Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:21][CH3:22])[NH:9][C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].[H-].[Na+].I[CH3:26]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10]([O:20][CH3:26])[N:9]=[C:8]([S:21][CH3:22])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(SC)[nH]c(=O)c1OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(SC)nc(OC)c1OCc1ccccc1
Yield: 9 %

Procedure:
5-Benzyloxy-2-methylsulfanyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (6.190 g, 19.32 mmol) in dry N,N-dimethylformamide (60 ml) was reacted at 10° C. with sodium hydride (0.90 g of a 60% dispersion in mineral oil, 22.5 mmol) and iodomethane (1.4 ml, 21.7 mmol) and chromatographed to give first 0.581 g (9% yield) of 5-benzyloxy-6-methoxy-2-methylsulfanyl-pyrimidine-4-carboxylic acid ethyl ester as white crystals; mp 48–49° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.32 (3H, t, J=7.1 Hz, CH3), 2.56 (3H, s, SCH3), 4.07 (3H, s, OCH3), 4.36 (2H, q, J=7.1 Hz, CH2), 5.04 (2H, s, OCH2), 7.3–7.45 (5H, m, aromatics). HRMS (FAB POS) calculated for C16H19N2O4S [M+H+]: 335.106554. found: 335.106641, δ −0.3 ppm. The following fractions then gave 5.836 g (90% yield) of the title ester as white needles; mp 84–85° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.33 (3H, t, J=7.0 Hz, CH3), 2.62 (3H, s, SCH3), 3.57 (3H, s, NCH3), 4.35 (2H, q, J=7.0 Hz, CH2), 5.22 (2 H, s, OCH2), 7.3–7.5 (5H, m, aromatics). Anal. Calcd for C16H18N2O4S: C 57.47, H 5.43, N 8.38. Found: C 57.37, H 5.42, N 8.36.
Reaction SMILES: [C:1]1([S:7]([N@:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]1([S:7]([N:10]2[CH2:12][C@@H:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:38]2=[O:39])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3C[N@@]3S(=O)(=O)c3ccccc3)CC2)c1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 2, ((S)-1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone was reacted with sodium iodide and phenylisocyanate to give the title compound as a colorless solid. MS: 519.3 ([M+H]+)
Reaction SMILES: Cl.[F:2][C:3]1[C:23]([CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C@H:6]1[CH2:9][C@H:8]([CH2:10][N:11](C)[C:12](=O)OC(C)(C)C)[CH2:7]1>O1CCOCC1>[F:2][C:3]1[C:23]([CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C@H:6]1[CH2:9][C@H:8]([CH2:10][NH:11][CH3:12])[CH2:7]1
Reactant: CN(C[C@H]1C[C@H](Oc2cccc(CN3CCCC3)c2F)C1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNC[C@H]1C[C@H](Oc2cccc(CN3CCCC3)c2F)C1
Reaction time: 20 h

Procedure:
4M HCl in dioxane (6.05 ml) was added to a solution of example 390, tert-butyl ({trans-3-[2-fluoro-3-(pyrrolidin-1-ylmethyl)phenoxy]cyclobutyl}methyl)methylcarbamate (1.9 g, 4.84 mmol) in 2 ml of dioxane. The mixture was stirred for 20 h and evaporated to dryness. The residue was recrystallized from MeOH-Et2O. The crystals were separated by filtration and dryed, then CH2Cl2 (30 mL) and saturated 10N NaOH (pH 12) were added under stirring. The layers were separated; the water solution was extracted with CH2Cl2 (3×20 mL). The combined extracts were dried (Na2SO4) and evaporated; the residue was dried in vacuo to give the title compound (1.1 g, 79%) as a yellow oil. LC/MS data: 294.4, 293.4 (M+H) (calculated for C17H25FN2O 292.5). 1H NMR-data (DMSO-d6): 6.98-7.04 (m, 1H, Ar—H); 6.88-6.94 (m, 1H, Ar); 6.78-6.84 (m, 1H, Ar—H); 4.77-4.86 (m, 1H), 3.60 (s, 2H); 2.57 (d, 2H, J=7.4 Hz); 2.33-2.47 (m, 5H); 2.30 (s, 3H, NCH3); 2.20-2.28 (m, 4H); 1.64-1.73 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[CH3:8].Br[CH:12]([CH2:22][O:23][CH3:24])[C:13]([NH:15][C:16]([CH3:21])([CH3:20])[C:17]#[C:18][CH3:19])=[O:14]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:9])[C:7]=1[CH3:8])[O:10][CH:12]([CH2:22][O:23][CH3:24])[C:13]([NH:15][C:16]([CH3:21])([CH3:20])[C:17]#[C:18][CH3:19])=[O:14]
Reactant: CC#CC(C)(C)NC(=O)C(Br)COC
Reactant: Cc1cc(O)cc(C)c1C
Product: CC#CC(C)(C)NC(=O)C(COC)Oc1cc(C)c(C)c(C)c1

Procedure:
In a similar procedure to Example 3 Stage 2, 3,4,5-trimethylphenol was reacted with 2-bromo-N-(4-methylpent-2-yn-4-yl) 3-methoxypropionamide to give the title product as a colourless gum. 1H NMR (CDCl3) δ: 1.61(6H, s); 1.80(3H, s); 2.11(3H, s); 2.26(6H, s); 3.40(3H, s); 3.82(2H, m); 4.53(1H, t); 6.62(2H, s); 6.66(1H, s).
Reaction SMILES: CS(O)(=O)=O.CS(O[CH:11]([C:20]([CH3:30])([S:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH3:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19])(=O)=O.[I-:31].[Na+]>CC(C)=O>[I:31][CH:11]([C:20]([CH3:30])([S:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH3:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19]
Reactant: Cc1ccc(SC(C)(C)C(Cc2cccc[n+]2[O-])OS(C)(=O)=O)cc1
Reactant: [I-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ccc(SC(C)(C)C(I)Cc2cccc[n+]2[O-])cc1
Yield: 62.1 %

Procedure:
A solution of 3.35 g of 2-[2-methanesulphonyloxy-3-methyl-3-(4-methylthiophenoxy)butyl]pyridine N-oxide methanesulphonic acid salt and 2.25 g of sodium iodide in 50 ml of acetone was heated under reflux for 2 hours. The mixture was filtered and the filtrate was evaporated. The residue was partitioned between water and dichloromethane and the organic phase was evaporated. The residue was taken up in 50 ml of acetone and heated under reflux for 2 hours with 2.25 g of sodium iodide. The cooled reaction mixture was then evaporated and the residue was partitioned between water and dichloromethane. The organic phase was evaporated and the residue was crystallized from dichloromethane/ethyl acetate to give 1.8 g of 2-[2-iodo-3-methyl-3-(4-methylthiophenoxy)butyl]pyridine N-oxide in the form of a pale yellow solid of melting point 191°-193° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH3:36])[CH:31]=[CH:30][C:29]=4[F:37])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:41]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][CH:2]([CH3:3])[CH3:41])[CH:31]=[CH:30][C:29]=4[F:37])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNC)ccc4F)cc23)CC1
Reactant: CN
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNCC(C)C)ccc4F)cc23)CC1
Yield: 62.9 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide trifluoroacetate, substituting 2-methyl-1-propanamine (53 μL, 0.524 mmol) for methanamine to afford 15 mg of the title compound (62.9%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:3]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(Cl)c2N2CCOCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cccc(CN2CCNCC2)c1N1CCOCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A 50 mL round-bottom flask was charged with tert-butyl 4-[[3-chloro-2-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate (800 mg, 2.02 mmol, 1.00 equiv), dichloromethane (15 mL). The mixture was cooled to 0° C. Trifluoroacetic acid (2.5 mL) was added dropwise at 0° C. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to yield 580 mg (crude) of 4-[2-chloro-6-(piperazin-1-ylmethyl)phenyl]morpholine as colorless oil. LCMS (ESI, m/z): 296 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[S:3]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])=[O:4].[CH3:12][C:13]1([CH3:21])[O:17]C(CCO)[CH2:15][O:14]1.FC(F)(F)S([O-])(=O)=O>C(Cl)(Cl)(Cl)Cl>[F:11][C:2]([F:10])([F:1])[S:3]([O:6][CH2:7][CH2:8][CH:9]1[CH2:15][O:14][C:13]([CH3:21])([CH3:12])[O:17]1)(=[O:4])=[O:5]
Reactant: CC1(C)OCC(CCO)O1
Reactant: C=CCOS(=O)(=O)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OCC(CCOS(=O)(=O)C(F)(F)F)O1

Procedure:
2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethyl trifluoromethane sulfonate was prepared in carbon tetrachloride solution and used as a dried solution in this example in the same way as 2-propen-1-yl trifluoromethanesulfonate was prepared and used in Examples 41 through 44, starting with 2,2-di-methyl-4-(2-hydroxyethyl)1,3-dioxolane and trifluoromethanesulfonate.
Reaction SMILES: [Na].[CH3:2][C:3]1([CH3:10])[CH2:8][NH:7][C:6]([NH2:9])=[N:5][CH2:4]1.[C:11](OCC)(=[O:16])[CH2:12][C:13]([O-])=[O:14]>CO>[OH:16][C:11]1[N:9]=[C:6]2[NH:7][CH2:8][C:3]([CH3:10])([CH3:2])[CH2:4][N:5]2[C:13](=[O:14])[CH:12]=1
Reactant: CC1(C)CN=C(N)NC1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Na]
Solvent: CO
Product: CC1(C)CNc2nc(O)cc(=O)n2C1
Temperature: 100 °C
Yield: 72 %

Procedure:
1.4 g of sodium are added in a fractionated way to 15 mL of MeOH. After total dissolution, 2.7 g of 5,5-dimethyl-1,4,5,6-tetrahydropyrimidin-2-amine solubilized beforehand in 5 mL of MeOH, and then 16.5 mL of ethyl malonate are added. The mixture is heated to 100° C., after 4 h of heating, the medium is dry concentrated. The obtained oil is taken up in ether. The precipitate is filtered and then the residue is taken up in 7 mL of H2O and acidified with conc. HCl up to pH 3-4. The precipitate formed is filtered, washed with ether and dried in the oven in vacuo. 2 g (yield=72%) of 2-hydroxy-7,7-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained as a beige solid used as such.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=S)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:29]>>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[NH:29])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: FC(F)(F)c1ccc(NC(=S)Nc2ncccc2OCc2ccccc2)cc1
Product: N=C(Nc1ccc(C(F)(F)F)cc1)Nc1ncccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of N-(3-benzyloxypyrid-2-yl)-N'-(4-trifluoromethylphenyl)thiourea (3.08 g, 0.0076 mol), yellow mercuric oxide (2 g, 0.0092 mol) and methanolic ammonia solution (40 ml) was stirred for 48 hours at room temperature, then the solvent was removed in vacuo and the residue extracted with boiling chloroform and filtered hot. Evaporation of the filtrate and recrystallisation from acetonitrile gave the desired product. Yield 2.05 g (70%), m.p. 154°-155 ° C.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:27])=[C:9]([S:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:19])[C:10]([CH3:17])=[N:11]2.CO.[OH-].[Na+]>C(O)=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:28])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([S:18]([C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[O:19])=[C:8]2[CH3:27]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(S(=O)c3ccc(Cl)cc3)c(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=CO
Product: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(C)c1S(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of [8-chloro-3-(4-chlorobenzenesulfinyl)-2,4-dimethylquinolin-5-yloxy]acetic acid methyl ester (0.050 g), methanol (3.0 mL) and 1.0 M aqueous sodium hydroxide solution (0.57 mL) was stirred at room temperature for 3 hours. The pH of the mixture was adjusted to 5 by the addition of formic acid and the solvent removed under reduced pressure. Purification of the residue by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water gave title compound as a pale yellow solid, 0.029 g.
Reaction SMILES: B([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(O)O.Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.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>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)[CH:15]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Brc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccc(-c2cccnc2)cc1
Yield: 85.3 %

Procedure:
To a solution of 4-boronobenzoic acid (1.66 g, 10 mmol) and 3-bromopyridine (1.72 g, 11 mmol) in acetonitrile (40 mL) and water (40 mL), potassium carbonate (5.5 g, 40 mmol), bis(triphenylphosphine)palladium(II) chloride (400 mg, 0.37 mmol) were added. The mixture was degassed and purged withed nitrogen. The mixture was stirred under reflux for 24 h. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH=3 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 1.7 g of white solid of 4-(pyridin-3-yl)benzoic acid. Yield: 85%. LC-MS (ESI) m/z: 200 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=2)[CH:3]=1.[NH2:33][NH2:34]>CN(C)C=O>[NH2:9][C:8]1[C:7]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:12][CH:11]=3)=[N:5][C:4]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=3)=[CH:3][C:2]=2[NH:34][N:33]=1
Reactant: NN
Reactant: CC(=O)Nc1ccc(-c2cc(Cl)c(C#N)c(-c3ccc(Oc4ccccc4)cc3)n2)cc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(-c2cc3[nH]nc(N)c3c(-c3ccc(Oc4ccccc4)cc3)n2)cc1
Temperature: 120 °C

Procedure:
A mixture of N-(4-(4-chloro-5-cyano-6-(4-phenoxyphenyl)pyridin-2-yl)phenyl)acetamide (24.9 mg, 0.057 mmol), 35% aqueous hydrazine (20 μL, 0.637 mmol) and N,N-dimethylformamide (0.5 mL) in a sealed tube was heated to 100° C. for 3 h, 120° C. for 6 h and concentrated. Silica gel chromatography, eluting with 0-10% methanol in dichloromethane, gave the desired product. The material was triturated with dichloromethane and filtered to give Example 200 as light yellow solid (9.4 mg, 38% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.20 (1H, s), 10.08 (1H, s), 8.11 (2H, δ, J=8.78 Hz), 7.81-7.84 (2H, m), 7.69 (2H, δ, J=8.78 Hz), 7.63 (1H, s), 7.43-7.48 (2H, m), 7.13-7.23 (5H, m), 4.83 (2H, s), 2.07 (3H, s); MS (ES+) m/z: 436 (M+H); LC retention time: 3.200 min (analytical HPLC Method A).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CC1C=CC(S(O[CH2:16][CH2:17][N:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=[C:19]2[CH3:29])(=O)=O)=CC=1>CN(C)C=O>[N:1]([CH2:16][CH2:17][N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[C:19]1[CH3:29])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCn2cc(-c3ccccc3)cc2C)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccccc2)cn1CCN=[N+]=[N-]
Temperature: 90 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
Sodium azide (327 mg, 5.02 mmol) was added to a solution of 2-(2-methyl-4-phenyl-pyrrol-1-yl)ethyl 4-methylbenzenesulfonate (1.19 g, 3.35 mmol) in dry dimethylformamide (10 mL) and heated to 90° C. and stirred for 1 h. The reaction mixture was allowed to cool to ambient temperature and partitioned between water (20 mL) and ethyl acetate (25 mL). After stirring for 5 min, the organic layer was separated and washed successively with water (2×30 mL), brine (2×30 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to yield 1-(2-azidoethyl)-2-methyl-4-phenyl-pyrrole (650 mg, 86%) as a brown liquid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1.[C:29](Cl)(=[O:31])[CH3:30]>N1C=CC=CC=1>[CH3:18][S:17][C:13]1[N:12]=[C:11]([C:8]2[CH:9]=[C:10]3[C:2]([NH:1][C:29](=[O:31])[CH3:30])=[N:3][NH:4][C:5]3=[N:6][C:7]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CC(=O)Cl
Reactant: CSc1nccc(-c2cc3c(N)n[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Solvent: c1ccncc1
Product: CSc1nccc(-c2cc3c(NC(C)=O)n[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Yield: 35.1 %

Procedure:
A solution of 3-amino-5-[2-(methylsulfanyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine (200 mg, 0.5 mmol, obtained in example 123) and acetyl chloride (39 mg, 0.5 mmol) in pyridine (10 mL) was stirred at room temperature for 3 h. It was concentrated and the residue was taken up in a mixture of EtOAc and 1 N NaOH. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 78 mg of the title compound (yield: 37%)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=[CH:7]3)[CH2:3][CH2:2]2)(=[O:25])=[O:24])=[CH:21][CH:22]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Product: COc1ccc(S(=O)(=O)N2CCC3(C=Cc4ccccc43)CC2)cc1

Procedure:
The procedure of example 3 was carried out using 20 mg (0.108 mmol) of spiro(1H-indene-1,4'-piperidine), and substituting p-methoxybenzenesulfonyl chloride (21 mg, 0.1 mmol) for the p-bromo derivative. The title compound was obtained as a solid: (m.p. 181°-183°).
Reaction SMILES: [CH:1]([N:3]([CH2:16][C:17](=O)[CH3:18])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH3:15])=O.C([O-])(=O)C.[NH4+:24].N.C(OCC)(=O)C>C(O)(=O)C>[CH3:15][O:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[N:3]1[CH:16]=[C:17]([CH3:18])[N:24]=[CH:1]1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(N(C=O)CC(C)=O)c(OC)c1
Agent: CC(=O)[O-]
Agent: N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-n2cnc(C)c2)c(OC)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A solution of methyl 4-[formyl-(2-oxopropyl)amino]-3-methoxybenzoate (118 g) and ammonium acetate (172 g) in acetic acid (255 mL) was heated and stirred at 140° C. for one hour. After the reaction was completed, the reaction solution was neutralized with aqueous ammonia under ice-cooling. Ethyl acetate was added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then filtered on a silica gel pad, and the filtrate was concentrated under reduced pressure. tert-Butyl methyl ether and heptane were added to the residue, and the precipitated solid was collected by filtration and washed with a solution of 50% tert-butyl methyl ether in heptane. The resulting solid was air-dried overnight to obtain 68.4 g of the title compound. Further, the crystallization mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 22.3 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3=[N:15][C:16]4[C:17](=[N:18][CH:19]=[CH:20][CH:21]=4)[N:13]3[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[N:10]1([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[C:14]2=[N:15][C:16]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(N2CCn3c2nc2cccnc23)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCn3c2nc2cccnc23)cc1
Reaction time: 24 h
Yield: 79 %

Procedure:
A mixture of 1-(4-nitrophenyl)-2,3-dihydro-1H-imidazo[2′,1′:2,3]imidazo[4,5-b]pyridine (1.7 g) and 10% palladium on carbon (50% wet, 1.0 g) in MeOH (150 ml) was hydrogenated under balloon pressure at room temperature for 1 day. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (1.2 g).
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:22])([CH3:21])[CH3:20])[C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1)=O.[NH2:23][CH:24]1[CH2:29][CH2:28][CH:27]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH2:26][CH2:25]1>CN1C(=O)CCC1.O>[OH:22][C:19]([C:18]1[C:13]2[N:14]([C:10]([C:8]3[CH:7]=[CH:6][N:5]=[C:4]([NH:23][CH:24]4[CH2:29][CH2:28][CH:27]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH2:26][CH2:25]4)[N:9]=3)=[CH:11][N:12]=2)[CH:15]=[CH:16][CH:17]=1)([CH3:20])[CH3:21]
Reactant: CS(=O)c1nccc(-c2cnc3c(C(C)(C)O)cccn23)n1
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(O)c1cccn2c(-c3ccnc(NC4CCC(NS(C)(=O)=O)CC4)n3)cnc12
Temperature: 105 °C
Yield: 40.3 %

Procedure:
A mixture of 2-[3-(2-methanesulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyridine-8-yl]-propan-2-ol (0.15 g) and N-(4-amino-cyclohexyl)-methanesulfonamide (0.325 g) in NMP (1.5 mL) was treated with TEA (0.33 mL) and heated at 105° C. for 18 h. The reaction mixture was then cooled to RT and diluted with water. The resulting precipitate was filtered, washed with water, and dried. The product was purified by ISCO using 100% DCM to 15% MeOH/DCM. Pure fractions were collected, concentrated, and titurated with EtOAc. The resulting solid was filtered and dried at 50° C. under vacuum overnight to provide N-(4-{4-[8-(1-hydroxy-1-methyl-ethyl)-imidazo[1,2-a]pyridine-3-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanesulfonamide (compound 3, 84.9 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:21]=[CH:20][C:14]([C:15](OCC)=[O:16])=[CH:13][CH:12]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:15]([C:14]2[CH:20]=[CH:21][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[O:16])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(OC)cc1
Reactant: Cc1cccc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2cccc(Cl)n2)cc1
Temperature: 45 °C
Yield: 85.8 %

Procedure:
To a cold (0° C.) solution of 6-chloro-2-picoline (18.3 mL 166.5 mmol) and ethyl 4-methoxybenzoate (30.0 g, 166.5 mmol) in tetrahydrofuran (300 mL) was added lithium bis(trimethylsilyl)amide (333 mL, 1.0 M in tetrahydrofuran, 332.7 mmol) dropwise via a pressure equalizing funnel over 1 hour. Upon complete addition, the cold bath was removed and the resulting solution was heated at 45 ° C. for 15 hours. The mixture was cooled to room temperature, and the solution was concentrated. Methanol was added to quench the reaction, resulting in the formation of a yellow precipitate. The precipitate was collected by filtration and dried to give 2-(6-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone (37.4 g, 86%) as a yellow solid. 1H NMR (CDCl3): δ 7.99 (d, 2 H), 7.57 (t, 1 H), 7.22–7.19 (m, 2 H), 6.90 (d, 2H), 4.39 (s, 2H), 3.83 (s, 3 H); MS m/z 262 (M+1).