extracts were washed with brine, dried over MgSO4, and purified by chromatography to afford 220 mg (63%) of 5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)oxazol-2-yl)-2-isopropoxybenzonitrile 56 as a light yellow solid. LCMS-ESI (m/z) calculated for C22H20N2O3: 360.4; found 343.0 [M−OH]+, tR=2.30 min. 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J=2.2 Hz, 1H), 8.26 (dd, J=8.9, 2.2 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.3 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.10 (d, J=8.9 Hz, 1H), 5.35 (d, J=4.8 Hz, 1H), 4.78 (dt, J=12.2, 6.1 Hz, 1H), 3.30 (ddd, J=16.4, 8.7, 4.8 Hz, 1H), 3.13-2.94 (m, 1H), 2.64 (dddd, J=13.3, 8.4, 7.1, 4.8 Hz, 1H), 2.17-2.08 (m, 1H), 1.86 (s, 1H), 1.60 (s, 1H), 1.46 (dd, J=13.9, 6.0 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([O:13]C)=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C)=O>CC#N.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 4-chlorophenol (500 mg), methyl bromoacetate (0.368 ml), cesium carbonate (1.9 g) and 5 ml of acetone was stirred at room temperature for 12 h. Ethyl acetate and water were then added to the reaction solution, and the organic phase was washed twice with water, dried over sodium sulfate and filtered, and the solvent was removed in vacuo. The crude product was dissolved in a 1:1 THF/water mixture (10 ml), and potassium hydroxide (417 mg) was added. The reaction was stirred at room temperature for 12 h. Ethyl acetate and water were then added to the reaction solution, and the aqueous phase was adjusted to pH 2 and extracted several times with ethyl acetate. The combined organic phases were washed twice with water, dried over sodium sulfate and filtered, and the solvent was removed in vacuo. The product with the molecular weight of 186.6 (C8H7ClO3) was obtained in this way; MS (ESI): 227.0 (M+CH3CN).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1.Cl.[CH3:15][O:16][NH:17][CH3:18].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.[Na+].[Cl-]>[CH3:15][O:16][N:17]([CH3:18])[C:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][CH3:1])=[CH:10][N:9]=1)=[O:13]
Reactant: CCCCc1ccc(C(=O)O)nc1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCCCc1ccc(C(=O)N(C)OC)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of fusaric acid (896 mg, 5.0 mmol), O,N-dimethylhydroxyl-amine hydrochloride (488 mg, 5 mmol), EDC (1.05 g, 5.5 mmol), HOBT (675 mg, 5.0 mmol) and NEt3 (1.4 ml, 10 mmol) in DMF (100 ml) was stirred at room temperature for 2 h. The reaction mixture was diluted with saturated aqueous NaCl and extracted with EtOAc (2×). The combined organic extracts were washed with 0.5 M citric acid, saturated aqueous NaHCO3, saturated aqueous NaCl, dried, and concentrated under vacuum to give the desired product I-2A-38a as a viscous oil (940 mg): MS 232.2 (M+1)+; 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.60-7.50 (m, 2H), 3.72 (s, 3H), 3.37 (s, 3H), 2.61 (t, 2H, J=7.5Hz), 1.62-1.53 (m, 2H), 1.38-1.28 (m, 2H), 0.89 (t, 3H, J=7.5Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si](C(C)C)(C(C)C)C(C)C)[CH:9]=[CH:10][C:3]=12.[Li]C(CC)C.CN([CH:29]=[O:30])C.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[C:7]([CH:29]=[O:30])=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: O=Cc1cnc2[nH]ccc2c1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A flask was charged with 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (25.2 g, 82.0 mmol) in THF (400 mL) and cooled to about −78° C. sec-BuLi (1.4 M in cyclohexane, 116 mL, 163 mmol) was added drop-wise over about 15 min. The mixture was stirred at −78° C. for about 1 h. To the mixture was added DMF (18.9 mL, 245 mmol) drop-wise and the temperature was maintained at about −78° C. for about 1 h. The mixture was quenched by the slow addition of a solution of HCl (4.0 M in 1,4-dioxane, 20.4 mL, 82.0 mmol) followed by the addition of saturated aqueous NaHCO3 (100 mL). The mixture was extracted with EtOAc (500 mL). The organic layer was allowed to sit at rt overnight. The precipitate formed was collected by filtration. The filtrate formed more precipitate which was collected by filtration again. The precipitated material from both filtrations was combined to give 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (12.9 g, 88%): LC/MS (Table 2, Method a) Rt=1.85 min; MS m/z 181 (M+H)+
Reaction SMILES: C(OC([CH:8]([C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([O:26][CH2:27][CH3:28])[C:17]=1[CH3:29])=[O:15])[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10])=O)(C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:11]1([C:9](=[O:10])[CH2:8][C:14]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([O:26][CH2:27][CH3:28])[C:17]=2[CH3:29])=[O:15])[CH2:13][CH2:12]1
Reactant: CCOc1c(S(C)(=O)=O)ccc(C(=O)C(C(=O)OC(C)(C)C)C(=O)C2CC2)c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOc1c(S(C)(=O)=O)ccc(C(=O)CC(=O)C2CC2)c1C
Yield: 91.6 %

Procedure:
A mixture of crude 2-tert-butoxycarbonyl-1-cyclopropyl-3-(2-methyl-3-ethoxy-4-methylsulfonylphenyl)-1,3-propanedione (10 g) and 4-toluenesulfonic acid (2 g) in dry toluene (150 mL) was stirred and heated at reflux for 2 hours. The cooled mixture was washed with a saturated sodium bicarbonate solution (50 mL), dried over magnesium sulfate, and concentrated in vacuo to afford 7 g of the crude product as a yellow oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([OH:16])=O.[F:21][C:22]([S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=1)(=[O:27])=[O:26])([F:24])[F:23]>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[F:23][C:22]([F:21])([F:24])[S:25]([C:28]1[CH:29]=[C:30]([NH:34][C:14]([CH2:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:17][C:18]([OH:20])=[O:19])=[O:16])[CH:31]=[CH:32][CH:33]=1)(=[O:26])=[O:27]
Reactant: Nc1cccc(S(=O)(=O)C(F)(F)F)c1
Reactant: O=C(O)Cc1ccccc1CC(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccccc1CC(=O)Nc1cccc(S(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Oxalyl chloride (0.285 mL) was added to a solution of 1,2-phenylenediacetic acid (100 mg, 0.515 mmol) in dichloromethane, followed by 5 drops of DMF. The mixture was stirred at room temperature for 1.5 hours and cooled to 0° C. To the cooled mixture was added DMAP (63 mg, 0.62 mmol) and 3-aminophenyl trifluoromethyl sulfone (116 mg, 0.515 mmol). The mixture was allowed to warm to room temperature and extracted with ethyl acetate. The organic layer was washed with water, brine, dried and purified to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.31 (br s, 1H), 8.51 (s, 1H), 8.04 (m, 1H), 7.75 (d, J=5.1 Hz, 2H), 7.28 (m, 1H), 7.19 (m, 3H), 3.75 (s, 2H, CH2), 3.62 (s, 2H, CH2). MS 401.9 [M++1].
Reaction SMILES: O.[ClH:2].[F:3][C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[F:10].Br[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1.C(=O)(O)[O-].[Na+].Cl>C(O)C>[ClH:2].[ClH:2].[F:3][C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH:13]2[CH2:18][CH2:17][N:16]([CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: BrCc1ccc2ccccc2c1
Reactant: Fc1ccc(C(Nc2ccc(F)c(F)c2)C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Fc1ccc(C(Nc2ccc(F)c(F)c2)C2CCN(Cc3ccc4ccccc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.5 %

Procedure:
A mixture of 3.10 g (7.5 mmol) of 4-[[(3,4-difluorophenyl)amino](4-fluorophenyl)methyl]piperidine hydrochloride hydrate, 1.70 g (7.7 mmol) of 2-bromomethylnaphthalene and 5.1 g (60.7 mmol) of sodium bicarbonate in 200 mL of absolute ethanol was stirred at room temperature for 20 h. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute NaOH. The organic phase was dried (Na2SO4), and the solvent was removed in vacuo. The residue was subjected to flash chromatography (silica gel, elution with 1-4% MeOH in CH2Cl2) to give an oil. This was converted to the HCl salt, and the salt was recrystallized from a mixture of methanol and diethylether to give 1.53 g (38.3%) of the title compound as a crystalline solid, mp 187°-190° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:16])[NH:11][C:12](=[S:15])[NH:13][CH:14]=2)=[CH:4][N:3]=1.[CH3:17]C[O-].[Na+].CI>C(O)C>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][C:9]2[C:10](=[O:16])[N:11]=[C:12]([S:15][CH3:17])[NH:13][CH:14]=2)=[CH:6][N:7]=1
Reactant: Cc1ncc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CSc1nc(=O)c(Cc2cnc(C)nc2)c[nH]1
Yield: 38 %

Procedure:
5-(2-Methyl-pyrimidin-5-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (210 mg, 234.28 gmol−1, 0.90 mmol, 1 eq) and NaOEt (2 eq, 128 mg) were stirred in 5 ml of absolute ethanol at room temperature for 30 minutes. In the suspension was then added methyl iodide (2.5 eq, 140 μl) and the mixture was stirred for 35 hours. Solvent was then evaporated. In the mixture was added 3 ml of water and pH was adjusted to 5-6 range using 3N HCl water solution. The resulting precipitate was collected and dried to afford 5-(2-methyl-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (85 mg, yield=36.6%, purity=96%) in form of white powder. MS: [M+H]+=249.22 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.45 (s, 3H), 2.54 (s, 3H), 3.57 (s, 2H), 7.87 (br.s., 1H), 8.56 (s, 2H), 12.79 (br.s., 1H).