Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].I[CH2:27][CH3:28]>CN(C=O)C>[CH2:27]([O:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH3:28]
Reactant: N#Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
2-hydroxy-4-[(4-nitrophenyl)oxy]benzonitrile (Intermediate 127, 87.2 mg) was dissolved in DMF (5 mL). K2CO3 (92.2 mg, 0.67 mmol) and iodoethane (32 μL, 0.40 mmol) were added. The reaction mixture was stirred at r.t. After 16 h, the reaction mixture was evaporated to dryness to give the crude product that was purified by silica gel chromatography (from 100:0 to 50:50 Cyclohexane/EtOAc in 10 CV; then 50:50 Cyclohexane/EtOAc for 10 CV) to obtain 84.9 mg of the title compound as a yellow solid.
Reaction SMILES: [C:1]([NH:4][N:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[NH:3])[NH2:2].[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:16]=1[C:17](=O)[CH2:18]Br>C(O)C>[NH2:3][C:1]1[N:4]([N:5]=[CH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:18]=[C:17]([C:16]2[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:15]=2[O:14][CH3:13])[N:2]=1
Reactant: COc1ccc(OC)c(C(=O)CBr)c1
Reactant: N=C(N)NN=Cc1ccccc1
Solvent: CCO
Product: COc1ccc(OC)c(-c2cn(N=Cc3ccccc3)c(N)n2)c1

Procedure:
A solution of 1.62 g (0.01 mol) of benzaldehyde guanylhydrazone and 1.34 g of 2,5-dimethoxyphenacyl bromide (Aldrich, Buchs, Switzerland, 97%, Cat. no. 10,458-2) in 5 ml of ethanol is boiled under reflux for 45 minutes. After cooling, the product that has crystallized out is filtered off with suction and recrystallized from ethanol. In that manner there is obtained the title compound, m.p. 180°-181° C., 1H-NMR (DMSO): δ=8.62 (s, 1H); 7.97 (m, 2H); 7.90 (s, 1H); 7.42-7.60 (m, 4H); 6.95 (d, 1H); 6.76 (m, 1H); 6.18 (s, 2H); 3.9 (s, 3H); 3.73 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[CH:28]1([S:31](Cl)(=[O:33])=[O:32])[CH2:30][CH2:29]1>N1C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:31]([CH:28]3[CH2:30][CH2:29]3)(=[O:33])=[O:32])=[CH:3][CH:4]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:21]([CH3:27])[CH:22]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(N)cc1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(NS(=O)(=O)C2CC2)cc1

Procedure:
In analogy to example 353, step 2, 5-[3-(4-amino-phenyl)-3-(4-chloro-2-methyl-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 353, step 1) was reacted with cyclopropane-sulfonyl chloride in pyridine to give the title compound as an off-white solid, MS (ESI+): m/z=485.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+:54]>C(O)C>[Na+:54].[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([CH:44]=[C:45]([C:47]([F:48])([F:50])[F:49])[CH:46]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH2:38][CH2:39][CH2:40][C:41]([O-:43])=[O:42])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: O=C(O)CCCOc1ccccc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])CCCOc1ccccc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1

Procedure:
Ethyl 4-(2′-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4′-trifluoromethyl-biphenyl-2-yloxy)-butyrate (157 mg) is dissolved in ethanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 4-(2′-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4′-trifluoromethyl-biphenyl-2-yloxy)-butyric acid (146 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml), and thereto is added 1N-aqueous sodium hydroxide solution (197 μl) and the reaction solution is concentrated under reduced pressure to give 4-(2′-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4′-trifluoromethyl-biphenyl-2-yloxy)-butyric acid sodium salt (146 mg). MS (m/z): 741 [M−Na]−
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(O)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:19]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH:5]=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1cncc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: O=S(=O)(Nc1cncc(Br)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
To a round bottom flask was added 5-bromopyridin-3-amine (0.80 g, 4.6 mmol, Matrix Scientific, Columbia S.C.), ethanol (15 mL) and 4-fluorobenzenesulfonyl chloride (2.2 g, 12 mmol, Fluka, St. Louis, Mo.). The mixture was allowed to stir at ambient temperature overnight. The mixture was diluted with CH2Cl2 and sat. NaHCO3, then the solution was extracted with CH2Cl2 (3×25 ml). The combined extracts were dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (10-30% EtOAc/CH2Cl2) afforded the title compound as an off-white crystalline solid (0.35 g, 23% yield). MS (ESI pos. ion) m/z: 333 (M+1). 1H NMR (400 MHz, MeOH-d4) δ ppm 8.35 (s, 1H), 8.22 (s, 1H), 7.83-7.89 (m, 2H), 7.76-7.81 (m, 1H), 7.25-7.32 (m, 2H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](=O)[C:15](OCC)=[O:16]>CO>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[C:15](=[O:16])[NH:7][C:2]2[C:1]([N:8]=1)=[CH:6][CH:5]=[CH:4][CH:3]=2
Reactant: CCOC(=O)C(=O)c1cccs1
Reactant: Nc1ccccc1N
Solvent: CO
Product: O=c1[nH]c2ccccc2nc1-c1cccs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.1 %

Procedure:
A mixture of o-phenylenediamine (2.16 g, 20 mmol) and ethyl thiophene-2-glyoxylate (3.68 g, 20 mmol.) in anhydrous methanol (60 mL) was stirred at room temperature for 12 hours under nitrogen atmosphere. The precipitate formed during this time was collected and washed with methanol to give a crude yellow solid, which was recrystallized from ethanol to give pure 3(2-thienyl)quinoxalin-2(1 H)-one (3.2 g, 70%). 1 H NMR (400 MHz, DMSO-d6) δ 12.7 (s, 1 H), 8.39 (d, J=4.4 Hz, 1 H), 7.83 (d, J=5.2 Hz, 1 H), 7.77 (d, J=8.0 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.35˜7.29 (m, 1 H), 7.22 (t, J=4.8 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][O:32]2)=[CH:27][C:26]=1[F:38]>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][O:32]2)=[CH:27][C:26]=1[F:38])=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1cc(OCC2CCCO2)ccc1Br
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OCC2CCCO2)cc1F)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and rac-2-(4-bromo-3-fluoro-phenoxymethyl)-tetrahydro-furan (Intermediate 26) in analogy to Example 1a): colorless gum.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[C:11]([F:21])=[C:12]3[C:17](=[CH:18][C:19]=2[F:20])[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]([NH2:22])=[N:4][CH:3]=1.[N:23]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][C:10]3[C:11]([F:21])=[C:12]4[C:17](=[CH:18][C:19]=3[F:20])[N:16]=[CH:15][CH:14]=[CH:13]4)[N:23]=[N:22][C:5]2=[N:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1ncc(Br)nc1NCc1c(F)cc2ncccc2c1F
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Fc1cc2ncccc2c(F)c1Cn1nnc2ncc(Br)nc21
Reaction time: 3 h
Yield: 66 %

Procedure:
To a solution of 6-bromo-N2-(5,7-difluoroquinolin-6-ylmethyl)pyrazine-2,3-diamine (1.5 g, 4.10 mmol) in acetic acid (50 mL) and water (10 mL) was added a solution of sodium nitrite (283 mg, 4.10 mmol) in water (3 mL). After stirring at it for 3 h, the solvent was removed in vacuo, the residue was taken with NaHCO3 (aq.), extracted with CH2Cl2. The organic layer was washed with NH4Cl (aq.), dried over Na2SO4, filtered and concentrated in vacuo and purified by silica gel chromatography with hexanes:EtOAc to provide 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)-5,7-difluoroquinoline (1.02 g, 65%). 1H-NMR (400 MHz, CDCl3) δ ppm 8.99 (d, 1H), 8.79 (s, 1H), 8.43 (d, 1H), 7.65 (d, 1H), 7.49 (m, 1H), 6.13 (s, 2H). LCMS (method B): [MH]+=376.8, tR=2.23 min.
Reaction SMILES: C(OC(=O)C)(=O)C.[NH2:8][C:9]1[N:14]=[C:13]([Cl:15])[C:12]([CH:16]([OH:25])[CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)=[C:11]([Cl:26])[N:10]=1>CS(C)=O>[NH2:8][C:9]1[N:10]=[C:11]([Cl:26])[C:12]([C:16](=[O:25])[CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)=[C:13]([Cl:15])[N:14]=1
Reactant: CC1(C)OCC(CC(O)c2c(Cl)nc(N)nc2Cl)O1
Solvent: CC(=O)OC(C)=O
Solvent: CS(C)=O
Product: CC1(C)OCC(CC(=O)c2c(Cl)nc(N)nc2Cl)O1
Temperature: 0 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
Acetic anhydride (149 ml) was added dropwise to a mixture composed of the above 1-(2-amino-4,6-dichloropyrimidin-5-yl)-2-(2,2-dimethyl-[1,3]dioxolan-4-yl)ethan-1-ol (74.70 g) and dimethyl sulfoxide (600 ml) at room temperature over 15 minutes under cooling in an ice bath. The reaction mixture was then stirred at the same temperature as above for 18 hours. After the disappearance of the materials had been confirmed, the reaction solution was poured into ice water. The precipitated solid was collected by filtration, so as to obtain the title compound (68.26 g).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][N:6]=[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:4]=1)#[CH:2].I[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]1([C:44]([O:46][CH3:47])=[O:45])[CH2:43][CH2:42][CH2:41]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCN(CC)CC.[Cu]I.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>[CH3:47][O:46][C:44]([C:40]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:2]#[C:1][C:3]2[C:8]([C:9]([F:10])([F:12])[F:11])=[CH:7][N:6]=[C:5]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]4)=[CH:18][CH:19]=3)[N:4]=2)[CH2:43][CH2:42][CH2:41]1)=[O:45]
Reactant: C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Reactant: COC(=O)C1(c2ccccc2I)CCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C1(c2ccccc2C#Cc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)CCC1

Procedure:
A suspension of tert-butyl 4-(4-((4-ethynyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate A51 (169 mg, 0.380 mmol), methyl 1-(2-iodophenyl)cyclobutanecarboxylate A53 (100 mg, 0.316 mmol), PPh3 (8 mg, 0.03 mmol) and CuI (3 mg, 0.02 mmol) in DMF (3 mL) and Et3N (0.5 mL) was sonicated for 10 minutes before PdCl2(PPh3)2 (22 mg, 0.032 mmol) was added. The reaction mixture was irradiated in the microwave at 120° C. for 20 minutes, adsorbed onto silica gel and purified using column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-30% EtOAc in petroleum benzine 40-60° C. (column run twice)) to give the title compound A54 as a yellow oil (33 mg, 16%). LCMS-A: rt 7.919 min; m/z 635 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:29][OH:30])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)=[O:19]>>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:16][CH:17]([C:18](=[O:19])[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH2:29][OH:30])[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: COc1cccc(NC(=O)C(N)CO)c1
Product: COc1cccc(NC(=O)C(CO)Nc2nc3ccc(Cl)cc3cc2C(=O)O)c1

Procedure:
In close analogy to the procedure described in Example 43, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-hydroxy-N-(3-methoxy-phenyl)-propionamide to provide the title compound in good yield. LCMS m/z 416 (M+1).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([C:9]1[CH:10]=[N:11][NH:12][C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1)#[N:8]>O.CO>[C:7]([C:9]1[CH:10]=[N:11][NH:12][C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20]([CH3:21])=[O:1])[N:15]=1)#[N:8]
Reactant: CSc1nccc(-c2[nH]ncc2C#N)n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)c1nccc(-c2[nH]ncc2C#N)n1
Reaction time: 20 h

Procedure:
A solution of Oxone (475 mg, 0.77 mmol, 1.2 equiv) in water(10 mL) was added to a solution of 4-(4-cyano-1H-pyrazol-5-yl)-2-(methylthio)pyrimidine (4-3, 670 mg, 2.86 mmol, 1 equiv) in methanol (150 mL), and the resulting mixture was stirred under ambient condition for 20 hours. The reaction was concentrated and the resulting residue was sonicated in water and filtered to provide 4-(4-cyano-1H-pyrazol-5-yl)-2-(methylsulfinyl)pyrimidine (4-4) as a solid. 1H NMR (500 MHz, DMSO-d6) δ 9.11(dd, 1H, J=5 Hz), 8.83 (br s, 1H), 8.10 (dd, 1H, J=5 Hz), 3.04 (s, 3H).
Reaction SMILES: [OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16](=[S:19])[NH:15][C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH3:23])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[OH-].[Na+].[CH3:26]I.Cl>O.CCO>[OH:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]3[NH:18][C:17]4[C:16]([S:19][CH3:26])=[N:15][C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH3:23])[C:12]=4[N:11]=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: CCCn1c(=O)[nH]c(=S)c2[nH]c(C34CCC(O)(CC3)CC4)nc21
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCn1c(=O)nc(SC)c2[nH]c(C34CCC(O)(CC3)CC4)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8-(4-Hydroxy-bicyclo[2.2.2]oct-1-yl)-3-propyl-6-thioxo-1,3,6,7-tetrahydro-purin-2-one (120 mg, 0.36 mmol) was suspended in 3 mL of H2O and 1.5 mL of EtOH. NaOH was added as a solution in 0.4 mL of H2O, followed by MeI. The reaction mixture was stirred at rt for 1 h. It was then neutralized with 0.1 N HCl and extracted with CHCl3. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford essentially quantitative amount of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Br:32][C:29]1[CH:30]=[CH:31][C:23]([NH:22][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)=[C:24]([CH:28]=1)[C:25]([NH2:27])=[O:26]
Reactant: NC(=O)c1cc(Br)ccc1N
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc(Br)cc4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (4.0 g, 11.7 mmol) and 2-amino-5-bromobenzamide (7.6 g, 35.2 mmol), 5-bromo-2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide was isolated as a yellow solid (2.1 g, 35% Yield); 1H NMR (400 MHz, DMSO-d6) δppm 2.36 (s, 3 H), 6.70 (d, J=3.66 Hz, 1 H), 7.46 (d, J=8.42 Hz, 2 H), 7.74-7.78 (m, 2 H), 7.88 (s, 1 H), 7.97 (d, J=8.42 Hz, 2 H), 8.00 (d, J=2.20 Hz, 1 H), 8.35 (d, J=8.79 Hz, 1 H), 8.39 (s, 1 H), 12.16 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[I:13]I>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[I:13][C:8]1[CH:9]=[C:10]([O:11][CH3:12])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: II
Reactant: COc1ccc(C=O)cc1OC
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COc1cc(I)c(C=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.2 %

Procedure:
To a solution of 3,4-dimethoxybenzaldehyde (2.00 g, 12.0 mmol) in EtOH (100 mL) under nitrogen was added iodine (3.65 g, 14.4 mmol) and silver sulfate (4.49 g, 14.4 mmol) and the mixture was stirred for 3 hours at room temperature. The solvent was removed, water was added and the mixture was extracted with DCM. The organic extracts were washed with brine, dried over sodium sulfate and the solvent was removed under reduce pressure. The residue was purified by flash chromatography using petroleum ether/ethyl acetate 2:1 (v:v) as eluent to give 2-iodo-4,5-dimethoxybenzaldehyde (2.81 g, 80%). LC-MS (ES-API); rt 8.52 min; m/z calculated for C9H9IO3 [M+H]+ 293.0, found 293.0.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[O:3].[CH:11](OCC)(OCC)[O:12][CH2:13][CH3:14].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][C:2]([C:4]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=[CH:11][O:12][CH2:13][CH3:14])=[O:3]
Reactant: CC(=O)Cc1ccncc1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCOC=C(C(C)=O)c1ccncc1

Procedure:
In one of its aspects, the invention resides in the three-step process which comprises reacting pyridinylmethyl lower-alkyl ketone of the formula ##STR1## with tri-(lower-alkyl)orthoformate, acetic anhydride and acetic acid to produce 2-(lower-alkoxy)-1-(pyridinyl)ethenyl lower-alkyl ketone of formula II, ##STR2## reacting said ketone (II) with cyanoacetamide or malonamide in the presence of a basic condensing agent and neutralizing the reaction mixture to produce 1,2-dihydro-6-R-2-oxo-5-PY-nicotinonitrile or 1,2-dihydro-6-R-2-oxo-5-PY-nicotinamide of formula III, ##STR3## where R and R' are each lower-alkyl, PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, and Q is cyano or carbamyl, respectively. In preferred embodiments 4(or 3)-pyridinylmethyl methyl ketone is first reacted with triethyl or trimethyl orthoformate, acetic anhydride and acetic acid to produce 2-ethoxy(or methoxy)-1-(4- or 3-pyridinyl)ethenyl methyl (or ethyl) ketone, the latter ketone is next reacted with cyanoacetamide or malonamide in the presence of an alkali lower-alkoxide, preferably sodium methoxide, and then the reaction mixture is neutralized to produce 1,2-dihydro-6-methyl(or ethyl)-2-oxo-5-[4(or 3)-pyridinyl]-nicotinonitrile or 1,2-dihydro-6-methyl(or ethyl)-2-oxo-5-[4(or 3)-pyridinyl]nicotinamide, respectively. In a particularly preferred embodiment 4-pyridinylmethyl methyl ketone is first reacted with triethyl orthoformate, acetic anhydride and acetic acid to produce 2-ethoxy-1-(4-pyridinyl)ethenyl methyl ketone, said latter ketone is reacted with cyanoacetamide in the presence of sodium methoxide, and the reaction mixture is neutralized to produce 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([S:12]([CH3:15])(=[O:14])=[O:13])=[N:9][C:5]2=[N:6][C:7]=1[I:8].C(N(CC)CC)C.Cl[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[N:9]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:5]2=[N:6][C:7]=1[I:8]
Reactant: CS(=O)(=O)c1nc2nc(I)c(Cl)cc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(Cl)c(I)nc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-Chloro-5-iodo-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyridine (for preparation see WO 2012116145; 1.5 g) and triethylamine (875 μL) are dissolved in tetrahydrofurane (12 mL), cooled to 0° C. and treated with (2-(chloromethoxy)ethyl)trimethylsilane (SEM-CI; 890 μL). The mixture is stirred for 30 minutes while warming to room temperature. Then the mixture is partitioned between saturated aqueous NH4Cl and ethylacetate. The organic phase is washed with water and brine. After drying (MgSO4) the solvents are evaporated in vacuo to give the title compound. LC (method 1): tR=1.22 min; Mass spectrum (ESI+): m/z=488 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:55][CH:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)=[O:15])=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To a solution of 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (76 mg, 0.24 mmol) and TBTU (86 mg, 0.27 mmol) in DMF (1.2 mL) was added DIPEA (209 μL, 1.22 mmol). Then 4-aminotetrahydropyran (27 mg, 0.27 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (67 mg, 70%) as a white solid after recrystallisation from methanol/water. MS: m/e=395.1 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C@@H:7]1[C:11]([CH3:13])([CH3:12])[CH2:10][O:9][C:8]1=[O:14])(=O)=O.[N-:17]=[N+:18]=[N-:19].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCOCC>[N:17]([C@H:7]1[C:11]([CH3:13])([CH3:12])[CH2:10][O:9][C:8]1=[O:14])=[N+:18]=[N-:19]
Reactant: CC1(C)COC(=O)[C@@H]1OS(=O)(=O)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC1(C)COC(=O)[C@H]1N=[N+]=[N-]
Reaction time: 5 h

Procedure:
To a solution containing the product from Example 174A (4.6 g, 17.56 mmol) in toluene (80.0 mL) was added tetra-n-butylammonium azide (5.0 g, 17.57 mmol) at room temperature, and the mixture was stirred for 5 hours. The reaction was diluted with ether and washed with water, dilute NaHCO3, 10% citric acid and brine. The organic layer was dried over MgSO4, filtered and concentrated to give the crude product, which was used without further purification (2.79 g).