Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][C:6]1=2.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:24]1([NH:30][C:31](=[O:32])[NH:1][CH2:2][CH2:3][S:4][CH:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][O:8][C:7]3[CH:16]=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][C:6]2=3)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)c1ccc2c(c1)C(SCCN)c1ccccc1CO2
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)C(SCCNC(=O)Nc1ccccc1)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound f, 2.0 g, obtained in Reference Example 6 was dissolved in 100 ml of methylene chloride and 0.7 ml of phenyl isocyanate was added to the solution. The mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The residue was extracted with 200 ml of ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate=2:1) to give 2.2 g of the desired compound.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[S:34][C:35]([CH2:38][CH3:39])=[CH:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([C:35]1[S:34][C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])=[CH:37][CH:36]=1)[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: CCc1ccc(CCl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)s1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (1.20 g, compound B50) and 2-(chloromethyl)-5-ethylthiophene (480 mg, compound D27) in dry DMF (15 ml) is added potassium carbonate (778 mg). The mixture is stirred for 1 h at 100° C. and subsequently poured into ice-cold water. After stirring for 5 min the resulting precipitate is filtered off and dried in vacuo. The residue is purified by flash column chromatography [silica gel, eluent: cyclohexane/EtOAc, 5/1 (v/v)] to afford the title compound as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[CH3:25][NH2:26]>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:6]2[C:7]3[CH2:8][CH2:9][N:26]([CH3:25])[C:2]=3[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:5]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CN
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Product: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3C)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and methylamine, the desired compound was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]2[S:13][CH:14]=[CH:15][C:10]2=[CH:9][C:8]=1[CH:16]([NH2:18])[CH3:17].Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[NH:22][CH:23]=[N:24]2.C(N(C(C)C)CC)(C)C>C(O)CCC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]2[S:13][CH:14]=[CH:15][C:10]2=[CH:9][C:8]=1[CH:16]([NH:18][C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2)[CH3:17]
Reactant: CC(N)c1cc2ccsc2nc1-c1ccccn1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1cc2ccsc2nc1-c1ccccn1
Temperature: 110 °C

Procedure:
To a reaction flask containing 1-(6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethanamine (134 mg, 0.525 mmol), 6-chloropurine (97 mg, 0.63 mmol, 1.2 eq) and diisopropylethylamine (137 μL, 0.79 mmol, 1.5 eq) was added 5 mL of n-butanol. The reaction was heated to 110° C. for 24 h, then cooled to rt and concentrated in vacuo. The residue was dissolved in ethyl acetate (˜50 mL) with heat and sonication, then washed with 5 mL water and 5 mL brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography using 0-80% gradient of (90:9:1 DCM:MeOH:NH4OH) in dichloromethane afforded racemic N-(1-(6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethyl)-9H-purin-6-amine. The room temperature NMR spectrum in CDCl3 exists as a roughly 3:1 mixture of isomers. 1H NMR (400 MHz, CDCl3) δ 8.80 (br d, J=4.3 Hz, 0.75 H), 8.73 (br d, J=3.1 Hz, 0.25 H), 8.55 (s, 0.25 H), 8.36-8.26 (series of m, 1.75 H), 8.15-8.03 (series of m, 1.5 H), 7.93 (br s, 0.75 H), 7.88 (m, 1.4 H), 7.56 (m, 0.5 H), 7.55 (d, J=5.9 Hz, 0.75 H), 7.37 (dd, J=6.6, 5.1 Hz, 0.75 H), 7.26 (d, J=5.9 Hz, 0.75 H), 7.20 (d, J=5.9 Hz, 0.25 H), 6.65 (m, 0.25 H), 6.35 (m, 0.25 H), 6.15 (br s, 0.75 H), 1.55 (d, J=7.0 Hz, 2.25 H), 1.35 (d, J=6.3 Hz, 0.75 H) ppm. LC/MS (M+1, found=374.0). Chiral SFC separation of the racemate afforded the individual enantiomers, (S)—N-(1-(6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethyl)-9H-purin-6-amine and (R)—N-(1-(6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethyl)-9H-purin-6-amine.
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: CN1CCCC1=O
Solvent: 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: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(N(CC)CC)C.NCCN(CCN)CCN>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:34]2[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: NCCN(CCN)CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (15 mg, 0.038 mmol), prepared in Step A of Example 13a, 4-chlorobenzenesulfonyl chloride (5 eq), and triethylamine (5 eq) in CH2Cl2 (1-2 mL) was stirred at room temperature for 72 h. Additional 4-chlorobenzenesulfonyl chloride (5 eq) and triethylamine (5 eq) were added and the reaction was stirred for 24 h followed by addition of tris(2-aminoethyl)amine on polymer support. The reaction was stirred for 24 h and the resin was removed by filtration with the aid of CH2Cl2. The organic solution was washed sequentially with 5.5% aqueous HCl and saturated NaHCO3 solution. The organic solution was concentrated and was used in Step B without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:3][N:4]=[C:5]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=12.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Cl:15][CH2:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][C:5]2=[N:4][O:3][C:2]([CH3:1])=[C:6]2[CH2:7]1
Reactant: Cc1onc2c1CNCC2
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1onc2c1CN(CCCCl)CC2
Temperature: 25 °C
Yield: 39 %

Procedure:
A mixture of 3-methyl-4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine (1.60 g), 1-bromo-3-chloropropane (3.50 mL) and cesium carbonate in acetone was heated to reflux for 24 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as yellow oil (0.97 g, 39.00%), HPLC: 85.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 215.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:13]1[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:11]=[C:12]1[CH3:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: BrCc1ccccc1
Product: Cc1cc(C#Cc2cn(Cc3ccccc3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=288.1 (M+H30), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and benzylbromide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[N+:11]([O-])([OH:13])=[O:12]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1ccccc1C=O
Reactant: O=[N+]([O-])O
Product: COc1ccc([N+](=O)[O-])cc1C=O
Temperature: 0 °C

Procedure:
Finely-divided 2-methoxybenzaldehyde (49 g) was added to ice-cold concentrated sulphuric acid (95 ml) and the mixture was stirred to give a deep red solution which was cooled to -5°. The mixture was cooled in a CO2 /acetone bath while fuming nitric acid (sp.gr. 1.5; 20 ml) was added dropwise with stirring whilst the temperature of the reaction remained below 10°.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:21]=[CH:22][C:15]=23)=[C:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[N:6]=1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>>[CH2:33]([NH:35][C:36]([NH:11][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:21]=[CH:22][C:15]=23)=[CH:13][CH:12]=1)=[O:37])[CH3:34]
Reactant: CCN=C=O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4sc(C)nc4-c4ccc(N)cc4)ccnc32)cc1
Product: CCNC(=O)Nc1ccc(-c2nc(C)sc2-c2ccnc3c2ccn3S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
Following the procedure described in Example 1 with 4-(2-methyl-5-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1,3-thiazol-4-yl)aniline and ethyl isocyanate provided the title product. ESMS [M+H]+: 532.2
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].[NH:15]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]2[N:27]=[CH:26][C:25]([NH:28][C:29]([C:31]3[CH:32]=[N:33][N:34]([C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=4)[C:35]=3[CH3:36])=[O:30])=[CH:24][C:23]=2[CH3:47])[CH2:17][CH2:16]1.C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C=O>[CH3:8][N:9]([CH3:14])[S:10]([N:15]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]2[N:27]=[CH:26][C:25]([NH:28][C:29]([C:31]3[CH:32]=[N:33][N:34]([C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:45])([F:44])[F:46])=[CH:39][N:38]=4)[C:35]=3[CH3:36])=[O:30])=[CH:24][C:23]=2[CH3:47])[CH2:17][CH2:16]1)(=[O:12])=[O:11]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCCN(S(=O)(=O)N(C)C)CC1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
Triethylamine (0.16 ml) and dimethylsulfamoyl chloride (157 mg) were added at room temperature to a solution of N-[6-(azepan-4-yl)-5-methylpyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (250 mg) described in Example K66(1) in tetrahydrofuran (5.5 ml) and N,N-dimethylformamide (5.5 ml), and stirred at 60° C. for three hours. After completion of the reaction, the reaction solution was cooled to room temperature, saturated aqueous solution of sodium bicarbonate was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (chloroform/methanol) to give the titled compound (133 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][C:13]1[C:21]2[C:20]([OH:22])=[CH:19][CH:18]=[CH:17][C:16]=2[NH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:22][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:21]=1[C:13]([CH3:12])=[N:14][NH:15]2
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cc1n[nH]c2cccc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1n[nH]c2cccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 50 °C
Reaction time: 5 h

Procedure:
100 mg (0.63 mmol) of 3,4-difluoronitrobenzene, 93.1 mg (0.63 mmol) of 3-methyl-1H-indazol-4-ol (from example I) and 95.6 mg (0.69 mmol) of potassium carbonate are suspended in 5 ml of anhydrous dimethylformamide and stirred at 50° C. for five hours. The reaction solution is then diluted with water and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography. The mobile phase used is a mixture of cyclohexane and ethyl acetate (1:1).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:18])[CH:3]=1.[I:19]N1C(=O)CCC1=O>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:10]([I:19])=[C:6]2[N:5]=[C:4]([CH3:18])[CH:3]=1
Reactant: Cc1cc(Cl)n2nc(-c3ccccc3Cl)cc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)n2nc(-c3ccccc3Cl)c(I)c2n1
Reaction time: 1.5 h

Procedure:
To a solution of 7-chloro-2-(2-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine (I-1A-3g; 370 mg, 1.33 mmol) in 5:1 methylene chloride/chloroform (9 ml) cooled in an ice bath was added N-iodosuccinimide (449 mg, 2.0 mmol), portionwise, to give a heterogeneous mixture. After 1.5 hours, the ice bath was removed and the reaction was stirred an additional 2.5 hours to give a homogenous, pink solution. The reaction was extracted from aqueous NaHCO3 with methylene chloride. The combined extracts were washed with saturated aqueous Na2S2O4 and brine, dried (MgSO4), and then concentrated, in vacuo, to afford product I-1A-3h as a tan solid (535 mg, quantitative): +ESI MS (M+1) 403.9; 1H NMR (400 MHz, CD2Cl2) δ 7.57–7.40 (m, 4H), 6.99 (s, 1H), 2.66 (s, 3H).
Reaction SMILES: Br[CH:2]1[CH2:7][N:6]([CH2:8][CH2:9][N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:5](=[O:15])[C:4]2[C:16]([CH3:31])=[C:17]([CH:19]=[C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=4)[NH:22][C:21]3=[O:30])[NH:18][C:3]1=2.BrCC1C2C(=[O:50])N(CCN(CC)CC)CCC=2NC=1C=C1C2C(=CC=C(F)C=2)NC1=O.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:13]([N:10]([CH2:11][CH3:12])[CH2:9][CH2:8][N:6]1[CH2:7][CH2:2][C:3]2[NH:18][C:17]([CH:19]=[C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=4)[NH:22][C:21]3=[O:30])=[C:16]([CH2:31][OH:50])[C:4]=2[C:5]1=[O:15])[CH3:14]
Reactant: CCN(CC)CCN1CC(Br)c2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(C)c2C1=O
Reactant: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(CBr)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(CO)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A solution of 7-bromo-5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one and 3-bromomethyl-5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one in 10 ml of methanol was added with saturated potassium carbonate (2 ml). The mixture was stirred at room temperature overnight, added with water (20 ml) and extracted with the 6 to 1 mixture of dichloromethane and methanol (10 ml×4). The combined extracts were concentrated to give 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-hydroxymethyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (13 mg, 72%) as a yellow solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[CH:26])[CH2:20][CH2:19][C:18]4([O:24][CH2:23][CH2:22][O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>N1CCCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:20][CH2:19][C:18]4([O:21][CH2:22][CH2:23][O:24]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Brc1ccccn1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC2(CC1)OCCO2
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCNCC1
Product: COc1ccc(C2(C#Cc3ccccn3)CCC3(CC2)OCCO3)cc1OC1CCCC1

Procedure:
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-ethynylcyclohexane (0.15 g, 0.42 mmol) and 2-bromopyridine (0.040 mL, 0.42 mmol) in piperidine (2 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)-palladium(0) (0.02 g, 4%), copper(I) iodide (0.005 g, 6%) and a small crystal of triphenylphosphine, and the mixture was heated at 80° C. for 0.5 h. Water was added and the mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(2-pyridylethynyl)cyclohexane as a white foam. mp 41°-42° C. 1H-NMR (400 MHz, CDC3) δ 8.58 (d, J=4.6 Hz, 1H), 7.65 (t, J=7.7 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.21 (m, 2H), 7.17 (d, J=8.5 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 4.81 (m, 1H), 3.99 (s, 4H), 3.84 (s, 3H), 2.25 (m, 2H), 2.15 (m, 4H), 1.8-2.0 (m, 8H), 1.59 (m, 2H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[C@H:31]([OH:32])[CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@H:27]4[C@H:31]([OH:32])[CH2:30][N:29]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CNC[C@H]1O
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f10) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH3:17][C:18]1[C:22](/[CH:23]=[CH:24]/[C:25](O)=[O:26])=[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:20][N:19]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:26])/[CH:24]=[CH:23]/[C:22]2[C:18]([CH3:17])=[N:19][O:20][C:21]=2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: Cc1noc(-c2ccccc2)c1/C=C/C(=O)O
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(NC(=O)/C=C/c2c(C)noc2-c2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (0.43 g), (E)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenoic acid (0.50 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.38 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.45 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and (E)-N-(4-diethylphosphonomethylphenyl)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenamide (0.71 g, yield 83%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 155–156° C.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[N:5]=[C:4]([CH3:13])[N:3]=1.[CH3:14][O-:15].[Na+]>CO>[I:8][C:7]1[C:2]([O:15][CH3:14])=[N:3][C:4]([CH3:13])=[N:5][C:6]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Cc1nc(Cl)c(I)c(C(F)(F)F)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(C)nc(C(F)(F)F)c1I
Yield: 57.3 %

Procedure:
4-Chloro-5-iodo-2-methyl-6-trifluoromethylpyrimidine (23.0 g) was dissolved in methanol (150 ml) and sodium methoxide (30% methanol solution, 12.8 g) was added under ice cooling with stirring. After stirring over night at room temperature, the solvent was removed under reduced pressure. The residue was mixed with water and extracted with benzene, and then benzene layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate). The crude fraction was concentrated, and then washed with cold hexane to give 5-iodo-4-methoxy-2-methyl-6-trifluoromethylpyrimidine (13.0 g) as colorless crystalline solid, mp 44-45° C.