Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[CH2:17][O:16]2)=[CH:9][CH:8]=1)(C)(C)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:35]3[C:34]([N:36]4[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]4)=[N:33][CH:32]=[N:31][C:30]=3[S:29][CH:28]=2)=[CH:23][CH:22]=1>CC(O)C.CS(C)=O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:35]3[C:34]([N:36]4[CH2:41][CH2:40][CH:39]([NH:42][CH2:17][CH:15]([OH:16])[CH2:14][O:13][C:10]5[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=5)[CH2:38][CH2:37]4)=[N:33][CH:32]=[N:31][C:30]=3[S:29][CH:28]=2)=[CH:23][CH:22]=1
Reactant: NC1CCN(c2ncnc3scc(-c4ccc(F)cc4)c23)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCC2CO2)cc1
Solvent: CS(C)=O
Solvent: CC(C)O
Product: Oc1ccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5ccc(F)cc5)c34)CC2)cc1
Yield: 45 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 10 h), using 200 μmol tert-butyldimethyl(4-(oxiran-2-ylmethoxy)phenoxy)silane and 1-(5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give O-silylated intermediate upon purification by prep. HPLC (reversed phase) with 45% yield. Product was obtained by deprotection according to SP7 and purification by prep. HPLC (reversed phase) with 74% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:18])=[N:4][C:5]([CH3:17])=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=1.[C:19](OC(=O)C)(=O)[CH3:20]>C(O)(=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([N:8]2[C:7]3[CH:6]=[C:5]([CH3:17])[N:4]=[C:3]([CH3:18])[C:2]=3[N:1]=[C:19]2[CH3:20])=[CH:10][CH:11]=1)#[N:16]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(Nc2ccc(C#N)cc2)c(N)c(C)n1
Solvent: CC(=O)O
Product: Cc1cc2c(nc(C)n2-c2ccc(C#N)cc2)c(C)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
A mixture of 3-amino-4-(4-cyanophenyl)amino-2,6-dimethyl-pyridine (4.20 g, 17.6 mmol), acetic anhydride (12.6 ml) and acetic acid (12.6 ml) was stirred at 100° C. for 16 hours. The excess of reagents was removed under reduced pressure, and the residual gum was dissolved in water and the solution was rendered basic by the addition of concentrated aqueous ammonia. The white solid which precipitated was filtered off and dried in vacuo to give the title compound (4.06 g, 88%), mp 260°-262° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[I:9]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:8][C:4]1[CH:3]=[C:2]([NH2:1])[C:7]([I:9])=[CH:6][N:5]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1cc(Cl)ncc1I
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Silver sulfate (7.1 g, 22.8 mmol) and 4-amino-2-chloropyridine (4.06 g, 31.6 mmol) were added to a solution of iodine (5.65 g, 22.3 mmol) in ethanol (100 mL) and the reaction mixture stirred at rt for 72 h. The bright yellow suspension was filtered, washed with methanol and the filtrate concentrated in vacuo. The residue was partitioned between saturated Na2CO3 solution (200 mL) and ethyl acetate (200 ml). After separation the organic layer was washed with Na2S2O3 solution (50 mL, 25%) and brine (50 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with iso-hexane/ethyl acetate (3:1 to 2.5:1) to give the title compound. δH (CDCl3): 4.81 (2H, br s), 6.63 (1H, s), 8.38 (1H, s); m/z (ES+)=254.86 [M+H]+; RT=2.51 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([OH:37])([CH3:36])[CH2:23][CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:38][C:39]1[NH:40][CH:41]=[C:42]([N+:44]([O-:46])=[O:45])[N:43]=1.C(=O)([O-])O.[Na+].CN(C)C=O>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([OH:37])([CH3:36])[CH2:23][CH2:24][N:40]3[CH:41]=[C:42]([N+:44]([O-:46])=[O:45])[N:43]=[C:39]3[Cl:38])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(O)COc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)(CCn1cc([N+](=O)[O-])nc1Cl)COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 95 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
4-{4-[2-Hydroxy-2-methyl-4-(toluene-4-sulfonyloxy)butoxy]phenyl}piperazine-1-carboxylic acid tert-butyl ester (4.69 g, 8.77 mmol), 2-chloro-4-nitro-1H-imidazole (1.55 g, 10.52 mmol), sodium hydrogen carbonate (0.88 g) and dimethylformamide (47 ml) were mixed, and the mixture was stirred at 90 to 100° C. overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, and dried over magnesium sulfate. After filtering under reduced pressure, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0→3:7) to afford the title compound as a yellow amorphous solid (2.12 g).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][S:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20]OS(C)(=O)=O)(=[O:8])=[O:7].C(O)C>O>[CH3:5][S:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][N:1]=[N+:2]=[N-:3])(=[O:8])=[O:7]
Reactant: CS(=O)(=O)OCCOCCOCCOCCOS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)OCCOCCOCCOCCN=[N+]=[N-]
Yield: 47.1 %

Procedure:
Sodium azide (1.0 g) is added to a solution of tetraethyleneglycol dimethanesulphonate (5.25 g, 15 mmol), obtained according to A. W. Chwabacher et al. (J. Org. Chem. 1998, 65(5), 1717), in 18 mL of 95° ethanol. The reaction mixture is taken to reflux for 24 hours. Then the solvent is evaporated off, the reaction crude is added to 100 mL of salt water and extracted with ether 3×100 mL. The organic phase is dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on a silica column using a gradient of AcOEt in hexane (1/1 to 3/1) as eluents. 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl mono-methanesulphonate 47 (2.10 g, 47%) is obtained, which is used directly in the following stage.
Reaction SMILES: C(O)C.[CH2:4]([C:6]1[CH:26]=[CH:25][C:9]([O:10][C:11]2[C:12]([NH:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20][CH2:19]3)=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:8][CH:7]=1)[CH3:5].[Cl:27]C1C(OC2C=CC(CC)=CC=2)=CN=CN=1>C(OCC)(=O)C>[ClH:27].[CH2:4]([C:6]1[CH:26]=[CH:25][C:9]([O:10][C:11]2[C:12]([NH:17][C@H:18]3[CH2:19][CH2:20][C@H:21]([OH:24])[CH2:22][CH2:23]3)=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:8][CH:7]=1)[CH3:5]
Reactant: CCc1ccc(Oc2cncnc2Cl)cc1
Agent: CCc1ccc(Oc2cncnc2N[C@H]2CC[C@H](O)CC2)cc1
Agent: CCc1ccc(Oc2cncnc2N[C@H]2CC[C@H](O)CC2)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cl

Procedure:
Science, 230-440 mesh) (13×4 cm column bed) using ethyl acetate as the eluent for the first 1.2 L and then with 5% ethanol in ethyl acetate. The fractions that contained homogeneous product were spin evaporated in vacuo to give a syrup. The pure 5-(4-ethylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine was converted to the hydrochloride by the same procedure described in Example 4. The residue was triturated under ethyl acetate to give a white solid which was collected, washed with ethyl acetate and dried in vacuo to give 1.25 g (77% yield) of 5-(4-ethylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine hydrochloride as a white solid, mp 245-243° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:12][N:13]=[C:14]=[S:15]>CCO>[I:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[NH:1][C:14](=[S:15])[N:13]([CH3:12])[C:4]2=[O:5]
Reactant: CN=C=S
Reactant: Nc1c(I)cccc1C(=O)O
Solvent: CCO
Product: Cn1c(=S)[nH]c2c(I)cccc2c1=O
Temperature: 100 °C
Yield: 92.9 %

Procedure:
A sealable flask was charged with 2-amino-3-iodobenzoic acid (Bosche Scientific; 10 g, 38.0 mmol) and methyl isothiocyanate (5.56 g, 76 mmol) in EtOH (120 mL) followed by TEA (7.93 mL, 57.0 mmol). The flask was sealed and heated in an oil bath at 100° C. for 4 h with a blast shield. The mixture was cooled to RT and the solvent was removed in vacuo. The residue was triturated with Et2O (40 mL) and filtered, dried to give 8-iodo-3-methyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (11.22 g, 35.3 mmol, 93% yield) as an off white solid. Crude material was used in the next step. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.97 (1H, br.), 8.23 (1H, d, J=8.4 Hz), 8.00 (1H, d, J=8.0 Hz), 7.15 (1H, t, J=7.5 Hz), 3.65 (3H, s).). m/z (ES, +ve) 318.8 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH3:11])[CH:3]=1.[NH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])=[C:19]([Br:30])[C:18]=2[CH:31]=1>C(O)C>[Br:30][C:19]1[C:18]2[CH:31]=[C:14]([CH2:13][NH:12][C:2]3[N:7]4[N:8]=[CH:9][CH:10]=[C:6]4[N:5]=[C:4]([CH3:11])[CH:3]=3)[CH:15]=[CH:16][C:17]=2[O:21][C:20]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]#[N:29]
Reactant: N#Cc1ccccc1-c1oc2ccc(CN)cc2c1Br
Reactant: Cc1cc(Cl)n2nccc2n1
Solvent: CCO
Product: Cc1cc(NCc2ccc3oc(-c4ccccc4C#N)c(Br)c3c2)n2nccc2n1
Temperature: 25 °C

Procedure:
A solution of 1.7 g (10.1 mmol) 7-chloro-5-methylpyrazolo[1,5-a]pyrimidine (prepared according to Y. Makisumi, Chem. Pharm. Bull. 1962, 10,620)and 3.27 g (10.0 mmol) 5-(aminomethyl)-3-bromo-2-(2-cyanophenyl)benzofuran (prepared according to WO 92/09600) in 50 ml dry ethanol was heated with reflux for 5 h. The title compound precipitated upon cooling to room temperature, was filtered with suction, and recrystallized from ethanol to give colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4][CH2:3]1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.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>[CH3:15][Si:16]([C:19]#[C:20][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH3:14])([CH3:1])[CH2:3][CH2:4][C:5]2=[O:13])=[CH:10][CH:9]=1)([CH3:18])[CH3:17]
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)CCC(=O)c2cc(C#C[Si](C)(C)C)ccc21
Reaction time: 24 h

Procedure:
To a solution (flushed for 15 minutes with a stream of argon) of 7 g (27.6 mmol) of 3,4-dihydro-4,4-dimethyl-7-bromo-1(2H)-naphthalenone (Compound B) in 150 ml of triethylamine was added 0.97 g (1.3 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.26 g (1.3 mmol) of cuprous iodide. The solution mixture was flushed with argon for 5 minutes and then 39 ml (36.6 mmol) of (trimethylsilyl)acetylene was added. The reaction mixture was sealed in a pressure tube and placed in a preheated oil bath (100° C.) for 24 hours. The reaction mixture was then filtered through Celite, washed with Et2O and the filtrate concentrated in vacuo to give crude 7-(trimethylsilyl)ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one. To a solution of this crude TMS-acetylenic compound in 50 ml of methanol was added 0.6 g (4.3 mmol) of K2CO3. The mixture was stirred for 8 hours at ambient temperature and then filtered. The filtrate was concentrated in vacuo, diluted with Et2O, washed with water, 10% HCl and brine, dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid. PMR (CDCl3): δ1.39 (6H, s), 2.02 (2H, t, J=7.0 Hz), 2.73 (2H, t, J=7.0 Hz), 3.08 (1H, s), 7.39 (1H, d, J=8.2 Hz), 7.61 (1H, dd, J=1.8 , 8.2 Hz), 8.14 (1H, d, J=9 1.8 Hz).
Reaction SMILES: [C:1]1([C:13]([OH:15])=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[C:47]([NH:50][NH2:51])(=[O:49])[CH3:48]>CN(C)C=O>[C:47]([NH:50][NH:51][C:13]([C:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1)=[O:15])(=[O:49])[CH3:48]
Reactant: O=C(O)c1cn2c3c(cccc13)CCC2
Reactant: CC(=O)NN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NNC(=O)c1cn2c3c(cccc13)CCC2
Temperature: 80 °C

Procedure:
To a solution of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid (20 mg, 100 μmol) in dry N,N-dimethylformamide (700 μL) were added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 110 μmol), triethylamine (21 μL, 150 μmol), and acetohydrazide (10 μmol). The reaction was heated at 80° C. for 24 hours. The solvent was removed under reduced pressure. To the residue were added 1.5 mL of mixture of butanol and 1,2-dichloroethane (1:2.5) and 1.0 mL of sat. NaHCO3. The organic layer was separated and the solvent was removed under reduced pressure to afford N′-acetyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carbohydrazide (55). The crude was used for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:15]([C:16]([O:18]C)=O)=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21].[NH2:23][C:24]1[S:25][C:26]([CH3:30])=[C:27]([CH3:29])[N:28]=1>>[CH3:1][N:2]1[C:15]([C:16]([NH:23][C:24]2[S:25][C:26]([CH3:30])=[C:27]([CH3:29])[N:28]=2)=[O:18])=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21]
Reactant: COC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1C
Reactant: Cc1nc(N)sc1C
Product: Cc1nc(NC(=O)C2=C(O)c3c(c4ccccc4n3C)S(=O)(=O)N2C)sc1C
Yield: 87 %

Procedure:
2,5-Dihydro-2,5-dimethyl-N-(4,5-dimethyl-2-thiazolyl)-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from methyl 2,5-Dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indol-3-carboxylate 1,1-dioxide and 2-amino-4,5-dimethyl-thiazole with a yield of 87% of theory; M.p. 265° C. (decomposition).
Reaction SMILES: [Cl-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)C=CC=CC=1.[C:29]1(=[O:41])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[N:31][NH:30]1.N1C=CC=C(/C=C\C2C3C(=CC=CC=3)C(=O)NN=2)C=1>>[CH3:16][C:13]1[N:12]=[CH:11][C:10](/[CH:9]=[CH:39]\[C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:29](=[O:41])[NH:30][N:31]=2)=[CH:15][CH:14]=1
Reactant: O=Cc1n[nH]c(=O)c2ccccc12
Reactant: Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=c1[nH]nc(/C=C\c2cccnc2)c2ccccc12
Agent: [Cl-]
Product: Cc1ccc(/C=C\c2n[nH]c(=O)c3ccccc23)cn1

Procedure:
Prepared by Wittig reaction of triphenyl-(6-methylpyridin-3-yl-methyl)phosphonium chloride and phthalazin-1(2H)-one-4-carbaldehyde as described in expl. 4d): HPLC5-40 tR=11.7/12.2.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[N:6]=1)(=[O:4])=[O:3].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[SH:25].C1C=CC(I(OC(C(F)(F)F)=O)OC(C(F)(F)F)=O)=CC=1.[Na+].[Cl-]>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[S:25][C:11]1[C:10]([O:15][CH3:16])=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[CH:14][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6]2
Reactant: Fc1ccc(S)c(F)c1
Reactant: COc1ccc2nc(S(C)(=O)=O)ccc2c1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Product: COc1ccc2nc(S(C)(=O)=O)ccc2c1Sc1ccc(F)cc1F
Reaction time: 0.5 h

Procedure:
A solution of 2-methanesulfonyl-6-methoxy-quinoline (237 mg, 1 mmole) and 2,4-difluorobenzenethiol (296 mg, 2 mmoles) was treated with PIFA (645 mg, 1.5 mmoles) and stirred for 30 min. The solution was poured into dilute NaCl solution and extracted with ethyl acetate (EtOAc). The organic layer was dried (MgSO4) and evaporated. The resulting oil was crystallized to yield 5-(2,4-difluoro-phenylsulfanyl)-2-methanesulfonyl-6-methoxy-quinoline 101.; ([M+H]+)=382 The yield is typically 80–90%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH2:10][CH2:9][C:8]=2[CH:21]=1)([O-])=O.S1C=CC=C1.[H][H]>CO.[Pd]>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[O:14][CH2:13][CH:11]1[CH2:10][CH2:9][C:8]2[CH:21]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]=2[O:12]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCC(COC1CCCCO1)O2
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: Nc1ccc2c(c1)CCC(COC1CCCCO1)O2
Yield: 100 %

Procedure:
A mixture of 34 parts of 3,4-dihydro-6-nitro-2-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-2H-1-benzopyran, 1 part of a solution of thiophene in methanol 4% and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 31 parts (100%) of 3,4-dihydro-2-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-2H-1-benzopyran-6-amine as an oily residue (intermediate 10).
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH:11]=[C:10]([NH:13][C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([C@:21]([OH:25])([CH3:24])[CH2:22][OH:23])=[CH:17][CH:16]=4)[N:9]=[CH:8][C:7]=3[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[Br:27]N1C(=O)CCC1=O>CN(C)C=O.[Cl-].[Na+].O>[Br:27][C:6]1[C:7]2[CH:8]=[N:9][C:10]([NH:13][C:14](=[O:26])[C:15]3[CH:20]=[CH:19][C:18]([C@:21]([OH:25])([CH3:24])[CH2:22][OH:23])=[CH:17][CH:16]=3)=[CH:11][C:12]=2[N:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@](O)(CO)c1ccc(C(=O)Nc2cc3c(ccn3C3CC3)cn2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CO)c1ccc(C(=O)Nc2cc3c(cn2)c(Br)cn3C2CC2)cc1
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
In a 250 ml round bottom flask was added (R)—N-(1-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide (17, 3.2 g, 9.2 mmol) in N,N-dimethylformamide (31 ml). The mixture was cooled in ice bath, followed by addition of N-bromosuccinimide (1.477 g, 8.30 mmol) in portions. The mixture was stirred in ice bath for 30 min, at which point about ˜10% starting material remained. Another 0.1 equivalence (160 mg) of N-bromosuccinimide was added to the reaction mixture, which was stirred in an ice bath for another 30 min. Brine (200 ml) was added, followed by extraction with EtOAc (2×200 mL). Organic layers were combined. After drying and filtering, a suspension was obtained upon concentration. The solid was collected on a filtered, and then washed with 10 ml EtOAc. The resulting 2 g of filtrated solid was purified by silica gel column chromatography, eluting with 5-10% MeOH in EtOAc. Product-containing fractions were combined and concentrated to yield a solid which was washed twice with EtOAc (2×10 ml). The title compound (22, 0.62 g, 16%) was obtained as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98-1.04 (m, 2H) 1.05-1.13 (m, 2H) 1.42 (s, 3H) 3.42-3.54 (m, 3 H) 4.71 (t, J=5.81 Hz, 1H) 4.99 (s, 1H) 7.58 (d, J=8.59 Hz, 2H) 7.62 (s, 1H) 8.01 (d, J=8.59 Hz, 2H) 8.48 (d, J=0.76 Hz, 2H) 8.51 (d, J=0.76 Hz, 2H) 10.63 (s, 1H); ESI-MS: m/z 432 (M+H)+. Additional amounts of the title compound were obtained by combining filtrates and re-purifying them by silica gel column chromatography.
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@H:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].C1(C)C=CC=CC=1.C1(C(O)=O)CC1.C1(C)C=CC(S(O[CH:36]([C:50]#[N:51])[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH:38]=2)(=O)=O)=CC=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@H:6]([C:7]([O:9][CH:36]([C:50]#[N:51])[C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:38]=2)=[O:8])[C:5]1([CH3:10])[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)cc1
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)C1CC1
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1

Procedure:
Cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (22 g, 0.105 M) was added to a solution of an inorganic base in water (50 ml). Toluene (100 ml), tetra-n-butylammonium bromide (1.6 g, 5 mole % based on the cyclopropane carboxylic acid) and alpha-cyano-3-phenoxybenzyl p-toluenesulphonate (37.9 g, 0.1 M) were added to the stirred mixture which was then heated at 40°-45° C. for 24 hours. The reaction mixture was then treated as in Example 1 to yield cis-alpha-cyano-3-phenoxybenzyl 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate as a pale amber oil containing less than 1% trans-isomers.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:33])[C:4]([C:6]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:9]2[N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:17][N:16]=3)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][CH2:42][F:43]>C(#N)C.CN(C=O)C>[CH3:2][N:3]([CH3:33])[C:4]([C:6]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:9]2[N:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:22][CH2:23][N:24]([CH2:41][CH2:42][F:43])[CH2:25][CH2:26]4)=[CH:17][N:16]=3)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5]
Reactant: FCCBr
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CCF)CC4)cn3)nc2n1C1CCCC1
Temperature: 80 °C
Yield: 55 %

Procedure:
To a solution of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide hydrochloride (150 mg, 0.318 mmol) and potassium carbonate (132 mg, 0.955 mmol) in acetonitrile (3 mL) and DMF (2 mL) is added 1-bromo-2-fluoroethane (0.035 mL, 0.478 mmol) and the reaction mixture is heated to 80° C. for 24 h in a sealed reaction vial. Upon cooling, the reaction mixture is partitioned between dichloromethane and water. The organic layer is separated and the aqueous layer extracted further with dichloromethane. The combined organics are ished with brine, dried (MgSO4), filtered and concentrated. The crude product is purified using silica gel chromatography (0 to 10% methanol/dichloromethane) to give 7-cyclopentyl-2-{5-[4-(2-fluoro-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (84 mg, 55%) as an off white solid.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[OH:27][C:28]1[CH:29]=[C:30]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:37]2[CH2:36][CH2:35][N:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([OH:27])[CH:29]=3)[CH2:39][CH2:38]2)=[O:26])[C:11]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(Oc2ccccc2)nc1C
Reactant: Oc1cccc(N2CCNCC2)c1
Product: CCc1cc(NC(=O)N2CCN(c3cccc(O)c3)CC2)c(Oc2ccccc2)nc1C
Yield: 72 %

Procedure:
Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(3-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][N:10]=[CH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[NH:4][C:3]1=[O:22].C(N(CC)CC)C.[CH:30]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([OH:37])=[O:36])=O>CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:30]([C:32]3[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=3)[C:35]([OH:37])=[O:36])[N:10]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][CH:13]=3)[N:9]=[C:5]2[NH:4][C:3]1=[O:22]
Reactant: Cn1c(=O)cc(NN=Cc2cccc3ccccc23)[nH]c1=O
Reactant: O=Cc1cccc(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c2nn(Cc3cccc4ccccc34)c(-c3cccc(C(=O)O)c3)c2c1=O
Temperature: 90 °C
Reaction time: 16 h

Procedure:
1-naphthaldehyde (1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)hydrazone (2.12 g) and triethylamine (0.8 ml) was added to a suspension of Resin bound 3-formylbenzoic acid in dimethylformamide (15 ml), and the mixture was shaken at 90° C. for 16 hours. The resin was filtered and washed (3 times) DMF, CH2Cl2, MeOH, CH2Cl2, and dried in vacuum to give the subtitle compound.